Enclomiphene

Overview

Enclomiphene is the trans-stereoisomer of clomiphene citrate, a non-steroidal selective estrogen receptor modulator (SERM) that stimulates endogenous testosterone production. It is not a peptide, but is widely tracked in the peptide and TRT community as an off-label, compounded alternative to testosterone replacement therapy for men who wish to preserve fertility. Clomiphene itself is a ~60:40 mixture of enclomiphene (trans, estrogen-antagonist) and zuclomiphene (cis, weak long-acting estrogen-agonist); isolating the trans-isomer is intended to deliver the HPG-axis effect without the zuclomiphene-driven side effects.

Mechanism of Action

Enclomiphene blocks estrogen receptors at the hypothalamus, disinhibiting GnRH pulse generation. The resulting rise in LH and FSH stimulates testicular Leydig-cell testosterone production and Sertoli-cell spermatogenesis. Because it lacks the estrogenic zuclomiphene component and is not exogenous testosterone, it raises endogenous T without suppressing gonadotropins or intratesticular testosterone.

Research Summary

Phase 3 trials ZA-304 and ZA-305 (Repros Therapeutics; Wiehle, Kaminetsky, Kim et al.) showed 12.5 mg and 25 mg once-daily enclomiphene citrate raised serum testosterone into the normal range while preserving LH, FSH, and sperm counts, in contrast to testosterone gel (AndroGel 1.62%), which suppressed gonadotropins and spermatogenesis. Despite these results, the FDA issued Complete Response Letters in 2014 and 2016 citing endpoint and trial-design concerns, and the Androxal NDA was never approved. Repros subsequently wound down, and as of April 2026 no FDA-approved enclomiphene product exists. It is dispensed off-label through 503A compounding pharmacies for secondary hypogonadism and as a post-TRT/HPTA-restart adjunct. Clomiphene citrate (the parent racemate) remains FDA-approved only for female ovulation induction, not for male hypogonadism.

Dosing Information

Reported Side Effects

• Headache
• Nausea
• Hot flashes
• Mood changes
• Visual disturbances — blurred vision, light sensitivity, scintillations (SERM class effect; discontinue if they occur)
• Thromboembolism (rare SERM class effect)

Research References

• Testosterone restoration using enclomiphene citrate in men with secondary hypogonadism: a pharmacodynamic and pharmacokinetic study (Wiehle et al., BJU Int) (2013)
• Oral enclomiphene citrate stimulates the endogenous production of testosterone and sperm counts in men with low testosterone: comparison with testosterone gel (Kaminetsky et al., J Sex Med) (2013)
• Oral enclomiphene citrate raises testosterone and preserves sperm counts in obese hypogonadal men, unlike topical testosterone: restoration instead of replacement (Kim et al., BJU Int — Phase 3 ZA-304/ZA-305) (2016)