Enclomiphene

Enclomiphene is the trans, or (E), geometric isomer of clomiphene, a nonsteroidal estrogen receptor ligand of the triphenylethylene family. Clomiphene citrate is roughly a 60:40 mixture of enclomiphene and zuclomiphene, its cis or (Z) isomer (Nelson et al., 2016), and the two isomers act differently at the estrogen receptor (Jordan et al., 1981). Enclomiphene is studied as a selective estrogen receptor modulator (SERM) acting on the hypothalamic-pituitary-gonadal axis: by opposing estrogen's negative feedback it raises luteinizing hormone (LH) and follicle-stimulating hormone (FSH) (Rodriguez et al., 2016).

Mind the salt: if the 12.5MG label refers to the citrate, as the product name indicates, each capsule holds about 20.9 micromoles, or about 8.5MG of free base.

Published work on enclomiphene falls into six areas. Each summary states its model; much of the human and mouse data comes from the developer.

Two isomers with different actions

In the immature rat uterine weight test, enclomiphene was partially estrogenic with antiestrogenic properties, as tamoxifen was, while zuclomiphene was predominantly estrogenic (Jordan et al., 1981). In sheep pituitary cells, enclomiphene blocked estradiol's effect on the LH response to LHRH, while zuclomiphene mimicked estradiol; rat pituitary cultures had shown estrogenic action for enclomiphene, a species difference the authors stressed (Huang and Miller, 1983).

A 1976 paper corrected the stereochemistry assigned to the two isomers in the earlier literature (Ernst et al., 1976), so read older work by isomer name rather than by cis or trans. Models: rat uterus and sheep pituitary cell culture.

Bone and uterus in ovariectomized rats

In ovariectomized rats with established bone loss, zuclomiphene acted as a potent estrogen agonist on every tissue measured. Enclomiphene's effects on most measures resembled those of clomiphene, and it reduced zuclomiphene's growth effect on the uterus; on bone volume and architecture, the two isomers together had larger effects than either alone (Turner et al., 1998). Model: 7-month-old ovariectomized female rats.

Male reproductive tissues in mice

In a chronic oral study in male mice, zuclomiphene produced marked changes in Leydig cells, epididymis, seminal vesicles and kidneys and altered testosterone, FSH and LH. Isolated enclomiphene raised testosterone production and left testicular histology unchanged (Fontenot et al., 2016). The study came from the developer's laboratory. Model: male mice.

Pharmacokinetics and isomer persistence

In men with secondary hypogonadism, peaks in serum enclomiphene did not line up with LH or testosterone peaks, and the effects on LH and testosterone lasted at least a week after the last exposure (Wiehle et al., 2013). Zuclomiphene is the isomer that lingers.

In 15 men on long-term clomiphene, median serum zuclomiphene was 44.0 ng/mL against 2.2 ng/mL for enclomiphene, a 20:1 ratio (Helo et al., 2017), and in an open-label study of 12 healthy men exposed daily for 30 days, zuclomiphene stayed detectable in urine 121 to more than 261 days from the first exposure (Miller et al., 2019). Clomiphene forms 22 metabolites, mainly through CYP3A4 and CYP2D6 (Mazzarino et al., 2013). Models: clinical studies in men, human urine and expressed enzymes.

Clinical development as Androxal

In a phase 2 study of 48 men with secondary hypogonadism, three oral amounts of enclomiphene citrate raised testosterone into the normal range and raised LH and FSH, while a testosterone gel raised testosterone but suppressed LH; TSH, ACTH, cortisol, lipids and bone markers did not change significantly (Wiehle et al., 2013). A second phase 2 trial reported rises in morning testosterone and estradiol similar to those with a topical gel, higher LH and FSH, and conserved sperm counts (Wiehle et al., 2014).

In two parallel placebo-controlled phase 3 trials in overweight men, testosterone rose with both enclomiphene and the gel at 16 weeks; FSH and LH rose with enclomiphene and fell with the gel, and sperm concentration stayed in the normal range with enclomiphene but fell markedly with the gel (Kim et al., 2016). A 2025 meta-analysis of randomized trials of clomiphene or enclomiphene found higher total testosterone, LH and FSH than placebo (Hohl et al., 2025). Model: randomized trials in men.