Enclomiphene Citrate Mental Health and Mood Impact

What the regulators said

Enclomiphene is an oral selective estrogen receptor modulator. It blocks estrogen receptors in the pituitary, so the pituitary releases more LH and FSH and the testes make more testosterone [1].

EMA's committee adopted a negative opinion on 25 January 2018, recommending refusal of marketing authorisation for EnCyzix (enclomifene). It said the studies showed higher testosterone but did not examine whether symptoms improved, such as bone strength, weight gain, impotence or libido; the review covered 4 main studies in 588 patients [2].

In the US, the sponsor Repros Therapeutics submitted a new drug application for enclomiphene (Androxal) for secondary hypogonadism. In 2015 the company announced a complete response letter, which as summarised by FDA 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 [1]. No approval followed. FDA's May 2018 guidance on secondary hypogonadism, as described by FDA in 2022, 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 [1].

What the trials measured instead

Two parallel randomised, double-blind, double-dummy, placebo-controlled phase 3 studies, ZA-304 and ZA-305, published in BJU International in 2016, compared two doses of enclomiphene with AndroGel 1.62% in overweight men aged 18 to 60 with secondary hypogonadism over 16 weeks [3]. 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 spermatogenesis fell markedly on the gel [3]. The outcomes the paper reports are hormonal and semen parameters.

An earlier randomised phase 2 trial in Fertility and Sterility (2014) likewise reported hormones and sperm: enclomiphene raised morning testosterone, estradiol and LH to levels similar to 1% testosterone gel, raised FSH, and preserved sperm counts [6]. A 2025 systematic review and meta-analysis of randomised trials of clomiphene and enclomiphene in men with functional hypogonadism had testosterone, FSH and LH as its primary endpoints; SERM therapy raised total testosterone against placebo by a mean 273.76 ng/dL (95% CI 191.87 to 355.66), with high heterogeneity (I2 89%) [8].

Mood-related events in the record

In the phase 3 and EMA data, the most frequent side effects of enclomiphene were headache, hot flushes, nausea and muscle spasm, and the reasons men stopped included blurred vision, muscle spasm, headache and aggression [4].

Clomiphene citrate, the two-isomer mixture and not enclomiphene alone, has its own psychiatric record. Its label, which covers ovulation induction in women, lists depression, insomnia and nervous tension among events reported in fewer than 1% of patients in clinical trials, and lists anxiety, irritability, mood changes and psychosis among postmarketing reports [9]. That label does not describe men treated for low testosterone, and it does not describe enclomiphene by itself.

Does raising testosterone this way lift mood?

Testosterone given directly has been studied for depressive symptoms. A 2019 systematic review and meta-analysis in JAMA Psychiatry pooled 27 randomised placebo-controlled trials including 1,890 men with depressive symptoms on validated scales and found testosterone treatment associated with a significant reduction in depressive symptoms compared with placebo (Hedges g 0.21, 95% CI 0.10 to 0.32), with an efficacy odds ratio of 2.30 (95% CI 1.30 to 4.06) [10]. Those trials tested testosterone itself. No enclomiphene trial report gives depression scores, so it is not known whether testosterone raised by enclomiphene has the same effect on mood [3].

Cognition

The enclomiphene trial reports describe hormones and sperm, not cognition [3]. For testosterone given directly, a 2006 review of the clinical evidence in older men found that placebo-controlled results were mixed but generally indicated moderate positive effects on selective cognitive domains such as spatial ability [11].

Approval status

Enclomiphene has no FDA-approved product, 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, an enforcement-discretion position that is not an approval and not a finding of safety or effectiveness [12]. The 2026 British Society of Sexual Medicine position statement says enclomiphene is not approved by FDA or EMA, that its manufacturer discontinued development in 2021, and advises use only by experienced clinicians in specialist or research settings because long-term efficacy and safety data are lacking [13].