Enclomiphene Citrate Real-World Evidence: What Registries and RWE Studies Actually Show

What real-world evidence exists for enclomiphene?

The main real-world study is one retrospective comparison of enclomiphene against clomiphene in 66 men [1]. The rest is the randomized phase 2 and phase 3 trial data run for the Androxal application, some of it available only as ClinicalTrials.gov results postings [2][3]. Enclomiphene has no FDA-approved product in the United States and no EU authorisation [4][5].

A 2026 British Society of Sexual Medicine position statement describes the evidence base as small short-term studies and advises use only by experienced clinicians in specialist or research settings [6].

The one real-world comparison: 66 men on clomiphene, then enclomiphene

Saffati and colleagues (Translational Andrology and Urology, 2024) reviewed patients at a single academic center who had been prescribed clomiphene and later enclomiphene for hypogonadism. Labs were recorded before clomiphene, at the last visit before clomiphene was stopped, and again across the enclomiphene course, with the clomiphene values used as the updated baseline [1].

In 66 men, the median testosterone increase was 166 ng/dL on enclomiphene against 98 ng/dL on clomiphene, a difference that did not reach statistical significance (P=0.20). Estradiol moved in opposite directions: a change of -5.92 pg/mL on enclomiphene versus +17.50 pg/mL on clomiphene (P=0.001). Adverse effects were significantly less frequent with enclomiphene, odds ratio 0.18 (95% CI 0.07 to 0.44) [1].

It is a retrospective, sequential within-patient comparison rather than a randomized trial. It reports hormone values and side-effect counts, as medians from a small single-center group.

What the randomized trials reported

ZA-301 and ZA-302. Two identically designed phase 3 studies: randomized, double-blind, placebo-controlled, 12 weeks, in overweight men aged 18 to 60 with morning testosterone below 300 ng/dL and normal sperm concentration. In ZA-301 (151 men), 78.8% of pooled enclomiphene patients (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; the pre-set success bar was a lower confidence limit of at least 67%, and FDA did not require a placebo comparison for that endpoint [2]. In ZA-302 (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 range [3].

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

Enclomiphene versus testosterone gel. Kim and colleagues (BJU International, 2016) reported two parallel randomized, 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 lower. Men took one of two enclomiphene doses or AndroGel 1.62% for 16 weeks. Total testosterone rose in every treatment group. 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 paper reports the direction of these changes, not their size [7].

Earlier phase 2 work. A randomized, single-blind, two-center phase 2 study in 48 men compared enclomiphene 6.25, 12.5 and 25 mg daily with AndroGel for 6 weeks; testosterone and LH rose with enclomiphene [8]. A second phase 2 trial found that enclomiphene raised morning testosterone, estradiol and LH to levels similar to 1% testosterone gel, raised FSH and LH, and conserved sperm counts [9]. In a 12-man open-label study of men previously on topical testosterone, total testosterone at 6 months was similar on testosterone gel and on enclomiphene, and sperm counts rose in 7 of 7 men receiving enclomiphene at 3 months; the gel did not raise counts above 20 million/mL in any of 5 men, and testosterone fell back to pre-treatment values one month after stopping [10].

Pooled SERM data. A 2025 meta-analysis of randomized trials of clomiphene and enclomiphene combined, in men with functional hypogonadism, found total testosterone higher than placebo by a mean 273.76 ng/dL (95% CI 191.87 to 355.66) with high heterogeneity (I2 89%), and LH and FSH also higher. There was no significant difference in testosterone against testosterone gel [11]. That figure is for the two SERMs together, not for enclomiphene alone.

What the data do not answer

Symptoms. The trials measured testosterone, LH, FSH and sperm counts [2][3]. FDA's 2018 guidance on secondary hypogonadism 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 semen-parameter changes alone are not enough [4]. EMA's refusal notice for EnCyzix made the same point: the studies showed higher testosterone but did not examine whether symptoms such as bone strength, weight gain, impotence or libido improved [5].

Safety concerns regulators flagged. FDA listed the concerns it drew from 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 [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].

Side effects the data do show

In the phase 3 and EMA data, the most frequent side effects were headache, hot flushes, nausea and muscle spasm. Reasons for stopping included blurred vision, muscle spasm, headache and aggression. 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 Clomid label carries a visual-symptom warning and lists contraindications including liver disease, uncontrolled thyroid or adrenal dysfunction and pituitary tumor. That label covers clomiphene, the two-isomer mixture, and its warnings are not proven for enclomiphene alone [12].

Why there is no approved product behind these numbers

FDA's own advisory-committee presentation from June 8, 2022 states that no FDA-approved drugs contain enclomiphene as an active ingredient [4]. The sponsor, Repros Therapeutics, filed a new drug application for Androxal in secondary hypogonadism in fertile men; in 2015 the company announced a complete response letter, which as summarized by FDA said the design of the phase 3 studies was not adequate to demonstrate clinical benefit and raised concerns about entry criteria, titration and bioanalytical method validation [4].

In Europe, EMA's CHMP adopted a negative opinion on 25 January 2018 recommending refusal of marketing authorisation for EnCyzix, based on 4 main studies in 588 patients [5]. FDA lists enclomiphene citrate as a Category 1 bulk substance under evaluation, which reflects enforcement discretion under conditions rather than a finding of safety or efficacy [13]. At the June 2022 advisory committee, FDA proposed that enclomiphene citrate not be added to the list of bulk substances allowed in compounding, and the committee voted 4 yes, 8 no [14].

What this means if you are weighing enclomiphene

Testosterone rose on enclomiphene in the trials [2][3][7] and in the one real-world comparison [1], and in the phase 3 gel comparison sperm concentration stayed in the normal range on enclomiphene [7]. The trials measured hormones and sperm counts rather than symptoms, a gap that FDA and EMA both flagged [4][5].