Enclomiphene Citrate Safety in Adults (30 to 49): What the Evidence Shows

What safety evidence exists for adults aged 30 to 49?

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

Men in their 30s and 40s sit inside the age range the trials enrolled. The two 16-week phase 3 studies that compared enclomiphene with testosterone gel enrolled men aged 18 to 60 [9], and the 12-week placebo-controlled study ZA-301 enrolled 151 men aged 18 to 60 [3]. The record consists of short courses plus one longer safety study: 6 weeks in a phase 2 dose-finding trial of 48 men at 6.25, 12.5 and 25 mg daily [5]; 12 weeks in ZA-301 and ZA-302 [3][4]; 16 weeks in ZA-304 and ZA-305 [9]; and a six-month open-label safety study in 499 men aged 18 to 65, ZA-300 [16]. The phase 3 protocols used 12.5 mg once daily, up-titrated to 25 mg at week 6 if morning testosterone stayed below 300 ng/dL [3].

One limit shapes everything below. These trials measured testosterone, LH, FSH and sperm counts; they did not show whether symptoms of low testosterone improved, and both FDA and EMA said that was a gap [1][2]. EMA's refusal of EnCyzix in January 2018 rested on that point plus a risk of venous thromboembolism, based on four main studies in 588 patients [2].

Which side effects showed up most often?

Headache, hot flushes, nausea and muscle spasm were the most frequent side effects across the phase 3 programme and EMA's review, and the reasons men stopped treatment included blurred vision, muscle spasm, headache and aggression [4].

The clearest counts come from ZA-302, a 12-week study of 181 men. 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 [4].

A retrospective chart review at one academic centre followed 66 men who took clomiphene and later enclomiphene and found fewer side effects on enclomiphene, with an odds ratio of 0.18 (95% CI 0.07 to 0.44) [10]. That is not a randomised comparison, so it is a signal rather than a reliable rate.

Heart, clotting and blood-count concerns

FDA's 2022 review, drawing on published trials, adverse event reports and EMA's assessment, listed cardiac and thromboembolic events — including pulmonary embolism and deep vein thrombosis in a safety study — along with raised estradiol, raised PSA and raised hematocrit [1]. EMA noted a slightly higher rate of cardiac and thromboembolic events than with testosterone [1].

FDA also noted that there are no long-term safety data [1], and EMA treated venous thromboembolism as a risk when it refused the marketing application [2].

Cataracts appeared in nonclinical studies and were not conclusively linked to enclomiphene in people; EMA wanted ocular monitoring [1].

Does enclomiphene lower sperm count?

The usual pattern is preservation, with a minority of men dropping. In ZA-301, sperm concentration fell by 50% or more in 14.2% of men on enclomiphene versus 2.6% on placebo; in ZA-302 the figures were 14.2% versus 4.3% [3][4].

In the two 16-week phase 3 studies against AndroGel 1.62%, total testosterone rose in every treatment group, LH and FSH rose with enclomiphene and fell with the gel, sperm concentration stayed in the normal range on enclomiphene, and spermatogenesis fell markedly on the gel [9]. An earlier randomised phase 2 trial found that enclomiphene raised morning testosterone, estradiol and LH to levels similar to 1% testosterone gel while sperm counts were conserved [11]. A 12-man phase 2b study 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 [12].

Vision, liver and the clomiphene label

Enclomiphene is one of the two isomers in clomiphene citrate, which is a different drug. The clomiphene label's warnings apply to the mixture and have not been shown separately for enclomiphene alone [1][13].

The Clomid label warns that blurring, spots or flashes can occur, become more frequent with higher total dose or longer duration, and are usually reversible, but that prolonged and possibly irreversible visual disturbance has been reported [13]. The label contraindicates clomiphene in liver disease or a history of liver dysfunction, uncontrolled thyroid or adrenal dysfunction, pituitary tumour and pregnancy [13]. Its postmarketing list includes increased transaminases and hepatitis [13].

The same label has no male indication. It covers ovulatory dysfunction in women who want to become pregnant, states there are no adequate or well-controlled studies demonstrating effectiveness in male infertility, and notes that testicular tumours and gynecomastia have been reported in men using clomiphene, with cause and effect not known [13].

What happens after stopping, and what longer follow-up shows

In one 12-man study, testosterone fell back to pre-treatment values one month after enclomiphene stopped [12].

The largest enclomiphene safety study is ZA-300, an open-label six-month study of 499 men aged 18 to 65 with secondary hypogonadism taking 12.5 or 25 mg daily. Mean morning testosterone at 26 weeks was 511.6 ng/dL on 12.5 mg and 416.7 ng/dL on 25 mg, with mean LH rises of 4.81 and 4.27 mIU/mL [16]. A 2026 British Society of Sexual Medicine position statement notes that long-term efficacy and safety data are lacking; it calls enclomiphene promising for men with secondary hypogonadism who want to preserve fertility, describes the evidence as small and short-term, notes that the manufacturer discontinued development in 2021, and advises use only by experienced clinicians in specialist or research settings [14].

Regulatory and compounding status

The sponsor, Repros Therapeutics, received a complete response letter in 2015; FDA's summary 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]. EMA's committee refused EnCyzix in 2018 [2].

Enclomiphene citrate has 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'; 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 enforcement discretion, not a finding of safety or effectiveness [6]. At the 8 June 2022 meeting of FDA's Pharmacy Compounding Advisory Committee, FDA proposed not adding enclomiphene citrate to the allowed list and the committee voted 4 yes, 8 no [7]. It is not on FDA's list of bulk substances that raise significant safety risks [15].

For athletes: WADA's 2026 Prohibited List names clomifene under S4 hormone and metabolic modulators, prohibited at all times; enclomiphene is not named separately, but the list says 'including, but not limited to', and enclomiphene is an isomer of clomifene [8].