Enclomiphene
The trans-isomer of clomiphene citrate — a selective estrogen receptor modulator (SERM) that stimulates endogenous testosterone production by blocking estrogen negative feedback at the hypothalamus and pituitary. Used in men's health clinics as an alternative to testosterone replacement therapy that preserves fertility and testicular function. Unlike mixed clomiphene (Clomid), enclomiphene lacks the estrogenic cis-isomer (zuclomiphene) that causes many of clomiphene's side effects.
Typical Dosage
Standard: 12.5-25 mg oral once daily. Some protocols use up to 50 mg. Often used as monotherapy for secondary hypogonadism or alongside GH peptides. Continuous use or cycled depending on protocol and lab monitoring.
Administration
Oral
Mechanism of Action
Enclomiphene is the trans-stereoisomer of clomiphene citrate, a selective estrogen receptor modulator (SERM). Clomiphene (Clomid) contains a roughly equal mixture of two geometric isomers: enclomiphene (trans) and zuclomiphene (cis). Enclomiphene is the pharmacologically desired isomer for testosterone elevation because it acts as a pure estrogen receptor antagonist in the hypothalamus and pituitary, while zuclomiphene has mixed agonist/antagonist activity that can cause unwanted estrogenic effects and has a much longer half-life (weeks), accumulating with chronic dosing.
Enclomiphene competitively binds to estrogen receptors (ERα) in the hypothalamus and anterior pituitary gland, blocking the binding of circulating estradiol. Normally, estradiol exerts negative feedback on the hypothalamic-pituitary axis: estradiol binding to ERα in the hypothalamus reduces GnRH pulse frequency and amplitude, while estradiol binding in the pituitary reduces gonadotroph sensitivity to GnRH. By blocking these receptors, enclomiphene removes the negative feedback signal — the hypothalamus 'perceives' low estrogen levels regardless of actual estradiol concentrations and responds by increasing GnRH pulse frequency. The pituitary, also freed from estrogen-mediated suppression, responds more robustly to each GnRH pulse, producing increased LH and FSH secretion.
Elevated LH stimulates Leydig cells in the testes to produce more testosterone (via the LHCGR/cAMP/StAR steroidogenic pathway), while elevated FSH stimulates Sertoli cells to support spermatogenesis. This is the critical advantage of enclomiphene over exogenous testosterone replacement: it raises endogenous testosterone production through the natural HPG axis while preserving (and potentially enhancing) fertility. Exogenous testosterone, by contrast, suppresses LH/FSH through negative feedback, causing testicular atrophy and often azoospermia. The 10-hour half-life of enclomiphene allows once-daily dosing, and its pure antagonist profile at ERα avoids the estrogenic side effects (hot flashes, visual disturbances, mood changes) that zuclomiphene contributes in mixed clomiphene formulations.
Regulatory Status
Not FDA approved as a standalone drug (Androxal failed to gain approval). Available through compounding pharmacies. Clomiphene citrate (which contains both isomers) is FDA approved for female ovulatory dysfunction.
Risks & Safety
Common: headache, nausea, hot flashes, mild mood changes. Serious: visual disturbances (blurred vision, phosphenes — less common than with mixed clomiphene), potential overstimulation of testosterone production. Rare: thromboembolic events (SERM class effect), significant mood changes, visual scotomata. Significantly fewer estrogenic side effects than clomiphene (Clomid) due to absence of zuclomiphene. Not FDA approved as a standalone product.
Research Papers
1Published: October 8, 2025
Abstract
This study aimed to evaluate the efficacy and safety of selective estrogen receptor modulators (SERMs), specifically clomiphene and enclomiphene, in treating men with functional hypogonadism.
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