Enclomiphene Citrate Side Effects: Potentially Permanent Adverse Events Explained

Does enclomiphene have any documented permanent side effects?

The treatment periods were short: 6 weeks in the dose-finding study [1], 12 weeks in the phase 3 trials [3][9], 16 weeks in the two studies against testosterone gel [4], and 6 months in one study of 12 men [2]. Enclomiphene was also studied for six months in an open-label safety study of 499 men (ClinicalTrials.gov NCT01534208). FDA's 2022 presentation lists no long-term safety data among its concerns [6].

FDA's 2022 review listed cardiac and thromboembolic events, raised estradiol, raised PSA and raised hematocrit among its concerns about enclomiphene [6]. The 2026 British Society of Sexual Medicine position statement notes that the manufacturer discontinued development in 2021 and advises use only by experienced clinicians in specialist or research settings [10].

FDA's June 2022 advisory committee presentation states that no FDA-approved drug contains enclomiphene as an active ingredient [6]. EMA's committee refused marketing authorization for EnCyzix (enclomifene) in January 2018 after reviewing 4 main studies in 588 patients, citing a risk of venous thromboembolism and the fact that the studies showed higher testosterone without showing whether symptoms improved [7].

Can enclomiphene cause permanent vision problems?

The vision warning most people have read comes from the clomiphene label, and that label covers the two-isomer mixture used for ovulation induction, not enclomiphene [5]. It says blurring, spots or flashes (scintillating scotomata) may occur, that these symptoms become more frequent with increasing total dose or duration, and that they are usually reversible. The same section states that prolonged visual disturbance has been reported, some of it after the drug was stopped, and that the disturbances may be irreversible, especially with increased dosage or duration [5]. It adds that visual symptoms can make driving or operating machinery more hazardous, particularly in variable lighting [5].

The clomiphene label says these visual symptoms appear to involve intensified, prolonged after-images, often first noticed in bright light [5]. It reports one patient on 200 mg daily who developed blurring on day 7, progressing to severe loss of visual acuity by day 10, with acuity back to normal 3 days after treatment stopped; ophthalmologically defined scotomata and electroretinographic changes have also been reported [5]. Its postmarketing list includes cataract, macular edema, optic neuritis, retinal hemorrhage, retinal thrombosis, retinal vascular spasm and temporary or prolonged loss of vision, possibly irreversible [5]. The label directs patients who develop any visual symptoms to discontinue treatment and have a complete ophthalmological evaluation promptly [5].

For enclomiphene itself, blurred vision appears among the reasons men stopped treatment in the phase 3 and EMA data [9]. EMA also asked for ocular monitoring after cataracts appeared in nonclinical studies, which were not conclusively linked to people [6].

Blood clots and cardiac events

Thromboembolic and cardiac events are on FDA's 2022 list of concerns for enclomiphene. The agency's summary, drawn from published trials, FDA adverse event reports and EMA's review, names cardiac and thromboembolic events including pulmonary embolism and deep vein thrombosis in a safety study, plus raised estradiol, raised PSA and raised hematocrit [6]. EMA noted a slightly higher rate of cardiac and thromboembolic events than with testosterone, and its refusal of the marketing application cited venous thromboembolism risk [6][7].

The clomiphene label separately lists pulmonary embolism, thrombophlebitis, chest pain and shortness of breath among postmarketing events for clomiphene, not enclomiphene [5].

Liver effects

Clomiphene's label contraindicates the drug in patients with liver disease or a history of liver dysfunction, and its postmarketing section lists increased transaminases and hepatitis [5]. Those statements belong to the mixture. The enclomiphene concerns FDA listed in 2022 were cardiac and thromboembolic events and changes in estradiol, PSA and hematocrit [6].

Does enclomiphene permanently affect fertility?

In ZA-301, 151 men were randomized to enclomiphene 12.5 mg or 25 mg once daily or placebo for 12 weeks; sperm concentration fell by 50% or more in 14.2% of men on enclomiphene versus 2.6% on placebo [3]. In ZA-302, which enrolled 181 men, the same threshold was met by 14.2% on enclomiphene versus 4.3% on placebo [9]. Those are semen measurements taken over 12 weeks, so they speak to the treatment period, not to whether sperm concentration recovered afterward, and they are not fertility outcomes.

Against testosterone gel the comparison runs the other way. In the two parallel phase 3 studies ZA-304 and ZA-305, both 16 weeks, sperm concentration stayed in the normal range on enclomiphene while spermatogenesis fell markedly on AndroGel 1.62% [4]. An earlier phase 2 trial found enclomiphene raised morning testosterone, estradiol and LH to levels similar to 1% testosterone gel while sperm counts were conserved [11].

A 12-man open-label study enrolled men who had been using topical testosterone. At 3 months, sperm counts had risen in 7 of 7 men on enclomiphene, while the gel did not raise counts above 20 million/mL in any of 5 men, and testosterone fell back to pretreatment values one month after stopping [2].

Estradiol, breast symptoms and mood

Raised estradiol is on FDA's concern list [6]. In a retrospective review of 66 men at one academic center who took clomiphene and later enclomiphene, estradiol changed by -5.92 pg/mL on enclomiphene versus +17.50 pg/mL on clomiphene (P=0.001), and side effects were less frequent on enclomiphene (odds ratio 0.18, 95% CI 0.07 to 0.44) [12]. The design was retrospective and not randomized [12].

Clomiphene's label notes that gynecomastia and testicular tumors have been reported in males using clomiphene, with cause and effect not known [5]. Its postmarketing psychiatric list includes anxiety, irritability, mood changes and psychosis [5]. In the enclomiphene phase 3 and EMA data, aggression was one of the reasons men stopped treatment, along with blurred vision, muscle spasm and headache [9].

How long does enclomiphene stay in the body?

Oral enclomiphene peaks 2 to 3 hours after a dose and has a half-life of about 10 hours; its main metabolite is 4-hydroxy enclomiphene and excretion is mainly in feces [6]. The clomiphene label notes that the cis isomer, zuclomiphene, has a longer half-life than enclomiphene (trans) and that zuclomiphene was detectable for longer than a month [5].

Is compounded enclomiphene checked for safety?

No enclomiphene product is FDA-approved, and there is no FDA label setting a dose, a contraindication list or a monitoring schedule [6]. The clomiphene label's contraindications, which include liver disease, uncontrolled thyroid or adrenal dysfunction, pituitary tumor and pregnancy, describe the mixture [5].

FDA lists enclomiphene citrate in Category 1 of its bulk substances list, 'Bulk Drug Substances Under Evaluation'; that is enforcement discretion under conditions, not an approval [13]. At the June 8, 2022 advisory committee, FDA proposed that enclomiphene citrate not be added to the list of bulk substances allowed in compounding, and the committee voted 4 yes, 8 no [14]. Compounded drugs are not FDA-approved, and FDA does not review their safety, effectiveness or quality before they are marketed [8].