Enclomiphene Citrate for Secondary Hypogonadism: Evidence, Dosing, and What to Expect

What secondary hypogonadism means for this drug

Secondary (hypogonadotropic) hypogonadism is a failure of the signal rather than the testis. The pituitary does not release enough LH and FSH, the Leydig cells are under-stimulated, and testosterone falls [1]. Enclomiphene acts on that upstream step, which is why it would not be expected to work in primary hypogonadism, where the testis itself has failed [1].

Diagnosis comes first. The AUA guideline uses a total testosterone below 300 ng/dL on two separate early-morning measurements, together with symptoms or signs [7]. The Endocrine Society requires symptoms plus consistently low fasting morning testosterone, confirmed on repeat testing, then further testing to separate primary from secondary causes [8]. For context, a harmonized reference range built from 9,054 men put the 2.5th percentile at 264 ng/dL and the 5th percentile at 303 ng/dL for healthy non-obese men aged 19 to 39 [9].

How enclomiphene works

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

It is one half of clomiphene. Clomiphene citrate is a mixture of two geometric isomers, enclomiphene (trans) and zuclomiphene (cis), and the USP monograph gives an enclomiphene content of 50 to 70 percent [1]. Zuclomiphene is the more estrogenic of the pair; enclomiphene is the more anti-estrogenic, pro-gonadotropic isomer [10].

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]. The clomiphene label notes that zuclomiphene has a longer half-life than enclomiphene and that detectable zuclomiphene levels persisted for longer than a month in single-dose studies [11].

What the trials found

The largest numbers come from two 12-week phase 3 trials. ZA-301 (NCT01532414) randomised 151 overweight men aged 18 to 60 with acquired hypogonadotropic hypogonadism and morning testosterone under 300 ng/dL to enclomiphene 12.5 mg, 25 mg or placebo. Pooled across the enclomiphene arms, 78.8% (95% CI 70.3 to 85.3, n=113) reached an average 24-hour testosterone in the normal 300 to 1040 ng/dL range [2]. ZA-302 (NCT01739595) ran the same design in 181 men, and 81.3% (95% CI 73.9 to 87.0, n=134) reached that range [3].

Sperm concentration fell by 50% or more in 14.2% of men on enclomiphene versus 2.6% on placebo in ZA-301, and in 14.2% versus 4.3% in ZA-302 [2][3].

The direct comparison with testosterone gel is Kim et al., BJU International 2016, reporting two parallel randomised, double-blind, double-dummy, placebo-controlled phase 3 studies (ZA-304 and ZA-305) in overweight men aged 18 to 60 with morning testosterone of 300 ng/dL or less [12]. Men received one of two enclomiphene doses or AndroGel 1.62% for 16 weeks. Total testosterone rose in all treatment groups; LH and FSH rose with enclomiphene and fell with testosterone gel; sperm concentration stayed in the normal range on enclomiphene while there was a marked reduction in spermatogenesis on the gel. The study reported the direction of that sperm-count difference without giving a numerical estimate [12].

Earlier and smaller studies point the same way. A randomised single-blind phase 2 trial in 48 men compared enclomiphene 6.25, 12.5 and 25 mg daily with AndroGel for 6 weeks and found testosterone and LH rose with enclomiphene [5]. A randomised phase 2 trial in Fertility and Sterility in 2014 found enclomiphene raised morning testosterone, estradiol and LH to levels similar to 1% testosterone gel, raised FSH and LH, and preserved sperm counts [13]. An open-label phase 2b study in 12 men previously on topical testosterone reported similar total testosterone on gel and on enclomiphene at 6 months; 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 [14].

A 2025 meta-analysis pooled randomised trials of SERMs (clomiphene and enclomiphene together) in men with functional hypogonadism: total testosterone was 273.76 ng/dL higher than placebo (95% CI 191.87 to 355.66) with high heterogeneity (I2 89%), LH and FSH were also higher, and there was no significant difference in testosterone versus testosterone gel [15]. A 2024 retrospective review of 66 men who took clomiphene and later enclomiphene found a median testosterone rise of 166 versus 98 ng/dL (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) [16].

Testosterone rose in these studies, but they did not establish whether symptoms improved: the 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 [1][4].

What the FDA and EMA concluded

No FDA-approved drug contains enclomiphene as an active ingredient, according to the FDA's own advisory-committee presentation of June 8, 2022 [1]. The sponsor, Repros Therapeutics, filed a new drug application for enclomiphene (Androxal) for secondary hypogonadism in fertile men. In 2015 the company announced a complete response letter; as FDA summarised it, the design of the phase 3 studies was not adequate to demonstrate clinical benefit and there were concerns about entry criteria, titration and bioanalytical method validation. No approval has followed [1].

In Europe, the CHMP adopted a negative opinion on 25 January 2018 recommending refusal of marketing authorisation for EnCyzix (enclomifene) for hypogonadotropic hypogonadism in overweight men with a BMI of at least 25, citing a risk of venous thromboembolism; the assessment rested on 4 main studies in 588 patients [4].

The British Society of Sexual Medicine position statement of 2026 says enclomiphene is not approved by the FDA or EMA, that its manufacturer discontinued development in 2021, and that it should be used only by experienced clinicians in specialist or research settings because long-term efficacy and safety data are lacking [10]. It also calls the drug promising for men with secondary hypogonadism who want to preserve fertility, while noting that the evidence comes from small, short-term studies [10].

Doses that have been studied

There is no approved dose [1]. The phase 2 dose-finding trial used 6.25, 12.5 and 25 mg once daily for 6 weeks [5]. The phase 3 trials used 12.5 mg once daily, with an increase to 25 mg daily at week 6 if morning testosterone remained below 300 ng/dL [2].

Side effects and safety signals

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

The safety concerns the FDA listed in 2022, drawn from published trials, adverse-event reports and the EMA review, were 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]. The 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 it wanted ocular monitoring [1].

Some warnings belong to clomiphene, the mixture, and have not been proven for enclomiphene alone: visual symptoms such as blurring, scotomata and flashes, which are usually reversible but may rarely persist, and contraindications in liver disease, uncontrolled thyroid or adrenal dysfunction, pituitary tumour and pregnancy [11]. The same label states that there are no adequate or well-controlled studies demonstrating the effectiveness of clomiphene citrate in male infertility, and that testicular tumours and gynecomastia have been reported in males using clomiphene, with cause and effect not known [11].

Does it preserve fertility?

In short-term studies, sperm concentration stayed in the normal range with enclomiphene while spermatogenesis fell markedly with testosterone gel; whether enclomiphene improves the chance of pregnancy was not established [12]. Sperm concentration still fell by half or more in 14.2% of men on enclomiphene in each of the two 12-week phase 3 trials, so the drug does not remove that risk [2][3]. For comparison, the Endocrine Society recommends against starting testosterone in men planning fertility in the near term, and the AUA position is that exogenous testosterone should not be prescribed to men currently trying to conceive [8][7].

Can you get it, and in what form?

There is no approved product. Because enclomiphene has no FDA-approved product, no USP monograph, and is not on the FDA's final list of bulk substances that can be used in compounding, pharmacies cannot compound it as a routine matter [17]. The FDA's list, updated 14 May 2026, places enclomiphene citrate in Category 1, bulk drug substances under evaluation; the agency 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 enforcement discretion rather than a finding of safety or effectiveness [17].

At the FDA Pharmacy Compounding Advisory Committee meeting on 8 June 2022, the FDA proposed that enclomiphene citrate not be added to the list of allowed bulk substances, and the committee voted 4 yes, 8 no; members who voted no cited a lack of clinical efficacy evidence [18]. Enclomiphene is not on the FDA's list of bulk substances that may present significant safety risks [19]. No enclomiphene product is FDA-approved [1]. HealthRX.com offers compounded enclomiphene by prescription.

What about drug testing?

WADA's 2026 Prohibited List places clomifene in S4.2, anti-estrogenic substances, prohibited at all times [6]. Enclomiphene is not named separately and the list is described as including, but not limited to, the named substances; because enclomiphene is an isomer of clomifene, athletes should treat it as prohibited and check with their anti-doping organisation [6].