Enclomiphene

Clomiphene citrate has been approved for women's infertility since 1976 and is widely used off label in men [1]. It is a mix of two mirror-image forms: enclomiphene (trans) and zuclomiphene (cis) [5]. Most of the testosterone-raising effect is attributed to enclomiphene, while zuclomiphene lingers in the body and has different biochemical and toxicological properties [6][7]. Enclomiphene was developed on its own as Androxal to treat men with secondary hypogonadism, low testosterone caused by too little LH from the pituitary [1].

Testosterone. In a 6-week trial in 44 men, 25 mg a day raised morning testosterone to 604 ng/dL against 500 ng/dL on testosterone gel; all three doses tested (6.25, 12.5 and 25 mg) raised average and peak testosterone across the day [8]. Two identical phase 3 trials (ZA-304 and ZA-305) in overweight men aged 18–60 compared 12.5 and 25 mg with testosterone gel and placebo for 16 weeks. Testosterone rose in every active group; LH and FSH rose on enclomiphene and fell on the gel [2]. A 2025 meta-analysis of randomised trials of enclomiphene and clomiphene found testosterone about 274 ng/dL higher than on placebo, and no difference from testosterone gel [3].

Sperm. This is where it differs from testosterone. In the phase 3 trials, sperm concentration stayed in the normal range on enclomiphene but fell markedly on the gel [2]. In a smaller 6-month trial in men coming off testosterone gel, enclomiphene raised sperm counts in all 7 men at 3 months (75–334 million/mL), while the gel failed to do so [5]. The 12-week phase 2 trial found the same pattern [9].

Against clomiphene. In a retrospective study of 66 men switched from clomiphene to enclomiphene, testosterone rose by a median 166 ng/dL on enclomiphene against 98 ng/dL on clomiphene (not significant), oestradiol rose less, and side effects such as lower libido, low energy and mood changes were less common [10]. In another clinic series, both drugs raised testosterone, but only enclomiphene raised LH, FSH and total motile sperm count [11].

Regulatory history. The US FDA declined to approve enclomiphene in 2007 because it did not accept a rise in testosterone, normalised LH or quality-of-life gains as enough for a non-testosterone treatment of hypogonadism; it was willing to reconsider on fertility grounds [1]. The European Medicines Agency assessed it as EnCyzix and did not approve it, the manufacturer stopped development in 2021, and it is now available only through compounding pharmacies. The British Society for Sexual Medicine does not recommend routine use outside specialist settings [4].

Oestradiol made from testosterone tells the hypothalamus and pituitary to cut back LH and FSH. Enclomiphene is a non-steroidal oestrogen receptor antagonist that blocks this feedback, so the pituitary releases more LH, which drives the testes to make testosterone, and more FSH, which supports sperm production [1]. This is the opposite of testosterone therapy, which suppresses LH and FSH and with them sperm production [2]. Because it works through the testes, it only helps men whose testes can still respond [1].

The effect on the hormonal axis persists after the drug has left the blood: testosterone and LH stayed raised over 24 hours despite a half-life of about 7 hours [8]. Oestradiol rises along with testosterone [9], although less than with clomiphene in a retrospective comparison [10].

Enclomiphene is the (E)- or trans-isomer of clomiphene [1]. The distinction matters for long-term use: after a single dose of clomiphene, zuclomiphene was still measurable three weeks later and its exposure far exceeded enclomiphene's [12], and in men taking 25 mg of clomiphene daily for a median of 26 months, zuclomiphene levels were twenty times higher than enclomiphene [7]. Pure enclomiphene avoids that build-up.

In the phase 3 trials, 21% of men had adverse events possibly related to a study drug, none severe or serious, and enclomiphene did not cause more adverse events than placebo [3]. In a phase 2 dose-finding trial, adverse events occurred in 9–20% of each group; on enclomiphene they included one mild rise in oestradiol and two headaches, and nobody stopped because of side effects [3]. Six weeks of enclomiphene did not change lipids, thyroid hormone, cortisol or bone markers [8].

Long-term safety data exist only for clomiphene, the parent mixture. Among 400 men on clomiphene for up to 7 years, 8% of those treated for more than 3 years reported side effects, most often mood changes, blurred vision and breast tenderness, with no serious adverse events [14]. Another series of 46 men reported none over 3 years, and bone density improved [15]. Whether enclomiphene behaves the same over years is untested.

Enclomiphene is taken instead of testosterone, not with it, since testosterone suppresses the LH and FSH that enclomiphene raises [2]. No drug interaction studies were found. Clomiphene has been combined with Human chorionic gonadotropin (hCG) in a randomised trial without new safety problems [16].