Current management of endometriosis-associated pain combines surgery and pharmacological treatment, depending on symptom severity, disease characteristics, and reproductive goals (Kalaitzopoulos et al. 2021).

Pharmacological management mainly relies on hormonal therapies and nonsteroidal anti-inflammatory drugs (NSAIDs). Hormonal therapies suppress ovarian function or modulate estrogen and progesterone signaling, thereby reducing the growth and activity of endometriotic lesions. Current therapeutic options include progestins, combined estrogen–progestin contraceptives, gonadotropin-releasing hormone (GnRH) agonists and antagonists, selective estrogen receptor modulators (SERMs), selective progesterone receptor modulators (SPRMs), and aromatase inhibitors (AIs) (Fig. 2). Supplementary Tables S1–S5 summarize the principal clinical studies evaluating hormonal therapies. Additional included studies are discussed in the text when they provide complementary information on comparative efficacy, combination therapies, long-term follow-up, safety, or specific clinical observations.

Fig. 2

Current hormonal therapies and emerging pharmacological strategies for endometriosis-associated pain. Hormonal therapies, including progestins, combined estrogen–progestin contraceptives, and GnRH analogs/antagonists, primarily suppress ovarian function and reduce estrogen-dependent lesion activity, leading to improvements in CPP, dysmenorrhea, and quality of life. However, these treatments are mainly suppressive rather than curative and are limited by adverse effects, symptom recurrence after treatment discontinuation, and their limited impact on the inflammatory and neuroimmune mechanisms underlying pain persistence. Emerging pharmacological strategies, including immunomodulatory therapies, anti-inflammatory and antioxidant compounds, and drug repurposing approaches, aim to target the inflammatory microenvironment and may complement endocrine therapies to improve long-term clinical outcomes. Created with BioRender.com

Progestogens (Supplementary Table S1 )

Nomegestrol acetate binds specifically to the progesterone receptor, exerting strong antiestrogenic effects and potent antigonadotropic activity. Due to its long half-life (50 h), it can cover the hormone-free interval for 4 days. Treatment with nomegestrol acetate is typically combined with 17β-estradiol (E2), resulting in a 24/4 oral contraceptive regimen. Treatment with E2/nomegestrol acetate (1.5 mg/2.5 mg) increased amenorrhea over time while reducing CPP and improving sexual activity and QoL (Caruso et al. 2020).

Dienogest (DNG) is a highly selective progesterone receptor agonist that can be administered continuously without causing major metabolic disturbances. Since its approval in Europe in 2010 for the treatment of endometriosis, oral DNG (2 mg/day) has become one of the most widely used hormonal therapies (Heinemann et al. 2020). Treatment should be maintained for at least 3 months, with 6–12 months generally required to achieve significant reductions in inflammation and endometrioma size. The most common adverse effects include abnormal uterine bleeding, weight gain, headache, and breast tenderness (Cho et al. 2020). Clinical studies have consistently demonstrated that DNG reduces dysmenorrhea, dyspareunia, CPP, endometrioma size, and deep endometriotic lesions while improving QoL (Grandi et al. 2015; Piacenti et al. 2021; Saglik Gokmen et al. 2023). Compared with levonorgestrel/ethinylestradiol, DNG provided greater overall pain relief, whereas both treatments similarly improved dyspareunia, reduced NSAID use, and enhanced QoL (Piacenti et al. 2021). Additional benefits have also been reported when DNG was combined with ethinylestradiol or estradiol valerate, including improvements in dysuria (Del Forno et al. 2023).

In patients newly diagnosed with endometriosis and adenomyosis who were not candidates for surgical treatment, a prolonged flexible oral contraceptive regimen (2 mg of DNG/30 µg of ethinylestradiol) was proposed, consisting of 120 consecutive 30-day cycles of active tablets followed by a 4-day tablet-free interval. A significant decrease in inflammation and in the size of ovarian endometriomas and in uterosacral ligament involvement in adenomyosis was observed at the 12-month follow-up (Carrillo Torres et al. 2023).

Etonogestrel (3-keto-desogestrel), the active metabolite of desogestrel, is administered as a 68-mg subdermal implant (Nexplanon® or Implanon®) that inhibits ovulation for up to 3 years. Clinical studies have shown significant reductions in dysmenorrhea, dyspareunia, and CPP, together with improvements in QoL, including physical pain, general health, vitality, social functioning, and mental health (Sansone et al. 2018). Niu et al. (2021) conducted a 24-month trial in which 66 patients experienced complete remission of CPP. The most common adverse events were vaginal bleeding and menstrual disturbances, together with generally mild systemic side effects, including weight gain, acne, breast tenderness, mood changes, decreased libido, sleep disturbances, constipation, and skin-related symptoms.

The levonorgestrel-releasing intrauterine system (LNG-IUS) continuously releases levonorgestrel (20 µg/day) into the uterine cavity for up to 5 years. Treatment significantly improved endometriosis-associated symptoms within the first 12–18 months, with sustained clinical benefit during follow-up. The most common adverse effects were menstrual irregularities, persistent pelvic pain, and weight gain (Lockhat et al. 2005). In a comparative study, the LNG-IUS and the etonogestrel subdermal implant showed similar efficacy in reducing non-menstrual pelvic pain (NMPP) and dysmenorrhea, while improving QoL without inducing hypoestrogenism (Carvalho et al. 2018).

Medroxyprogesterone acetate is administered as a 150-mg intramuscular injection every 3 months. In a comparative study with the etonogestrel subdermal implant (Implanon®), both treatments achieved a similar reduction in endometriosis-associated pain (approximately 50%) during the first 3 months, with generally mild and transient adverse effects. After one year, amenorrhea was observed in a similar proportion of women receiving either treatment (14–15%) (Walch et al. 2009). Likewise, postoperative treatment with medroxyprogesterone acetate and combined oral contraceptives showed comparable efficacy in pain control and a similar safety profile (Cheewadhanaraks et al. 2012).

Dydrogesterone has high oral bioavailability and, at relatively low doses, is associated with a favorable safety profile. Unlike other progestins, it does not exert androgenic effects or inhibit ovulation (Schweppe 2009). In the ORCHIDEA study, dydrogesterone administered either cyclically (10 mg two or three times daily from days 5 to 25 of the menstrual cycle) or continuously for 6 months significantly reduced CPP, dysmenorrhea, and analgesic use, while improving sexual well-being and QoL. Uterine bleeding was reported in only 1.1% of participants (Sukhikh et al. 2021).

Danazol has shown limited clinical use because of its unfavorable safety profile. Oral administration (600 mg/day for 6 months) was associated with poor tolerability, with the most frequent adverse effects including weight gain, acne, vaginal bleeding, generalized spasms, vaginitis, pain, hypertonia, and an unfavorable lipid profile characterized by increased LDL and decreased HDL cholesterol, potentially increasing cardiovascular risk (Cheng et al. 2005). In contrast, intrauterine administration of danazol through a danazol-loaded intrauterine device (400 mg for 6 months) effectively reduced dysmenorrhea, pelvic pain, and dyspareunia in women with moderate-to-severe endometriosis while minimizing systemic adverse effects (Cobellis et al. 2004).

Combined estrogen-progestin contraceptive therapy (Supplementary Table S2)

Combined estrogen–progestin contraceptives are widely used as first-line therapy for women with endometriosis who do not wish to conceive. Their therapeutic effect is based on ovulation suppression and the reduction of estrogen-dependent stimulation of endometriotic lesions.

Treatment with drospirenone (3 mg)/ethinylestradiol (20 µg) stabilized symptom severity and health-related QoL in women with posterior deep infiltrating endometriosis (DIE), while preventing lesion progression, inflammation, and worsening of dysmenorrhea and dyspareunia compared with untreated controls (Mabrouk et al. 2011). No significant differences in symptom relief, lesion progression, or tolerability were observed between continuous and cyclic (24/4) regimens, although intermenstrual spotting and headache were the most common adverse effects (Mabrouk et al. 2012).

Beyond symptom control, combined oral contraceptives may also modulate the immune microenvironment. Treatment with ethinylestradiol/desogestrel reduced macrophage infiltration while increasing NK and Treg cell populations in endometriotic tissue, together with decreased cell proliferation and increased apoptosis in the eutopic endometrium (Waiyaput et al. 2021).

More recently, continuous treatment with estetrol (14 mg)/drospirenone (3 mg) for 6 months significantly reduced CPP and dyspareunia, completely resolved dysmenorrhea through amenorrhea induction, and reduced endometrioma size by approximately 30%, although intermenstrual spotting was the most frequent adverse event (Dell´Aquila et al. 2026).

Gonadotropin-releasing hormone (GnRH) analogs (Supplementary Table S3)

GnRH agonists suppress ovarian estrogen production through pituitary desensitization and are effective in reducing endometriosis-associated pain. In a comparative study, depot goserelin (3.6 mg every 28 days) and intranasal nafarelin (200 µg twice daily) produced similar reductions in dysmenorrhea, dyspareunia, and CPP, with no significant differences in efficacy. The most common adverse effects were hot flashes, sweating, vaginal dryness, and headache, while nasal irritation was reported only with nafarelin (Bergqvist 2000).

A randomized comparative trial showed that 4 months of triptorelin followed by 8 months of combined estrogen–progestin therapy (gestodene/ethinylestradiol) provided pain relief comparable to that achieved with continuous combined hormonal contraception for 12 months (Parazzini et al. 2000). More recently, a Phase III randomized trial demonstrated that triptorelin acetate administered every 3 months (15 mg) achieved comparable efficacy and safety to the conventional monthly regimen (3.75 mg), while reducing the frequency of injections and maintaining pain relief throughout the 24-week treatment period (Li et al. 2022).

GnRH Antagonists (Supplementary Table S3)

Elagolix was the first oral GnRH antagonist approved for the management of endometriosis-associated pain. In the ELARIS EM trial, both approved doses (150 mg once daily and 200 mg twice daily) significantly reduced dysmenorrhea and analgesic use, with greater efficacy observed at the higher dose (Taylor et al. 2017). Long-term treatment effectively controlled menstrual pelvic pain while minimizing hypoestrogenic effects, particularly at the lower dose, which was associated with only minimal changes in BMD and may be used for up to 24 months (Abrao et al. 2021; Abbas Suleiman et al. 2020).

Relugolix also demonstrated efficacy comparable to leuprorelin while avoiding the initial hormonal flare associated with GnRH agonists and allowing a faster recovery of menstruation after treatment discontinuation (Osuga et al. 2021). In the SPIRIT 1 and SPIRIT 2 trials, once-daily relugolix combination therapy (relugolix, estradiol, and norethisterone acetate) significantly improved dysmenorrhea, NMPP, and overall endometriosis-related pain, while reducing opioid use and minimizing bone mineral density loss (Giudice et al. 2022).

The EDELWEISS clinical development programme established linzagolix as another effective oral GnRH antagonist. Early studies identified 75 mg/day as the optimal dose to relieve pain while maintaining estradiol concentrations within the therapeutic window and minimizing hypoestrogenic adverse effects (Donnez et al. 2020). Subsequently, the Phase III EDELWEISS 3 trial demonstrated that both 75 mg monotherapy and 200 mg combined with add-back therapy significantly improved dysmenorrhea and NMPP, with the higher dose providing greater symptom control while minimizing vasomotor symptoms and bone loss (Donnez et al. 2024). Long-term extension data confirmed sustained improvements in pain, QoL, dyschezia, dyspareunia, and analgesic use, with only minimal reductions in BMD after 12 months of treatment (Donnez et al. 2026).

Opigolix demonstrated dose-dependent efficacy in reducing overall pelvic pain, dysmenorrhea, and menstrual pelvic pain in the Phase II TERRA study. The treatment was generally well tolerated, with headache, hot flashes, insomnia, tinnitus, and gastrointestinal symptoms representing the most common adverse events (D’Hooghe et al. 2019).

Selective estrogen receptor modulators (SERMs) (Supplementary Table S4)

Bazedoxifene is a selective estrogen receptor modulator that antagonizes estrogen-induced endometrial stimulation while preserving the beneficial estrogenic effects on bone and the central nervous system. Treatment with bazedoxifene combined with conjugated estrogens reduced menstrual flow and pelvic pain in a patient with stage III endometriosis (Flores et al. 2018). In a single case report, prolonged treatment with bazedoxifene/conjugated estrogens in combination with leuprolide effectively controlled endometriosis-associated pain while reducing the vasomotor symptoms and bone mineral density loss typically associated with GnRH agonists (Hill et al. 2018).

Selective progesterone receptor modulators (SPRMs) (Supplementary Table S4)

Mifepristone, a progesterone receptor antagonist, has been evaluated as an alternative treatment for endometriosis-associated pain. In a 24-week clinical trial, combination therapy with mifepristone (12.5 mg/day) and gestrinone achieved greater clinical efficacy than gestrinone alone, significantly reducing dysmenorrhea, dyspareunia, pelvic pain, pelvic tenderness, and induration. In addition to pain relief, this combination reduced hormone levels and was associated with improved pregnancy outcomes (Xue et al. 2016).

A retrospective clinicopathological study also reported that prolonged mifepristone exposure may induce morphological changes in ovarian endometriosis that can mimic borderline endometrioid tumors. These findings highlight the importance of careful histopathological interpretation and appropriate clinical correlation, rather than suggesting malignant transformation (Pan et al. 2022).

Ulipristal acetate (15 mg/day) also improved pain symptoms in a patient with treatment-resistant endometriosis; however, treatment was associated with reversible endometrial changes resembling hyperplasia after less than 3 months of therapy (Bressler 2017).

Evidence for both SERMs and SPRMs remains limited compared with progestins and GnRH analogs, highlighting the need for further clinical studies to define their role in the management of endometriosis-associated pain.

Aromatase inhibitors (AIs) (Supplementary Table S5)

Aromatase inhibitors have been evaluated mainly in combination therapies for women with refractory or severe endometriosis. Anastrozole has demonstrated efficacy both as monotherapy and in combination with oral contraceptives. Combined treatment with anastrozole (1 mg/day) and ethinylestradiol/levonorgestrel provided greater symptom relief than oral contraceptives alone, although pelvic pain exacerbation associated with intermenstrual bleeding was reported in some patients. Adverse effects, including headache, hot flashes, mood changes, and myalgia, were generally mild and resolved during follow-up (Amsterdam et al. 2005). More recently, preoperative treatment with anastrozole (1 mg/day for 6 months) significantly improved dysmenorrhea and CPP while delaying symptom recurrence after surgery (Acién et al. 2021).

Clinical studies with letrozole have focused primarily on combination therapy for rectovaginal endometriosis. Letrozole plus norethisterone acetate was associated with fewer adverse effects, lower treatment discontinuation rates, greater patient satisfaction, and no significant loss of BMD compared with letrozole plus triptorelin. Both regimens significantly reduced pain symptoms, although the reduction in the volume of endometriotic nodules was greater with triptorelin (Ferrero et al. 2011). Likewise, the combination of letrozole with oral contraceptives achieved greater reductions in CPP and dyspareunia than oral contraceptives alone, with a lower incidence of adverse effects (Zhao et al. 2021).