Enclomiphene Citrate in Adults 65 and Older: What the Evidence Says About Safety

How much of the evidence comes from older men?

Enclomiphene is an oral selective estrogen receptor modulator. It blocks estrogen receptors in the pituitary, so the pituitary releases more luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and the testes respond by making more testosterone [1]. That mechanism fits secondary hypogonadism, where the testes are healthy but under-stimulated, and would not be expected to work in testicular failure [1].

ZA-300 was an open-label six-month safety study that enrolled 499 men aged 18 to 65 with secondary hypogonadism, taking 12.5 or 25 mg daily [14]. The efficacy trials were narrower in age. ZA-301 randomized 151 overweight men aged 18 to 60 with morning testosterone under 300 ng/dL to enclomiphene or placebo for 12 weeks [3], and ZA-302 used the same design in 181 men [5]. The two 16-week studies against AndroGel 1.62% also enrolled men aged 18 to 60 [4].

So the program reaches to age 65 but not beyond. A 2026 position statement from the British Society of Sexual Medicine notes that long-term efficacy and safety data are lacking and advises use only by experienced clinicians in specialist or research settings [6].

What regulators said about safety

FDA's June 2022 advisory-committee presentation summarises the safety record. It lists cardiac and thromboembolic events (including pulmonary embolism and deep vein thrombosis seen in a safety study), raised estradiol, raised PSA, raised hematocrit and the absence of long-term safety data [1]. The same document notes that EMA's review recorded a slightly higher rate of cardiac and thromboembolic events than with testosterone, and that cataracts appeared in nonclinical studies, although a link in people was not established [1].

EMA refused marketing authorisation for EnCyzix (enclomifene) on 25 January 2018. Its stated reasons: the studies showed higher testosterone but did not look at whether symptoms such as bone strength, weight gain, impotence or libido improved, and there was a risk of venous thromboembolism [2]. The assessment rested on four main studies in 588 patients [2].

Earlier, in 2015, the sponsor received a complete response letter; as FDA summarised it, the phase 3 designs were not adequate to demonstrate clinical benefit, with concerns about entry criteria, titration and bioanalytical method validation [1]. No approval has followed [1].

Does raising testosterone this way carry heart or clot risk at 65?

The phase 3 trials measured testosterone, LH, FSH and sperm counts, not symptoms or clinical outcomes, and both FDA and EMA said that was a gap [1]. For context, TRAVERSE, a large cardiovascular safety trial of testosterone, enrolled 5,246 men aged 45 to 80 with existing or high cardiovascular risk and found testosterone gel noninferior to placebo (primary endpoint event 7.0% vs 7.3%; hazard ratio 0.96, 95% CI 0.78 to 1.17) over mean follow-up of 33 months, with a higher incidence of atrial fibrillation, acute kidney injury and pulmonary embolism in the testosterone group [7]. TRAVERSE tested testosterone gel, not a SERM [7].

Monitoring and study length

Enclomiphene has no approved label, so no label sets a hematocrit or PSA threshold or a monitoring interval [1]. The efficacy data come from 12-week and 16-week studies, which cannot establish long-term safety [3][4][6].

Vision

The Clomid label covers clomiphene citrate, the two-isomer mixture, not enclomiphene alone. The label warns that blurring, spots and flashes may occur, that these increase in incidence with total dose and duration of therapy, and that they are usually reversible but may be irreversible. It also says patients with any visual symptoms should discontinue treatment and have a complete ophthalmological evaluation carried out promptly [8]. In the label's clinical studies of women treated for ovulatory dysfunction, visual symptoms were reported in 1.5% of 8,029 patients [8].

In the enclomiphene program, blurred vision was one of the reasons men stopped treatment [5].

Side effects reported in the trials

Headache, hot flushes, nausea and muscle spasm were the most frequent side effects in the phase 3 and EMA data, and reasons for stopping included blurred vision, muscle spasm, headache and aggression [5]. In ZA-302, headache was reported by 7 of 112 men on 12.5 mg and 1 of 47 on placebo; nausea by 4 of 112 and 3 of 47 [5]. Those figures come from 12 weeks of treatment in men aged 18 to 60 [5].

Kidney function and clearance

Enclomiphene is absorbed quickly (peak 2 to 3 hours after a dose), has a half-life of about 10 hours, is metabolised mainly to 4-hydroxy enclomiphene, and is excreted mainly in feces [1]. Because no dose is approved, there is no approved dose adjustment for older adults or for reduced kidney function. The Clomid label contraindicates clomiphene in liver disease; that applies to the mixture, not to enclomiphene alone [8].

Supply and regulatory status

Enclomiphene citrate is not on FDA's list of bulk substances that may present significant safety risks, and it is not on the list of bulk substances that may be used in compounding; FDA's list updated 14 May 2026 places it in Category 1, under evaluation [11][12]. 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 an enforcement-discretion position and not an approval or a finding of safety [11]. At the June 2022 advisory committee meeting FDA proposed not adding it to the allowed list, and the committee voted 4 yes, 8 no [13]. Compounded enclomiphene has not been reviewed by FDA for safety, effectiveness or quality [12].

Bottom line for a man over 65

The benefit side of the ledger is inferred from trials in men aged 18 to 60 that measured hormone levels rather than symptoms [3][4][1]. The safety side is the list regulators cited when they declined to approve the drug: clots, cardiac events, hematocrit, PSA, estradiol and eyes [1][2]. The oldest men in the program were 65 [1].