RESEARCH MONOGRAPH · KDC-MN-274
Clomiphene
Clomiphene (Clomid) is the original ovulation-induction drug, FDA-approved in 1967 and still in widespread fertility use. It is a SERM sold as a roughly 60/40 racemic mixture of two isomers with opposite estrogen-receptor effects. The dominant active form, enclomiphene, blocks estrogen receptors in the hypothalamus, lifting the brake on the pituitary and triggering FSH and LH surges that stimulate ovulation. The minor agonist isomer, zuclomiphene, has a long half-life and produces lingering estrogenic effects (hot flashes, mood effects) that some users find unpleasant. Off-label, it is used in men to raise endogenous testosterone while preserving fertility, and as post-cycle therapy by steroid users. Not stocked by Kodiac. This monograph is provided for research and educational reference.
Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.
Triphenylethylene SERM (mixed isomers)
A racemic mixture of enclomiphene (anti-estrogen) and zuclomiphene (estrogen agonist); the prototype ovulation-inducing agent.
Abstract
Clomiphene (2-[4-[(E/Z)-2-chloro-1,2-diphenylvinyl]phenoxy]-N,N-diethylethanamine; CAS 911-45-5; molecular formula C26H28ClNO; molecular weight 405.96) is a triphenylethylene SERM developed at Merrell and approved by the FDA in 1967 under the trade name Clomid. The compound is sold as a racemic mixture of approximately 38 percent zuclomiphene ((Z)-isomer, an ER agonist) and 62 percent enclomiphene ((E)-isomer, an ER antagonist). The therapeutic effect in ovulation induction is driven primarily by enclomiphene-mediated antagonism of hypothalamic ER, releasing the negative feedback on GnRH and consequently increasing pituitary FSH and LH; the resulting follicular development drives ovulation. The zuclomiphene component is approximately 5-fold longer half-life than enclomiphene (zuclomiphene t1/2 approximately 30 days, enclomiphene t1/2 approximately 30 hours), causing the agonist component to dominate at later cycles and produce some unwanted estrogen-like effects (cervical mucus changes, antiestrogen rebound). Approved for ovulation induction in anovulatory women. Off-label use in male hypogonadism (induces endogenous testosterone via the same FSH/LH route) is common. Used as the canonical triphenylethylene SERM with HPG-stimulating activity.
Mechanism of action
Racemic SERM (38 percent agonist zuclomiphene, 62 percent antagonist enclomiphene). Enclomiphene-mediated hypothalamic ER antagonism increases FSH/LH. Zuclomiphene's long half-life produces residual agonist activity.
Reported research dose ranges
Clinical 50 to 100 mg in the published literature for 5 days per cycle (ovulation induction); off-label male hypogonadism 25 to 50 mg. Rodent studies 1 to 10 mg/kg.
References
- Mikkelson TJ, et al. Single-dose pharmacokinetics of clomiphene citrate in normal volunteers. Fertil Steril 1986.
- Greenblatt RB, et al. Induction of ovulation with MRL/41. JAMA 1961.
- Shabsigh A, et al. Clomiphene citrate effects on testosterone/estrogen ratio in male hypogonadism. J Sex Med 2005.
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The full reference document is provided strictly for research use only. It reports research dose ranges from the published literature, not instructions for use in humans or animals.
FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.