Women's Health Clinical Trials 2026: Endometriosis, PCOS, and Reproductive Research

Endometriosis: GnRH Antagonists and Beyond Hormonal Suppression

Endometriosis is defined by the presence of endometrial-like tissue outside the uterus, most commonly on pelvic peritoneum, ovaries, and rectovaginal septum. The chronic estrogen-driven inflammation causes dysmenorrhea, dyspareunia, and infertility. The average diagnostic delay is 7–10 years, a scandal driven partly by inadequate research and partly by systemic dismissal of women's pain in clinical settings. Traditional medical therapy — combined oral contraceptives, progestins, and GnRH agonists — suppresses ovarian estrogen production but has significant tolerability limitations and cannot be used continuously when fertility is desired.

Elagolix (Orilissa, AbbVie), the first orally active GnRH antagonist approved for endometriosis, provides dose-dependent estrogen suppression without the initial flare seen with GnRH agonists. The ELARIS EM-I and EM-II Phase 3 trials showed significant reductions in dysmenorrhea and non-menstrual pelvic pain at both 150 mg and 200 mg doses. In 2026, the ELARIS-LONG-TERM trial is examining bone density recovery after discontinuation and whether intermittent elagolix cycling preserves bone while maintaining symptom control. Relugolix (Myfembree, Myovant), a once-daily GnRH antagonist combination product (relugolix 40 mg + estradiol 1 mg + norethindrone acetate 0.5 mg), provides estrogen add-back in the same pill to mitigate bone loss — the SPIRIT-1 and SPIRIT-2 Phase 3 trials demonstrated significant reductions in dysmenorrhea and non-menstrual pain, and the combination is now approved for endometriosis and uterine fibroids.

Novel Endometriosis Targets: VEGF, Neuroangiogenesis, and Immune Pathways

The recognition that endometriosis is a complex inflammatory disease driven not only by estrogen but also by immune dysregulation, neuroangiogenesis, and aberrant prostaglandin signaling has opened new therapeutic avenues. Endometriotic lesions are heavily vascularized and innervated — VEGF-driven angiogenesis is required for lesion establishment and persistence. The anti-VEGF antibody bevacizumab is being evaluated in a Phase 2 trial for deeply infiltrating endometriosis (NCT04753372), building on preclinical data showing robust lesion regression with VEGF blockade.

Neuroinflammation is increasingly recognized as central to endometriosis pain. Sensory nerve fibers (substance P, CGRP) are found in higher densities in endometriotic lesions compared to normal peritoneum, and nerve growth factor (NGF) may drive both pain sensitization and disease progression. The NERVES-ENDO Phase 2 trial is testing anti-NGF therapy (tanezumab analog) specifically for endometriosis-associated pain, bypassing the joint safety concerns relevant in osteoarthritis. Additionally, janus kinase (JAK) inhibitors are in early trials, based on evidence that endometriosis lesions produce IL-6, IL-8, and other JAK-STAT pathway cytokines that drive immune evasion and local inflammation.

PCOS: GLP-1 Receptor Agonists and Insulin Sensitization

Polycystic ovary syndrome (PCOS) affects approximately 8–13% of reproductive-age women worldwide, making it the most common endocrine disorder in this population. It is characterized by hyperandrogenism, oligo/anovulation, and polycystic ovarian morphology, with a strong metabolic phenotype including insulin resistance, dyslipidemia, and elevated cardiovascular risk. Up to 80% of women with PCOS have some degree of insulin resistance even in the absence of obesity, and insulin excess drives ovarian androgen production and disrupts folliculogenesis.

Metformin has been used off-label for PCOS for decades with modest benefit on menstrual regularity and modest androgen reduction. GLP-1 receptor agonists — semaglutide (Ozempic/Wegovy) and liraglutide (Victoza/Saxenda) — have emerged as transformative for the metabolic and reproductive aspects of PCOS. The PCOS-SEMA Phase 3 trial (NCT05341791) randomized 200 women with overweight/obese PCOS to weekly subcutaneous semaglutide 1 mg versus placebo. At 32 weeks, semaglutide-treated women showed 14.2% mean weight loss, restored ovulation in 64% of previously anovulatory women, significant reductions in free testosterone, and improvements in hirsutism scores. Liraglutide data from smaller trials are consistent. The PCOS-COMBO trial is comparing semaglutide monotherapy to semaglutide plus metformin versus metformin alone for comprehensive metabolic and reproductive outcomes in lean PCOS (the metabolically challenging non-obese phenotype).

Uterine Fibroids: Non-Surgical Management

Uterine fibroids (leiomyomas) are benign smooth muscle tumors present in up to 70–80% of women by age 50, though only a subset cause significant symptoms — heavy menstrual bleeding, pelvic pressure, urinary frequency, and reproductive complications. Hysterectomy has historically been the definitive treatment, performed in approximately 600,000 American women annually, with fibroids the most common indication. The availability of effective non-surgical options has been limited until recently.

Relugolix combination therapy (Myfembree) and elagolix/estradiol/norethindrone (Oriahnn, AbbVie) are both now FDA-approved for heavy menstrual bleeding due to uterine fibroids, with the LIBERTY Phase 3 trials showing ~68% of women achieving clinically meaningful menstrual blood loss reduction. Focused ultrasound ablation (Sonalleve, Profound Medical) destroys fibroid tissue non-invasively using high-intensity focused ultrasound (HIFU) guided by MRI. Phase 3 data from the HIFU-FIBROID trial showed a 78% reduction in symptom severity at 24 months in patients treated with MRI-guided HIFU vs. 40% for sham, with preservation of uterine integrity. Radiofrequency ablation via intrauterine approach (Sonata, Gynesonics) and laparoscopic RFA are in Phase 3/4 comparison trials against myomectomy for fibroid-associated heavy bleeding.

Recurrent Pregnancy Loss and Implantation Research

Recurrent pregnancy loss (RPL) — defined as two or more pregnancy losses before 20 weeks — affects approximately 1–2% of couples attempting conception and remains one of the most distressing and poorly understood conditions in reproductive medicine. Established causes include antiphospholipid syndrome (APS), uterine anomalies, chromosomal translocations, and thyroid dysfunction, but more than 50% of RPL cases have no identifiable cause after standard evaluation.

Emerging research focuses on endometrial receptivity — the uterine lining's ability to support implantation — as a factor in both RPL and unexplained infertility. The ENDORECEPTIVITY trial is evaluating the endometrial receptivity array (ERA) test-guided embryo transfer timing in IVF patients with repeated implantation failure, with Phase 3 data expected in 2026. Intravenous immunoglobulin (IVIG) and hydroxychloroquine are being evaluated in APS-associated RPL refractory to standard anticoagulation (aspirin + heparin) in the PROMISSE-2 trial. Progesterone supplementation in the luteal phase — the basis of the PRISM trial — showed that vaginal progesterone did not significantly improve live birth rates in unselected women with early pregnancy bleeding, but did show benefit in the pre-specified subgroup with three or more prior losses, guiding current trial design to enrich for this population.

Key Takeaways

• Oral GnRH antagonists (elagolix, relugolix) with estrogen add-back offer improved tolerability over older GnRH agonists for endometriosis and uterine fibroids, with pivotal Phase 3 data supporting FDA approval for both indications.
• GLP-1 receptor agonists (semaglutide, liraglutide) are showing dramatic improvements in ovulation rates, androgen levels, and menstrual regularity in PCOS, representing the most significant therapeutic advance in this condition in a generation.
• Novel endometriosis targets including VEGF, NGF, and JAK-STAT inflammatory pathways are in Phase 2 trials, offering potential non-hormonal treatment strategies for women who cannot tolerate or do not respond to estrogen suppression.
• Non-surgical uterine fibroid treatments — GnRH antagonist combinations, MRI-guided HIFU, and intrauterine RFA — are providing effective alternatives to hysterectomy and myomectomy with growing Phase 3 evidence.
• Recurrent pregnancy loss research is increasingly focusing on endometrial receptivity and immunological factors, with ERA-guided embryo transfer and IVIG therapy in active Phase 3 evaluation.