Enclomiphene Citrate for Men 65 and Older: Transitioning to Adult Care

Who was studied at 65 and older?

The phase 3 efficacy trials, ZA-301 and ZA-302, enrolled men aged 18 to 60 with secondary hypogonadism and morning testosterone under 300 ng/dL [2][8]. The two phase 3 studies comparing enclomiphene with testosterone gel also enrolled men aged 18 to 60 [3].

A separate open-label safety study ran six months, included men up to age 65, and gave 12.5 or 25 mg daily to 499 men. Mean morning testosterone at 26 weeks was 511.6 ng/dL on 12.5 mg and 416.7 ng/dL on 25 mg [1].

What the trials measured

In the 12-week ZA-301 trial, 78.8% (95% CI 70.3 to 85.3) of 113 men on enclomiphene reached an average 24-hour testosterone of 300 to 1040 ng/dL; sperm concentration fell by 50% or more in 14.2% on enclomiphene versus 2.6% on placebo [2]. In the 12-week ZA-302 trial, 81.3% (95% CI 73.9 to 87.0) of 134 men reached that range, with sperm falling 50% or more in 14.2% versus 4.3% on placebo [8].

Both trials measured hormones and sperm, not symptoms. FDA and EMA both said the program had not shown that raising testosterone improved symptoms such as bone strength, weight, impotence or libido [1][4].

Safety concerns regulators flagged

FDA's 2022 summary listed cardiac and thromboembolic events, including pulmonary embolism and deep vein thrombosis in a safety study, plus raised estradiol, raised PSA, raised hematocrit, and no long-term safety data [1]. EMA noted a slightly higher rate of cardiac and thromboembolic events than with testosterone, and wanted eye monitoring after cataracts appeared in nonclinical studies [1].

The most frequent side effects were headache, hot flushes, nausea and muscle spasm; in ZA-302 headache occurred in 7 of 112 men on 12.5 mg versus 1 of 47 on placebo [8]. The clomiphene label covers the two-isomer mixture that contains enclomiphene. It warns of visual symptoms and lists contraindications that include liver disease, uncontrolled thyroid or adrenal dysfunction, pituitary tumor and pregnancy. Those are statements about the mixture and are not proven for enclomiphene alone [9].

Approval and compounding status

No FDA-approved drug contains enclomiphene [1]. Repros Therapeutics received a complete response letter in 2015, citing inadequate phase 3 design and concerns about entry criteria, titration and bioanalytical methods [1]. EMA's committee recommended refusing authorisation for EnCyzix in January 2018 [4], and a 2026 British Society of Sexual Medicine statement says the manufacturer discontinued development in 2021 and advises specialist or research use only [10].

FDA lists enclomiphene citrate as under evaluation for compounding (Category 1). That is an enforcement-discretion policy, not an approval and not a finding that the product is safe or effective. In 2022 FDA proposed not adding it to the allowed list, and its advisory committee voted 4 yes to 8 no [6][7]. HealthRX.com offers compounded enclomiphene by prescription.