Enclomiphene Citrate: History & Development

Where enclomiphene came from

Clomiphene citrate is FDA-approved for ovulatory dysfunction in women who want to become pregnant [5], and its original approval dates to 1967 [6]. It is not one molecule. It is a mixture of two geometric isomers, enclomiphene (trans) and zuclomiphene (cis) [1]. FDA's 2022 review notes that the USP monograph gives an enclomiphene content of 50 to 70 percent for clomiphene [1].

The two isomers behave differently. Zuclomiphene is the more estrogenic of the pair and enclomiphene the more anti-estrogenic, pro-gonadotropic one [3]. The approved clomiphene label records that zuclomiphene has a longer half-life than enclomiphene, and that detectable zuclomiphene persisted for longer than a month in single-dose studies of normal volunteers [5]. Enclomiphene is absorbed quickly, with a peak 2 to 3 hours after a dose and a half-life of about 10 hours; its main metabolite is 4-hydroxy enclomiphene and excretion is mainly in feces [1].

Enclomiphene blocks estrogen receptors in the pituitary, and because estrogen normally suppresses the pituitary-testis axis, the pituitary releases more LH and FSH, which tells the testes to make more testosterone and keep making sperm [1].

Repros Therapeutics and the Androxal programme

Repros Therapeutics submitted a new drug application for enclomiphene under the brand name Androxal, for secondary hypogonadism in fertile men [1]. Secondary hypogonadism is the form in which the testes are healthy but under-stimulated; enclomiphene would not be expected to work in primary hypogonadism from testicular failure [1].

Three phase 2 studies built the case.

A 2013 proof-of-principle study in the Journal of Sexual Medicine was small: 12 men who had been using topical testosterone, randomized open-label to enclomiphene or gel [7]. Sperm counts rose in 7 of 7 men on enclomiphene at 3 months, while the gel did not raise counts above 20 million/mL in any of 5 men at 3 months, and testosterone fell back to pre-treatment values one month after stopping [7].

A randomized, single-blind, two-center phase 2 study in 48 men compared enclomiphene at 6.25, 12.5 and 25 mg daily with 5 g of transdermal testosterone gel for six weeks; total testosterone and LH rose with enclomiphene [8]. A randomized phase 2 trial published in Fertility and Sterility in 2014 found that enclomiphene raised morning testosterone, estradiol and LH to levels similar to 1 percent testosterone gel, raised FSH and LH, and preserved sperm counts [9].

What the phase 3 trials measured

Two parallel randomized, double-blind, double-dummy, placebo-controlled phase 3 studies, ZA-304 and ZA-305, compared two doses of enclomiphene with AndroGel 1.62 percent in overweight men aged 18 to 60 with morning testosterone of 300 ng/dL or lower, over 16 weeks [10]. Total testosterone rose in all treatment groups [10]. LH and FSH rose with enclomiphene and fell with the testosterone gel [10]. Sperm concentration stayed in the normal range on enclomiphene, while there was a marked reduction in spermatogenesis on the gel [10].

Two further phase 3 trials were run, and their results are posted on ClinicalTrials.gov only. ZA-301 enrolled 151 men in a randomized, double-blind, placebo-controlled 12-week study [11]. Pooled across doses, 78.8 percent of men on enclomiphene (95 percent CI 70.3 to 85.3, n=113) reached an average 24-hour testosterone in the normal range of 300 to 1040 ng/dL, against a pre-set success bar requiring the lower confidence limit to be at least 67 percent, and FDA did not require a placebo comparison for that endpoint [11]. Sperm concentration fell by 50 percent or more in 14.2 percent of men on enclomiphene versus 2.6 percent on placebo [11]. ZA-302 enrolled 181 men: 112 on 12.5 mg, 22 on 25 mg and 47 on placebo [12]. Testosterone came into the normal range in 81.3 percent (95 percent CI 73.9 to 87.0, n=134), and sperm concentration fell by 50 percent or more in 14.2 percent on enclomiphene versus 4.3 percent on placebo [12].

Phase 3 protocols used 12.5 mg once daily, up-titrated to 25 mg at week 6 if morning testosterone stayed below 300 ng/dL [11].

The trials raised testosterone [10][9]. They did not establish whether symptoms improved, and both regulators later said so [1][2]. FDA's May 2018 guidance on secondary hypogonadism says it is unclear whether raising testosterone in this population gives clinical benefit, that trials should show meaningful improvement in at least one symptom or sign, and that semen-parameter changes alone are not enough to establish efficacy [1].

The 2015 FDA complete response letter

In 2015 Repros announced a complete response letter from FDA [1]. As summarized by FDA, the letter 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 FDA approval has followed [1].

The 2018 EMA refusal

The EMA's Committee for Medicinal Products for Human Use adopted a negative opinion on 25 January 2018 recommending refusal of a marketing authorisation for EnCyzix (enclomifene), applicant Renable Pharma Limited, for hypogonadotropic hypogonadism in overweight men with a BMI of at least 25 [2]. The reasons given were that the studies showed higher testosterone but did not examine whether symptoms such as bone strength, weight gain, impotence or libido improved, and that there is a risk of venous thromboembolism [2]. The assessment rested on four main studies in 588 patients [2].

Where that left the drug

Because enclomiphene has no approved product, no USP monograph and is not on FDA's final list of bulk substances that can be used in compounding, pharmacies cannot simply compound it as a routine matter [4]. FDA's list, updated 14 May 2026, places enclomiphene citrate in Category 1, bulk drug substances under evaluation [4]. 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; that is an enforcement-discretion policy, not an approval and not a finding that the product is safe or effective [4]. Enclomiphene is not on FDA's separate list of bulk substances that may present significant safety risks [13].

At the FDA Pharmacy Compounding Advisory Committee meeting on 8 June 2022, FDA proposed that enclomiphene citrate not be added to the list of allowed bulk substances [14]. The committee voted Yes 4, No 8, Abstain 0 on adding it; members who voted No cited a lack of clinical efficacy evidence, one said more studies were needed, and a Yes voter noted that clomiphene citrate has a USP monograph [14].

The 2026 British Society of Sexual Medicine position statement says enclomiphene is not currently approved by the FDA or EMA and that its manufacturer discontinued development in 2021 [3]. It advises use only by experienced clinicians in specialist or research settings because long-term efficacy and safety data are lacking [3].

Athletes have a separate consideration. WADA's 2026 Prohibited List places clomifene in S4, hormone and metabolic modulators, prohibited at all times [15]. Enclomiphene is not named separately, but the section 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 [15].

Safety concerns on the record

FDA's 2022 review listed, from published trials, FDA adverse event reports and the EMA review: cardiac and thromboembolic events, including pulmonary embolism and deep vein thrombosis in a safety study; raised estradiol; raised PSA; raised hematocrit; and no 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, and wanted ocular monitoring [1].

In the phase 3 and EMA data the most frequent side effects were headache, hot flushes, nausea and muscle spasm [12]. Reasons for stopping included blurred vision, muscle spasm, headache and aggression [12]. In ZA-302, headache was reported by 7 of 112 men on 12.5 mg and 1 of 47 on placebo, and nausea by 4 of 112 and 3 of 47 [12].

The visual warnings come from the approved clomiphene mixture label, which says blurring, spots or flashes are usually reversible but that prolonged and possibly irreversible visual disturbance has been reported; the label also contraindicates use in liver disease, uncontrolled thyroid or adrenal dysfunction, pituitary tumor and pregnancy [5]. That label covers the mixture, not enclomiphene on its own.

Later evidence

The pooled evidence combines two different drugs. A 2025 systematic review and meta-analysis of randomized trials of SERMs, clomiphene and enclomiphene combined, in men with functional hypogonadism found total testosterone higher than placebo by a mean of 273.76 ng/dL (95 percent CI 191.87 to 355.66) with high heterogeneity (I2 89 percent), higher LH and FSH, and no significant difference in total testosterone against testosterone gel [16].

One retrospective single-centre study of 66 men who took clomiphene and later enclomiphene found a median testosterone rise of 166 ng/dL with enclomiphene versus 98 ng/dL with 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 percent CI 0.07 to 0.44). It was not randomized [17].

The 2026 BSSM statement calls enclomiphene promising for men with secondary hypogonadism who want to preserve fertility, notes that the evidence comes from small short-term studies, and does not recommend routine use outside specialist settings [3].