Enclomiphene side effects: what the clinical trials reported

In clinical trials of enclomiphene citrate, the side effects reported most often were headache, hot flushes, nausea, and muscle spasms, and most were mild or moderate. Less common but more serious events also turned up, including blood clots, and those are a large part of why European regulators declined to approve the drug in 2018. This article walks through what the trials and the two regulatory reviews actually recorded, what is still unknown, and which symptoms mean you should call your prescriber.

One point of context first. There is no FDA-approved enclomiphene product, so there is no official U.S. label listing its side effects. What we know comes mostly from 13 phase 2 and phase 3 studies sponsored by the drug's developers, summarized in a 2018 European Medicines Agency (EMA) assessment and a 2022 FDA review. When a provider prescribes compounded enclomiphene, it is prepared by a pharmacy and used off-label.

What are the most common side effects of enclomiphene?

The EMA reviewed safety data on 1,403 men who took enclomiphene in phase 2 and phase 3 studies. In that pooled group, the EMA reported treatment-emergent adverse events (side effects that began during treatment, whatever their cause) in 17.7% of men on enclomiphene, 19.7% of men on testosterone gel (AndroGel), and 8.7% of men on placebo. Most were rated mild (12.1%) or moderate (4.6%); 0.9% were rated severe.

Across those studies, the EMA named headache, hot flushes, nausea, and muscle spasms as the side effects reported most often. The side effects that most often led men to stop taking it were blurred vision, muscle spasm, headache, and aggression.

The largest single study gives a sense of scale. In a 26-week open-label safety study of 499 men (ZA-300), the FDA's review lists headache in 35 men, muscle spasms in 22, hot flushes in 11, and dizziness in 11. Upper respiratory infections such as colds were also common in that study.

Percentages in the table come from the EMA's pooled phase 2 and 3 data. They describe what was reported in studies of mostly overweight men aged 18 to 60, treated for weeks to months at 12.5 mg or 25 mg a day, and they are not a prediction for any one person.

Hot flushes, nausea, and other effects tied to how it works

Enclomiphene is a selective estrogen receptor modulator, or SERM. It blocks estrogen's signal at the pituitary gland and hypothalamus so the body releases more luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which in turn prompt the testes to make more testosterone. Hot flushes are a known effect of drugs in this class, and the EMA noted that hot flushes and erectile dysfunction were the two side effects reported more often with enclomiphene than with testosterone gel. Otherwise, the EMA described enclomiphene's overall side effect profile as similar to that of testosterone gel.

Erectile dysfunction is worth a note because it can be confusing: low testosterone itself can cause it, and men often try enclomiphene hoping to improve sexual function. In the pooled data it was reported in 0.6% of men on enclomiphene. In one phase IIb trial, one man on the 25 mg dose stopped because of trouble reaching climax and reduced sensation, which investigators judged possibly related to the drug.

Does enclomiphene affect your vision?

Vision gets special attention because clomiphene, the parent drug, is known to cause visual symptoms such as blurring, spots, or flashes of light. In enclomiphene's trials, eye symptoms were uncommon and not clearly more frequent than on placebo: eye disorders were reported in 1.6% of men on enclomiphene and 2.4% on placebo in the placebo-controlled studies, and blurred vision, counting all reports whatever the cause, in 1.0% versus 0.8%. Blurred vision judged at least possibly related to the drug was reported in 0.5% versus 0%. Even so, blurred vision was one of the most common reasons men stopped treatment.

Cataracts were a separate question. A long-term dog study at high doses found changes in the lens, later described in a pathology review commissioned by the company as minimal lens fiber swelling, so eye exams were built into the human trials. The EMA concluded the human data did not provide conclusive evidence that enclomiphene causes new cataracts or worsens existing ones, but it recommended continued eye monitoring. Men with symptomatic cataracts were excluded from the pivotal trials.

If your vision changes while taking enclomiphene, contact your prescriber right away. Clomiphene's label tells patients with vision symptoms to stop treatment and get a prompt eye exam, and your prescriber may advise the same.

Can enclomiphene affect mood?

Mood effects showed up in small numbers. In the pooled data, psychiatric side effects judged at least possibly related to treatment were reported in 3.2% of men. Aggression judged at least possibly related to treatment was reported in 0.5% of men on enclomiphene and none on placebo, and it was among the most common reasons for stopping. Anxiety was reported at about the same rate on enclomiphene and placebo (0.4%). In the phase III trials published by Kim and colleagues, one man on 25 mg had depression and one on 12.5 mg had anxiety, both recorded as severe events.

Tell your prescriber about irritability, aggression, low mood, or anxiety that is new or worse, and about any history of mental health conditions before you start.

Estradiol, hematocrit, and PSA: the lab changes

Some effects do not cause symptoms and only show up on blood work, which is one reason prescribers recheck labs during treatment.

• Estradiol. Estradiol (the main estrogen) rose significantly on both enclomiphene and testosterone gel in the EMA's pooled data. In a separate phase IIb trial reviewed by the FDA, estradiol was still higher than baseline a month after enclomiphene was stopped.
• Hematocrit. Rising testosterone can raise the share of red blood cells in the blood. An increase in hematocrit was judged at least possibly related to treatment in 0.6% of men on enclomiphene, compared with 1.4% on testosterone gel and none on placebo. In the phase III trials, one man on enclomiphene left the study because of high hematocrit or hemoglobin.
• PSA. Prostate-specific antigen can rise when testosterone rises. The EMA found PSA elevations at similar rates with enclomiphene and testosterone gel, and no prostate cancers were reported in the trials. In the phase III trials, one man on 25 mg left the study because of a high PSA.

Your prescriber decides which labs to check and when. The formulation page notes that total testosterone is typically monitored, along with semen analysis when fertility is a goal.

Does enclomiphene cause blood clots?

This is the most serious concern on record. Four men taking enclomiphene in the trials had a blood clot event: one had a deep vein thrombosis (DVT) and a pulmonary embolism, two had DVTs, and one had a fatal ischemic stroke. No clot events were reported in men on testosterone gel or placebo. Each of the four men had other risk factors, such as obesity, diabetes, heart rhythm problems, or a high hematocrit, and the EMA said it was unclear whether the cause was the rise in testosterone and red blood cells, the rise in estradiol, the men's other conditions, or the drug class itself. It concluded that, despite the small numbers, an increased risk could not be excluded.

That clot risk, together with a lack of evidence that symptoms improved, was the basis for the EMA's January 2018 recommendation to refuse marketing authorization. The FDA's 2022 review listed cardiac and thromboembolic events among its safety concerns, including the slow heart rate, atrial flutter, low blood pressure, DVT, pulmonary embolism, and stroke reported in the trials. Heart-related side effects overall were uncommon: in the placebo-controlled studies, 1.0% of men on enclomiphene and 0.4% on placebo had one. Clomiphene's own label also lists pulmonary embolism and retinal thrombosis among events reported after it was marketed, though it notes a cause could not be established.

In the phase III studies, the protocols were amended to stop enclomiphene if a clot was suspected and four weeks before any planned major surgery. If you have had a blood clot before, have a clotting disorder, or have surgery coming up, make sure your prescriber knows.

Enclomiphene vs clomiphene side effects

Clomiphene citrate (Clomid) is a mixture of two isomers: enclomiphene and zuclomiphene, the longer-lasting isomer with estrogen-like activity. Enclomiphene contains only the first. We cover the chemistry in enclomiphene vs clomiphene.

One retrospective study from Baylor College of Medicine looked at 66 men who took clomiphene and then switched to enclomiphene. Side effects were documented in 47% of men while on clomiphene and 13.8% while on enclomiphene, with less frequent low libido, low energy, and mood changes, and estradiol fell slightly after the switch rather than rising. The authors flagged real limits: it was a single-center chart review, there was no washout period between the drugs, men switched for different reasons, and some may have already improved on clomiphene. They called for randomized trials. Read it as a signal worth studying, not as proof that one drug is better tolerated than the other.

Enclomiphene vs testosterone side effects

The two raise testosterone by different routes, so their side effects differ in places. Testosterone therapy supplies testosterone from outside the body and suppresses LH and FSH, which can lower sperm production. In two phase III trials, men on enclomiphene kept sperm concentrations in the normal range while men on testosterone gel had marked drops, although the EMA judged the overall sperm-preservation results inconclusive. In the EMA's pooled data, overall side effect rates were similar between the two (17.7% vs 19.7%), but hot flushes and erectile dysfunction were reported more often with enclomiphene, and the four clot events all occurred on enclomiphene. Enclomiphene is also an oral capsule, so it carries none of the skin-to-skin transfer risk of topical testosterone. See our overview of testosterone therapy for that side of the comparison.

Neither option is right for everyone, and this comparison is not a claim that one is safer. Your prescriber weighs these trade-offs against your goals, such as whether fertility matters to you now.

What is still unknown about enclomiphene's safety

Both regulators were clear that the evidence has gaps:

• Short exposure. The pivotal trials lasted 12 to 18 weeks. Of the 1,403 men in the safety pool, 482 took enclomiphene for more than six months and 116 for more than a year. The EMA noted that rare side effects may not have been detected.
• Liver and kidney problems. Blood levels of enclomiphene were higher in men with moderate liver impairment and in men with moderate or severe kidney impairment, and the EMA said the long-term consequences are not known. Clomiphene's label says it should not be used in people with liver disease or a history of liver problems.
• Drug processing. The body breaks enclomiphene down mainly through the liver enzymes CYP2D6 and CYP3A4. The EMA asked for more data on men who process CYP2D6 slowly and on older men.
• No U.S. post-marketing record. Because no enclomiphene product has been marketed in the U.S., there is no post-marketing safety record. The FDA's 2021 search of its adverse event reporting system found no reports.

When to call your prescriber or get emergency care

Call your prescriber about side effects that are bothersome or do not go away, such as headache, hot flushes, nausea, muscle cramps, breast discomfort, or mood changes. Contact your prescriber right away about any change in your vision.

Get emergency care right away for signs of a blood clot or stroke: swelling, pain, warmth, or redness in one leg; sudden shortness of breath or chest pain; or sudden weakness or numbness on one side, trouble speaking, or loss of vision. Also get emergency care for a serious allergic reaction, such as swelling of the face or throat or trouble breathing.

Is compounded enclomiphene legal?

Currently, yes, with a prescription from a licensed provider. In June 2022, the FDA proposed not adding enclomiphene citrate to its list of bulk substances allowed for compounding, and its advisory committee voted 8 to 4 against adding it. The agency has not finalized that decision. As of FDA's May 14, 2026 update, enclomiphene citrate remains in Category 1, substances still under evaluation. Under FDA's interim policy, 503A pharmacies may compound a Category 1 substance for individual patient prescriptions while it stays in that category, provided the policy's other conditions are met. That status could change if the FDA acts.

How Bayview prepares enclomiphene

On a prescriber's order, Bayview compounds enclomiphene citrate capsules in 6.25 mg, 12.5 mg, 25 mg, and 50 mg strengths under USP 795 non-sterile standards. Bayview does not prescribe or decide whether enclomiphene is right for you. If side effects are a concern, raise them with your prescriber; a Bayview pharmacist can answer questions about your filled prescription at (401) 284-4505. For men whose prescriber chooses a manufactured option instead, Bayview also dispenses generic clomiphene citrate tablets.