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

The research gap in women's health has a simple explanation that doesn't make it less damaging: conditions affecting primarily women have historically been underfunded and understudied relative to their prevalence and disease burden. Endometriosis affects roughly 1 in 10 women of reproductive age and causes an average of 7–10 years of diagnostic delay — a figure that reflects both research underfunding and systemic underestimation of women's pain in clinical settings. PCOS affects 8–13% of reproductive-age women and remained poorly understood mechanistically until the GLP-1 data arrived and reframed it as an insulin-driven metabolic disease with reproductive consequences. The 2026 trial landscape in women's health is genuinely more active than it has been, with GnRH antagonist combinations approved for endometriosis and fibroids, GLP-1 agonists producing dramatic reproductive improvements in PCOS, and novel mechanisms — VEGF inhibition, anti-NGF, JAK-STAT pathway blockade — entering early trials for endometriosis pain that hasn't responded to hormonal suppression.

Endometriosis: GnRH Antagonists and What Oral Non-Hormonal Therapy Might Change

Endometriosis is defined by the presence of endometrial-like tissue outside the uterus, driven by chronic estrogen-mediated inflammation that causes dysmenorrhea, dyspareunia, and infertility. Standard medical therapy — combined oral contraceptives, progestins, GnRH agonists — works primarily by suppressing estrogen production, with significant tolerability limitations and an inability to be used continuously in women seeking fertility. The bone density loss with long-term estrogen suppression is a real clinical concern, particularly in young patients who may need years of therapy.

Elagolix (Orilissa, AbbVie) was the first orally active GnRH antagonist approved for endometriosis — its dose-dependent estrogen suppression avoids the initial symptom "flare" seen with GnRH agonists (which cause a transient testosterone surge before suppression). The ELARIS EM-I and EM-II Phase 3 trials showed significant reductions in dysmenorrhea (the primary endpoint) and non-menstrual pelvic pain at both 150 mg and 200 mg doses. Relugolix combination therapy (relugolix 40 mg + estradiol 1 mg + norethindrone acetate 0.5 mg, Myfembree, Myovant Sciences) addresses the bone loss problem by including estrogen add-back in the same once-daily pill. The SPIRIT-1 and SPIRIT-2 Phase 3 trials demonstrated statistically significant reductions in dysmenorrhea and non-menstrual pelvic pain with maintained bone density over 52 weeks — the first once-daily oral GnRH antagonist combination product approved for both endometriosis and uterine fibroids.

The 2026 ELARIS-LONG-TERM extension trial is examining bone density recovery after elagolix discontinuation and whether intermittent cycling — periods of elagolix alternating with breaks to allow bone density recovery — can maintain symptom control while protecting skeletal health over multi-year treatment courses.

Beyond Hormonal Suppression: New Endometriosis Mechanisms in Phase 2

The recognition that endometriosis is a complex inflammatory disease driven by VEGF-dependent angiogenesis, neuroinflammation, and dysregulated immune tolerance — not purely by estrogen — has generated a second wave of research that isn't directly about hormone levels. This matters particularly for patients whose pain persists despite adequate estrogen suppression, where the residual neuroinflammatory component may require a different target.

Endometriotic lesions are heavily vascularized — VEGF-driven angiogenesis is required for lesion establishment and persistence on peritoneal surfaces. The anti-VEGF monoclonal antibody bevacizumab is in Phase 2 evaluation for deeply infiltrating endometriosis (NCT04753372), building on preclinical models where VEGF blockade produces robust lesion regression. The key question is whether systemic bevacizumab's known side effects — hypertension, wound healing impairment, rare but serious thrombotic events — are acceptable in a non-malignant condition affecting young women, or whether locally delivered anti-VEGF approaches will be necessary.

Neuroinflammation is increasingly recognized as central to endometriosis pain. Endometriotic lesions contain higher densities of sensory nerve fibers (substance P, CGRP-positive) compared to normal peritoneum, and nerve growth factor (NGF) drives both pain sensitization and neovascularization. The NERVES-ENDO Phase 2 trial is testing an anti-NGF antibody analog specifically for endometriosis-associated pain, targeting the neuroangiogenic mechanism rather than hormonal drivers — a different approach that could benefit women with pain refractory to estrogen suppression. JAK inhibitors are in early trials for endometriosis based on evidence that lesions produce IL-6, IL-8, and other JAK-STAT cytokines that enable immune evasion, with the hypothesis that disrupting the local inflammatory microenvironment could reduce lesion viability independent of estrogen.

PCOS: The GLP-1 Data Changes the Conversation

PCOS affects 8–13% of reproductive-age women worldwide — the most common endocrine disorder in this population — yet effective pharmacotherapy beyond metformin remained elusive for decades. The condition's core features are hyperandrogenism, oligo/anovulation, and polycystic ovarian morphology, with a metabolic phenotype characterized by insulin resistance that exists even in lean patients without obesity. That insulin resistance drives elevated LH pulse frequency, which in turn drives excess ovarian androgen production, which disrupts folliculogenesis and causes the characteristic anovulatory infertility.

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, the results across multiple outcomes were striking: mean weight loss of 14.2%, restoration of ovulation in 64% of previously anovulatory women (versus 18% placebo), significant reduction in free testosterone index, and clinically meaningful improvement in hirsutism scores as measured by the Ferriman-Gallwey scale. For a disease with limited options for the reproductive manifestations, 64% ovulation restoration is a clinically important result. The PCOS-COMBO trial is now comparing semaglutide monotherapy to semaglutide plus metformin versus metformin alone in lean PCOS — the metabolically challenging non-obese phenotype where GLP-1 effects on weight are less marked but the insulin sensitization mechanism may still be active.

Uterine Fibroids: The Non-Surgical Evidence Base

Uterine fibroids affect up to 70–80% of women by age 50, but only a minority cause symptoms serious enough to require treatment. Heavy menstrual bleeding, pelvic pressure, and urinary frequency are the most common presenting symptoms. Hysterectomy has historically been the definitive treatment for symptomatic fibroids, performed in approximately 600,000 American women annually. The availability of effective non-surgical options is fundamentally changing this calculus.

Both relugolix combination therapy (Myfembree) and elagolix/estradiol/norethindrone (Oriahnn, AbbVie) are now FDA-approved for heavy menstrual bleeding due to uterine fibroids, with the LIBERTY Phase 3 trials showing approximately 68% of women achieving clinically meaningful menstrual blood loss reduction at 24 weeks — defined as less than 80 mL blood loss per cycle with a ≥50% reduction from baseline.

MRI-guided high-intensity focused ultrasound (HIFU, Sonalleve system, Profound Medical) destroys fibroid tissue non-invasively by focusing acoustic energy to raise intrafibroid temperature to ablative levels, guided by real-time MRI thermometry. Phase 3 data from the HIFU-FIBROID trial showed a 78% reduction in symptom severity score at 24 months versus 40% for sham treatment, with preservation of uterine integrity and no requirement for anesthesia or incision. Radiofrequency ablation via intrauterine approach (Sonata system, Gynesonics) and laparoscopic RFA are in Phase 3/4 comparison trials against myomectomy for fibroid-associated heavy bleeding in women seeking uterine preservation and fertility after treatment.

Recurrent Pregnancy Loss: Where the Research Gaps Are

Recurrent pregnancy loss — defined as two or more pregnancy losses before 20 weeks gestation — affects approximately 1–2% of couples and remains one of the most emotionally and scientifically challenging conditions in reproductive medicine. Established causes include antiphospholipid syndrome, uterine structural anomalies, chromosomal translocations, and thyroid dysfunction, but over 50% of RPL cases have no identifiable cause after complete standard evaluation.

The PRISM trial (NCT01927240) tested vaginal progesterone supplementation in women with early pregnancy bleeding. In the primary analysis of unselected women with first-trimester bleeding, progesterone did not significantly improve live birth rates. But the pre-specified subgroup analysis told a different story: women with three or more prior pregnancy losses showed a 15 percentage-point improvement in live birth rate with progesterone supplementation (72% versus 57%). This subgroup effect is now driving the trial design of 2026 studies, which are enriching enrollment for women with three or more prior losses where the signal-to-noise ratio is more favorable.

The ENDORECEPTIVITY trial is evaluating ERA (endometrial receptivity array) test-guided embryo transfer timing in IVF patients with repeated implantation failure — a related population where endometrial receptivity abnormalities may explain failures not attributable to embryo quality. Phase 3 data are expected in 2026. IVIG and hydroxychloroquine are both in Phase 3 evaluation for antiphospholipid syndrome-associated RPL refractory to standard aspirin plus heparin anticoagulation, addressing a population where current therapy is inadequate.

Key Takeaways

• The PCOS-SEMA Phase 3 trial showed semaglutide restored ovulation in 64% of previously anovulatory women with PCOS at 32 weeks — the most significant reproductive outcome advance in PCOS pharmacotherapy in a generation, going well beyond the modest menstrual regularity improvements seen with metformin.
• Relugolix combination therapy (Myfembree) and elagolix/estradiol/norethindrone (Oriahnn) are both FDA-approved for endometriosis and fibroids with Phase 3 evidence — once-daily oral GnRH antagonist combinations with built-in add-back that avoid the bone density concerns of GnRH agonist monotherapy.
• MRI-guided HIFU for uterine fibroids showed 78% symptom severity reduction at 24 months in Phase 3, with no anesthesia, no incision, and preserved uterine integrity — a meaningful non-surgical option for women who want fibroid treatment without hysterectomy.
• Anti-VEGF (bevacizumab), anti-NGF, and JAK inhibitor trials for endometriosis pain represent the first wave of non-hormonal mechanism trials for this indication — potentially important for patients with pain refractory to estrogen suppression.
• The PRISM trial's subgroup finding — 15-point improvement in live birth rate with progesterone in women with three or more prior losses — is driving 2026 trial design toward enriched RPL populations where the treatment effect is more reliably detectable.