Enclomiphene Citrate Safety in Young Adults (18 to 29): What the Evidence Shows

What the evidence actually covers for men in their twenties

Enclomiphene is an oral selective estrogen receptor modulator that blocks estrogen receptors in the pituitary, so the pituitary releases more LH and FSH and the testes make more testosterone [1]. It is taken by mouth and peaks in the blood 2 to 3 hours after a dose, with a half-life of about 10 hours [1].

The main controlled data come from two phase 3 trials, ZA-301 and ZA-302, which enrolled men aged 18 to 60 with morning testosterone under 300 ng/dL and normal sperm concentration, randomised to enclomiphene 12.5 mg, 25 mg or placebo for 12 weeks [4][5]. A further pair of phase 3 studies, published in BJU International in 2016, compared enclomiphene with AndroGel 1.62% over 16 weeks in overweight men aged 18 to 60 [3].

The trials included men as young as 18 [4][3].

Is enclomiphene approved, and what happened to the applications?

No. FDA's own advisory-committee presentation from 8 June 2022 states that no FDA-approved drugs contain enclomiphene as the active ingredient [1]. The sponsor, Repros Therapeutics, filed a new drug application for enclomiphene (Androxal) for secondary hypogonadism in fertile men; in 2015 it announced a complete response letter from FDA which, as FDA summarized it, 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 [1]. No approval has followed [1].

In Europe, EMA's committee adopted a negative opinion on 25 January 2018 for EnCyzix (enclomifene) in hypogonadotropic hypogonadism in overweight men with a BMI of at least 25, based on four main studies in 588 patients. Testosterone rose, but the studies did not look at whether symptoms such as bone strength, weight gain, impotence or libido improved, and there was a risk of venous thromboembolism [2].

A 2026 British Society of Sexual Medicine position statement notes that the manufacturer discontinued development in 2021 and advises use only by experienced clinicians in specialist or research settings [8].

Compounding status matters too. Enclomiphene citrate has no USP monograph, and FDA lists it in Category 1 as a bulk drug substance under evaluation (list updated 14 May 2026), meaning FDA does not intend to act against a compounder that meets its guidance conditions — an enforcement-discretion policy, not an approval or a finding of safety [9].

What the trials found in the men they did study

ZA-301. Of 151 men, 78.8% on enclomiphene (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%. Sperm concentration fell by 50% or more in 14.2% of men on enclomiphene, versus 2.6% on placebo [4]. These results are a ClinicalTrials.gov posting [4].

ZA-302. ZA-302 enrolled 181 men. Among the 134 assigned enclomiphene, 81.3% reached the normal testosterone range (95% CI 73.9 to 87.0). Sperm concentration fell by half or more in 14.2% on enclomiphene versus 4.3% on placebo [5].

Enclomiphene versus testosterone gel (BJU Int 2016). 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 with enclomiphene while there was a marked reduction in spermatogenesis with the gel [3].

Earlier, smaller work points the same way. A phase 2 trial in 12 men previously 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, and testosterone fell back to pre-treatment values a month after stopping [11]. A 48-man dose-finding study of 6.25, 12.5 and 25 mg daily found testosterone and LH rose [6].

A 2025 meta-analysis pooling randomized trials of clomiphene and enclomiphene together found total testosterone 273.76 ng/dL higher than placebo (95% CI 191.87 to 355.66) with high heterogeneity, and no significant difference versus testosterone gel [12]. A 2024 retrospective review of 66 men who took clomiphene and later enclomiphene found fewer side effects on enclomiphene (odds ratio 0.18, 95% CI 0.07 to 0.44); it was not randomized [13].

Side effects reported during treatment

In the phase 3 and EMA data, the most frequent side effects were headache, hot flushes, nausea and muscle spasm, and the reasons given 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 summary of published trials, adverse-event reports and EMA's review listed 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].

The Clomid (clomiphene citrate) label carries a warning about visual symptoms — blurring, spots, flashes and scotomata — that are usually reversible but may rarely persist, and lists contraindications in liver disease, uncontrolled thyroid or adrenal dysfunction and pituitary tumor [14]. That label covers the clomiphene mixture, not enclomiphene alone, so those statements have not been established for enclomiphene by itself [14].

Doses used in the studies

There is no FDA-approved dose [1]. A phase 2 dose-finding trial used 6.25, 12.5 and 25 mg once daily for 6 weeks [6]. The 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].

What is not established

Whether the testosterone rise relieves symptoms is not established: FDA's 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]. EMA said the studies did not look at whether symptoms improved [2]. The British Society of Sexual Medicine statement reaches a similar conclusion, describing the evidence as small and short-term [8].

Enclomiphene would not be expected to work in primary hypogonadism, where the testes themselves cannot respond to LH and FSH [1].

Athletes

WADA's 2026 Prohibited List, class S4 (hormone and metabolic modulators), names clomifene among anti-estrogenic substances and SERMs [7]. Enclomiphene is not named separately, but the list is described as including, but not limited to, the named substances, and enclomiphene is an isomer of clomifene, so athletes should treat it as prohibited and check with their anti-doping organisation [7].