Preoperative medical therapy before surgery for uterine fibroids

Background Uterine fibroids occur in up to 40% of women over 35 years of age. Up to 50% of uterine fibroids cause symptoms that warrant treatment: anaemia caused by heavy menstrual bleeding, pelvic pain, dysmenorrhoea, infertility and poor quality of life. Surgery is the first choice of treatment, but medical therapies have been used prior to surgery to improve outcomes. Gonadotropin‐hormone‐releasing analogues (GnRHa) induce a low‐oestrogen state that shrinks fibroids, but they have unacceptable side effects if used long‐term. Other potential hormonal treatments include progestins and selective progesterone‐receptor modulators (SPRMs). This updates a Cochrane review published in 2017.

To assess the benefits and risks of medical treatments prior to surgery for uterine fibroids. Search methods We searched the Cochrane Gynaecology and Fertility Group Specialized Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL on 8 August 2024. We also searched trials registers (ClinicalTrials.gov; WHO ICTRP), theses and dissertations, and grey literature, as well as handsearching reference lists of retrieved articles and contacting pharmaceutical companies. Selection criteria We included randomised controlled trials of premenopausal women receiving medical therapy before myomectomy, hysterectomy or hysteroscopic resection for uterine fibroids versus placebo, no pretreatment or another medical therapy. Data collection and analysis We used standard Cochrane methods. We assessed the certainty of the evidence using GRADE. Main results We included 41 RCTs, which involved 3982 women. Thirty‐six studies evaluated GnRHa: the comparators were no pretreatment (19 studies), placebo (9 studies), or other medical pretreatments (progestin, SPRMs, selective oestrogen receptor modulators (SERMs), dopamine agonists, oestrogen receptor antagonists) (8 studies). Five studies evaluated SPRMs versus placebo. Most results provided low‐certainty evidence due to poor reporting of randomisation procedures, lack of blinding, imprecision and inconsistency. Some outcomes were not measured or did not have usable data. The use of ulipristal acetate (an SPRM) is suspended at this time (March 2025) because of an association with cases of liver failure. GnRHa versus placebo or no pretreatment before surgery for uterine fibroids GnRHa pretreatment may reduce uterinevolume (mean difference (MD) −175.34 mL, 95% confidence interval (CI) −219.04 to −131.65; 13 studies, 858 participants; I² = 67%; low‐certainty evidence) and fibroid volume (MD range 5.7 mL to 155.4 mL; 5 studies to heterogeneous to pool, 427 participants; low‐certainty evidence), and probably increases preoperative haemoglobin (MD 0.88 g/dL, 95% CI 0.68 to 1.08; 10 studies, 834 participants; I² = 0%; moderate‐certainty evidence). However, there is probably a greater likelihood of adverse events with GnRHa (odds ratio (OR) 2.78, 95% CI 1.77 to 4.36; 5 studies, 755 participants; I² = 28%; moderate‐certainty evidence). No usable data were available for preoperative bleeding. Hysterectomy Duration of hysterectomy may be reduced amongst women who receive GnRHa treatment (−10.11 minutes, 95% CI −16.96 to −3.25; 6 studies, 617 participants; I² = 57%; low‐certainty evidence). Results are uncertain for intraoperative blood loss (4 heterogeneous studies, 258 participants; MD range 25 mL to 148 mL, in favour of GnRHa; very low‐certainty evidence). There are probably fewer blood transfusions with GnRHa (OR 0.54, 95% CI 0.29 to 1.01; 6 studies, 601 participants; I² = 0%; moderate‐certainty evidence) and less postoperative morbidity (OR 0.54, 95% CI 0.32 to 0.91; 7 studies, 772 participants; I² = 28%; moderate‐certainty evidence). Myomectomy There is uncertainty about the effects of GnRHa pretreatment on surgery duration (7 heterogeneous studies, 443 participants) (very low‐certainty evidence) and intraoperative blood loss during myomectomy (11 studies too heterogenous to pool, 549 participants; very low‐certainty evidence). GnRHa may make little to no difference to blood transfusions (OR 0.85, 95% CI 0.26 to 2.75; 4 studies, 121 participants; I² = 0%; low‐certainty evidence) or postoperative morbidity (OR 1.07, 95% CI 0.43 to 2.64; I² = 0%; 5 studies, 190 participants; low‐certainty evidence). Hysteroscopic resection GnRHa treatment before hysteroscopic resection of uterine myomas may result in little to no difference in surgery duration (2 studies,123 participants; low‐certainty evidence). One study reported no cases of postoperative morbidity in either group (84 participants; low‐certainty evidence). GnRHa versus other medical therapies before surgery ‐ preoperative outcomes GnRHa may be associated with a greater reduction in uterine volume than other medical therapies (−47% compared to −20% and −22% with 5 mg and 10 mg ulipristal acetate, respectively; low‐certainty evidence). There may be little to no difference in bleeding reduction (ulipristal acetate 5 mg: OR 0.71, 95% CI 0.30 to 1.68; 1 study, 199 participants; low‐certainty evidence), and there is probably little to no difference in preoperativehaemoglobin (MD −0.02, 95% CI −0.41 to 0.37; 242 participants; moderate‐certainty evidence). We are uncertain whether there is any difference in fibroid volume between GnRHa and cabergoline (MD 12.71 mL, 95% CI −5.92 to 31.34; 2 studies, 110 participants; I² = 0%; low‐certainty evidence). Adverse events such as hot flushes may be more likely with GnRHa (OR 2.83, 95% CI 1.68 to 4.77; 6 studies, 507 participants; I² = 59%; low‐certainty evidence). SPRMs versus placebo before surgery ‐ preoperative outcomes SPRMs (mifepristone, CDB‐2914, ulipristal acetate and asoprisnil) before surgery probably reduce uterine volume (2 heterogenous studies, 275 participants; moderate‐certainty evidence) and may reduce fibroid volume (5 heterogeneous studies, 451 participants; low‐certainty evidence). SPRMs probably increase preoperative haemoglobin (MD 0.93 g/dL, 95% CI 0.52 to 1.34; 2 studies, 173 participants; I² = 0%; moderate‐certainty evidence), and they may reduce bleeding before surgery (ulipristal acetate 5 mg: OR 41.41, 95% CI 15.26 to 112.38; 1 study, 143 participants; asoprisnil: MD −166.9 mL; 95% CI −277.60 to −56.20; 1 study, 22 participants; low‐certainty evidence). Results were very imprecise for adverse events (low‐certainty evidence). Authors' conclusions Pretreatment with gonadotropin‐hormone‐releasing analogues may reduce uterine and fibroid volume and probably increases preoperative haemoglobin levels, but probably also increases the number of adverse events. Blood transfusions and operation time during hysterectomy may be reduced, with fewer women experiencing postoperative morbidity. SPRMs, such as ulipristal acetate, seem to offer similar advantages: they probably reduce uterine volume and increase haemoglobin level before surgery, and may reduce fibroid volume and fibroid‐related bleeding. However, replication of these studies is advised as the certainty of the evidence is moderate to low. Plain language summary What are the benefits and risks of medications given before surgery to remove non‐cancerous growths in the womb (uterine fibroids)? Key messages ‐ Gonadotropin‐releasing hormone analogues (GnRHa) are medications that may be able to reduce womb and fibroid size and increase haemoglobin (a protein that helps transport oxygen in red blood cells) levels before surgery to treat uterine fibroids (non‐cancerous growths in the womb). Pretreatment with GnRHa may also reduce the time taken to undergo the operation, the need for blood transfusion, and some complications that can occur during or after surgery. ‐ Women taking GnRHa before surgery are more likely to experience unwanted side effects such as hot flushes. ‐ Further research is needed. What are fibroids? Fibroids are smooth muscle tumours (non‐cancerous growths) found in a woman's uterus (womb) that can make it difficult to become pregnant. They cause pain in the stomach area and heavy bleeding when a woman has her period. Fibroids can make it more likely for a woman to lose her baby through miscarriage. How are fibroids treated? Fibroids are often treated by surgery. Some medications, particularly gonadotropin‐releasing hormone analogues (GnRHa), might reduce the size of the womb and fibroid(s), making surgery easier, and they might also control heavy bleeding. However, they cannot be used for longer than six months because they may cause bone loss. Other medications that might have similar short‐term effects include progestins, dopamine agonists, selective progesterone receptor modulators (SPRMS), oestrogen receptor antagonists and selective oestrogen receptor modulators (SERMS). However, these medications tend to be expensive. What did we want to find out? We wanted to find out whether pretreatment with the above‐mentioned medications was helpful for: ‐ reducing heavy blood loss; ‐ making surgery easier by shrinking the size of the womb and the fibroid growths; ‐ reducing the time taken to do the operation, number of blood transfusions, amount of bleeding during the operation and complications after the operation. We also wanted to find out if any of the medications caused unwanted effects. What did we do? We searched for studies that looked at medications used before a fibroid operation, either compared with each other or compared with placebo (fake treatment) or no treatment. We summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes. What did we find? We found 41 studies, which included 3982 premenopausal women who were waiting for an operation to remove fibroids that were causing symptoms. Many of the women were anaemic (had low levels of red blood cells or haemoglobin, which affects the oxygen‐carrying capacity of the blood). The operations were hysterectomy (uterus removal), myomectomy (removal of the fibroids from the uterus wall) or hysteroscopic resection (removal of fibroids from the uterine cavity). The studies tested three comparisons: GnRHa versus no treatment or placebo; GnRHa versus other medical therapies; and selective progesterone receptor modulators (SPRMs) versus placebo. Some of the studies were supported by the companies that made the medications being tested. Main results GnRHa versus placebo or no pretreatment Gonadotropin‐releasing hormone analogues (GnRHa) may reduce womb size and fibroid size before surgery. There was no useful information about their effect on bleeding before surgery. GnRHa probably increase haemoglobin levels. However, women taking GnRHa are more likely to experience hot flushes. Hysterectomy The time taken to perform a hysterectomy may be less for women who have pretreatment with GnRHa drugs. Their effect on other outcomes measured in the hysterectomy studies is very uncertain: blood loss during the operation, blood transfusions, and complications after the operation. Myomectomy The results of these outcomes measured in the myomectomy studies are very uncertain: the length of the operation, blood loss during the operation, blood transfusions, and complications after the operation. Hysteroscopic resection GnRHa treatment before hysteroscopic resection for uterine fibroids may make little or no difference to how long the operation takes. One study measured complications after the operation; none were reported. Blood loss and blood transfusions were not measured for hysteroscopic resection. GnRHa versus other medical therapies Before surgery GnRHa pretreatment may reduce womb size before surgery compared to other medical therapies. GnRHa pretreatment may make little or no difference to bleeding or fibroid size. It probably does not affect haemoglobin levels. However, GnRHa may result in more unwanted effects such as hot flushes. SPRMs versus placebo Before surgery Compared to placebo medication, SPRMs (such as mifepristone, CDB‐2914, ulipristal acetate and asoprisnil) before surgery probably reduce womb size and increase haemoglobin levels. They may reduce fibroid size and bleeding. Results were imprecise for unwanted effects. What are the limitations of the evidence? Our certainty in the evidence for most outcomes is low or very low, due to poor reporting in the studies and lack of outcome assessor 'blinding' (i.e. the people measuring the outcomes knew who was in each group, which could have influenced their findings). In addition, results varied across studies, and some results were based on only one study. How up‐to‐date is this evidence? This review updates one published in 2017 and is up to date to August 2024. Summary of findings Summary of findings 1. GnRHa pretreatment versus placebo or no pretreatment before surgery for uterine fibroids. | Gonadotropin‐hormone releasing analogue (GnRHa) pretreatment versus placebo or no pretreatment before surgery for uterine fibroids | |||||||| | Patient or population: women with uterine fibroids Setting: hospitals or outpatient clinics Intervention: GnRHa Comparator: placebo or no pretreatment | |||||||| | Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | No of participants (studies) | Certainty of the evidence (GRADE) | Comments | ||| | Assumed risk | Corresponding risk | ||||||| | Placebo or no pretreatment | GnRHa pretreatment | ||||||| | Uterine volume (mL) (preoperative) | Mean uterine volume in control group ranged from 255 mL to 920 mL | Mean uterine volume (mL) (preoperative) in intervention groups was 175.34 mL lower (219.04 mL to 131.65 mL lower) | ‐ | 858 (13 studies) | ⊕⊕⊝⊝ low1,2 | This overall estimate assessed effects from studies with two types of control group, either no treatment or placebo. | || | Fibroid volume (mL) (preoperative) | Estimates were too heterogeneous for pooling. Fibroid volume ranged from a mean reduction of 5.7 mL to 155.4 mL in the GnRHa group compared to control. | Not estimable | 427 (5 studies) | ⊕⊕⊝⊝ low3,4 | ‐ | ||| | Preoperative haemoglobin (g/dL) | Mean haemoglobin ranged from 10.9 g/dL to 13.4 g/dL | Mean haemoglobin (g/dL) (preoperative) in intervention groups was 0.88 mL higher (0.68 mL to 1.08 mL higher) | ‐ | 834 (10 studies) | ⊕⊕⊕⊝ moderate5 | This overall estimate assessed effects from studies with two types of control group, either no treatment or placebo. | || | Preoperative bleeding | This outcome was not measured by validated scales. | Not estimable | ‐ | ‐ | ‐ | ||| | Adverse events (related to the preoperative treatment) | 579 per 1000 | 793 per 1000 (709 to 857) | OR 2.78 (1.77 to 4.36) | 755 (5 studies) | ⊕⊕⊕⊝ moderate6 | ‐ | || | Duration of surgery (minutes) | For hysterectomy | Mean duration of surgery in control group ranged from 53 to 115 minutes | Mean duration of surgery in intervention groups was 10.11 minutes shorter (16.96 to 3.25 shorter) | ‐ | 617 (6 studies) | ⊕⊕⊝⊝ low1,2 | An additional 3 studies had findings presented in data tables (2 reported no difference between groups; 1 reported a difference of 21 minutes between groups, favouring GnRHa pretreatment). | | | For myomectomy | Substantial heterogeneity, so estimates could not be pooled. Trial where laparoscopic myomectomy was undertaken indicated that GnRHa was associated with greater duration of surgery than control, but no other factors were identified to explain the variation and no estimates could be shown. | Not estimable | 443 (7 studies) | ⊕⊝⊝⊝ very low3,7 | ‐ | ||| | For hysteroscopic resection | Mean duration of surgery in control group was 21 minutes | Mean operating time in intervention groups was 0.17 minutes shorter (11.22 shorter to 10.88 longer) | ‐ | 123 (2 studies) | ⊕⊕⊝⊝ low8,9 | ‐ | || | Intraoperative blood loss (mL) | For hysterectomy | Substantial heterogeneity, so estimates could not be pooled. Differences in blood loss (mL) between GnRHa and control group participants ranged from 25 mL to 148 mL. | Not estimable | 258 (4 studies) | ⊕⊝⊝⊝ very low2,10,11 | ‐ | || | For myomectomy | Substantial heterogeneity, so estimates could not be pooled. All but one of the trials found a difference in intraoperative blood loss between GnRHa and control ranging from 22 mL to 157 mL. A single trial where laparoscopic myomectomy was compared with control found that GnRHa pretreatment was associated with 82 mL greater blood loss than control. | Not estimable | 549 (11 studies) | ⊕⊝⊝⊝ very low7,11 | |||| | For hysteroscopic resection | No studies measured this outcome. | Not estimable | ‐ | ‐ | |||| | Frequency of blood transfusions | For hysterectomy | 104 per 1000 | 59 per 1000 (33 to 105) | OR 0.54 (0.29 to 1.01) | 601 (6 studies) | ⊕⊕⊕⊝ moderate10 | Fixed‐effect model: OR 0.54 (95% CI 0.30 to 0.95) | | | For myomectomy | vs no pretreatment | 143 per 1000 | 124 per 1000 (42 to 314) | OR 0.85 (0.26 to 2.75) | 121 (4 studies) | ⊕⊕⊝⊝ low12,15 | ‐ | | | vs placebo | 194 per 1000 | 170 per 1000 (59 to 398) | |||||| | For hysteroscopic resection | No studies measured this outcome. | Not estimable | ‐ | ‐ | ‐ | ||| | Postoperative morbidity | For hysterectomy | 195 per 1000 | 116 per 1000 (72 to 181) | OR 0.54 (0.32 to 0.91) | 772 (7 studies) | ⊕⊕⊕⊝ moderate14 | ‐ | | | For myomectomy | vs no pretreatment | 146 per 1000 | 154 per 1000 (68 to 311) | OR 1.07 (0.43 to 2.64) | 190 (5 studies) | ⊕⊕⊝⊝ low13,15 | ‐ | | | vs placebo | 188 per 1000 | 199 per 1000 (91 to 379) | |||||| | For hysteroscopic resection | 1 study reported the outcome. | ‐ | No cases in any group | 84 (1 study) | ⊕⊕⊝⊝ low8,9 | ‐ | || | *The basis for the assumed risk is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; OR: odds ratio; vs: versus | |||||||| | GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | 1Evidence certainty downgraded 1 level for serious limitations in study design (few studies had adequate sequence generation, allocation concealment baseline comparability and blinding, although lack of blinding was not expected to influence findings. 7 studies had a low risk of attrition and reporting bias) 2Evidence certainty downgraded 1 level for inconsistency (there was wide variability in the estimates) 3Evidence certainty downgraded 1 level for serious limitations in study design (only 1 study had a low risk of selection, reporting, performance and detection bias, and 2 of 5 had a low risk of attrition bias) 4Evidence certainty downgraded 1 level for substantial heterogeneity 5Evidence certainty downgraded 1 level for serious limitations in study design (sequence generation and allocation concealment were unclear or inadequate in 7 of 10 studies; selective reporting and completeness of data were unclear or inadequate in 5 of 10 studies; blinding was only assured in 6 studies for participants and investigators, and 2 studies for assessors; and other bias was possible in 6 studies) 6Evidence certainty downgraded 1 level for serious limitations in study design (most trials had a low risk of selection, reporting and performance biases, but the risk of detection and attrition bias was unclear or high) 7Evidence certainty downgraded 2 levels for substantial heterogeneity 8Evidence certainty downgraded 1 level for serious limitations in study design (lack of blinding and unclear reporting bias) 9Evidence certainty downgraded 1 level for imprecision (small trial(s)) 10Evidence certainty downgraded 1 level because of serious limitations in study design (half of the studies had unclear selection, reporting and attrition bias. Lack of blinding in the studies was unlikely to affect the results) 11Evidence certainty downgraded 1 level because of serious imprecision (wide confidence intervals) 12Evidence certainty downgraded 1 level for serious limitations in study design (no studies had a low risk of selection, performance, detection and reporting bias) 13Evidence certainty downgraded 1 level for serious limitations in study design (only 1 study with a total of 5 participants had low risk of selection bias (allocation concealment) and performance and detection bias (blinding) 14Evidence certainty downgraded 1 level because of serious limitations in study design (approximately half the studies had unclear risk of selection, performance and attrition bias, and the risk of detection bias was unclear in all studies) 15Evidence certainty downgraded 1 level for imprecision (wide confidence interval) Summary of findings 2. GnRHa pretreatment versus other medical therapies before surgery for uterine fibroids (preoperative outcomes only). | Gonadotropin‐hormone releasing analogue (GnRHa) treatment versus other medical therapies before surgery for uterine fibroids (preoperative outcomes only) | |||||| | Patient or population: women with uterine fibroids Setting: hospitals or outpatient clinics (only preoperative outcomes) Intervention: GnRHa Comparator: other medical therapy | |||||| | Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | No of participants (studies) | Certainty of the evidence (GRADE) | Comments | | | Assumed risk | Corresponding risk | ||||| | Control (other medical therapies) | GnRHa pretreatment | ||||| | Preoperative uterine volume (cm³) | Studies too heterogeneous for pooling. One study comparing a GnRHa with an SERM and another study comparing GnRHA with mifepristone found no difference between groups. One trial comparing GnRHa with ulipristal acetate found a greater reduction with GnRHa (−47%) compared to 5 mg (−20%) and 10 mg (−22%) ulipristal acetate. | Not estimable | 502 (6 studies) | ⊕⊕⊕⊝ moderate1 | ‐ | | | Preoperative fibroid volume (cm³) | Fibroid volume in comparator (cabergoline) groups ranged from 86 cm³ to 278 cm³ | Mean fibroid volume in intervention groups was 12.71higher (5.92 lower to 31.34 higher) | ‐ | 110 (2 studies) | ⊕⊕⊝⊝ low1,2 | 2 additional studies with skewed data not suitable for pooling reported no differences between groups (GnRHa vs raloxifene, GnRHa vs ulipristal acetate). One additional study found a greater reduction with GnRHa when compared to multiple doses of fulvestrant. | | Preoperative haemoglobin (g/dL) | Mean haemoglobin at end of preoperative treatment in comparator (ulipristal acetate) groups was 10.55 g/dL | Mean haemoglobin at end of preoperative treatment in intervention groups was 0.02 lower (0.41 lower to 0.37 higher) | ‐ | 242 (2 studies) | ⊕⊕⊕⊝ moderate3 | ‐ | | Preoperative bleeding: reduction in fibroid‐related bleeding to PBAC < 75 ulipristal acetate 5 mg | 898 per 1000 | 862 per 1000 (725 to 937) | OR 0.71 (0.30 to 1.68) | 199 (1 study) | ⊕⊕⊝⊝ low2,3 | ‐ | | Preoperative bleeding: reduction in fibroid‐related bleeding to PBAC < 75 ulipristal acetate 10 mg | 941 per 1000 | 862 per 1000 (691 to 944) | OR 0.39 (0.14 to 1.06) | 203 (1 study) | ⊕⊕⊝⊝ low2,3 | ‐ | | Adverse events related to the preoperative treatment: hot flushes | 233 per 1000 | 695 per 1000 (549‐881) | OR 2.83 (1.68 to 4.77) | 507 (6 studies) | ⊕⊕⊝⊝ low4 | These findings were for hot flushes (GnRHa compared to raloxifene, ulipristal acetate, mifepristone, cabergoline and lynestrenol). Headache (with comparators raloxifene, ulipristal acetate, cabergoline and lynestrenol), sleep disorder (vs lynestrenol) and bone sensitivity (vs cabergoline) were also increased with GnRHa compared to other medical treatments, but fewer studies contributed data. We are uncertain about the evidence for headache, nausea, weight gain, oedema, sleep disorder, mood disorder or anxiety, vaginal dryness, cutaneous disorder, abdominal or pelvic pain, procedural pain, fatigue, anaemia, nasopharyngitis, breast pain or tenderness, influenza, insomnia, pharyngitis, dizziness, bone sensitivity, muscular stiffness. No studies compared total numbers of adverse events. | | Only preoperative outcomes were measured because data were insufficient to distinguish between types of surgery, which could influence intraoperative or postoperative outcomes. | |||||| | The basis for the assumed risk is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; OR: odds ratio; PBAC: pictorial blood assessment chart; SERM: selective oestrogen receptor modulators; vs: versus | |||||| | GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | 1Evidence certainty downgraded 1 level for limitations in study design (unclear risk of selection bias and attrition bias and lack of blinding) 2Evidence certainty downgraded 1 level because of imprecision (two small trials with wide confidence intervals) 3Evidence certainty downgraded 1 level (study had pharmaceutical support, but it was not possible to determine whether this had influenced the findings.) 4Evidence certainty downgraded 1 level for serious limitations in study design (most studies had significant risk of bias) and 1 level for inconsistency (variation between estimates in the studies) Summary of findings 3. SPRM pretreatment versus placebo or no pretreatment before surgery for uterine fibroids (preoperative outcomes). | Selective progesterone‐receptor modulators (SPRM) compared to placebo before surgery for uterine fibroids (preoperative outcomes only) | |||||| | Patient or population: women with uterine fibroids Setting: hospitals or outpatient clinics Intervention: selective progesterone‐receptor modulators (SPRM) Comparator: placebo | |||||| | Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | Number of participants (studies) | Certainty of the evidence (GRADE) | Comments | | | Assumed risk | Corresponding risk | ||||| | Placebo | SPRM | ||||| | Preoperative uterine volume (cm³) | Two studies could not be pooled. One study found a greater proportion of women taking ulipristal acetate had a reduction in uterine volume > 25% than placebo (34% (ulipristal acetate 5 mg) and 28% (ulipristal acetate 10 mg) vs placebo 6%). The other study found no difference in this outcome with asoprisnil compared to placebo. | Not estimable | 275 (2 studies) | ⊕⊕⊕⊝ moderate1 | The largest trial (242 participants) was founded by the pharmaceutical producer of ulipristal acetate. | | | Preoperative fibroid volume (cm³) | Four studies could not be pooled. The studies found a greater reduction with SPRMs (regardless of type) compared to placebo (other than for the lower dose of asoprisnil (10 mg)). Reductions with ulipristal acetate, mifepristone, CDB‐2914 and asoprisnil 25 mg ranged from 12% to 29% compared to a range of 3% to 6% with placebo. | Not estimable | 451 (5 studies) | ⊕⊕⊝⊝ low1,2 | The larger study (242 participants) was funded by the pharmaceutical company that supplied the intervention. 3 of the studies were very small. | | | Preoperative haemoglobin (g/dL) | Mean haemoglobin ranged from 12.2 to 12.6 g/dL | Mean haemoglobin (g/dL) in intervention groups was 0.93 higher (0.52 to 1.34 higher) | ‐ | 297 (3 studies) | ⊕⊕⊕⊝ moderate2 | Although one study reported receiving pharmaceutical company funding, results were very similar to the other studies, so funding was unlikely to have influenced the results. | | Preoperative bleeding: reduction in fibroid‐related bleeding to PBAC < 75, ulipristal acetate 5 mg | 188 per 1000 | 905 per 1000 (779 to 963) | OR 41.41 (15.26 to 112.38) | 143 (1 study) | ⊕⊕⊝⊝ low1,2 | Study was funded by the pharmaceutical company that supplied the intervention. | | Preoperative bleeding: reduction in fibroid‐related bleeding to PBAC < 75, ulipristal acetate 10 mg | 83 per 1000 | 878 per 1000 (686 to 959) | OR 78.83 (24.02 to 258.74) | 146 (1 study) | ⊕⊕⊝⊝ low1,2 | Study was funded by the pharmaceutical company that supplied the intervention. | | Preoperative bleeding: change in fibroid‐related bleeding from baseline to end of treatment | Mean menstrual blood loss change score (menstrual pictogram) increased from baseline of 12.6 (menstrual bleeding score) | Mean change in menstrual blood loss from baseline to end of treatment in intervention groups was 166.9 lower (277.6 to 56.2 lower) | ‐ | 22 (1 study) | ⊕⊕⊝⊝ low3 | ‐ | | Adverse events related to the preoperative treatment | 42 per 1000 | 0 per 1000 | OR 0.05 (0.00 to 1.02) | 241 (1 study) (dysmenorrhoea) | ⊕⊕⊝⊝ low3 | No evidence of a difference in serious adverse events. Results were very imprecise for specific adverse events that were less serious. We are uncertain about the effect for other individual adverse events. | | 0 per 1000 | 429 per 1000 | OR 25.24 (1.27 to 503.38) | 30 (1 study) (hot flushes) | ||| | 63 per 1000 | 500 per 1000 | OR 15.0 (1.54 to 146.54) | 30 (1 study) (change in mood) | ||| | Only preoperative outcomes were measured because data were insufficient to distinguish between types of surgery, which could influence intraoperative or postoperative outcomes. | |||||| | *The basis for the assumed risk is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; OR: odds ratio; PBAC: pictorial blood assessment chart; UPA: ulipristal acetate; vs: versus | |||||| | GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | 1Evidence certainty downgraded 1 level because of potential influence from pharmaceutical company funding 2Evidence certainty downgraded 1 level for imprecision (wide confidence intervals) 3Evidence certainty downgraded 2 levels because of imprecision (very small trial with wide confidence intervals)

Description of the condition Uterine fibroids (also known as myomas or leiomyomas) are the most common benign tumour of the female reproductive tract. They are thought to affect approximately 20% to 40% of women of reproductive age (Jacoby 2010; Wallach 1992), although it is possible that the prevalence may be even higher ‐ ultrasound detention studies report their presence in more than 80% in women of African ancestry and nearly 70% of white women, by the age of 50 (Baird 2003; Giuliani 2020). The global burden of uterine fibroids increased between 1990 and 2019, and reported incidence and disability‐adjusted life years (DALY) increased substantially worldwide (Cheng 2022). Fibroids are classified according to their anatomic location as subserosal, intramural and submucosal types (Yang 2011). Many fibroids are asymptomatic, but a proportion of women have heavy menstrual bleeding (30%), anaemia, dysmenorrhoea, pelvic pain and pressure symptoms (34%), reduced quality of life and reduced fertility (27%) (Giuliani 2020). The standard treatments for symptomatic uterine fibroids are surgical (hysterectomy ‐ total removal of the uterus ‐ or myomectomy ‐ removal of the fibroids from the uterus wall) and radiological interventions. Fibroids are the most common indication for hysterectomy (Merrill 2008); less invasive procedures include myomectomy (in women wishing to preserve their fertility), hysteroscopic removal, uterine artery embolisation and other radiological interventions (Patel 2014). Fibroids represent one of the most frequent indications for major surgery in premenopausal women (Carls 2008). As such, they constitute a major public health cost. The economic impact of uterine fibroid management is significant, and there is a need for new treatments to be developed to provide better alternatives to surgical management (Donnez 2016; Yu 2018). Despite the widespread occurrence of uterine fibroids and newer treatment options, there is a lack of high‐quality data available to formulate evidence‐based guidelines that address important unmet patient needs (Al‐Hendy 2017; Donnez 2020 ; Donnez 2022). Description of the intervention Some medical therapies are currently being investigated as stand‐alone treatments for fibroids, but the role of this review is to investigate medical therapies before surgery. These preoperative medical treatments include gonadotropin‐releasing hormone analogues (GnRHa), progestins, selective oestrogen receptor modulators, dopamine agonists, prostaglandin analogues and selective progesterone receptor modulators. Since the 1980s, GnRHa treatments, which induce a low‐oestrogen state by suppressing pituitary ovarian function, have been investigated for women with fibroids. The main effects of this treatment are the temporary control of bleeding and reduction of fibroid and uterine size, making surgery easier and with better postoperative results, but side effects include menopausal symptoms and bone loss with long‐term use. After therapy is stopped, there is re‐growth of both the tumours and the uterus to almost their pretreatment size, and in most women, a recurrence of symptoms (Matta 1989). Thus, they have been approved only for short‐term use, as a preoperative adjunct to surgery. Other potential hormonal therapies have also been investigated as preoperative treatment. Progestins have been used to reduce heavy menstrual bleeding induced by fibroids but have thromboembolic and metabolic risks (Jourdain 1996). Selective oestrogen receptor modulators (SERMs) are approved for the prevention and treatment of osteoporosis but preclinical studies suggest they may inhibit the proliferation of fibroid cells, consequently limiting their growth (Jirecek 2004). Selective progesterone receptor modulators (SPRMs), such as asoprisnil, mifepristone and ulipristal acetate, have more recently been investigated, and in 2012, ulipristal acetate was licenced by the European Medicines Agency for the treatment of symptomatic fibroids over a maximum of three months for preoperative management (Pérez Lopez 2014). In February 2018 and March 2020, two urgent safety measures were taken as a consequence of drug alerts issued by the European Medicines Agency (EMA) and UK Medicines and Healthcare products Regulatory Agency (MHRA) following reports of serious liver injury in patients receiving ulipristal acetate treatment. In March 2020, the EMA temporarily suspended the use of ulipristal acetate for a second time, while a further safety review was undertaken. The EMA revoked the marketing authorisation for ulipristal acetate in September 2020. Currently, the indication of ulipristal acetate (UPA) 5 mg for uterine fibroids has been further restricted due to the risk of serious liver injury and liver failure, with some cases requiring liver transplantation. Although the temporary suspension has been lifted, UPA should only be used for intermittent treatment of moderate to severe symptoms of uterine fibroids before menopause and when surgical procedures (including uterine fibroid embolisation) are not suitable or have failed (EMA 2021; MHRA). The licence is unlikely to be extended, despite rates of drug‐induced liver injury remaining extremely low, being 11:100,000, a risk comparable to or lower than several drugs that are not subject to liver function monitoring, such as diclofenac and several antibiotics. Surgical interventions, particularly hysterectomy, are associated with better quality of life but are typically fertility‐ending and carry a higher risk of serious complications, and rates of mortality are markedly higher compared to that of fatal liver injury following UPA treatment (> 1:1000 vs 0.1:100,000) (Middelkoop 2021; Middelkoop 2022 ; UCON 2023). How the intervention might work Although the pathogenesis of fibroids is not well established, it has been recognised that fibroid growth and maintenance are stimulated by oestrogen and affected by hormonal cyclic changes (Friedman 1990). Oestradiol and progesterone receptors have been identified in myomatous tissue (Tamaya 1985; Wilson 1980). Because of this dependence of fibroids on steroid hormones, it follows that medications to reduce the levels of gonadal steroids might be options for the treatment of uterine fibroids. If a state of reduced oestrogen secretion could be induced, this would likely result in a reduction in the growth of fibroids and even their regression. Additionally, as progesterone is known to promote the growth of fibroids, modulating the progesterone pathway by acting on progesterone receptors in myometrial tissue may control heavy menstrual bleeding and reduce fibroid size (Donnez 2012a; Donnez 2016; Donnez 2022). Pretreatment with medical therapy before hysterectomy is considered particularly useful for women with severe anaemia and to reduce blood loss during surgery. Other indications have included large fibroids or other factors that make surgery technically difficult (West 1992). Pretreatment with medical therapy may also enable greater use of vaginal hysterectomy (Stovall 1991) compared to abdominal hysterectomy or even more conservative surgical options such as laparoscopic or hysteroscopic removal. Conservative surgery, or myomectomy, has generally been used for women who wish to preserve or enhance their fertility but is often regarded as a more difficult procedure than hysterectomy, with a high risk of postoperative pyrexia (fever), pelvic haematoma formation and postoperative adhesions. Moreover, intraoperative haemorrhage can necessitate emergency blood transfusion or hysterectomy. Myomectomy may be performed via laparotomy, laparoscopy or hysteroscopy, and the method must be distinguished in the evaluation of pretreatment with medical agents. Potential benefits of preoperative medical therapies are reduction in blood loss during the operation, ease of operability, better anatomical reconstruction and the possibility of using a transverse (Pfannenstiel‐type) rather than vertical midline incision at laparotomy. However, concern has been expressed that the fibroid capsule would become less evident and may be missed, tumours will not 'shell out' cleanly and the excision may be more difficult (Friedman 1989; Stovall 1989). A less invasive surgical option, hysteroscopic resection, is often used in women with submucous fibroids. This option offers advantages over myomectomy such as reduced trauma, shorter hospitalisation and recovery times and decreased risk of adhesion formation. GnRH analogues have been used preoperatively before this surgery for some time, but the evidence to support this practice is weak (Parazzini 1998). Controlled non‐randomised studies have been undertaken but have reported conflicting results (Campo 2005; Perino 1993). Why it is important to do this review Fibroids represent one of the most frequent indications for major gynaecological surgery in premenopausal women. GnRH analogues, and latterly, other types of medical therapy, have been investigated before surgery for uterine fibroids to improve intraoperative and postoperative outcomes. It is important to determine precisely the specific advantages and disadvantages of this practice compared to no presurgical therapies and to compare the effectiveness of individual presurgical therapies. This is an update of a Cochrane review first published in 2001 and previously updated in 2017 (Lethaby 2017). This update has been prompted by the decision of the European Medicines Agency to suspend the use of ulipristal acetate for the treatment of uterine fibroids (EMA 2021).

To assess the benefits and risks of medical treatments prior to surgery for uterine fibroids.

Criteria for considering studies for this review Types of studies All randomised controlled trials (RCTs) of medical therapies versus placebo or no treatment when administered before any surgery for uterine fibroids All RCTs of individual medical therapies versus other individual medical therapies when administered before surgery for uterine fibroids We did not include trials of medical therapies used as the sole treatment for uterine fibroids, without the expectation of subsequent surgery. Had we found any cross‐over, multi‐arm or cluster‐randomised trials, these would have been excluded. Types of participants We included studies of premenopausal women, without any other underlying uterine pathology, intending to undergo any surgery for uterine fibroids: either hysterectomy (abdominal, vaginal or laparoscopic), myomectomy (laparotomy or laparoscopy) or hysteroscopic resection for uterine fibroids. Types of interventions Versions of this review published before 2017 focused on gonadotropin‐hormone releasing analogue (GnRHa) treatment versus no treatment, placebo or other medical therapy before surgery for uterine fibroids. In this 2025 update, we expanded the scope of the review to include any other types of treatment used before fibroid surgery. The following interventions were also included and compared either with placebo, no treatment or with each other: progestins; selective progesterone receptor modulators (SPRMs); selective oestrogen receptor modulators (SERMs); dopamine agonists; and oestrogen receptor antagonists. Misoprostol, another therapy that has been used, particularly before myomectomy, was not included; its effectiveness was considered (along with other interventions for the prevention of haemorrhage specifically in myomectomy) in another Cochrane review (Kongnyuy 2014). We made the following comparisons: GnRHa versus placebo or no pretreatment; GnRHa versus other medical therapies (progestin, SPRM, SERM, dopamine agonist, oestrogen receptor antagonist); and SPRMs versus placebo or no pretreatment. The GnRHa comparison was further structured according to the types of outcomes measured. Where outcomes were preoperative, all relevant trials were included; where the outcomes were measured during or after surgery, the comparisons were structured by type of surgery: hysterectomy, myomectomy or hysteroscopic resection. Types of outcome measures We analysed the following outcomes where data were available. We stratified the outcomes into different groups, according to whether they were measured before, during or after surgery. We excluded from the review any trials that measured only surrogate outcomes. Primary outcomes 1. Preoperative assessment Uterine volume or fibroid volume or both (as reported in the primary study) Preoperative haemoglobin Preoperative bleeding (only if measured by a validated scale) 2. Operative difficulties and postoperative assessment Duration of surgery Intraoperative blood loss Frequency of blood transfusions Postoperative morbidity (complications such as pyrexia, haematoma formation and incidence of postoperative adhesions) Secondary outcomes 1. Preoperative assessment Adverse events (related to the preoperative treatment) Quality of life (related to the preoperative assessment, assessed subjectively by the participant on a validated scale) 2. Operative difficulties and postoperative assessment Difficulty of surgery (assessed subjectively by the surgeon) Proportion of women undergoing vaginal hysterectomy (in women undergoing hysterectomy) Type of abdominal incision (Pfannenstiel transverse versus vertical) Duration of hospital stay (days) Intraoperative hysterectomy (for women undergoing myomectomy) Frequency of postoperative recurrence of myomas Postoperative haemoglobin Search methods for identification of studies In August 2024, we searched for all published and unpublished randomised controlled trials (RCTs) of preoperative treatment before surgery in women with fibroids with either GnRHa, selective progesterone receptor modulators (SPRMs), selective oestrogen receptor modulators (SERMs), oestrogen receptor antagonists, progestins or dopamine antagonists. The searches were conducted without language or date restriction and in consultation with the Cochrane Gynaecology and Fertility Group Information Specialist. Electronic searches We searched the following electronic databases. Cochrane Gynaecology and Fertility Specialised Register, ProCite platform (inception to 8 August 2024) (Appendix 1) CENTRAL via the Cochrane Register of Studies Online (CRSO), Web platform (searched 8 August 2024) (Appendix 2). CENTRAL now also contains records from two trial registries (clinicaltrials.gov (www.clinicaltrials.gov) and the World Health Organization International Clinical Trials Registry Platform (trialsearch.who.int)) and CINAHL (Cumulative Index to Nursing and Allied Health Literature) MEDLINE, Ovid platform (1946 to 8 August 2024) (Appendix 3) Embase, Ovid platform (1980 to 8 August 2024) (Appendix 4) PsycINFO, Ovid platform (1806 to 8 August 2024) (Appendix 5) CINAHL, EBSCO platform (1961 to 19 August 2019; all later CINAHL references are included in the 2024 CENTRAL output) (Appendix 6) We also searched the following electronic sources of trials on 8 August 2024. Epistemonikos Web of Science conference abstracts and other trials OpenGrey for unpublished literature from Europe PubMed Google Scholar The MEDLINE search was limited by the Cochrane highly sensitive search strategy filter for identifying randomised trials, which appears in the Cochrane Handbook of Systematic Reviews of Interventions (Lefebvre 2023) We combined the Embase searches with trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN) (www.sign.ac.uk/what-we-do/methodology/search-filters/. Searching other resources We handsearched the reference lists of included studies and relevant reviews retrieved by the search for additional trials. We also contacted the pharmaceutical company that supplies ulipristal acetate ‐ HRA Pharma ‐ for any clinical trials that may have been undertaken and not published. No reply has been received to date. Data collection and analysis Selection of studies For the original version of the review, two review authors (a methodologist (AL) and a clinical expert (BV)) selected studies for the review. For the 2017 and 2024 updates, two review authors (a methodologist (AL) and a topic area specialist (LP)) independently selected potentially relevant trials from the search results according to the review eligibility criteria. Where studies appeared eligible, they were retrieved in full‐text format for further investigation for eligibility; this was done in duplicate. We resolved any disagreements over selection by consensus. We documented the selection process in a PRISMA flow chart (Figure). Data extraction and management For previous versions of the review, two review authors independently extracted and managed data. For the 2017 and 2024 updates, two review authors (AL, LP) independently extracted data from the eligible studies using a data extraction form that was designed and pilot tested by AL. Disagreements were resolved by discussion. The extracted data included relevant study characteristics and effect estimates. Where there were multiple intervention groups (e.g. different doses of GnRHa), we combined the data where possible. If combined data could not be calculated, then we took the following approach. For binary outcomes with a common placebo group, we entered the dosage group data into the meta‐analysis separately and divided the placebo numbers as equally as possible between the arms of the intervention. For continuous outcomes, we extracted the data from the intervention with the lowest dosage. Where there were multiple groups of participants (e.g. women with different uterine size: 14 to 18 and over 18 gestational weeks), we used data from the group with the smaller uterine size in the meta‐analysis. Where studies had multiple publications, we used the main trial report as the reference and derived additional details from secondary papers, if necessary. Where data were not clearly reported, we corresponded with the principal author of the study to obtain clarification. Assessment of risk of bias in included studies For previous review versions, two review authors (AL, BV) independently assessed the studies for risk of bias in a descriptive format. In the 2017 and 2024 review updates, two review authors (AL, LP) independently assessed the included studies for risk of bias using the Cochrane risk of bias assessment tool (Higgins 2011). We assessed the following domains and judged them as low, unclear or high risk of bias: generation of allocation sequence; allocation concealment; blinding of participants, study personnel and assessors; incomplete outcome data; selective reporting; and other bias (e.g. baseline comparability, early stopping of trial). We resolved disagreements by consensus. We recorded the reasons for our judgments in risk of bias tables, and we summarised the assessments for each study in Figure and across studies in Figure. Measures of treatment effect For dichotomous data (e.g. incidence of adverse events), we used the number of events in the control (or other treatment) and intervention groups of each study to calculate Mantel‐Haenszel odds ratios (OR). For continuous data (e.g. uterine volume), we calculated the mean difference (MD) between treatment groups. We reversed the direction of effect of different studies, when required, to ensure consistency across trials. We presented 95% confidence intervals (CIs) for all outcomes. We compared the magnitude and direction of effect reported by studies with how they were presented in the review, taking account of legitimate differences. Unit of analysis issues The unit of analysis is the randomised participant (Li 2024). Dealing with missing data The data were analysed on an intention‐to‐treat (ITT) basis, as far as possible, and we made attempts to obtain missing data from the original trialists. Where data to calculate ORs or MDs were not available, we used the most detailed numerical data available that facilitated similar analyses of the included studies (e.g. test statistics, P values, standard error of the mean) (Li 2024). Where this was not possible (e.g. missing measure of variation), we imputed values for the missing data by entering the largest comparable measure used by the other pooled studies. Any imputation was subjected to sensitivity analysis. Otherwise, if imputation was not feasible or realistic, we analysed only the available data. Assessment of heterogeneity We considered whether the clinical and methodological characteristics of the included studies were sufficiently similar for meta‐analysis to provide a clinically meaningful summary. Where the decision was made to pool studies, we assessed statistical heterogeneity by inspection of the Chi² test results and the I² statistic. A rough guide to interpretation of I² values is as follows (Deeks 2023): 0% to 40% might not be important; 30% to 60% may represent moderate heterogeneity; 50% to 90% may represent substantial heterogeneity; and 75% to 90% represents considerable heterogeneity. These overlapping categories were considered, together with the unique characteristics of the outcomes, in our assessment of heterogeneity. Assessment of reporting biases We attempted to minimise the potential impact of reporting bias by ensuring a comprehensive search for eligible studies and by being alert to the duplication of data. We planned to use funnel plots, if sufficient studies were identified, to further investigate potential publication bias or small‐study effects. Data synthesis Since many of the outcomes assessed were likely to be influenced by other factors, such as different hospital policies in different countries (e.g. hospital stay, duration of surgery) or differences in participants' characteristics (size of fibroids, haemoglobin levels), we combined data using the random‐effects model to compare intervention with control (or other treatment) using RevMan (RevMan 2024). We assessed outcomes with continuous data for the likelihood of skew. Where the authors of individual studies reported a median and range, or where the methods used to analyse the data were non‐parametric, we considered that skew was likely. For other outcomes, where a mean and SD were reported, we made a rough check, where possible, by calculating the observed mean minus the lowest possible value (or the highest possible value minus the observed mean) and dividing this by the standard deviation. Where this ratio was less than 1, we considered that skew was likely. Where we considered that skew was likely, we did not pool the outcome data in a meta‐analysis but displayed these data in other data tables. We included the findings of each of these studies in the interpretation of overall results for each outcome. Subgroup analysis and investigation of heterogeneity As assessment of some outcomes could have been influenced if participants knew they were receiving pretreatment, we conducted subgroup analyses (where possible) for primary outcomes to explore any differences in findings according to whether control group women with fibroids went on to immediate surgery or had no pretreatment (as they would be aware of group differences), or whether there was placebo control. No other subgroup analysis was undertaken. In most cases, we calculated a pooled effect estimate combining the results of both subgroups, but where there were markedly different estimates, we did not calculate a summary effect measure. The findings within each subgroup informed the interpretation of the results. Where moderate heterogeneity was detected (I² > 50%), we explored this by checking the data and by examining clinical and methodological differences amongst studies to determine whether there was any plausible explanation. We took statistical heterogeneity into account when interpreting the results, particularly when there was variation in the direction of effect. Where substantial ('considerable') statistical heterogeneity was detected (I² > 75%), we did not pool the studies; instead, we displayed individual study results on a forest plot without calculating a summary effect estimate (Deeks 2023). Sensitivity analysis We conducted sensitivity analyses, where possible, for the primary outcomes to determine whether the conclusions were robust to the decisions we made regarding eligibility and analysis (Deeks 2023). These analyses included consideration of whether the review conclusions would have differed if: we had restricted eligibility to studies without a high risk of bias; or we had used the fixed‐effect model for meta‐analysis. We also undertook sensitivity analysis for comparison 5: GnRHa versus other medical treatments, i.e. SPRMs, SERMs, dopamine agonists, progestins and oestrogen receptor antagonists. Data from the included studies assessing these other treatments are scarce, so we will continue to combine these treatments in our analysis until there are sufficient data to make it sensible to consider them separately. We recognised that the different treatments might have different effects on the outcomes and undertook sensitivity analyses, where necessary, to assess whether these effects could be distinguished. Summary of findings and assessment of the certainty of the evidence One review author (AL) generated summary of findings (SoF) tables using GRADEpro software (GRADEpro GDT 2015). Another review author (LP) checked the SoF tables for errors; no disagreements between authors were identified. The SoF tables displayed findings for all the primary outcomes (i.e. those considered critical), as well as adverse events (a secondary outcome). The primary outcomes for preoperative assessment were: reduction in uterine volume, reduction in fibroid volume, preoperative haemoglobin, preoperative bleeding and adverse events related to the preoperative treatment. The primary outcomes for intraoperative and postoperative assessment were: duration of surgery, intraoperative blood loss, frequency of blood transfusions and postoperative morbidity (complications). We evaluated the overall certainty of the body of evidence for these outcomes, using GRADE criteria (study limitations (risk of bias), consistency of effect, imprecision, indirectness, and publication bias). We documented our judgments about the certainty of the evidence (very low, low, moderate or high) for: GnRHa versus placebo or no pretreatment (before hysterectomy, myomectomy or hysteroscopic resection of fibroids) ‐ preoperative, intraoperative and postoperative outcomes; GnRHa versus other medical therapies before surgery for uterine fibroids ‐ preoperative outcomes only; SPRMs versus placebo before surgery for uterine fibroids ‐ preoperative outcomes only.

Description of studies Searches for the 2025 update The 2017 version of the review included 38 studies. In searches to August 2024, we found 2493 records after removing duplicates. We screened 1076 records and rejected 1067 records. We assessed nine full‐text articles for eligibility: we excluded one full‐text article because it was a conference abstract with insufficient detail and no data; two articles are ongoing studies (Kawahara 2024; Kitade 2024), and we are awaiting clarification from the authors of three studies (Benagiano 1992; Gambardella 1995; Sun 2021). In this update, we included three new studies in qualitative and quantitative synthesis (Bian 2021; Favilli 2017; De Milliano 2020), bringing the total number of studies in the review to 41. Details of the search results and study selection are included in Figure. Included studies We included 41 RCTs, including 3982 women, for this 2024 update. We added three more studies to the 2017 version, with broadened scope (Bian 2021; Favilli 2017; De Milliano 2020). See Characteristics of included studies table for full details. Study design and funding source All trials were parallel‐group RCTs. Eighteen reported that they were multicentre trials (Audebert 1994; Benagiano 1996; Bian 2021; De Milliano 2020; Donnez 2003; Donnez 2012a; Donnez 2012b; Gerris 1996; Lumsden 1994; Muneyyirci‐Delale 2007; Muzii 2010; Seraccholi 2003; Shaw 1996; Stovall 1995; Vercellini 1998; Verspyck 2000; Wilkens 2008; Zullo 1998). The rest of the studies were single‐centre trials (Balasch 1995; Baytur 2007; Bustos López 1995; Cagnacci 1994; Campo 1999; Cetin 1995; D'Anna 1994; De Falco 2009; Engman 2009; Favilli 2017; Fedele 1990; Golan 1993; Hudecek 2012; Levens 2008; Mavrelos 2010; Nikolov 1999; Reinsch 1994; Sayyah‐Melli 2007; Sayyah‐Melli 2009; Shaw 1989; Stovall 1994; Vercellini 2003). Fifteen studies were either wholly or partially funded by pharmaceutical companies (Benagiano 1996; Bustos López 1995; De Milliano 2020; Donnez 2003; Donnez 2012a; Donnez 2012b; Friedman 1989; Gerris 1996; Levens 2008; Muneyyirci‐Delale 2007; Shaw 1996; Stovall 1994; Stovall 1995; Vercellini 1998; Wilkens 2008), and three were funded by institutions or hospitals (Engman 2009; Mavrelos 2010; Sayyah‐Melli 2009). The source of funding was unclear for the remaining trials (Audebert 1994; Balasch 1995; Baytur 2007; Bian 2021; Campo 1999; Cetin 1995; D'Anna 1994; De Falco 2009; Favilli 2017; Fedele 1990; Golan 1993; Hudecek 2012; Lumsden 1994; Muzii 2010; Nikolov 1999; Reinsch 1994; Sayyah‐Melli 2007; Seraccholi 2003; Shaw 1989; Vercellini 2003; Verspyck 2000; Zullo 1998). Participants Participants in all studies had symptomatic fibroids, mostly diagnosed by ultrasound, and were scheduled for surgery. About half of the studies did not specify any details regarding the size or type of fibroid. The remaining trials had various inclusion and exclusion criteria: some excluded submucous or subserous fibroids, and others only included these types of fibroids; where the size of the uterus in gestational weeks was a requirement, this was specified as greater than 8, 12, 14 and 16 gestational weeks, with two trials assessing women with large uteri (over 18 gestational weeks in Stovall 1994; 600 cm³ or more in Friedman 1989). Where the size of fibroids was a requirement, this was usually specified as larger than 2 cm or larger than 3 cm. Six studies required that women had evidence of anaemia (two required haemoglobin less than 12 g/dL; two required haemoglobin less than 10 g/dL; and two required diagnosis of iron deficiency anaemia). Two other studies required women to have haemoglobin values over 10 g/dL. Two studies enroled women with fibroids and infertility (Campo 1999; Zullo 1998). The type of surgery varied amongst the studies. Surgery was either unspecified or was described as either myomectomy or hysterectomy in 15 studies. Participants had hysterectomy (unspecified or abdominal) in 12 studies, and in one study, participants received laparoscopic hysterectomy (Seraccholi 2003). Myomectomy (unspecified) was performed in seven studies (Bustos López 1995; Cetin 1995; De Falco 2009; Fedele 1990; Friedman 1989; Golan 1993; Shaw 1989); three studies had laparoscopic myomectomy (Campo 1999; De Milliano 2020; Zullo 1998); and one study had both laparotomic and laparoscopic myomectomy (Hudecek 2012). Three studies offered women fibroid resection via hysteroscopy, but only data from Muzii 2010 and Favilli 2017 could be included in analyses; only a proportion of the women in Mavrelos 2010 went on to have surgery. Interventions Before the 2017 update, the review was restricted to gonadotropin‐releasing hormone analogues (GnRHa) as pretreatment. In 2017, we expanded the scope of the review to include other types of pretreatment for fibroid surgery: progestins, selective progesterone receptor modulators (SPRMs), selective oestrogen receptor modulators (SERMs), dopamine agonists and oestrogen receptor antagonists. GnRHa We included 20 studies that compared GnRHa to no pretreatment (Audebert 1994; Balasch 1995; Bustos López 1995; Cagnacci 1994; Campo 1999; Cetin 1995; De Falco 2009; Favilli 2017; Fedele 1990; Gerris 1996; Golan 1993; Hudecek 2012; Muzii 2010; Nikolov 1999; Seraccholi 2003; Shaw 1989; Stovall 1994; Vercellini 1998; Vercellini 2003; Zullo 1998) and eight studies that compared GnRHa to placebo (Benagiano 1996; D'Anna 1994; Friedman 1989; Lumsden 1994; Mavrelos 2010; Muneyyirci‐Delale 2007; Shaw 1996; Stovall 1995). Some different GnRHa preparations were administered via different routes and regimens. Leuprolide acetate, goserelin and triptorelin were given either by intramuscular depot injection or subcutaneous depot implant every four weeks before surgery; in three studies, nafarelin or buserelin were given daily by nasal spray (Bustos López 1995; Cetin 1995; Fedele 1990). The duration of treatment ranged from two to three months in 27 studies, and in one study, participants were treated for four months (Shaw 1989). In those trials with a no‐pretreatment arm, control group participants had surgery either immediately or as soon as practicable, but in two studies there was a three‐month observation period before surgery, which was equivalent to the duration of treatment in the GnRHa group (Nikolov 1999; Cagnacci 1994). For the 2025 update of the review, we added a study using three injections of triptorelin 3.75 mg given 28 days apart, followed by cold loop hysteroscopic myomectomy within four weeks of the last injection (Favilli 2017). Dosages for depot formulations were 3.6 mg (goserelin), 3.75 mg (leuprolide acetate or triptorelin) or 3.2 mg (triptorelin). However, in two studies, a larger dose was administered to cover the three‐month pretreatment period (Muneyyirci‐Delale 2007; Seraccholi 2003). In Seraccholi 2003, triptorelin was administered as one injection of 11.25 mg, and goserelin was administered as one injection of 10.8 mg in Muneyyirci‐Delale 2007. Two doses of leuprolide acetate (3.75 mg and 7.5 mg) were compared with placebo in Stovall 1995. Two of the placebo trials included iron in both treatment arms since participants were anaemic (Benagiano 1996; Stovall 1995). Benagiano 1996 also included a GnRHa + placebo iron arm, which was not considered in this review. GnRHa was compared to no treatment in 21 studies and to placebo in eight studies. In four studies, various dosages, formulations and timings of GnRHa treatment were compared in head‐to‐head trials. Progestins One trial compared a dose of 10 mg (2 tablets of 5 mg given orally per day) of lynestrenol during days 5 to 26 of the menstrual cycle with four injections of leuprorelin monthly for four months (Verspyck 2000). No other trials used progestin pretreatment. Selective progesterone receptor modulators (SPRMs) The SPRMs assessed as pretreatment included ulipristal acetate (5 mg and 10 mg daily), mifepristone (50 mg every other day or 25 mg or 10 mg daily), asoprisnil (10 mg or 25 mg daily) and CDB‐2914 (10 mg or 20 mg daily). Three trials compared SPRMs with GnRHa pretreatment: Donnez 2012b compared 5 mg and 10 mg of ulipristal acetate versus once‐monthly leuprolide acetate injections of 3.75 mg for three months; Reinsch 1994 compared 25 mg of mifepristone daily versus once monthly leuprolide acetate for three months; and De Milliano 2020 compared a single placebo injection plus ulipristal acetate, 5 mg tablets, daily for 12 consecutive weeks versus a single injection of leuprolide acetate 11.25 mg plus daily placebo tablets for 12 consecutive weeks. Five trials compared SPRMs with placebo: Donnez 2012a assessed 5 mg or 10 mg of ulipristal acetate; Engman 2009 assessed 50 mg of mifepristone every other day; Bian 2021 assessed 10 mg of mifepristone daily; Wilkens 2008 assessed asoprisnil 10 mg or 25 mg; and Levens 2008 assessed CDB‐2914 10 mg or 20 mg daily. Selective oestrogen receptor modulators (SERMs) Baytur 2007 compared 60 mg daily of raloxifene with three cycles of monthly goserelin 3.6 mg. Dopamine agonists Two studies from Iran compared the dopamine agonist cabergoline (0.5 mg once per week for six weeks) with triptorelin (administered once monthly for four weeks) in women with fibroids scheduled for surgery to examine the impact on fibroid regression and side effects (Sayyah‐Melli 2007; Sayyah‐Melli 2009). Oestrogen receptor antagonists Donnez 2003 compared different doses of fulvestrant (50 mg, 125 mg or 250 mg given as an intramuscular injection once per month for four months) with goserelin (3.6 mg subcutaneous injection once per month for four months) and placebo in women with fibroids awaiting hysterectomy. Outcomes Outcomes from the included studies were characterised within the comparisons as preoperative, intraoperative or postoperative. Since the type of surgery influenced intraoperative or postoperative outcomes, it was necessary to divide the timing of the outcomes in the comparisons, so that these outcomes were measured in separate comparisons according to the type of surgery performed. There were sufficient studies to distinguish the comparisons in this way when GnRHa was compared with no treatment or placebo, but not when other types of preoperative treatments were compared. Preoperative outcomes Primary review outcomes In 24 studies, preoperative uterine volume or fibroid volume or both were calculated either by the prolate ellipsoid method and the formula V = 0.5233 (D1 X D2 X D3), where D1, D2 and D3 are the longitudinal, transverse and cross‐sectional diameters of the uterus or fibroid, respectively (Geirsson 1993), or by the water displacement method or by magnetic resonance imaging. Other preoperative outcomes were haemoglobin levels (after pretreatment and before surgery commenced (21 studies)) and bleeding before surgery (three trials evaluating an SPRM (ulipristal acetate)): Donnez 2012a and Donnez 2012b measured the influence of interventions on menstrual bleeding before surgery using the pictorial blood assessment chart (PBAC) score, and Wilkens 2008 used a similar assessment for menstrual bleeding (a menstrual pictogram). Secondary review outcomes Studies reported adverse events (from pretreatment (21 studies)) and withdrawal because of adverse events. However, data on adverse events in some trials were either too poorly reported or were not given for the control group; data could not be extracted from these trials. Where adverse events were measured, some studies reported total frequencies (with no other detail), while others reported the frequencies for specific adverse events. We assessed both of these as separate outcomes. Quality of life was measured in four trials: two piloted a Measurement of Discomfort due to Fibroids questionnaire; one study used the SF‐36 and Uterine Fibroid Symptom and Health‐Related Quality of Life Questionnaire (UFS‐QoL); and one study used only the UFS‐QoL (but data for these latter two studies were insufficient for extraction). Operative difficulties Primary review outcomes Duration of surgery was measured by 21 studies (but data could only be extracted from 19 studies). Because of numerous confounding factors likely to influence these outcomes, we did not pool the studies, but individual estimates for each trial were shown on forest plots. Intraoperative blood loss, reported in 22 studies, was estimated by measuring the weight of swabs and the volume of blood collected into receptacles such as aspiration bottles. Sixteen studies also reported whether participants required blood transfusions during surgery. Secondary review outcomes Other intraoperative outcomes included: the degree of difficulty of surgery (estimated by surgeons) (8 studies), rate of performance of vaginal hysterectomy (5 studies) (in hysterectomy participants), and rate of vertical incisions (5 studies). Duration of hospital stay was measured by 12 studies; however (as with the duration of surgery), because of numerous confounding factors likely to influence these outcomes, the studies were not pooled, but individual estimates for each trial were shown on forest plots. One study measured the rate of intraoperative hysterectomy in participants undergoing myomectomy (Bian 2021). Postoperative assessment Primary review outcomes Intraoperative and postoperative complications were measured in 12 trials. Secondary review outcomes After surgery, postoperative haemoglobin was measured in eight trials and the recurrence of fibroids in two studies (at six months and from 27 to 38 months after surgery, respectively). Excluded studies We excluded 26 studies. Our reasons for exclusion were that the interventions were not preoperative; the intervention included add‐back (this is covered by another Cochrane review: Moroni 2015); the study investigated misoprostol (also covered by another Cochrane review: Kongnyuy 2014); outcomes were surrogate measures; there was no control group; the trial was not a true RCT; or the trial contained a mixed population, with data on women with fibroids not available (see Characteristics of excluded studies table). Studies awaiting classification We categorised three studies as awaiting classification. Benagiano 1992: we are awaiting a response from the author to clarify whether the study was randomised. Gambardella 1995: we require a translation of this paper from Italian. Sun 2021: we are awaiting a response from the author to clarify the methods and results. Risk of bias in included studies Summaries of the risk of bias assessments are presented in Figure and Figure. Allocation Almost half of the studies (n = 19) specified an appropriate method for sequence generation (randomisation method), such as computer‐generated randomisation; these studies were considered to be at low risk of bias (Campo 1999; De Falco 2009; De Milliano 2020; Donnez 2003; Donnez 2012a; Donnez 2012b; Engman 2009; Favilli 2017; Levens 2008; Lumsden 1994; Mavrelos 2010; Muneyyirci‐Delale 2007; Muzii 2010; Shaw 1996; Stovall 1994; Vercellini 1998; Vercellini 2003; Wilkens 2008; Zullo 1998). We judged one study to be at high risk of bias because it created a subgroup of randomised participants within a much larger study where the remaining participants all received the intervention (Cagnacci 1994). We assessed the remaining studies as being at unclear risk of bias; they reported that participants were randomised but did not specify which method was used for the sequence generation. Fewer than half of the studies (n = 18) indicated that allocation to randomised groups was concealed, either because there was centralised control of the allocation, sealed envelopes were used for allocation or a web integrated interactive voice system was used (Baytur 2007; Bian 2021; Benagiano 1996; De Milliano 2020; Donnez 2003; Donnez 2012a; Donnez 2012b; Engman 2009; Favilli 2017; Friedman 1989; Levens 2008; Lumsden 1994; Mavrelos 2010; Muneyyirci‐Delale 2007; Muzii 2010; Nikolov 1999; Shaw 1996; Vercellini 1998; Vercellini 2003); these studies were considered to be at low risk of bias. We considered the remaining studies to have an unclear risk of bias because the authors did not report methods used to conceal allocation. Blinding We assessed blinding of participants, investigators and assessors, although for some outcomes, participants were the assessors (pictorial blood assessment chart (PBAC) scores) and for others, the investigators also undertook assessment: duration of surgery and intraoperative blood loss. The risk of bias assessments in Characteristics of included studies attempted to clarify this for each study. Blinding of participants and investigators Fewer than half the studies (n = 15) reported double‐blinding or provided clear evidence that both participants and investigators were blinded to treatment (Balasch 1995; Benagiano 1996; Bustos López 1995; De Milliano 2020; Donnez 2012a; Donnez 2012b; Engman 2009; Friedman 1989; Levens 2008; Lumsden 1994; Mavrelos 2010; Muneyyirci‐Delale 2007; Shaw 1996; Stovall 1995; Wilkens 2008). One study blinded surgeons, but participants knew their allocation because treatments were administered differently (De Falco 2009). Six studies were at high risk of bias for blinding of participants and investigators because they were clearly reported as open studies with different types of treatment administration (Favilli 2017; Muzii 2010; Sayyah‐Melli 2007; Sayyah‐Melli 2009; Vercellini 2003; Verspyck 2000). The remaining studies were at unclear risk of bias; the authors did not report whether blinding was undertaken. Blinding of assessors Only 12 studies provided clear evidence that assessors were blinded; we considered these studies at low risk of bias (Bustos López 1995; De Falco 2009; De Milliano 2020; Donnez 2012a; Donnez 2012b; Engman 2009; Favilli 2017; Fedele 1990; Friedman 1989; Levens 2008; Mavrelos 2010; Wilkens 2008). Four studies were at high risk of bias (Donnez 2003; Muzii 2010; Vercellini 2003; Verspyck 2000) and the remainder at unclear risk of bias. Incomplete outcome data Half of the studies (n = 21) were at low risk of attrition bias (Balasch 1995; Baytur 2007; Bian 2021Benagiano 1996; Bustos López 1995; Campo 1999; De Falco 2009; De Milliano 2020; Donnez 2012a; Donnez 2012b; Engman 2009; Fedele 1990; Friedman 1989; Lumsden 1994; Muzii 2010; Sayyah‐Melli 2007; Stovall 1994; Vercellini 1998; Vercellini 2003; Wilkens 2008; Zullo 1998). These 21 studies either included all participants in the analysis or had minimal withdrawals that were balanced between groups or used methods to account for missing data. We assessed a further nine studies at high risk of bias (Audebert 1994; D'Anna 1994; Donnez 2003; Gerris 1996; Levens 2008; Mavrelos 2010; Muneyyirci‐Delale 2007; Shaw 1989; Stovall 1995), mostly because withdrawals were substantial or were unbalanced between randomised groups. We assessed the remaining studies to be at unclear risk of attrition bias. Selective reporting Over half of the studies (n = 25) were at low risk of reporting bias due to selective outcome reporting (Balasch 1995; Baytur 2007; Campo 1999; D'Anna 1994; Favilli 2017De Falco 2009; De Milliano 2020; Donnez 2003; Donnez 2012a; Donnez 2012b; Engman 2009; Fedele 1990; Friedman 1989; Gerris 1996; Hudecek 2012; Lumsden 1994; Mavrelos 2010; Muneyyirci‐Delale 2007; Sayyah‐Melli 2007; Sayyah‐Melli 2009; Shaw 1996; Stovall 1994; Vercellini 2003;Vercellini 1998 ; Wilkens 2008). In these studies, all prespecified outcomes were reported fully, or published protocols indicated there was no evidence of selective outcome reporting. A further seven studies were considered at high risk of reporting bias (Benagiano 1996; Bustos López 1995; Cagnacci 1994; Golan 1993; Seraccholi 2003; Shaw 1989; Stovall 1995). In these studies, outcome data were only reported for the intervention group and not for the control group, so a valid comparison could not be made. For the remaining studies, the likelihood of reporting bias due to selective outcome reporting was unclear because some prespecified outcomes were not fully reported. Other potential sources of bias Almost half of the studies (n = 20) had low risk of other sources of bias (Baytur 2007; Bian 2021; De Falco 2009; Donnez 2003; Donnez 2012a; Donnez 2012b; Engman 2009; Favilli 2017; Friedman 1989; Levens 2008; Lumsden 1994; Muzii 2010; Sayyah‐Melli 2007; Sayyah‐Melli 2009; Seraccholi 2003; Shaw 1996; Vercellini 1998; Vercellini 2003; Wilkens 2008; Zullo 1998), mostly because participant groups were comparable at baseline and no other potential bias was detected. Three studies had imbalanced groups at baseline, and we considered them to be at high risk of other bias (Audebert 1994; Stovall 1994; Verspyck 2000), mainly because the imbalances were likely to influence the findings of the study. For the remaining studies, the risk of other bias was unclear; there were some discrepancies in the comparability of the groups at baseline, but it was unclear whether this would bias the results. There were insufficient studies included in the individual comparisons to construct funnel plots to check for potential reporting biases. Effects of interventions See: Summary of findings 1 GnRHa pretreatment versus placebo or no pretreatment before surgery for uterine fibroids; Summary of findings 2 GnRHa pretreatment versus other medical therapies before surgery for uterine fibroids (preoperative outcomes only); Summary of findings 3 SPRM pretreatment versus placebo or no pretreatment before surgery for uterine fibroids (preoperative outcomes) We included 41 studies that evaluated six comparisons. Comparison 1: GnRHa versus placebo or no pretreatment (preoperative outcomes, regardless of type of subsequent surgery) Comparison 2: GnRHa versus placebo or no pretreatment before hysterectomy (intraoperative or postoperative outcomes) Comparison 3: GnRHa versus placebo or no pretreatment before myomectomy (intraoperative or postoperative outcomes) Comparison 4: GnRHa versus placebo or no pretreatment before hysteroscopic resection of fibroids (intraoperative or postoperative outcomes) Comparison 5: GnRHa versus other medical therapies before surgery (preoperative outcomes only). Data were insufficient to distinguish between types of surgery, which could influence intraoperative or postoperative outcomes. Comparison 6: SPRMs versus placebo or no pretreatment before surgery (preoperative outcomes only). Data were insufficient to distinguish between types of surgery, which could influence intraoperative or postoperative outcomes. In our Methods, we set out three comparisons, but, to analyse and present the data in the most meaningful way, we subdivided the first (GnRHa versus placebo or no pretreatment) into four, according to timing of outcome measurement and type of subsequent surgery planned for participants. The structure of the comparisons is outlined in Table. 1. Structure of comparisons according to measured outcomes and type of surgery. | Comparison | Outcomes | ||| | Preoperative | Intraoperative/postoperative + hysterectomy | Intraoperative/postoperative + myomectomy | Intraoperative/postoperative + resection | | | GnRHa versus no treatment or placebo | Comparison 1 | Comparison 2 | Comparison 3 | Comparison 4 | | Primary .Reduction in uterine volume · Reduction in fibroid volume · Preoperative Hb · Preoperative bleeding Secondary · Adverse events · QoL | Primary · Duration of operation · Intraoperative blood loss · Frequency of blood transfusions Secondary · Difficulty of surgery · Proportion of women undergoing vaginal hysterectomy · Type of abdominal incision · Duration of hospital stay · Postoperative morbidity · Postoperative recurrence · Postoperative Hb | Primary · Duration of operation · Intraoperative blood loss · Frequency of blood transfusions Secondary · Difficulty of surgery ·Intraoperative hysterectomy · Type of abdominal incision · Duration of hospital stay · Postoperative morbidity · Postoperative recurrence · Postoperative Hb | Primary · Duration of operation · Intraoperative blood loss · Frequency of blood transfusions Secondary · Difficulty of surgery · Type of abdominal incision · Duration of hospital stay · Postoperative morbidity · Postoperative recurrence · Postoperative Hb | | | GnRHa versus other medical therapies | Comparison 5 | ||| | Primary · Reduction in uterine volume · Reduction in fibroid volume · Preoperative Hb · Preoperative bleeding Secondary · Adverse events · QoL | not applicable | not applicable | not applicable | | | SPRMs versus placebo | Comparison 6 | ||| | Primary · Reduction in uterine volume · Reduction in fibroid volume · Preoperative Hb · Preoperative bleeding Secondary · Adverse events · QoL | not applicable | ‐ | ‐ | GnRHa: gonadotropin‐releasing hormone analogues; Hb: haemoglobin; QoL: quality of life; SPRM: selective progesterone receptor modulator Comparison 1: GnRHa pretreatment versus placebo or no pretreatment (preoperative outcomes, regardless of type of subsequent surgery) See Table. Primary outcomes Uterine volume See Analysis 1.1; Analysis 1.2. 1.2. Analysis. Comparison 1: GnRHa versus placebo or no pretreatment (preoperative outcomes, regardless of type of subsequent surgery), Outcome 2: Uterine volume (preoperative) (data table) | Uterine volume (preoperative) (data table) | |||| | Study | Number in study | Comparison | Results | Comment | | GnRHa vs no pretreatment | |||| | Golan 1993 | 53 | GnRHa (D‐Trp LHRH) vs no pretreatment | Results reported as "average" with range (likely to be median plus range) prior to surgery: D‐Trp: median 380 mL (300 to 400) No pretreatment: median 496 mL (370 mL to 600 mL) | Authors did not report whether the reduction in uterine volume was significantly different between groups. | | GnRHa vs placebo | |||| | Lumsden 1994 | 69 | GnRHa (goserelin) vs placebo | Difference between goserelin and placebo at end of treatment (%): 27.7% (95% CI 10.3 to 45.2), P = 0.002 | Statistical test reported as "calculation of limits of agreement". | | Muneyyirci‐Delale 2007 | 110 | GnRHa (goserelin) + iron vs iron + placebo | Goserelin/iron vs iron + placebo Change in uterine volume: median (IQR): −233.1 (IQR not reported) vs +18.9 (IQR not reported) cm³ (NS) | Authors reported that there were no significant differences between groups. | | Stovall 1995 | 179 | GnRHa (leuprolide acetate depot) + iron (7.5 mg and 3.75 mg) vs placebo + iron | Median change from baseline to presurgery Leuprolide/iron 7.5 mg: −31% (no range reported) Leuprolide/iron 3.75 mg: −39% (no range reported) Placebo/iron: +10% (no range reported) | Authors reported that the change from baseline in both leuprolide groups was significantly different from placebo (P < 0.01). | Seventeen studies evaluated this outcome (12 had a no‐pretreatment arm and five had a placebo arm). Four of these studies either had skewed data or the data were in a form that precluded pooling. The individual findings for these studies are reported in tabular format (Analysis 1.2). Given the substantial heterogeneity in the subgroup where GnRHa was compared to a no‐treatment control group, we investigated the characteristics of the studies to determine potential causes of the variation in effects. Some variation in the findings was to be expected given the variability in participants with respect to initial uterus size and number and type of fibroids. Although there was substantial heterogeneity in the body of evidence for this analysis, GnRHa reduced uterine volume when compared to control, with uterus volume ranging from a value of 80 cm3 to 570.1 cm3 in the GnRHa groups compared to a range of 255 cm3 to 920 cm3 in the control groups. When the overall estimates were combined, regardless of the type of control group (placebo or no pretreatment), we found that GnRHa pretreatment may be associated with a greater reduction in uterine volume compared to control (MD −175.34 mL, 95% CI −219.04 to −131.65; 13 studies, 858 participants; I² = 67%; low‐certainty evidence). Sensitivity analysis To test the robustness of our results, we removed the studies in our analysis at high risk of bias in at least one domain and compared the results. There was no change in the direction of the effect (favouring GnRha pretreatment compared to no treatment or placebo). Fibroid volume See Analysis 1.3; Analysis 1.4. 1.4. Analysis. Comparison 1: GnRHa versus placebo or no pretreatment (preoperative outcomes, regardless of type of subsequent surgery), Outcome 4: Fibroid volume (preoperative) (data table) | Fibroid volume (preoperative) (data table) | |||| | Study | Number in study | Comparison | Results | Comment | | GnRHa vs placebo | |||| | Muneyyirci‐Delale 2007 | 110 | (GnRHa (goserelin) + iron vs sham injection + iron | Median (range): GnRHa vs placebo: −35.4 cm3 (no range reported) vs +3.9 cm3 (no range reported) | Auhors reported that there were no significant between group differences. | | Stovall 1995 | 138 | GnRHa (leuprolide acetate (LA) depot 7.5mg and 3.75mg) + iron vs placebo + iron | Median % change from baseline: LA/iron 7.5mg: −23% (no range reported) LA/iron 3.75mg: −27% (no range reported) Placebo/iron: +8% (no range reported) | Authors reported that both leuprolide acetate groups had significantly greater changes from baseline compared to placebo (P < 0.01). | Seven trials with 675 participants evaluated this outcome; we presented five of them with a no‐pretreatment arm (Analysis 1.3) and two with a placebo arm (and skewed data) (Analysis 1.4). GnRHa pretreatment may be associated with a reduction in fibroid size ranging from 5.7 mL to 155.4 mL (data were too heterogeneous to calculate a summary effect measure) (low‐certainty evidence). In two other trials with placebo arms, we were uncertain whether there was any difference in fibroid volume compared to placebo. Sensitivity analysis To test the robustness of our results, we removed the studies in our analysis at high risk of bias in at least one domain and compared the results. There was no change in the direction of the effect (favouring GnRha pretreatment compared to no treatment). Preoperative haemoglobin See Analysis 1.5; Analysis 1.6. 1.6. Analysis. Comparison 1: GnRHa versus placebo or no pretreatment (preoperative outcomes, regardless of type of subsequent surgery), Outcome 6: Haemoglobin (preoperative) (data table) | Haemoglobin (preoperative) (data table) | |||| | Study | Number in study | Comparison | Results | Comment | | GnRHa vs placebo | |||| | Muneyyirci‐Delale 2007 | 110 | GnRHa (goserelin) + iron vs sham injection + iron | Difference of least squares mean: 1.17 g/dL (95% CI 0.7 to 1.7), P < 0.001 | Haemoglobin was significantly higher in goserelin group. | Eleven studies assessed preoperative haemoglobin (six compared to no pretreatment and five compared to placebo). Stovall 1995 included two comparisons reflecting differences in the dosage of GnRHa, 3.75 mg or 7.5 mg. One of the placebo‐controlled trials could not be pooled with other studies, and we reported its findings in tabular format (Analysis 1.6; Muneyyirci‐Delale 2007). Haemoglobin is probably increased in women who received GnRHa compared to control, regardless of whether placebo is used (MD 0.88 g/dL, 95% CI 0.68 to 1.08; 10 studies (one study contributing two rows of the analysis), 834 participants; I² = 0%; moderate‐certainty evidence). Sensitivity analysis To test the robustness of our results, we removed the studies in our analysis at high risk of bias in at least one domain and compared the results. This resulted in a narrow 95% CI favouring GnRHa over placebo (MD 0.68 g/dL, 95% CI 0.37 to 0.98; 4 studies, 526 participants). This suggests there was no change in the direction of the effect (favouring GnRHa pretreatment compared to no pretreatment). Preoperative bleeding (measured by a validated scale) No included studies measured preoperative bleeding using a validated scale. Secondary outcomes Adverse events (related to preoperative treatment) See Analysis 1.7, Analysis 1.8. Adverse events (any) are probably more common overall in women who receive GnRHa pretreatment when compared to women who receive placebo (OR 2.78, 95% CI 1.77 to 4.36; 4 studies, 755 participants; I² = 28%; moderate‐certainty evidence; Analysis 1.7). When we considered specific adverse events, we found low‐certainty evidence that the following may be more common with GnRHa pretreatment than with no treatment or placebo: hot flushes (OR 7.68, 95% CI 4.55 to 12.96; 6 studies, 877 participants; I² = 46%; Analysis 1.8.2), headache (OR 1.74, 95% CI 1.00 to 3.03; 6 studies, 877 participants; I² = 49%; Analysis 1.8.3), vaginitis (OR 4.18, 95% CI 1.58 to 11.05; 5 studies, 751 participants; I² = 28%; Analysis 1.8.10), change in breast size (OR 10.87, 95% CI 1.90 to 62.24; 2 studies, 261 participants; I² = 0%; Analysis 1.8.15) and sweating (OR 14.32, 95% CI 6.17 to 33.27; 4 studies, 497 participants; I² = 0%; Analysis 1.8.16). We found moderate‐certainty evidence that dizziness is probably more common with GnRHa pretreatment than with no treatment or placebo (OR 2.41, 95% CI 1.13 to 5.14; 2 studies, 505 participants; I² = 0%; Analysis 1.8.6). Individual adverse events that did not show evidence of a difference between groups were insomnia, pain, nausea, depression, arthralgia, asthenia, skin changes, abdominal and pelvic pain, hirsutism, change in libido, breast pain/tenderness and uterine haemorrhage (Analysis 1.8). No included studies assessed quality of life. Comparison 2: GnRHa versus placebo or no pretreatment before hysterectomy (intraoperative or postoperative outcomes) See Table. Primary outcomes Duration of surgery See Analysis 2.1; Analysis 2.2. 2.2. Analysis. Comparison 2: GnRHa versus placebo or no pretreatment before hysterectomy (intraoperative or postoperative outcomes), Outcome 2: Duration of surgery (data table) | Duration of surgery (data table) | |||| | Study | Number in study | Comparison | Results | Comment | | GnRHa vs no pretreatment | |||| | Balasch 1995 | 50 | GnRHa (triptorelin) vs no pretreatment | GnRHa vs no pretreatment: mean (standard deviation (SD)): 110 minutes (81.5) vs 107 mins (166.3) (not significant) | Authors reported that there was no evidence of a significant difference between groups. Data reported in table format as appear skewed | | Golan 1993 | 32 | GnRHa (triptorelin) vs no pretreatment | GnRHa vs no pretreatment: mean (SD): 49 (37.1) vs 70 (131.7) (P < 0.05) | Authors reported a significant difference between groups. Data reported in table format as appear skewed | | GnRHa vs placebo | |||| | Lumsden 1994 | 71 | GnRHa (goserelin) vs placebo | GnRHa vs placebo: mean (SD): 61 minutes (16) vs 68 minutes (208) (not significant) | The authors reported that there was no evidence of a significant difference between groups. Data reported in table format as appear skewed | Six studies comparing GnRHa with no pretreatment and three studies comparing GnRHa with placebo assessed the duration of surgery (and we reported two 'no pretreatment' trials and one placebo‐controlled trial in a table (Analysis 2.2)). We expected heterogeneity, given differences in the expertise of the surgeons, variable methods of measuring the length of the surgery and, in particular, the type of hysterectomy performed; for example, one trial undertook laparoscopic hysterectomy, and two studies performed vaginal as well as abdominal hysterectomy. Overall, when we combined studies (placebo‐control and no‐pretreatment groups combined), we found that GnRHa may reduce the duration of surgery by 10.11 minutes (95% CI −16.96 to −3.25; 6 studies, 617 participants; I² = 56%; low‐certainty evidence). The reported duration of surgery in the included studies was 50.5 to 115 minutes (SD 28.3). It is not clear whether this represents a clinically important difference. Sensitivity analysis To test the robustness of our results, we removed the studies in our analysis at high risk of bias in at least one domain and compared the results. There was no change in the direction of the effect (favouring GnRha pretreatment compared to no treatment), but there was a wider 95% CI. Intraoperative blood loss See Analysis 2.3; Analysis 2.4. 2.4. Analysis. Comparison 2: GnRHa versus placebo or no pretreatment before hysterectomy (intraoperative or postoperative outcomes), Outcome 4: Intraoperative blood loss (data table) | Intraoperative blood loss (data table) | |||| | Study | Number in study | Comparison | Results | Comment | | GnRHa vs no pretreatment | |||| | Golan 1993 | 32 | GnRHa (triptorelin) vs no pretreatment | GnRHa vs no pretreatment: mean (SD) 208 (263.9) vs 309 (313.7), P < 0.05 | Authors reported a significant difference between groups. Data reported in table format as appear skewed | | GnRHa vs placebo | |||| | Lumsden 1994 | 69 | GnRHa (goserelin) vs placebo | GnRHa vs placebo: median (range): 187 mls (60 to 600) vs 307.5 (118 to 1000), P < 0.05 | Authors reported a significant difference between groups Data reported in table format as appear skewed | Six studies (N = 359 participants) compared blood loss between groups that received GnRHa pretreatment and control. We did not calculate summary effect measures because of substantial heterogeneity, but all studies found that there may be less blood loss with GnRHa pretreatment, with a reduction ranging from 25 mL to 148 mL compared to control. Overall, the studies provided very low‐certainty evidence. Sensitivity analysis To test the robustness of our results, we removed the studies in our analysis that were at high risk of bias in at least one domain and compared the results. There was no change in the direction of the effect (favouring GnRha pretreatment compared to control). Frequency of intraoperative blood transfusions See Analysis 2.5. Six studies assessed the likelihood of blood transfusions during surgery. Overall, blood transfusions are probably less likely with GnRHa pretreatment compared to control (no pretreatment and placebo combined) (OR 0.54, 95% CI 0.29 to 1.01; 6 trials, 601 participants; I² = 0%; moderate‐certainty evidence). Sensitivity analysis To test the robustness of our results, we removed the studies in our analysis at high risk of bias in at least one domain and compared the results. There was no change in the direction of the effect (favouring GnRha pretreatment compared to control). Postoperative morbidity See Analysis 2.6; Analysis 2.7. Seven studies assessed any postoperative morbidity (five studies compared GnRHa with no pretreatment and two compared GnRHa with placebo). Overall, GnRHa probably reduced postoperative morbidity compared to control (OR 0.54, 95% CI 0.32 to 0.91; 7 studies, 772 participants; I² = 28%; moderate‐certainty evidence). One trial assessed individual complications in 212 participants (Hudecek 2012). There was little or no difference between groups for hypermenorrhoea (OR 0.36, 95% CI 0.11 to 1.24; low‐certainty evidence; Analysis 2.7.1), pelvic pain (OR 0.43, 95% CI 0.15 to 1.23) and difficult defecation (OR 0.76, 95% CI 0.11 to 5.52; low‐certainty evidence). The evidence is very uncertain for dysmenorrhoea (OR 3.9, 95% CI 0.19 to 82.29; very low‐certainty evidence; Analysis 2.7.2), difficult urination (OR 0.15, 95% CI 0.01 to 3.17; very low certainty evidence; Analysis 2.7.5) and dyspareunia (OR 3.90, 95% CI 0.19 to 82.29; very low certainty evidence; Analysis 2.7.6). Sensitivity analysis To test the robustness of our results, we removed the studies in our analysis at high risk of bias in at least one domain, and compared the results. There was no change in the direction of the effect (favouring GnRha pretreatment compared to control). Secondary outcomes Difficulty of surgery (assessed subjectively by the surgeon) See Analysis 2.8. Five trials assessed this outcome (two with a no‐pretreatment control group and three with a placebo‐control group). The overall summary effect estimate (regardless of the control group) indicated that difficult surgery may be less likely with GnRHa (OR 0.72, 95% CI 0.51 to 1.00; 5 studies, 712 participants; 1² = 0%; low‐certainty evidence). Proportion of women undergoing vaginal hysterectomy See Analysis 2.9. Three studies (395 participants) compared GnRHa with control (two studies had no pretreatment and one used a placebo‐control group). Studies were too heterogeneous to pool. Based on two studies with no‐pretreatment control, GnRHa may increase the odds of undergoing a vaginal procedure, but there were limitations in the study design, with substantial heterogeneity. One placebo‐controlled study, with moderate‐certainty evidence, did not report any differences between randomised groups. Type of abdominal incision (Pfannenstiel transverse versus vertical) See Analysis 2.10. Four studies assessed this outcome (two compared GnRHa with no pretreatment and two compared GnRHa with placebo). The odds of a vertical incision during hysterectomy are probably reduced with GnRHa pretreatment (overall OR 0.34, 95% CI 0.21 to 0.54; 4 studies, 529 participants; I² = 0%; moderate‐certainty evidence). Duration of hospital stay (days) See Analysis 2.11; Analysis 2.12. 2.12. Analysis. Comparison 2: GnRHa versus placebo or no pretreatment before hysterectomy (intraoperative or postoperative outcomes), Outcome 12: Duration of hospital stay (data table) | Duration of hospital stay (data table) | |||| | Study | Number in study | Comparison | Results | Comment | | GnRHa vs no pretreatment | |||| | Balasch 1995 | 50 | GnRHa (triptorelin) vs no pretreatment | GnRHa vs no pretreatment: mean (SD): 7.2 (2.9) vs 8.6 (18.7) (not significant) | Authors reported that there was no evidence of a significant difference between groups. Data reported in table format as appear skewed | Findings were mixed (and too heterogeneous to pool) in five trials (344 participants) assessing this outcome. Two trials reported that GnRHa pretreatment may be associated with less time in hospital when compared with no pretreatment (1 day to 2.6 days less), but three other trials reported no evidence of a difference in hospital stay between randomised groups. Postoperative recurrence of myomas No included studies assessed recurrence. Postoperative haemoglobin See Analysis 2.13. Three studies assessed this outcome (two studies with no pretreatment as a control and one placebo‐controlled trial). The overall summary effect estimate (regardless of the type of control group) suggested that GnRHa may improve postoperative haemoglobin levels (MD 0.85, 95% CI 0.31 to 1.38, 3 studies, 240 participants; I² = 41%; low‐certainty evidence). Comparison 3: GnRHa versus placebo or no pretreatment before myomectomy (intraoperative or postoperative outcomes) See Table. Primary outcomes Duration of surgery See Analysis 3.1; Analysis 3.2. 3.2. Analysis. Comparison 3: GnRHa versus placebo or no pretreatment before myomectomy (intraoperative or postoperative outcomes), Outcome 2: Duration of surgery (data table) | Duration of surgery (data table) | |||| | Study | Number of participants | Comparison | Results | Comment | | GnRHa vs no pretreatment | |||| | Cetin 1995 | 30 | GnRHa (buserelin 900 ugr/day for 3 months) vs no pretreatment (immediate surgery) | GnRHa (mean (SD)): 87 minutes (174.3) Control (mean (SD)): 102 minutes (135.6) | Authors reported that the difference was not statistically significant, P > 0.05. | | Golan 1993 | 21 | GnRHa (decapeptyl 3.2 mg for 3 months) vs no pretreatment | GnRHa (mean (SD)): 80 minutes (145.5 Control (mean (SD)): 96 minutes (138.0) | Authors reported that the difference was not statistically significant. | Nine trials, including 593 participants, assessed this outcome, seven comparing GnRHa to no pretreatment (Bustos López 1995; Campo 1999; De Falco 2009; Fedele 1990; Golan 1993; Hudecek 2012; Zullo 1998), and two comparing GnRHa to placebo (Favilli 2017; Friedman 1989). We did not pool trials due to substantial heterogeneity. There was no evidence that the duration of surgery was influenced by whether participants received GnRHa pretreatment or not. When GnRHa pretreatment was compared to no treatment, individual studies did not report differences between randomised groups, other than two studies comparing GnRHa pretreatment to no pretreatment before laparoscopic myomectomy was undertaken. In these two trials (Campo 1999; Hudecek 2012), GnRHa may be associated with an increase in the time taken to undertake laparoscopic myomectomy compared to no pretreatment (ranging from an increase of 18 minutes to 45 minutes). When GnRHa was compared to placebo (two studies), we were uncertain about whether there was any difference between treatment and placebo groups (MD 6.70 minutes, 95% CI 0.64 to 12.76; I2 = 0; 102 participants) (data not shown). It is not clear whether this represents a clinically important difference. Sensitivity analysis was not performed for this outcome. Intraoperative blood loss See Analysis 3.3. We included 10 studies (549 participants) that assessed this outcome (nine compared GnRHa to no pretreatment and one compared GnRHa to placebo). We did not pool the trials due to substantial heterogeneity and varied findings. Most trials reported that GnRHa may reduce blood loss, ranging from a reduction of 22 mL to 157 mL, although we judged the certainty of the evidence to be very low. Most trials reported that the surgery was myomectomy, either unspecified or open. Three trials where laparoscopic myomectomy was performed had mixed results: two trials reported that GnRHa pretreatment may reduce blood loss by either 37 mL or 60 mL, respectively (Campo 1999; Zullo 1998), and the other trial reported a greater intraoperative blood loss with GnRHa compared to control (82 mL) (Hudecek 2012). Sensitivity analysis To test the robustness of our results, we removed the studies in our analysis that were at high risk of bias in at least one domain and compared the results. The direction of the effect of favouring GnRHa pretreatment compared to the control for reducing intraoperative blood loss remained the same. Frequency of blood transfusions See Analysis 3.4. We are uncertain about whether there is any difference in the need for intraoperative blood transfusion between randomised groups (OR 0.85, 95% CI 0.26 to 2.75; 4 studies, 121 participants; I² = 0%; low‐certainty evidence). Sensitivity analysis To assess the robustness of our results, we excluded the studies in our analysis that were at high risk of bias in at least one domain and compared the outcomes. The uncertainty regarding the findings related to the need for intraoperative blood transfusion persisted. Postoperative morbidity See Analysis 3.5. The odds of any postoperative morbidity were assessed in five trials. We are uncertain whether there is any difference between groups (overall OR 1.07, 95% CI 0.43 to 2.64; 5 trials, 190 participants; I² = 0%; low‐certainty evidence). Sensitivity analysis To assess the robustness of our results, we excluded the studies in our analysis that exhibited a high risk of bias in at least one domain and compared the outcomes. The uncertainty in the findings, even with all studies included, persisted. Secondary outcomes Difficulty of surgery No included studies assessed this outcome. Type of abdominal incision (Pfannenstiel transverse versus vertical) See Analysis 3.6. One small trial with 28 participants found little or no difference in the need for vertical incision on the abdomen between GnRHa pretreatment and no presurgical treatment (OR 0.07, 95% CI 0.00 to 1.43; low‐certainty evidence) (Bustos López 1995). Duration of hospital stay (days) See Analysis 3.7. Three studies, including 290 participants, assessed this outcome, but heterogeneity was substantial, so we did not pool the data. There is uncertain evidence that GnRHa pretreatment shortened the duration of hospital stay when compared with no pretreatment or placebo. Intraoperative hysterectomy (for women undergoing myomectomy) No included studies assessed this outcome. Frequency of postoperative recurrence of myomas See Analysis 3.8. Findings were inconsistent in two very small trials assessing this outcome (Fedele 1990; Friedman 1989). The evidence is very uncertain about recurrence between randomised groups in the overall estimate (with placebo and no preoperative treatments combined) (OR 4.16, 95% CI 0.59 to 29.09; 2 studies, 42 participants; I² = 48%; very low‐certainty evidence). Postoperative haemoglobin See Analysis 3.9. One trial found that GnRHa pretreatment may increase postoperative haemoglobin when compared to no pretreatment (MD 0.80 g/dL, 95% CI 0.22 to 1.38; 67 participants; low‐certainty evidence) (Zullo 1996). Comparison 4: GnRHa versus placebo or no pretreatment before hysteroscopic resection of fibroids (intraoperative or postoperative outcomes) See Table. Three studies assessed intraoperative and postoperative outcomes during the hysteroscopic resection of fibroids (Favilli 2017; Mavrelos 2010; Muzii 2010), but in Mavrelos 2010, only a proportion of women randomised to groups went on to have surgery, so we did not extract outcome data for this trial. Primary outcomes Duration of surgery See Analysis 4.1. Two studies reported that there was little to no difference in the duration of surgery with GnRHa pretreatment when compared to no pretreatment (MD ‐0.17 minutes, 95% CI ‐11.22 to 10.88), 2 studies, 123 participants; low‐certainty evidence) (Favilli 2017; Muzii 2010). Intraoperative blood loss The included studies did not assess this outcome. Frequency of blood transfusions The included studies did not assess this outcome. Postoperative morbidity See Analysis 4.2. In one small trial with 84 participants (Favilli 2017), there were no postoperative complications in either group. Secondary outcomes Difficulty of surgery (assessed subjectively by the surgeon) See Analysis 4.3. One small trial with 39 participants found that there may be little to no difference in a visual analogue scale (VAS) (with categories of perceived difficulty) between women who received GnRHa pretreatment and those who did not receive pretreatment (MD −1.40, 95% CI −3.05 to 0.25; low‐certainty evidence) (Muzii 2010). Surgeons were not blinded, so it is not possible to exclude the possibility that knowledge of treatment influenced the findings. Duration of hospital stay (days) The included studies did not assess this outcome. Frequency of postoperative recurrence of myomas See Analysis 4.4. In one small trial with 39 participants (Muzii 2010), there were no incidences of fibroid recurrence over a mean of nine months after surgery in any participants. Postoperative haemoglobin The included studies did not assess this outcome. Comparison 5: GnRHa versus other medical therapies before surgery (preoperative outcomes) See Table. We compared GnRHa pretreatment with a combined group of 'other medical therapies' because there were few data on these other treatments. Given the established effectiveness of GnRHa as a pretreatment, at least some of the trials comparing GnRHa with other treatments were non‐inferiority trials, designed to establish whether they were as effective as GnRHa but without the associated adverse effects. Where necessary, we undertook sensitivity analyses to assess the differential effects of the other treatments. The structure of the comparisons is provided in Table. Seven studies were included in this analysis (Baytur 2007; Donnez 2003; Donnez 2012b; Reinsch 1994; Sayyah Melli 2007; Sayyah‐Melli 2009; Verspyck 2000). Verspyck 2000 assessed the effects of lynestrenol (a progestin); Donnez 2012b assessed the effects of two different doses of an SPRM (ulipristal acetate 5 mg and 10 mg); Reinsch 1994 assessed another type of SPRM (mifepristone); Baytur 2007 assessed a SERM (raloxifene); two studies assessed a dopamine agonist (cabergoline (Sayyah‐Melli 2007; Sayyah‐Melli 2009); and Donnez 2003 assessed multiple doses of an oestrogen receptor agonist (fulvestrant 50 mg, 125 mg and 250 mg). Donnez 2012b was the only trial that was placebo‐controlled with participants and investigators blinded to allocation. Only preoperative outcomes were measured because data were insufficient to distinguish between types of surgery, which could influence intraoperative or postoperative outcomes. Primary outcomes Uterine volume See Analysis 5.1. 5.1. Analysis. Comparison 5: GnRHa versus other medical therapies before surgery, Outcome 1: Uterine volume (data table) | Uterine volume (data table) | |||| | Study | Number in study | Comparison | Results | Comment | | Audebert 1994 | 47 | Subcutaneous goserelin 3.6 mg once every month for 3 months followed by hysterectomy or myomectomy vs immediate surgery (hysterectomy or myomectomy) | Pretreatment (ml) goserelin group 323.8 ± 167.6, immediate surgery group 495.1 ± 345.8 Preoperation (ml) goserelin group 207.5 ± 147.5, immediate surgery group 419.5 ± 230.8 | | | Balasch 1995 | 50 | Intramuscular decapeptyl 3.75 mg every 4 weeks for 2 injections before hysterectomy, duration 8 weeks vs abdominal hysterectomy within 4 weeks of randomisation | Pretreatment (ml) GnRHa group 512 ± 267, immediate surgery group 583 ± 349 Preoperation (ml) GnRHa group 340 ± 180, immediate surgery group 589 ± 349 | | | Baytur 2007 | 32 | GnRHa (goserelin 3.6 mg monthly for 3 months) vs SERM (raloxifene 60 mg daily orally) | Difference from baseline to after treatment (median (range)): GnRHa: 95 cc (37 to 452) Raloxifene: 62.5 (10 to 118) | Not significantly different between groups | | De Milliano 2020 | 52 | GnRHa (leuprolide acetate 11.25 mg) vs ulipristal acetate 5 mg for 3 months | −151.5 cm3 for GnRHa vs −28.1 cm3 for ulipristal acetate (median and IQR) | GnRHa was associated with a significantly greater reduction in uterine volume than ulipristal acetate. | | Donnez 2012b | 307 | GnRHa (leuprolide acetate (LA) 3.75 mg) vs ulipristal acetate (UA) (5 mg and 10 mg) | Per protocol results: Median percent change from baseline in uterine volume (IQ range): UA 5 mg: −20% (−40 to −3) UA 10 mg: −22% (−45 to 0) LA 3.75 mg: −47% (−57 to −35) Difference in % points: UA 5 mg vs LA 3.75 mg: 1.48 (1.25 to 1.74) UA 10 mg vs LA 3.75 mg: 1.41 (1.19 to 1.66) | Authors reported that leuprolide acetate was associated with a significantly greater reduction in uterine volume than either ulipristal acetate group. | | Reinsch 1994 | 14 | GnRHa (leuprolide acetate (LA) 3.75 mg) vs mifepristone (RU 486 25 mg) | Results reported in the text (median percentage reduction and range) LA 3.75 mg: 54% (22 to 84) RU 486 25 mg: 32% (1 to 65) | Three trials including 353 participants assessed uterine volume but could not be pooled because of skewed data. The evidence suggests that GnRHa pretreatment probably results in little to no difference in outcome compared to raloxifene (Baytur 2007) or mifepristone (Reinsch 1994). A large placebo‐controlled trial reported that leuprolide acetate pretreatment may result in a greater reduction in uterine volume (−47%) compared to either 5 mg of ulipristal acetate (−20%) or 10 mg of ulipristal acetate (−22%) (Donnez 2012b). Sensitivity analysis To test the robustness of our results, we removed the studies in our analysis at high risk of bias in at least one domain and compared the results. There was no change in the direction of the effect (favouring GnRha pretreatment compared to ulipristal acetate). Fibroid volume See Analysis 5.2; Analysis 5.3. 5.3. Analysis. Comparison 5: GnRHa versus other medical therapies before surgery, Outcome 3: Fibroid volume (data table) | Fibroid volume (data table) | |||| | Study | Number in study | Comparison | Results | Comment | | Baytur 2007 | 32 | GnRHa (goserelin 3.6 mg monthly for 3 months) vs selective estrogen receptor modulators (SERMs) (raloxifene 60 mg daily orally) | Difference from baseline to after treatment (median (range)): GnRHa: 30 cc (20 to 200) Raloxifene: 18 cc (12 to 65) | No significant difference between groups | | De Milliano 2020 | GnRHa (leuprolide acetate 11.25 mg vs ulipristal acetate 5 mg for 3 months | −80.2 cc (−183.6 to −33.2) for GnRHa vs −33 cc (−109.5 to 95.8) for ulipristal acetate (median and interquartile range) | Total reduction in volume of the fibroids that were planned for resection was less after ulipristal acetate than after GnRHa pre‐treatment | | | Donnez 2003 | 313 | GnRHa (goserelin 3.6 mg monthly for 3 months) vs fluvestrant (50 mg, 125 mg and 250 mg for 3 months) ‐ comparison not blinded | Ratio of the generalised least squares means (fulvestrant or goserelin): Fulvestrant 50 mg vs goserelin: 1.88 (95% CI 1.3 to 2.8), P = 0.001, n = 82 Fulvestrant 125 mg vs goserelin: 1.82 (95% CI 1.2 to 2.7), P = 0.0002, n = 80 Fulvestrant 250 mg vs goserelin: 1.56 (95% CI 1.1 to 2.3), P = 0.023, n = 83 | Authors reported that goserelin was associated with a significantly greater reduction in fibroid volume than any dose of fulvestrant. Note: this analysis was per protocol with significant attrition ‐ the ITT analyses were not reported. | | Donnez 2012b | 307 | GnRHa (leuprolide acetate (LA) 3.75 mg vs ulipristal acetate (UA) 5 mg and 10 mg | Per protocol results: Percentage change from baseline in 3 largest fibroids (IQ range) UA 5 mg: −36% (−58 to −11) UA 10 mg: −42% (−69 to −41) LA 3.75 mg: −53% (−69 to −36) Difference in % points: UA 5 mg vs LA 3.75 mg: 1.23 (0.99 to 1.52) UA 10 mg vs LA 3.75 mg: 1.12 (0.91 to 1.38) | Authors reported that all 3 treatments reduced the volume of the 3 largest fibroids. | Five trials assessed fibroid volume, but only two could be pooled (Sayyah Melli 2007; Sayyah‐Melli 2009); both trials compared GnRHa with cabergoline (a dopamine agonist). For these studies, the evidence suggests that GnRHa pretreatment may result in little to no difference in fibroid volume between groups (MD 12.71, 95% CI ‐5.92 to 31.34; 2 studies, 110 participants; I² = 0%; low‐certainty evidence; Analysis 5.2). The three trials that could not be pooled (646 participants) compared GnRHa with raloxifene (a SERM) (Baytur 2007), GnRHa with ulipristal acetate in two doses (Donnez 2012b; De Milliano 2020) and GnRHa with fulvestrant (an oestrogen receptor antagonist) in multiple doses (Donnez 2003). There was little to no difference between treatments other than in Donnez 2003, where GnRHa may be associated with a greater fibroid reduction than any dose of fulvestrant (see Analysis 5.3). The evidence is of low certainty. Sensitivity analysis To test the robustness of our results, we removed the studies in our analysis at high risk of bias in at least one domain and compared the results. There was no change in the direction of the effect (favouring GnRHa pretreatment compared to other treatments). Preoperative haemoglobin See Analysis 5.4. Two trials with 242 participants reported there was probably little to no difference between the levels of preoperative haemoglobin after pretreatment with GnRHa compared to ulipristal acetate (MD ‐0.02, 95% CI ‐0.41 to 0.37; I² = 36%; moderate‐certainty evidence) (Donnez 2012b; De Milliano 2020). Preoperative bleeding See Analysis 5.5. One non‐inferiority trial, with 307 participants, comparing GnRHa to ulipristal acetate assessed the proportion of women whose bleeding was reduced to less than 75 units by the PBAC (pictorial blood‐loss assessment chart) as a result of preoperative treatment (Donnez 2012b). There was likely little to no difference in bleeding rates between the two groups, leading the authors to conclude that ulipristal acetate was non‐inferior to GnRHa for controlling uterine bleeding (ulipristal acetate 5 mg: OR 0.71, 95% CI 0.30 to 1.68; moderate‐certainty evidence; ulipristal acetate 10 mg: OR 0.39, 95% CI 0.14 to 1.06; moderate‐certainty evidence). Secondary outcomes Adverse events See Analysis 5.10. Many individual adverse events were measured by only a few of the relevant trials and definitions may have varied, which affects the reliability of the results. As GnRHa was compared to other medical treatments before surgery, overall totals involving more than one trial need to be stratified. Hot flushes may be more likely with GnRHa pretreatment compared to other medical pretreatments (which include raloxifene, ulipristal acetate, mifepristone, cabergoline and lynestrenol) (OR 2.83, 95% CI 1.68 to 4.77; 6 studies, 507 participants; I² = 59%; low‐certainty evidence). Likewise, headache may be increased with GnRHa (OR 1.96, 95% CI 0.73 to 5.27; 5 studies, 493 participants; I² = 69%; low‐certainty evidence; Analysis 5.10.2). The evidence is uncertain for sleep problems (OR 2.90, 95% CI 0.03 to 284.58; 2 studies, 106 participants; very low‐certainty evidence; Analysis 5.10.6) and bone sensitivity (OR 37.00, 95% CI 2.35 to 582.21; 1 study, 50 participants; very low‐certainty evidence). There is no evidence of a difference between groups in other specific adverse events. Where there was more than one study in the comparison, we undertook sensitivity analyses to establish the differential effects of the other medical therapies (which were combined as control in the comparison). For hot flushes, GnRHa may be associated with greater odds of hot flushes when compared with other medical therapies alone, with odds ratios varying from 5.7 (ulipristal acetate), 6.45 (lynestrenol), 9.0 (raloxifene), 221.0 (mifepristone) and 327.9 (cabergoline). Two of the four studies measuring headache also reported that GnRHa may be independently associated with greater odds compared to cabergoline (OR 26.0) and lynestrenol (OR 5.3), but there was little or no difference with raloxifene (Baytur 2007) or ulipristal acetate (Donnez 2012b). Quality of life See Analysis 5.11 5.11. Analysis. Comparison 5: GnRHa versus other medical therapies before surgery, Outcome 11: Quality of life (Uterine Fibroid Symptom: symptom severity (SS) and health‐related quality of life (HRQoL)) | Quality of life (Uterine Fibroid Symptom: symptom severity (SS) and health‐related quality of life (HRQoL)) | |||| | Study | No of participants | Comparison | Results | Comment | | De Milliano 2020 | 49 | Ulipristal acetate (UA) 5 mg versus leuprolide acetate (LA) 11.25 mg | UFS‐SS: Change from baseline (median (IQR): ‐9.4 (‐34.4 to 5.5) for UA versus ‐12.5 (‐31.2 to 0.0) for LA UFS‐HRQoL: Change from baseline (median (IQR)): 6.5 (‐5.0 to 21.6) for UA versus 11.2 (0.0 to 17.2) | No significant difference between groups for either score | | Donnez 2012b | 281 | UA 5 mg or UA 10 mg versus LA 3.75 mg | UFS‐HRQoL: UA 5 mg vs LA (change from baseline): 2.5% (‐7.3 to 12.3) UA 10 mg vs LA (change from baseline: 5.6% (‐3.9 to 15.1) | No significant difference between groups | There was little or no difference between GnRHa and ulipristal acetate (either dose) with respect to quality of life (measured in a specific fibroid symptom questionnaire) (Donnez 2012b). The difference in the percentage change from baseline, compared to GnRHa, was 2.5% with ulipristal acetate 5 mg and 5.6% with ulipristal acetate 10 mg. Comparison 6: SPRMs versus placebo or no pretreatment before surgery (preoperative outcomes) See Table. Only preoperative outcomes were measured, as data were not sufficient to distinguish between types of surgery, which could influence intraoperative or postoperative outcomes. The structure of the comparisons according to the outcomes measured is provided in Table. Primary outcomes Uterine volume See Analysis 6.1. 6.1. Analysis. Comparison 6: SPRMs versus placebo or no pretreatment before surgery, Outcome 1: Uterine volume (mL) | Uterine volume (mL) | |||| | Study | Number in study | Comparison | Results | Comment | | Donnez 2012a | 242 | Ulipristal acetate 5 mg or 10 mg daily vs placebo | Reduction in uterine volume prior to surgery of 25% or greater: Ulipristal acetate 5 mg: 30/88 (34%) Ulipristal acetate 10 mg: 24/85 (28%) Placebo: 3/47 (6%) Difference ulipristal acetate 5 mg vs placebo: 28 (11 to 40) Difference ulipristal acetate 10 mg vs placebo: 22 (6 to 35) | The authors reported that both ulipristal acetate groups had a reduction in uterine volume of 25% or greater than the placebo group. | | Wilkens 2008 | 33 | Asoprisnil 10 mg and 25 mg vs placebo | Median percentage change (from baseline): Asoprisnil 10 mg vs placebo: 7.9% vs −2.1% (not significant) Asoprisnil 25 mg vs placebo: −5.1% vs −2.1% (not significant) | Authors reported no difference between groups. | Two studies with 275 participants compared either ulipristal acetate (5 mg and 10 mg) versus placebo (Donnez 2012a) or asoprisnil (10 mg or 25 mg) versus placebo (Wilkens 2008). The studies could not be pooled because of potentially skewed data (moderate certainty). Ulipristal acetate may be associated with a greater reduction in uterine volume than placebo (Donnez 2012a), but there was little or no difference between asoprisnil and placebo (Wilkens 2008). Sensitivity analysis To test the robustness of our results, we had planned to remove studies in our analysis at high risk of bias in at least one domain and compare the results. Neither study was at high risk of bias, but Wilkens 2008 was unclear about allocation concealment. Removing this study from our narrative synthesis left only Donnez 2012a, which favoured ulipristal acetate over placebo in the reduction of uterine volume. Fibroid volume See Analysis 6.2. 6.2. Analysis. Comparison 6: SPRMs versus placebo or no pretreatment before surgery, Outcome 2: Fibroid volume (mL) | Fibroid volume (mL) | |||| | Study | Number in study | Comparison | Study findings | Comment | | Bian 2021 | 124 | Mifepristone 10 mg/day vs placebo | Mean change in mifepristone group in maximum fibroid volume: −25.97% (95% CI −34.79% to −15.95%) Mean change in placebo group in maximum fibroid volume: −1.5% (95% CI −13.03% to 11.54%) Difference in mean change rate compared between groups mifepristone vs placebo: −24.84% (95% CI −36.56% to −10.94%) | This was greater than the 10% superiority threshold goal set by the study. | | Donnez 2012a | 242 | Ulipristal acetate (UA) 5 mg/day and 10 mg/day vs placebo | Median change: UA 5 mg vs placebo: −18.9% vs +1.9% (P = 0.002) Difference UA 5 mg vs placebo: −19.6% (−31.2 to −6.5) UA 10 mg vs placebo: −6.2% vs +1.9% (P = 0.006) Difference UA 10 mg vs placebo: −14.2% (−25.9 to −2.4) | Clinically significant differences between UA and placebo in both per protocol and modified ITT analyses | | Engman 2009 | 30 | Mifepristone 50 mg/every other day vs placebo | Mean % change from baseline (CI): MP vs placebo: ‐28% (−48 to −8) vs +6% (−13 to 25 (P = 0.02) | Authors reported that decrease with mifepristone was lower than placebo. | | Levens 2008 | 22 | CDB‐2914 10 mg/day and 20 mg/day vs placebo | Change: CDB‐2914 (combined dosages) vs placebo: +6% vs −29% (P = 0.01) | Not clear if mean or median change ‐ no variation measure reported | | Wilkens 2008 | 33 | Asoprisnil 10 mg/day and 25 mg/day vs placebo | Median percent change in largest fibroid volume: Asoprisnil 10 mg vs placebo: −0.4% vs 4.9% (not significant) Asoprisnil 25 mg vs placebo: −25.8% vs 4.9% (P = 0.04) | Authors reported that only the higher dose asoprisnil group reduction was different from placebo (lower dose not significant). | Five studies including 459 participants compared various SPRMs with placebo: either ulipristal acetate (5 mg or 10 mg) (Donnez 2012a), mifepristone (50 mg every other day) (Engman 2009), mifepristone 10 mg daily (Bian 2021), CDB‐2914 (10 mg or 20 mg) (Levens 2008) or asoprisnil (10 mg or 25 mg) (Wilkens 2008). The outcomes measured were mostly median change from baseline, which was compared between randomised groups, so studies were not pooled. All studies reported that SPRMs may be associated with greater reductions in uterine fibroids, other than for the lower dose of asoprisnil (10 mg) (Wilkens 2008). Donnez 2012a reported a 3% increase with placebo compared to a 21% and 12.3% decrease with ulipristal acetate 5 mg and 10 mg, respectively (Donnez 2012a). Engman 2009 reported a 6% increase with placebo compared to a 28% decrease with mifepristone. Levens 2008 found a 6% increase with placebo compared to a 29% decrease with CDB‐2914, and reported a 5% increase with placebo compared to a 26% decrease with asoprisnil. A 26% reduction in fibroid volume was reported by Bian 2021 after low‐dose mifepristone. Preoperative haemoglobin See Analysis 6.3. Three studies compared haemoglobin levels before surgery after ulipristal acetate pretreatment (5 mg or 10 mg) (Donnez 2012a) or mifepristone pretreatment (Bian 2021) compared to placebo. Both treatments were probably associated with an increased mean of almost 1 g/dL haemoglobin (MD 0.93, 95% CI 0.52 to 1.34; 3 studies, 305 participants; I² = 0%; moderate‐certainty evidence). Preoperative bleeding See Analysis 6.4; Analysis 6.5. One trial comparing ulipristal acetate with placebo assessed the proportion of women who achieved a reduction in bleeding to less than 75 units by PBAC after presurgical intervention (Donnez 2012a). Greater reduction in bleeding may be achieved in women receiving both doses of ulipristal acetate compared to placebo (ulipristal acetate 5 mg: OR 41.41, 95% CI 15.26 to 112.38; 1 study, 143 participants; low‐certainty evidence; Analysis 6.4; ulipristal acetate 10 mg: OR 78.83, 95% CI 24.0 to 258.74; 1 study, 146 participants; low‐certainty evidence; Analysis 6.4 (Donnez 2012b)). Another small study compared the change in menstrual blood loss from baseline to the end of treatment (asoprisnil) before surgery (Wilkens 2008). Asoprisnil may be associated with a reduction in blood loss when compared to placebo (MD ‐166.90, 95% CI ‐277.60 to ‐56.20; 1 study, 22 participants; low‐certainty evidence). Bian 2021 also reported that, at the end of treatment, the complete amenorrhoea rate (84% (52/62)) and menstrual blood loss disappearance rate (87% (54/62)) in the intervention group were probably higher than those in the control group. Secondary outcomes Adverse events See Analysis 6.6 and Analysis 6.7. Serious adverse events There may be little or no difference in the rates of breast cancer, uterine or ovarian haemorrhage, fibroid protrusion, menometrorrhagia or hyperplasia between groups in three studies (Donnez 2012a; Levens 2008; Wilkens 2008) where the SPRMs included ulipristal acetate (5 mg or 10 mg), asoprisnil (10 mg or 25 mg) or CDB‐2914 (10 mg or 20 mg), although many of these specific adverse events were measured by only one trial (Donnez 2012a). Other specific adverse events Four trials measured other less serious adverse events (Bian 2021; Donnez 2012a; Engman 2009; Wilkens 2008), although most of these events included data from only one trial (Donnez 2012a). The odds of hot flushes and change of mood may be increased with mifepristone in one small trial (hot flushes: OR 25.24, 95% CI 1.27 to 503.38; 30 participants; low‐certainty evidence (Engman 2009); mood change: OR 15.00, 95% CI 1.54 to 146.54; 30 participants; low‐certainty evidence. A larger trial, Donnez 2012a, found dysmenorrhoea may be less likely to be reported with ulipristal acetate pretreatment (OR 0.05, 95% CI 0.00 to 1.02; 1 study, 241 participants; low‐certainty evidence). The findings from these two studies should be treated with considerable caution, as the findings were very imprecise, with very wide confidence intervals. There was no evidence of differences between groups for any of the other adverse events. Quality of life See Analysis 6.8. 6.8. Analysis. Comparison 6: SPRMs versus placebo or no pretreatment before surgery, Outcome 8: Quality of life (Uterine Fibroid Symptoms and QoL questionnaire) | Quality of life (Uterine Fibroid Symptoms and QoL questionnaire) | |||| | Study | No of participants | Comparison | Results | Comment | | Donnez 2012a | 239 | UA 5 mg or UA 10 mg versus placebo | Questionnaire assessing discomfort from fibroids (ranging from 0 to 28 points): UA 5 mg vs placebo (change from baseline): ‐4.0 (‐6.0 to ‐1.0), P = 0.001 UA 10 mg vs placebo (change from baseline): ‐4.0 (‐7.0 to ‐2.0), P < 0.001 | Differences from placebo group significant | One trial with 239 participants found that either ulipristal acetate 5 mg or 10 mg may increase quality of life (by a median reduction of 4 points measured on a 28‐point questionnaire about uterine fibroid symptoms and quality of life) when compared to placebo (Donnez 2012a).

Summary of main results We assessed the effect of preoperative medical therapy on several important preoperative, intraoperative and postoperative outcomes for hysterectomy, myomectomy and hysteroscopic resection, and in the surgical treatment of women with uterine fibroids. A rationale for the use of preoperative medical therapy is to reduce the difficulty of any surgical procedure and thereby improve associated outcomes. The included studies did not contribute data to every outcome, and, for some outcomes, findings were stratified according to whether the control group received no pretreatment or placebo pretreatment. Summaries of overall results for the main outcomes, with overall certainty assessments, are presented in Table, Table and Table. Gonadotropin‐hormone‐releasing analogues (GnRHa) versus no pretreatment or placebo Preoperative outcomes The combined results of both placebo‐controlled and GnRHa versus no‐treatment trials suggest that, regardless of subsequent surgery, the use of GnRHa may be associated with an increase in preoperative haemoglobin (low certainty), and a reduction in both uterine and fibroid volume (low certainty), although this came at the expense of a greater likelihood (odds) of adverse events (moderate certainty), in particular hot flushes. Outcomes during and after hysterectomy Duration of surgery may be reduced by up to 10 minutes with GnRHa pretreatment, although some studies with skewed data did not find a benefit of pretreatment. Other effects of GnRHa pretreatment included: an uncertain reduction in blood loss, fewer blood transfusions, lower likelihood (odds) of difficult surgery (only in placebo trials) and improved postoperative haemoglobin levels. The odds of complications may also be reduced with GnRHa pretreatment. Outcomes during and after myomectomy In women undergoing myomectomy, although most trials found that GnRHa may reduce intraoperative blood loss, the certainty of the evidence was very low and substantial heterogeneity was found, so no overall pooled estimate could be calculated. We are uncertain about pretreatment‐influenced duration of surgery, and intraoperative blood transfusions. One trial found that pretreatment may be associated with greater postoperative haemoglobin levels. However, because of the small numbers, these findings are very uncertain. Outcomes during and after hysteroscopic resection of fibroids One small study found that there was little to no difference in the duration of surgery with GnRHa pretreatment when compared to no pretreatment. There was little or no difference in the perception of difficult surgery or recurrence of fibroids with GnRHa pretreatment. GnRHa versus other medical therapies (lynestrenol, selective progesterone‐receptor modulators (SPRMs), selective oestrogen receptor modulators (SERMs), dopamine agonists, oestrogen receptor agonists) For most comparisons and outcomes, only one trial contributed data, because control groups were stratified according to the type of medical therapy being compared to GnRHa. Two trials compared GnRHa with multiple doses of the control medical therapy (ulipristal acetate, fulvestrant). Only the trial comparing GnRHa versus ulipristal acetate was placebo‐controlled with double‐blinding. Because of the lack of data, we combined the other medical therapies in one control group, and we undertook sensitivity analyses to determine the differential effects of the treatments. Concerning uterine volume, there was probably little or no difference between GnRHa and raloxifene or mifepristone, but GnRHa pretreatment may be associated with a greater reduction in volume than ulipristal acetate, regardless of the dosage of ulipristal acetate. Concerning fibroid volume, there was little or no difference between groups (in comparisons against control groups with dopamine agonist, raloxifene and ulipristal acetate); however, GnRHa may be associated with a greater reduction in volume than either dose of fulvestrant. There was little or no difference between groups for other outcomes: preoperative haemoglobin, reduced bleeding and quality of life. No data on blood transfusion was provided. However, GnRHa was more likely to be associated with hot flushes than other medical therapies. SPRMs versus placebo SPRMs were associated with greater reductions in uterine volume (ulipristal acetate and asoprisnil) and fibroid volume (ulipristal acetate, mifepristone, CDB2914 and asoprisnil) than placebo pretreatment, and with increased preoperative haemoglobin levels (ulipristal acetate and asoprisnil). Ulipristal acetate and asoprisnil were also associated with a greater reduction in bleeding before surgery than placebo, and quality of life was better with ulipristal acetate pretreatment. There was insufficient evidence to determine adverse events rates because these were mostly measured in only one trial. Overall completeness and applicability of evidence This update included 41 randomised controlled trials (RCTs), with 3982 participants, but there were multiple comparisons with different types of interventions, which meant that some comparisons were underpowered. Hence, results based on small numbers of participants should be treated with caution. Only 13 of the 41 studies had 100 participants or more. Participants in the studies all had symptomatic fibroids, with the expectation of surgery, but there was substantial variation amongst studies in the types of fibroids, size of the uterus, degree of anaemia and type of subsequent surgery, limiting the generalisability of the results. Evidence on GnRHa pretreatment was based on a reasonable number of participants, but results from other medical pretreatments were based on much smaller numbers of women. Adverse events were sometimes only anecdotally reported in text format in the included studies, but the larger studies mostly provided full tables of individual symptoms associated with pretreatment. Although endometrial hyperplasia rates did not differ, the authors of two large trials comparing ulipristal acetate with placebo or GnRHa (Donnez 2012a; Williams 2012) noted that a spectrum of morphological endometrial changes was associated with three months of treatment with ulipristal acetate (which had been described previously in women receiving SPRM treatment), but these changes disappeared two months after the end of therapy. Quality of the evidence We assessed the risk of bias in each individual study, and we gave an overall certainty grading for the body of the evidence for each outcome, based on GRADE criteria, which are limitations in study design (risk of bias), consistency, indirectness, imprecision and publication bias. Only three of the included studies had a low risk of bias for all domains. When summarised as a body of evidence (Figure), less than half of the included studies were at low risk of bias for allocation, blinding of participants and investigators, or other potential bias, such as baseline comparability. About 30% of the included studies had a low risk of bias for outcome assessment, and about 50% had a low risk of bias for incomplete outcome data and selective reporting. The remainder of the included trials had either unclear or high risk of bias for each of these domains. A number of the included studies reported receiving pharmaceutical company funding or support; for these studies, it was not possible to determine whether the conflict of interest had influenced the findings. With respect to the overall certainty assessment, heterogeneity was substantial for many of the outcomes (particularly those influenced by different hospital policies, participants' uterine size, fibroid type, experience of surgeons, etc). Thus, for many outcomes, pooled estimates could not be calculated, and instead, the forest plots display individual study estimates because combining these was not sensible. Imprecision ‐ with findings based on either small trials, a low number of events or very wide confidence intervals ‐ was also a characteristic of the effect estimates of some outcomes, leading to uncertainties about benefits and harms. As a result, for most of the primary outcomes reported in the summary of findings tables, the overall certainty of the evidence (using GRADE criteria) is low, with some exceptions. This suggests there are some uncertainties associated with many of the findings in this review, and future research could change our conclusions. For summaries of the primary outcome results together with GRADE overall certainty assessments, see Table; Table; Table. Potential biases in the review process We made efforts to retrieve all eligible studies by thorough searching of electronic databases and trial registers. However, the possibility remains that some unpublished studies were not retrieved. We followed rigorous processes for the identification and selection of studies, data extraction and data entry, with efforts undertaken to access missing or unclear data from the publications to ensure accuracy of all data. At least two review authors were involved in study selection, data extraction, data entry and risk of bias assessment. One of the authors, LP, is also an author of one of the included studies, so data extraction and assessment for this study were carried out by a different review author to minimise any bias. Agreements and disagreements with other studies or reviews Three systematic reviews have evaluated the role of GnRHa preoperatively: before any surgery (Zhang 2014), before laparoscopic myomectomy (Chen 2011) and before hysteroscopic resection (for submucous fibroids) (Kamath 2014). One systematic review and network meta‐analysis provided a more general analysis of the role of medical therapies for fibroids, both before surgery and when used alone (Gurusamy 2016). Two analyses have been undertaken to assess the economic effects of ulipristal acetate; one was a cost‐effectiveness analysis (Nagy 2014), and the other, a cost minimisation and budget impact analysis (Zakiyah 2017). The findings of this review broadly reflect the findings of the Zhang 2014 review, which included 26 studies: their findings were that preoperative GnRHa reduces fibroid volume, increases haemoglobin levels, reduces the chance of a vertical incision, increases the chance of a vaginal procedure, without any increase in postoperative complications. In addition, our review also found a reduction in uterine volume before surgery, a reduction in blood loss (during either hysterectomy or myomectomy), a reduced chance of blood transfusions and postoperative complications (where surgery was hysterectomy). However, GnRHa was associated with an increased risk of adverse events before surgery (in particular, hot flushes). Reduction in intraoperative blood loss when surgery was restricted to laparoscopic myomectomy was also reported in the systematic review by Chen 2011. The systematic review by Kamath 2014 included both trials from this review where women underwent hysteroscopic resection for submucous fibroids. Kamath 2014 concluded there was insufficient evidence of benefit to support the routine use of GnRHa before resection for this particular indication; this finding mirrors our conclusion. The network meta‐analysis by Gurusamy 2016 ranked all potential medical treatments before any surgery, according to different outcomes. Gurusamy 2016 found that trials were at high risk of bias and overall certainty of evidence was low. Gurusamy 2016 concluded that no medical treatment could currently be recommended before surgery for fibroids without consideration of the relative importance that women ascribe to adverse events and without consideration of cost‐effectiveness analyses. A group of authors from Hungary undertook a cost‐effectiveness analysis of ulipristal acetate using a Markov model and based estimates on the findings from Pearl I (Donnez 2012a) (a study included in the current review), together with a multicentre cohort study and estimates from an expert panel (Nagy 2014). Nagy 2014 found that adding three months of preoperative ulipristal acetate before surgery rather than immediate hysterectomy resulted in an incremental cost‐effectiveness ratio of EUR 3575 per quality‐adjusted life year in women with moderate to severe bleeding as a result of their fibroids. This finding was limited to effects on symptoms. Nagy 2014 did not assess the cost‐effectiveness of any other preoperative treatment. A cost‐minimisation analysis was undertaken to compare ulipristal acetate to leuprolide, which was considered the standard of care in the Netherlands (Zakiyah 2017). Zakiyah 2017 concluded that ulipristal acetate was a cost‐saving option for preoperative treatment of moderate and severe symptoms of fibroids compared to leuprolide in the short term, with the potential to provide savings on the healthcare budget in the Netherlands. The study published by De Milliano 2020 was done in the Netherlands and total healthcare costs, absenteeism costs, and total societal costs were higher in the ulipristal acetate group compared to GnRHa‐group. However, these outcomes were not significantly different between groups after adjusting for fibroid size at baseline. Authors' conclusions Implications for practice. One of the most frequently asked questions in our daily clinical practice is whether preoperative treatment actually makes fibroid surgery easier. There is low‐ to moderate‐certainty evidence from randomised controlled trials (RCTs) that preoperative gonadotropin‐hormone‐releasing analogues (GnRHa) might reduce both uterine and fibroid volume and improve haemoglobin levels, although at the expense of increased adverse effects such as hot flushes. Rates of blood loss may also be reduced (in women undergoing hysterectomy or myomectomy), and women may be less likely to have postoperative complications when undergoing hysterectomy. There was little or no benefit for other patient or surgical outcomes, such as duration of surgery or hospital stay. Recent RCTs suggest that ulipristal acetate, a selective progesterone receptor modulator (SPRM), may offer an alternative pretreatment to enhance outcomes during and after surgery in women with fibroid‐related anaemia. Compared to GnRHa, ulipristal acetate was not as effective at reducing uterine volume, but both pretreatments appeared to have similar effects on other outcomes, although, to date, use of the product is suspended because of an association with cases of liver failure. Implications for research. Although duration of surgery, total blood loss, postoperative haemoglobin and postoperative complications can be used as surrogate outcomes, few blinded placebo‐controlled trials have conclusively measured surgical difficulty. Future trials should be blinded and should evaluate operative difficulty in a reproducible way. Cost‐effectiveness data are lacking in all published trials, and given the very significant cost of preoperative agents, some attempts should be made to generate such data in future trials. Whether the chance of fibroid recurrence is decreased and women's quality of life is increased after the use of preoperative medical therapy should also be evaluated further in future randomised trials. What's new | Date | Event | Description | |---|---|---| | 4 April 2025 | New citation required but conclusions have not changed | The addition of four new studies has not led to a change in the conclusions of this review. | | 4 April 2025 | New search has been performed | New authors added at this update: Ioana‐Marta Melinte, Dr Marian Showell and Helen Nagels. Search updated and four new studies added (Bian 2021, De Milliano 2020; Favilli 2017; Sun 2021). | History Protocol first published: Issue 4, 1997 Review first published: Issue 4, 1998 | Date | Event | Description | |---|---|---| | 13 June 2017 | New search has been performed | Updated in 2017 ‐ 17 additional studies added (Baytur 2007; De Falco 2009; Donnez 2003; Donnez 2012a; Donnez 2012b; Engman 2009; Hudecek 2012; Levens 2008; Mavrelos 2010; Muneyyirci‐Delale 2007; Muzii 2010; Reinsch 1994; Sayyah‐Melli 2007; Sayyah‐Melli 2009; Seraccholi 2003; Vercellini 2003; Wilkens 2008) | | 13 June 2017 | New citation required and conclusions have changed | Review scope changed. From inception, the review assessed only GnRHa as preoperative treatment. In 2017, the scope was broadened to include all preoperative treatment. | | 17 June 2008 | Amended | Converted to new review format | | 10 January 2001 | New citation required and conclusions have changed | Substantive amendment |

The authors acknowledge the helpful comments of those who refereed previous versions of this review. The authors are also very grateful for the translations of papers carried out by Ms Christine Aguilar, San Antonio Cochrane Centre, Petr Tomek of Auckland University and Ms Kirsten Duckitt, Royal College of Obstetrics and Gynaecology, London, and to all trialists who provided additional material for this review: Dr A Cagnacci, Dr AJ Friedman, Kristof Chwalisz and Dr A Nikolov. Special thanks are due to Ms Ruth Jepson, Ms Sarah Hetrick and Ms Helen Nagels, Managing Editors, for their professionalism and help with the inevitable problems that arise, to Mrs Sue Furness and Mrs Marian Showell, Trials Search Co‐ordinators, for their assistance with identifying trials and to Mrs Sue Hall, Secretary of the Review Group, for her secretarial help (Lethaby 2000; Lethaby 2001). We thank Dr Amita Ray, Dr Sujoy Ray, Dr Aneesh George, Dr Martin Sowter and Antonia Steed for their contributions to an early draft of the 2017 update of this review. For the 2017 and 2025 updates, Marian Showell (Information Specialist) assisted with additional searches. Editorial and peer‐reviewer contributions The Cochrane Gynaecology and Fertility Group supported the authors in the development of this review. The following people conducted the editorial process for this article. Sign‐off Editor (final editorial decision): Vanessa Jordan, Department of Obstetrics and Gynaecology, University of Auckland Managing Editor (selected peer reviewers, provided editorial guidance to authors, edited the article): Leanne Jones, Cochrane Central Editorial Service Editorial Assistant (conducted editorial policy checks, collated peer‐reviewer comments and supported editorial team): Leticia Rodrigues, Cochrane Central Editorial Service Copy Editor (copy editing and production): Laura MacDonald, Cochrane Central Production Service Peer reviewers (provided comments and recommended an editorial decision): Nuala Livingstone, Cochrane Evidence Production and Methods Directorate (methods); Jo Platt, Central Editorial Information Specialist (search); Dr Jan JA Bosteels, MD, PhD, Dept OB GYN, Imelda Hospital Bonheiden, Belgium (clinical); Karla Duque Jacome MD, MPH (clinical); Radheshyam Meher, All India Institute of Medical Sciences, New Delhi, India (consumer) Appendices Appendix 1. Cochrane Gynaecology and Fertility Group specialised register search strategy ProCite platform Searched from inception to 8 August 2024 1

CONTAINS "myomectomy" or "Hysterectomy" or "Hysterectomy,abdominal" or "hysterectomy, laparoscopically assisted vaginal" or "myoma" or "myomas" or "myomata" or "myomatous uterus" or "fibroids" or "Leiomyoma" or "leiomyomata" or "abdominal hysterectomy" or "abdominal myomectomy" or "laparoscopic" or "laparoscopic hysterectomy" or "laparoscopic myomectomy" or "uterine fibroids" or "uterine leiomyomas" or Title CONTAINS "myomectomy" or "Hysterectomy" or "Hysterectomy,abdominal" or "hysterectomy, laparoscopically assisted vaginal" or "myoma" or "myomas" or "myomata" or "myomatous uterus" or "fibroids" or "Leiomyoma" or "leiomyomata" or "abdominal hysterectomy" or "abdominal myomectomy" or "laparoscopic" or "laparoscopic hysterectomy" or "laparoscopic myomectomy" or "uterine fibroids" or" uterine leiomyomas" AND

CONTAINS "Gonadorelin" or "GnRH analogue" or "GnRH analog" or "GnRh" or "GnRHa" or "GnRHa‐gonadotropin" or "gonadotrophin" or "gonadotropin" or "gonadotropin‐releasing hormone" or "Goserelin" or "Gosereline " or "Lh recombinant" or "LHRH" or "luteinizing hormone" or "Fsh" or "leuprolide " or "leuprorelin" or "leuprolin" or "Zoladex" or "Lupron" or "decapeptyl" or "goserelin pretreatment" or "Pretreatment" or Title CONTAINS "Gonadorelin" or "GnRH analogue" or "GnRH analog" or "GnRh" or "GnRHa" or "GnRHa‐gonadotropin" or "gonadotrophin" or "gonadotropin" or "gonadotropin‐releasing hormone" or "Goserelin" or "Gosereline " or "Lh recombinant" or "LHRH" or "luteinizing hormone" or "Fsh" or "leuprolide " or "leuprorelin" or "leuprolin" or "Zoladex" or "Lupron" or "decapeptyl" or "goserelin pretreatment" or "Pretreatment" (474 records) 2

CONTAINS "myomectomy" or "Hysterectomy" or "Hysterectomy,abdominal" or "hysterectomy, laparoscopically assisted vaginal" or "myoma" or "myomas" or "myomata" or "myomatous uterus" or "fibroids" or "Leiomyoma" or "leiomyomata" or "abdominal hysterectomy" or "abdominal myomectomy" or "laparoscopic" or "laparoscopic hysterectomy" or "laparoscopic myomectomy" or "uterine fibroids" or "uterine leiomyomas" or Title CONTAINS "myomectomy" or "Hysterectomy" or "Hysterectomy,abdominal" or "hysterectomy, laparoscopically assisted vaginal" or "myoma" or "myomas" or "myomata" or "myomatous uterus" or "fibroids" or "Leiomyoma" or "leiomyomata" or "abdominal hysterectomy" or "abdominal myomectomy" or "laparoscopic" or "laparoscopic hysterectomy" or "laparoscopic myomectomy" or "uterine fibroids" or" uterine leiomyomas" AND

CONTAINS "mifepristone" or "RU486" or "selective progesterone receptor modulator" or "CDB‐2914" or "asoprisnil" or "Ulipristal" or Title CONTAINS "mifepristone" or "RU486" or "selective progesterone receptor modulator" or "CDB‐2914" or "asoprisnil" or "Ulipristal" (76 records) 3

CONTAINS "myomectomy" or "Hysterectomy" or "Hysterectomy,abdominal" or "hysterectomy, laparoscopically assisted vaginal" or "myoma" or "myomas" or "myomata" or "myomatous uterus" or "fibroids" or "Leiomyoma" or "leiomyomata" or "abdominal hysterectomy" or "abdominal myomectomy" or "laparoscopic" or "laparoscopic hysterectomy" or "laparoscopic myomectomy" or "uterine fibroids" or "uterine leiomyomas" or Title CONTAINS "myomectomy" or "Hysterectomy" or "Hysterectomy,abdominal" or "hysterectomy, laparoscopically assisted vaginal" or "myoma" or "myomas" or "myomata" or "myomatous uterus" or "fibroids" or "Leiomyoma" or "leiomyomata" or "abdominal hysterectomy" or "abdominal myomectomy" or "laparoscopic" or "laparoscopic hysterectomy" or "laparoscopic myomectomy" or "uterine fibroids" or" uterine leiomyomas" AND

CONTAINS "progestagen" or "progesteron" or "Progesterone" or "progesterone, micronized" or "progestin" or "progestins" or "progestogen" or "progestogens" or "*Medrogestone" or "medroxyprogesterone" or "Medroxyprogesterone Acetate*"or "Depoprovera" or "depot medroxyprogesterone" or "depot medroxyprogesterone acetate" or "levonorgestrel intrauterine system" or "levonorgestrel‐releasing intrauterine device" or "levonorgestrel‐releasing intrauterine system" or "Levonorgestrel‐Therapeutic‐Use" or "LNG‐IUS" or "Mirena" or "norethindrone" or "noresthisterone" or "Norethisterone" or "Norgestimate" or "Norgestrel" or "desogestrel" or "desogestral" or "Gestagen" or "gestodene" or "Levonorgestrel" or Title CONTAINS "progestagen" or "progesteron" or "Progesterone" or "progesterone, micronized" or "progestin" or "progestins" or "progestogen" or "progestogens" or "*Medrogestone" or "medroxyprogesterone" or "Medroxyprogesterone Acetate*"or "Depoprovera" or "depot medroxyprogesterone" (247 records) 4

CONTAINS "myomectomy" or "Hysterectomy" or "Hysterectomy,abdominal" or "hysterectomy, laparoscopically assisted vaginal" or "myoma" or "myomas" or "myomata" or "myomatous uterus" or "fibroids" or "Leiomyoma" or "leiomyomata" or "abdominal hysterectomy" or "abdominal myomectomy" or "laparoscopic" or "laparoscopic hysterectomy" or "laparoscopic myomectomy" or "uterine fibroids" or "uterine leiomyomas" or Title CONTAINS "myomectomy" or "Hysterectomy" or "Hysterectomy,abdominal" or "hysterectomy, laparoscopically assisted vaginal" or "myoma" or "myomas" or "myomata" or "myomatous uterus" or "fibroids" or "Leiomyoma" or "leiomyomata" or "abdominal hysterectomy" or "abdominal myomectomy" or "laparoscopic" or "laparoscopic hysterectomy" or "laparoscopic myomectomy" or "uterine fibroids" or" uterine leiomyomas" AND

CONTAINS "androgen antagonists" or "androgens" or "danazol" or "gestrinone" or Title CONTAINS "androgen antagonists" or "androgens" or "danazol" or "gestrinone" (58 records) 5

CONTAINS "myomectomy" or "Hysterectomy" or "Hysterectomy,abdominal" or "hysterectomy, laparoscopically assisted vaginal" or "myoma" or "myomas" or "myomata" or "myomatous uterus" or "fibroids" or "Leiomyoma" or "leiomyomata" or "abdominal hysterectomy" or "abdominal myomectomy" or "laparoscopic" or "laparoscopic hysterectomy" or "laparoscopic myomectomy" or "uterine fibroids" or "uterine leiomyomas" or Title CONTAINS "myomectomy" or "Hysterectomy" or "Hysterectomy,abdominal" or "hysterectomy, laparoscopically assisted vaginal" or "myoma" or "myomas" or "myomata" or "myomatous uterus" or "fibroids" or "Leiomyoma" or "leiomyomata" or "abdominal hysterectomy" or "abdominal myomectomy" or "laparoscopic" or "laparoscopic hysterectomy" or "laparoscopic myomectomy" or "uterine fibroids" or" uterine leiomyomas" AND

CONTAINS "aromatase inhibition" or "aromatase inhibitor" or "letrozole" or "anastrozole" or "arimidex" or Keywords CONTAINS "aromatase inhibition" or "aromatase inhibitor" or "letrozole" or "anastrozole" or "arimidex" (18 records) Appendix 2. CENTRAL via The Cochrane Register of Studies (CRS Online) Web platform Searched 8 August 2024 #1 MESH DESCRIPTOR Gonadotropin‐Releasing Hormone EXPLODE ALL TREES 3264 #2 (GnRH* or lhrh or gn‐rh or lfrh or lh‐rh or lhfshrh):TI,AB,KY 5352 #3 (Gonadotropin‐Releasing Hormone*):TI,AB,KY 2897 #4 (Gonadotrophin‐Releasing Hormone*):TI,AB,KY 534 #5 (luteini?ing hormone releasing):TI,AB,KY 525 #6 (fsh releasing hormone*):TI,AB,KY 1 #7 (gonadorelin or luliberin or luteinizing hormone‐releasing hormone or cystorelin):TI,AB,KY 883 #8 (dirigestran or factrel or gonadoliberin):TI,AB,KY 7 #9 (buserelin or goserelin or leuprolide or nafarelin or triptorelin):TI,AB,KY 3515 #10 (luprorelin or Zoladex):TI,AB,KY 335 #11 (suprecur or suprefact):TI,AB,KY 29 #12 (lupron or prostap):TI,AB,KY 96 #13 (enantone or lucrin):TI,AB,KY 51 #14 (trenantone or synarel):TI,AB,KY 14 #15 (synarella or decapeptyl or gonapeptyl):TI,AB,KY 173 #16 Elagolix:TI,AB,KY 141 #17 (Pretreatment or pre treatment):TI,AB,KY 23323 #18 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 31081 #19 MESH DESCRIPTOR Receptors, Progesterone EXPLODE ALL TREES 689 #20 (selective progesterone receptor modulator*):TI,AB,KY 78 #21 SPRM*:TI,AB,KY 39 #22 MESH DESCRIPTOR Mifepristone EXPLODE ALL TREES 699 #23 Mifepristone:TI,AB,KY 1993 #24 mifegyne:TI,AB,KY 16 #25 mifeprex:TI,AB,KY 1 #26 (r38486 or ru‐38486 or ru38486 or ru‐486 or ru486):TI,AB,KY 178 #27 Asoprisnil:TI,AB,KY 22 #28 J867:TI,AB,KY 3 #29 (Telapristone or Progenta):TI,AB,KY 12 #30 (Ulipristal or Ella):TI,AB,KY 229 #31 (Proellex or esmya or CDB‐4124):TI,AB,KY 41 #32 antiprogest*:TI,AB,KY 104 #33 (progesterone receptor antagonist*):TI,AB,KY 16 #34 CDB‐2914:TI,AB,KY 26 #35 #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 2996 #36 MESH DESCRIPTOR progesterone EXPLODE ALL TREES 3975 #37 MESH DESCRIPTOR Medroxyprogesterone Acetate EXPLODE ALL TREES 1214 #38 (progesterone or medroxyprogesterone):TI,AB,KY 10594 #39 (progest?gen* or progestin*):TI,AB,KY 3183 #40 DPMA:TI,AB,KY 3 #41 (LNG‐IUS or IUS or mirena):TI,AB,KY 593 #42 (hormone‐releasing intrauterine system*):TI,AB,KY 2 #43 (Norethisterone or norethindrone or Utovlan*):TI,AB,KY 1431 #44 (ethynyltestosterone or progestational):TI,AB,KY 135 #45 (megestrol or Megace):TI,AB,KY 675 #46 Lynestrenol:TI,AB,KY 94 #47 (desogestrel or gestodene or norgestimate or dienogest):TI,AB,KY 1364 #48 (drospirenone or levonorgestrel):TI,AB,KY 2622 #49 #36 OR #37 OR #38 OR #39 OR #40 OR #41 OR #42 OR #43 OR #44 OR #45 OR #46 OR #47 OR #48 16353 #50 (androgen* or danazol):TI,AB,KY 9569 #51 gestrinone:TI,AB,KY 81 #52 #50 OR #51 9617 #53 MESH DESCRIPTOR Aromatase Inhibitors EXPLODE ALL TREES 1912 #54 (Aromatase Inhibitor*):TI,AB,KY 2601 #55 letrozole:TI,AB,KY 2589 #56 (Anastrozole or Arimidex):TI,AB,KY 1392 #57 #53 OR #54 OR #55 OR #56 5002 #58 #18 OR #35 OR #49 OR #52 OR #57 58029 #59 MESH DESCRIPTOR Leiomyoma EXPLODE ALL TREES 892 #60 MESH DESCRIPTOR Myoma EXPLODE ALL TREES 45 #61 MESH DESCRIPTOR Uterine Myomectomy EXPLODE ALL TREES 132 #62 (uter* adj2 fibroma*):TI,AB,KY 26 #63 (leiomyom* or Myomectom*):TI,AB,KY 1913 #64 (myoma* or hysteromyom*):TI,AB,KY 1516 #65 fibromyom*:TI,AB,KY 21 #66 fibroid*:TI,AB,KY 1302 #67 #59 OR #60 OR #61 OR #62 OR #63 OR #64 OR #65 OR #66 3094 #68 #58 AND #67 915 Appendix 3. MEDLINE search strategy Ovid platform From 1946 to 8 August 2024 1 exp Gonadotropin‐Releasing Hormone/ (34970) 2 (GnRH$ or lhrh or gn‐rh or lfrh or lh‐rh or lhfshrh).tw. (36089) 3 Gonadotropin‐Releasing Hormone$.tw. (16600) 4 Gonadotrophin‐Releasing Hormone$.tw. (3253) 5 luteini?ing hormone releasing.tw. (6346) 6 fsh releasing hormone$.tw. (55) 7 (gonadorelin or luliberin or luteinizing hormone‐releasing hormone or cystorelin).tw. (6064) 8 (dirigestran or factrel or gonadoliberin).tw. (175) 9 (buserelin or goserelin or leuprolide or nafarelin or triptorelin).tw. (5462) 10 (luprorelin or Zoladex).tw. (397) 11 (suprecur or suprefact).tw. (30) 12 (lupron or prostap).tw. (201) 13 (enantone or lucrin).tw. (45) 14 (trenantone or synarel).tw. (15) 15 (synarella or decapeptyl or gonapeptyl).tw. (232) 16 Elagolix.tw. (149) 17 (Pretreatment or pre treatment).tw. (245441) 18 or/1‐17 (295386) 19 exp Receptors, Progesterone/ (21028) 20 selective progesterone receptor modulator$.tw. (331) 21 SPRM$.tw. (247) 22 exp Mifepristone/ (6558) 23 Mifepristone.tw. (4226) 24 mifegyne.tw. (14) 25 mifeprex.tw. (17) 26 r38486.tw. (1) 27 ru‐38486.tw. (443) 28 ru38486.tw. (388) 29 ru‐486.tw. (1725) 30 ru486.tw. (2425) 31 Asoprisnil.tw. (60) 32 J867.tw. (13) 33 Telapristone.tw. (18) 34 Progenta.tw. (1) 35 Ulipristal.tw. (580) 36 Ella.tw. (645) 37 Proellex.tw. (9) 38 CDB‐4124.tw. (18) 39 esmya.tw. (20) 40 antiprogest$.tw. (1503) 41 progesterone receptor antagonist$.tw. (380) 42 CDB‐2914.tw. (43) 43 or/19‐42 (30946) 44 exp progesterone/ or exp medroxyprogesterone acetate/ (74393) 45 progesterone.tw. (93046) 46 medroxyprogesterone.tw. (6719) 47 progest?gen$.tw. (8194) 48 progestin$.tw. (13005) 49 DPMA.tw. (117) 50 LNG‐IUS.tw. (915) 51 hormone‐releasing intrauterine system$.tw. (14) 52 IUS.tw. (1722) 53 mirena.tw. (338) 54 (Norethisterone or norethindrone or Utovlan$).tw. (3474) 55 ethynyltestosterone.tw. (19) 56 progestational.tw. (1763) 57 (megestrol or Megace).tw. (1545) 58 Lynestrenol.tw. (390) 59 (desogestrel or gestodene or norgestimate or dienogest).tw. (2423) 60 drospirenone.tw. (926) 61 levonorgestrel.tw. (5515) 62 or/44‐61 (144368) 63 androgen$.tw. (94434) 64 danazol.tw. (2604) 65 gestrinone.tw. (208) 66 or/63‐65 (96813) 67 exp Aromatase Inhibitors/ (10299) 68 Aromatase Inhibitor$.tw. (8831) 69 letrozole.tw. (4065) 70 (Anastrozole or Arimidex).tw. (2153) 71 or/67‐70 (14946) 72 fibroid$.tw. (8799) 73 exp Leiomyoma/ or exp Uterine Myomectomy/ (23883) 74 (uter$ adj2 fibroma$).tw. (365) 75 exp Uterine Neoplasms/ and fibroid$.tw. (3873) 76 (leiomyom$ or Myomectom$).tw. (19703) 77 exp Myoma/ (3053) 78 myoma$.tw. (6698) 79 hysteromyom$.tw. (142) 80 fibromyom$.tw. (764) 81 or/72‐80 (37963) 82 18 or 43 or 62 or 66 or 71 (533180) 83 81 and 82 (3324) 84 randomized controlled trial.pt. (618528) 85 controlled clinical trial.pt. (95585) 86 randomized.ab. (655629) 87 randomised.ab. (128845) 88 placebo.tw. (257456) 89 clinical trials as topic.sh. (202959) 90 randomly.ab. (439303) 91 trial.ti. (314991) 92 (crossover or cross‐over or cross over).tw. (103175) 93 or/84‐92 (1704586) 94 exp animals/ not humans.sh. (5246181) 95 93 not 94 (1571594) 96 83 and 95 (465) Appendix 4. Embase search strategy Ovid platform From 1980 to 8 August 2024 1 exp gonadorelin derivative/ or gonadorelin/ or gonadorelin agonist/ (80236) 2 (GnRH or lhrh or gn‐rh or lfrh or lh‐rh or lhfshrh).tw. (43191) 3 Gonadotropin‐Releasing.tw. (19389) 4 (gonadorelin or luliberin or luteinizing hormone‐releasing hormone or cystorelin).tw. (5860) 5 (dirigestran or factrel or gonadoliberin).tw. (301) 6 (buserelin or goserelin or leuprolide or nafarelin or triptorelin).tw. (8341) 7 fsh releasing hormone$.tw. (12) 8 Gonadotrophin‐Releasing Hormone$.tw. (3596) 9 (luprorelin or Zoladex).tw. (2233) 10 (suprecur or suprefact).tw. (1370) 11 (lupron or prostap).tw. (2162) 12 (enantone or lucrin).tw. (772) 13 (trenantone or synarel).tw. (402) 14 (synarella or decapeptyl or gonapeptyl).tw. (2380) 15 Elagolix.tw. (296) 16 (Pretreatment or pre treatment).tw. (310405) 17 or/1‐16 (398788) 18 exp progesterone receptor modulator/ (744) 19 selective progesterone receptor modulator$.tw. (547) 20 SPRM$.tw. (392) 21 exp mifepristone/ (14672) 22 Mifepristone.tw. (5659) 23 mifegyne.tw. (202) 24 mifeprex.tw. (124) 25 r38486.tw. (1) 26 ru38486.tw. (428) 27 ru‐38486.tw. (937) 28 ru‐486.tw. (4412) 29 ru486.tw. (2978) 30 Asoprisnil.tw. (79) 31 J867.tw. (15) 32 Telapristone.tw. (40) 33 Progenta.tw. (4) 34 Ulipristal.tw. (1036) 35 Ella.tw. (881) 36 Proellex.tw. (29) 37 CDB‐4124.tw. (55) 38 esmya.tw. (117) 39 antiprogest$.tw. (1639) 40 progesterone receptor antagonist$.tw. (443) 41 CDB‐2914.tw. (113) 42 or/18‐41 (18531) 43 exp progeria/ or exp progesterone/ or exp gestagen/ (178299) 44 medroxyprogesterone acetate.m_titl. (2118) 45 exp medroxyprogesterone acetate/ or exp injectable contraceptive agent/ (19906) 46 progesterone.tw. (107192) 47 medroxyprogesterone.tw. (7803) 48 progest?gen$.tw. (8658) 49 progestin$.tw. (14859) 50 DPMA.tw. (127) 51 LNG‐IUS.tw. (1401) 52 hormone‐releasing intrauterine system$.tw. (21) 53 IUS.tw. (3079) 54 mirena.tw. (1809) 55 exp levonorgestrel/ (14803) 56 (Norethisterone or norethindrone or Utovlan$).tw. (3390) 57 ethynyltestosterone.tw. (10) 58 progestational.tw. (1103) 59 (megestrol or Megace).tw. (2316) 60 Lynestrenol.tw. (176) 61 (desogestrel or gestodene or norgestimate or dienogest).tw. (3335) 62 drospirenone.tw. (1459) 63 levonorgestrel.tw. (7263) 64 or/43‐63 (225515) 65 androgen$.tw. (121495) 66 danazol.tw. (3575) 67 gestrinone.tw. (240) 68 or/65‐67 (124744) 69 exp aromatase inhibitor/ (41194) 70 Aromatase Inhibitor$.tw. (14896) 71 letrozole.tw. (7850) 72 (Anastrozole or Arimidex).tw. (4957) 73 or/69‐72 (43080) 74 17 or 42 or 64 or 68 or 73 (739431) 75 fibroid$.tw. (15122) 76 exp leiomyoma/ or exp myomectomy/ (45658) 77 (uter$ adj2 fibroma$).tw. (345) 78 (leiomyom$ or Myomectom$).tw. (26889) 79 exp uterus myoma/ (21563) 80 myoma$.tw. (8883) 81 hysteromyom$.tw. (247) 82 or/75‐81 (54676) 83 74 and 82 (7133) 84 Clinical Trial/ (1077835) 85 Randomized Controlled Trial/ (830564) 86 exp randomization/ (99941) 87 Single Blind Procedure/ (55661) 88 Double Blind Procedure/ (218803) 89 Crossover Procedure/ (78849) 90 Placebo/ (401784) 91 Randomi?ed controlled trial$.tw. (353995) 92 Rct.tw. (58723) 93 random allocation.tw. (2686) 94 randomly.tw. (580859) 95 randomly allocated.tw. (48113) 96 allocated randomly.tw. (3062) 97 (allocated adj2 random).tw. (888) 98 Single blind$.tw. (33320) 99 Double blind$.tw. (247129) 100 ((treble or triple) adj blind$).tw. (2151) 101 placebo$.tw. (377040) 102 prospective study/ (932117) 103 or/84‐102 (3192380) 104 case study/ (102164) 105 case report.tw. (568578) 106 abstract report/ or letter/ (1291786) 107 or/104‐106 (1946113) 108 103 not 107 (3124062) 109 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.) (6961382) 110 108 not 109 (2916027) 111 83 and 110 (1512) Appendix 5. PsycINFO search strategy Ovid platform From 1806 to 8 August 2024 1 exp Gonadotropic Hormones/ (4547) 2 (GnRH$ or lhrh or gn‐rh or lfrh or lh‐rh or lhfshrh).tw. (1432) 3 Gonadotropin‐Releasing Hormone$.tw. (914) 4 Gonadotrophin‐Releasing Hormone$.tw. (255) 5 luteini?ing hormone releasing.tw. (250) 6 fsh releasing hormone$.tw. (1) 7 (gonadorelin or luliberin or luteinizing hormone‐releasing hormone or cystorelin).tw. (238) 8 (dirigestran or factrel or gonadoliberin).tw. (2) 9 (buserelin or goserelin or leuprolide or nafarelin or triptorelin).tw. (158) 10 (luprorelin or Zoladex).tw. (4) 11 (suprecur or suprefact).tw. (0) 12 (lupron or prostap).tw. (23) 13 (enantone or lucrin).tw. (2) 14 (trenantone or synarel).tw. (0) 15 (synarella or decapeptyl or gonapeptyl).tw. (3) 16 Elagolix.tw. (2) 17 (Pretreatment or pre treatment).tw. (21168) 18 or/1‐17 (26441) 19 selective progesterone receptor modulator$.tw. (7) 20 SPRM$.tw. (7) 21 Mifepristone.tw. (326) 22 Mifegyne.tw. (0) 23 mifeprex.tw. (1) 24 r38486.tw. (0) 25 ru‐38486.tw. (44) 26 ru‐486.tw. (98) 27 Ulipristal.tw. (14) 28 CDB‐4124.tw. (2) 29 or/19‐28 (456) 30 exp progesterone/ (2448) 31 medroxyprogesterone.tw. (308) 32 progesterone.tw. (4805) 33 progest?gen$.tw. (258) 34 progestin$.tw. (716) 35 levonorgestrel‐releasing intrauterine.tw. (37) 36 DPMA.tw. (8) 37 LNG‐IUS.tw. (40) 38 hormone‐releasing intrauterine system$.tw. (1) 39 IUS.tw. (249) 40 mirena.tw. (13) 41 or/30‐40 (5899) 42 18 or 29 or 41 (32167) 43 fibroid$.tw. (101) 44 Leiomyoma$.tw. (31) 45 exp Gynecological Disorders/ and fibroid$.tw. (21) 46 (uter$ adj2 fibroma$).tw. (5) 47 myoma$.tw. (28) 48 (hysteromyom$ or myomectom$).tw. (16) 49 fibromyom$.tw. (1) 50 or/43‐49 (162) 51 42 and 50 (6) Appendix 6. CINAHL search strategy EBSCO platform Searched from 1961 to 19 August 2019 (All later CINAHL references are included in the 2023 CENTRAL search output) | # | Query | Results | | S77 | S63 AND S75 | 137 | | S75 | S64 OR S65 OR S66 OR S67 OR S68 OR S69 OR S70 OR S71 OR S72 OR S73 OR S74 | 1,343,247 | | S74 | TX allocat* random* | 10,832 | | S73 | (MH "Quantitative Studies") | 23,107 | | S72 | (MH "Placebos") | 11,409 | | S71 | TX placebo* | 58,283 | | S70 | TX random* allocat* | 10,832 | | S69 | (MH "Random Assignment") | 56,105 | | S68 | TX randomi* control* trial* | 173,405 | | S67 | TX ( (singl* n1 blind*) or (singl* n1 mask*) ) or TX ( (doubl* n1 blind*) or (doubl* n1 mask*) ) or TX ( (tripl* n1 blind*) or (tripl* n1 mask*) ) or TX ( (trebl* n1 blind*) or (trebl* n1 mask*) ) | 1,027,894 | | S66 | TX clinic* n1 trial* | 248,542 | | S65 | PT Clinical trial | 86,828 | | S64 | (MH "Clinical Trials+") | 264,453 | | S63 | S61 AND S62 | 508 | | S62 | S13 OR S27 OR S45 OR S49 OR S54 | 63,407 | | S61 | S55 OR S56 OR S57 OR S58 OR S59 OR S60 | 5,189 | | S60 | TX hysteromyom* | 11 | | S59 | TX myoma* | 833 | | S58 | TX fibroid* | 2,016 | | S57 | TX (uter* N2 fibroma*) | 18 | | S56 | TX Leiomyoma* | 4,105 | | S55 | (MM "Leiomyoma") | 2,827 | | S54 | S50 OR S51 OR S52 OR S53 | 3,123 | | S53 | TX (Anastrozole or Arimidex) | 657 | | S52 | TX letrozole | 789 | | S51 | TX Aromatase Inhibitor* | 2,516 | | S50 | (MH "Aromatase Inhibitors+") | 1,902 | | S49 | S46 OR S47 OR S48 | 249 | | S48 | TX gestrinone | 18 | | S47 | TX danazol | 239 | | S46 | (MM "Danazol") | 57 | | S45 | S28 OR S29 OR S30 OR S31 OR S32 OR S33 OR S34 OR S35 OR S36 OR S37 OR S38 OR S39 OR S40 OR S41 OR S42 OR S43 OR S44 | 9,787 | | S44 | TX levonorgestrel | 1,869 | | S43 | TX drospirenone | 262 | | S42 | TX(desogestrel or gestodene or norgestimate or dienogest) | 304 | | S41 | TX Lynestrenol | 8 | | S40 | TX (megestrol or Megace) | 312 | | S39 | TX progestational | 2,230 | | S38 | TX (Norethisterone or norethindrone or Utovlan*) | 274 | | S37 | TX mirena | 117 | | S36 | TX hormone‐releasing intrauterine | 13 | | S35 | TX LNG‐IUS | 215 | | S34 | TX DPMA | 7 | | S33 | TX progestin* | 1,608 | | S32 | TX progest?gen* | 775 | | S31 | TX medroxyprogesterone | 1,639 | | S30 | (MM "Medroxyprogesterone Acetate") | 395 | | S29 | (MH "Progestational Hormones, Synthetic+") | 1,812 | | S28 | (MH "Progestational Hormones+") OR (MM "Megestrol") | 4,994 | | S27 | S14 OR S15 OR S16 OR S17 OR S18 OR S19 OR S20 OR S21 OR S22 OR S23 OR S24 OR S25 OR S26 | 1,502 | | S26 | TX CDB‐4124 | 2 | | S25 | TX Ulipristal | 248 | | S24 | TX Telapristone | 3 | | S23 | TX J867 | 1 | | S22 | TX Asoprisnil | 6 | | S21 | TX ru‐486 | 53 | | S20 | TX ru‐38486 | 1 | | S19 | TX ru38486 | 9 | | S18 | TX mifeprex | 25 | | S17 | TX Mifepristone | 1,148 | | S16 | (MM "Mifepristone") | 526 | | S15 | TX SPRM* | 26 | | S14 | TX selective progesterone receptor modulator* | 140 | | S13 | S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9 OR S10 OR S11 OR S12 | 50,064 | | S12 | TX (Pretreatment or pre treatment) | 47,207 | | S11 | TX (suprecur or suprefact) | 2 | | S10 | TX (luprorelin or Zoladex) | 26 | | S9 | TX (buserelin or goserelin or leuprolide or nafarelin or triptorelin) | 815 | | S8 | TX (gonadorelin or luliberin or cystorelin) | 1,517 | | S7 | TX follicle N2 releasing hormone* | 177 | | S6 | TX fsh releasing hormone* | 89 | | S5 | TX luteini?ing hormone releasing | 396 | | S4 | TX (GnRH* or lhrh or gn‐rh or lfrh or lh‐rh or lhfshrh) | 1,248 | | S3 | TX gonadotrophin releasing hormone* | 143 | | S2 | TX gonadotropin‐releasing hormone* | 890 | | S1 | TX (MH "Gonadorelin+") | 1,948 | Data and analyses Comparison 1. GnRHa versus placebo or no pretreatment (preoperative outcomes, regardless of type of subsequent surgery). | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 1.1 Uterine volume (mL) (preoperative) | 13 | 858 | Mean Difference (IV, Random, 95% CI) | ‐175.34 [‐219.04, ‐131.65] | | 1.1.1 GnRHa vs no pretreatment | 11 | 810 | Mean Difference (IV, Random, 95% CI) | ‐178.68 [‐224.63, ‐132.74] | | 1.1.2 GnRHa vs placebo | 2 | 48 | Mean Difference (IV, Random, 95% CI) | ‐113.76 [‐314.60, 87.08] | | 1.2 Uterine volume (preoperative) (data table) | 4 | Other data | No numeric data | | | 1.2.1 GnRHa vs no pretreatment | 1 | Other data | No numeric data | | | 1.2.2 GnRHa vs placebo | 3 | Other data | No numeric data | | | 1.3 Fibroid volume (mL) (preoperative) | 5 | Mean Difference (IV, Random, 95% CI) | Totals not selected | | | 1.3.1 GnRHa vs no pretreatment | 5 | Mean Difference (IV, Random, 95% CI) | Totals not selected | | | 1.4 Fibroid volume (preoperative) (data table) | 2 | Other data | No numeric data | | | 1.4.1 GnRHa vs placebo | 2 | Other data | No numeric data | | | 1.5 Haemoglobin (preoperative) | 10 | 834 | Mean Difference (IV, Random, 95% CI) | 0.88 [0.68, 1.08] | | 1.5.1 GnRHa vs no pretreatment | 6 | 308 | Mean Difference (IV, Random, 95% CI) | 0.91 [0.52, 1.30] | | 1.5.2 GnRHa vs placebo | 4 | 526 | Mean Difference (IV, Random, 95% CI) | 0.87 [0.62, 1.13] | | 1.6 Haemoglobin (preoperative) (data table) | 1 | Other data | No numeric data | | | 1.6.1 GnRHa vs placebo | 1 | Other data | No numeric data | | | 1.7 Total frequency of adverse events | 4 | 755 | Odds Ratio (M‐H, Random, 95% CI) | 2.78 [1.77, 4.36] | | 1.7.1 GnRHa vs placebo | 4 | 755 | Odds Ratio (M‐H, Random, 95% CI) | 2.78 [1.77, 4.36] | | 1.8 Individual adverse events | 6 | Odds Ratio (M‐H, Random, 95% CI) | Subtotals only | | | 1.8.1 Insomnia | 1 | 110 | Odds Ratio (M‐H, Random, 95% CI) | 12.56 [0.68, 232.82] | | 1.8.2 Hot flushes | 6 | 877 | Odds Ratio (M‐H, Random, 95% CI) | 7.68 [4.55, 12.96] | | 1.8.3 Headache | 6 | 877 | Odds Ratio (M‐H, Random, 95% CI) | 1.74 [1.00, 3.03] | | 1.8.4 Pain | 2 | 505 | Odds Ratio (M‐H, Random, 95% CI) | 0.63 [0.36, 1.12] | | 1.8.5 Nausea | 2 | 505 | Odds Ratio (M‐H, Random, 95% CI) | 2.41 [0.14, 40.59] | | 1.8.6 Dizziness | 2 | 505 | Odds Ratio (M‐H, Random, 95% CI) | 2.41 [1.13, 5.14] | | 1.8.7 Depression | 2 | 505 | Odds Ratio (M‐H, Random, 95% CI) | 2.12 [0.87, 5.17] | | 1.8.8 Arthralgia | 2 | 505 | Odds Ratio (M‐H, Random, 95% CI) | 1.29 [0.55, 3.02] | | 1.8.9 Asthenia | 3 | 615 | Odds Ratio (M‐H, Random, 95% CI) | 0.99 [0.41, 2.39] | | 1.8.10 Vaginitis | 5 | 751 | Odds Ratio (M‐H, Random, 95% CI) | 4.18 [1.58, 11.05] | | 1.8.11 Abdominal/pelvic pain | 3 | 615 | Odds Ratio (M‐H, Random, 95% CI) | 2.43 [0.98, 6.05] | | 1.8.12 Skin changes | 2 | 261 | Odds Ratio (M‐H, Random, 95% CI) | 1.23 [0.48, 3.13] | | 1.8.13 Hirsutism | 1 | 65 | Odds Ratio (M‐H, Random, 95% CI) | 6.35 [0.70, 57.72] | | 1.8.14 Change in libido | 3 | 332 | Odds Ratio (M‐H, Random, 95% CI) | 1.84 [0.76, 4.46] | | 1.8.15 Change in breast size | 2 | 261 | Odds Ratio (M‐H, Random, 95% CI) | 10.87 [1.90, 62.24] | | 1.8.16 Sweating | 4 | 497 | Odds Ratio (M‐H, Random, 95% CI) | 14.32 [6.17, 33.27] | | 1.8.17 Breast pain/tenderness | 2 | 505 | Odds Ratio (M‐H, Random, 95% CI) | 0.73 [0.35, 1.52] | | 1.8.18 Uterine haemorrhage | 1 | 110 | Odds Ratio (M‐H, Random, 95% CI) | 0.14 [0.01, 2.78] | Comparison 2. GnRHa versus placebo or no pretreatment before hysterectomy (intraoperative or postoperative outcomes). | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 2.1 Duration of surgery (minutes) | 6 | 617 | Mean Difference (IV, Random, 95% CI) | ‐10.11 [‐16.96, ‐3.25] | | 2.1.1 GnRHa vs no pretreatment | 4 | 321 | Mean Difference (IV, Random, 95% CI) | ‐14.19 [‐25.01, ‐3.38] | | 2.1.2 GnRHa vs placebo | 2 | 296 | Mean Difference (IV, Random, 95% CI) | ‐5.03 [‐12.17, 2.12] | | 2.2 Duration of surgery (data table) | 3 | Other data | No numeric data | | | 2.2.1 GnRHa vs no pretreatment | 2 | Other data | No numeric data | | | 2.2.2 GnRHa vs placebo | 1 | Other data | No numeric data | | | 2.3 Intraoperative blood loss (mL) | 4 | Mean Difference (IV, Random, 95% CI) | Totals not selected | | | 2.3.1 GnRHa vs no pretreatment | 4 | Mean Difference (IV, Random, 95% CI) | Totals not selected | | | 2.4 Intraoperative blood loss (data table) | 2 | Other data | No numeric data | | | 2.4.1 GnRHa vs no pretreatment | 1 | Other data | No numeric data | | | 2.4.2 GnRHa vs placebo | 1 | Other data | No numeric data | | | 2.5 Frequency of blood transfusions | 6 | 601 | Odds Ratio (M‐H, Random, 95% CI) | 0.54 [0.29, 1.01] | | 2.5.1 GnRHa vs no pretreatment | 5 | 487 | Odds Ratio (M‐H, Random, 95% CI) | 0.49 [0.22, 1.08] | | 2.5.2 GnRHa vs placebo | 1 | 114 | Odds Ratio (M‐H, Random, 95% CI) | 0.64 [0.23, 1.78] | | 2.6 Postoperative morbidity (complications) | 7 | 772 | Odds Ratio (M‐H, Random, 95% CI) | 0.54 [0.32, 0.91] | | 2.6.1 GnRHa vs no treatment | 5 | 507 | Odds Ratio (M‐H, Random, 95% CI) | 0.59 [0.29, 1.23] | | 2.6.2 GnRHa vs placebo | 2 | 265 | Odds Ratio (M‐H, Random, 95% CI) | 0.47 [0.19, 1.11] | | 2.7 Proportion with individual complications | 1 | Odds Ratio (M‐H, Random, 95% CI) | Totals not selected | | | 2.7.1 Hypermenorrhoea | 1 | Odds Ratio (M‐H, Random, 95% CI) | Totals not selected | | | 2.7.2 Dysmenorrhoea | 1 | Odds Ratio (M‐H, Random, 95% CI) | Totals not selected | | | 2.7.3 Pelvic pain | 1 | Odds Ratio (M‐H, Random, 95% CI) | Totals not selected | | | 2.7.4 Difficult defecation | 1 | Odds Ratio (M‐H, Random, 95% CI) | Totals not selected | | | 2.7.5 Difficult urination | 1 | Odds Ratio (M‐H, Random, 95% CI) | Totals not selected | | | 2.7.6 Dyspareunia | 1 | Odds Ratio (M‐H, Random, 95% CI) | Totals not selected | | | 2.8 Proportion with difficult surgery | 5 | 712 | Odds Ratio (M‐H, Random, 95% CI) | 0.72 [0.51, 1.00] | | 2.8.1 GnRH vs no pretreatment | 2 | 347 | Odds Ratio (M‐H, Random, 95% CI) | 0.89 [0.54, 1.44] | | 2.8.2 GnRH vs placebo | 3 | 365 | Odds Ratio (M‐H, Random, 95% CI) | 0.59 [0.38, 0.94] | | 2.9 Proportion undergoing vaginal rather than abdominal procedure | 3 | Odds Ratio (M‐H, Random, 95% CI) | Totals not selected | | | 2.9.1 GnRHa vs no treatment | 2 | Odds Ratio (M‐H, Random, 95% CI) | Totals not selected | | | 2.9.2 GnRHa vs placebo | 1 | Odds Ratio (M‐H, Random, 95% CI) | Totals not selected | | | 2.10 Proportion with vertical incision | 4 | 529 | Odds Ratio (M‐H, Random, 95% CI) | 0.34 [0.21, 0.54] | | 2.10.1 GnRHa vs no pretreatment | 2 | 301 | Odds Ratio (M‐H, Random, 95% CI) | 0.32 [0.18, 0.59] | | 2.10.2 GnRHa vs placebo | 2 | 228 | Odds Ratio (M‐H, Random, 95% CI) | 0.36 [0.17, 0.75] | | 2.11 Duration of hospital stay (days) | 4 | Mean Difference (IV, Random, 95% CI) | Totals not selected | | | 2.11.1 GnRHa vs no pretreatment | 3 | Mean Difference (IV, Random, 95% CI) | Totals not selected | | | 2.11.2 GnRHa vs placebo | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | | | 2.12 Duration of hospital stay (data table) | 1 | Other data | No numeric data | | | 2.12.1 GnRHa vs no pretreatment | 1 | Other data | No numeric data | | | 2.13 Postoperative haemoglobin | 3 | 240 | Mean Difference (IV, Random, 95% CI) | 0.85 [0.31, 1.38] | | 2.13.1 GnRHa vs no pretreatment | 2 | 173 | Mean Difference (IV, Random, 95% CI) | 1.05 [0.39, 1.71] | | 2.13.2 GnRHa vs placebo | 1 | 67 | Mean Difference (IV, Random, 95% CI) | 0.40 [‐0.35, 1.15] | Comparison 3. GnRHa versus placebo or no pretreatment before myomectomy (intraoperative or postoperative outcomes). | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 3.1 Duration of surgery (minutes) | 6 | Mean Difference (IV, Random, 95% CI) | Totals not selected | | | 3.1.1 GnRHa vs no pretreatment | 5 | Mean Difference (IV, Random, 95% CI) | Totals not selected | | | 3.1.2 GnRHa vs placebo | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | | | 3.2 Duration of surgery (data table) | 2 | Other data | No numeric data | | | 3.2.1 GnRHa vs no pretreatment | 2 | Other data | No numeric data | | | 3.3 Intraoperative blood loss (mL) | 10 | Mean Difference (IV, Random, 95% CI) | Totals not selected | | | 3.3.1 GnRHa vs no pretreatment | 9 | Mean Difference (IV, Random, 95% CI) | Totals not selected | | | 3.3.2 GnRHa vs placebo | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | | | 3.4 Frequency of blood transfusions | 4 | 121 | Odds Ratio (M‐H, Random, 95% CI) | 0.85 [0.26, 2.75] | | 3.4.1 GnRHa vs no pretreatment | 3 | 103 | Odds Ratio (M‐H, Random, 95% CI) | 0.79 [0.20, 3.19] | | 3.4.2 GnRHa vs placebo | 1 | 18 | Odds Ratio (M‐H, Random, 95% CI) | 1.00 [0.11, 9.23] | | 3.5 Postoperative morbidity (complications) | 5 | 190 | Odds Ratio (M‐H, Random, 95% CI) | 1.07 [0.43, 2.64] | | 3.5.1 GnRHa vs no pretreatment | 4 | 172 | Odds Ratio (M‐H, Random, 95% CI) | 1.25 [0.44, 3.54] | | 3.5.2 GnRHa vs placebo | 1 | 18 | Odds Ratio (M‐H, Random, 95% CI) | 0.64 [0.10, 4.11] | | 3.6 Proportion with vertical incision | 1 | Odds Ratio (M‐H, Random, 95% CI) | Subtotals only | | | 3.6.1 GnRHa vs no pretreatment | 1 | 28 | Odds Ratio (M‐H, Random, 95% CI) | 0.07 [0.00, 1.43] | | 3.7 Duration of hospital stay (days) | 3 | Mean Difference (IV, Random, 95% CI) | Totals not selected | | | 3.7.1 GnRHa vs no pretreatment | 2 | Mean Difference (IV, Random, 95% CI) | Totals not selected | | | 3.7.2 GnRHa vs placebo | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | | | 3.8 Proportion with postoperative recurrence of myomas | 2 | 42 | Odds Ratio (M‐H, Random, 95% CI) | 4.16 [0.59, 29.09] | | 3.8.1 GnRHa vs no pretreatment | 1 | 24 | Odds Ratio (M‐H, Random, 95% CI) | 11.67 [1.49, 91.54] | | 3.8.2 GnRHa vs placebo | 1 | 18 | Odds Ratio (M‐H, Random, 95% CI) | 1.60 [0.24, 10.81] | | 3.9 Postoperative haemoglobin | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | | | 3.9.1 GnRHa vs no pretreatment | 1 | 67 | Mean Difference (IV, Random, 95% CI) | 0.80 [0.22, 1.38] | Comparison 4. GnRHa versus placebo or no pretreatment before hysteroscopic resection of fibroids (intraoperative or postoperative outcomes). | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 4.1 Duration of surgery (minutes) | 2 | 123 | Mean Difference (IV, Random, 95% CI) | ‐0.17 [‐11.22, 10.88] | | 4.2 Postoperative morbidity (complications) | 1 | 84 | Odds Ratio (M‐H, Fixed, 95% CI) | Not estimable | | 4.3 Difficulty of surgery (visual analogue scale) | 1 | 39 | Mean Difference (IV, Random, 95% CI) | ‐1.40 [‐3.05, 0.25] | | 4.4 Fibroid recurrence | 1 | 39 | Odds Ratio (M‐H, Random, 95% CI) | Not estimable | Comparison 5. GnRHa versus other medical therapies before surgery. | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 5.1 Uterine volume (data table) | 0 | Other data | No numeric data | | | 5.2 Fibroid volume | 3 | Mean Difference (IV, Random, 95% CI) | Subtotals only | | | 5.2.1 GnRHa vs ulipristal acetate | 1 | 49 | Mean Difference (IV, Random, 95% CI) | ‐47.20 [‐106.24, 11.84] | | 5.2.2 GnRHa vs cabergoline | 2 | 110 | Mean Difference (IV, Random, 95% CI) | 12.71 [‐5.92, 31.34] | | 5.3 Fibroid volume (data table) | 0 | Other data | No numeric data | | | 5.4 Haemoglobin at end of preoperative treatment | 2 | 242 | Mean Difference (IV, Random, 95% CI) | ‐0.02 [‐0.41, 0.37] | | 5.5 Reduction in bleeding to PBAC < 75 | 1 | Odds Ratio (M‐H, Random, 95% CI) | Subtotals only | | | 5.5.1 Ulipristal acetate 5 mg | 1 | 199 | Odds Ratio (M‐H, Random, 95% CI) | 0.71 [0.30, 1.68] | | 5.5.2 Ulipristal acetate 10 mg | 1 | 203 | Odds Ratio (M‐H, Random, 95% CI) | 0.39 [0.14, 1.06] | | 5.6 PBAC scores prior to surgery | 0 | Other data | No numeric data | | | 5.7 Duration of surgery (data table) | 0 | Other data | No numeric data | | | 5.8 Intraoperative blood loss > 1000 ml | 1 | 49 | Odds Ratio (M‐H, Random, 95% CI) | 0.52 [0.09, 3.17] | | 5.9 Postoperative morbidity (complications) | 0 | Other data | No numeric data | | | 5.10 Adverse events | 6 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | | | 5.10.1 Hot flushes | 6 | 507 | Risk Ratio (M‐H, Random, 95% CI) | 2.83 [1.68, 4.77] | | 5.10.2 Headache | 5 | 493 | Risk Ratio (M‐H, Random, 95% CI) | 1.96 [0.73, 5.27] | | 5.10.3 Nausea | 3 | 407 | Risk Ratio (M‐H, Random, 95% CI) | 0.43 [0.12, 1.58] | | 5.10.4 Weight gain | 1 | 56 | Risk Ratio (M‐H, Random, 95% CI) | 0.46 [0.08, 2.56] | | 5.10.5 Oedema | 1 | 56 | Risk Ratio (M‐H, Random, 95% CI) | 2.09 [0.23, 18.86] | | 5.10.6 Sleep disorder | 1 | 56 | Risk Ratio (M‐H, Random, 95% CI) | 11.15 [1.59, 78.29] | | 5.10.7 Mood disorder or anxiety | 2 | 106 | Risk Ratio (M‐H, Random, 95% CI) | 2.90 [0.03, 284.58] | | 5.10.8 Vaginal dryness | 3 | 120 | Risk Ratio (M‐H, Random, 95% CI) | 12.94 [2.53, 66.25] | | 5.10.9 Cutaneous disorder | 2 | 357 | Risk Ratio (M‐H, Random, 95% CI) | 1.46 [0.52, 4.05] | | 5.10.10 Abdominal or pelvic pain | 3 | 383 | Risk Ratio (M‐H, Random, 95% CI) | 1.43 [0.88, 2.32] | | 5.10.11 Procedural pain | 2 | 333 | Risk Ratio (M‐H, Random, 95% CI) | 1.11 [0.24, 5.11] | | 5.10.12 Fatigue | 1 | 301 | Risk Ratio (M‐H, Random, 95% CI) | 0.54 [0.15, 1.89] | | 5.10.13 Anaemia | 1 | 301 | Risk Ratio (M‐H, Random, 95% CI) | 1.24 [0.42, 3.69] | | 5.10.14 Nasopharyngitis | 1 | 301 | Risk Ratio (M‐H, Random, 95% CI) | 0.40 [0.09, 1.77] | | 5.10.15 Breast pain or tenderness | 1 | 301 | Risk Ratio (M‐H, Random, 95% CI) | 0.50 [0.11, 2.29] | | 5.10.16 Influenza | 1 | 301 | Risk Ratio (M‐H, Random, 95% CI) | 2.48 [0.68, 9.02] | | 5.10.17 Insomnia | 1 | 301 | Risk Ratio (M‐H, Random, 95% CI) | 2.48 [0.68, 9.02] | | 5.10.18 Pharyngitis | 1 | 301 | Risk Ratio (M‐H, Random, 95% CI) | 0.79 [0.16, 4.01] | | 5.10.19 Dizziness | 1 | 50 | Risk Ratio (M‐H, Random, 95% CI) | 0.11 [0.01, 1.96] | | 5.10.20 Bone sensitivity | 1 | 50 | Risk Ratio (M‐H, Random, 95% CI) | 37.00 [2.35, 582.21] | | 5.10.21 Muscular stiffness | 1 | 50 | Risk Ratio (M‐H, Random, 95% CI) | 5.00 [0.25, 99.16] | | 5.11 Quality of life (Uterine Fibroid Symptom: symptom severity (SS) and health‐related quality of life (HRQoL)) | 0 | Other data | No numeric data | | | 5.12 Difficulty of the entire surgical procedure | 0 | Other data | No numeric data | | | 5.13 Postoperative haemoglobin | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | 5.6. Analysis. Comparison 5: GnRHa versus other medical therapies before surgery, Outcome 6: PBAC scores prior to surgery | PBAC scores prior to surgery | ||| | Study | Ulipristal acetate | GnRHa | Comment | | De Milliano 2020 | n = 26 Change from baseline (median and (IQR): ‐321 (‐515 to ‐85) | n = 23 Change from baseline (median and IQR): ‐348 (‐818 to ‐112) | No significant difference was found between groups (P = 0.49). | 5.7. Analysis. Comparison 5: GnRHa versus other medical therapies before surgery, Outcome 7: Duration of surgery (data table) | Duration of surgery (data table) | |||| | Study | Ulipristal acetate 5 mg | Time of surgery (median, minutes) | GnRH/leuprolide acetate 11.25 mg | Time of surgery (median, minutes) | | De Milliano 2020 | 26 participants | 188 (IQR = 132‐2310) | 23 participants | 125 (IQR = 100‐175) | 5.9. Analysis. Comparison 5: GnRHa versus other medical therapies before surgery, Outcome 9: Postoperative morbidity (complications) | Postoperative morbidity (complications) | ||| | Study | GnRHa | Ulipristal acetate | Comment | | De Milliano 2020 | n = 23 2 complications: ‐ wound infection ‐ re‐operation one day after surgery because of persistent abdominal pain and drop in haemoglobin level | n = 26 4 complications: ‐ temporary fever ‐ ileus ‐ severe dyspnoea (pneumothorax) ‐ severe vaginal bleeding | Not possible to analyse differences between groups | 5.12. Analysis. Comparison 5: GnRHa versus other medical therapies before surgery, Outcome 12: Difficulty of the entire surgical procedure | Difficulty of the entire surgical procedure | |||||| | Study | Intervention group (ulipristal acetate, 5 mg) | Change from baseline (median) | Change from baseline (IQR) | Control group (GnRHa) | Change from baseline (median) | Change from baseline (IQR) | | De Milliano 2020 | Ulipristal acetate group (n) | Median | IQR | GnRH group (n) | Median | IQR | | 26 | 4 | 3.0‐5.0 | 23 | 3 | 2.0‐4.0 | Comparison 6. SPRMs versus placebo or no pretreatment before surgery. | Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size | |---|---|---|---|---| | 6.1 Uterine volume (mL) | 0 | Other data | No numeric data | | | 6.2 Fibroid volume (mL) | 0 | Other data | No numeric data | | | 6.3 Haemoglobin (g/dL) | 3 | 297 | Mean Difference (IV, Random, 95% CI) | 0.93 [0.52, 1.34] | | 6.3.1 Comparator was UPA | 1 | 143 | Mean Difference (IV, Random, 95% CI) | 0.90 [0.45, 1.35] | | 6.3.2 Comparator was mifepristone | 2 | 154 | Mean Difference (IV, Random, 95% CI) | 1.05 [0.07, 2.04] | | 6.4 Reduction in bleeding (PBAC < 75) | 1 | Odds Ratio (M‐H, Random, 95% CI) | Subtotals only | | | 6.4.1 Ulipristal acetate 5 mg | 1 | 143 | Odds Ratio (M‐H, Random, 95% CI) | 41.41 [15.26, 112.38] | | 6.4.2 Ulipristal acetate 10 mg | 1 | 146 | Odds Ratio (M‐H, Random, 95% CI) | 78.83 [24.02, 258.74] | | 6.5 Change in menstrual blood loss from baseline to treatment end | 1 | 22 | Mean Difference (IV, Random, 95% CI) | ‐166.90 [‐277.60, ‐56.20] | | 6.6 Serious adverse events | 4 | Odds Ratio (M‐H, Random, 95% CI) | Subtotals only | | | 6.6.1 Breast cancer | 1 | 241 | Odds Ratio (M‐H, Random, 95% CI) | 0.08 [0.00, 2.04] | | 6.6.2 Uterine haemorrhage | 2 | 274 | Odds Ratio (M‐H, Random, 95% CI) | 0.24 [0.00, 12.70] | | 6.6.3 Ovarian haemorrhage | 1 | 241 | Odds Ratio (M‐H, Random, 95% CI) | 0.76 [0.03, 18.84] | | 6.6.4 Fibroid protruding through cervix | 1 | 241 | Odds Ratio (M‐H, Random, 95% CI) | 0.08 [0.00, 2.04] | | 6.6.5 Menometrorrhagia | 2 | 365 | Odds Ratio (M‐H, Random, 95% CI) | 0.49 [0.02, 11.16] | | 6.6.6 Hyperplasia | 2 | 263 | Odds Ratio (M‐H, Random, 95% CI) | 0.38 [0.02, 8.38] | | 6.7 Other adverse events | 4 | Odds Ratio (M‐H, Random, 95% CI) | Subtotals only | | | 6.7.1 Headache | 4 | 428 | Odds Ratio (M‐H, Random, 95% CI) | 0.63 [0.15, 2.70] | | 6.7.2 Breast pain or tenderness | 3 | 398 | Odds Ratio (M‐H, Random, 95% CI) | 2.37 [0.47, 11.87] | | 6.7.3 Abdominal pain | 4 | 428 | Odds Ratio (M‐H, Random, 95% CI) | 1.99 [0.68, 5.79] | | 6.7.4 Pyrexia | 1 | 241 | Odds Ratio (M‐H, Random, 95% CI) | 0.61 [0.12, 3.25] | | 6.7.5 Hypercholesterolaemia | 1 | 241 | Odds Ratio (M‐H, Random, 95% CI) | 1.25 [0.14, 10.96] | | 6.7.6 Hypothyroidism | 1 | 241 | Odds Ratio (M‐H, Random, 95% CI) | 3.36 [0.19, 60.73] | | 6.7.7 Constipation | 2 | 274 | Odds Ratio (M‐H, Random, 95% CI) | 0.60 [0.13, 2.79] | | 6.7.8 Hypertriglyceridaemia | 1 | 241 | Odds Ratio (M‐H, Random, 95% CI) | 0.99 [0.11, 9.11] | | 6.7.9 Influenza | 1 | 241 | Odds Ratio (M‐H, Random, 95% CI) | 0.99 [0.11, 9.11] | | 6.7.10 Dizziness | 2 | 365 | Odds Ratio (M‐H, Random, 95% CI) | 2.14 [0.33, 13.89] | | 6.7.11 Nasopharyngitis | 2 | 274 | Odds Ratio (M‐H, Random, 95% CI) | 0.45 [0.09, 2.31] | | 6.7.12 Dysmenorrhoea | 1 | 241 | Odds Ratio (M‐H, Random, 95% CI) | 0.05 [0.00, 1.02] | | 6.7.13 Bladder pressure | 1 | 30 | Odds Ratio (M‐H, Random, 95% CI) | 0.33 [0.03, 3.64] | | 6.7.14 Micturition problem | 2 | 63 | Odds Ratio (M‐H, Random, 95% CI) | 1.91 [0.28, 13.23] | | 6.7.15 Lower back pain | 2 | 63 | Odds Ratio (M‐H, Random, 95% CI) | 1.33 [0.29, 6.15] | | 6.7.16 Proctodynia | 1 | 30 | Odds Ratio (M‐H, Random, 95% CI) | 3.67 [0.14, 97.49] | | 6.7.17 Coital pain | 1 | 30 | Odds Ratio (M‐H, Random, 95% CI) | 6.60 [0.29, 150.07] | | 6.7.18 Hot flushes | 1 | 30 | Odds Ratio (M‐H, Random, 95% CI) | 25.24 [1.27, 503.38] | | 6.7.19 Nausea | 3 | 187 | Odds Ratio (M‐H, Random, 95% CI) | 1.99 [0.57, 6.93] | | 6.7.20 Vomiting | 2 | 154 | Odds Ratio (M‐H, Random, 95% CI) | 3.05 [0.12, 76.30] | | 6.7.21 Diarrhoea | 3 | 187 | Odds Ratio (M‐H, Random, 95% CI) | 1.66 [0.26, 10.41] | | 6.7.22 Change of mood | 1 | 30 | Odds Ratio (M‐H, Random, 95% CI) | 15.00 [1.54, 146.54] | | 6.7.23 Lowered libido | 1 | 30 | Odds Ratio (M‐H, Random, 95% CI) | 6.00 [0.58, 61.84] | | 6.7.24 Weakness | 1 | 30 | Odds Ratio (M‐H, Random, 95% CI) | 2.80 [0.43, 18.38] | | 6.7.25 Fatigue | 2 | 154 | Odds Ratio (M‐H, Random, 95% CI) | 1.37 [0.38, 5.02] | | 6.7.26 Dental pain | 1 | 33 | Odds Ratio (M‐H, Random, 95% CI) | 1.35 [0.12, 14.82] | | 6.7.27 Vaginal infections | 2 | 157 | Odds Ratio (M‐H, Random, 95% CI) | 2.72 [0.29, 25.61] | | 6.7.28 Vaginal discharge | 1 | 33 | Odds Ratio (M‐H, Random, 95% CI) | 1.35 [0.12, 14.82] | | 6.8 Quality of life (Uterine Fibroid Symptoms and QoL questionnaire) | 0 | Other data | No numeric data | Characteristics of studies Characteristics of included studies [ordered by study ID] Audebert 1994. | Study characteristics | || | Methods | Non‐blinded, parallel‐group RCT, follow‐up 3 months (treatment group only) Randomisation method not given | | | Participants | Setting: a number of different hospitals in France Sample size Number randomised: 71 Number completed: 47 (24 withdrawals: 6 before treatment, 9 before surgery, 1 immediately after surgery and 8 during follow‐up) Participant (baseline) characteristics Age: premenopausal women aged over 25 years Inclusion criteria: diagnosed with uterine fibroids confirmed by ultrasound scan and awaiting hysterectomy or myomectomy Exclusion criteria: pregnancy, receiving hormone treatment and serious concomitant illnesses | | | Interventions | Intervention group: subcutaneous goserelin 3.6 mg once every month for 3 months followed by hysterectomy (n = 15) or myomectomy (n = 10) Comparator group: immediate surgery (hysterectomy n = 23, myomectomy n = 8) | | | Outcomes | Preoperativeoutcomes: preoperative haemoglobin, preoperative uterine volume (mL), preoperative fibroid volume (mL) Intraoperative outcomes: intraoperative blood loss, difficulty of surgery, duration of surgery (minutes) Postoperative outcomes: duration of hospital stay (days), frequency of blood transfusions, postoperative haemoglobin (g/dL), pelvic symptom score, adverse events | | | Notes | Groups not comparable at baseline (preoperative uterine and fibroid size greater in the immediate surgery group). Hysterectomy and myomectomy were both performed as surgical procedures and intraoperative and postoperative outcomes not reported separately for each type of surgery, so only preoperative outcomes were considered in the review. No power calculation made and no ITT analysis The author was contacted for additional data but no reply was received. No source of funding given | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | “Patients were randomized either to immediate surgery or to treatment” – randomisation method not reported | | Allocation concealment (selection bias) | Unclear risk | No details of allocation concealment reported | | Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Participants were not blinded due to the control group having immediate surgery. It is not stated whether personnel were blinded. | | Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | It is not stated whether personnel were blinded. | | Incomplete outcome data (attrition bias) All outcomes | High risk | 24 of 71 participants withdrew before completion of study. “The results of the study must be viewed in light of these withdrawals”. “The immediate surgery group assessment did not include 7 patients who required intraoperative blood transfusion.” Intention‐to‐treat analysis was not used. | | Selective reporting (reporting bias) | Unclear risk | Protocol not available. Results did not specify numbers included in the results, so the results could not be included in a meta‐analysis. | | Other bias | High risk | Groups not comparable at baseline for pre‐operative uterine and fibroid size. “Although the patients not receiving goserelin were scheduled to immediate surgery, the operation took place at a mean of 76 days after randomization” | Balasch 1995. | Study characteristics | || | Methods | Parallel‐group RCT, ultrasonographer and surgeon blinded Method of randomisation not stated | | | Participants | Setting: single centre in Spain Sample size Number randomised: n = 50 Number completed: n = 50 (no withdrawals reported) Participant (baseline) characteristics Age: women aged 37 to 52 years with uterine fibroids and menorrhagia, pelvic pain or pressure Inclusion criteria: fibroids ≥ 12 weeks gestational size, no suspicion of uterine or ovarian malignancy, endometriosis or pelvic inflammatory disease from clinical or ultrasound examination, stable general condition Exclusion criteria: not stated | | | Interventions | Intervention group: intramuscular decapeptyl 3.75 mg every 4 weeks for 2 injections before hysterectomy (n = 23), duration 8 weeks Comparator group: abdominal hysterectomy within 4 weeks of randomisation (n = 27) | | | Outcomes | Preoperativeoutcomes: preoperative haemoglobin (g/dL), preoperative haematocrit (%), preoperative uterine volume (mL) Intraoperative outcomes: duration of surgery, type of incision Postoperative outcomes: frequency of blood transfusions, duration of hospital stay (days), postoperative complications | | | Notes | Groups not comparable at baseline (measurements of uterine volume and pretreatment haemoglobin and haematocrit lower in the treatment than in the control group) No power calculation made No source of funding reported Author contacted for additional data but no reply received | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | “The patients were randomised to pre‐operative gonadotropin releasing hormone agonist treatment or to immediate hysterectomy”. Did not state allocation method | | Allocation concealment (selection bias) | Unclear risk | No details were reported. | | Blinding of participants and personnel (performance bias) All outcomes | Low risk | “All ultrasonic measurements of fibroid dimensions were performed by the same blinded ultrasonographer”. “The operations were performed by a staff specialist and a senior gynaecology resident who were blinded as to the treatment groups.” No information was provided regarding participants being blinded to treatment allocation. | | Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | No details relating to outcome assessment were available. | | Incomplete outcome data (attrition bias) All outcomes | Low risk | No missing data; no participants withdrew from the study. | | Selective reporting (reporting bias) | Low risk | All prespecified and expected outcomes of interest were reported. | | Other bias | Unclear risk | Pretreatment uterine volume and haemoglobin/haematocrit between comparison groups were not comparable at baseline. | Baytur 2007. | Study characteristics | || | Methods | Apparently non‐blinded, parallel‐group RCT Randomisation method not reported | | | Participants | Setting: single centre in Turkey Sample size Number randomised: n = 32 Number completed: n = 32 (6 and 5 women in each group did not proceed to surgery but outcomes measured preoperatively) Participant (baseline) characteristics Age: mean ages 46.6 years and 45.2 years Inclusion criteria: healthy premenopausal women with regular cycles (ranging from 25 to 35 days); mild fibroid symptoms such as anaemia, pain or pressure symptoms Exclusion criteria: women requiring emergency surgery due to severe fibroid symptoms and disorders such as anaemia (Hb < 10 mg/dL), pain, dysmenorrhoea, menstrual bleeding and osteoporosis, severe vasomotor symptoms, blood coagulation diseases, history or family history of vascular thrombosis, suspicion of systemic neoplastic and infectious disease, suspicion of uterine malignancies, endometrial abnormalities detected by Pipelle endometrial biopsy and transvaginal ultrasound | | | Interventions | Intervention group: GnRHa (goserelin) depot 3.6 mg by monthly subcutaneous injections for 3 cycles starting within the first 5 days of the cycle (n = 16) Comparator group: raloxifene (Evista) 60 mg/day PO for 3 cycles starting within the first 5 days of the cycle (n = 16) Interventions were compared with a control group (age matched but not randomised) but this group has not been included in comparisons in this review. | | | Outcomes | Preoperativeoutcomes: change in fibroid volume between randomised groups, adverse effects The other outcomes measured were not included in this review. | | | Notes | Power calculation for sample size calculated; 16 participants per group to detect a difference of 25 cm³ in 3 months fibroid volume chance between groups Source of funding not reported | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | Method of randomisation not reported | | Allocation concealment (selection bias) | Low risk | Closed envelopes | | Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Blinding unlikely | | Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not reported | | Incomplete outcome data (attrition bias) All outcomes | Low risk | No dropouts before surgery ‐ outcomes measured before surgery (substantial attrition from both groups for surgery). | | Selective reporting (reporting bias) | Low risk | All prespecified outcomes reported | | Other bias | Low risk | Groups appeared comparable at baseline | Benagiano 1996. | Study characteristics | || | Methods | Double‐blinded, parallel‐group RCT Randomisation scheme controlled by Zeneca and women allocated sequentially as they entered the study | | | Participants | Setting: multicentre (Denmark, the Netherlands, Spain, Finland, Norway, Scotland, Portugal, Northern Ireland, Italy) Sample size Number randomised: n = 185 Number completed: n = 168 (withdrawals n = 17: 2 refused treatment, 10 during treatment and 5 at the end of the study) Participant (baseline) characteristics Age: premenopausal women aged over 25 years Inclusion criteria: women with menorrhagia or metrorrhagia and anaemia associated with uterine fibroids and awaiting hysterectomy; fibroids confirmed from manual exam, haemoglobin < 12 g/dL, negative cervical smear within previous 12 months, informed consent Exclusion criteria: serious renal, hepatic, haemopoietic or endocrine disorders other than anaemia due to fibroids, history of drug and/or alcohol abuse within the previous year, gynaecological malignancy, sex hormone therapy within the past month or GnRHa treatment within the past 6 months, blood transfusions within the previous 3 months or other therapy affecting menstrual loss, sensitivity to GnRHa or iron replacement, any medical condition that would render the woman unsuitable | | | Interventions | Intervention group a: goserelin acetate depot 3.6 mg once monthly + iron 600 mg/day before hysterectomy, n = 55 (ITT not performed) Intervention group b: goserelin acetate depot 3.6 mg once monthly + placebo iron, n = 54 Comparator group: sham injection once monthly + iron 600 mg/day before hysterectomy, n = 59 Duration: 3 months | | | Outcomes | Preoperativeoutcomes: preoperative haemoglobin (g/dL), preoperative haematocrit (%), preoperative uterine volume (mL), preoperative fibroid volume (mL), pelvic symptoms, adverse events Intraoperative outcomes: intraoperative blood loss (mL), difficulty of surgery, duration of surgery (minutes), Postoperative outcomes: frequency of blood transfusions | | | Notes | Groups comparable at baseline for age, weight and height but differences in fibroid volumes, uterine volumes and haemoglobin concentrations Author contacted for additional information but no reply received The outcomes with suitable data considered in the review were duration and difficulty of surgery, transfusion rate and withdrawal because of adverse effects. For all other outcomes, data were not suitable. The second treatment group was not considered in the review because the control group was not comparable. Power calculation made for sample size and ITT analysis Source of funding: Zeneca Pharmaceuticals (UK). Zeneca Pharmaceuticals produced the randomisation scheme (pharmaceutical company producing Zoladex). | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | “A separate randomization scheme was produced for each centre by the Biometrics group, Zeneca Pharmaceuticals and patients were randomised in a ratio of 1:1:1…strictly sequentially as patients entered the study”. Unclear as to whether quasi‐random | | Allocation concealment (selection bias) | Low risk | Central control of allocation | | Blinding of participants and personnel (performance bias) All outcomes | Low risk | “The study was a… double‐blind comparison”. Sham injection given to control group | | Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | No details reported on blinding of assessment | | Incomplete outcome data (attrition bias) All outcomes | Low risk | “All analyses were performed on an intention‐to‐treat basis”. 185 participants were recruited; 17 withdrew with reasons given. | | Selective reporting (reporting bias) | High risk | The outcomes with suitable data considered in the review were duration and difficulty of surgery, transfusion rate and withdrawal because of adverse effects. For all other outcomes, the results were reported incompletely only as P values. | | Other bias | Unclear risk | Difference in baseline values for fibroid and uterine volumes between groups | Bian 2021. | Study characteristics | || | Methods | Double‐blind, parallel‐group RCT | | | Participants | Setting: multicentre in China Sample size Number randomised: n = 132 Number completed: n = 124 Participant (baseline) characteristics Age: not stated Inclusion criteria: symptomatic uterine fibroids confirmed by ultrasound scan and awaiting hysterectomy or myomectomy Exclusion criteria: postmenopausal women, simple submucosal uterine fibroids, highly suspicious uterine fibroids with malignant transformation or endometrial malignant lesions, combined with appendages or obvious intrauterine fibroids, membrane ectopic disease where coagulation dysfunction result in bleeding tendency, severe anaemia (haemoglobin < 60 g/L), suspected pregnancy or breastfeeding, hepatic and renal dysfunction, those who have a history of mifepristone treatment within 3 months | | | Interventions | Intervention group: 10 mg mifepristone for 84 days, n = 66 Comparator group: placebo, n = 66 Duration of treatment: 3 months | | | Outcomes | Preoperative outcomes: reduction in uterine volume or fibroid volume or both (as reported in the primary study); preoperative haemoglobin; preoperative bleeding (only if measured by a validated scale, e.g. 10‐point VAS); adverse events; quality of life Operative difficulties and postoperative outcomes: duration of surgery; intraoperative blood loss; frequency of blood transfusions; postoperative morbidity (complications such as pyrexia, haematoma formation and incidence of postoperative adhesions); difficulty of surgery (assessed subjectively by surgeon); proportion of women undergoing vaginal hysterectomy (in women undergoing hysterectomy); type of abdominal incision (Pfannenstiel transverse versus vertical); duration of hospital stay (days); intraoperative hysterectomy (for women undergoing myomectomy); frequency of postoperative recurrence of myomas; postoperative haemoglobin | | | Notes | Text in Chinese. Data extracted with help from native Chinese speaker | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | Not described | | Allocation concealment (selection bias) | Low risk | Random number code controlled by outside statistician | | Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Blinding not described but placebo‐controlled | | Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Blinding of outcome assessment not described but placebo‐controlled | | Incomplete outcome data (attrition bias) All outcomes | Low risk | 20 of 132 participants lost to follow‐up | | Selective reporting (reporting bias) | Unclear risk | Not all outcomes reported | | Other bias | Low risk | Low risk of bias according to Chinese translation | Bustos López 1995. | Study characteristics | || | Methods | Single‐centre, parallel‐group, double‐blind (investigator and assessor, not participants) RCT Randomisation method not stated | | | Participants | Setting: single centre in Mexico City Sample size Number randomised: n = 28 Number completed: n = 28 Participant (baseline) characteristics Age: women aged up to 40 years Inclusion criteria: diagnosis of uterine fibroids confirmed by clinical examination, ultrasonography and/or laparoscopy and with a desire to preserve their fertility; informed consent, normal endometrial biopsy and cervical cytology Exclusion criteria: women with intolerable side effects, desire to discontinue the study, suspicion of malignancy | | | Interventions | Intervention group: nafarelin intranasal spray 200 µg twice daily before myomectomy, n = 13 Comparator group: no preoperative treatment before myomectomy, n = 15 Duration: 3 months | | | Outcomes | Preoperativeoutcomes: preoperative uterine volume (cc), preoperative myoma volume (cc), preoperative haemoglobin (g/dL) Intraoperative outcomes: type of incision, intraoperative blood loss (mL) | | | Notes | Authors contacted but no reply received Paper translated by Christine Aguilar Some of the calculations with the raw data did not match the means reported in the tables. No power calculation performed Source of funding: Syntex | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | Participants randomised to 2 groups ‐ method of randomisation was not reported. | | Allocation concealment (selection bias) | Unclear risk | Not reported | | Blinding of participants and personnel (performance bias) All outcomes | Low risk | Investigators were blinded but participants were not blinded ‐ but the outcomes could not be influenced by the participants' knowledge of group assignment. | | Blinding of outcome assessment (detection bias) All outcomes | Low risk | Assessors blinded | | Incomplete outcome data (attrition bias) All outcomes | Low risk | There did not appear to be any dropouts from the study. | | Selective reporting (reporting bias) | High risk | The outcomes were measured in the intervention group at baseline, 30, 60 and 90 days but were only measured in the control group at baseline so a true comparison between groups could not be made. Postsurgical complication rates were not clearly reported. | | Other bias | Unclear risk | There appear to be differences between groups at baseline. | Cagnacci 1994. | Study characteristics | || | Methods | Single‐centre, unblinded, parallel‐group RCT | | | Participants | Setting: single centre in Italy Sample size Number randomised: n = 20 Number completed: n = 20 Participant (baseline) characteristics Age: premenopausal women aged 30 to 49 years Inclusion criteria: in good health and with ultrasound evidence of uterine fibroids awaiting hysterectomy or myomectomy, voluntary informed consent Exclusion criteria: abnormal pap test, uterine cancer, alterations of coagulation, glucose or lipid metabolism and liver or kidney disease | | | Interventions | Intervention group: goserelin depot 3.6 mg every 28 days before surgery, n = 10 Comparator group: no treatment before surgery (type not specified by authors), n = 10 Duration: 3 months | | | Outcomes | Preoperativeoutcomes: uterine volume (cc), fibroid volume (cc), preoperative haematocrit (%) Intraoperative outcomes: blood loss (mL) (data for this outcome not entered in review) | | | Notes | Authors contacted for additional information and reply received Groups not comparable at baseline (uterine and fibroid volume higher in controls) Type of surgery not reported No power calculation reported No source of funding reported No withdrawals | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | High risk | “Administered for 6 months to 22 subjects, and for 12 months to 8 subjects. The other 20 subjects… were randomly allocated for 3 months to no treatment or goserelin depot administration.” 20 women were randomised, the other 30 women were in groups of 22 and 8, and it is unclear whether they were randomised. The method of randomisation was not reported. | | Allocation concealment (selection bias) | Unclear risk | Not reported | | Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Participants were not blinded. Unclear whether personnel were blinded | | Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | None reported | | Incomplete outcome data (attrition bias) All outcomes | Unclear risk | No withdrawals from the study were mentioned, but final numbers were not reported in results. | | Selective reporting (reporting bias) | High risk | Data were not reported for the 20 women randomised who required surgery. Adverse events were not reported. | | Other bias | Unclear risk | Baseline variables between groups not reported | Campo 1999. | Study characteristics | || | Methods | Non‐blinded, parallel‐group RCT Randomisation according to a computer‐generated sequence but no description of attempts to conceal allocation and no blinding | | | Participants | Setting: single centre in Italy Sample size Number randomised: n = 30 Number completed: n = 30 Participant (baseline) characteristics Age: premenopausal women aged 25 to 42 years Inclusion criteria: presence of symptomatic subserosal or intramural myomas, presence of uterine myomas as the only plausible explanation for a history of recurrent abortion or infertility, diagnosis by transvaginal sonography indicated by fibroid symptoms, selected for laparoscopic myomectomy indicated by fibroid symptoms Exclusion criteria: submucous myomas; myomas > 10 cm in diameter; women with more than 3 myomas > 4 cm in diameter | | | Interventions | Intervention group: decapeptyl 3.75 mg intramuscularly every 28 days for 3 months before surgery, n = 30 Comparator group: no preoperative treatment before surgery, n = 30 Duration: 3 months | | | Outcomes | Intraoperative outcomes: intraoperative blood loss (mL), duration of surgery (minutes) Postoperative outcomes: duration of hospital stay (days), frequency of blood transfusions, postoperative complications, fertility rate (number of pregnancies) | | | Notes | No power calculation reported No source of funding reported | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | “Patients included in the present series were randomized according to a computer‐generated sequence.” | | Allocation concealment (selection bias) | Unclear risk | No details regarding allocation concealment were provided. | | Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Participants were not blinded, as they either received immediate surgery or treatment and delayed surgery. It is not stated whether personnel were blinded. | | Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | No details were provided. | | Incomplete outcome data (attrition bias) All outcomes | Low risk | All women were followed‐up for a minimum 6 months. No missing data | | Selective reporting (reporting bias) | Low risk | Outcomes of interest were reported. | | Other bias | Unclear risk | No details provided of baseline variables between groups | Cetin 1995. | Study characteristics | || | Methods | Non‐blinded, parallel‐group RCT Randomisation method not specified | | | Participants | Setting: single centre in Turkey Sample size Number randomised: n = 30 Number completed: n = 30 Participant (baseline) characteristics Age: not stated Inclusion criteria: women diagnosed with uterine fibroids confirmed by pelvic, abdominal and ultrasonographic examination and awaiting hysterectomy or myomectomy Exclusion criteria: no other pathology Main symptoms were infertility in 14 women and menorrhagia in 6 women. | | | Interventions | Intervention group: buserelin intranasally 900 μg/day in 3 doses for 3 months, n = 15 Comparator group: no preoperative treatment, n = 15 Duration: 3 months | | | Outcomes | Preoperativeoutcomes: volume of myomas (cm³), preoperative haemoglobin (g/dL) Intraoperative outcomes: intraoperative blood loss (mL), duration of surgery (minutes), side effects | | | Notes | The principal review author noted an error in the published paper, which was confirmed by the principal study author. The authors were contacted for additional information on side effects rates but reply has not yet been received. No power calculation reported No source of funding reported | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | “Subjects were randomly divided into two groups”. “Prospective, randomised, controlled study”. Method of randomisation not stated | | Allocation concealment (selection bias) | Unclear risk | Not reported | | Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | No blinding of participants. Most likely no blinding of personnel | | Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | “Ultrasonographic examinations were performed by the same sonographers in all cases”. “All of the myomectomies were performed by the same surgeons”. Did not state whether these personnel were blinded | | Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Numbers included in analysis not stated in results. It appears there were no withdrawals from the study but this is unclear. | | Selective reporting (reporting bias) | Unclear risk | Mistake was acknowledged in paper by author via past contact. Assuming is related to lack of referenced tables in text. | | Other bias | Unclear risk | Unclear if baseline variables comparable between groups | D'Anna 1994. | Study characteristics | || | Methods | Apparently non‐blinded, parallel‐group RCT Randomisation method not stated | | | Participants | Setting: single centre in Messina, Italy Sample size: Number randomised: n = 30 Number completed: n = 30 Participant (baseline) characteristics: Age: premenopausal women aged 36 to 50 years Inclusion criteria: diagnosed with uterine fibroids with an average diameter of 3 cm and awaiting hysterectomy Exclusion criteria: none reported | | | Interventions | Intervention group: leuprolide acetate depot 3.75 mg monthly before hysterectomy, n = 15 Comparator group: placebo monthly before hysterectomy, n = 15 Duration: 2 months | | | Outcomes | Preoperativeoutcomes: preoperative uterine volume (cc), adverse events (no control data provided so this outcome was not considered in the review) | | | Notes | Paper translated by Kirsten Duckitt Groups not comparable at baseline (uterine volume higher in treatment group compared to control group) No power calculation made No source of funding reported No withdrawals reported | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | “In a randomised manner”. Randomisation method not stated | | Allocation concealment (selection bias) | Unclear risk | No allocation concealment reported | | Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | A placebo was used to blind participants; no detail was provided as to what the placebo was. | | Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | No details were reported. | | Incomplete outcome data (attrition bias) All outcomes | High risk | 12 dropouts. Adverse events reported with treatment were not compared to adverse events reported with placebo. | | Selective reporting (reporting bias) | Low risk | No protocol viewed but all outcomes reported in the methods section were reported in the results section. | | Other bias | Unclear risk | It is not reported whether or not the difference between the groups of uterine volume pretreatment is statistically significant. | De Falco 2009. | Study characteristics | || | Methods | Parallel‐group RCT Sequential numerical allocation to a randomisation list | | | Participants | Setting: single centre in Italy Sample size Number randomised: n = 62 Number completed: n = 62 (ITT not mentioned but all participants included in analysis) Participant (baseline) characteristics: Age: not stated Inclusion criteria: premenopausal women with single intramural symptomatic uterine leiomyoma Exclusion criteria: taking hormonal therapy, delivered within 12 months of the study, or had malignant neoplasm, or previous pelvic surgery, uterine malformations, present or past pelvic inflammatory disease, coagulation disorders and unstable general conditions | | | Interventions | Intervention group: 33 women received 3.75 mg triptorelin subcutaneous depot injection, once a month for 3 months, surgery carried out at the latest 3 weeks after third injection Comparator group: 29 women underwent immediate surgery during follicular phase of the menstrual cycle Duration: 3 months for treatment group | | | Outcomes | Preoperativeoutcomes: fibroid diameter Intraoperative outcomes: intraoperative blood loss, duration of surgery (minutes) Postoperative outcomes: clear identification of cleavage plane, PCNA expression, CD34 expression | | | Notes | Power calculation and source of funding not mentioned | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | "...patients were randomised using a sequential numerical allocation to a randomisation list prepared before commencing the study" | | Allocation concealment (selection bias) | Unclear risk | Method of allocation concealment not stated | | Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Control group participants did not receive a placebo injection, and thus participants were aware of study allocation. “Surgeons were blinded to the pre‐surgical medical treatment.” | | Blinding of outcome assessment (detection bias) All outcomes | Low risk | "Surgeons were blinded to the pre‐surgical medical treatment." “Sections were examined and immunostaining was graded without previous knowledge of the clinical data of the patients.” | | Incomplete outcome data (attrition bias) All outcomes | Low risk | No mention of ITT analysis. Authors did not state whether all participants included in the analyses, but it appears there were no dropouts because of the percentages quoted for dichotomous outcomes. | | Selective reporting (reporting bias) | Low risk | Protocol not viewed. All outcomes described in methods were reported in results section. | | Other bias | Low risk | In addition to participants enrolled in the study, 20 samples obtained retrospectively were randomly selected from the Pathology Unit database. It was not specified how these samples were randomly selected, or whether these samples were demographically similar to the women enrolled in the study; however, the outcome evaluated was not relevant to this review. Randomised groups appeared similar at baseline. | De Milliano 2020. | Study characteristics | || | Methods | Double‐blind, parallel‐group RCT Computer‐generated randomisation sequences stratified per centre | | | Participants | Setting: multicentre (9 centres, Netherlands) Sample size Number randomised: n = 55 Number completed: n = 49 - Number withdrawn/dropped out: UPA: 4/30 (1 did not meet inclusion criteria and no follow‐up, 1 withdrew informed consent directly after allocation, 1 underwent abdominal hysterectomy due to persistent abdominal pain, 1 refused surgery) LA: 2/25 (1 refused surgery, 1 had reduction in fibroid to < 1.5 cm) Participant (baseline) characteristics Age: 38.4 ± 5.8 vs 41.4 ± 5.6 Inclusion criteria: premenopausal women with symptomatic fibroids and eligible for laparoscopic myomectomy; resection of maximum of 2 FIGO type 3, 4, 5, 6, fibroids OR 2‐5 fibroids with diameter of 5‐12 cm Exclusion criteria: pregnant, had a suspicion of malignancy, used hormonal agents and not willing to discontinue use, used anticoagulants, used NSAIDs impacting bleeding before surgery, had contraindication to laparoscopy, had allergy to leuprolide acetate or ulipristal acetate, had coagulopathy, had any type 0 to 2 fibroids smaller than 5 cm, had more than 2 type 3 to 6 fibroids > 5 cm that needed to be removed (except type 7 fibroids of any size) | | | Interventions | Intervention group: ulipristal acetate 5 mg tablets, once daily for 3 months + 1 monthly saline injection, n = 30 Comparator group: GnRHa ‐ intramuscular leuprolide acetate depot 11, 25 mg monthly, for 3 months + 1 placebo tablet daily for 3 months, n = 25 Duration: 3 months | | | Outcomes | Preoperativeoutcomes: preoperative haemoglobin, preoperative uterine volume (mL), preoperative fibroid volume (mL) Intraoperative outcomes: intraoperative blood loss, difficulty of surgery, duration of surgery (minutes) Postoperative outcomes: postoperative haemoglobin, conversion rate to laparotomy, complication rate, re‐intervention rate, duration of surgery, surgical ease, quality of life | | | Notes | Contact: [email protected]. Contacted the contact author and details of the trial from the register were confirmed: NCT02288130 Modified ITT (only those who had pretreatment and surgery) Power calculation: based on the hypothesis that UPA was non‐inferior to LA with a maximum difference of 150 mL of blood loss during surgery. Required a sample size of 90 women (45 in each group), not achieved Source of founding: PregLem (pharmaceutical company), developer of UPA | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | Computer‐generated randomisation system and stratified by centre | | Allocation concealment (selection bias) | Low risk | “Participants and gynecologists were blinded to treatment allocation during the entire study period.” | | Blinding of participants and personnel (performance bias) All outcomes | Low risk | “Study materials and medication packaging were identical for both groups.” | | Blinding of outcome assessment (detection bias) All outcomes | Low risk | "An independent statistician blinded to the allocated study groups...” | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Dropouts were > 10% but were balanced between groups and reasons given. It is unlikely that their missing data would influence the study estimates. | | Selective reporting (reporting bias) | Low risk | All prespecified primary and secondary outcomes reported | | Other bias | Unclear risk | Most demographic variables were similar at baseline between groups other than that the mean diameter of the largest fibroid was significantly greater in the UPA group. | Donnez 2003. | Study characteristics | || | Methods | Parallel‐group RCT Women were randomised to one of five groups on a 1:1:1:1:1 basis with 50 participants per group. Placebo group was subrandomised to each of the four placebo arms. Overall randomisation 4:4:4:4:1:1:1:1:1 Due to nature of injections, both medical personnel and participant could not be blinded to the two different (GnRHa and fulvestrant) injections, but they were blinded to whether it was placebo or active. | | | Participants | Setting: multicentre (Belgium, Spain, Czech Republic, France) Sample size Number randomised: n = 313 Number completed: n = 301 (withdrawals: 4 from fulvestrant 50 mg, 3 from fulvestrant 125 mg, 1 from 250 mg and 4 from goserelin groups) Participant (baseline) characteristics Age: premenopausal women mean age 44 years Inclusion criteria: premenopausal women with measurable fibroids that required hysterectomy, not involved in night shift work, prepared to use barrier contraception for the study period and could provide signed informed consent Exclusion criteria: used GnRHa in the past for > 3 months or had finished the same treatment within 3 months of study entry, used sex hormone therapy, oral contraceptives or danazol within 4 weeks of study entry, had disease affecting bone or steroid metabolism, had changes in menstrual frequency or any changes reflecting the onset of menopause | | | Interventions | Intervention group a: fulvestrant 50 mg IM injection once every 4 weeks for 3 injections, n = 59 Intervention group b: fulvestrant 125 mg IM injection once every 4 weeks for 3 injections, n = 66 Intervention group c: fulvestrant 250 mg IM injection once every 4 weeks for 3 injections, n = 62 Intervention group d: goserelin 3.6 mg SC every 4 weeks for 3 injections, n = 66 Comparator group: each of the groups had a placebo group which received fulvestrant matched placebo or sham goserelin, n = 60 | | | Outcomes | Preoperativeoutcomes: endometrial thickness, fibroid volume, bone resorption index, uterine volume, ovarian stimulation, preoperative haemoglobin, preoperative uterine volume (mL), preoperative fibroid volume (mL) Intraoperative outcomes: intraoperative blood loss, difficulty of surgery, duration of surgery (minutes) Postoperative outcomes: duration of hospital stay (days), frequency of blood transfusions, postoperative haemoglobin (g/dL), pelvic symptom score, adverse events, changes in endometrial histology (endometrial biopsy), change in the levels of sex hormones (oestradiol, FSH and LH, SHBG), biochemical (lipoproteins, antithrombin III), vaginal blood loss, adverse effects | | | Notes | Intraoperative outcomes not assessed Haematocrit values assessed at baseline only and not as outcome No blinding as regards to fulvestrant and GnRHa, but that should not be considered significant as all outcomes except vaginal blood loss were objective. Power calculation done Supported by Astra Zeneca ITT analysis was done but not presented. The per‐protocol analyses had substantial withdrawals for most outcomes. | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | "The treatment received by individual patients was determined centrally, with separate schemes produced for each center." | | Allocation concealment (selection bias) | Low risk | Central allocation to treatment | | Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Participants and medical personnel were aware of allocation to fulvestrant or goserelin arm of the trial, but could not distinguish between active drug and placebo. “Because of the differences in the nature of injections, both patients and medical personnel could distinguish between the two medications and, because of the differences in volumes, between the doses of fulvestrant being given. However, it was impossible to distinguish between active agent and placebo (sham) for any of the treatments.” However, most outcomes were objective and unlikely to be influenced by knowledge of treatment. | | Blinding of outcome assessment (detection bias) All outcomes | High risk | Medical personnel were aware of drug assignment (fulvestrant or goserelin) but were not aware of placebo vs active drug. | | Incomplete outcome data (attrition bias) All outcomes | High risk | Methods section states that both ITT analysis and per‐protocol analysis carried out; however, ITT data not provided in study and the data from per protocol analyses suggested significant attrition. | | Selective reporting (reporting bias) | Low risk | Protocol not viewed. All outcomes from methods section of paper were reported in the results section. | | Other bias | Low risk | Baseline variables similar between groups | Donnez 2012a. | Study characteristics | || | Methods | Double‐blind, parallel‐group RCT | | | Participants | Setting: multicentre: 38 academic centres in Belgium, Ukraine, France, Romania, Hungary, Czech Republic, Switzerland, UK Sample size Number randomised: n = 242 Number completed: n = 241 (modified ITT) but per‐protocol analyses also undertaken; 1 withdrawal in the 5 mg ulipristal acetate group before she received the study drug Participant (baseline) characteristics Age: women aged 18 to 50 years Inclusion criteria: PBAC > 100 during days 1 to 8 of menstruation, fibroid related anaemia (Hb ≤ 10.2 g/dL without macrocytosis, fibroid uterus with a size equivalent to a uterus of 16 weeks or less of gestation, at least 1 fibroid ≥ 3.cm in diameter but with no fibroid measuring more than 10.cm in diameter (US), BMI 18 to 40 kg/m² Exclusion criteria: history of uterine surgery, endometrial ablation or uterine artery embolisation, history of current gynaecological cancer, current endometrial hyperplasia, Hb ≤ 6 g/dL or any condition requiring immediate blood transfusion, known haemoglobinopathy, known severe coagulation disorder, large uterine polyp (> 2 cm), one or more ovarian cysts ≥ 4 cm in diameter (U/S), previous or current treatment for fibroids with an SPRM or a GnRHa, treatment with agents known to affect hepatic cytochrome CYP3A4, progestins, acetylsalicylic acid, mefenamic acid, anticoagulants, antifibrinolytic drugs or systemic glucocorticoid treatments | | | Interventions | Intervention group: ulipristal acetate orally once per day 5 mg (n = 96) or 10 mg (n = 98) Comparator group: placebo (identical pill) orally once per day, n = 48 Duration: 13 weeks of treatment (before surgery) with follow‐up at weeks 17, 26 and 38 | | | Outcomes | Preoperativeoutcomes: proportion of participants who had a reduction in uterine bleeding at week 13 (PBAC < 75), change in total fibroid volume from screening to week 13 (MRI), bleeding pattern (PBAC), reduction in fibroid and uterine volume, change in haemoglobin, pain (measured by Short Form McGill Pain Questionnaire), quality of life (measured by questionnaire measuring discomfort from fibroids), adverse effects, preoperative haemoglobin, preoperative uterine volume (mL), preoperative fibroid volume (mL) Intraoperative outcomes: intraoperative blood loss, difficulty of surgery, duration of surgery (minutes) Postoperative outcomes: duration of hospital stay (days), frequency of blood transfusions, postoperative haemoglobin (g/dL), pelvic symptom score, adverse events | | | Notes | Protocol and supplementary data were available. Power calculation performed for sample size: based on the endpoint of change in fibroid volume Source of funding: PregLem (data handled by independent data management organisation) | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | "Computer generated list" | | Allocation concealment (selection bias) | Low risk | "Web integrated interactive voice system" under central control | | Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical treatments; placebo‐controlled study | | Blinding of outcome assessment (detection bias) All outcomes | Low risk | Assessors were not aware of participant allocation. | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Modified ITT analysis (1 participant excluded, withdrawn before taking medication) | | Selective reporting (reporting bias) | Low risk | Protocol viewed and all predetermined outcomes reported in full | | Other bias | Low risk | Participant groups comparable at baseline | Donnez 2012b. | Study characteristics | || | Methods | Double‐blind, parallel‐group RCT | | | Participants | Setting: multi‐centre: in Belgium, Poland, Spain, Ukraine, France, Romania, Hungary, Czech Republic, Switzerland, UK Sample size: Number randomised: n = 307 Number completed: n = 301 (for safety), n = 297 for modified ITT analysis and n = 281 for per protocol analyses; withdrawals: 1 in ulipristal acetate 5 mg group (did not receive study drug), 2 in ulipristal acetate 10 mg group (did not receive study drug, missing efficacy data), 2 in LA group (missing efficacy data) Participant (baseline) characteristics: Age: women aged 18 to 50 years Inclusion criteria: premenopausal women aged 18 to 50 years, BMI between 18 and 40, heavy uterine bleeding caused by fibroids, at least one fibroid measuring 3 cm or more in diameter (no fibroid measuring > 10 cm), uterine size equivalent to a pregnancy of no more than 18 weeks in gestation; eligible for surgery Exclusion criteria: history of uterine surgery, endometrial ablation or uterine artery embolisation, history of current gynaecological cancer, current endometrial hyperplasia, Hb ≤ 6 g/dL or any condition requiring immediate blood transfusion, known haemoglobinopathy, known severe coagulation disorder, large uterine polyp (> 2 cm), one or more ovarian cysts ≥ 4 cm in diameter (U/S), previous or current treatment for fibroids with an SPRM or a GnRHa, treatment with agents known to affect hepatic cytochrome CYP3A4, progestins, acetylsalicylic acid, mefenamic acid, anticoagulants, antifibrinolytic drugs or systemic glucocorticoid treatments | | | Interventions | Intervention group: ulipristal acetate (SPRM) orally once per day plus intramuscular saline injection once monthly, 5 mg (n = 98) or 10 mg (n = 9104) Comparator group: daily oral placebo + intramuscular injection of 3.75 mg leuprolide acetate (GnRHa) once monthly, n = 101 Duration: 13 weeks (before surgery) with follow‐up at weeks 17, 26 and 38 Iron supplementation could be used at the discretion of the physician. | | | Outcomes | Preoperativeoutcomes: proportion of participants who had a reduction in uterine bleeding at week 13 (PBAC < 75), adverse events, bleeding pattern (PBAC), amenorrhoea, changes from baseline in uterine and fibroid volume, global pain score, uterine fibroid symptom and quality of life questionnaire scores, Hb levels | | | Notes | Non‐inferiority trial ‐ PEARL II Power calculation for sample size (based on non‐inferiority of LA with ulipristal acetate) Source of funding: PregLem (supplied ulipristal acetate) | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | Computer‐generated | | Allocation concealment (selection bias) | Low risk | Web integrated voice system under central control | | Blinding of participants and personnel (performance bias) All outcomes | Low risk | Double‐blind, double‐dummy trial with uterine volume assessed by ultrasound at each centre | | Blinding of outcome assessment (detection bias) All outcomes | Low risk | Biopsy samples were assessed by 3 independent pathologists who were unaware of the study group assignments, the visit sequence and each other's assessment. | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Modified ITT ‐ did not include 5 participants (2 participants (one in each ulipristal acetate group) who did not receive the study drug and were not followed, and 3 participants (1 who was assigned to receive ulipristal acetate 10 mg and 2 in the LA group) with missing efficacy data after baseline. Per protocol analysis also performed (modified ITT population with the exclusion of women with major protocol deviations and a compliance rate of < 80%) | | Selective reporting (reporting bias) | Low risk | Protocol published and viewed ‐ all outcomes reported | | Other bias | Low risk | Groups comparable at baseline | Engman 2009. | Study characteristics | || | Methods | Parallel‐group RCT | | | Participants | Setting: single‐centre, Karolinska University Hospital, Stockholm, Sweden Sample size Number randomised: n = 30 Number completed: n = 28 (2 withdrawals from placebo group) Participant (baseline) characteristics Age: non‐pregnant women with mean age 41 years Inclusion criteria: healthy non‐pregnant women referred for evaluation to outpatient clinic due to fibroid related problems indicating surgical intervention Exclusion criteria: steroid hormonal therapy for a minimum of 3 months before recruitment, any history of breast cancer or other malignancy, uncontrollable bleeding requiring urgent surgical treatment, abnormal mammogram or breast biopsy at baseline, adnexal abnormality or suspicion of leiomyosarcoma upon TVUS, abnormal FSH and LH levels or any other hormonal dysfunction of clinical significance, lab findings that would give suspicion of blood, liver or renal dysfunction, abnormal Pap smear at screening, any other contraindication to mifepristone | | | Interventions | Intervention group: mifepristone 50 mg every other day, n = 14 Comparator group: placebo ‐ identical tablets of B vitamin, n = 16 Duration of treatment: 3 months (ended the day before surgery) | | | Outcomes | Preoperativeoutcomes: reduction in uterine fibroid size, number of bleeding days, endometrial assessment (from biopsy), symptom scores | | | Notes | Power calculation for sample size (at least 10% in % fibroid volume change between groups) Source of funding: Swedish Research Council, Karolinska Institute and Stockholm City | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | Computer‐generated randomisation method | | Allocation concealment (selection bias) | Low risk | Central control from pharmacy | | Blinding of participants and personnel (performance bias) All outcomes | Low risk | Described as double‐blind | | Blinding of outcome assessment (detection bias) All outcomes | Low risk | Assumed that assessors were the same as study staff | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Attrition 12% from placebo group (reasons unrelated to intervention) | | Selective reporting (reporting bias) | Low risk | All prespecified outcomes reported | | Other bias | Low risk | Groups were generally comparable at baseline. | Favilli 2017. | Study characteristics | || | Methods | Single‐blind, parallel‐group RCT | | | Participants | Setting: single centre in Rome, Italy Sample size Number randomised: n = 99 Number completed: n = 84 (7 in intervention group and 8 in control group did not receive the allocated intervention) Participant (baseline) characteristics Age: women with mean age 40 years Inclusion criteria: at least 1 suspected submucous myoma on ultrasound Exclusion criteria: women with multiple myomas, endometrial polyps, scheduled combined surgical procedures (hysteroscopy with laparoscopy), a present or past history of cancer, ongoing pregnancy, and a postmenopausal status | | | Interventions | Intervention group: GnRHa: 3 injections of triptorelin 3.75 mg given 28 days apart followed by cold loop hysteroscopic myomectomy within 4 weeks of last injection, n = 44 Comparator group: operative hysteroscopy (myomectomy) between the 7th and 12th day of menstrual cycle, n = 50 | | | Outcomes | Intraoperative outcomes: intraoperative complications, duration of procedure Postoperative outcomes: success of 1‐step procedure (surgery accomplished In 1 step), intrauterine adhesions as a result of surgery by hysteroscopic assessment after 1 month of follow‐up | | | Notes | Trial register record NCT01873378 | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | Pregenerated randomisation scheme used to allocate patients to 2 groups | | Allocation concealment (selection bias) | Low risk | “a sealed opaque envelope” opened by statistical consultant | | Blinding of participants and personnel (performance bias) All outcomes | High risk | Participants unlikely to be blinded | | Blinding of outcome assessment (detection bias) All outcomes | Low risk | Surgeons/assessors blinded | | Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Modified ITT 14% of intervention group not analysed 16% of control group not analysed (did not get the allocated treatment) No further losses | | Selective reporting (reporting bias) | Low risk | All prespecified primary and secondary outcomes reported | | Other bias | Low risk | Groups appeared comparable at baseline. No other potential bias | Fedele 1990. | Study characteristics | || | Methods | Non‐blinded, parallel‐group RCT Randomisation list on a 1:2 ratio | | | Participants | Setting: single centre in Milan, Italy Sample size Number randomised: n = 24 Number completed: n = 24 Participant (baseline) characteristics Age: women aged 24 to 38 years (mean 33.6 years) Inclusion criteria: symptomatic multiple uterine fibroids, prevalent symptoms were infertility in 18 and menorrhagia in 6 women Exclusion criteria: not reported | | | Interventions | Intervention group: intranasal buserelin 1200 µg/day before myomectomy, n = 8 Comparator group: immediate myomectomy surgery, n = 16 Duration: 3 months | | | Outcomes | Preoperativeoutcomes: preoperative uterine volume (mL), Intraoperative outcomes: duration of surgery (minutes), intraoperative blood loss (mL), adverse events Postoperative outcomes: postoperative febrile complications, recurrence of myomas at 6 months | | | Notes | Author contacted for additional information on adverse events but no reply received No power calculation reported No source of funding reported | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | “Using a randomisation list the patients were allocated in a 1:2 ratio”. Unclear whether list was sequential or random | | Allocation concealment (selection bias) | Unclear risk | No information pertaining to allocation concealment was provided. | | Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | No information pertaining to blinding was provided but unlikely as control participants had immediate surgery ‐ however, recurrence is an objective outcome. | | Blinding of outcome assessment (detection bias) All outcomes | Low risk | “Measurements were performed…in all patients by a physician unaware of the patient’s group allocation.” | | Incomplete outcome data (attrition bias) All outcomes | Low risk | There were no withdrawals from the study. Data for all 24 participants were reported. | | Selective reporting (reporting bias) | Low risk | No previous protocol information was available but all outcomes from methods section were reported in the results section. | | Other bias | Unclear risk | Insufficient information to determine if groups comparable at baseline | Friedman 1989. | Study characteristics | || | Methods | Double‐blind, parallel‐group RCT Randomisation by permuted blocks controlled by pharmacy and stratified into 2 groups: moderate (< 600 cm³) or large (≥ 600 cm³) | | | Participants | Setting: single centre in Massachusetts, USA Sample size Number randomised: n = 20 Number completed: n = 18 (2 exclusions post randomisation in 1992 study (because myomectomy technique different) Participant (baseline) characteristics Age: premenopausal women aged 29 to 41 years Inclusion criteria: aged < 42 years, premenopausal (FSH 3 cm in diameter or at least 50 cm³ with multiple fibroids on ultrasound, absence of uterine calcification on ultrasound, moderate to severe symptoms from fibroids Exclusion criteria: pregnant or lactating, suspicion of ovarian or uterine malignancy from physical examination or ultrasound, hyperplasia on endometrial sample in women with menorrhagia | | | Interventions | Intervention group: intramuscular leuprolide acetate depot 3.75 mg monthly for 4 injections before myomectomy, n = 9 Comparator group: intramuscular placebo monthly for 4 injections before myomectomy, n = 9 Duration: 12 treatment weeks before myomectomy (follow‐up 27 to 38 months after surgery) | | | Outcomes | Preoperativeoutcomes: preoperative uterine volume (cc), preoperative haemoglobin (g/dL), preoperative haematocrit (%) Intraoperative outcomes: duration of surgery (minutes), intraoperative blood loss (mL) Postoperative outcomes: postoperative morbidity, frequency of blood transfusion, duration of hospital stay (days), recurrence of myomas, change in quality of life | | | Notes | Author contacted for additional information and reply received. Study population stratified into 2 groups after pretreatment ultrasound: uterine volume < 600 cc and ≥ 600 cc and sensitivity analysis performed in different strata. Outcomes from 2 separate publications but same study population Same surgical technique performed on participants No power calculation made and not ITT Source of funding: Takeda‐Abbott Research and Development and General Clinical Research Centre, Brigham and Womens' Hospital | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | “...patients were randomised by permuted blocks.” The size of the blocks was not stated. Treatment allocation can be predicted at the end of each block. | | Allocation concealment (selection bias) | Low risk | Central control of allocation | | Blinding of participants and personnel (performance bias) All outcomes | Low risk | “…to receive either LA depot 3.75mg or placebo intramuscularly every 4 weeks for four injections” “All patients and examiners were blinded with respect to treatment group throughout the study.” | | Blinding of outcome assessment (detection bias) All outcomes | Low risk | Assumed that examiners were also the assessors of outcomes. | | Incomplete outcome data (attrition bias) All outcomes | Low risk | “All patients enrolled completed the study protocol and were included in data analysis.” | | Selective reporting (reporting bias) | Low risk | No protocol available but all outcomes appear to have been reported in full. | | Other bias | Low risk | Groups appear comparable at baseline | Gerris 1996. | Study characteristics | || | Methods | Parallel‐group RCT Randomisation method not given | | | Participants | Setting: multicentre, 6 clinics in Belgium, the Netherlands, Portugal, Sweden, UK Sample size Number randomised: n = 254 Number completed: n = 215 (7 withdrawals post randomisation and before treatment; 32 withdrawals after treatment and before surgery (20 from treatment group: 7 due to side effects, 11 unable/unwilling to continue, 1 ovarian cyst, 1 lost to follow up; 12 from surgery only group: 5 unwilling/unable to continue, 3 lost to follow up, 1 menopausal symptoms, 1 started norethisterone, 2 operation could not be performed)) Participant (baseline) characteristics Age: premenopausal women aged over 25 years Inclusion criteria: premenopausal, diagnosis of benign uterine fibroids from ultrasound, awaiting hysterectomy, and either symptomatic, haemoglobin level 12 weeks in gestational size Exclusion criteria: pregnant or breastfeeding, concomitant illness that would warrant exclusion, sex hormone therapy within 2 months of entry into the study | | | Interventions | Intervention group: subcutaneous goserelin 3.6 mg monthly before hysterectomy, n = 127 Comparator group: no treatment before hysterectomy, n = 127 Duration: 3 months | | | Outcomes | Preoperativeoutcomes: preoperative uterine volume (cc), preoperative fibroid volume (cc), preoperative haemoglobin (g/dL), preoperative haematocrit (%), pelvic symptoms score, withdrawal due to adverse events Intraoperative outcomes: intraoperative blood loss (mL), difficulty of surgery, duration of surgery (minutes), type of operative incision Postoperative outcomes: postoperative haemoglobin (g/dL), postoperative haematocrit (%), duration of hospital stay (days), frequency of blood transfusions | | | Notes | Author contacted for additional information and request forwarded to Zeneca but no reply received 2 women randomised to zoladex had surgery alone and 3 women randomised to surgery alone had zoladex. Outcomes considered in this review were uterine and fibroid volume, pelvic symptom score, transfusion rate, difficulty of surgery, type of incision and withdrawal due to adverse events. Data were unsuitable for all other outcomes. No power calculation made but ITT analysis Source of funding: Zeneca Pharmaceuticals | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | “...patients were randomised.” Method of randomisation not reported | | Allocation concealment (selection bias) | Unclear risk | Allocation concealment not reported | | Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | “Patients were randomized to surgery alone…. Or to Zoladex treatment 3.6mg every month subcutaneously for 3 months prior to surgery” Participants were not blinded. No mention of personnel being blinded to study allocation | | Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Blinding is not reported and unlikely. | | Incomplete outcome data (attrition bias) All outcomes | High risk | Attrition unbalanced between groups ‐ higher in treatment than control group. | | Selective reporting (reporting bias) | Low risk | No protocol available but all outcomes in methods section were reported in full in the results section. | | Other bias | Unclear risk | The authors acknowledged that the mean uterine volume for the zoladex group was approximately 50 cm³ bigger than the surgery alone group mainly due to larger fibroids. Also, women in the surgery alone group had higher mean haemoglobin than the zoladex group at entry. | Golan 1993. | Study characteristics | || | Methods | Non‐blinded, parallel‐group RCT Randomisation method not stated | | | Participants | Setting: single centre in Israel Sample size Number randomised: n = 53 Number completed: n = 53 Participant (baseline) characteristics Age: premenopausal women, age not stated Inclusion criteria: women with symptomatology related to uterine fibroids Exclusion criteria: none stated Note: all uteri were at least the size of 12 weeks gestation | | | Interventions | Intervention group: intramuscular D‐Trp LHRH 3.2 mg micro capsules (decapeptyl) monthly before surgery (hysterectomy, n = 17; myomectomy, n = 12) Comparator group: no preoperative treatment (hysterectomy, n = 15; myomectomy, n = 9) Duration: 2 months | | | Outcomes | Preoperativeoutcomes: preoperative uterine volume (mL), preoperative haemoglobin (g/dL) Intraoperative outcomes: duration of surgery (minutes), intraoperative blood loss (mL) Postoperative outcomes: duration of hospital stay (days), frequency of blood transfusions, postoperative complications | | | Notes | Author contacted for additional information but unable to supply this information. Each treatment group had a combination of hysterectomy and myomectomy surgery. No power calculation reported No source of funding reported | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | “The patients were randomly allocated”. Method of randomisation not reported | | Allocation concealment (selection bias) | Unclear risk | No details were provided regarding allocation concealment. | | Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Blinding not reported and unlikely | | Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | No details regarding blinding of outcome assessment were recorded. | | Incomplete outcome data (attrition bias) All outcomes | Unclear risk | It is not reported whether any participants dropped out during the study | | Selective reporting (reporting bias) | High risk | No protocol available but all outcomes from methods section were reported in the results section. | | Other bias | Unclear risk | “Intraoperative blood loss estimated by the senior surgeon based of the volume of aspirated blood by the suction apparatus and the count of soaked abdominal pads.” Not convinced this is an accurate way of measuring blood loss when this was considered to be a primary outcome. This was acknowledged in the discussion. It is also not clear whether the groups were comparable at baseline. | Hudecek 2012. | Study characteristics | || | Methods | Parallel‐group RCT | | | Participants | Setting: single centre in Brno, Czech Republic Sample size Number randomised: n = 212 Number completed: n = 212 (assumed, not stated) Participant (baseline) characteristics Age: premenopausal women, age not stated Inclusion criteria: reproductive aged females with uterine symptomatic myomatosis Exclusion criteria: not reported | | | Interventions | Intervention group: subcutaneous goserelin acetate 3.6 mg 3 times once every 4 weeks, n = 120 Comparator group: no pretreatment before surgery, n = 92 42.5% of participants had laparoscopic myomectomy and 57.5% of participants had open laparotomic myomectomy | | | Outcomes | Intraoperative outcomes: intraoperative blood loss, duration of surgery, perioperative complications Postoperative outcomes: duration of hospital stay, postoperative complications | | | Notes | Translated from Czech by Petr Tomek, Auckland University No power calculation reported No source of funding reported | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | Method of randomisation not reported | | Allocation concealment (selection bias) | Unclear risk | Not reported | | Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Not reported | | Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not reported | | Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Not reported but described as ITT | | Selective reporting (reporting bias) | Low risk | All prespecified outcomes reported. SLL outcomes not reported as these were not measured in this review. | | Other bias | Unclear risk | Czech and English abstracts of the article report different numbers of women treated with open myomectomy (78 vs 44, respectively). | Levens 2008. | Study characteristics | || | Methods | Parallel‐group RCT | | | Participants | Setting: single centre in USA Sample size Number randomised: n = 22 Number completed: n = 18 (4 withdrawals but secondary analysis performed to evaluate whether significant differences existed between dropouts and completers) Participant (baseline) characteristics Age: women aged 33 to 50 years with regular menses Inclusion criteria: one or more leiomyomata > 2 cm in diameter, desiring hysterectomy, haemoglobin > 10 g/dL, current use of non‐hormonal contraception, BMI 20 mU/mL), cervical dysplasia, adnexal mass, genetic cause of rapid growth of leiomyomata, unexplained vaginal bleeding, use of glucocorticoids, progestins or agents that alter ovarian or hepatic function | | | Interventions | Intervention group: CDB‐2914 (SPRM) 10 mg daily (n = 8) or CDB‐2914 (SPRM) 20 mg daily (n = 6) Comparator group: placebo, n = 8 Duration: 3 cycles or 90 to 102 days if no menses occurred | | | Outcomes | Preoperativeoutcomes: fibroid volume (determined by MRI) Intraoperative outcomes: intraoperative blood loss, difficulty of surgery, duration of surgery (minutes) Postoperative outcomes: proportion of amenorrhoea, change in haemoglobin and haematocrit, ovulation inhibition, quality of life | | | Notes | Target enrolment was 36 participants but recruitment was terminated after 22 participants enrolled because of slow recruitment. No power calculation reported Source of funding: (in part) Reproductive Biology and Medicine branch (NIH, Bethseda Maryland) and HRA Pharma France | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | Computer‐generated blocks of 6 | | Allocation concealment (selection bias) | Low risk | Authors stated that allocation concealment was "assured". | | Blinding of participants and personnel (performance bias) All outcomes | Low risk | "...both patients and health care providers" were blinded. | | Blinding of outcome assessment (detection bias) All outcomes | Low risk | We assume that assessors were also blinded. | | Incomplete outcome data (attrition bias) All outcomes | High risk | Very small study with 18% withdrawals overall (25% withdrawal from 2 of the 3 randomised groups). Quality of life assessments performed in only 50% of original participants | | Selective reporting (reporting bias) | Unclear risk | Quality of life assessments not reported in full | | Other bias | Low risk | Groups appeared comparable at baseline. | Lumsden 1994. | Study characteristics | || | Methods | Double‐blind, parallel‐group RCT Randomisation by third party who opened the code‐break | | | Participants | Setting: multicentre (Edinburgh, Glasgow and Newcastle, UK) Sample size Number randomised: n = 71 Number completed: n = 65 (6 withdrawals, 3 from treatment group due to adverse events and 3 from the placebo group: 1 due to pregnancy, 1 due to inclusion criteria not met, the other not specified) Participant (baseline) characteristics Age: premenopausal women with mean age 43 years Inclusion criteria: awaiting total abdominal hysterectomy for uterine fibroids confirmed by ultrasound Exclusion criteria: none reported Note: all women had regular menstrual cycles; there was no recent history of dilatation and curettage and none were pregnant. | | | Interventions | Intervention group: subcutaneous goserelin 3.6 mg monthly before hysterectomy, n = 35 Comparator group: subcutaneous placebo monthly before hysterectomy, n = 6 Duration: 3 months | | | Outcomes | Preoperativeoutcomes: preoperative uterine volume (cc), preoperative haemoglobin (g/dL), pelvic symptoms (score), adverse events Intraoperative outcomes: intraoperative blood loss (mL), duration of surgery (minutes), difficulty of surgery, type of operative incision Postoperative outcomes: duration of hospital stay (days), postoperative haemoglobin (g/dL) | | | Notes | Author contacted for additional data. Request forwarded to Zeneca but reply not received Previous pilot study conducted Power calculation for sample size performed ITT analysis Source of funding not reported | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | “Patients were randomised by a third party who opened the code‐break bearing the next consecutive patient number which contained the randomisation to either goserelin or placebo treatment”. | | Allocation concealment (selection bias) | Low risk | “Randomisation was performed by the research nurses involved so that the medical staff did not know into which group the patients fell”. | | Blinding of participants and personnel (performance bias) All outcomes | Low risk | Participants and personnel were blinded. “Randomisation was performed by the research nurses involved so that the medical staff did not know into which group the patients fell.” “All applicators (goserelin and sham) were provided with transparent windows covered with a previously coded label so that they look identical, although the sham applicator was actually empty.” “Surgeons were requested not to ask the date of the last menstrual period at the time of the pre‐operative ward round as this would un‐blind the study.” | | Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | “Randomisation was performed by the research nurses involved so that the medical staff did not know into which group the patients fell.” No further information on whether these medical staff performed outcome assessment | | Incomplete outcome data (attrition bias) All outcomes | Low risk | ITT analysis: “all randomised patients recruited into the study for whom data were available were included in the efficacy analysis.” 3 women in each group withdrew, with details reported on each and it appears they were included in the analyses. | | Selective reporting (reporting bias) | Low risk | Prespecified outcomes of interest reported Previous pilot study reported same outcomes as full study | | Other bias | Low risk | Groups appeared comparable at baseline. | Mavrelos 2010. | Study characteristics | || | Methods | Double‐blind, parallel‐group RCT Randomisation carried out by a computer‐generated simple randomisation sequence with opaque sealed envelopes and staff nurses who were not part of the trial. | | | Participants | Setting: single centre in London, UK Sample size Number randomised: n = 47 Number completed: n = 40 (7 women did not undergo planned operation, 3 in treatment group, 4 in placebo group; allergic reaction in 1 woman, 2 women opted for abdominal myomectomy, 4 did not attend for operation) Participant (baseline) characteristics Age: mean age in intervention group: 38.8 years, in control group: 44.5 years Inclusion criteria: history of heavy or irregular menstrual periods, diagnosis of Type I or Type II submucous fibroid on ultrasound. Type 1: fibroids with < 50% contained within the myometrium; Type II: ≥ 50% contained within the myometrium Exclusion criteria: no specific exclusion criteria stated | | | Interventions | Intervention group: goserelin 3.6 mg (zoladex, AstraZeneca) 3 injections given at weekly intervals for 4 weeks; surgery took place 4 weeks after the last injection, n = 24 Comparator group: subcutaneous injections of placebo (5 mL 1% lignocaine), 3 injections given at weekly intervals for 4 weeks; surgery took place 4 weeks after the last injection, n = 23 Duration: 3 months, with postoperative follow‐up at 6 weeks | | | Outcomes | Intraoperative outcomes: duration of surgery Postoperative outcomes: completion of fibroid resection, volume of fluid infusion, fluid deficit > 1500 mL, complications, recurrence of myomas | | | Notes | Primary outcome ITT analysis Power calculation carried out Study supported by Kings College Hospital NHS Foundation Trust | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | Randomisation carried out by a computer‐generated simple randomisation sequence with staff nurses who were not part of the trial. | | Allocation concealment (selection bias) | Low risk | "...consecutively numbered, opaque, sealed envelopes." | | Blinding of participants and personnel (performance bias) All outcomes | Low risk | "...both patients and clinicians were blinded to the group allocation." | | Blinding of outcome assessment (detection bias) All outcomes | Low risk | “Patients underwent hysteroscopic transcervical resection of myoma by a single experienced operator.” "clinicians blinded to group allocation" | | Incomplete outcome data (attrition bias) All outcomes | High risk | Substantial attrition. Only postoperative complications were assessed in all participants. | | Selective reporting (reporting bias) | Low risk | Protocol viewed ‐ all outcomes stated in methods and protocol were reported. | | Other bias | Unclear risk | Participants in treatment group were younger than those in control group. | Muneyyirci‐Delale 2007. | Study characteristics | || | Methods | Double‐blind, parallel‐group RCT Randomisation schedule prepared by Biometrics Group, AstraZeneca Pharmaceuticals; study personnel had to contact the randomisation desk for allocation of treatment. | | | Participants | Setting: multicentre (sites in North America) Sample size Number randomised: n = 110 Number completed: n = 72 (38 participants dropped out of the study, 20 from treatment group and 18 from control. Reasons included: loss to follow‐up; adverse event or intercurrent illness; protocol non‐compliance, or withdrawal of informed consent Participant (baseline) characteristics Age: premenopausal women aged over 18 years Inclusion criteria: women with a history of excessive menstrual bleeding causing iron‐deficiency anaemia (IDA) who were candidates for hysterectomy or myomectomy. Participants underwent screening to demonstrate uterus ≥ 8 weeks gestation in size and the presence of ≥ 1 non‐calcified leiomyoma of ≥ 3 cm diameter. Participants were required to have a negative cervical smear test within 6 months of trial entry and a negative endometrial biopsy within the 45‐day period before randomisation. Exclusion criteria: women with any blood disorder other than IDA (thalassaemia, sickle cell anaemia, folic‐acid deficiency, coagulopathy). Women with renal or hepatic impairment, gynaecological malignancy or premalignancy, adrenal, pancreatic, ovarian or pituitary tumours, osteoporosis, osteopenia or metabolic bone disease. Women with any other medical condition that might confound the haematologic parameters. Blood transfusion within 8 weeks of randomisation or blood donation within 2 weeks was not permitted. Women who had received treatment with an LHRH analogue within previous 6 months, or who had a known hypersensitivity to LHRH, LHRH agonists or analogues, or any of the components of the study medication. Pregnant women were excluded. | | | Interventions | Intervention group: injection of goserelin acetate 10.8 mg depot 12 weeks before planned surgery, supplied as a pre‐filled sterile delivery device, and dispersed in a cylindrical rod of D,L, lactide glycolide polymer, n = 54 Comparator group: sham depot injection containing copolymer only, supplied in a sterile syringe applicator identical to goserelin device, 12 weeks before planned surgery, n = 56 Every study participant received 325 mg ferrous sulphate taken 3 times daily, for 12 weeks until surgery. | | | Outcomes | Preoperativeoutcomes: haemoglobin concentration at time of surgery (g/dL), percentage of women achieving an increase in Hb ≥ 2 g/dL, percentage of women achieving haematological recovery where Hb ≥ 12 g/dL, symptoms associated with uterine leiomyomas, requirement for blood transfusion at preoperative visit, ability to donate blood for autologous transfusion, fibroid and total uterine volume measured by ultrasound (cm³) Intraoperative outcomes: requirement for perioperative blood transfusion Postoperative outcomes: requirement for postoperative blood transfusion | | | Notes | Author contacted for additional data on 21 November 2011; no reply received. Power calculation performed. ITT analysis carried out for primary outcome. Study funded by AstraZeneca | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | "Treatment group was determined by a randomisation schedule prepared by the Biometrics Group, AstraZeneca Pharmaceuticals." | | Allocation concealment (selection bias) | Low risk | "Investigators were instructed to contact the randomisation desk for a subject number and allocation." | | Blinding of participants and personnel (performance bias) All outcomes | Low risk | "sham injection in a double‐blind manner." “The sham depot was… identical to the goserelin device.” Treatment administrators were blinded. | | Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | No details regarding blinding of surgeons or ultrasonographers | | Incomplete outcome data (attrition bias) All outcomes | High risk | ITT analysis only carried out for Hb levels and adverse events. “Of the 110 subjects treated, 72 completed the trial.” 34.5% of participants withdrew from the study. “Reasons for withdrawal were similar in the 2 groups”, although more participants were lost to follow‐up in the goserelin group than the sham group and more were lost due to protocol noncompliance in the sham group compared to the goserelin group. | | Selective reporting (reporting bias) | Low risk | All outcomes in methods section were reported in the results section. Adverse events reported in full | | Other bias | Unclear risk | Unclear if groups comparable at baseline | Muzii 2010. | Study characteristics | || | Methods | Parallel‐group RCT | | | Participants | Setting: multicentre, 3 tertiary care hospitals in Rome, Italy Sample size Number randomised: n = 39 Number completed: n = 39 Participant (baseline) characteristics Age: premenopausal women, mean age 42 years Inclusion criteria: premenopausal women with submucous fibroids (diagnosed by TVUS) with diameter between 10 mm and 35 mm, grade GO or G1 (fibroids either completely intracavity or with an intramural portion of < 50%), BMI between 18 and 30 kg/m² Exclusion criteria: present or past history of cancer, a preoperative clinical suspicion of associated multiple or large polyps, planned associated non‐hysteroscopic surgical procedures or > 2 fibroids requiring hysteroscopic resection | | | Interventions | Intervention group: GnRHa (triptorelin 3.75 mg intramuscular injection for 2 consecutive injections 28 days apart before resectoscopic resection), n = 20 Comparator group: direct surgery (resectoscopic resection), n = 19 | | | Outcomes | Intraoperative outcomes: duration of surgery, fluid absorption, difficulty of the operation, intraoperative complications Postoperative outcomes: surgeon satisfaction with the procedure, postoperative complications, postoperative pain, patient satisfaction | | | Notes | Power calculation for sample size (reduction of 50% in operating time with GnRHa) Source of funding: not reported | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | "...computer generated sequence" | | Allocation concealment (selection bias) | Low risk | "...sealed opaque envelopes" | | Blinding of participants and personnel (performance bias) All outcomes | High risk | No blinding | | Blinding of outcome assessment (detection bias) All outcomes | High risk | No blinding | | Incomplete outcome data (attrition bias) All outcomes | Low risk | No withdrawals | | Selective reporting (reporting bias) | Unclear risk | Prespecified outcomes not reported in full | | Other bias | Low risk | Groups comparable at baseline | Nikolov 1999. | Study characteristics | || | Methods | Non‐blinded, parallel‐group RCT Randomisation by sealed opaque sequentially numbered identical envelopes | | | Participants | Setting: single centre in Sofia, Bulgaria Sample size Number randomised: n = 34 Number completed: n = 34 Participant (baseline) characteristics Age: premenopausal women aged 25 to 50 years Inclusion criteria: women aged 25 to 50 years awaiting surgery for uterine fibroids, benign uterine fibroids confirmed by ultrasound, anaemia (Hb < 10 g/dL or 7 nmol/L) or with pelvic mass < 12 gestational weeks Exclusion criteria: pregnant or breastfeeding, sex hormone therapy for last 12 months, severe illness interfering with the aims of the study | | | Interventions | Intervention group: subcutaneous goserelin 3.6 mg monthly before myomectomy (n = 6) or hysterectomy (n = 11) Comparator group: no treatment before hysterectomy surgery (n = 17) but observation period for 3 months Duration: 3 months | | | Outcomes | Preoperativeoutcomes: preoperative uterine volume (mL), preoperative fibroid volume (mL), preoperative haemoglobin levels (g/dL) Intraoperative outcomes: intraoperative blood loss (mL), duration of surgery | | | Notes | Data given separately for intraoperative outcomes according to whether myomectomy or hysterectomy performed, but data entered only for hysterectomy because this was the only surgery performed in the control group. Author contacted for additional information and reply received No power calculation performed Source of funding not reported No withdrawals or loss to follow‐up | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | No mention of the method of random sequence generation. "...the women were subdivided into two groups by randomisation principle." | | Allocation concealment (selection bias) | Low risk | Sealed, opaque, sequentially‐numbered identical envelopes | | Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | No mention of blinding of participants and personnel | | Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | No mention of blinding of outcome assessment | | Incomplete outcome data (attrition bias) All outcomes | Unclear risk | It seems there were no losses to follow‐up. In the treatment group, 6 women had myomectomy and 11 had hysterectomy, while in the control group, all 17 had hysterectomy. | | Selective reporting (reporting bias) | Unclear risk | For all continuous variables (as outcome measures), the authors did not present the numbers experiencing the event. | | Other bias | Unclear risk | Unclear if groups similar at baseline | Reinsch 1994. | Study characteristics | || | Methods | Parallel‐group RCT | | | Participants | Setting: single‐centre, location not reported Sample size Number randomised: n = 14 Number completed: n = 14 Participant (baseline) characteristics Age: not reported Inclusion criteria: not clearly specified ‐ all women had uterine fibroids Exclusion criteria: not reported | | | Interventions | Intervention group: Ru 486 25 mg (oral once per day), n = 8 Comparator group: GnRHa (leuprolide acetate 3.75 mg IM each month for 3 months), n = 6 | | | Outcomes | Preoperativeoutcomes: uterine artery blood flow, uterine volume, adverse effects | | | Notes | Power calculation for sample size not reported Source of funding: not reported | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | "...randomly assigned" but method of randomisation not reported | | Allocation concealment (selection bias) | Unclear risk | Not reported | | Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Not reported but unlikely | | Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not reported but unlikely. | | Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Study authors did not report whether there were any withdrawals. | | Selective reporting (reporting bias) | Unclear risk | Prespecified outcomes not fully reported | | Other bias | Unclear risk | Study authors stated that groups were comparable at baseline but no values were reported. | Sayyah‐Melli 2007. | Study characteristics | || | Methods | Parallel‐group RCT | | | Participants | Setting: single‐centre from Alzahra University Hospital, Tabriz, Iran Sample size Number randomised: n = 50 Number completed: n = 50 Participant (baseline) characteristics Age: women mean age 30 and 32 years Inclusion criteria: women with uterine myoma nodules > 5 cm in diameter with irregular menstrual cycle and candidates for myomectomy Exclusion criteria: > 40 years of age, abnormal uterine pathology, infection, hypersensitivity to any ergot alkaloids, hepatic and renal disorders, history of toxemia of pregnancy, cardiovascular disease, peptic ulcer, taking antipsychotic medications | | | Interventions | Intervention group: GnRHa (diphereline 3.75 mg 4 times every 28 days), n = 25 Comparator group: dopamine agonist (cabergoline 0.5 mg once/week for 6 weeks), n = 25 | | | Outcomes | Preoperativeoutcomes: reduction in fibroid volume, symptoms, adverse effects | | | Notes | No power calculation for sample size reported Source of funding: not reported | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | "...assigned randomly" but no method reported | | Allocation concealment (selection bias) | Unclear risk | Not reported | | Blinding of participants and personnel (performance bias) All outcomes | High risk | Blinding not reported and highly unlikely because of different administration of intervention regimens (injection and tablet) | | Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Blinding not reported and unlikely | | Incomplete outcome data (attrition bias) All outcomes | Low risk | No reported withdrawals | | Selective reporting (reporting bias) | Low risk | All prespecified outcomes fully reported | | Other bias | Low risk | Groups appeared comparable at baseline. | Sayyah‐Melli 2009. | Study characteristics | || | Methods | Parallel‐group RCT | | | Participants | Setting: single centre in Iran Sample size Number randomised: n = 60 Number completed: n = 60 Participant (baseline) characteristics Age: women of reproductive age Inclusion criteria: women of reproductive age who had abnormal bleeding or infertility with uterine intramural fibroids Exclusion criteria: submucous or subserous fibroids, abnormal uterine pathology and infection, aged ≥ 43 years | | | Interventions | Intervention group: dipheredine 3.75 mg (GnRHa) 4 times every 28 days, n = 30 Comparator group: dostinex (cabergoline) 0.5 mg once per week for 6 weeks, n = 30 Only a proportion of women went on to have surgery. Duration of treatment: 6 weeks to 4 months | | | Outcomes | Preoperativeoutcomes: preoperative fibroid volume, adverse effects | | | Notes | Data on adverse effects were inconsistent between table and text so were not extracted. Intraoperative outcomes could not be used in the review as only a small proportion of women went on to have surgery. Power calculation for sample size not reported Source of funding: grant from Tabriz University of Medical Sciences, no funding from drug company | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | Method of randomisation not described | | Allocation concealment (selection bias) | Unclear risk | Not reported | | Blinding of participants and personnel (performance bias) All outcomes | High risk | Participants were obviously not blinded because of different treatment administration schedules. | | Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not reported | | Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Not reported if any participants withdrew | | Selective reporting (reporting bias) | Low risk | All prespecified outcomes reported | | Other bias | Low risk | Groups appeared comparable at baseline. | Seraccholi 2003. | Study characteristics | || | Methods | Parallel‐group RCT | | | Participants | Setting: single centre in Italy Sample size Number randomised: n = 62 Number completed: unclear Participant (baseline) characteristics Age: treatment group 47.6 ± 3.5 years, control group 48.4 ± 4.6 years Inclusion criteria: women with symptomatic fibroid, with mobile uterus and vaginal accessibility with uterus size between 16 to 20 weeks clinically and volume between 380 mL and 680 mL ultrasonographically Exclusion criteria: women with pelvic pathology as prolapse, pelvic floor relaxation, SI, adnexal mass; women with medical conditions requiring monitoring as diabetes, IHD; women who had therapy with GnRHa, danazol or progestational agents in last 6 months; women who had undergone surgery requiring longitudinal laparotomy; women with any contraindication to operative laparoscopy | | | Interventions | Intervention group: triptorelin depot 11.25 mg starting in mid luteal phase 3 months before surgery, n = 31 Comparator group: no therapy, n = 31. | | | Outcomes | Preoperativeoutcomes: uterine volume and weight, haemoglobin, uterine bleeding, pelvic pain, urinary urgency Intraoperative outcomes: time of operation from skin incision and pneumoperitoneum to closure Postoperative outcomes: haemoglobin (drop), fever, hospital stay in days, blood transfusions, adverse events | | | Notes | Power calculation not reported and unclear if ITT analysis Source of funding not reported | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | “Patients were assigned at a ratio 1:1 by random selection” – method of randomisation not specified | | Allocation concealment (selection bias) | Unclear risk | No details were provided. | | Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Women were randomised to injection or no treatment. No details on personnel blinding | | Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | No details regarding outcome assessment were provided. | | Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Unclear whether all participants were included in analysis | | Selective reporting (reporting bias) | High risk | The study authors only reported adverse events and changes in uterine volume/weight in the intervention group before surgery ‐ no comparison was made with control so this outcome was not relevant to the review. Introduction mentions evaluating “operating time, surgical complications, conversion to laparotomy, blood loss, hospital stay, and costs”. Results report all of these except costs. | | Other bias | Low risk | Groups appear comparable at baseline. | Shaw 1989. | Study characteristics | || | Methods | Non‐blinded, parallel‐group RCT Method of randomisation not stated | | | Participants | Setting: single centre in UK Sample size Number randomised: no information given about actual numbers randomised or withdrawals Number completed: n = 32 Participant (baseline) characteristics Age: not stated Inclusion criteria: women with large fibroid uteri, from 14 to 30 weeks in gestational size were recruited Exclusion criteria: no specific inclusion or exclusion criteria reported | | | Interventions | Intervention group: goserelin depot 3.6 mg before surgery (myomectomy and hysterectomy) (n = ?) Comparator group: no treatment before surgery (myomectomy and hysterectomy (n = ?) Duration in treatment group: 4 months | | | Outcomes | Preoperativeoutcomes: preoperative uterine volume (mL) (data not given). Intraoperative outcomes: intraoperative blood loss (mL) (reported separately for myomectomy and hysterectomy) Postoperative outcomes: blood transfusion rate (given for myomectomy only) | | | Notes | Data not provided for uterine volume before surgery Author contacted for additional information but no reply received No power calculation for sample size or ITT analysis reported Source of funding not stated | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | “They were randomised to receive Zoladex depot for 4 months or to act as controls with no treatment.” Method of randomisation not specified | | Allocation concealment (selection bias) | Unclear risk | No details on allocation concealment reported | | Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Blinding of participants or personnel not reported and unlikely because of the differing treatment regimens | | Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | It is not specified who assessed the outcomes or whether the assessor (or assessors) was blinded. | | Incomplete outcome data (attrition bias) All outcomes | High risk | 32 women were included in the analysis. It is not stated how many were recruited or randomised, or if there were any withdrawals. | | Selective reporting (reporting bias) | High risk | Uterine volume before surgery was not reported. Intraoperative blood loss was reported, without the numbers of the groups provided. Blood transfusion rate only provided for one group. No adverse effects information was reported. | | Other bias | Unclear risk | No characteristics of the two assigned groups were provided so we could not confirm if they were comparable at baseline. | Shaw 1996. | Study characteristics | || | Methods | Double‐blind, parallel‐group RCT Randomisation on a 1:1 basis according to a randomisation schedule controlled by Hoechst and stratified according to uterine size to minimise bias | | | Participants | Setting: multicentre, 21 medical centres in the UK and 2 in Israel Sample size Number randomised: n = 210 Number completed: n = 196 (ITT), n = 164 (per protocol) Participant (baseline) characteristics Age: women aged 29 to 52 years Inclusion criteria: women aged ≥ 20 years; willing and able to participate; informed consent; fibroids clinically diagnosed at gynaecological examination and confirmed by US; uterus with size at least 8 weeks of pregnancy; menorrhagia and/or other symptoms of sufficient intensity to require hysterectomy Exclusion criteria: persistent symptoms characteristic of menopause; FSH levels suggestive of ovarian failure; rapidly increasing uterine size; irregular vaginal bleeding of unknown origin; requirement for immediate hysterectomy; pregnancy or breastfeeding; history of hypersensitivity to the study medication or similar drugs; likelihood of requiring treatment during the study with drugs not permitted by study protocol; treatment with any other investigational drug in the last 3 months; terminal disease; history of drug or alcohol abuse; any serious endocrine disorder other than stable diabetes; impaired renal or hepatic function; impaired mental condition; history of major depression within last 3 years; treatment with LHRH analogue in previous 6 months; evidence of uncooperative attitude; treatment with oral contraceptives or progestogens; previous entry to the study | | | Interventions | Intervention group: buserelin 3.6 mg monthly (intramuscular), n = 98 Comparator group: placebo monthly, n = 98 Duration: 3 months | | | Outcomes | Preoperativeoutcomes: menstrual blood loss during treatment, fibroid/uterine volume, haemoglobin levels Intraoperative outcomes: blood loss during surgery, ease of surgery, type of incision, type of hysterectomy, duration of surgery Postoperative outcomes: change in symptoms, adverse events | | | Notes | Unpublished study released by Hoechst ITT analysis and power calculation performed for sample size Source of funding: Hoechst UK | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | “Subjects were randomised to the trial of whom 98 received buserelin and 98 placebo.” Randomisation on a 1:1 basis according to a randomisation schedule controlled by Hoechst and stratified according to uterine size to minimise bias. | | Allocation concealment (selection bias) | Low risk | Central control | | Blinding of participants and personnel (performance bias) All outcomes | Low risk | “This study was a…double blind comparison.” Participants received either buserelin 3.6 mg monthly or placebo monthly for 3 months. | | Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | It was not specified who assessed the outcomes or whether the assessment was performed by a blinded party. | | Incomplete outcome data (attrition bias) All outcomes | Unclear risk | 210 women randomised, 196 women ITT analysis, 164 participants per‐protocol analysis. Both analyses presented and reasons given for withdrawals. | | Selective reporting (reporting bias) | Low risk | All prespecified outcomes were reported. | | Other bias | Low risk | Groups comparable at baseline | Stovall 1994. | Study characteristics | || | Methods | Non‐blinded, parallel‐group RCT Randomisation by computer‐generated random number table | | | Participants | Setting: single centre in Tennessee, USA Sample size Number randomised: n = 150 (in 1994 study) Number completed: n = 150 (no withdrawals reported) Participant (baseline) characteristics Age: premenopausal women aged 29 to 51 years Inclusion criteria: women with symptomatic uterine fibroids scheduled to undergo hysterectomy, FSH < 30 mIU/mL, negative urine pregnancy test, presence of fibroids ≥ 14 gestational weeks on pelvic examination, absence of uterine calcification on ultrasound examination, symptoms of increased vaginal bleeding, pain or pressure, no evidence of ovarian or uterine malignancy from pelvic examination or ultrasonography, benign endometrial histologic features where sampling was indicated and normal cervical cytologic characteristics Exclusion criteria: no specific exclusion criteria reported | | | Interventions | Intervention group: either subcutaneous leuprolide acetate 0.5 mg daily or intramuscular depot leuprolide acetate 3.75 mg monthly before hysterectomy, n = 45 Comparator group: no preoperative treatment before hysterectomy, n = 45 Data were only analysed from the subgroup who had gestational size of 14 to 18 weeks. Duration: 2 months (treatment group only) | | | Outcomes | Preoperativeoutcomes: preoperative uterine size (gestational weeks), preoperative uterine volume (mL) measured by ultrasound, preoperative haemoglobin and haematocrit (from smaller number of participants in 1991 study) Intraoperative outcomes: duration of surgery (minutes), intraoperative blood loss (mL) Postoperative outcomes: postoperative complications, frequency of blood transfusions, duration of hospital stay (days), proportion undergoing vaginal rather than abdominal hysterectomy, postoperative haemoglobin and haematocrit (from smaller number of participants in 1991 study) | | | Notes | Author contacted for additional information, but no reply received Subgroup analysis performed in 2 separate treatment and control groups: women with uterine size 14 to 18 gestational weeks and women with uterine size > 18 gestational weeks Vaginal hysterectomy attempted if uterus mobile and ≤ 14 weeks in gestational size Participants from earlier study in 1991 were a subset of later study in 1994 and haematological parameters were provided only for the this subset of women. No power calculation made Source of funding: TAP Pharmaceticals Inc (in part) | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | “Patients were randomised by a computer‐generated random number table.” | | Allocation concealment (selection bias) | Unclear risk | “Patients were randomised by a computer‐generated random number table.” No other details were given with respect to concealing allocation. | | Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Immediate and delayed surgery so participants were unable to be blinded. Not clear if personnel blinded | | Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | It was not specified who assessed the outcomes or whether the assessment was performed by a blinded party. | | Incomplete outcome data (attrition bias) All outcomes | Low risk | It appears there were no withdrawals from the study by checking the percentages recorded for dichotomous outcomes. | | Selective reporting (reporting bias) | Low risk | All prespecified outcomes were reported. | | Other bias | High risk | The first 10 participants in the group receiving GnRHa therapy were given leuprolide acetate 0.5 mg subcutaneously daily for 8 weeks; the remaining women received two intramuscular injections of depot leuprolide acetate, 3.75 mg 4 weeks apart ‐ not clear whether this could cause bias. In addition, there was a short‐stay protocol for vaginal hysterectomy resulting in a reduction in hospital stay unrelated to the treatment with GnRHa therapy. | Stovall 1995. | Study characteristics | || | Methods | Double‐blind, parallel‐group RCT Randomisation method not stated | | | Participants | Setting: multicentre, 50 centres in the USA Sample size Number randomised: n = 309 Number completed: n = 218 (44 exclusions after randomisation due to insufficient washout period after hormone therapy or failure to meet stated haematologic criteria; 47 additional withdrawals, women who decided not to have surgery) Participant (baseline) characteristics Age: women aged 23 to 52 years Inclusion criteria: not pregnant or lactating, aged > 18 years, free of gynaecological malignancy, history of prolonged or excessive bleeding for 3 months, pelvic masses consistent with fibroids established by history and pelvic exam and confirmed by ultrasound and MRI, consent to surgical management, haematocrit ≤ 30% and/or haemoglobin ≤ 10.2, no evidence of concomitant disease with the potential for producing bleeding that would result in iron‐deficiency anaemia Exclusion criteria: no additional exclusion criteria reported | | | Interventions | Intervention group: intramuscular leuprolide acetate depot 7.5 mg + iron monthly, n = 107; intramuscular leuprolide acetate depot 3.75 mg + iron monthly, n = 104 Comparator group: placebo + iron monthly, N = 98 Duration: 3 months | | | Outcomes | Preoperativeoutcomes: preoperative haemoglobin (g/dL), preoperative haematocrit (%), preoperative uterine size (gestational weeks), preoperative fibroid volume, preoperative fibroid volume, preoperative pelvic symptoms, frequency of adverse events (listed) Intraoperative outcomes: not reported Postoperative outcomes: frequency of blood transfusions (not recorded in the review because different types of surgery performed and these data not given separately) | | | Notes | Study author contacted for additional information but no reply received Different types of surgery performed (hysterectomy in 137 women (63%), myomectomy in 80 women (37%) and endometrial ablation in 1 woman) The only outcomes considered in this review were preoperative haemoglobin and hematocrit (no SD given), pelvic symptoms and adverse events. For all other outcomes, data were not in a suitable form for meta‐analysis. Results analysed in 2 strata: A: baseline haematocrit ≤ 28%; B: baseline haematocrit > 28% Data from the first treatment group with the higher dosage of 7.5 mg leuprolide acetate not considered in the review Power calculation for sample size performed and ITT analysis Source of funding: TAP Pharmaceuticals Inc | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | Participants stratified “arbitrarily” into one of two strata based on their pre‐study haematocrit level. “Within each stratum, patients were randomised to one of three treatment arms.” Method of randomisation not reported | | Allocation concealment (selection bias) | Unclear risk | No details on allocation concealment reported | | Blinding of participants and personnel (performance bias) All outcomes | Low risk | “A blinded central reader was used for all bone mineral densitometry scans.” “Each patient received an intramuscular injection of study drug or placebo.” Study described as “double‐blinded” | | Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | No information was reported. | | Incomplete outcome data (attrition bias) All outcomes | High risk | 309 women were enrolled and treated; of these, only 265 women (86%) were evaluated for efficacy. 47/265 women “decided not to have surgery” so surgical outcomes were not reported. There was also substantial attrition for some other outcomes. All women were included in the adverse event analysis. | | Selective reporting (reporting bias) | High risk | Data for main outcomes not fully reported | | Other bias | Unclear risk | The study authors reported that there were no significant differences between randomised groups but did not clearly report the individual values. | Vercellini 1998. | Study characteristics | || | Methods | Single‐blind, parallel‐group RCT Method of randomisation by computer‐generated randomisation sequences stratified per centre with consecutively numbered, opaque sealed envelopes | | | Participants | Setting: multicentre, 4 centres in northern Italy Sample size Number randomised: n = 127 Number completed: n = 125 (4 withdrawals, 2 in each group; one who refused treatment, one for personal nonmedical reasons, one due to menopause and one who decided to have surgery in another hospital) Participant (baseline) characteristics Age: premenopausal women with median age 46 years (range 43 to 48 years) Inclusion criteria: premenopausal (FSH < 30 mIU/mL), symptomatic fibroids requiring hysterectomy, uterine volume of 12 to 16 gestational weeks, mobile uterus with volume 380 mL to 680 mL on ultrasound, regular vaginal accessibility, no adnexal tumours at clinical and ultrasound examination Exclusion criteria: uncertainty about future childbearing, use of GnRHa in the past 6 months, previous pelvic interventions apart from caesarean section, pelvic inflammatory disease or endometriosis, urinary stress incontinence, moderate or severe genital prolapse, clotting disorders, unstable general conditions | | | Interventions | Intervention group: intramuscular triptorelin depot injections 3.75 mg (decapeptyl) monthly before hysterectomy, n = 62 Comparator group: immediate surgery (hysterectomy), n = 65 Duration: 3 months | | | Outcomes | Preoperativeoutcomes: preoperative uterine volume (mL) Intraoperative outcomes: duration of surgery (minutes), intraoperative blood loss (mL), difficulty of surgery Postoperative outcomes: frequency of blood transfusions, proportion undergoing vaginal rather than abdominal hysterectomy, postoperative complications, postoperative haemoglobin (g/dL), postoperative haematocrit (%), patient satisfaction (not included in the review) | | | Notes | Hysterectomy was by both the vaginal and abdominal route, but as data not provided separately for these groups, separate analysis was not possible. Power calculation for sample size performed and ITT analysis Source of funding not reported | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | “Performed in a separate setting in accordance with computer‐generated randomisation sequences stratified per centre.” | | Allocation concealment (selection bias) | Low risk | “Using consecutively numbered opaque, sealed envelopes.” “The evaluator was blinded with regard to treatment allocation.” | | Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Surgeon was not allowed to interview participants, and participants were requested to avoid mention of their last menstrual period. However, participants were not blinded, as they either received immediate surgery or treatment and delayed surgery. | | Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Outcome was vaginal vs abdominal hysterectomy; no women who were recommended vaginal hysterectomy required conversion to abdominal hysterectomy. The surgeon who evaluated which surgery the woman would have was blinded to the treatment allocation (same surgeon as above), but “it is possible that the evaluator could have recalled examining the same woman three months before” as “only the patients allocated to pre‐operative medical treatment were examined twice.” | | Incomplete outcome data (attrition bias) All outcomes | Low risk | 4 women withdrew after randomisation and before surgery, 2 from each arm. These 4 participants were also included in the efficacy analysis. “The inclusion of the four withdrawn patients in the analysis did not modify the appreciably the above estimates”. All women operated on attended the follow‐up evaluation. | | Selective reporting (reporting bias) | Low risk | All prespecified outcomes were reported clearly. | | Other bias | Low risk | Randomised groups appeared comparable at baseline | Vercellini 2003. | Study characteristics | || | Methods | Single‐blind, parallel‐group RCT Method of randomisation in a proportion of 1:1 by a computer generated randomisation sequence using serially numbered, sealed opaque envelopes | | | Participants | Setting: single centre Sample size Number randomised: n = 100 Number completed: n = 97 (3 withdrawals: 2 in immediate surgery group (one became pregnant, and one opted for surgery at different hospital), 1 in the GnRHa group had to undergo hysterectomy) Participant (baseline) characteristics Age: premenopausal women aged 18 to 40 years Inclusion criteria: women with symptomatic intramural or subserous fibroid > 3 cm Exclusion criteria: if predominantly intracavitary fibroids, previous pelvic surgery for leiomyomas or other genital abnormalities, uterine malformations, present or past pelvic inflammatory diseases, use of GnRHa up to 6 months prior, ultrasonography showing signs of uterine calcifications, coagulation disorders and unstable general conditions | | | Interventions | Intervention group: intramuscular triptorelin depot injections 3.75 mg (Decapeptyl) on 2 occasions 28 days apart starting during mid luteal phase, n = 50 Comparator group: immediate surgery (abdominal myomectomy), n = 50 Duration: 2 months | | | Outcomes | No preoperative evaluation Intraoperative outcomes: duration of surgery (minutes), intraoperative blood loss (mL), difficulty of surgery, frequency of blood transfusions Postoperative outcomes: duration of hospital stay, postoperative complications, postoperative haemoglobin (g/dL), postoperative haematocrit (%), patient satisfaction (not included in the review) | | | Notes | No preoperative assessment Power calculation for sample size performed and ITT analysis Source of funding not reported. Triptorelin depot injections provided by IPSEN Biotech Pharmaceuticals, Milan, Italy | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | "Treatment allocation was performed with a computer‐generated randomization sequence." | | Allocation concealment (selection bias) | Low risk | “...using serially numbered, opaque, sealed envelopes.” | | Blinding of participants and personnel (performance bias) All outcomes | High risk | Participants could not be blinded as they either received immediate surgery or treatment and delayed surgery. Study reported as "open label". | | Blinding of outcome assessment (detection bias) All outcomes | High risk | Open‐label trial | | Incomplete outcome data (attrition bias) All outcomes | Low risk | Withdrawals were low in number and were evenly distributed, and all available data appeared to be reported. After randomisation and before surgery, 3 women withdrew from the study, 2 from control group and 1 in triptorelin group and were not included in the analysis (reasons given). | | Selective reporting (reporting bias) | Low risk | It appears that all obvious outcomes were reported. | | Other bias | Low risk | Groups appear comparable at baseline | Verspyck 2000. | Study characteristics | || | Methods | Non‐blinded, parallel‐group RCT Balanced randomisation list predefined for each centre and balanced after every 4 women | | | Participants | Setting: multicentre (10 centres) in France Sample size Number randomised: n = 56 Number completed: n = 46 (10 women withdrew before the completion of the study (5 from each group), 2 for inefficacy, 6 for adverse events, 1 for protocol deviation and 1 lost to follow‐up) Participant (baseline) characteristics Age: women with mean age 41.3 years Inclusion criteria: women with symptomatic fibroids indicating surgery, baseline pelvic ultrasound showing evidence of ≥ 1 fibroid ≥ 5 cm in diameter or submucous fibroids Exclusion criteria: amenorrhoea, progestin or GnRHa treatment in previous 6 months, administration of another hormone therapy (except insulin), calcified fibroids, fibroids causing acute compressive complications | | | Interventions | Intervention group: leuprorelin 3.75 mg monthly (subcutaneous), n = 33 Comparator group: lynestrenol 5 mg twice daily from day 5 to 25 of the cycle, n = 23 Duration: 4 months | | | Outcomes | Preoperativeoutcomes: ultrasound reduction of myoma diameter, percentage decrease in myoma diameter, preoperative haemoglobin, intensity of pelvic pain Intraoperative outcomes: not reported Postoperative outcomes: proportion with change in pelvic pain, proportion with change in other symptoms, postoperative haemoglobin, blood transfusion rate, adverse events | | | Notes | No power calculation for sample size Source of funding not stated | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Unclear risk | “The treatments were allocated according to a randomisation list predefined for each centre as balanced after every four patients.” It is not clear how the balancing worked or whether it had the potential for bias. | | Allocation concealment (selection bias) | Unclear risk | No allocation concealment was reported. | | Blinding of participants and personnel (performance bias) All outcomes | High risk | “An open‐label study design was used because of the different administration conditions for the two products i.e. leuprorelin is injected subcutaneously and lynestrenol is administered orally. A double‐blind design would have been ideal, but the injection of a placebo for leuprorelin raises ethical problems.” | | Blinding of outcome assessment (detection bias) All outcomes | High risk | Open‐label study | | Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Exploratory ITT analysis, Withdrawals described, but substantial attrition for some outcomes. Details on surgical outcomes were only found for 25/33 participants for the leuprorelin group, and 17/23 in the lynestrenol group. | | Selective reporting (reporting bias) | Unclear risk | Some outcome details not clearly reported | | Other bias | High risk | Significant differences in characteristics between the two groups. Statistically significant difference in distribution by category, more participants with multiple myomas in the leuprorelin group. “Larger number of myomas observed in patients in the leuprorelin group compared to those in the lynestrenol group. Consequently, the group treated with leuprorelin would rather have been put a disadvantage.” In addition, there was poor recruitment, “Three centres had only enrolled the first patient list (leuprorelin group each time).” | Wilkens 2008. | Study characteristics | || | Methods | Multicentre (4 centres in the UK), parallel‐group RCT (phase 2 trial) | | | Participants | Setting: multicentre (4 centres in the UK) Sample size: Number randomised: n = 33 Number completed: n = 33 (no withdrawals) Participant (baseline) characteristics: Age: premenopausal women aged over 18 years Inclusion criteria: premenopausal women scheduled for hysterectomy due to symptomatic fibroids, general good health, menstrual cycle between 17 and 42 days, symptoms related to fibroid size, pressure and/or heavy menstrual bleeding, at least one intramural non‐pedunculated, submucosal or subserosal fibroid with a diameter of at least 2 cm or multiple small fibroids with uterine volume 200 cm³ on ultrasonography, age over 18 years; negative pregnancy test, a washout period of 2 to 12 months for hormonal therapies, serum FSH 30 mIU/mL 21 at commencement, agreement to use double barrier method of contraception (condom/diaphragm/sponge plus spermicide) throughout the study until hysterectomy, unless surgically sterile by bilateral tubal ligation or vasectomy of partner and normal Papanicolaou test Exclusion criteria: abnormal endometrial biopsy report based on an adequate specimen taken within 3 months of commencement | | | Interventions | Intervention groups: asoprisnil 10 mg or 25 mg orally once daily for 12 weeks, n = 12 and n = 11 Comparator group: placebo, n = 10 All women then proceeded to hysterectomy. | | | Outcomes | Preoperativeoutcomes: volume of the largest fibroid and the uterus, menstrual blood loss (measured by menstrual pictogram), adverse events Intraoperative outcomes: not reported Postoperative outcomes: quality of life (measured by Uterine Fibroid Symptom and Health‐Related Quality of Life Questionnaire (UFS‐QOL) | | | Notes | The primary outcomes in this study were not part of this review. Power calculation for sample size: 95% power to detect a 0.08 difference between asoprisnil and placebo in RI (resistance index) Source of funding: TAP Pharmaceutical Products Inc (2 authors appear to have major conflicts of interest) | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | Quote: "After successful enrollment based on inclusion and exclusion criteria, women were sequentially assigned subject numbers in ascending numerical order that encoded the assignment of the woman, via a randomization schedule, to one of the three treatment arms of the study." | | Allocation concealment (selection bias) | Unclear risk | Not reported | | Blinding of participants and personnel (performance bias) All outcomes | Low risk | Participants and all study personnel were blinded. | | Blinding of outcome assessment (detection bias) All outcomes | Low risk | Participants and all study personnel were blinded. | | Incomplete outcome data (attrition bias) All outcomes | Low risk | No withdrawals | | Selective reporting (reporting bias) | Low risk | All prespecified outcomes reported | | Other bias | Low risk | Groups comparable at baseline | Zullo 1998. | Study characteristics | || | Methods | Non‐blinded, parallel‐group RCT Computer‐generated random assignment to 2 centres in the study, with no blinding | | | Participants | Setting: 2 centres in Italy Sample size Number randomised: n = 74 Number completed: n = 67 (2 exclusions after randomisation: 2 from Rx group and 5 from control group, either because fibroid pedunculated or < 4 cc in volume or because of severe adhesions or endometriosis Participant (baseline) characteristics Age: women aged 24 to 45 years Inclusion criteria: women with symptomatic fibroids, history of infertility > 3 years or recurrent abortions, symptoms of increased vaginal bleeding, pelvic pain or pressure, lack of pedunculation of the main myoma with size 4 cc to 500 cc from ultrasound, presence of ≤ 4 myomas per woman, absence of submucosal fibroids from hysteroscope, absence of calcification in main myoma from ultrasound, absence of atypical hyperplasia from endometrial biopsy, absence of abnormal pap smear, negative urine pregnancy test result Exclusion criteria: no additional criteria stated | | | Interventions | Intervention group: intramuscular leuprolide acetate depot 3.75 mg followed by laparoscopic myomectomy, n = 35 Comparator group: no preoperative treatment before laparoscopic myomectomy, n = 32 Duration of GnRHa treatment: 2 months | | | Outcomes | Preoperativeoutcomes: preoperative uterine volume (cc), preoperative fibroid volume (cc) Intraoperative outcomes: duration of surgery (also analysed separately in strata, number of fibroids, volume of fibroids and echogenicity), intraoperative blood loss (mL), intraoperative blood transfusion rate Postoperative outcomes: postoperative haemoglobin (g/dL), postoperative complication rate, change in fertility status (data not provided) | | | Notes | Attempt made to contact author for additional data but no reply received Power calculation performed and ITT analysis Source of funding not stated | | | Risk of bias | || | Bias | Authors' judgement | Support for judgement | | Random sequence generation (selection bias) | Low risk | “The enrolled patients were allocated to one of the two groups according to the same computer‐generated random assignment for both centres.” | | Allocation concealment (selection bias) | Unclear risk | Not reported | | Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Participants would not be blinded to immediate or delayed surgery. There were no details on whether personnel were blinded. | | Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | No details provided | | Incomplete outcome data (attrition bias) All outcomes | Low risk | “All randomized patients recruited for the study for whom data were available were included in the efficacy analysis.” No loss to follow‐up: “All 67 patients have a clinical follow‐up of at least 6 months.” | | Selective reporting (reporting bias) | Unclear risk | Outcomes not clearly reported | | Other bias | Low risk | Groups appeared comparable at baseline | BMI: body mass index; cc: cubic centimetres; CD34: haematopoietic progenitor cell antigen; CDB‐2914: a type of selective progesterone receptor modulator; cm³: cubic centimetres; CYP384: a type of oxidising enzyme; D‐Trp: D‐Tryptophan, an amino acid; FIGO: International Federation of Gynaecology and Obstetrics; FSH: follicle stimulating hormone; g/dL: grams per decilitre; G1: fibroids with intramural portion of < 50%; GnRHa: gonadotropin‐releasing hormone analogues; GO: fibroids completely intracavity; Hb: haemoglobin; IDA: iron deficiency anaemia; IM: intramuscular; ITT: intention to treat; kg/m²: kilograms per square metre; LA: leucocyte antigen; LH: luteinising hormone; LHRH: luteinising hormone releasing hormone; mg: milligram; mL: millilitre; MRI: magnetic resonance imaging; N: number of participants; NIH: National Institute of Health; nmol/L: nanomoles per litre; NSAIDs: non‐steroidal anti‐inflammatory drugs; PBAC: pictorial blood assessment chart; PCNA: anti‐proliferating cell nuclear antigen; RCT: randomised controlled trial; Ru 486: mifepristone; Rx: treatment; SC: subcutaneous; SD: standard deviation; SI:stress incontinence; SHBG: sex hormone binding globulin; SLL: second look laparoscopy; SPRM: selective progesterone receptor modulator; TVUS: transvaginal ultrasound; UFS‐QOL: Uterine Fibroid Symptom and Health‐Related Quality of Life Questionnaire; UPA: ulipristal acetate; VAS: visual analogue scale; vs: versus Characteristics of excluded studies [ordered by study ID] | Study | Reason for exclusion | |---|---| | Bassaw 2014 | Randomisation was alternate, which is subject to bias. | | Bigatti 2014 | Conference abstract, no data or full text Randomisation method not provided. Total number of participants = 7, divided into 5 study groups with 0 participants in 3 out of 5 groups | | Bizzari 2015 | Prospective study but not randomised | | Bondi 2016 | Retrospective analysis of a prospectively collected database | | Coddington 2009 | Objective of trial was to measure outcomes not included in the review | | De Falco 2006 | Intervention was not relevant to this review. | | Di Lieto 2005 | Trial of add‐back therapy, which is covered in another Cochrane review (Moroni 2015) | | Donnez 2014 | Intervention was given long term and women participants were trying to avoid surgery. | | Elzaher 2013 | Participants had either fibroids or adenomyosis and no disaggregated data were provided for women with fibroids. | | Ferrero 2016a | Retrospective analysis of a prospectively collected database | | Ferrero 2016b | Prospective study but not randomised | | Hasan 2014 | Intervention was misoprostol, which is covered in another Cochrane review (Kongnyuy 2014) | | Hutsikava 2016 | No indication whether the study was randomised ‐ unequal numbers in the two groups. | | Mizutani 2005 | The intervention in this study was not relevant to this review. | | Nakano 1998 | Appeared to be a dose finding study of different types of GnRHa without a control arm | | Palomba 2001 | Trial of add‐back therapy, which is covered in another Cochrane review (Moroni 2015) | | Parsanezhad 2010 | Wrong participants ‐ no mention of surgery after interventions | | Russo 1998 | Not RCT ‐ participants could chose their treatment. | | Rutgers 1995 | Did not measure outcomes relevant to the review | | Shipika 2023 | Wrong study population | | Simon 2016 | RCT, but treatment was not given preoperatively ‐ no indication whether the participants went on to have surgery. | | Tabatabai 2015 | Intervention was misoprostol, which is covered in another Cochrane review (Kongnyuy 2014) | | Triolo 2006 | Participants had either endometrial polyps, submucous myoma or septate uterus and results were reported for the whole group. | | Weeks 2000 | The women in this study did not have fibroids. | | Ylikorkala 1995 | The study author was contacted for extra information not contained in the publication but no reply was received. The study population consisted of women with fibroids and women with menometrorrhagia and pelvic pain and data were not provided separately for the women with fibroids. | GnRHa: gonadotropin‐hormone releasing analogues; RCT: randomised controlled trial Characteristics of studies awaiting classification [ordered by study ID] Benagiano 1992. | Methods | Review | | Participants | | | Interventions | | | Outcomes | | | Notes | Trial authors contacted for information regarding participant selection | Gambardella 1995. | Methods | Parallel‐group RCT | | Participants | N = 58, aged 25 to 51 years, with symptomatic fibroids | | Interventions | Goserelin depot 3.6 mg/month for 6 months followed by surgery (unspecified) versus immediate surgery without preoperative medical therapy | | Outcomes | Uterine volume, intraoperative blood loss and adverse events | | Notes | Study published in Italian, translation pending | Sun 2021. | Methods | RCT | | Participants | 180 | | Interventions | 90 participants received 12.5 mg daily mifepristone pretreatment 3 months before laparoscopic myomectomy versus 90 participants with no intervention | | Outcomes | Surgery time, intraoperative blood loss, postoperative haemoglobin, QoL, hospital stay | | Notes | Several attempts to contact the authors were made, unsuccesfully, in order to clarify methods and data. | QoL: quality of liife; RCT: randomised controlled trial Characteristics of ongoing studies [ordered by study ID] Kawahara 2024. | Study name | Kawahara 2024 | | Methods | RCT, non‐blinded, parallel assignment Target sample size 140 | | Participants | Inclusion criteriaWomen diagnosed with uterine leiomyoma Scheduled for an abdominal or laparoscopic hysterectomy or myomectomy Premenopausal female Age at the time of consent is between 20 and 51 years old (under 51) Capacity to consent and is able to give written consent of her own will ECOG‐PS1 or lower (within 1)(ECOG‐PS1 means that the patient is limited in strenuous activities, but can walk and perform light or sedentary work) Exclusion criteria Complicated uterine adenomyosis Use of sex hormones within 4 weeks prior to obtaining consent Previous treatment with uterine artery embolisation or focused ultrasound therapy Diagnosed with a malignant tumour Diagnosed with a disease with abnormal blood coagulation Undertreatment of an anticoagulant Pregnant or susceptible to pregnancy, or in lactation Abnormal genital bleeding without a diagnosis Allergy history to relugolix or synthetic luteinising hormone‐releasing hormone (LH‐RH) or LH‐RH derivatives Continuously taking erythromycin or rifampicin Patients who are deemed unsuitable for this study by the principal investigator or collaborator | | Interventions | The initial dose of relugolix is 40 mg orally once daily before meals, starting on days 1–5 of the menstrual cycle until day 56. On day 57, the control group will continue taking 40 mg of relugolix every day, and the intervention group will switch to 40 mg of relugolix every other day. However, change to another group will not be permitted. | | Outcomes | Primary The primary endpoint will be the change rate of leiomyoma volume before and after the administration of Relugolix. Secondary Change in uterine volume from pretreatment at 24 weeks post‐treatment (%) Change in total Kupperman Index score at 24 weeks post‐treatment from pretreatment (points) Change in bone mineral density (BMD) from baseline at 24 weeks post‐treatment (%) Change in bone metabolism markers (BAP) from baseline at 24 weeks after study drug administration (%) | | Starting date | 26 July 2023 Actual date of first enrolment 25 October 2023 | | Contact information | shoichiroyamanaka@naramed‐u.ac.jp naoki35@naramed‐u.ac.jp | | Notes | Japan Registry of Clinical Trials jRCTs051230078. Registered on 26 July 2023 | Kitade 2024. | Study name | Kitade 2024 | | Methods | Multicentre, randomised, open‐label, parallel‐group, noninferiority trial | | Participants | Premenopausal women ≥ 20 years of age, diagnosed with uterine fibroids and scheduled for laparoscopic myomectomy. Participants (n = 80) will be recruited in the clinical setting of participating institutions. Inclusion criteria Age ≥ 20 years Premenopausal women Diagnosis of uterine fibroids by magnetic resonance imaging (MRI) ≤ 5 uterine fibroids, ≥ 2 cm at the largest dimension (MRI findings during screening) Largest uterine fibroid diameter ≥ 4 cm and ≤ 12 cm (MRI findings during screening) Scheduled for LM Can give written, informed consent for participation in the study Exclusion criteria History of pelvic surgery (excluding caesarean section) Complicating of ovarian cysts or endometriosis (diagnostic imaging) Complicating of uterine adenomyosis Sex hormones used within 4 weeks before the signing of the informed consent form GnRH analogues used within 19 weeks (sustained‐release formulation) or 15 weeks before the signing of the informed consent form Contraindicated for laparoscopic surgery Presence of malignant tumours Coagulation abnormalities Anticoagulant use Suspected or confirmed pregnancy, or breastfeeding Undiagnosed abnormal genital bleeding Hypersensitivity to any component of relugolix tablets or leuprorelin for injection, LH‐RH or LH‐RH derivatives | | Interventions | Relugolix group: one oral relugolix 40 mg tablet daily before one meal for 12 weeks. Leuprorelin group: participants will receive a subcutaneous (SC) leuprorelin injection of 1.88 mg or 3.75 mg (according to body weight and degree of uterine enlargement) at the medical institution once every four weeks for 12 weeks | | Outcomes | PrimaryIntraoperative blood loss Secondary Surgical outcomes (operative time, extracted myoma weight and number, required blood transfusion or not, switch to open surgery or not, postoperative drainage volume, length of postoperative hospital stays) Per cent change from baseline in uterine fibroid size at the end of preoperative drug treatment (week 12) Percent change from baseline in uterine volume at the end of preoperative drug treatment (week 12) and post‐surgical week 12 Change from the predose value in haemoglobin at the end of preoperative drug treatment (week 12) and post‐surgical day 1, week 4, and week 12 Change from the predose value in menopausal‐like symptoms: Kupperman Konenki Shogai Index (KKSI) at week 4, week 8, and week 12 of preoperative drug treatment and post‐surgical week 4 and week 12 Change from the predose value in disease‐specific QOL: Uterine Fibroid Symptom Health‐Related Quality of Life (UFS‐QOL) at the end of preoperative drug treatment (week 12) and post‐surgical week 12 Safety outcome measures Adverse events; adverse drug reactions; intraoperative complications; postoperative complications Blood pressure Endocrinology (estradiol, progesterone, luteinising hormone, follicle‐stimulating hormone) Blood chemistry (aspartate aminotransferase, alanine aminotransferase, triglycerides, total cholesterol, high‐density lipoprotein cholesterol, low‐density lipoprotein cholesterol) Bone mineral density Bone turnover markers (tartrate‐resistant acid phosphatase‐5b, bone‐specific alkaline phosphatases) Menstrual status (start and end dates) Endometrial thickness Histopathological examination of the extracted myoma, including examination for malignancy or cellular degeneration | | Starting date | Recruitment began on 19 January 2022 and ended on 31 December 2023. The current protocol is version 5.0, dated on 7 July 2023. | | Contact information | [email protected] | | Notes | jRCTs031210564 was registered on 19 January 2022 in the Japan Registry of Clinical Trials (https://jrct.niph.go.jp). This protocol was published after recruitment ended. | RCT: randomised controlled trial Differences between protocol and review In the original version of the review, gonadotropin‐releasing hormone analogues (GnRHa) alone were assessed as treatment before fibroid surgery. In 2017, the review authors and the Co‐ordinating Editor of the Cochrane Gynaecology and Fertility Group decided to expand the scope of the review. The scope of eligible interventions was expanded to include all preoperative medical agents used when surgery was expected to follow. This change in scope meant that we changed the previous title from Pre‐operative GnRH analogue therapy before hysterectomy or myomectomy for uterine fibroids to Preoperative medical therapy before surgery for uterine fibroids. We also decided to clarify the inclusion criteria, stating that any trials that measured only surrogate outcomes were not eligible for inclusion. All methods used in this updated version of the review comply with current Cochrane standards. Contributions of authors Beverley Vollenhoven selected trials for inclusion in the first review published in 1998, assessed the included trials for quality and performed data extraction, reviewed both the protocol and final draft of the review and wrote the conclusions section in the abstract. Martin Sowter wrote the discussion and conclusions sections of the review and commented on the final draft. Anne Lethaby registered the title, prepared the protocol and incorporated suggested changes, performed searches, selected trials for inclusion in the review, assessed the included trials for quality and performed data extraction, entered data, prepared the final draft of the review and incorporated suggested changes from the peer review. The review was updated in October 2000 (Lethaby 2000). Additional searches were performed by Anne Lethaby, Sue Furness and information specialists employed by BMJ Clinical Evidence. Anne Lethaby and Beverley Vollenhoven selected additional trials for inclusion and extracted data from the included trials. Anne Lethaby entered the data and made modifications to the text of the review. For the 2017 and 2025 updates, Anne Lethaby conducted additional searches. Anne Lethaby, Lucian Puscasiu and Beverley Vollenhoven selected additional trials for inclusion and extracted data in duplicate. Anne Lethaby entered data and these were checked by Lucian Puscasiu. Both authors made modifications to the text of the review. Ioana‐Marta Melinte contributed to the wording in the background and results sections. Helen Nagels advised on content and format throughout. Beverley Vollenhoven made some suggestions for the revised background and approved the revised review. Marian Showell conducted database searches and reviewed the abstract and searching section text. One author involved in previous published versions of this review in 1999 and 2001 is no longer on the author byline: Martin Sowter. Some of the content retained in this review reflects his contributions. Sources of support Internal sources - Department of Obstetrics and Gynaecology, University of Auckland, New Zealand Editorial spport External sources - Health Research Council, Auckland, New Zealand Salary support for author of 2001 review Dr Martin Sowter Declarations of interest Anne Lethaby: is a copy editor for Cochrane Central Production Service but has had no involvement in the editorial process for any version of this review. She was the first author for previous versions of this review (prior to becoming a copy editor). Lucian Puscasiu (LP): is a co‐author of an included trial in this review (Donnez 2012a); he took no part in selecting or assessing this study for the current published version or the 2017 version of this review. LP has received publication and speaking fees as well as travel expenses and fees in connection with ESMYA launch symposium in March 2012 in Barcelona from the company Gedeon‐Richter. LP also received investigator's fees from the company ICON during the PEARL I study in 2010. Beverley Vollenhoven: none known Ioana‐Marta Melinte: none known Marian Showell: is the information specialist for Cochrane Gynaecology and Fertility Group but has had no involvement in the editorial process for this update. Helen Nagels: is managing editor of Cochrane Gynaecology and Fertility but has had no involvement in the editorial process for this update. New search for studies and content updated (no change to conclusions)

References to studies included in this review Audebert 1994 {published data only} - Audebert AJM, Madenelat P, Querleu D, Pontonnier G, Racinet C, Renaud R, et al. Deferred versus immediate surgery for uterine fibroids: clinical trial results. British Journal of Obstetrics and Gynaecology 1994;101(Suppl):29-32. [DOI] [PubMed] [Google Scholar] Balasch 1995 {published data only} - Balasch J, Manau D, Mimó J, Duran M, Puerto B, Vanrell JA. Trial of routine gonadotropin releasing hormone agonist treatment before abdominal hysterectomy for leiomyoma. Acta Obstetricia et Gynecologica Scandinavica 1995;74(7):562-5. [DOI] [PubMed] [Google Scholar] Baytur 2007 {published data only} - Baytur YB, Ozbilgin K, Cilaker S, Lacin S, Kurtul O, Oruc S, et al. A comparative study of the effect of raloxifene and gosereline on uterine leiomyoma volume changes and estrogen receptor, progesterone receptor, bcl-2 and p53 expression immunohistochemically in premenopausal women. European Journal of Obstetrics, Gynecology, and Reproductive Biology 2007;135(1):94-103. [DOI] [PubMed] [Google Scholar] Benagiano 1996 {published data only} - Benagiano G, Kivinen ST, Fadini R, Cronje H, Klintorp S, Van der Spuy Z. Zoladex (goserelin acetate) and the anemic patient: results of a multicenter fibroid study. Fertility and Sterility 1996;66(2):223-9. [PubMed] [Google Scholar] Bian 2021 {published data only} - Bian M, Huang M, Zhang Z, Liu S, Sun J, Fang F, et al. Preoperative treatment of uterine fibroids with low-dose mifepristone: a multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Chinese Journal of Obstetrics and Gynecology 2021;56(5):317-27. [DOI] [PubMed] [Google Scholar] Bustos López 1995 {published data only} - Bustos López HH, Miranda Rodríguez JA, Kably Ambe A, Serviere Zaragoza C, Espinoza de los Monteros A, Alvarado Durán A. Pre-operative medical treatment of uterine leiomyomatosis with hypophysiary gonadotropin releasing hormone analogues [Tratamiento médico preoperatorio de leiomiomatosis uterina con análogos de hormona liberadora de gonadotropinas hipofisiarias]. Ginecología y Obstetricia de México 1995;63(8):356-64. [PubMed] [Google Scholar] Cagnacci 1994 {published data only} - Cagnacci A, Paoletti AM, Soldani R, Angiolucci M, Arangino S, Falqui A, et al. Role of goserelin-depot in the clinical management of uterine fibroids. Clinical and Experimental Obstetrics & Gynecology 1994;21(4):263-5. [PubMed] [Google Scholar] Campo 1999 {published data only} - Campo S, Garcea N. Laparoscopic myomectomy in premenopausal women with and without preoperative treatment using gonadotropin-releasing hormone analogues. Human Reproduction (Oxford, England) 1999;14(1):44-8. [DOI] [PubMed] [Google Scholar] Cetin 1995 {published data only} - Cetin MT, Vardar MA, Demir SC Kibar M. Administration of preoperative gonadotropin releasing hormone agonist (buserelin) for uterine leiomyomas. Annals of Medical and Health Sciences Research 1995;4:102-8. [Google Scholar] D'Anna 1994 {published data only} - D'Anna R, Palmara V, Lo Re C, Scilipoti A, Leonardi I. Short treatment with leuprolide acetate depot before hysterectomy for uterine leiomyomata [Breve trattamento con leuprolide acetato depot prima di intervento chirurgico per leiomiomatosi uterina]. Minerva Ginecologica 1994;46(6):343-6. [PubMed] [Google Scholar] De Falco 2009 {published data only} - De Falco M, Staibano S, Mascolo M, Mignogna C, Improda L, Ciociola F, et al. Leiomyoma pseudocapsule after presurgical treatment with gonadotropin-releasing hormone agonists: relationship between clinical features and immunohistochemical changes. European Journal of Obstetrics, Gynecology, and Reproductive Biology 2009;144(1):44-7. [DOI] [PubMed] [Google Scholar] De Milliano 2020 {published data only} - De Milliano I, Huirne JAF, Radder C, Bongers MY, Van Vliet H, Van de Lande J, et al. Ulipristal acetate vs gonadotropin‐releasing hormone agonists prior to laparoscopic myomectomy (MYOMEX trial): short‐term results of a double‐blind randomized controlled trial. Acta Obstetrica Gynecologica Scandinavica 2019;99:89-98. [DOI: 10.1111/aogs.13713] [DOI] [PMC free article] [PubMed] [Google Scholar] - De Milliano I, Middelkoop MA, Huirne JA, Kwee J, Geomini PMAJ, Schoot BC, et al. Ulipristal acetate versus gonadotropin-releasing hormone agonists prior to laparoscopic myomectomy (MYOMEX trial): long term results of a double-blind randomized controlled trial. European Journal of Obstetrics, Gynecolology and Reproductive Biology 2020;252:256-64. [DOI: 10.1016/j.ejogrb.2020.06.035] [DOI] [PubMed] [Google Scholar] - NCT02288130. Ulipristal acetate vs GnRHa prior to laparoscopic myomectomy (MYOMEX). https://clinicaltrials.gov/study/NCT02288130 (first received 6 November 2014). Donnez 2003 {published data only} - Donnez J , Vivancos B, Kudela M, Audebert A, Jadoul P. A randomized, placebo-controlled, dose-ranging trial comparing fulvestrant with goserelin in premenopausal patients with uterine fibroids awaiting hysterectomy. Fertility and Sterility 2003;79(6):1380-9. [DOI] [PubMed] [Google Scholar] Donnez 2012a {published data only} - Donnez J, Tatarchuk TF, Bouchard P, Puscasiu L, Zakharenko NF, Ivanova T, et al, PEARL I Study Group. Ulipristal acetate versus placebo for fibroid treatment before surgery. New England Journal of Medicine 2012;366(5):409-20. [DOI] [PubMed] [Google Scholar] Donnez 2012b {published data only} - Donnez J, Tomaszewski J, Vázquez F, Bouchard P, Lemieszczuk B, Baró F, et al, PEARL II Study Group. Ulipristal acetate versus leuprolide acetate for uterine fibroids. New England Journal of Medicine 2012;366(5):421-32. [DOI] [PubMed] [Google Scholar] Engman 2009 {published data only} - Engman M, Granberg S, Williams AR, Meng CX, Lalitkumar PGL, Gemzell-Danielsson K. Mifepristone for treatment of uterine leiomyoma. A prospective randomised placebo controlled trial. Human Reproduction (Oxford, England) 2009;24(8):1870-9. [DOI] [PubMed] [Google Scholar] Favilli 2017 {published data only} - Favilli A, Mazzon I, Grasso M, Horvath S, Bini V, Di Renzo GC, et al. Intraoperative effect of preoperative gonadotropin-releasing hormone analogue administration in women undergoing cold loop hysteroscopic myomectomy: a randomized controlled trial. Journal of Minimally Invasive Gynecology 2017;25(4):706-14. [DOI] [PubMed] [Google Scholar] - NCT01873378. GnRH agonist pretreatment in hysteroscopic myomectomy. clinicaltrials.gov/ct2/show/NCT01873378 (first received 1 June 2013). Fedele 1990 {published data only} - Fedele L, Vercellini P, Bianchi S, Brioschi D, Dorta M. Treatment with GnRH agonists before myomectomy and the risk of short-term myoma recurrence. British Journal of Obstetrics and Gynaecology 1990;97(5):393-6. [DOI] [PubMed] [Google Scholar] Friedman 1989 {published data only} - Friedman AJ, Daly M, Juneau-Norcross M, Fine C, Rein MS. Recurrence of myomas after myomectomy in women pretreated with leuprolide acetate depot or placebo. Fertility and Sterility 1992;58(1):205-8. [DOI] [PubMed] [Google Scholar] - Friedman AJ, Rein MS, Harrison-Atlas D, Garfield JM, Doubilet PM. A randomized, placebo-controlled, double-blind study evaluating leuprolide acetate depot treatment before myomectomy. Fertility and Sterility 1989;52(5):728-33. [PubMed] [Google Scholar] Gerris 1996 {published data only} - Gerris J, Degueldre M, Peters AAW, Romao F, Stjernquist M, Aal-Taher H. The place of Zoladex in deferred surgery for uterine fibroids. Zoladex Myoma Study Group. Hormone Research 1996;45(6):279-84. [DOI] [PubMed] [Google Scholar] Golan 1993 {published data only} - Golan A, Bukovsky I, Pansky M, Schneider D, Weinraub Z, Caspi E. Pre-operative gonadotropin-releasing hormone agonist treatment in surgery for uterine leiomyomata. Human Reproduction (Oxford, England) 1993;8(3):450-2. [DOI] [PubMed] [Google Scholar] - Golan A, Bukovsky I, Schneider D, Pansky M, Caspi E. Preoperative GnRH-analog treatment in surgery for uterine myomas. In: 3rd International Sympoisum on Gynaecological Endocrinology, Switzerland, 25-28 Feb 1993. 1993:15. Hudecek 2012 {published data only} - Hudecek R, Ivanová Z, Smerdová M, Pánková S, Krajcovicová R. Effect of GnRH analogues pre-treatment on myomectomy outcomes in reproductive age women. Ceska Gynekologie 2012;77(2):109-17. [PubMed] [Google Scholar] Levens 2008 {published data only} - Levens ED, Potlog-Nahari C, Armstrong AY, Wesley R, Premkumar A, Blithe DL, et al. CDB-2914 for uterine leiomyomata treatment. Obstetrics and Gynecology 2008;111(5):1129-36. [DOI] [PMC free article] [PubMed] [Google Scholar] Lumsden 1994 {published data only} - Lumsden MA, West CP, Thomas E, Coutts J, Hillier H, Thomas N, et al. Treatment with the gonadotropin releasing hormone-agonist goserelin before hysterectomy for uterine fibroids. British Journal of Obstetrics and Gynaecology 1994;101(5):438-42. [DOI] [PubMed] [Google Scholar] Mavrelos 2010 {published data only} - Mavrelos D, Ben-Nagi J, Davies A, Lee C, Salim R, Jurkovic D. The value of preoperative treatment with GnRH analogues in women with submucous fibroids: a double blind placebo controlled randomised trial. Human Reproduction (Oxford, England) 2010;25(9):2264-9. [DOI] [PubMed] [Google Scholar] Muneyyirci‐Delale 2007 {published data only} - Muneyyirci-Delale O, Richard-Davis G, Morris T, Armstrong J. Goserelin acetate 10.8 mg plus iron monotherapy prior to surgery in premenopausal women with iron deficiency anemia due to uterine leiomyomas: results from a phase III, randomized, multicenter, double blind, controlled trial. Clinical Therapeutics 2007;29(8):1682-91. [DOI] [PubMed] [Google Scholar] Muzii 2010 {published data only} - Muzii L, Boni T, Bellati F, Marana R, Ruggiero A, Zullo MA, et al. GnRH analogue treatment before hysteroscopic resection of submucous myomas: a prospective, randomised, multicenter study. Fertility and Sterility 2010;94(4):1496-9. [DOI] [PubMed] [Google Scholar] Nikolov 1999 {published data only} - Nikolov A, Karag'osov I. Comparative study on the efficacy of preoperative use of GnRH agonists in patients with uterine fibromyomas. Akuserstvo i Ginekologija 1999;38(4):38-42. [PubMed] [Google Scholar] - Nikolov N, Karag'osov I. Preoperative use of Zoladex for treatment of uterine fibromyomas (abstract). Acta Obstetricia et Gynecologica Scandinavica 1997;76(Suppl):31. [Google Scholar] Reinsch 1994 {published data only} - Reinsch RC, Murphy AA, Morales AJ, Yen SSC. The effects of RU 486 and leuprolide acetate on uterine artery blood flow in the fibroid uterus: a prospective randomised study. American Journal of Obstetrics and Gynecology 1994;170(6):1623-8. [PubMed] [Google Scholar] Sayyah‐Melli 2007 {published data only} - Sayyah-Melli M, Farzadi L, Madarek EO. Comparison of the effect of gonadotropin-releasing hormone analog (Diphereline) and Cabergoline (Dostinex) treatment on uterine myoma regression. Saudi Medical Journal 2007;28(3):445-50. [PubMed] [Google Scholar] Sayyah‐Melli 2009 {published data only} - Sayyah-Melli M, Tehrani-Gadim S, Dastranj-Tabrizi A, Gatrehsamani F, Morteza G, Ouladesahebmadarek E, et al. Comparison of the effect of gonadotropin-releasing hormone agonist and dopamine receptor agonist on uterine myoma growth. Saudi Medical Journal 2009;30(8):1024-33. [PubMed] [Google Scholar] Seraccholi 2003 {published data only} - Seracchioli R, Venturoli S, Colombo F, Bagnoli A, Vianello F, Govoni F, et al. GnRH agonist treatment before total laparoscopic hysterectomy for large uteri. Journal of the American Association of Gynecologic Laparoscopists 2003;10(3):316-9. [DOI] [PubMed] [Google Scholar] Shaw 1989 {published data only} - Shaw RW. Mechanism of LHRH analogue action in uterine fibroids. Hormone Research 1989;32(Suppl 1):150-3. [DOI] [PubMed] [Google Scholar] Shaw 1996 {unpublished data only} - Shaw RW. Placebo controlled comparison of the effectiveness of the microparticles depot formulation of buserelin in the pre-operative management of patients with uterine fibroids. Clinical/biometric report, Hoechst Marion Roussel, UK Ltd (accessed prior to 5 August 2024). Stovall 1994 {published data only} - Stovall TG, Ling FW, Henry LC, Woodruff MR. A randomised trial evaluating leuprolide acetate before hysterectomy as treatment for leiomyomas. American Journal of Obstetrics and Gynecology 1991;164(6 Pt 1):1420-5. [DOI] [PubMed] [Google Scholar] - Stovall TG, Summitt Jr RL, Washburn SA, Ling FW. Gonadotropin-releasing hormone agonist use before hysterectomy. American Journal of Obstetrics and Gynecology 1994;170(6):1744-51. [PubMed] [Google Scholar] Stovall 1995 {published data only} - Stovall TG, Muneyyirci-Delale O, Summitt Jr RL, Scialli AR, Leuprolide Acetate Study Group. GnRH agonist and iron versus placebo and iron in the anemic patient before surgery for leiomyomas: a randomized controlled trial. Obstetrics and Gynecology 1995;86(1):65-71. [DOI] [PubMed] [Google Scholar] Vercellini 1998 {published data only} - Vercellini P, Crosignani PG, Mangioni C, Imparato E, Ferrari A, De Giorgi O. Treatment with a gonadotrophin releasing hormone agonist before hysterectomy for leiomyomas: results of a multicentre, randomised controlled trial. British Journal of Obstetrics and Gynaecology 1998;105(11):1148-54. [DOI] [PubMed] [Google Scholar] Vercellini 2003 {published data only} - Vercellini P, Trespidi L, Zaina B, Vicentini S, Stellato G, Crosignani PG. Gonadotropin-releasing hormone agonist treatment before abdominal myomectomy: a controlled trial. Fertility and Sterility 2003;79(6):1390-5. [DOI] [PubMed] [Google Scholar] Verspyck 2000 {published data only} - Verspyck E, Marpeau L, Lucas C. Leuporelin depot 3.75 mg versus lynestrenol in the preoperative treatment of symptomatic uterine myomas: a multicentre randomised trial. European Journal of Obstetrics, Gynecology, and Reproductive BIology 2000;89(1):7-13. [DOI] [PubMed] [Google Scholar] Wilkens 2008 {published data only} - Wilkens J, Chwalisz K, Han C, Walker J, Cameron IT, Ingamells S, et al. Effects of the selective progesterone receptor modulator asoprisnil on uterine artery blood flow, ovarian activity and clinical symptoms in patients with uterine leiomyomata scheduled for hysterectomy. Journal of Clinical Endocrinology and Metabolism 2008;93(12):4664-71. [DOI] [PubMed] [Google Scholar] - Williams ARW, Critchley HOD, Osei J, Ingamells JS, Cameron IT, Han C, et al. The effects of the selective progesterone receptor modulator asoprisnil on the morphology of uterine tissues after 3 months treatment in patients with symptomatic uterine leiomyomata. Human Reproduction 2007;22(6):1696–1704. [DOI: 10.1093/humrep/dem026] [DOI] [PubMed] [Google Scholar] Zullo 1998 {published data only} - Zullo F, Pellicano M, De Stefano R, Zupi E, Mastrantonio P. A prospective randomised study to evaluate leuprolide acetate treatment before laparascopic myomectomy: efficacy and ultrasonographic predictors. American Journal of Obstetetrics and Gynecology 1998;178(1 Pt 1):108-12. [DOI] [PubMed] [Google Scholar] - Zullo F, Pellicano M, Di Carlo C, De Stefano R, Mastrantonio P, Nappi C. GnRH-a pretreatment and laparoscopic intramural myomectomy: efficacy and ultrasonographic correlations (abstract). In: American Society for Reproductive Medicine. 1996:S134.

to studies excluded from this review Bassaw 2014 {published data only} - Bassaw B, Mohammed N, Jaggat A, SIngh-Bhola M, Ramkissoon A, Singh P, et al. Experience with a gonadotropin-releasing hormone agonist prior to myomectomy - comparison of twice- vs thrice-monthly doses and a control group. Journal of Obstetrics and Gynaecology 2014;34(5):415-9. [DOI] [PubMed] [Google Scholar] Bigatti 2014 {published data only} - Bigatti G, Iemmello R, Desgro M, Pollini S, Santirocco M. Progesterone preoperative treatment before myomectomy with the Intrauterine Bigatti Shaver (IBS). Gynecological Surgery 2014;11(1 Suppl 1):119-20. [Google Scholar] Bizzari 2015 {published data only} - Bizzarri N, Ghirardi V, Remorgida V, Venturini PL, Ferrero S. Three-month treatment with triptorelin, letrozole and ulipristal acetate before hysteroscopic resection of uterine myomas: prospective comparative pilot study. European Journal of Obstetrics, Gynecology, and Reproductive Biology 2015;192:22-6. [DOI] [PubMed] [Google Scholar] Bondi 2016 {published data only} - Bondi C, Maggiore LRU, Alessandri F, Venturini PL, Vellone VG, Ferrero S. Three-month treatment with ulipristal acetate prior to laparoscopic myomectomy of large uterine myomas. Human Reproduction 2016;31(Suppl 1):i467. [DOI] [PubMed] [Google Scholar] Coddington 2009 {published data only} - Coddington CC, Grow D, Ahmed MS, Toner JP, Cook E, Diamond MP. Gonadotropin-releasing hormone agonist pretreatment did not decrease postoperative adhesion formation after abdominal myomectomy in a randomized control trial. Fertility and Sterility 2009;91(5):1909-13. [DOI] [PubMed] [Google Scholar] De Falco 2006 {published data only} - De Falco M, Staibano S, D'Armiento FP, Mascolo M, Salvatore G, Busiello A. Preoperative treatment of uterine leiomyomas: clinical findings and expression of transforming growth factor-beta3 and connective tissue growth factor. Journal of the Society for Gynecologic Investigation 2006;13(4):297-300. [DOI] [PubMed] [Google Scholar] Di Lieto 2005 {published data only} - Di Lieto A, De Falco M, Mansueto G, De Rosa G, Pollio F, Staibano S. Preoperative administration of GnRH-a plus tibolone to premenopausal women with uterine fibroids: evaluation of the clinical response, the immunohistochemical expression of PDGF, bFGF and VEGF and the vascular pattern. Steroids 2005;70(2):95-102. [DOI] [PubMed] [Google Scholar] Donnez 2014 {published data only} - Donnez J, Vazquez F, Tomaszewski J, Nouri K, Bouchard P, Fauser BCJM, et al, the PEARL III and PEARL III extension study group. Long term treatment of uterine fibroids with ulipristal acetate. Fertility and Sterility 2014;10(6):1565-73. [DOI] [PubMed] [Google Scholar] Elzaher 2013 {published data only} - Elzaher MA, Moawad A, Madkour WA, Ali M, Salah Eldin Abdel Hamid AM, Zaheer H. Does medical debulking with gonadotropin-releasing hormone agonist facilitate vaginal hysterectomy with a moderate enlarged uterus? A randomised controlled study. European Journal of Obstetrics, Gynecology, and Reproductive Biology 2013;169(2):326-30. [DOI] [PubMed] [Google Scholar] Ferrero 2016a {published data only} - Ferrero S, Racca A, Tafi E, Alessandri F, Venturini PL, Maggiore LRU, et al. Ulipristal acetate before high complexity hysteroscopic myomectomy: a retrospective comparative study. Journal of Minimally Invasive Gynecology 2016;23(3):390-5. [DOI] [PubMed] [Google Scholar] Ferrero 2016b {published data only} - Ferrero S, Racca A, Tafi E, Scala C, Alessandri F, Venturini PL, et al. Ulipristal acetate versus triptorelin prior to laparoscopic myomectomy: prospective study. Journal of Minimally Invasive Gynecology 2016;23(7 Suppl 1):S199. [Google Scholar] Hasan 2014 {published data only} - Hasan M, Nasir A, Saba E. Color Doppler misoprostol response study (CDMRS): an evaluation tool for patients awaiting myomectomy. Journal of Medical Ultrasound 2014;22(2):78-82. [Google Scholar] Hutsikava 2016 {published data only} - Hutsikava L. The preoperative treatment of women with myoma of the uterus using ulipristal acetate. Gynecological Endocrinology 2016;32(Suppl 1):50. [Google Scholar] Mizutani 2005 {published data only} - Mizutani T, Sugihara A, Honma H, Komura H, Nakamuro K, Terada N. Effect of steroid add-back therapy on the proliferative activity of uterine leiomyoma cells under gonadotropin-releasing hormone agonist therapy. Gynecological Endocrinology 2005;20(2):80-3. [DOI] [PubMed] [Google Scholar] Nakano 1998 {published data only} - Nakano H, Kawasima M, Okada S, Igarashi T, Maejima M, Ogino M. The study of the effect of presurgical GnRH agonist treatment for women with uterine leiomyoma - effect on the myoma volume and the operation. Japanese Journal of Fertility and Sterility 1998;43:289-93. [Google Scholar] Palomba 2001 {published data only} - Palomba S, Massimiliano P, Affinito P, Di Carlo C, Zullo F, Nappi C. Effectiveness of short term administration of tibolone plus gonadotropin-releasing hormone analogue on the surgical outcome of laparoscopic myomectomy. Fertility and Sterility 2001;75(2):429-33. [DOI] [PubMed] [Google Scholar] Parsanezhad 2010 {published data only} - Parsanezhad ME, Azmoon M, Alborzi S, Rajaeefard A, Zarei A, Kazerooni T, et al. A randomised controlled clinical trial comparing the effects of aromatase inhibitor (letrazole) and gonadotropin-releasing hormone agonist (triptorelin) on uterine leiomyoma volume and hormonal status. Fertility and Sterility 2010;93(1):192-8. [DOI] [PubMed] [Google Scholar] Russo 1998 {published data only} - Russo P, Ciolli P, Atlante M, Carico EE, Mancini R, Russo R, et al. Clinical use of leuprolide acetate depot in a group of gynecologic patients in the preoperative period. Minerva Ginecologica 1998;50(11):499-502. [PubMed] [Google Scholar] Rutgers 1995 {published data only} - Rutgers J, Spong C, Sinow R, Heiner J. Leuprolide acetate treatment and myoma arterial size. Obstetrics and Gynecology 1995;86(3):386-8. [DOI] [PubMed] [Google Scholar] Shipika 2023 {published data only} - Shipika D. Ulipristal acetate versus placebo for fibroid treatment. International Journal of Advanced Research 2023;11(07):1348-54. [DOI: 10.21474/IJAR01/17351] [DOI] [Google Scholar] Simon 2016 {published data only} - Simon J, Catherino WH, Segars J, Blakesley R, Chan A, Sniukiene V, et al. First US-based phase 3 study of ulipristal acetate (UPA) for symptomatic uterine fibroids (UF): results of VENUS-1. Fertility and Sterility 2016;106(3):e376. [Google Scholar] Tabatabai 2015 {published data only} - Tabatabai A, Karimi-Zarchi M, Meibodi B, Vaghefi M, Yazdian P, Zeidabadi M, et al. Effects of a single rectal dose of Misoprostol prior to abdominal hysterectomy in women with symptomatic leiomyoma: a randomised double blind clinical trial. Electronic Physician 2015;7(6):1372-5. [DOI] [PMC free article] [PubMed] [Google Scholar] Triolo 2006 {published data only} - Triolo O, De Vivo A, Benedetto V, Falcone S, Antico F. Gestrinone versus danazol as preoperative treatment for hysteroscopic surgery: a prospective randomised evaluation. Fertility and Sterility 2006;85(4):1027-31. [DOI] [PubMed] [Google Scholar] Weeks 2000 {published data only} - Weeks A , Duffy S, Walker J. A double-blind randomised trial of leuprorelin acetate prior to hysterectomy for dysfunctional uterine bleeding. British Journal of Obstetrics and Gynaecology 2000;107(3):323-8. [DOI] [PubMed] [Google Scholar] - Weeks AD, Duffy SRG, Walker JJ. Uterine ultrasonographic changes with gondatrophin-releasing hormone agonists. American Journal of Obstetrics and Gynecology 1999;180(1):8-13. [DOI] [PubMed] [Google Scholar] Ylikorkala 1995 {published data only} - Ylikorkala O, Tiitinen A, Hulkko S, Kivinen S, Nummi S. Decrease in symptoms, blood loss and uterine size with nafarelin acetate before abdominal hysterectomy: a placebo-controlled, double-blind study. Human Reproduction 1995;10(6):1470-4. [PubMed] [Google Scholar]

to studies awaiting assessment Benagiano 1992 {published data only} - Benagiano G, Morini A, Primiero FM. Fibroids: overview of current and future treatment options. British Journal of Obstetrics and Gynaecology 1992;99(Suppl 7):18-22. [DOI] [PubMed] [Google Scholar] Gambardella 1995 {published data only} - Gambardella F, Capicotto V, Cuneo P, Daminani A, Proto M. Using analogous preoperative Gn-RH in the treatment of symptomatic uterine leiomyomatosis [Uso preoperatorio degli analoghi del Gn-RH nel trattamento della leiomiomatosi uterina sintomatica]. Giornarle Italiano di Ostetrica e Ginecologica 1995;11:658-62. [Google Scholar] Sun 2021 {published data only} - Sun L, Zhou R, Shan X, Lu R. Clinical outcome of pretreatment with mifepristone before laparoscopic myomectomy. Indian Journal of Pharmaceutical Sciences 2021;82(1):72-5. [Google Scholar]

to ongoing studies Kawahara 2024 {published data only} - Kawahara N, Kawaguchi R Yamamoto K, Nishikawa K, Matsuoka M, Maehana T, et al. The clinical trial of alternative relugolix administration for uterine leiomyoma prior to surgically treatment: a study protocol for Non-Adverse Relugolix Administration (NARA) trial. Trials 2024;25:68. [DOI: 10.1186/s13063-024-07923-2] [DOI] [PMC free article] [PubMed] [Google Scholar] Kitade 2024 {published data only} - Kitade M, Kumakiri J, Kobori H, Murakami K. The effectiveness of relugolix compared with leuprorelin for preoperative therapy before laparoscopic myomectomy in premenopausal women, diagnosed with uterine fibroids: protocol for a randomized controlled study (MyLacR study). Trials 2024;25:343. [DOI: 10.1186/s13063-024-08170-1] [DOI] [PMC free article] [PubMed] [Google Scholar] Additional references Al‐Hendy 2017 - Al-Hendy A, Myers ER, Stewart E. Uterine fibroids: burden and unmet medical need. Seminars in Reproductive Medicine 2017;35(6):473-80. [DOI: 10.1055/s-0037-1607264] [DOI] [PMC free article] [PubMed] [Google Scholar] Baird 2003 - Baird DD, Dunson DB, Hill MC, Cousins D, Schectman JM. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. American Journal of Obstetrics and Gynecology 2003;188(1):100-7. [DOI] [PubMed] [Google Scholar] Campo 2005 - Campo S, Campo V, Gambadauro P. Short term and long term results of resectoscopic myomectomy with and without pretreatment with GnRH analogs in premenopausal women. Acta Obstetricia et Gynecologica Scandinavica 2005;84(8):756-60. [DOI] [PubMed] [Google Scholar] Carls 2008 - Carls GS, Lee DW, Ozminkowski RJ, Wang S, Gibson TB, Stewart E. What are the total costs of surgical treatment for uterine fibroids? Journal of Women's Health 2008;17(7):1119-32. [DOI] [PubMed] [Google Scholar] Chen 2011 - Chen I, Motan T, Kiddoo D. Gonadotropin-releasing hormone agonist in laparoscopic myomectomy: systematic review and meta-analysis of randomised controlled trials. Journal of Minimally Invasive Gynecology 2011;18(3):303-9. [DOI] [PubMed] [Google Scholar] Cheng 2022 - Cheng LC, Li HY, Gong QQ, Huang CY, Zhang C, Yan JZ. Global, regional, and national burden of uterine fibroids in the last 30 years: estimates from the 1990 to 2019 Global Burden of Disease Study. Frontiers in Medicine (Lausanne) 2022;9:1003605. [DOI: 10.3389/fmed.2022.1003605] [DOI] [PMC free article] [PubMed] [Google Scholar] Deeks 2023 - Deeks JJ, Higgins JPT, Altman DG (editors). Chapter 10: Analysing data and undertaking meta-analyses. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.4 (updated August 2023). Cochrane, 2023. Available from www.training.cochrane.org/handbook. In: Cochrane Handbook for Systematic Reviews of Interventions version 6.4. Cochrane, 2023, 2023. [Google Scholar] Donnez 2016 - Donnez J, Dolmans MM. Uterine fibroid management: from the present to the future. Human Reproduction Update 2016;22(6):665-8. [DOI: 10.1093/humupd/dmw023] [DOI] [PMC free article] [PubMed] [Google Scholar] Donnez 2020 - Donnez J, Dolmans MM. Fibroids and medical therapy: bridging the gap from selective progesterone receptor modulators to gonadotropin-releasing hormone antagonist. Fertility and Sterility 2020;114(4):739-41. [DOI: ] [DOI] [PubMed] [Google Scholar] Donnez 2022 - Donnez J, Taylor HS, Stewart EA, Bradley L, Marsh E, Archer D, et al. Linzagolix with and without hormonal add-back therapy for the treatment of symptomatic uterine fibroids: two randomised, placebo-controlled, phase 3 trials. Lancet 2022;17(400 (10356)):896-907. [DOI: 10.1016/S0140-6736(22)01475-1.] [DOI] [PubMed] [Google Scholar] EMA 2021 - EMA. Ulipristal-acetate-uterine-fibroids. https://www.ema.europa.eu/en/documents/referral/ulipristal-acetate-5mg-medicinal-products-article-31-referral-ulipristal-acetate-uterine-fibroids_en.pdf. (accessed 30 September 2022). Friedman 1990 - Friedman AJ, Lobel SM, Rein MS, Barbieri RL. Efficacy and safety considerations in women with uterine leiomyomas treated with gonadotrophin-releasing hormone agonists: the estrogen window hypothesis. American Journal of Obstetrics and Gynecology 1990;163(4 Part 1):1114-9. [DOI] [PubMed] [Google Scholar] Geirsson 1993 - Geirsson RT. Intrauterine volume measurement techniques and uteroplacental growth. In: Chervenak FA, Isaacson GC, Campbell S, editors(s). Ultrasound in Obstetrics and Gynecology. Boston: Little, Brown and Company, 1993:405-12. [Google Scholar] Giuliani 2020 - Giuliani E, As-Sanie S, Marsh EE. Epidemiology and management of uterine fibroids. International Journal of Gynaecology and Obstetrics 2020;149(1):3-9. [DOI: 10.1002/ijgo.13102] [DOI] [PubMed] [Google Scholar] GRADEpro GDT 2015 [Computer program] - GRADEpro GDT. Version accessed prior to 18 July 2017. Hamilton (ON): McMaster University (developed by Evidence Prime), 2015. Available at gradepro.org. Gurusamy 2016 - Gurusamy KS, Vaughan J, Fraser IS, Best LMJ, Richards T. Medical therapies for uterine fibroids - a systematic review and network meta-analysis of randomised controlled trials. PloS One 2016;11(2):e0149631. [DOI] [PMC free article] [PubMed] [Google Scholar] Higgins 2011 - Higgins JPT, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from training.cochrane.org/handbook/archive/v5.1. Jacoby 2010 - Jacoby VL, Fujimoto VY, Guidice LC, Kupperman M, Washington AE. Racial and ethnic disparities in benign gynecologic conditions and associated surgeries. American Journal of Obstetrics and Gynecology 2010;202(6):514-21. [DOI] [PMC free article] [PubMed] [Google Scholar] Jirecek 2004 - Jirecek S, Lee A, Pavo I, Crans G, Eppel W, Wenzl R. Raloxifene prevents the growth of uterine leiomyomas in premenopausal women. Fertility and Sterility 2004;81(1):132-6. [DOI] [PubMed] [Google Scholar] Jourdain 1996 - Jourdain O, Descamps P, Abusada N, Ventrillon E, Dallay D, Lansac J, et al. Treatment of fibromas. European Journal of Obstetrics, Gynecology, and Reproductive Biology 1996;66(2):99-107. [DOI] [PubMed] [Google Scholar] Kamath 2014 - Kamath MS, Kalampokas EE, Kalampokas TE. Use of GnRH analogues preoperatively for hysteroscopic resection of submucous fibroids: a systematic review and metaanalysis. European Journal of Obstetrics, Gynecology, and Reproductive Biology 2014;177:11-8. [DOI] [PubMed] [Google Scholar] Kongnyuy 2014 - Kongnyuy EJ, Wiysonge CS. Interventions to reduce haemorrhage during myomectomy for fibroids. Cochrane Database of Systematic Reviews 2014, Issue 8. Art. No: CD005355. [DOI: 10.1002/14651858.CD005355.pub5] [DOI] [PMC free article] [PubMed] [Google Scholar] Lefebvre 2023 - Lefebvre C, Glanville J, Briscoe S, Featherstone R, Littlewood A, Metzendorf M-I et al. Chapter 4: Searching for and selecting studies. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 6.4 (updated October 2023). Cochrane, 2023. Available from https://training.cochrane.org/handbook. Li 2024 - Li T, Higgins JPT, Deeks JJ. Chapter 5: Collecting data [last updated October 2019]. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.5. Cochrane, 2024. Available from www.training.cochrane.org/handbook. Matta 1989 - Matta WHM, Shaw RW, Nye M. Long-term follow-up of patients with uterine fibroids after treatment with the LHRH agonist buserelin. British Journal of Obstetrics and Gynaecology 1989;96(2):200-6. [DOI] [PubMed] [Google Scholar] Merrill 2008 - Merrill RM. Hysterectomy surveillance in the United States, 1997 to 2005. Medical Science Monitor 2008;14(1):CR24-31. [PubMed] [Google Scholar] MHRA - Medicines & Healthcare Products Regulatory Agency (MHRA). https://www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatory-agency 2021 (accessed November 2023). Middelkoop 2021 - Middelkoop M-A, Bet PM, Drenth JPH, Huirne JAF, Hehenkamp WJK. Risk-efficacy balance of ulipristal acetate compared to surgical alternatives. British Journal of Clinical Pharmacology 2021;87(7):2685-97. [DOI: ] [DOI] [PMC free article] [PubMed] [Google Scholar] Middelkoop 2022 - Middelkoop MA, De Lange ME, Clark JT, Mol BWJ, Bet PM, Huirne JAF, et al. Evaluation of marketing authorization and clinical implementation of ulipristal acetate for uterine fibroids. Human Reproduction 2022;37(5):884-94. [DOI: ] [DOI] [PMC free article] [PubMed] [Google Scholar] Moroni 2015 - Moroni RM, Martins WP, Ferriani RA, Vieria CS, Nastri CO, Candido Dos Reis FJ, et al. Add-back therapy with GnRH analogues for uterine fibroids. Cochrane Database of Systematic Reviews 2015, Issue 3. Art. No: CD010854. [DOI: 10.1002/14651858.CD010854.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar] Nagy 2014 - Nagy B, Timar G, Józwiak-Hagymásy J, Kovács G, Merész G, Vámossy I, et al. The cost effectiveness of ulipristal acetate tablets in treating patients with moderate to severe symptoms of uterine fibroids. European Journal of Obstetrics, Gynecology, and Reproductive Biology 2014;175:75-81. [DOI] [PubMed] [Google Scholar] Parazzini 1998 - Parazzini F, Vercellini P, De Giorgi O, Pesole A, Ricci E, Crosignani PG. Efficacy of preoperative medical treatment in facilitating hysteroscopic endometrial resection, myomectomy and metroplasty: literature review. Human Reproduction (Oxford, England) 1998;13(9):2592-7. [DOI] [PubMed] [Google Scholar] Patel 2014 - Patel A, Malik M, Britten J, Cox J, Catherino WH. Alternative therapies in management of leiomyomas. Fertility and Sterility 2014;102(3):649-55. [DOI] [PubMed] [Google Scholar] Perino 1993 - Perino A, Chianchiano N, Petronio M, Cittadini E. Role of leuprolide acetate depot in hysteroscopic surgery: a controlled study. Fertility and Sterility 1993;59:507-10. [DOI] [PubMed] [Google Scholar] Pérez Lopez 2014 - Pérez-López FR, Ornat L, Ceausu I, Depypere H, Erel CT, Lambrinoudaki I, et al. EMAS position statement: management of uterine fibroids. Maturitas 2014;79(1):106-16. [DOI] [PubMed] [Google Scholar] RevMan 2024 [Computer program] - Review Manager (RevMan). Version 7.12.0. The Cochrane Collaboration, 2024. Available at https://revman.cochrane.org. Stovall 1989 - Stovall TG. Rationale for the short-term use of luteinising hormone-releasing hormone analogues in the treatment of uterine myomata. Hormone Research 1989;32(Suppl 1):134-6. [DOI] [PubMed] [Google Scholar] Stovall 1991 - Stovall TG, Ling FW, Henry LC, Woodruff MR. A randomized trial evaluating leuprolide acetate before hysterectomy as a treatment for leiomyomas. American Journal of Obstetrics and Gynecology 1991;164(6 Pt 1):1420-5. [DOI] [PubMed] [Google Scholar] Tamaya 1985 - Tamaya T, Fujimoto J, Okada H. Comparison of cellular levels of steroid receptors in uterine leiomyomas and myometrium. Acta Obstetricia et Gynaecologica Scandinavica 1985;64(4):307-9. [DOI] [PubMed] [Google Scholar] UCON 2023 - Whitaker LHR, Middleton JL, Daniels JP, Williams ARW, Priest L, Odedra S, et al, UCON Collaborative. Ulipristal acetate versus levonorgestrel-releasing intrauterine system for heavy menstrual bleeding (UCON): a randomised controlled phase III trial. eClinicalMedicine 2023;60:101995. [DOI: doi.org/10. 1016/j.eclinm.2023. 101995] [DOI] [PMC free article] [PubMed] [Google Scholar] Wallach 1992 - Wallach EE. Myomectomy. In: Thompson JD, Rock JA, editors(s). Te Linde's Operative Gynaecology. 7th edition. Philadelphia: Lippincott, 1992:647-62. [Google Scholar] West 1992 - West CP, Lumsden MA, Baird DT. Goserelin (Zoladex) in the treatment of fibroids. British Journal of Obstetrics and Gynaecology 1992;99(Suppl 7):27-30. [DOI] [PubMed] [Google Scholar] Williams 2012 - Williams ARW, Bergeron C, Barlow DH, Ferenczy A. Endometrial morphology after treatment of uterine fibroids with the selective progesterone receptor modulator, ulipristal acetate. International Journal of Gynecological Pathology 2012;31(6):556-69. [DOI] [PubMed] [Google Scholar] Wilson 1980 - Wilson EA, Yang F, Rees ED. Estradiol and progesterone binding in uterine leiomyomata and in normal uterine tissue. Obstetrics and Gynecology 1980;55(1):20-4. [PubMed] [Google Scholar] Yang 2011 - Yang JH, Chen MJ, Chen DC, Chen CL, Ho HN, Yang YS. Impact of submucous fibroid on the severity of anemia. Fertility and Sterility 2011;95(5):1769-72. [DOI] [PubMed] [Google Scholar] Yu 2018 - Yu O, Scholes D, Schulze-Rath R, Grafton J, Hansen K, Reed SD, et al. A US population-based study of uterine fibroid diagnosis incidence, trends, and prevalence: 2005 through 2014. American Journal of Obstetrics and Gynecology 2018;219(6):591.e1-8. [DOI] [PubMed] [Google Scholar] Zakiyah 2017 - Zakiyah N, Van Asselt ADI, Postma MJ. Ulipristal acetate for pre-operative treatment of moderate-to-severe uterine fibroids in women of reproductive age in the Netherlands: cost minimisation analysis and budget impact analysis. Journal of Medical Economics 2017;20(3):280-7. [DOI] [PubMed] [Google Scholar] Zhang 2014 - Zhang Y, Sun L, Guo Y, Cheng J, Wang Y, Fan S, et al. The impact of preoperative gonadotropin-releasing hormone agonist treatment on women with uterine fibroids: a metaanalysis. Obstetrical & Gynecological Survey 2014;69(2):100-8. [DOI] [PubMed] [Google Scholar]

to other published versions of this review Lethaby 2000 - Lethaby A, Vollenhoven B, Sowter M. Pre-operative GnRH analogue therapy before hysterectomy or myomectomy for uterine fibroids. Cochrane Database of Systematic Reviews 2000, Issue 1. Art. No: CD000547. [DOI: 10.1002/14651858.CD000547] [DOI] [PubMed] [Google Scholar] Lethaby 2001 - Lethaby A, Vollenhoven B, Sowter M. Pre-operative GnRH analogue therapy before hysterectomy or myomectomy for uterine fibroids. Cochrane Database of Systematic Reviews 2001, Issue 1. Art. No: CD000547. [DOI: 10.1002/14651858.CD000547] [DOI] [PubMed] [Google Scholar] Lethaby 2017 - Lethaby A , Puscasiu L , Vollenhoven B. Preoperative medical therapy before surgery for uterine fibroids. Cochrane Database of Systematic Reviews 2017, Issue 11. Art. No: CD000547. [DOI: 10.1002/14651858.CD000547.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]