Enclomiphene Citrate for Fertility: Off-Label Use, Evidence, and Dosing Protocol

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Is enclomiphene approved for male fertility?

No. FDA's own advisory committee briefing stated in June 2022 that no FDA-approved drugs contain enclomiphene as an active ingredient [1]. On 25 January 2018 the European Medicines Agency's CHMP adopted a negative opinion recommending refusal of a marketing authorisation for EnCyzix (enclomifene) for hypogonadotropic hypogonadism in overweight men with a BMI of at least 25 [2].

Repros Therapeutics sought approval of Androxal for secondary hypogonadism. In 2015 the company announced a complete response letter which, as FDA summarises it, said the design of the phase 3 studies was not adequate to demonstrate clinical benefit and raised concerns about study entry criteria, titration and bioanalytical method validation [1]. No approval has followed. A 2026 British Society of Sexual Medicine position statement notes that enclomiphene is not approved by the FDA or EMA, that the manufacturer discontinued development in 2021, and that use should be confined to experienced clinicians in specialist or research settings because long-term efficacy and safety data are lacking [7].

How enclomiphene works

Enclomiphene is an oral selective estrogen receptor modulator. It blocks estrogen receptors in the pituitary; estrogen normally suppresses the pituitary-testis axis, so blocking it releases more LH and FSH, which tell the testes to make testosterone and keep making sperm [1]. That fits secondary (hypogonadotropic) hypogonadism, where the testes are healthy but under-stimulated. In primary hypogonadism, where the testes themselves have failed, it would not be expected to work [1].

Enclomiphene is the trans isomer of clomiphene citrate and the more anti-estrogenic, pro-gonadotropic of the two; zuclomiphene, the cis isomer, is more estrogenic [7]. After an oral dose, enclomiphene peaks at 2 to 3 hours, has a half-life of about 10 hours, is metabolised mainly to 4-hydroxy enclomiphene and is excreted mainly in feces [1].

What the fertility trials actually measured

Testosterone and sperm against testosterone gel

A pair of parallel randomized, double-blind, double-dummy, placebo-controlled phase 3 studies (ZA-304 and ZA-305), published in BJU International in 2016, enrolled overweight men aged 18 to 60 with morning testosterone of 300 ng/dL or lower. They compared two doses of enclomiphene with AndroGel 1.62% for 16 weeks. Total testosterone rose in every treatment group. LH and FSH rose with enclomiphene and fell with testosterone gel, and sperm concentration stayed in the normal range on enclomiphene while there was a marked reduction in spermatogenesis on the gel [3].

Sperm falls in the placebo-controlled trials

ZA-301 randomized 151 overweight men to 12.5 mg, 25 mg or placebo for 12 weeks. Pooled across the two doses, 78.8% (95% CI 70.3 to 85.3, n=113) reached an average 24-hour testosterone between 300 and 1040 ng/dL; FDA did not require a placebo comparison for that endpoint [4]. Sperm concentration fell by 50% or more in 14.2% of men on enclomiphene versus 2.6% on placebo [4].

ZA-302 used the same design in 181 men (112 on 12.5 mg, 22 on 25 mg, 47 on placebo). 81.3% (95% CI 73.9 to 87.0, n=134) reached the normal testosterone range, and a fall of 50% or more in sperm concentration occurred in 14.2% on enclomiphene versus 4.3% on placebo [5].

Earlier phase 2 work

A randomized phase 2 trial compared oral enclomiphene with 1% topical testosterone gel. Morning testosterone, estradiol and LH rose to similar levels with either treatment, FSH and LH rose with enclomiphene, and sperm counts were conserved [8]. A smaller open-label phase 2b study in 12 men previously using topical testosterone reported total testosterone at 6 months of 545 pg/dL with gel and 525 pg/dL with enclomiphene, as published. Sperm counts rose in 7 of 7 men on enclomiphene at 3 months; gel did not raise counts above 20 million/mL in any of the 5 men at 3 months. Testosterone returned to pre-treatment values one month after stopping [9].

Pooled and observational data

A 2025 meta-analysis pooled randomized trials of SERMs in men with functional hypogonadism, combining clomiphene and enclomiphene. Total testosterone was 273.76 ng/dL higher than placebo (95% CI 191.87 to 355.66), with high heterogeneity (I2 89%), and LH and FSH were also higher. There was no significant difference in total testosterone against testosterone gel [10].

A retrospective single-center study of 66 men who took clomiphene and later enclomiphene found a median testosterone rise of 166 ng/dL on enclomiphene versus 98 ng/dL on clomiphene (P=0.20), an estradiol change of -5.92 versus +17.50 pg/mL (P=0.001), and fewer side effects on enclomiphene (odds ratio 0.18, 95% CI 0.07 to 0.44) [11]. It was not randomized.

What the trials did not measure

The phase 3 program measured testosterone, LH, FSH and sperm counts, and its reported results do not include pregnancy or live-birth outcomes. Neither regulator treated those endpoints as proof of benefit: FDA's 2018 guidance on secondary hypogonadism says it is unclear whether raising testosterone in this population gives clinical benefit and that semen-parameter changes alone are not enough to establish efficacy, and EMA's refusal noted that the studies showed higher testosterone but did not look at whether symptoms such as bone strength, weight gain, impotence or libido improved [1][2].

Dosing used in the trials

There is no FDA-approved dose [1]. A phase 2 dose-finding study randomized 48 men to 6.25, 12.5 or 25 mg once daily versus AndroGel for 6 weeks [6]. Phase 3 protocols used 12.5 mg once daily, with up-titration to 25 mg daily at week 6 if morning testosterone stayed below 300 ng/dL [4]. The compounding nomination proposed capsules or tablets of 12.5, 25 and 50 mg [4]. Controlled treatment periods ran 12 weeks in ZA-301 and ZA-302 and 16 weeks in ZA-304 and ZA-305 [4][5][3].

Side effects and safety signals

The most frequent side effects in the phase 3 and EMA data were headache, hot flushes, nausea and muscle spasm; reasons for stopping included blurred vision, muscle spasm, headache and aggression [5]. In ZA-302, headache occurred in 7 of 112 men on 12.5 mg versus 1 of 47 on placebo, and nausea in 4 of 112 versus 3 of 47 [5].

FDA's 2022 review listed cardiac and thromboembolic events, including pulmonary embolism and deep vein thrombosis in a safety study, raised estradiol, raised PSA, raised hematocrit, and the absence of long-term safety data [1]. EMA noted a slightly higher rate of cardiac and thromboembolic events than with testosterone, and cataracts in nonclinical studies that were not conclusively linked in people; EMA wanted ocular monitoring [1].

The Clomid label's warnings cover clomiphene, not enclomiphene alone. They describe visual symptoms such as blurring, scotomata and flashes that are usually reversible, though prolonged and possibly irreversible visual disturbance has been reported, especially with higher doses or longer therapy, and they list liver disease, uncontrolled thyroid or adrenal dysfunction, pituitary tumor and pregnancy as contraindications [12].

Enclomiphene versus clomiphene

They are not the same drug. Clomiphene citrate is a mixture of two geometric isomers, enclomiphene (trans) and zuclomiphene (cis); per FDA, the USP monograph gives enclomiphene content of 50 to 70 percent [1]. Clomiphene is FDA-approved only for ovulatory dysfunction in women who want to become pregnant, and its label states that there are no adequate or well-controlled studies demonstrating effectiveness in male infertility and that testicular tumors and gynecomastia have been reported in men using clomiphene, with cause and effect not known [12].

Zuclomiphene is eliminated far more slowly: the label notes that detectable levels persisted for longer than a month in single-dose studies, which may reflect stereospecific enterohepatic recycling or sequestering [12]. Enclomiphene's half-life is about 10 hours [1]. In the 66-man retrospective comparison, enclomiphene lowered estradiol where clomiphene raised it and produced fewer side effects [11].

Regulation, supply and sport

No FDA-approved enclomiphene product exists. Compounded enclomiphene products are not FDA-approved and have not been reviewed by FDA for safety, effectiveness or quality [13]. FDA's list of bulk drug substances, updated 14 May 2026, places enclomiphene citrate in Category 1, bulk drug substances under evaluation; FDA says it does not intend to take action against a compounder using a Category 1 substance if the conditions in its guidance are met, which is an enforcement-discretion policy, not an approval or a finding that the product is safe or effective [14]. At the 8 June 2022 meeting of FDA's Pharmacy Compounding Advisory Committee, FDA proposed that enclomiphene citrate not be added to the allowed list, and the committee voted 4 yes and 8 no [15]. Enclomiphene is not on FDA's Category 2 list of bulk substances that may present significant safety risks [13].

WADA's 2026 Prohibited List names clomifene under S4 hormone and metabolic modulators, prohibited at all times. Enclomiphene is not named separately, but the list is written as including but not limited to, and enclomiphene is an isomer of clomifene, so athletes should treat it as prohibited and check with their anti-doping organisation [16].