Enclomiphene

See our Evidence Standards for how we grade the research below.

What It Is

Enclomiphene is one of the two isomers that make up clomiphene citrate (Clomid), an FDA-approved fertility medication for women. Enclomiphene works as a selective estrogen receptor modulator: it blocks estrogen's negative feedback signal at the hypothalamus, which increases the pituitary's release of LH and FSH, which in turn stimulates the testes to produce more of their own testosterone. This is a fundamentally different mechanism from testosterone replacement therapy, which supplies testosterone directly and, in doing so, suppresses the body's own LH and FSH production, which is what shuts down sperm production. Because enclomiphene works upstream of the testes rather than replacing testosterone directly, it's studied specifically as an option for men who want to raise low testosterone without compromising fertility.

Regulatory status: not FDA-approved, and the story behind it matters. Enclomiphene has never been approved by the FDA for any use. Its manufacturer received a Complete Response Letter from the FDA in December 2015, which stated that the design of the completed Phase III studies was no longer adequate to demonstrate clinical benefit given evolving scientific standards, and asked for an additional confirmatory Phase III trial. That trial was never completed, and development was discontinued in 2021. This wasn't a case of the drug failing an efficacy trial; it was a regulatory and development-strategy dead end after a design-standards shift. Enclomiphene remains available today only through compounding pharmacies, under an off-label prescription.

The Evidence

Wiehle RD, Fontenot GK, Wike J, Hsu K, Nydell J, Lipshultz L; ZA-203 Clinical Study Group. "Enclomiphene Citrate Stimulates Testosterone Production While Preventing Oligospermia: A Randomized Phase II Clinical Trial Comparing Topical Testosterone." Fertility and Sterility. 2014 Sep;102(3):720-727. PMID: 25044085. Randomized, placebo-controlled Phase II trial in men with secondary hypogonadism, comparing two doses of oral enclomiphene, topical testosterone gel, and placebo over 3 months. Enclomiphene raised morning testosterone, estradiol, and LH to levels comparable with the testosterone gel, while also raising FSH, something testosterone gel does not do. Sperm counts were conserved in the enclomiphene groups, consistent with the mechanism, while the expected suppression of sperm parameters occurred in the testosterone gel group.

Phase II RCT Endpoint: Clinical outcome (hormone levels, sperm parameters)

Kim ED, McCullough A, Kaminetsky J. "Oral Enclomiphene Citrate Raises Testosterone and Preserves Sperm Counts in Obese Hypogonadal Men, Unlike Topical Testosterone: Restoration Instead of Replacement." BJU International. 2016 Apr;117(4):677-685. PMID: 26496621. Two parallel, randomized, double-blind, double-dummy, placebo-controlled Phase III trials (ZA-304 and ZA-305), 256 overweight men aged 18-60 with secondary hypogonadism, comparing two doses of enclomiphene against testosterone gel (AndroGel 1.62%) and placebo over 16 weeks. Enclomiphene restored mean testosterone from roughly 205 ng/dL at baseline into the normal range (413-446 ng/dL across the two studies), a significant improvement over placebo in both trials. Sperm concentration was preserved in the enclomiphene groups (only 2-5% of men fell below a normal threshold), while the testosterone gel groups saw marked reductions in sperm concentration (24-49% falling below the same threshold), a statistically significant difference. This is the largest and most rigorous dataset available for enclomiphene.

Two Phase III RCTs (N=256) Endpoint: Clinical outcome (testosterone restoration, sperm preservation)

Hohl A, Chavez MP, Pasqualotto E, Ferreira ROM, Sande-Lee SV, Ronsoni MF. "Clomiphene or Enclomiphene Citrate for the Treatment of Male Hypogonadism: A Systematic Review and Meta-Analysis of Randomized Controlled Trials." Archives of Endocrinology and Metabolism. 2025 Oct 8;69(5):e250093. Systematic review and meta-analysis of 10 RCTs comparing SERM therapy (clomiphene or enclomiphene, pooled) against placebo, testosterone gel, or hCG in men with functional hypogonadism, searched through July 2024. SERM therapy significantly increased total testosterone by a mean of about 274 ng/dL versus placebo, with no significant difference compared with testosterone gel, meaning comparable testosterone-raising efficacy to standard TRT. SERM therapy significantly improved LH and FSH compared with both placebo and testosterone gel, and sperm parameters were better preserved than with either comparator. No substantial adverse events were reported. Reviewer commentary published alongside the paper noted real limitations: included trials spanned heterogeneous populations and mostly reported hormone levels rather than validated symptom or quality-of-life scales, and pregnancy or live-birth outcomes weren't available from any included trial.

Worth being precise about what "clomiphene" means here. Clomiphene citrate itself is a mixture of two isomers, enclomiphene and zuclomiphene, the latter with a much longer half-life and different receptor activity than enclomiphene alone. This meta-analysis pools trials of clomiphene (both isomers) and enclomiphene (one isomer) together. The authors, responding to a published critique, reported that the direction of effect was consistent across both drugs despite this difference, which is reassuring, but it means this meta-analysis is evidence about the SERM class broadly, not proof that clomiphene and enclomiphene behave identically to each other in every respect.

Meta-analysis of 10 RCTs (clomiphene + enclomiphene pooled) Endpoint: Clinical outcome (hormone levels, sperm parameters); QoL and pregnancy outcomes not available

What's Reported in Practice

Anecdotal / clinical experience, not yet trial-tested

Patients on enclomiphene commonly report improvements in energy, mood, and libido similar to what's reported with testosterone therapy, along with the specific reassurance of maintained fertility. The trial data above supports the fertility-preservation and testosterone-restoration mechanism directly, but broader wellbeing outcomes (energy, mood, general quality of life) were not the primary focus of either trial and haven't been rigorously measured the way testosterone's broader effects have on the Testosterone page. We think it's reasonable to expect similar broad benefits given the shared downstream hormone, but that's an inference from mechanism, not something these specific trials measured directly.

What the Research Doesn't Yet Show

This is where we're most eager to see more research investment, not a mark against enclomiphene. The existing trials are genuinely solid on their specific endpoints, testosterone restoration and sperm preservation, but they were designed as registration trials for a specific population (overweight men with secondary hypogonadism) and a specific comparison (versus testosterone gel), not as broad quality-of-life studies. Actual pregnancy and live-birth outcomes, the results that matter most to men using this specifically for fertility preservation, haven't been reported from a randomized trial. Long-term safety data beyond 16 weeks is limited, since the confirmatory trial the FDA requested was never completed. And because enclomiphene isn't FDA-approved, it hasn't gone through the additional post-marketing surveillance that approved drugs accumulate over time. This looks like a compound with a genuinely strong efficacy signal on its core mechanism, held back more by a stalled development and regulatory process than by any negative trial result, and a completed confirmatory trial with pregnancy outcomes is exactly what this field needs next.

Not FDA-approved; available only through compounding pharmacies as an off-label prescription. Sourcing and appropriateness are discussed at your visit.

Next Step

This page covers mechanism and evidence. Dosing, monitoring, and whether this is appropriate for you are individual clinical decisions made with your provider.

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