Enclomiphene Citrate Evidence Base Graded by GRADE

What the evidence base actually contains

Enclomiphene's human data are a small, uneven set. Three published phase 2 studies compared enclomiphene with testosterone gel [6][7][8]. Two 12-week phase 3 trials, ZA-301 and ZA-302, have results posted on ClinicalTrials.gov, and no peer-reviewed publication of them was found [1][2]. A separate open-label safety study, ZA-300, enrolled 499 men and ran six months, longer than either 12-week trial [18]. A 16-week phase 3 comparison with AndroGel 1.62% appeared in BJU International in 2016 [3]. One retrospective chart review compared enclomiphene with clomiphene in 66 men [9], and a 2025 meta-analysis pooled clomiphene and enclomiphene trials together rather than enclomiphene alone [10].

The certainty ratings on this page are an editorial GRADE-style appraisal of the evidence described, using the GRADE approach to rating quality of evidence [17]; they are not ratings published by a guideline body.

The British Society of Sexual Medicine's 2026 position statement describes the evidence as coming from small, short-term studies and advises use only by experienced clinicians in specialist or research settings because long-term efficacy and safety data are lacking [11].

How certain is the testosterone result?

Reasonably, but not strongly. In ZA-301, 151 overweight men aged 18 to 60 with morning testosterone under 300 ng/dL and normal sperm concentration took 12.5 mg or 25 mg daily or placebo for 12 weeks; 78.8% of the pooled enclomiphene group (95% 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 of a lower confidence limit of at least 67% [1]. ZA-302, the same design in 181 men, reported 81.3% (95% CI 73.9 to 87.0, n=134) [2].

Pooled randomized data push in the same direction: across SERM trials in men with functional hypogonadism, total testosterone was higher than placebo by a mean 273.76 ng/dL (95% CI 191.87 to 355.66) with high heterogeneity (I2 89%), and there was no significant difference against testosterone gel [10]. That analysis combined clomiphene and enclomiphene trials, so it cannot isolate enclomiphene.

On GRADE terms the short-term testosterone rise lands at low to moderate certainty. Two randomized trials point the same way, but published detail for them is incomplete, and the pooled analysis shows high heterogeneity (I2 89%) while mixing clomiphene with enclomiphene, so it cannot establish inconsistency for enclomiphene alone [1][2][10]. What the trials support is the direction of the rise; confidence in its size is limited. Symptom benefit remains unproven, and long-term safety is uncertain [4][5].

Did any trial test whether men felt better?

The phase 3 trials did not measure it. FDA's May 2018 guidance on secondary hypogonadism, as FDA itself described it in 2022, says it is unclear whether raising testosterone in this population produces clinical benefit, that trials should show meaningful improvement in at least one symptom or sign, and that changes in semen parameters alone are not enough to establish efficacy [4]. EMA's refusal of EnCyzix in January 2018 made the same point: across 4 main studies in 588 patients the studies showed higher testosterone but did not look at whether symptoms such as bone strength, weight gain, impotence or libido improved [5]. Certainty for symptom or quality-of-life benefit is very low.

Sperm: preserved on average, reduced in some men

The 2016 BJU International paper reported two parallel randomized, double-blind, double-dummy, placebo-controlled phase 3 trials, ZA-304 and ZA-305, in overweight men aged 18 to 60 with morning testosterone of 300 ng/dL or lower. Men received one of two enclomiphene doses, AndroGel 1.62% or placebo 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. The abstract reports the direction of the testosterone, hormone and sperm findings but gives no numerical results [3].

The average hides the outliers. In ZA-301, sperm concentration fell by 50% or more in 14.2% of men on enclomiphene versus 2.6% on placebo; in ZA-302 the figures were 14.2% versus 4.3% [1][2]. An earlier open-label phase 2b study of 12 men who had been using topical testosterone found 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 [8].

Certainty for 'preserves sperm better than testosterone gel' is best described as low to moderate. Two randomized 16-week trials agree on direction, but the abstract gives no numerical results, and the 14.2% figures show the average result does not hold for every man [1][2][3].

Enclomiphene versus clomiphene

Clomiphene citrate is a mixture of two geometric isomers, enclomiphene (trans) and zuclomiphene (cis); per FDA, the USP monograph gives an enclomiphene content of 50 to 70 percent [4]. The two are related drugs, not the same drug. The Clomid label, which covers clomiphene citrate, 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, and that some data suggest zuclomiphene has greater estrogenic activity [12]. Enclomiphene peaks 2 to 3 hours after a dose and has a half-life of about 10 hours [4].

The head-to-head human comparison is a retrospective review of 66 men at one academic centre who took clomiphene and later enclomiphene: median testosterone rose 166 ng/dL on enclomiphene versus 98 ng/dL on clomiphene (P=0.20), estradiol changed by -5.92 versus +17.50 pg/mL (P=0.001), and side effects were less frequent on enclomiphene (odds ratio 0.18, 95% CI 0.07 to 0.44) [9]. A retrospective review cannot show that the switch caused the difference, so certainty for any claim that enclomiphene outperforms clomiphene is low.

Clomiphene citrate itself is FDA-approved, but only for ovulatory dysfunction in women who want to become pregnant. Treating low testosterone in men is off-label, and the Clomid 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 males using clomiphene, with cause and effect not known [12].

Safety evidence and its certainty

FDA's 2022 presentation of the enclomiphene file listed the safety concerns raised by published trials, adverse event reports and EMA's review: cardiac and thromboembolic events, including pulmonary embolism and deep vein thrombosis in a safety study; raised estradiol, raised PSA and raised hematocrit; and no long-term safety data [4]. EMA noted a slightly higher rate of cardiac and thromboembolic events than with testosterone, and cataracts in nonclinical studies, and wanted ocular monitoring [4].

The most frequent side effects in the phase 3 and EMA data were headache, hot flushes, nausea and muscle spasm. 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; reasons for stopping included blurred vision, muscle spasm, headache and aggression [2].

Certainty for safety is very low. The trials ran for weeks to months, and FDA listed the absence of long-term safety data as a concern [4]. Warnings about visual symptoms such as blurring, scotomata and flashes belong to the clomiphene mixture and have not been shown to apply to enclomiphene alone [12].

Regulatory status and what it means for certainty

Enclomiphene is not FDA-approved; FDA's own advisory-committee presentation from June 2022 states that no FDA-approved drugs contain enclomiphene as an active ingredient [4]. In 2015 the sponsor, Repros Therapeutics, announced a complete response letter for Androxal in secondary hypogonadism; as summarised by FDA, the agency 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 [4]. EMA's CHMP adopted a negative opinion on 25 January 2018 recommending refusal of marketing authorisation for EnCyzix (enclomifene) for hypogonadotropic hypogonadism in overweight men with BMI at least 25 [5]. The British Society of Sexual Medicine notes that the manufacturer discontinued development in 2021 [11].

Enclomiphene has no USP monograph and is not on FDA's final list of bulk substances that can be used in compounding. FDA's list, 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 rather than an approval or a finding that the product is safe or effective [13]. At the 8 June 2022 meeting of FDA's Pharmacy Compounding Advisory Committee, FDA proposed that enclomiphene citrate not be added to the allowed bulk substances list and the committee voted Yes 4, No 8, Abstain 0, with members who voted No citing lack of clinical efficacy evidence [14]. Enclomiphene does not appear on FDA's list of bulk substances that raise significant safety risks, and compounded enclomiphene has not been reviewed by FDA for safety, effectiveness or quality [15].

For athletes, WADA's 2026 Prohibited List covers anti-estrogenic substances and SERMs under S4 and names clomifene; enclomiphene is not named separately, but the list is written as 'including, but not limited to' and enclomiphene is an isomer of clomifene [16].

GRADE summary

• Testosterone rise over 12 weeks: low to moderate. Two randomized trials agree on direction; confidence is limited by incomplete published detail for those trials and by the wide spread of effect sizes, and the high heterogeneity in the pooled SERM analysis (I2 89%) comes from an analysis that mixes clomiphene with enclomiphene [1][2][10].
• Testosterone beyond the trial windows: very low. Long-term efficacy data are lacking [11].
• Symptom or quality-of-life improvement: very low. The phase 3 trials measured hormones and sperm, not symptoms, a gap both regulators flagged [4][5].
• Sperm preservation versus testosterone gel: low to moderate. Two randomized 16-week trials agree on direction but their abstract gives no numerical results, and 14.2% of treated men in the 12-week trials had a 50% or greater fall in sperm concentration [1][2][3].
• Long-term safety, including cardiac and thromboembolic risk: very low [4].
• Enclomiphene versus clomiphene: low. One retrospective review, not randomized [9].