Enclomiphene Citrate for Fertility: Approval, Evidence, Safety

Is enclomiphene approved for fertility?

No, and there is no approved enclomiphene product for any use. FDA's June 2022 advisory-committee materials state that no FDA-approved drug contains enclomiphene as an active ingredient [1]. The sponsor, Repros Therapeutics, sought approval of Androxal for secondary hypogonadism in fertile men; in 2015 Repros announced a complete response letter, which FDA summarized as saying the phase 3 study designs were not adequate to demonstrate clinical benefit and raising concerns about entry criteria, titration and bioanalytical method validation [1]. No approval has followed.

Europe reached a similar endpoint. EMA's CHMP adopted a negative opinion on 25 January 2018 recommending refusal of a marketing authorisation for EnCyzix (enclomifene) in overweight men with hypogonadotropic hypogonadism, based on 4 main studies in 588 patients. The committee said the studies showed higher testosterone but did not examine whether symptoms such as bone strength, weight gain, impotence or libido improved, and noted a risk of venous thromboembolism [4].

The 2026 British Society of Sexual Medicine position statement says enclomiphene is not currently approved by 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 [7].

Clomiphene citrate is a different situation. It is FDA-approved, but only for ovulatory dysfunction in women desiring pregnancy, and its label states there are no adequate or well-controlled studies demonstrating its effectiveness in male infertility [8].

What the trials actually measured

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 to establish efficacy [1]. Enclomiphene's phase 3 trials measured testosterone, LH, FSH and sperm counts, not symptoms [1].

Two randomized, double-blind, placebo-controlled 12-week phase 3 trials enrolled overweight men aged 18 to 60 with morning testosterone under 300 ng/dL and normal sperm concentration. ZA-301 (NCT01532414) enrolled 151 men; 78.8 percent of those on enclomiphene (95 percent CI 70.3 to 85.3) 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 percent, and FDA did not require a placebo comparison for that endpoint [3]. ZA-302 (NCT01739595) enrolled 181 men, 112 on 12.5 mg, 22 on 25 mg and 47 on placebo, and 81.3 percent (95 percent CI 73.9 to 87.0) reached the normal range [9]. Both sets of results are posted on ClinicalTrials.gov; no peer-reviewed publication is available for either.

A 2025 meta-analysis pooled randomized trials of SERMs, clomiphene and enclomiphene together, in men with functional hypogonadism. Total testosterone rose by a mean 273.76 ng/dL over placebo (95 percent CI 191.87 to 355.66) with high heterogeneity (I2 89 percent), LH by 4.66 IU/L and FSH by 4.59 IU/L, and there was no significant difference in testosterone against testosterone gel [10].

These trials report hormone and sperm endpoints. None of the enclomiphene trials described on this page reports pregnancy or live-birth rates.

Sperm counts: preserved, not untouched

The fertility case for enclomiphene rests on what happens to sperm, and the answer is not uniform. In ZA-301, sperm concentration fell by 50 percent or more in 14.2 percent of men on enclomiphene versus 2.6 percent on placebo [3]; in ZA-302 the figures were 14.2 percent versus 4.3 percent [9].

Against testosterone, the contrast is sharper. Two parallel randomized, double-blind, double-dummy, placebo-controlled phase 3 studies, ZA-304 and ZA-305, published in BJU International in 2016, compared two enclomiphene doses with AndroGel 1.62 percent for 16 weeks in overweight men aged 18 to 60 with morning testosterone of 300 ng/dL or lower. 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 [2].

Earlier, smaller trials pointed the same way. A phase 2 trial in men with secondary hypogonadism found enclomiphene raised morning testosterone, estradiol and LH to levels similar to 1 percent testosterone gel, raised FSH and LH, and preserved sperm counts [11]. A 12-man open-label phase 2b study in men previously using topical testosterone reported sperm counts rising 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; testosterone fell back to pretreatment values one month after stopping [12].

Enclomiphene versus clomiphene

Clomiphene citrate is a mixture of two geometric isomers, enclomiphene (trans) and zuclomiphene (cis); per FDA, the USP monograph gives enclomiphene content of clomiphene as 50 to 70 percent [1]. The two are related, not interchangeable. Zuclomiphene is the more estrogenic of the two and enclomiphene the more anti-estrogenic, pro-gonadotropic isomer [7]. Enclomiphene peaks 2 to 3 hours after a dose and has a half-life of about 10 hours [1].

The direct human comparison is thin. A retrospective single-center study 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 minus 5.92 versus plus 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) [13]. It was not randomized.

Who it fits, and who it does not

Enclomiphene blocks estrogen receptors in the pituitary. Estrogen normally suppresses the pituitary-testis axis, so blocking it makes the pituitary release more LH and FSH, which tells the testes to make more testosterone and keep making sperm [1]. That treats secondary, or hypogonadotropic, hypogonadism, where the testes are healthy but under-stimulated. It would not be expected to work in primary hypogonadism, where the testes themselves are failing [1].

The BSSM statement calls enclomiphene promising for men with secondary hypogonadism who want to preserve fertility, while noting the evidence comes from small short-term studies, and it does not recommend routine use outside specialist settings [7].

The clomiphene label's contraindications, which include liver disease, uncontrolled thyroid or adrenal dysfunction, pituitary tumor and pregnancy, are written for the mixture and have not been proven for enclomiphene alone [8].

Doses used in the trials

No FDA-approved dose exists [1]. The phase 2 dose-finding study randomized 48 men to enclomiphene 6.25, 12.5 or 25 mg once daily or AndroGel for 6 weeks; testosterone and LH rose with enclomiphene [5]. 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 [3].

Safety signals regulators flagged

There is no label-specified monitoring schedule for enclomiphene because no approved product exists, and this page does not set out a monitoring protocol. 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, plus raised estradiol, raised PSA, raised hematocrit and the absence of long-term safety data [1]. EMA noted a slightly higher rate of cardiac and thromboembolic events than with testosterone, saw cataracts in nonclinical studies (not conclusively linked in people) and wanted ocular monitoring [1].

The trials themselves judged response on total testosterone, LH, FSH and semen analysis [3][2]. On diagnosis, the Endocrine Society's 2018 guideline recommends confirming hypogonadism with symptoms plus consistently low fasting morning total testosterone, measured again before treatment, and recommends against starting testosterone therapy in men planning fertility in the near term [14].

Side effects

In 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 [9]. 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 [9].

The clomiphene citrate label reports visual symptoms such as blurring, spots, flashes and scotomata; it says they are usually reversible but may persist or be irreversible, particularly with higher doses or longer treatment, and advises prompt ophthalmological evaluation for visual symptoms [8]. These warnings are written for clomiphene citrate, the mixture, and have not been established for enclomiphene alone, although EMA wanted ocular monitoring for it [1].

Compounded enclomiphene and the law

Because no FDA-approved product exists, enclomiphene cannot simply be compounded as a routine matter, and its regulatory position is unsettled. It has no USP monograph and is not on FDA's final list of bulk substances that can be used in compounding [6]. 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, not an approval and not a finding that the product is safe or effective [6].

At FDA's Pharmacy Compounding Advisory Committee on 8 June 2022, FDA proposed that enclomiphene citrate not be added to the allowed bulk substances list; the committee voted 4 yes, 8 no, with members who voted no citing a lack of clinical efficacy evidence [15]. Enclomiphene is not on FDA's list of bulk substances that raise significant safety risks, but compounded enclomiphene products are not FDA-approved and have not been reviewed by FDA for safety, effectiveness or quality [16].