Enclomiphene

Clomiphene citrate is FDA-approved for ovulation induction in women but has been used off-label for decades for secondary hypogonadism in men. Clomiphene is a mixture of two isomers: enclomiphene (trans, antiestrogenic) and zuclomiphene (cis, longer half-life and weakly estrogenic). Enclomiphene as a single isomer was developed and submitted for FDA approval as a treatment for secondary hypogonadism but has not received final approval at the time of writing.

Enclomiphene blocks the estrogen receptor at the hypothalamus and pituitary. The hypothalamus interprets the absence of the estrogen signal as low estrogen and increases gonadotropin-releasing hormone output. The pituitary responds by increasing LH and FSH, which signal the testes to produce more testosterone and sperm.

The result: testosterone rises through the body's natural physiologic axis. Sperm production is preserved or enhanced. Testicular volume is preserved. This makes enclomiphene a compelling alternative to conventional TRT for men with secondary hypogonadism who want to preserve fertility or testicular function.

Off-label dosing is typically 12.5-25 mg daily, sometimes alternating days. Most responders see meaningful testosterone increases within 4-6 weeks.

Side effects can include mood effects (more associated with the older clomiphene preparation containing zuclomiphene), visual disturbances (halos, blurring, generally reversible on discontinuation), headache, hot flashes, and acne. A theoretical thromboembolism risk is shared with other SERMs.

Enclomiphene is most effective in secondary hypogonadism (low testosterone with low or low-normal LH/FSH) and less effective in primary hypogonadism (where the testes themselves are unresponsive). Off-label use should be discussed with your clinician.