Enclomiphene Side Effects: What the Trials Actually Reported

The Evidence in Brief

Enclomiphene Side Effects: The Evidence in Brief

Enclomiphene side effects in the clinical trials were mostly mild. Headache, hot flashes, nausea and muscle spasms were the most frequently reported, according to the European Medicines Agency's 2018 assessment report, which pooled 1,403 people who received at least one dose in phase II and III studies. The same report lists blurred vision, muscle spasm, headache and aggression as the most common adverse events that led men to stop the drug.

Serious events were uncommon and they were not trivial. The EMA identified three venous blood clots and one fatal ischemic stroke in men taking enclomiphene, and cited the risk of venous thromboembolism when it refused the drug.

Enclomiphene is an unapproved drug. It is not FDA-approved for any use, and enclomiphene dispensed in the United States is a compounded preparation; compounded drugs are not FDA-approved. Protocol Health prescribes enclomiphene to selected men after labs and a clinician's evaluation, so we have a commercial interest and say so here.

How the drug works and who it suits is covered in enclomiphene for men. This page covers what can go wrong, how often it was recorded, and how much is still unmeasured.

Trial Data

Enclomiphene Side Effects in Men: What the Clinical Trials Recorded

The most detailed public record of enclomiphene side effects in men is the set of adverse-event tables the developer, Repros Therapeutics, posted on ClinicalTrials.gov. These are sponsor-run studies of enclomiphene citrate capsules at 12.5 mg or 25 mg a day, the doses the trials used and not a recommendation.

ZA-300: the six-month safety study

ZA-300 was an open-label phase III safety study that enrolled 499 men aged 18 to 65 with secondary hypogonadism for 26 weeks of treatment. Adverse events were collected until eight weeks after the last dose. The posted table counts 490 men for safety.

Twenty-three of the 499 enrolled men left the study because of an adverse event, and 393 completed it. ZA-300 had no comparison group, so it cannot show which of these events enclomiphene caused.

ZA-301 and ZA-302: the placebo comparison

Two double-blind phase III studies in overweight men compared enclomiphene with placebo capsules. In ZA-301, headache was reported by 5 of 113 men on enclomiphene and 2 of 38 on placebo, and no participant in any arm had a serious adverse event. In ZA-302, headache was reported by 7 of 134 men on enclomiphene and 1 of 47 on placebo; nausea by 5 of 134 and 3 of 47. One man on enclomiphene in ZA-302 had a serious event recorded as abdominal pain, diarrhea, vomiting and weakness.

ZA-203 and the published phase III trials

ZA-203 was a three-month phase IIb study with placebo and testosterone gel arms. None of the 60 men on enclomiphene had a serious adverse event. The FDA's 2022 review of that study describes two events in the 25 mg group that led to withdrawal and were judged possibly related: one man reported inability to climax and loss of sensation during intercourse, another mild nausea and dry heaving.

The two phase III trials published by Kim and colleagues in BJU International, ZA-304 and ZA-305, treated 256 overweight men for 16 weeks with enclomiphene, testosterone gel or placebo. The FDA's summary of that paper states that 53 men (21%) had adverse events considered possibly, probably or definitely related to a study drug, that none of those was severe or serious, and that the groups did not differ. It also records two deaths in the 12.5 mg arm: a road traffic accident, and an ischemic stroke in a 59-year-old man with diabetes, obesity and atrial fibrillation, which investigators judged highly unlikely to be drug-related.

Common Effects

Enclomiphene Headache, Hot Flushes, Nausea and Muscle Spasms

Headache is the most consistently reported enclomiphene side effect. It appears in three of the four posted trial tables, at 7.1% over six months in ZA-300 and at roughly 4% to 5% over the shorter placebo-controlled studies, where placebo rates ran from 2% to 5%.

• Headache. Slightly more common on placebo than on enclomiphene in ZA-301, and more common on enclomiphene in ZA-302.
• Hot flashes. 11 of 490 men in ZA-300. The EMA report puts drug-related hot flashes at 1.1% on enclomiphene and 0.5% on placebo.
• Nausea. Listed by the EMA among the four most frequent events. In ZA-302 it was reported by 3.7% of men on enclomiphene and 6.4% on placebo.
• Muscle spasms. 22 of 490 men in ZA-300, and one of the EMA's four most common reasons for stopping.

Severity matters as much as frequency. Across the pooled phase II and III data, the EMA report describes adverse events as mild in 12.1% of men on enclomiphene, moderate in 4.6% and severe in 0.9%. Overall, 5.3% of men receiving enclomiphene withdrew from a trial because of an adverse event, against 1.5% on placebo.

Estrogen

Does Enclomiphene Raise Estrogen? Estradiol and Gynecomastia

Yes. Enclomiphene raises estradiol in men, even though it blocks estrogen receptors. The phase IIb trial published in Fertility and Sterility reported that enclomiphene citrate increased morning testosterone, estradiol and LH to a degree similar to testosterone gel. The EMA's pooled analysis found a statistically significant rise in estradiol on both enclomiphene and testosterone gel, significant against placebo at the end of treatment.

Enclomiphene blocks estrogen's signal at the hypothalamus and pituitary, the testes respond by making more testosterone, and the body converts part of that testosterone into estradiol. The FDA's review of the same phase IIb study adds that estradiol was still elevated one month after enclomiphene was stopped.

What a higher estradiol means

A higher estradiol number is not automatically a problem. In a New England Journal of Medicine experiment that manipulated both hormones in 400 healthy men, estrogen deficiency primarily accounted for increases in body fat, and both androgen and estrogen deficiency contributed to declining sexual function. Men need estradiol. Suppressing it has costs, which is the subject of anastrozole for men.

The consequences clinicians watch for are breast tenderness and breast tissue growth. In the EMA's pooled data, breast enlargement judged at least possibly related to the drug was reported in 0.2% of men on enclomiphene and none on placebo, and gynecomastia in 0.07%. Enclomiphene gynecomastia is therefore documented and rare in trials that lasted months. The FDA listed elevated estradiol among its safety concerns in 2022, and the EMA raised increased estradiol as one possible explanation for the blood clots described below, without being able to settle the question.

Blood Clots

Enclomiphene and Blood Clots: What the EMA and FDA Found

Venous blood clots are the most serious signal in the enclomiphene record. The EMA assessment report identified five thromboembolic events across the trial program. Four occurred in men taking enclomiphene: one deep vein thrombosis with pulmonary embolism, two deep vein thromboses alone, and one fatal ischemic stroke. One, a heart attack, occurred in a man on placebo. All four men on enclomiphene had other risk factors.

The EMA could not say why. Its report lists four candidate explanations: higher testosterone driving red blood cell production, an effect of the drug class (selective estrogen receptor modulators as a class are associated with venous thromboembolism), the fact that participants were overweight, or the rise in estradiol. The committee wrote that the exact magnitude of the risk remains unknown.

The FDA reached a compatible conclusion when it reviewed enclomiphene for compounding in 2022. Its briefing document states that safety concerns for enclomiphene citrate include cardiac and thromboembolic events. On cardiac events, the EMA's placebo-controlled pool recorded cardiac disorders in 1.0% of men on enclomiphene and 0.4% on placebo.

Vision

Enclomiphene Vision Side Effects: Trial Data vs the Clomiphene Label

Enclomiphene vision side effects are mostly inferred from clomiphene, and the two bodies of evidence should be kept apart. The strong warnings belong to clomiphene. The Clomid label on DailyMed warns that blurring, spots or flashes may occur, that they become more frequent with higher total dose or longer treatment, and that visual disturbances may be prolonged and possibly irreversible. Visual symptoms were recorded in 1.5% of patients in clomiphene trials. Those patients were women taking short courses for ovulation.

Enclomiphene's own data are milder. In the placebo-controlled trials, the EMA report records eye disorders in 1.6% of men on enclomiphene and 2.4% on placebo. Blurred vision was the most common visual complaint: 14 men (1.0%) on enclomiphene and 3 (0.8%) on placebo. Blurred vision was still one of the four most common reasons men gave for stopping.

Cataracts were a specific question. Lens changes described as cataracts appeared in animal studies, so the trials included eye examinations read by a single blinded expert. The EMA concluded that the available data do not provide conclusive evidence that enclomiphene causes new cataracts or worsens existing ones, and recommended continued ocular safety monitoring.

The practical rule comes from the clomiphene label and applies by caution: any new blurring, flashes, spots or loss of vision should be reported to the prescriber promptly.

Mood and Libido

Mood, Libido and Sexual Side Effects of Enclomiphene

Mood and sexual side effects of enclomiphene were recorded in the trials at low rates. In the EMA's pooled data, aggression judged at least possibly related to the drug was reported in 0.5% of men on enclomiphene and none on placebo, and it was among the four most common reasons for stopping. Anxiety was reported at the same rate, 0.4%, on enclomiphene and placebo. Psychiatric disorders as a category were the most frequent drug-related adverse events, at 3.2% of the pooled population.

Sexual effects ran in an unexpected direction for a testosterone-raising drug. Erectile dysfunction was reported in 0.6% of men on enclomiphene and none on testosterone gel or placebo, and testicular pain in 0.4% against none on placebo. One man in the phase IIb study withdrew over inability to climax. Erectile dysfunction is common in untreated hypogonadism, so these small figures cannot separate the drug from the condition.

Stronger mood warnings exist for clomiphene. The Clomid label lists anxiety, irritability, mood changes and psychosis among postmarketing reports, and depression, insomnia and nervous tension in under 1% of trial patients. A retrospective study of 66 men who switched from clomiphene to enclomiphene documented mood changes in 9.1% on clomiphene and in none on enclomiphene. That study's limits are set out below.

Hair Loss

Does Enclomiphene Cause Hair Loss?

No trial has shown that enclomiphene causes hair loss, and no trial was designed to look. Hair loss does not appear in any of the four adverse-event tables posted on ClinicalTrials.gov, and the text of the EMA report does not mention it as a clinical adverse event. Those tables only show events above a 3% or 5% threshold, so absence from them is weak evidence.

Two facts explain why the question keeps being asked. First, the Clomid label lists hair loss or dry hair among events reported in fewer than 1% of clomiphene trial patients, who were women. Second, male pattern hair loss is driven by an androgen. MedlinePlus describes it as related to dihydrotestosterone (DHT), and the FDA's summary of the phase IIb trial notes that DHT rose significantly in all three active arms, the two enclomiphene doses and testosterone gel.

So the honest position on enclomiphene hair loss is that a mechanism is plausible, any drug that raises testosterone shares it, and the rate has not been measured.

Hematocrit and PSA

Hematocrit, PSA and Other Lab Changes on Enclomiphene

Enclomiphene can move the same lab markers that testosterone therapy moves, because the changes follow testosterone and not the route by which it rises. The FDA's 2022 review lists increased hematocrit and increased prostate-specific antigen (PSA) among its safety concerns for enclomiphene.

• Hematocrit. In the published phase III trials, one man on enclomiphene 25 mg stopped because of high hematocrit or hemoglobin, as did one man on testosterone gel. The EMA report describes one case of polycythemia, a hematocrit of 55.4%, judged possibly related to enclomiphene; that man developed a deep vein thrombosis and bilateral pulmonary emboli during ZA-300. What clinicians do about a rising count is covered in how to lower hematocrit.
• PSA. One man on enclomiphene 25 mg in the same trials stopped because of a high PSA. The trial authors attributed PSA and hematocrit changes on both drugs to the rise in testosterone.
• IGF-1. A six-week phase II study in BJU International found that enclomiphene lowered IGF-1 more than testosterone gel did, with values staying inside the normal range. The authors wrote that they were uncertain what it means.

That same six-week study reported no significant effect of enclomiphene on TSH, ACTH, cortisol, lipids or bone markers.

Long-Term Safety

Enclomiphene Long-Term Side Effects: What Is Not Known

Enclomiphene long-term side effects are largely unmeasured. The EMA assessment report gives the exposure plainly: 1,403 people received at least one dose in phase II and III studies, 482 took it daily for more than six months, and 116 for twelve months or longer. The pivotal trials lasted 12 to 18 weeks. The committee wrote that the ability to detect rare adverse reactions is limited, especially those that might follow prolonged exposure.

Several specific questions have no answer in the public record:

• Clot risk over years. The EMA stated that the true effect after long-term treatment cannot be determined.
• Bone. The CHMP noted that the studies did not examine whether enclomiphene improves symptoms such as bone strength. A bone density study, ZA-303, is registered as completed on ClinicalTrials.gov with no results posted.
• Eyes. Ocular monitoring was recommended, not concluded.
• Kidney and liver impairment. The FDA noted that pharmacokinetic data are limited, including on dose adjustment in renal or hepatic impairment.
• Real-world reports. The FDA searched its adverse event reporting system (FAERS) for enclomiphene citrate through October 13, 2021 and retrieved no reports. In the same document the agency listed cardiac and thromboembolic events as safety concerns, so an empty database was not treated as a clean record.

Enclomiphene is now prescribed, in compounded form, for longer than any trial ran. How long a man stays on it is a clinician's judgment against his labs, revisited and not assumed.

After Stopping

Enclomiphene Side Effects After Stopping

What the trials measured after stopping enclomiphene is hormone levels, not symptoms. In a phase IIb study of 12 men published in the Journal of Sexual Medicine, total testosterone fell back to pretreatment values one month after the last dose. A separate phase II study found that the effects on LH and testosterone persisted for at least one week after stopping.

Enclomiphene works while it is taken; it does not reset the system. None of the published trials describes a distinct withdrawal syndrome, and none was built to find one. Estradiol, by the FDA's account of a separate three-month trial (ZA-203), was still above baseline one month after discontinuation.

Stopping is a clinical decision like starting. Tell the prescriber before stopping, so that the labs taken afterward can be read against the right baseline.

vs Clomiphene and TRT

Enclomiphene vs Clomiphene Side Effects, and How TRT Compares

Clomiphene is a mixture of two isomers, enclomiphene and zuclomiphene. The case for enclomiphene alone, as a 2016 review sets it out, is that zuclomiphene acts as an estrogen agonist, has a far longer half-life, and may account for some of clomiphene's side effects. The review calls that a hypothesis yet to be proven in hypogonadal men. It has had one direct clinical test since.

The test is a retrospective study from Baylor College of Medicine of 66 men who were prescribed clomiphene and later switched to enclomiphene. Documented adverse effects were less frequent on enclomiphene (13.8% against 47%), including decreased libido (8.6% against 33.3%) and mood changes (none against 9.1%). Median estradiol rose by 17.5 pg/mL on clomiphene and changed by -5.92 pg/mL after the switch.

Read those figures with the design in mind. There was no washout, every man took clomiphene first, the enclomiphene baseline was the on-clomiphene value, and side effects were pulled from chart notes at one center. The estradiol result means estradiol was lower than it had been on clomiphene, not lower than before any treatment. The authors themselves call for a blinded randomized trial. No such trial has been published.

Against testosterone therapy

Against testosterone gel, the EMA found the overall incidence of adverse events similar: 17.7% on enclomiphene and 19.7% on AndroGel, against 8.7% on placebo. The decisive difference is fertility. In the phase III trials, sperm concentration stayed in the normal range on enclomiphene and fell markedly on testosterone gel. The broader comparison is in TRT vs enclomiphene, and the fertility question in TRT and fertility. Testosterone products are FDA-approved and carry a label; enclomiphene has neither.

FDA Status

Is Enclomiphene Safe? Why It Is Not FDA-Approved

Whether enclomiphene is safe has been put to two regulators, and neither approved it. The record, from primary sources:

1. 2015: the US application

   Repros Therapeutics filed new drug application 207959 for enclomiphene citrate 12.5 mg and 25 mg capsules, for secondary hypogonadism in overweight men. The FDA scheduled an advisory committee to discuss it (Federal Register, August 2015).

2. December 2015: complete response letter

   Repros announced that the FDA had issued a complete response letter, meaning the application could not be approved in its present form. By the company's account, the FDA said the design of the phase III studies was no longer adequate to demonstrate clinical benefit, recommended an additional phase III study or studies, and noted concerns about study entry criteria, titration and bioanalytical method validation. This is the sponsor's description; the letter is not public.

3. January 2018: refusal in Europe

   The EMA's human medicines committee adopted a negative opinion on the same drug under the name EnCyzix. Its published reasons: the studies showed a rise in testosterone and did not look at whether symptoms improved, and there is a risk of venous thromboembolism.

4. June 2022: the compounding review

   The FDA proposed that enclomiphene citrate not be added to the list of bulk substances that pharmacies may compound under section 503A. Its Pharmacy Compounding Advisory Committee voted 8 to 4 against placing it on the list, with several members citing a lack of clinical efficacy evidence.

5. October 2026: still under evaluation

   No final rule has followed. On the FDA's list of nominated 503A bulk drug substances, updated May 14, 2026 and checked on October 8, 2026, enclomiphene citrate sits in Category 1, "Bulk Drug Substances Under Evaluation." That is a holding status, not an approval and not a finding that the drug is safe.

Neither agency disputed that enclomiphene raises testosterone. The objection was that raising a lab value was never shown to improve symptoms, which leaves the risks with nothing proven on the other side of the scale. Enclomiphene is therefore unapproved, not off-label: off-label describes an approved drug used for a different purpose.

Who Trials Excluded

Enclomiphene Risks: Who the Trials Left Out

The safety figures above describe the men the trials enrolled, and the trials were selective. Enclomiphene risks in men the studies excluded are unknown by construction.

• High red cell counts. ZA-300 excluded men with a hematocrit of 51% or higher or a hemoglobin of 17 g/dL or higher.
• Uncontrolled blood pressure. ZA-300 excluded uncontrolled hypertension.
• Eye disease. The phase III protocols described by the EMA excluded symptomatic cataracts and abnormal retinal findings such as central retinal vein occlusion.
• Older men. ZA-300 stopped at age 65, and the published phase III trials at 60.
• Liver disease. The Clomid label contraindicates clomiphene in patients with liver disease or a history of liver dysfunction. Enclomiphene has no label, and the EMA found drug exposure was higher in hepatic and renal impairment.

A history of blood clots is the question to raise first, given the thromboembolic events described above. These are subjects for a clinician who knows the full history, not a self-screening checklist.

Our Approach

How Protocol Health Prescribes and Monitors Enclomiphene

Protocol Health is a physician-led practice with one in-person clinic, in Scarsdale, New York, and telehealth care for patients in New York, New Jersey, Connecticut, Florida and California. The clinic prescribes compounded enclomiphene, which is unapproved (not FDA-approved for any use), and testosterone therapy, and so has a commercial interest in both.

The side-effect record is the reason labs come first. Protocol Health's Male Hormone and Longevity Assessment combines a hormone and performance blood panel, a body-composition scan, grip strength testing and a consultation, and it gives later results a baseline to be read against. A clinician reviews the labs and the history and decides whether enclomiphene, testosterone or neither is appropriate, and at what dose. The markers the trials showed can move on enclomiphene are estradiol, hematocrit and PSA; ask any prescriber how each will be followed. This article sets no dose and gives no individual advice.

Enclomiphene side effects in the trials were mostly mild: headache, hot flashes, nausea and muscle spasms. The serious signal is venous blood clots, rare in the trials and unexplained. Estradiol rises, vision warnings come mainly from clomiphene, and almost nothing is known beyond one year. Enclomiphene is unapproved, so a decision to take it belongs with a clinician who has your labs, and it starts with the enclomiphene consultation.

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