Compounds / TRT and hormones

Enclomiphene

Enclomiphene Citrate

Trans-isomer of clomiphene; estrogen receptor antagonist at the hypothalamus that drives endogenous LH/FSH and testosterone production while preserving spermatogenesis. Originally developed by Repros Therapeutics as Androxal for secondary hypogonadism in men wanting to retain fertility. NDA was effectively rejected via Complete Response Letter (Dec 2015), additional phase 3 work never completed, and development discontinued April 2021 after Allergan acquisition. Currently dispensed in the US ONLY through 503A/503B compounding pharmacies; not FDA-approved as a finished product.

At a glance

Half-life

~10 h Reported 7-10h in Wiehle 2013 BJU Int. Tmax ~2.5h.

Routes

Oral

Evidence base

2 studies 2 human

Mechanism

Selective estrogen receptor modulator (SERM): competitive antagonist at hypothalamic estrogen receptors, blocking negative feedback from circulating estradiol. Result: increased GnRH pulse frequency → ↑LH and ↑FSH from the pituitary → ↑testosterone and preserved spermatogenesis from the testes. Phase 2: 25 mg/day produced TT 604±160 ng/dL comparable to topical testosterone, while preserving sperm count. Phase 3: enclomiphene maintained sperm concentration vs testosterone gel which suppressed it. Unlike exogenous testosterone, does NOT suppress the HPG axis.

Dosing

Where a study reports an amount, it appears in that study's entry below, attributed to the source.

Published evidence

1. Human RCT 2016

   Oral enclomiphene citrate raises testosterone and preserves sperm counts in obese hypogonadal men

   Kim ED, McCullough A, Kaminetsky J BJU Int

   Phase 3 review: enclomiphene maintained sperm concentration vs testosterone gel which suppressed it; T levels comparable. Both phase 3 trials missed FDA-required endpoints.

   PMID 26727010

2. Human RCT 2013

   Enclomiphene citrate stimulates testosterone production while preventing oligospermia: a randomized phase II clinical trial comparing topical testosterone

   Wiehle RD, Fontenot GK, Wike J, Hsu K, Nydell J, Lipshultz L BJU Int

   6-week PD/PK in secondary hypogonadism; 25mg/d enclomiphene produced TT 604±160 ng/dL vs 500±278 ng/dL with AndroGel: comparable T elevation while preserving sperm count.

   PMID 23875626

Reported side effects

Mood changes (irritability, low mood)

Common Moderate · Class effect of clomiphene-family SERMs. Generally milder than racemic clomiphene because the zuclomiphene (cis) isomer that drives most CNS-mood effects is removed.

Visual disturbances

Rare Serious · Halos, blurring, persistent afterimages. Clomiphene-class ocular toxicity may be permanent, and the class labelling directs discontinuation for severe visual symptoms.

Headache

Common Mild · Reported in Wiehle 2013 cohort; usually transient.

Hot flashes

Occasional Mild · Estrogen-receptor antagonism at hypothalamus.

Reduced IGF-1

Common Moderate · Statistically significant decrease vs baseline in Wiehle 2013; counterintuitive given T elevation. Mechanism unclear; consider monitoring if IGF-1 is a treatment target.

Elevated estradiol

Occasional Mild · Less than clomiphene but possible; downstream from elevated T via aromatization. Monitor sensitive E2 if symptomatic.

Interactions

• Clomiphene Redundant

  Both are SERMs with overlapping hypothalamic estrogen-blockade mechanism. Stacking is additive and increases mood/visual side effects without adding T elevation.

• Anastrozole Caution

  Both reduce estrogenic signal: enclomiphene blocks ER, AI blocks aromatase synthesis. Combined risk of E2 over-suppression with bone, lipid, and CNS consequences.

• Test Cypionate Contraindicated

  Exogenous testosterone suppresses the HPG axis at the hypothalamus and pituitary, defeating the SERM mechanism. The point of enclomiphene is to drive endogenous T while preserving fertility; adding exogenous T eliminates both benefits.

Storage

Room temperature, dry, original container; protect from light.