Suppression of gonadotropins and estradiol in premenopausal women by oral administration of the nonpeptide gonadotropin-releasing hormone antagonist elagolix

J Clin Endocrinol Metab. 2009 Feb;94(2):545-51. doi: 10.1210/jc.2008-1695. Epub 2008 Nov 25.


Context: Parenteral administration of peptide GnRH analogs is widely employed for treatment of endometriosis and fibroids and in assisted-reproductive therapy protocols. Elagolix is a novel, orally available nonpeptide GnRH antagonist.

Objective: Our objective was to evaluate the safety, pharmacokinetics, and inhibitory effects on gonadotropins and estradiol of single-dose and 7-d elagolix administration to healthy premenopausal women.

Design: This was a first-in-human, double-blind, placebo-controlled, single- and multiple-dose study with sequential dose escalation.

Participants: Fifty-five healthy, regularly cycling premenopausal women participated.

Interventions: Subjects were administered a single oral dose of 25-400 mg or placebo. In a second arm of the study, subjects received placebo or 50, 100, or 200 mg once daily or 100 mg twice daily for 7 d. Treatment was initiated on d 7 (+/-1) after onset of menses.

Main outcome measures: Safety, tolerability, pharmacokinetics, and serum LH, FSH, and estradiol concentrations were assessed.

Results: Elagolix was well tolerated and rapidly bioavailable after oral administration. Serum gonadotropins declined rapidly. Estradiol was suppressed by 24 h in subjects receiving at least 50 mg/d. Daily (50-200 mg) or twice-daily (100 mg) administration for 7 d maintained low estradiol levels (17 +/- 3 to 68 +/- 46 pg/ml) in most subjects during late follicular phase. Effects of the compound were rapidly reversed after discontinuation.

Conclusions: Oral administration of a nonpeptide GnRH antagonist, elagolix, suppressed the reproductive endocrine axis in healthy premenopausal women. These results suggest that elagolix may enable dose-related pituitary and gonadal suppression in premenopausal women as part of treatment strategies for reproductive hormone-dependent disease states.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Down-Regulation / drug effects
  • Estradiol / blood
  • Estradiol / metabolism*
  • Female
  • Gonadotropin-Releasing Hormone / antagonists & inhibitors*
  • Gonadotropins / blood
  • Gonadotropins / metabolism*
  • Gonads / drug effects
  • Gonads / metabolism
  • Hormone Antagonists / administration & dosage*
  • Hormone Antagonists / adverse effects
  • Hormone Antagonists / pharmacokinetics
  • Humans
  • Hydrocarbons, Fluorinated / administration & dosage*
  • Hydrocarbons, Fluorinated / adverse effects
  • Hydrocarbons, Fluorinated / pharmacokinetics
  • Hypothalamo-Hypophyseal System / drug effects
  • Hypothalamo-Hypophyseal System / metabolism
  • Placebos
  • Premenopause / drug effects
  • Premenopause / metabolism
  • Pyrimidines / administration & dosage*
  • Pyrimidines / adverse effects
  • Pyrimidines / pharmacokinetics
  • Young Adult


  • Gonadotropins
  • Hormone Antagonists
  • Hydrocarbons, Fluorinated
  • Placebos
  • Pyrimidines
  • Gonadotropin-Releasing Hormone
  • Estradiol
  • elagolix