Endometriosis: what it is, treatment and the GnRH evidence

What is endometriosis and how many women have it?

Endometriosis is a chronic inflammatory disease in which tissue resembling the endometrium is found outside the uterus, mainly on pelvic organs and tissues². Retrograde menstruation is regarded as an important origin of the deposits, but a favourable endocrine and metabolic environment, epithelial-mesenchymal transition and altered immune and inflammatory responses in genetically susceptible women are also involved². It is an estrogen-dependent condition that causes dysmenorrhea and pelvic pain¹³.

According to the World Health Organization, it affects an estimated 10% (190 million) of reproductive-age women worldwide¹. The review by Zondervan and colleagues in Nature Reviews Disease Primers puts it at 5-10% of women of reproductive age, about 176 million, and notes that its costs to society are comparable to those of other chronic conditions such as type 2 diabetes, Crohn's disease and rheumatoid arthritis². The WHO adds that 25% to 50% of women with infertility have it¹.

Symptoms and how endometriosis is diagnosed

The WHO lists severe pain during menstruation, heavy menstrual bleeding and chronic pelvic pain as symptoms, along with infertility¹. Women may seek care for years: the delay between first symptoms and surgical diagnosis has been described as 4 to 11 years³, and the WHO cites 4 to 12 years¹.

For decades the standard was surgical visualization with histological confirmation. The 2018 review notes that diagnosis is reliably established only this way, although ovarian endometrioma and deep nodular disease can be detected with ultrasonography and MRI². Thinking has shifted: a 2019 call to action proposes treating the disease as chronic, systemic, inflammatory and heterogeneous, and basing clinical diagnosis on symptoms, signs and examination findings to shorten the delay³. The 2022 guideline of the European Society of Human Reproduction and Embryology (ESHRE), with 109 recommendations, challenges laparoscopy and histology as the gold-standard diagnostic tests⁴.

Standard treatment today: what the guidelines recommend

No existing treatment definitively cures the disease; the aim is to control symptoms and limit long-term impact¹. The ESHRE guideline lists analgesics, medical treatments and surgery as options for pain, plus non-pharmacological approaches, and surgery or assisted reproduction for infertility; it acknowledges that, on existing evidence, firm recommendations on the most appropriate treatments could not be formulated⁴.

Among hormonal treatments, progestagens are a mainstay. The 2025 Cochrane review (33 trials, 5059 participants) concluded that oral progestagens, compared with placebo, probably reduce overall pain (mean difference -2.58 on a visual analogue scale, moderate certainty) and improve quality of life (high certainty)⁶. Compared with oral contraceptives there was probably little to no difference in pelvic pain (moderate certainty), and compared with GnRH agonists none in overall pain (low certainty), with more cumulative side effects with oral progestagens (RR 1.44)⁶.

A network meta-analysis of 31 trials and 8665 patients found that, against placebo, leuprolide with a combined oral contraceptive, dienogest, leuprolide alone and the combined oral contraceptive improved endometriosis-associated pelvic pain¹¹. Another, of 8 studies and 3259 patients, concluded that the oral GnRH antagonist was the most effective for dysmenorrhea and non-menstrual pelvic pain, while dienogest had the best safety profile and was more beneficial for dyspareunia¹². Both analyses compare different trials indirectly, and the authors call for larger, more rigorous studies¹¹.

What peptide research has shown on GnRH analogues

GnRH is a hypothalamic decapeptide that governs the reproductive axis. Peptide agonist analogues given continuously desensitize the receptor and suppress ovarian estrogen production, which is why they are used in an estrogen-dependent disease. This is the peptide application closest to an approved indication in this condition; the wider history of the class is in A century of therapeutic peptides and its role in prostate cancer in Peptides in oncology.

Leuprolide. It is FDA-approved: the Lupron Depot label indicates management of endometriosis, including pain relief and reduction of lesions, and use with norethindrone acetate for initial management of painful symptoms and recurrence; total duration with add-back therapy should not exceed 12 months because of concerns about bone mineral density⁷. The 2023 Cochrane review found, for GnRH analogues against placebo, a possible reduction in pain at three months (for example pelvic pain scores RR 2.14; 95% CI 1.41 to 3.24), but based on a single trial of 87 patients and low-certainty evidence⁵. In a double-blind randomized trial of 47 women over 48 weeks, leuprolide with add-back and continuous oral contraceptives both reduced pain, with no significant difference between groups⁹.

Goserelin. Its FDA label lists the management of endometriosis among its indications, alongside oncology uses, and requires excluding pregnancy for benign gynecological conditions⁸. Recent meta-analyses compare mainly leuprolide; there are fewer comparative data on goserelin in the sources consulted¹¹¹².

Add-back therapy. To counter bone loss, a low dose of hormones is added to the agonist. In a 52-week randomized trial of 201 patients treated with monthly leuprolide, bone mineral density stayed at or above baseline in all add-back groups, while the loss in the group without add-back reversed slowly and had not returned to baseline at final follow-up; symptom relief lasted at least eight months after treatment ended¹⁰.

The newest antagonists are not peptides. This is the least known part of the story: the drugs that have changed the landscape are small oral molecules. Elagolix is an oral, nonpeptide GnRH antagonist; in two phase 3 trials with 872 and 817 women, the dysmenorrhea response at 3 months was 46.4% and 75.8% (lower and higher dose) versus 19.6% with placebo in the first, and 43.4% and 72.4% versus 22.7% in the second¹³. Its label indicates it for moderate to severe pain associated with endometriosis and limits duration by dose¹⁴. Relugolix combined with estradiol and norethisterone acetate reached dysmenorrhea response in 75% versus 27% (SPIRIT 1) and 75% versus 30% (SPIRIT 2) at 24 weeks, and non-menstrual pelvic pain response of 58% versus 40% and 66% versus 43%¹⁵; in the two-year open-label extension, responses were 84.8% and 75.8%¹⁶. Linzagolix, also nonpeptide²³, with add-back therapy reached a 72.9% dysmenorrhea response versus 23.5% with placebo in EDELWEISS 3 (486 subjects)¹⁷, and 91.0% at 12 months in EDELWEISS 6¹⁸.

Peptide antagonists. Peptide GnRH antagonists exist, such as cetrorelix, ganirelix and degarelix; reviews note that cetrorelix and ganirelix dominate assisted reproduction and degarelix advanced prostate cancer²². The endometriosis trials reviewed here used nonpeptide molecules.

Safety: adverse effects and precautions

The main limitation of GnRH analogues is hypoestrogenism. The leuprolide label warns of loss of bone mineral density, embryo-fetal toxicity, severe cutaneous adverse reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis) and depression; the most common adverse reactions in trials (over 10%) were hot flashes and sweats, headache or migraine, vaginitis, depression or emotional lability, pain, weight changes, nausea, decreased libido and dizziness⁷. The label also describes an initial flare of symptoms and convulsions⁷.

In a meta-analysis of 37 studies, agonists with add-back reduced bone density by 0.89% at 6 months and 1.50% at 12; leuprolide with add-back, 1.33% at 6 months; and antagonists, 2.17% at 6 months, although most of those studies lacked add-back. The authors stress that clinical significance remains uncertain¹⁹. In combined relugolix trials, mean loss was under 1% at week 24 and then plateaued through 104 weeks¹⁶.

In adolescents, a questionnaire follow-up of 25 of 41 patients treated with depot leuprolide and add-back found that 24 of 25 reported side effects during treatment and 9 of 20 considered some of them irreversible, including memory loss, insomnia and hot flashes; even so, most rated it the most effective hormonal medication²⁰. It is a small study with partial response and self-report.

Summary by agent

Frequently asked questions

How many women have endometriosis? About 10% of reproductive-age women, roughly 190 million worldwide, according to the WHO; other estimates put it at 5-10%¹².

Is there an approved peptide for endometriosis? Yes: leuprolide and goserelin, peptide GnRH analogues, list endometriosis among their indications on FDA labels⁷⁸. No other peptide has that indication in the sources consulted.

Do GnRH analogues cure endometriosis? No. The WHO states no treatment definitively cures the disease¹, and in the 2023 Cochrane review the evidence is of low to very low quality⁵. Symptoms often persist or recur after treatment is initiated¹, and the label contemplates retreatment only with add-back therapy and prior bone assessment⁷.

Do they improve fertility? There is no evidence of benefit. A Cochrane review of 24 trials found a pregnancy odds ratio of 0.79 (95% CI 0.54 to 1.14) with ovulation suppression versus placebo or no treatment, and concluded there is no evidence of benefit in subfertile women who wish to conceive²¹.

Are oral antagonists better than agonists? In indirect comparisons the high-dose oral antagonist showed the largest effect on dysmenorrhea and non-menstrual pelvic pain¹², but these are indirect comparisons, and the pivotal elagolix and relugolix trials were funded by the manufacturers¹³¹⁵.

Are there alternatives without full estrogen suppression? Oral progestagens reduced overall pain versus placebo with moderate certainty and showed no clear difference in pain versus GnRH agonists, with low certainty⁶.