Elagolix
The first oral GnRH antagonist for endometriosis pain, dosed to lower estrogen partly or almost completely
Elagolix is a small molecule, not a peptide: it blocks the pituitary receptor for the peptide hormone GnRH, lowering estrogen within hours, with no flare. Approved in 2018 as Orilissa for endometriosis pain, it is also part of Oriahnn for fibroid bleeding; its dose limits come from bone loss.
What is it?
Elagolix is a small molecule, not a peptide, but it acts on a peptide system: it blocks the pituitary receptor for gonadotropin-releasing hormone (GnRH), so LH and FSH fall and the ovaries make less estradiol. Unlike agonists such as leuprolide, which first stimulate the receptor and cause a hormone flare, an antagonist lowers hormones from the first dose.
The dose sets how far estrogen falls. In healthy women, 150 mg once daily suppressed it partly and 200 mg twice daily almost fully, within hours of the first dose; the drug peaks within 1.5 hours and has a half-life of 4 to 6 hours. The higher dose relieved more period pain in the trials but costs more bone, so the label limits it to 6 months, against 24 for the lower dose.
The approval rests on the Elaris EM-I and EM-II trials in 1,689 women with endometriosis. At three months, 46.4% and 43.4% of women on 150 mg daily had a meaningful fall in period pain, and 75.8% and 72.4% on 200 mg twice daily, against about a fifth on placebo. Pain between periods improved less. Extension studies showed responses holding at 12 months while bone density fell and lipids rose.
Against an established treatment, the low dose held its own: in a 2026 Indian trial of 230 women, elagolix 150 mg daily was non-inferior to the progestin dienogest for endometriosis pain over 24 weeks.
Add-back therapy is the answer to bone loss. Adding estradiol 1 mg with norethindrone acetate 0.5 mg to the full-suppression dose kept more than 60% of women responding for period pain at six months, and in four-year extensions in endometriosis and in fibroids, mean bone density fell less than 2%. Most women whose density had fallen recovered partly or fully within a year of stopping.
Oriahnn packages that combination for heavy bleeding from fibroids: elagolix 300 mg twice daily with estradiol and norethindrone acetate, for up to 24 months, under a boxed warning for blood clots, stroke and heart attack. In the Elaris UF trials, 68.5% and 76.5% of women met the bleeding target against 8.7% and 10% on placebo. Orilissa's label asks for non-hormonal contraception during treatment and for 28 days after.
Not every use worked. In polycystic ovary syndrome, a phase 2 trial in 114 women lowered LH, estradiol and testosterone but restored normal cycles in only 3. The label also warns of suicidal thoughts and mood changes and of dose-related liver enzyme rises.
Mechanism of Action
Elagolix competes with GnRH at its pituitary receptor, turning down the hormone chain that drives the ovaries.
GnRH receptor block
Competitive antagonist at the pituitary GnRH receptor; LH and FSH fall within hours, with no initial flare (dataset mechanism; Ng 2017).
Dose-dependent estrogen
150 mg once daily suppresses estradiol partly; 200 mg twice daily almost fully (Ng 2017).
Short half-life
Peaks within about 1.5 hours; half-life 4 to 6 hours (Orilissa label 12.3).
Published Research
The trials behind elagolix, read from their PubMed abstracts: Elaris EM-I and EM-II and their extensions, the add-back trials in endometriosis and fibroids with their four-year bone data, a head-to-head trial against dienogest, and a negative trial in PCOS. Doses from the current Orilissa and Oriahnn labels.
Elaris EM-I and EM-II
In 1,689 women with endometriosis, period-pain responders at 3 months were 46.4% and 43.4% on 150 mg daily and 75.8% and 72.4% on 200 mg twice daily, against 19.6% and 22.7% on placebo; pain between periods improved less (50-58% against 36.5%).
A year of treatment
In extension studies of 569 women, responses held at 12 months (period pain: 52.1% on 150 mg, 78.2% on 200 mg twice daily). Bone density fell and lipids rose; there were no adverse endometrial findings.
Against dienogest
In a double-blind trial of 230 Indian women with moderate-to-severe endometriosis pain, elagolix 150 mg daily was non-inferior to dienogest 2 mg daily at day 85 (difference 0.04 points on a 0-10 scale) and similar at 24 weeks; adverse events were 14.8% against 19.1%, with no significant bone density change.
Add-back for endometriosis
In 679 women, elagolix 200 mg twice daily with estradiol and norethindrone acetate gave more period-pain responders at 6 months than placebo (62.8% against 23.7%) and more for pain between periods (51.3% against 36.8%).
Four years with add-back: endometriosis
Of 380 women who entered the 36-month open-label extension of elagolix 200 mg twice daily with estradiol and norethindrone acetate, 140 completed it; mean bone density fell less than 2% at every site and time point, and no serious adverse event occurred in more than one patient per group.
Elaris UF-1 and UF-2: fibroids
In 790 women with fibroid bleeding, 68.5% and 76.5% on elagolix 300 mg twice daily with add-back met the bleeding target against 8.7% and 10% on placebo; add-back blunted the bone loss seen with elagolix alone.
Four years with add-back: fibroids
Among 277 women with fibroid bleeding who continued elagolix 300 mg twice daily with add-back for up to 48 months (103 completed), mean bone density fell less than 2% at the spine and hip throughout, and most of those with a decrease recovered partly or fully within 12 months of stopping.
How dose sets suppression
In 45 healthy women dosed for 21 days, elagolix peaked within 1.5 hours with a 4-6 hour half-life; FSH, LH and estradiol fell within hours, estradiol most at 200 mg twice daily.
Polycystic ovary syndrome: no benefit
In a phase 2 trial of 114 women with PCOS given doses from 25 mg twice daily to 300 mg twice daily or placebo, only 3 met the target of normal menstrual cycles; LH, estradiol and testosterone fell, but ovulatory cycles were not restored.
Dosing Data
Dosed by label, starting within seven days of a period, at the lowest effective dose; bone loss grows with dose and time.
Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
Side Effects & Contraindications
Reported Side Effects
From the Orilissa (version 112) and Oriahnn (version 41) labels.
Contraindications & Cautions
From the Orilissa label.
Legal Status
Approved in the US; its generics are only tentatively approved.
Frequently Asked Questions
?Is elagolix a peptide?
No. It is a small molecule that blocks the GnRH receptor; it is covered here because it competes with peptide GnRH drugs such as leuprolide.
?Why are there two doses?
Suppression rises with dose: 200 mg twice daily relieved more period pain in the Elaris trials but takes more bone, so the label caps it at 6 months, against 24 months for 150 mg daily.
?Is there a generic?
Not on sale: the generic elagolix and Oriahnn applications FDA has acted on hold only tentative approvals.
?How quickly does it work on hormones?
Within hours: in healthy women, FSH, LH and estradiol fell after the first dose, and the drug peaks within about 1.5 hours.
?What does add-back therapy do?
Low-dose estradiol with norethindrone acetate replaces some estrogen to protect bone. With it, four-year studies in endometriosis and fibroids found mean bone density loss under 2%.
?How does it compare with dienogest?
In a 2026 trial of 230 women, elagolix 150 mg daily relieved endometriosis pain as well as dienogest 2 mg daily over 24 weeks.
?Does it help polycystic ovary syndrome?
No. A phase 2 trial in 114 women lowered LH and testosterone but restored normal cycles in only 3.
?Is it safe in pregnancy?
No; pregnancy is a contraindication, and the Orilissa label asks for non-hormonal contraception during treatment and for 28 days after.
References
- [fda-pi] Orilissa (elagolix) tablets US prescribing information (DailyMed version 112, effective December 19, 2025); read September 30, 2026.
- [fda-pi] Oriahnn (elagolix, estradiol and norethindrone acetate; elagolix) capsules US prescribing information (DailyMed version 41, effective December 19, 2025); read October 1, 2026.
- [clinical-trial] Taylor HS, et al. "Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist." N Engl J Med, 2017;377(1):28-40. PMID: 28525302.
- [clinical-trial] Surrey E, et al. "Long-Term Outcomes of Elagolix in Women With Endometriosis: Results From Two Extension Studies." Obstet Gynecol, 2018;132(1):147-160. PMID: 29889764.
- [clinical-trial] Ng J, et al. "Dose-Dependent Suppression of Gonadotropins and Ovarian Hormones by Elagolix in Healthy Premenopausal Women." J Clin Endocrinol Metab, 2017;102(5):1683-1691. PMID: 28323948.
- [clinical-trial] Schlaff WD, et al. "Elagolix for Heavy Menstrual Bleeding in Women with Uterine Fibroids." N Engl J Med, 2020;382(4):328-340. PMID: 31971678.
- [clinical-trial] Miller CE, et al. "Efficacy, tolerability, and bone density outcomes of elagolix with add-back therapy for endometriosis-associated pain: twelve months of an ongoing randomized phase 3 trial." Am J Obstet Gynecol, 2024;231(6):630.e1-630.e13. PMID: 38955323.
- [clinical-trial] Bhoir S, et al. "Efficacy and Safety of Elagolix Versus Dienogest for Treatment of Moderate-to-Severe Endometriosis Pain: A Phase III, Multicentric, Double-Blind, Active-Controlled, Non-Inferiority Study." BJOG, 2026;133(11):2025-2034. PMID: 42116589.
- [clinical-trial] Kim JH, et al. "Safety of 48 months of elagolix with add-back therapy for endometriosis-associated pain." AJOG Glob Rep, 2026;6(1):100584. PMID: 41503019.
- [clinical-trial] Schnell VL, et al. "Bone mineral density with elagolix plus add-back therapy in women with heavy menstrual bleeding and uterine fibroids: open-label and post-treatment results of a 60-month phase 3 trial." AJOG Glob Rep, 2025;5(4):100578. PMID: 41321663.
- [clinical-trial] Snabes MC, et al. "Phase 2, double-blind, randomized, placebo-controlled study of the safety and efficacy of elagolix in women with polycystic ovary syndrome." F S Rep, 2023;4(2):206-212. PMID: 37398623.
Sources & Citations
Dosing and warnings from the Orilissa (DailyMed version 112, read September 30, 2026) and Oriahnn (version 41, read October 1, 2026) labels; approvals from Drugs@FDA; studies from PubMed abstracts.
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