Enclomiphene Citrate Safety in Older Adults Ages 50 to 64

Who was actually studied at these ages

The two 16-week phase 3 studies reported in the 2016 BJU International paper (ZA-304 and ZA-305) enrolled overweight men aged 18 to 60 with morning total testosterone of 300 ng/dL or lower and low or normal LH [5]. 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 on enclomiphene, while spermatogenesis fell markedly on the gel [5].

Two 12-week phase 3 studies, ZA-301 and ZA-302, used the same 18 to 60 age range [1][2]. In ZA-301, 78.8 percent of men on enclomiphene (95 percent CI 70.3 to 85.3, n=113) reached an average 24-hour testosterone in the normal range of 300 to 1040 ng/dL, and sperm concentration fell by 50 percent or more in 14.2 percent of men on enclomiphene versus 2.6 percent on placebo [1]. ZA-302 reported 81.3 percent (95 percent CI 73.9 to 87.0, n=134) reaching that range, and a 50 percent or greater fall in sperm concentration in 14.2 percent versus 4.3 percent on placebo [2]. Their results are posted on ClinicalTrials.gov only [1][2].

A man aged 50 to 60 could have taken part in these efficacy studies; a man aged 61 to 64 would have fallen outside that range [5][1][2]. ZA-300, a six-month open-label safety study, enrolled 499 men aged 18 to 65 with secondary hypogonadism, taking 12.5 or 25 mg daily, so its age range covered the whole 50 to 64 band [15]. None of the posted results are broken out by age, so nothing in the trial record separates how a 55-year-old responded from how a 30-year-old responded [1][2][5][15].

What regulators flagged

At its advisory committee meeting on 8 June 2022, FDA listed the safety concerns it had drawn from published trials, adverse-event reports and EMA's review: 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 [3].

EMA's committee refused marketing authorisation for EnCyzix (enclomifene) on 25 January 2018 [4]. It reviewed four main studies in 588 patients and found that testosterone rose, but that the studies did not look at whether symptoms such as bone strength, weight gain, impotence or libido improved, and it cited a risk of venous thromboembolism [4]. EMA also noted a slightly higher rate of cardiac and thromboembolic events than with testosterone, and asked for ocular monitoring after cataracts appeared in nonclinical studies, a link not conclusively established in people [3].

FDA's 2018 guidance on secondary hypogonadism, as FDA itself described it in 2022, states that 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 changes in semen parameters alone are not enough [3].

Blood counts, PSA and estradiol

Raised PSA, raised hematocrit and raised estradiol are three of the concerns FDA listed in 2022 [3]. In a randomized phase 2 trial, enclomiphene raised morning testosterone, estradiol and LH to levels similar to 1 percent testosterone gel, increased FSH, and preserved sperm counts [9].

One retrospective study followed 66 men at one academic centre who took clomiphene and later enclomiphene. Median testosterone rose 166 ng/dL on enclomiphene versus 98 ng/dL on clomiphene (P=0.20), estradiol changed by -5.92 versus +17.50 pg/mL (P=0.001), and side effects were less frequent with enclomiphene (odds ratio 0.18, 95 percent CI 0.07 to 0.44) [10]. The study was retrospective rather than randomised [10].

The label warnings that exist are written for clomiphene, the mixture of enclomiphene and zuclomiphene, not for enclomiphene alone: visual symptoms such as blurring, scotomata and flashes that are usually reversible but may rarely persist, and contraindications in liver disease, uncontrolled thyroid or adrenal dysfunction, pituitary tumour and pregnancy [11]. The same label notes that zuclomiphene has a longer half-life than enclomiphene and that detectable zuclomiphene levels persisted for longer than a month in single-dose studies [11].

Side effects reported in the trials

In the phase 3 and EMA data, the most frequent side effects were headache, hot flushes, nausea and muscle spasm; the reasons men stopped included blurred vision, muscle spasm, headache and aggression [2]. In ZA-302, headache was reported by 7 of 112 men on 12.5 mg and 1 of 47 on placebo, and nausea by 4 of 112 and 3 of 47 [2].

A 2026 British Society of Sexual Medicine position statement notes that enclomiphene is not 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 [12].

Regulatory status and how the drug reaches patients

Enclomiphene has no FDA approval. FDA's 2022 advisory-committee material states that no FDA-approved drug contains enclomiphene as an active ingredient [3]. The sponsor, Repros Therapeutics, submitted an application for Androxal for secondary hypogonadism in fertile men; in 2015 the company announced a complete response letter, which as FDA summarised 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 [3]. EMA refused EnCyzix in 2018 [4].

With no approved product, compounded enclomiphene is not FDA-approved and has not been reviewed by FDA for safety, effectiveness or quality [13]. 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 act against a compounder that uses a Category 1 substance if the conditions in its guidance are met, which is an enforcement-discretion policy and not an approval or a finding of safety or effectiveness [7]. In June 2022 FDA proposed that enclomiphene citrate not be added to the list of allowed bulk substances; the committee voted 4 yes, 8 no, and members who voted no cited lack of clinical efficacy evidence [8].

What dose was studied

No FDA-approved dose exists; the doses studied were 6.25, 12.5 and 25 mg once daily by mouth [6]. The phase 3 protocols used 12.5 mg once daily with up-titration to 25 mg at week 6 if morning testosterone stayed below 300 ng/dL [1]. A randomised single-blind phase 2 study of 48 men compared 6.25, 12.5 and 25 mg daily with AndroGel for six weeks; testosterone and LH rose with enclomiphene [6]. In a 12-man open-label study, testosterone fell back to pre-treatment values one month after stopping [14].

What the trials did not measure

Symptoms and quality of life were not measured in the phase 3 programme, which tracked hormones and sperm counts [3][1][2]. The efficacy trials lasted 12 to 16 weeks [1][2][5].