Efficacy of GnRH antagonists in the treatment of uterine fibroids: a meta-analysis.

1.1. Control of uterine bleeding (dichotomous variable): Patients treated with GnRH antagonists in comparison with patients treated with placebo had clinically relevant large bleeding control (RR= 5.09, 95% CI 3.19 to 8.14; DAR= 63%; five trials, n=883 participants; I 2 = 76%; risk of bias high) (Figure 4 ) ( NCT 01441635 , NCT 01817530 , NCT02654054 , NCT 03049735 , NCT 03103087 ). Fig. 4 Comparison of the risk of uterine bleeding control in patients treated with GnRH antagonists versus those receiving placebo after a follow-up period of 12 to 24 weeks. Red stands for high risk of bias, green stands for low risk of bias and yellow stands for unclear risk of bias Comparison of the risk of uterine bleeding control in patients treated with GnRH antagonists versus those receiving placebo after a follow-up period of 12 to 24 weeks. Red stands for high risk of bias, green stands for low risk of bias and yellow stands for unclear risk of bias The results of the study indicate that, on average, 63 more patients in the GnRH antagonist group than in the placebo group achieved control of uterine bleeding. This represents a favourable effect for the large intervention. 1.2. Control of bleeding after treatment in ml (continuous quantitative): No evidence of effect of GnRH antagonists compared with placebo on bleeding reduction assessed as a continuous quantitative variable (MD 1.33 95% CI – 31.78 to 34.44; three trials, n =323 participants; I 2 = 37%; high/low/unclear risk of bias) (Figure 5 ) ( NCT 01452659 , NCT 02654054 , NCT 03070899 , NCT 03070951 ). Fig. 5 Comparison of bleeding in ml after treatment with GnRH antagonists and placebo after a follow-up period of 12 to 24 weeks. Red stands for high risk of bias, green stands for low risk of bias and yellow stands for unclear risk of bias Comparison of bleeding in ml after treatment with GnRH antagonists and placebo after a follow-up period of 12 to 24 weeks. Red stands for high risk of bias, green stands for low risk of bias and yellow stands for unclear risk of bias 1.3. Percent reduction in fibroid volume (continuous quantitative): Patients treated with GnRH antagonists compared with placebo had a moderate reduction in clinically relevant fibroid volume (MD= −27.36, 95% CI −38.89 to −15.83; five trials, n =510 participants; I 2 = 95%; mostly high risk (three high risk and two low-risk studies) (Figure 6 ) ( NCT 01441635 , NCT 01817530 , NCT02654054 , NCT 03049735 , NCT 03103087 ). Fig. 6 Comparison of the percentage reduction in fibroid volume before and after treatment with GnRH antagonists versus placebo after a follow-up period of 12 to 24 weeks. Red stands for high risk of bias, green stands for low risk of bias and yellow stands for unclear risk of bias Comparison of the percentage reduction in fibroid volume before and after treatment with GnRH antagonists versus placebo after a follow-up period of 12 to 24 weeks. Red stands for high risk of bias, green stands for low risk of bias and yellow stands for unclear risk of bias 1.4 Presence of vasomotor symptoms (dichotomous). No evidence of the effect of GnRH antagonists compared with placebo on vasomotor symptom reduction assessed as a dichotomous variable (RR= 1.44, 95% CI 0.80 to 2.61; two trials, n =507 participants; I 2 = 0%; low risk of bias) (Figure 7 ) ( NCT 03049735 , NCT 03103087 ). Fig. 7 Comparison of the presence of vasomotor symptoms after treatment with GnRH antagonists versus placebo after a follow-up period of 12 to 24 weeks. Green stands for low risk of bias and yellow stands for unclear risk of bias Comparison of the presence of vasomotor symptoms after treatment with GnRH antagonists versus placebo after a follow-up period of 12 to 24 weeks. Green stands for low risk of bias and yellow stands for unclear risk of bias 1.5. Decrease in bone mineral density (continuous quantitative): Patients treated with GnRH antagonists compared with placebo had a smaller decrease in bone mineral density (BMD) with this moderate effect being clinically relevant, assessed as a continuous quantitative variable (MD −0.35 95% CI - 0.47 to −0.24; four trials, n =805 participants; I 2 = 63%; high-low risk of bias as there are two studies with high bias and two with low bias) (Figure 8 ) ( NCT 03049735 , NCT 03070899 , NCT 03070951 , NCT 03103087 ). Fig. 8 Comparison of BMD reduction after treatment with GnRH antagonists versus placebo after a follow-up period of 12 to 24 weeks. Red stands for high risk of bias and green stands for low risk of bias Comparison of BMD reduction after treatment with GnRH antagonists versus placebo after a follow-up period of 12 to 24 weeks. Red stands for high risk of bias and green stands for low risk of bias

2.1. Bleeding control after treatment in ml (continuous quantitative). Meta-analysis is not possible because we found only one study ( NCT02655237 ) (Figure 9 ). Fig. 9 Comparison of bleeding in ml after treatment with GnRH antagonists versus GnRH agonists after a follow-up period of 12 to 24 weeks. Red stands for high risk of bias, green stands for low risk of bias and yellow stands for unclear risk of bias Comparison of bleeding in ml after treatment with GnRH antagonists versus GnRH agonists after a follow-up period of 12 to 24 weeks. Red stands for high risk of bias, green stands for low risk of bias and yellow stands for unclear risk of bias 2.2. Percentage of fibroid volume reduction (dichotomous): Meta-analysis is not possible because we found only one study ( NCT02655237 ) (Figure 10 ). Fig. 10 Comparison of the percentage reduction in fibroid volume after treatment with GnRH antagonists versus GnRH agonists after a follow-up period of 12 to 24 weeks. Red stands for high risk of bias, green stands for low risk of bias and yellow stands for unclear risk of bias Comparison of the percentage reduction in fibroid volume after treatment with GnRH antagonists versus GnRH agonists after a follow-up period of 12 to 24 weeks. Red stands for high risk of bias, green stands for low risk of bias and yellow stands for unclear risk of bias 2.3. Presence of vasomotor symptoms (dichotomous): not reported. 2.4. Women with altered bone density (dichotomous). Meta-analysis is not possible because only one study was found ( NCT02655237 ) (Figure 11 ). Fig. 11 Comparison of BMD alteration after treatment with GnRH antagonists versus GnRH agonists after a follow-up period of 12 to 24 weeks. Red stands for high risk of bias, green stands for low risk of bias and yellow stands for unclear risk of bias Comparison of BMD alteration after treatment with GnRH antagonists versus GnRH agonists after a follow-up period of 12 to 24 weeks. Red stands for high risk of bias, green stands for low risk of bias and yellow stands for unclear risk of bias

A total of 97 studies were retrieved from the electronic database search (PubMed and Cochrane). Following the removal of duplicates, 15 studies were excluded. Of the 82 records initially identified through title and abstract screening, 56 were excluded due to failure to meet the inclusion criteria. Of the 26 remaining potentially eligible records, full texts were obtained for those belonging to clinical trial registries through the clinicaltrails.gov pages ( https://www.clinicaltrialsregister.eu ). For those not included in registries, full texts were obtained through PubMed or our hospital’s library. Upon evaluation of the full texts, five were excluded as they did not meet the publication criteria. The remaining 21 records, corresponding to 11 randomised clinical trials, met the inclusion criteria (Fig. 1 ). Fig. 1 Prism flow diagram: search results and articles selection Prism flow diagram: search results and articles selection All clinical trials included in this review are randomized. Studies NCT02655237 , NCT02654054 , NCT03103087 , NCT01452659 , NCT03070899 , NCT03070951 , NCT03049735 and NCT01817530 are multicenter. Study NCT00746031 is single-center. And for studies NCT01441635 and NCT01817530 no data are provided on the number of centers in which the study was performed. The 11 selected clinical trials include a total of 4164 patients. All the participants were premenopausal women aged between 18 and 51 at the time of screening, with a diagnosis of uterine fibroids and heavy menstrual bleeding. The exclusion criteria varied depending on the specific study. All studies evaluate a GnRH antagonist (Relugolix, Elagolix, Linzagolix or Cetrorelix). NCT02655237 , NCT03049735 , NCT03103087 and NCT01452659 studies investigate the efficacy of Relugolix. All of these studies compare Relugolix with a placebo, while the NCT02655237 study additionally compares it with a GnRH agonist (Leuprorelin). NCT02655237 presents 4 study arms: one of them with Relugolix, another with Relugolix placebo, another with Leuprorelin and the last one with Leuprorelin placebo. NCT03049735 : studies Relugolix with estradiol/ norethisterone acetate (E2/NETA) (with two different doses) and compares it with a placebo. NCT0310303087: studies Relugolix with E2/NETA administration. Another intervention group is Relugolix co-administered with a placebo clause and the other intervention group is with placebo. NCT01452659 : studies Relugolix and compares it with placebo. NCT02654054 , NCT01441635 , NCT01817530 , NCT01817530 study Elagolix. All of them compare Elagolix with a placebo and, in addition, in NCT01817530 it is compared with estradiol. NCT02654054 : studies Elagolix and compares it with placebo. The other intervention group compares Elagolix with norentinrone acetate. NCT01441635 : studies Elagolix and compares it with placebo, with E2/NETA, estradiol and progesterone. NCT01817530 : Elagolix (5 groups, 4 of them of different doses of elagolix and the other controlled with placebo). Another intervention group ELAGOLIX 200 MG with add back therapy E2/NETA and the last one Elagolix with add back therapy. NCT01817530 . One intervention group is elagolix, another elagolix placebo, another E2/NETA and the last E2/NETA placebo. NCT03070899 and NCT03070951 compared Linzagolix with placebo. NCT00746031 compares three groups of women: one is treated with Goserelix (agonist), another with Goserelix and Cetrorelix, and the third with no treatment. NCT02655237 , NCT03049735 , NCT03103087 and NCT01452659 studies investigate the efficacy of Relugolix. All of these studies compare Relugolix with a placebo, while the NCT02655237 study additionally compares it with a GnRH agonist (Leuprorelin). NCT02655237 presents 4 study arms: one of them with Relugolix, another with Relugolix placebo, another with Leuprorelin and the last one with Leuprorelin placebo. NCT03049735 : studies Relugolix with estradiol/ norethisterone acetate (E2/NETA) (with two different doses) and compares it with a placebo. NCT0310303087: studies Relugolix with E2/NETA administration. Another intervention group is Relugolix co-administered with a placebo clause and the other intervention group is with placebo. NCT01452659 : studies Relugolix and compares it with placebo. NCT02654054 , NCT01441635 , NCT01817530 , NCT01817530 study Elagolix. All of them compare Elagolix with a placebo and, in addition, in NCT01817530 it is compared with estradiol. NCT02654054 : studies Elagolix and compares it with placebo. The other intervention group compares Elagolix with norentinrone acetate. NCT01441635 : studies Elagolix and compares it with placebo, with E2/NETA, estradiol and progesterone. NCT01817530 : Elagolix (5 groups, 4 of them of different doses of elagolix and the other controlled with placebo). Another intervention group ELAGOLIX 200 MG with add back therapy E2/NETA and the last one Elagolix with add back therapy. NCT01817530 . One intervention group is elagolix, another elagolix placebo, another E2/NETA and the last E2/NETA placebo. NCT03070899 and NCT03070951 compared Linzagolix with placebo. NCT00746031 compares three groups of women: one is treated with Goserelix (agonist), another with Goserelix and Cetrorelix, and the third with no treatment. Uterine fibroid size is assessed in studies NCT02655237 , NCT03049735 , NCT03103087 , NCT01452659 , NCT01441635 , NCT01817530 , NCT00746031 . Bone density is assessed in studies NCT02655237 , NCT03049735 , NCT03103087 , NCT01452659 , NCT03070899 , NCT03070951 , NCT01817530 . Uterine bleeding volume reduction is evaluated in studies NCT02655237 , NCT02654054 , NCT03049735 , NCT03103087 , NCT01452659 , NCT01441635 , NCT03070899 , NCT03070951 , NCT01817530 . The presence of vasomotor symptoms is assessed in studies NCT03049735 , NCT03103087 , NCT01441635 , NCT01817530 . In the full-text screening section, five studies were excluded for various reasons. These included: 1 study that did not meet the objective criteria, 3 studies that did not meet the study type criteria and 1 study that did not meet the outcome measures criteria. The assessment of risk of bias is presented in Figs.  2 and 3 . Fig. 2 Risk of bias graph. This graph displays the review authors’ judgements about each risk of bias item, presented as percentages, across all included studies Fig. 3 Risk of bias summary: review authors’ judgements about each risk of bias item for each included study. Red stands for high risk of bias, green stands for low risk of bias and yellow stands for unclear risk of bias Risk of bias graph. This graph displays the review authors’ judgements about each risk of bias item, presented as percentages, across all included studies Risk of bias summary: review authors’ judgements about each risk of bias item for each included study. Red stands for high risk of bias, green stands for low risk of bias and yellow stands for unclear risk of bias In evaluating the generation of random sequences, all studies except NCT01452659 , NCT03049735 and NCT03103087 were found to have a high risk of bias. With regard to the concealment of allocation, all studies were found to have a low risk of bias. With regard to the blinding of participants and personnel, all studies were found to have a low risk of bias, with the exception of NCT01441635 and NCT01817530 , which lacked sufficient information to permit an assessment. With regard to the blinding of the assessors, the results were found to be more heterogeneous. Studies NCT00746031 , NCT01441635 , NCT01452659 and NCT01817530 did not provide sufficient information to enable assessment. Conversely, studies NCT02654054 , NCT03070899 and NCT03070951 are subject to a high risk of bias. Finally, studies NCT02655237 , NCT0303049735 and NCT03103087 are characterised by a low risk of bias. In the absence of complete outcome data and the use of assessor blinding, the results are highly variable. Studies NCT01441635 , NCT01452659 and NCT02655237 lack sufficient information to permit assessment. Studies NCT00746031 and NCT01817530 are at high risk of bias, while the remaining studies are at low risk of bias. Finally, all studies were found to have a low risk of bias with regard to selective reporting. To evaluate the effect of the interventions, we conducted a comparative analysis of the control of uterine bleeding, reduction of fibroid volume, presence of vasomotor symptoms and alteration of bone density in the comparison of GnRH antagonist versus placebo and GnRH antagonist versus GnRH agonist.

The present review included randomised clinical trials that evaluated the effect of GnRH antagonists in comparison to placebo or GnRH agonists. A bibliographic search was conducted in the electronic databases PubMed and Cochrane Central with the most recent search date being December 2023. The keywords used to define the search strategy were: Leiomyoma, fibromyoma, myoma, gonadotropin-releasing hormone, Relugolix, Elagolix, Linzagolix and Cetrorelix. The study included non-pregnant, premenopausal women with uterine fibroids and heavy menstrual bleeding. The women were required to have documented uterine fibroids, which could be confirmed by ultrasound or magnetic resonance imaging. The primary outcomes of interest in this review were a reduction in bleeding volume (assessed in millilitres (ml) and categorised as a dichotomous variable, indicating whether bleeding had been reduced or not) and a decrease in uterine myoma size (assessed in cubic centimetres (cm 3 ) or as a percentage). The secondary outcomes of interest in our review were bone density (assessed in percentage change by densitometry) and the presence of vasomotor symptoms, including hot flashes, hyperhidrosis, hypertension, night sweats and hot sensation (measured as presence or absence). Once the search was complete, Rayyan was employed to perform a systematic review. Prior to commencing the initial screening by title and abstract, duplicate articles were eliminated. Thereafter, records that did not meet the inclusion criteria were removed. The full texts of potentially eligible records were obtained through PubMed, the clinical trials (clinicaltrials.gov) and clinical trials registry ( https://www.clinicaltrialsregister.eu/ ) databases. The eligibility of the trials was assessed independently and the reasons for exclusion documented. Disagreements between reviewers were resolved through discussion. The data extracted from each of the selected trials was collated in a series of forms. These included details of the study methodology, the characteristics of the study population (number of participants, age, inclusion and exclusion criteria), the intervention and outcome measures assessed (uterine myoma size, bone density, uterine bleeding and presence of vasomotor symptoms). The risk of bias assessment was conducted using Revman 5.4, in accordance with the criteria defined in the Cochrane Handbook [ 14 ]. The domains of random sequence generation, allocation concealment, blinding of participants and healthcare personnel, blinding of assessors, incomplete data, and selective reporting were classified as high risk, low risk, or uncertain risk. In the event that the data does not permit the determination of whether the risk is high or low, the study will be classified as uncertain risk. A study is considered to be of low risk of bias when all domains are classified as low risk, of uncertain risk when there is no high-risk domain and at least one domain is classified as uncertain risk, and of high risk when one domain is classified as high risk. The measure of effect used for the dichotomous variables (reduction of uterine bleeding and presence of vasomotor symptoms) was the relative risk with a 95% confidence interval (CI), using a Mantel–Haenszel model and random effects. For this purpose, we obtained the data on the number of events and the total sample size of the intervention group and the comparator. For the continuous quantitative variables (reduction in bleeding in ml, percentage reduction in fibroid volume, decrease in bone density), we calculated the mean difference with a 95% CI, using an inverse variance model and random effects. To this end, we obtained the mean and standard deviation of each variable and the total sample of the intervention group and the comparator. To assess the heterogeneity between the different studies included, the I 2 statistic was employed. Results between 0 and 50% were classified as low heterogeneity, from 50 to 75% as moderate heterogeneity, and from 75 to 100% as very high heterogeneity. The data pertaining to the effect measures were subjected to analysis using the Review Manager 5.4 software. In the interpretation of the results of the meta-analysis, we were unable to ascertain the statistical significance of the overall effect. Instead, we considered the central estimate value and the 95% CI of the effect estimate. A sensitivity analysis was not performed due to the limited number of studies included in the meta-analysis. In the case of uterine bleeding, the results were assessed for their robustness when studies at low risk of bias were selected. This procedure was not performed because none of the meta-analyses included more than 10 studies.

It is important to note that there is a growing interest in GnRH antagonists, with recent studies [ 15 – 18 ] being published on the topic. This is attributable to the favourable side effect profile of GnRH antagonists and their capacity to provide more rapid symptomatic relief, which renders them a preferable option to GnRH agonists in certain cases. A systematic review [ 19 ] with a somewhat similar question to ours was published in January 2023, except that covers studies in which the interventions to be evaluated are different doses of GnRH antagonists and further [ 20 ] suggests that it may offer further benefits in the treatment of endometriosis. Likewise, it does not include randomized clinical trials. The present study regarding uterine bleeding control versus placebo indicates that, based on current evidence, GnRH antagonists provide clinically relevant bleeding control, at least as a qualitative variable (RR = 5.09, 95% CI 3.19 to 8.14) not seen as a quantitative variable as there isn´t enough evidence to determine whether the efficacy (MD 1.33 95% CI – 31.78 to 34.44). With regard to the reduction of fibroids’ volume versus placebo, a decrease of 27.36 cm 3 is reported, which is considered a moderate but clinically significant benefit (MD = −27.36, 95% CI −38.89 to −15.83). The impact of the reduction in volume of the fibroids is cumulative and can vary when GnRH antagonists are employed in conjunction with Adback therapy, potentially contingent on the specific GnRH antagonist utilised in comparison to a placebo. However, the available information does not allow us to conclude significant differences between GnRH antagonists and placebo in relation to the appearance of vasomotor symptoms. Finally, with regard to bone density, the use of antagonists versus placebo is associated with a decrease classified as intermediate, suggesting a significant but not extreme reduction in bone mineral density (MD −0.35, 95%CI 0.47 to 0.24). In accordance with the findings of this study, the majority of existing literature acknowledges that GnRH antagonists result in a reduction in menstrual bleeding, the volume of fibroids, and uterine volume. In another study [ 21 ], four trials were conducted, comparing either a placebo or elagolix and E2/NETA. Elagolix increased the number of patients who had menstrual blood loss of less than 80 ml or more than a 50% reduction from baseline compared to placebo. However, no difference was observed when elagolix was combined with E2/NETA. Furthermore, elagolix was observed to reduce the volume of fibromas and the volume of the uterus, as evidenced by our study, due to the hormone-dependent nature of these tumours. It is acknowledged that elagolix also increased health-related quality of life in both comparisons. This is reasonable given that patients perceived a lower quantity of blood loss, which was seen in our study as a dichotomous variable. However, this was not reflected in the quantitative variable in our study. Although our meta-analysis was unable to provide a quantitative assessment of the use of GnRH antagonists, this may be due to problems with the collection of quantitative blood data [ 22 ], such as heterogeneity in the designs of the included studies and variability in the outcome measures used. These methodological differences made direct comparison and quantitative analysis of the data difficult. Another study [ 23 ] of the efficacy and safety of GnRH antagonists was conducted by analysing nine randomised clinical trials, similar to ours, implying that premenopausal patients with symptomatic uterine fibroids exhibited notable improvements in both uterine bleeding and reduction in the size of leiomyomas. These results are in accordance with our study, which examined a qualitative bleeding control item (RR = 5.09, 95% CI 3.19 to 8.14) and observed a reduction in fibroid volume of 27.36 cm 3 (MD = −27.36, 95% CI −38.89 to −15.83). Furthermore, the quality of life of patients treated with these drugs alone or in combination with E2/NETA in this study also demonstrated improvement, as previously indicated. Additional literature has been published comparing the adverse effects of GnRH antagonists versus placebo; Muhammad et al. [ 21 ], analysed four randomized controlled trials with 1949 premenopausal women and found that more patients experienced adverse events such as hot flushes, headaches and loss of BMD with elagolix in monotherapy. However, these hypoestrogenic effects were found to be attenuated with the addition of E2/NETA. In contrast, our study found no evidence to suggest that GnRH antagonists have an effect on the reduction of vasomotor symptoms when compared to placebo. A systematic review [ 24 ] of oral pharmacotherapeutic options for the management of uterine fibroids, published in February 2022, revealed that higher doses of GnRH antagonists were associated with increased rates of hot flashes. However, this trend did not reach statistical significance. The addition of early hormonal add-back therapy with ethinyl estradiol and norethindrone acetate was found to reduce the incidence of hot flashes to less than 20%. Moreover, in their work, Niaz et al. [ 23 ] found that there were no statistically significant differences in BMD changes between the placebo and elagolix add-back groups. However, the elagolix monotherapy group exhibited a more significant loss of BMD than the other two groups. With regard to the lumbar spine, any reduction in BMD resulting from elagolix in combination with an add-back agent was less than 5% over the course of the 12-month study period. In accordance with our meta-analysis indicates that patients treated with GnRH antagonists exhibited a comparatively minor decline in BMD (MD -0.35, 95%CI 0.47 to 0.24), which may be regarded as clinically moderate, as other meta-analysis [ 21 ] suggests, though at the LIBERTY study [ 25 , 26 ] it is stated that BMD was preserved through week 52, with a longer period of time than ours. A relevant aspect that was not analysed is that complementary treatment with estrogens/progestogens reduces BMD loss, but it is true that the increased risk of thrombotic complications that may appear with synthetic estrogens should be studied. Another adverse outcome documented in the literature is the impact of antagonists on lipid metabolism, issue that it was not initially within the scope of our study objectives but important to mention within the safety of our patients [ 25 , 26 ]. As seen in a study based on endometriosis patients [ 27 ], elagolix administration resulted in a significant elevation in total cholesterol, triglycerides, and low-density lipoprotein cholesterol levels. This increase was also observed in postmenopausal women and in conjunction with other agents that suppress estradiol (E2). However, this has also been seen with linzagolix administration. The lipid levels returned to their pretreatment levels at the post-treatment follow-up. These small percentage increases did not result in an increased number of patients reaching levels of concern [ 28 ]. The different doses and regimens of GnRH antagonists present challenges in direct comparisons and in interpreting meta-analysis results. For example, linzagolix at 100 mg has a different side-effect profile compared to the 200 mg dose with add-back therapy (ABT). In contrast, relugolix is only available as a single 40 mg dose, making direct comparisons with other GnRH antagonists difficult. This heterogeneity in dosing and regimens highlights the importance of considering individual drug characteristics and patient factors when interpreting meta-analysis results and making clinical decisions. The findings of the studies suggest that antagonists may potentially exhibit a reduced incidence of adverse effects when compared with agonists. However, it is imperative to acknowledge the necessity for further research in this area. A proposed dosing scheme could be formulated on the basis of Relugolix with add-back and Linzagolix 200 mg with add-back, particularly in cases where the primary objective is the reduction of menstrual bleeding. Linzagolix 200 mg without add-back (maximum six months) could be used in cases where volume reduction is the goal, and Linzagolix 100 mg doses could be used for long-term maintenance. This review provides substantial evidence substantiating the utilisation of oral GnRH antagonists in premenopausal women presenting with symptomatic uterine fibroids improving their symptoms, volume and implied quality of life without a great detriment with possible side effects. Our review is constrained by the quality and heterogeneity of the included studies. The study highlights a significant gap in research representation among older women of fertile age, despite the notable prevalence of uterine fibroids in this demographic. With regard to the comparison of GnRH antagonists versus GnRH agonist drugs, only one study is available, which prevents us from performing a meta-analysis. It has been established that there is only one study with a low risk of bias in all domains. Another study had uncertain risk, while the remainder exhibited a high risk of bias. It is crucial to highlight that the outcome variables are frequently reported in disparate units. It should be recommend for further studies to utilise comparable outcomes that address analogous questions, thus facilitating the comparison of studies.

The results of this study indicate that GnRH antagonists, such as Elagolix, Relugolix and Linzagolix, are more effective than placebo in reducing bleeding, myoma volume and bone density. Therefore, GnRH antagonists may become the preferred treatment of choice, due to their favourable profile demonstrated in this study. However, further research is needed to compare the therapeutic and side effects of antagonists, in particular, antagonists versus agonists, as the evidence currently available is limited. In both cases, it would be beneficial to extend the follow-up period to mitigate bias and focus on three specific populations relevant to clinical practice: young women with reproductive desire, premenopausal women, and women with severe symptomatology due to fibroids and the prospect of surgery in the near future.

Uterine leiomyomas (also known as fibroids or myomas) are benign monoclonal tumours that originate from smooth muscle cells and fibroblasts of the myometrium. They are the most common cause of solid pelvic tumours in women and are the most frequent indication for hysterectomy in developed countries [ 1 ]. The prevalence of fibroids is uncertain, with estimates ranging from 60 to 80% based on ultrasound studies [ 2 ]. The symptoms of fibroids are diverse with approximately 30% of women experiencing abnormal uterine bleeding, pelvic pain, pain during intercourse and urinary symptoms. Furthermore, fibroids can affect fertility in approximately 27% of women, depending on the characteristics of the tumour [ 3 – 5 ]. The location of fibroids in the uterus is classified according to the International Federation of Gynecology and Obstetrics system [ 6 ], symptoms may vary according to location. The selection of the most suitable treatment for fibroids (medical, surgical, or radiological) is contingent upon a number of variables. These include the number and location of the fibroids, the size of the fibroid, associated symptoms, the patient's age and her reproductive desires. Medical treatment can be divided into two main groups: - Non-hormonal treatments: Non-hormonal treatments are those whose mechanism of action is limited to the control of symptoms associated with fibroids, such as bleeding or pain. However, these treatments have no effect on reducing myomas. Examples of non-hormonal treatments include nonsteroidal anti-inflammatory drugs and antifibrinolytics. - Hormonal treatments are divided into non-specific, including estrogens/ gestagens and levonorgestrel-releasing intrauterine devices; and those that control the aforementioned symptoms by acting on the myoma, thereby reducing its volume and menstrual bleeding. Examples in this category include gonadotropin-releasing hormone (GnRH) agonists, ulipristal acetate and GnRH antagonists [ 7 ]. In instances where symptoms do not resolve, other treatment options become available. Such options include uterine artery embolisation and fibroid radiofrequency ablation, representing minimally invasive non-pharmacological treatment options that are employed to address both bleeding and volume symptoms. These outcomes are already known in obstetrics [ 8 – 11 ], as with invasive treatments like myomectomies. Finally, there are interventional therapies such as endometrial ablation and hysterectomy for patients who do not desire a future pregnancy. A review of the most recent therapy options available for the treatment of fibroids will be conducted, with a focus on gonadotropin-releasing hormone (GnRH) agonists and antagonists. The mechanism of action of GnRH antagonists is based on the reversible blockade of GnRH receptors at the pituitary level. In contrast to GnRH agonists, where the initial continuous stimulus led to the final inhibition by depletion, determining the appearance of an initial stimulatory effect, the blockade of GnRH receptors by GnRH antagonists is reversible. In contrast to GnRH agonists, which exhibit a gradual and dose-dependent inhibition of the pituitary-ovarian axis, accompanied by a gradual reduction in circulating estrogen levels, GnRH antagonists demonstrate a rapid and dose-dependent inhibition of the pituitary-ovarian axis, accompanied by a rapid reduction in circulating estrogen levels, and without the appearance of the flare-up effect [ 12 ]. The development of non-peptide GnRH antagonists (Elagolix, Cetrorelix, Relugolix and Linzagolix) offers us the possibility of administering these drugs orally, in different schedules according to their plasma half-life. The oral route of administration offers greater ease of use with respect to depot presentations, as it allows for a rapid reversibility of the effects once treatment has been suspended, both in terms of adverse effects and benefits [ 12 , 13 ]. The main limitation of these drugs, as with GnRH agonists, is the hypoestrogenism that they induce. Consequently, add-back therapy should be administered in long-term treatments (over 4–6 months) to prevent the adverse effects of this hypoestrogenism [ 12 ]. The objective of this systematic review is to evaluate the safety and efficacy of GnRH antagonists in the treatment of uterine fibroids in comparison with placebo and GnRH agonists, with a particular focus on the reduction of fibroid size and improvement of symptoms.