Hormonal and complimentary treatments for endometriosis: a narrative review

Endometriosis is a chronic, estrogen-dependent disease characterized by the presence of ectopic endometrial tissue outside the uterus. It affects up to 15% of women of reproductive age ( 1 ) and although this benign condition can be asymptomatic, it very often causes infertility and pain (chronic pelvic pain, dysmenorrhea, dyspareunia, dyschezia) and is therefore associated with a high impact on quality of life ( 2 ). Because it is a chronic condition, endometriosis requires appropriate treatment and follow-up throughout a woman’s reproductive life. Management can be surgical or pharmacological, with or without complementary therapies. Although surgical treatment is associated with a significant and faster improvement in symptoms, it is also associated with risk of recurrence which can lead to reoperation, and complications of the procedure ( 3 , 4 ). Hormonal treatment aims to reduce endogenous estrogen synthesis and, consequently, suppresses menstrual cycles. In most cases, it is effective in relieving symptoms but does not provide a cure for the disease ( 5 ). Hormonal treatments include the combined oral pill, progestins and gonadotropin-releasing hormone (GnRH) analogues. Progestins can be administered orally, intramuscularly, subcutaneously or via intrauterine devices and implants ( 6 ). Complementary therapies encompass a wide range of health practices including physiotherapy, psychotherapy, mindfulness, physical activity, acupuncture, and diet for the management of endometriosis-related pain ( 7 ). The aim of this article is to review recent evidence on hormonal and complementary options to treat endometriosis-associated pelvic pain (EAPP) and their impact on quality of life. Prior to this review’s registration with PROSPERO, there was no other review solely dedicated to hormonal and complementary treatments for endometriosis. Other existing reviews discussed treatments (surgical, hormonal, and complementary) in a broader context. We present this article in accordance with the Narrative Review reporting checklist (available at https://gpm.amegroups.com/article/view/10.21037/gpm-25-13/rc ).

A multicenter, randomized, double-blind and placebo-controlled clinical trial conducted in China ( 8 ) demonstrated the superiority of dienogest over placebo in reducing the intensity of EAPP, with a mean difference in change of EAPP of −24.54 [95% confidence interval (CI): −29.93 to −19.15] in favor of dienogest (P<0.0001). There was no difference in the incidence of adverse events between the groups and no impact on bone mineral density was demonstrated. This study enrolled 255 women for 24 weeks and was later extended to evaluate the effects of dienogest for a longer period ( 9 ). In the extension study, all patients, regardless of prior study treatment, received dienogest for 28 weeks. The results confirmed that dienogest maintains or even increases its effectiveness in reducing pain over time. It was also associated with progressive improvement in bleeding patterns without affecting bone health. Morotti et al. ( 10 ) evaluated the effect of replacing norethisterone 2.5–5 mg/day with dienogest 2 mg/day in women with rectovaginal endometriosis with persistent pain despite treatment with norethisterone for 6 months. In this study with paired samples, pain, quality of life and level of satisfaction were assessed before and after replacing norethisterone with dienogest. It was observed an improvement in the degree of satisfaction of women, in quality of life and a reduction in the intensity of pain symptoms after the switch. However, it is important to note that the study design and the novelty effect are limitations of this trial. Other studies have compared dienogest with combined oral contraceptives. A randomized controlled trial ( 11 ) compared the efficacy of dienogest 2 mg/day with the formulation of 0.03 mg ethinylestradiol and 3 mg drospirenone. Seventy women were evaluated in total for 24 weeks and it was observed that both treatments reduced pain intensity significantly, with no difference between the groups; however, the use of analgesic medications was not monitored during the study. In addition, both are associated with improved quality of life. However, dienogest was associated with fewer adverse effects, with a safety profile and greater tolerability than the combined pill. Furthermore, dienogest was also compared to a combined oral contraceptive containing 1.5 mg 17β-estradiol and 2.5 mg nomegestrol acetate (E2/NOMAC) ( 12 ). A total of 197 women with clinical suspicion of endometriosis, were randomized, and those with rectovaginal lesions, endometriomas, or adenomyosis were excluded. There was an improvement in pain symptoms, quality of life and sexual function in both groups. But dienogest had a better improvement in pain and quality of life than women on E2/NOMAC markedly at 6-month follow-up for chronic pelvic pain (P=0.01; Cohen’s d=0.7), dysmenorrhea (P=0.02; Cohen’s d=1.8) and dyspareunia (P=0.003; Cohen’s d=2.5). Dienogest was evaluated as adjunctive therapy after laparoscopy for resection of endometriosis foci in three studies. Ceccaroni et al. ( 13 ) selected 146 women who underwent laparoscopy and had intestinal and parametrial involvement and randomized them into a GnRH group and a dienogest group. Interviews were conducted at two times, one after 6 months of treatment and the other after 30 months, in both evaluations it was demonstrated that dienogest is as effective as the GnRH agonist in reducing pain symptoms and preventing clinical and radiological recurrence of endometriosis after surgery. Vahid-Dastjedi et al. ( 14 ) compared dienogest 2 mg/day with medroxyprogesterone acetate 20 mg/day in a randomized controlled clinical trial involving 106 women who had undergone laparoscopy for resection of endometriosis foci. There was a reduction in the intensity of EAPP in the dienogest group, with a significant difference in relation to the medroxyprogesterone group. There was not statistically difference between two groups in terms of recurrence rate of endometriosis. A randomized, double-blind, placebo-controlled pilot study ( 15 ) conducted in Iran compared the effects of placebo, dienogest and a 0.03 mg ethinylestradiol with 0.3 mg levonorgestrel combined oral pill as post-surgical treatments. A total of 108 women were included and it was observed that both interventions, as opposed to the placebo group, culminated in a reduction in EAPP and dyspareunia (dysmenorrhea was not evaluated separately), in addition to an improvement in the quality-of-life score, with no statistical difference between the groups with medication after 6 months. Dienogest is an effective therapy for controlling pain in women with endometriosis. A randomized, placebo-controlled, double-blind clinical trial was conducted in 40 patients with moderate-to-severe EAPP who had undergone laparoscopic conservative surgery ( 16 ). The objective was to evaluate the effect of desogestrel as an adjuvant postoperative treatment compared to placebo. Both groups showed pain reduction, with a significant difference in favor of the intervention in pain reduction in general, dysmenorrhea, and acyclic pelvic pain. The degree of satisfaction reported by participants was higher in the desogestrel group (P=0.001) and the incidence of adverse effects was similar between the two groups. Desogestrel is an effective therapy for controlling pain in women with endometriosis. Oral medroxyprogesterone acetate has already been compared with dienogest as adjuvant therapies after laparoscopy in the previously cited study ( 14 ). A multicenter, open, randomized and controlled trial compared progestins, represented by depot medroxyprogesterone acetate and levonorgestrel-releasing intrauterine system (LNG-IUS 52 mg), versus 0.03 mg ethinyl estradiol with 150 mg levonorgestrel pill ( 17 ). A total of 405 women who had undergone laparoscopy for resection of endometriosis foci participated. The primary outcome was pain measured 3 years after randomization using the pain domain of the Endometriosis Health Profile 30 (EHP-30) questionnaire during 3 years of follow-up. There was no difference in pain scores between the two groups. Both groups showed a similar reduction of around 40% compared to preoperative values. Women in the progestin group underwent fewer surgical procedures or second-line treatments compared to the combined pill group. Considering its pragmatic design, only 37% and 25% maintained the use of progestogens and combined oral contraceptives, respectively, after 3 years. Subcutaneous medroxyprogesterone acetate was compared with elagolix, an oral GnRH antagonist, in a multicenter, phase II, randomized and double-blind study ( 26 ), as the objective of the study was to demonstrate the non-inferiority of elagolix, it will be described on GnRH antagonist section. Medroxyprogesterone acetate is an effective therapy for controlling pain in women with endometriosis. The role of LNG-IUS 52 mg was evaluated by Chen et al. as an adjuvant treatment after laparoscopy for resection of endometriosis foci ( 18 ). The study included 80 women who had undergone laparoscopy and monthly GnRH agonist administration for 6 months and were randomized to the 52 mg LNG-IUS intervention group (n=40) and control group (n=40). The aim of the study was to evaluate the rate of endometrioma recurrence 30 months after the intervention and, secondarily, the intensity of pain symptoms. There was no significant difference in endometrioma recurrence rates between the two groups. On the other hand, the group that received the intervention (LNG-IUS) reported lower intensity of pain, with main reduction of dysmenorrhea, with mean difference compared to the control group after 30 months of follow-up was 22.1 (95% CI: 10.7–33.5) (P<0.001). Carvalho et al. ( 19 ) conducted a randomized non-inferiority clinical trial to compare the effects of etonogestrel (ENG) implantation and LNG-IUS 52 mg in relieving endometriosis pain symptoms. A total of 103 women with moderate-severe dysmenorrhea or chronic pelvic pain associated with endometriosis were enrolled and were evaluated for up to 6 months after device insertion. In both groups, there was a significant reduction in the intensity of pain and an improvement in quality of life in relation to baseline. Among ENG implant users, visual analog scale (VAS) noncyclic pelvic pain and dysmenorrhea scores decreased significantly, with a mean difference of 5.6±1.7 (95% CI: −6.4 to −4.7) and 5.3±1.3 (95% CI: −6.6 to −4.3), respectively. As for the LNG-IUS users the mean differences were of 5.5±1.6 (95% CI: −6.2 to −4.4) and 5.4±1.3 (95% CI: −6.3 to −4.3). However, on intergroup analysis, there was no statistical difference between them in these parameters This study was extended with a longer follow-up period of 24 months ( 20 ). The rate of discontinuation or loss to follow-up was high in both groups, with 65% in the implant group and 63% in the LNG-IUS 52 mg. The pain intensity reported in both groups was significantly reduced in relation to the baseline; however, there was no difference between them after 24 months. Also, a previously mentioned study evaluated the action of two progestins as a group and compared with a combined oral pill ( 17 ). ENG implantation and LNG-IUS 52 mg are an effective therapy for controlling pain in women with endometriosis. Combined oral contraceptives have been compared with dienogest in previously mentioned studies ( 11 , 12 ). Only one clinical trial compared them with placebo ( 21 ), with the objective of evaluating pain improvement with ethinylestradiol 0.02 mg/drospirenone 3 mg in a flexible extended regimen. In this double-blind, randomized study, 312 women participated who were randomized into three groups: placebo, combined pill and dienogest. The latter group was not blinded, as it was used as a reference to compare bleeding patterns only. After 24 weeks, the intervention was observed to be superior to placebo in reducing pain associated with endometriosis (least square mean difference −26.3 mm; 95% CI: −31.6 to −20.9; P<0.0001). In Italian study conducted by Granese et al. ( 22 ), the quadriphasic formulation of estradiol valerate associated with dienogest has been evaluated and compared with GnRH agonist as adjunctive therapy after conservative laparoscopy for endometriosis. A total of 78 women were randomized to either combined oral pill or GnRH agonist, submitted to laparoscopy, and followed up for 3, 6 and 9 months after the intervention. Both groups showed improvement in pain intensity compared to the baseline, especially in the first 3 months; however, there was no statistical difference between the groups. Combined oral contraceptives are an effective therapy for controlling pain in women with endometriosis. In this review, GnRH agonists were mentioned in two previous trials, which compared them with dienogest ( 13 ) and combined oral contraceptive ( 22 ) as adjuvant therapies after surgery. Sadler Gallagher et al. ( 23 ) conducted a randomized, double-blind, controlled study with 50 adolescents to evaluate the impact of leuprorelin administration associated with different regimens of add back therapy on quality of life. Due to adverse effects of GnRH agonists, only adolescents with refractory to first-line treatment were enrolled and were randomized into two different add back therapy groups: (I) norethindrone acetate plus conjugated estrogens and (II) norethindrone alone. Regarding quality of life, assessed by the short form 36 (SF-36) questionnaire, both groups showed improvement. The results should not be generalized since the study was biased and the final sample was small, since 17 participants dropped out of the study due to failure to relieve pain or intolerance to side effects. GnRH agonists are an effective therapy for controlling pain in women with endometriosis but has many adverse effects. GnRH antagonists have emerged as an alternative to GnRH agonists, as they have an oral formulation and allow dose-dependent control of estradiol. There are currently three medications in this class: linzagolix, elagolix and relugolix. EDELWEISS trial (Treatment of endometriosis-associated pain with linzagolix, an oral gonadotropin-releasing hormone–antagonist: a randomized clinical trial) evaluated the effect of linzagolix on endometriosis, at different stages of the clinical trial. The phase II, multicenter, randomized, placebo-controlled clinical trial ( 24 ) had the objective of comparing different doses of linzagolix in the reduction of EAPP, quality of life, and safety. A total of 327 women were randomized into 6 groups: placebo and linzagolix at fixed doses of 50, 75, 100, and 200 mg/day, and a group with an initial dose of 75 mg/day, with subsequent titration according to estradiol levels. It was observed that from 75 mg/day, there was a significant reduction in EAPP in relation to placebo, initially noted in the 12th week, but maintained or improved after 24 weeks. Except for dyspareunia, which had a significant reduction compared to placebo with only the maximum dose of linzagolix. However, 200 mg/day linzagolix was associated with a higher rate of climacteric symptoms and a reduction in bone mineral density ≥3%, which would indicate the need for add back therapy. Phase III of EDELWEISS trial ( 25 ) compared linzagolix versus placebo in 486 women with endometriosis and moderate to severe pain, who were allocated into three groups: placebo, linzagolix 75 mg/day alone and 200 mg/day associated with add back therapy (1 mg estradiol + 0.5 mg norethisterone acetate). In the first three months of therapy, it was observed greater reduction in dysmenorrhea in linzagolix groups when compared to placebo, noted by the rate of responders of 23.5 (95% CI: 17.5–30.7) in placebo group, 44 (95% CI: 36.3–52; P<0.001) in linzagolix 75 mg and 72.9 (95% CI: 65.3–79.4; P<0.001) in linzagolix 200 mg. At 6-month follow-up, the same association was found, evidenced by mean differences between linzagolix 75 and 200 mg when compared to placebo of −0.44 (95% CI: −0.65 to −0.23; P<0.001) and −1.17 (95% CI: −1.38 to −0.97; P<0.001), respectively. Only the maximum dose of linzagolix had a significant reduction of acyclic pelvic pain when compared with placebo, with a mean difference of −1.19 (95% CI: −1.77 to −0.62; P<0.001). Carr et al. ( 26 ) conducted a phase II clinical study comparing elagolix and subcutaneous depot medroxyprogesterone acetate in the treatment of endometriosis, focusing on the impact on bone mineral density. A total of 252 women were recruited and randomized into three groups: elagolix 150 mg/day (1 time per day), elagolix 75 mg/day (2 times per day) and subcutaneous depot medroxyprogesterone acetate at a dose of 104 mg every 12 weeks. The three treatments had a minimal impact on bone mineral density, and it was not considered clinically relevant. All treatments showed improvement in pain symptoms in relation to baseline. However, only the dosage of 150 mg/day (1×) of elagolix showed non-inferiority in relation to medroxyprogesterone acetate in reducing dysmenorrhea and acyclic pelvic pain. The most common adverse effects reported in the elagolix group were headache, nausea, and nasopharyngitis. All groups had an increased rate of hot flashes after the institution of therapy. However, there was a higher discontinuation rate in the medroxyprogesterone acetate group, which was mainly attributed to menorrhagia. A phase III, randomized and double-blind trial ( 27 ) compared the effect of two doses of elagolix—150 mg/day and 200 mg 2 times a day—with placebo. A total of 872 women participated in the study, and the primary outcome analyzed was the proportion of women who had a good clinical response to dysmenorrhea and noncyclic pelvic pain after 3 months, assessed using a scale from 0 (no pain) to 3 (severe pain) and the use of rescue analgesics. Both groups that received the intervention had high response rates regarding dysmenorrhea and acyclic pelvic pain, which was sustained up to 6 months. However, there was an evident response to therapy, notably in relation to dysmenorrhea and in a more pronounced way in the group that received the higher dose. In addition, only the women who made up the highest dose group reported lower use of analgesic medications (including opioids) than the placebo group and showed statistically significant improvement in dyspareunia. The effect of elagolix on fatigue experienced by women with endometriosis was evaluated in another trial ( 28 ). A total of 860 women were evaluated and fatigue was measured by the questionnaire Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 6a. There was a significant reduction in fatigue reported in the elagolix-treated group compared to placebo at both the 3- and 6-month assessments and was sustained after 12 months of treatment. A strong relationship was observed between the clinical response in the pain symptomatology of endometriosis and the improvement of fatigue. SPIRIT 1 and 2 trials ( 29 ) assessed the response rate in relation to dysmenorrhea and acyclic pelvic pain from relugolix therapy versus placebo, in a randomized, double-blind, phase III design. A total of 638 and 623 women were selected in the SPIRIT 1 and SPIRIT 2 studies, respectively, who were randomized into three groups: (I) placebo; (II) relugolix 40 mg/days associated with add back therapy (1 mg of estradiol + 0.5 mg of norethisterone); and (III) relugolix 40 mg/day alone for 12 weeks, with the addition of add back therapy after. The latter group was included to evaluate the impact of add back therapy on bone mineral density and vasomotor symptoms. It was observed a greater reduction of dysmenorrhea and acyclic pelvic pain in relugolix groups when compared to placebo. In linzagolix group, 75% of patients met the dysmenorrhea responder definition, compared with 27% in placebo group. A similar effect was observed with acyclic pelvic pain. The incidence of adverse effects was similar between the groups, the most common being headache and nasopharyngitis. The change in bone densitometry (<1%) was not considered clinically relevant. Hot flashes and loss of bone density were significantly higher in the group that started the add back therapy later than in the other two groups. GnRH antagonists are an effective therapy for controlling pain in women with endometriosis but has many adverse effects.

The efficacy of TENS in the adjuvant treatment of endometriosis was initially evaluated in a randomized clinical trial with two groups: Group 1—acupuncture-like TENS (frequency: 8 Hz, pulse duration: 250 µs) (n=11) and Group 2—self-applied TENS (frequency: 85 Hz, pulse duration: 75 µs) (n=11) ( 30 ). All women had deep endometriosis with persistent pelvic pain, despite hormone therapy. There was a significant improvement in chronic pelvic pain, deep dyspareunia, and overall quality of life in relation to the baseline in the two TENS groups, with no statistical difference between them. However, only acupuncture-like TENS was associated with the improvement of dyschezia. No improvement in dysmenorrhea and dysuria was observed in any of the groups, and this finding was interpreted as inconclusive since such complaints were infrequent in the selected sample. A multicenter, randomized, controlled study with a larger sample size (n=101) compared hormonal treatment associated with self-administered TENS versus hormone therapy alone ( 31 ). Both groups showed improvement in dyspareunia and quality of life, and a reduction in the frequency of pain episodes and the use of analgesics after 8 weeks. However, only the TENS group showed improvement in chronic pelvic pain, with a 36% decrease (P<0.001), while control group showed a 3.68% decrease. Furthermore, TENS group was associated to a higher improvement in sexual function, assessed by the questionnaire Female Sexual Function Index (FSFI), with an increase in the scores for lubrication and pain during sexual intercourse. TENS is an adjunctive treatment for pain control. One small study (n=41) aimed to evaluate the effect of manual therapy in the treatment of endometriosis ( 32 ). In this trial, manual therapy was defined by means of a protocol, including manipulation of the spine, abdomen, and pelvis, as well as other techniques, described in the study methodology. Placebo group received a manual intervention, with lighter manipulation of the same points. The sessions lasted 30 minutes and were repeated every 15 days. Improvement in EAPP was observed in the group that received manual therapy, with a significant difference in relation to placebo right after the intervention (P=0.03; d=0.71) and at 6-month follow-up (P<0.001; d=1.81). However, a variety of techniques were termed as “manual therapy” in this study, and therefore it was not possible to attribute the effect to a specific technique. Manual therapy may be an adjunctive treatment for pain control. A randomized controlled clinical trial sought to evaluate the efficacy of a psychotherapy approach associated with somatosensory stimulation in the treatment of endometriosis ( 33 ). The intervention was described as a combination of elements of mindfulness, hypnosis, problem-solving therapy, and cognitive behavioral therapy, associated with somatosensory stimulation, which involved acupuncture, moxibustion, and cupping. Sixty-seven women diagnosed with endometriosis and persistent chronic pain, without hormonal treatment for at least 1 month, were enrolled. The primary outcome was the evaluation of changes in the central nervous system, evaluated by magnetic resonance imaging. However, in the presentation of the results, only the secondary outcomes (evaluation of pain and quality of life) were described. In intervention group was observed a larger reduction in maximal global pain (mean difference of −2.1; 95% CI: −3.4 to −0.8; P=0.002; Cohen’s d=0.87), average global pain (mean difference of −2.5; 95% CI: −3.5 to −1.4; P<0.001; Cohen’s d=1.18) and maximal dyschezia (mean difference of −3.5; 95% CI: −5.8 to −1.3; P=0.003; Cohen’s d=1.1). There was no significant reduction in dyspareunia. Dysmenorrhea was not evaluated in this study. Regarding quality of life, improvements in both the physical and mental aspects were significantly larger in the intervention group. Farshi et al. conducted a randomized controlled trial to evaluate the effect of self-care counseling on mental health in women with endometriosis ( 34 ). Seventy-six women participated in the study and were selected from medical records from hospitalizations for endometriosis in the last 5 years. The intervention group participated in 7 group sessions of 60–90 minutes, in which questions about endometriosis and self-care skills were addressed. The results showed that self-care counseling seems to be beneficial in reducing anxiety, evidenced by the reduction in state anxiety, compared to baseline, with a mean difference of −12 (95% CI: −14.4 to −9.6; P<0.001) and a reduction in trait anxiety, with a mean difference of −10.9 (95% CI: −12.7 to −9.1; P<0.001). Also, it was observed an improvement in quality of life, on both physical and mental scores, of women with endometriosis. However, there are some limitations of this study in relation to sample selection and randomization, since the intervention group already had higher levels of physical and mental health before the intervention. The effect of psychological interventions on improving pain and quality of life in women with severe pain associated with endometriosis was also researched by Hansen et al. ( 35 ). In this multicenter, controlled, randomized trial, 58 women were randomized into three groups: specific intervention based on mindfulness and yoga practices, non-specific psychological intervention, and control (waiting list). The specific and nonspecific interventions (relaxation with music combined with exercise) were compared with each other but were also both considered psychological interventions and compared to the control. Psychotherapy was performed in 10 sessions lasting 3 hours, with a detailed plan for each session described in the article. Compared to the control group, psychological interventions did not significantly reduce EAPP. However, both interventions significantly improved quality of life, in the aspects of “control and impotence”, “emotional well-being”, “social support” and in the evaluation of symptoms associated with endometriosis of “dyschezia” and “constipation”. None of the psychotherapy strategies proved to be superior. One of the limitations described in the study was the small sample, smaller than planned and calculated according to the power of analysis, at first of 81 people. One of the factors that hindered recruitment was the duration of the intervention, which was 3 hours per session. Psychotherapy may be an adjunctive treatment for pain control. The effect of mindfulness on endometriosis treatment was evaluated in two articles in this review, one of which was described above ( 35 ). The other trial included in this review assessed the brief mindfulness in the management of pain associated with endometriosis ( 36 ). The differences between the mindfulness and the brief mindfulness, detailed in the article, are the reduction of the duration of the intervention. Sixty-three women with deep endometriosis and chronic persistent pain despite conventional treatment (with progestins or combined oral contraceptives) were randomized into two groups: conventional treatment associated with brief mindfulness and conventional treatment alone. Evaluations were performed before the intervention, at 5- and 8-week follow-up. Brief mindfulness group was associated with an improvement in pelvic pain, dyschezia and the sensation of “pain unpleasantness”, a cognitive component of pain. At follow-up, in addition to the immediate effects, there was improvement in dysuria, dyspareunia, and dysmenorrhea. However, this trial did not compare the intervention with an active control group (sham mindfulness or other psychosocial intervention). Mindfulness may be an adjunctive treatment for pain control. Yoga is considered a mind-body practice. It is postulated that such practices can improve mental health, due to the direct and indirect potential effects on regulating immune system, stress, and pain control, and integrating body and mind ( 41 - 43 ). Although there is a lot of research demonstrating the beneficial effects of yoga practice in other chronic conditions ( 44 - 47 ), there was only one clinical study that evaluated the effect of yoga in the treatment of endometriosis. The study conducted by Gonçalves et al. ( 37 ) was a randomized, controlled study that evaluated the effects of yoga practice twice a week for eight weeks, and an improvement in the quality of life score and pain intensity was observed in the group that received the intervention. In this study, a predominant improvement was observed in aspects related to pain, feeling of control or powerlessness, emotional well-being, and self-image. Yoga may be an adjunctive treatment for pain control. In the period delimited by the methodology of this review, only one clinical study evaluating the efficacy of acupuncture in endometriosis-related pain, conducted in China, by Li et al. ( 38 ) with 106 women. It was conducted a multicenter, randomized, controlled study that sought to compare the efficacy of acupuncture versus sham (insertion of the needle outside the acupuncture points), with sessions three times a week for twelve weeks. During the study, the use of analgesics was allowed, if it was reported to the team, but no participant reported the use. None of the groups could receive any other type of treatment for endometriosis during the trial. In acupuncture group, a significant reduction in dysmenorrhea and duration of pelvic pain was observed compared to sham group. However, these results were not maintained twelve weeks after the end of the intervention. No difference was observed in the intensity of chronic pelvic pain and dyspareunia, which was attributed to the low intensity of these types of pain since the beginning of the study. In addition, an improvement was observed in the EHP-30 questionnaire, related to quality of life in the intervention group, however, maintaining the pattern of transient improvement, limited to the duration of intervention. Despite the positive results, some limitations of this study should be considered, the main one being that the acupuncture technique and sham acupuncture differed significantly, therefore it was not possible to blind the acupuncturists, and the blinding of the participants was not guaranteed. Acupuncture is an adjunctive treatment for pain control. In a pilot study, 62 women with endometriosis and persistent pain despite conventional treatment (unspecified) were selected and given the possibility to choose whether they would be part of the control group or one of the two interventions, the low-fat diet fermentable oligo-, di-, mono-saccharides and polyols (FODMAPs) or the “endometriosis diet” ( 39 ). The FODMAP-restricted diet is described in the literature, notably for irritable bowel syndrome, and consists of the elimination or restriction of some non-digestible carbohydrates, present in several foods. On the other hand, the so-called “endometriosis diet” was created from the shared experience of women with endometriosis in the Netherlands. This diet was characterized by the absence of red meat, gluten, dairy, sugars, sweeteners, and phytoestrogens, in addition to limiting caffeine intake to 200 mg per day. It was observed that both nutritional interventions reduced abdominal distension and improved the aspects of “social support” and “medical profession” when compared to the control. In addition, there was an improvement in dyspareunia in the group of nutritional interventions, when compared to the baseline. However, it is worth noting that some study participants reported difficulty in grading pain intensity, as it was performed retrospectively. The study conducted by Nodler et al. ( 40 ), sought to evaluate vitamin D and omega-3 supplementation in adolescents and young adults with endometriosis. This trial demonstrated the importance of placebo control in studies investigating pain and quality of life. A controlled clinical trial was conducted with 69 participants aged 12–25 years, most of whom had surgically confirmed stage I endometriosis, who were randomized into three groups: vitamin D supplementation (2,000 IU per day), omega-3 fish oil supplementation (1,000 mg per day), or placebo. All had vitamin D sufficiency, and most were taking hormone treatment. All study groups showed improvement in the intensity of the worst pain reported in the last month; in the vitamin D group the average was 7.0 to 5.5 (P=0.02), in fish oil it was 5.9 to 5.2 (P=0.39) and placebo from 6.0 to 4.4 (P=0.07). However, when the interventions were compared to placebo, no significant difference was observed. These results reinforce the importance of placebo control and the need to consider the effect of exposure to a new treatment. Appropriate diets may be an adjunctive treatment for pain control.

A narrative review on hormonal and complementary treatments for EAPP was carried out. Inclusion criteria were clinical trials that compared the effect of interventions with either placebo or first-line therapies for the treatment of endometriosis and which primary or secondary outcome assess pain or quality of life. Searches in the databases included articles from the following sources: PubMed, Virtual Health Library and Embase. All articles inserted in these databases were language English or Portuguese published between 2014 and 2024. We have included in this review clinical trials. We have excluded studies with no control group, with cross-sectional or case-control designs, case series, or retrospective studies. Two authors performed a distinct search using the strategic combination of keywords. The search strategy included these MESH terms: ‘Endometriosis’, ‘Endometrioma’, ‘Therapeutics’, ‘Progestins’, ‘Desogestrel’, ‘Dienogest’, ‘Intrauterine devices’, ‘Etonogestrel implant’, ‘Medroxyprogesterone Acetate’, ‘Norethindrone’, ‘Drospirenone’, ‘Contraceptives, Oral, Combined’, ‘Gonadotropin-Releasing Hormone’, ‘selective Estrogen Receptor Modulators’, ‘Complementary Therapies’, ‘Acupuncture Therapy’, ‘Acupuncture’, ‘Nutrition Therapy’, ‘Mentalization-Based Therapy’, ‘Physical Therapy Modalities’, ‘Exercise’ and ‘Yoga’. Other terms that are not listed in MeSH terms were included: “Dienogest”, “Etonogestrel implant”, “Drospirenone”, “Gonadotropin-Releasing Hormone” ( Table 1 ). A total of 1,201 articles were identified, and after excluding the duplicates, 638 studies remained. After excluding duplications and applying inclusion criteria 48 studies remained, of which 33 were selected for this review ( Figure 1 ). Study selection flow chart. BVS, Virtual Health Library. This review has been registered on the PROSPERO platform under the identification CRD42024611978.

The analysis of the 33 selected studies was divided into two sections, hormonal treatment and complementary treatment, which were subdivided according to the therapeutic class or the intervention performed ( Table 2 ). CI, confidence interval; DNG, dienogest; EHP-5, Endometriosis Health Profile 5; ENG, etonogestrel; EHP-30, Endometriosis Health Profile 30; FODMAP, fermentable oligo-, di-, mono-saccharides and polyols; GnRH, gonadotropin-releasing hormone; LNG-IUS, levonorgestrel-releasing intrauterine system; LSMD, least-square mean difference; MD, mean difference; MPA, medroxyprogesterone acetate; NETA, norethisterone acetate; SF-36, short form 36; TENS, transcutaneous electrical nerve stimulation.

The results of this review reinforce the efficacy of hormonal treatments in the management of endometriosis, with dienogest as one of the first-line options. Studies consistently demonstrate its effectiveness in reducing pain associated with endometriosis, with no significant impact on bone health in the short to medium term ( 9 ). Also, the comparison with other hormonal treatments, such as combined oral contraceptives ( 12 , 15 ), medroxyprogesterone acetate ( 14 ) and GnRH agonist ( 13 ) shows that dienogest has a favorable safety profile, being generally better tolerated by patients and associated with fewer side effects ( 8 - 15 ). Although there is less evidence for desogestrel, probably justified by the unavailability of its isolated in other countries, such as the United States, desogestrel demonstrated superiority over placebo as adjuvant treatment of pain ( 16 ). Long-acting reversible contraceptives, such as the LNG-IUS 52 mg and the ENG implant, have also been shown to be effective in reducing pain, specifically dysmenorrhea and chronic pelvic pain. However, they had a high discontinuation rate due to irregular bleeding ( 17 ). GnRH antagonists seem to be interesting alternatives, especially because they allow dose-dependent control of estradiol levels, which minimizes adverse effects related to bone health and vasomotor symptoms ( 24 - 29 ). However, dyspareunia seems to be less responsive to these treatments, and a reduction was observed only with higher doses of these medications. Further studies are needed to compare its effect with first-line therapies for endometriosis and to evaluate its long-term effects. TENS has shown positive results in reducing chronic pelvic pain and improving sexual function, but its effect is still uncertain regarding dysmenorrhea ( 30 , 31 ). Therefore, more placebo-controlled studies are needed to improve the degree of evidence for TENS. Acupuncture was the only complementary therapy studied in isolation, without concomitant hormonal treatment, and was compared with placebo (sham acupuncture). Dysmenorrhea and quality of life improved during the intervention, with no sustained effect after the end of the intervention and no evidence of improvement in other pain parameters ( 38 ). More studies are needed to evaluate the effects of acupuncture on the other domains of EAPP ( 48 ). Psychotherapy and interventions based on mindfulness appear to have a significant effect on improving quality of life, although their impact on pain reduction is not yet conclusive ( 33 - 36 ). Nutrition has been explored as an adjunct approach in the management of endometriosis, with diets such as FODMAP and the “endometriosis diet” showing potential to improve symptoms such as bloating ( 39 ). However, larger, controlled studies are still needed to validate these nutritional approaches. Vitamin D and omega-3 supplementation did not demonstrate superiority over placebo ( 40 ), highlighting the importance of placebo-controlled studies. The strengths of this study are the scope of the subject, including the evaluation of hormonal and complementary treatments; the inclusion of recent studies sourced from reliable databases, ensuring updated and relevant scientific evidence and the discussion of key gaps in the literature, particularly regarding complementary therapies. The structured organization and clear writing enhance readability, making it a valuable resource for guiding clinical decision-making. Some limitations were the study design, that is not capable of ensuring a systematic and reproducible selection of studies. Additionally, the lack of a meta-analysis prevents the calculation of pooled effect sizes, limiting the ability to quantitatively assess treatment efficacy. Although physical activity was included as a variable, there was no study assessing its role in endometriosis management.

Progestins and combined oral pills are first-line therapies for the treatment of endometriosis pain symptoms, while GnRH agonists and antagonists should be reserved for second-line treatment due to their hypoestrogenic effects and long-term use. Further studies are needed to evaluate complementary therapies.

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