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Enclomiphene Side Effects: What's Common, What's Rare, and What to Watch For
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Serious Side Effects and Risks
Of course, like with any medication, there is a risk of serious adverse events. We’ll dive into some of the most concerning ones below:
Blood Clot (VTE) Risk
What we know about the enclomiphene blood clot risk comes from our knowledge of clomiphene. Some case reports connect clomiphene to a risk of blood clots, according to research. Here’s why: As testosterone increases, hemoglobin and hematocrit levels (components of blood) may increase as well, says Jagan Kansal, MD, board-certified urologist and CEO and cofounder of Down There Urology in Chicago. This could increase blood thickness and raise the risk of developing blood clots.
For safety, Dr. Houman says that he carefully reviews a patient's history for prior blood clots before prescribing enclomiphene. Still, the risk of blood clots while taking enclomiphene is very low — less than 1%.
Cardiac Disorders
Although rarely reported, clomiphene has been linked to cardiac disorders, such as arrhythmia (abnormal heart rhythm), chest pain, hypertension, swelling, and heart attack, according to a case report in the journal Science Progress.
Elevated PSA
Enclomiphene treatment may cause prostate specific antigen (PSA) levels to rise. PSA is a protein produced by prostate cell glands, and elevated levels are associated with both benign prostate conditions as well as prostate cancer, according to the National Cancer Institute. TRT, clomiphene, and enclomiphene may all increase PSA, according to a study review and meta-analysis in the Archives of Endocrinology and Metabolism. That review cites research on clomiphene that found that PSA levels increased in men taking the medication, though PSA remained in normal range.
Your clinician may recommend getting your PSA levels checked earlier than recommended if you're taking enclomiphene. Currently, the US Preventative Services Task Force recommends that men ages 55 to 69 may elect to get screened for prostate cancer through a PSA test. Dr. Kansal has his patients on these medications get a PSA test 15 years earlier, starting at age 40 to record baseline levels. Your clinician may recommend something different — talk to them for recommendations specific to your situation.
Visual disturbances
What’s known about visual disturbances caused by enclomiphene comes from research on women taking the “parent drug” clomiphene, according to a drug profile in Expert Review of Endocrinology & Metabolism. As the researchers point out, the data may not perfectly translate to men. However, what we do know is that up to 1.5% of patients may experience visual symptoms like blurred vision, (scintillating scotoma) bright lights and patterns, double vision, or extreme sensitivity to light.
Although rarely reported, “visual disturbances are the side effect that should never be ignored,” says Dr. Houman. If you experience enclomiphene visual disturbances, such as blurred vision, floaters, or light sensitivity, call your doctor. This side effect typically requires a hard stop on the medication, he says.
Elevated Estradiol
Compared to clomiphene treatment, you can expect lower levels of estradiol when taking enclomiphene alone, according to research in Translational Andrology and Urology. That said, there are still estrogen-boosting effects from enclomiphene and estradiol levels will also rise.
Who Should Not Take Enclomiphene?
When it comes to who should not take enclomiphene, research in The World Journal of Men's Health indicates that key contraindications include:
History of liver disease
Uncontrolled adrenal or thyroid disfunction
Certain pituitary conditions
Allergy to clomiphene or enclomiphene
These reasons are mainly based on clomiphene’s labeling, since enclomiphene is not FDA-approved and has no official indications or contraindications.
Enclomiphene Side Effects by Dose: 12.5mg vs. 25mg
Is there a difference between enclomiphene 12.5mg vs 25mg side effects? The answer isn’t fully clear yet, but here's what the research says so far.
One review published in the Archives of Endocrinology and Metabolism noted that with a 12.5mg or 25mg dose of enclomiphene, there was no significant difference in side effects. Overall, 21% of men had side effects when taking enclomiphene, though none were rated severe or serious.
These dosages had slightly different effects on testosterone levels in a randomized phase 2 study published in Fertility and Sterility:
Dosage of 12.5mg enclomiphene: Increased testosterone from 217.2 ng/dL to 471.9 ng/dL after 3 months, for an increase of 254.7 ng/dL
Dosage of 25mg enclomiphene: Increased testosterone from 209.8 ng/dL to 405.8 ng/dL after 3 months, for an increase of 196 ng/dL
Discuss titration and dosage with your prescribing clinician. General guidelines advise beginning with a low 6.25mg daily dose and increasing weekly up to 25mg, as tolerated. It's important to remember, though, that your physician may adjust your enclomiphene dosing based on the response you have.
Enclomiphene vs. Clomiphene Side Effects
Side Effect | Enclomiphene | Clomiphene | Notes |
Decreased libido | 8.6% | 33.3% | Estrogen levels too high or too low can cause libido problems. |
Erectile dysfunction | 8.6% | 18.2% | Proper estrogen levels are needed for strong erections |
Fatigue | 6.9% | 18.2% | Hypogonadism alone can cause problems with fatigue and energy |
Decreased energy | 5.2% | 16.7% | Hypogonadism alone can cause problems with fatigue and energy |
Depressive thoughts | 0% | 4.5% | May signal low estrogen levels |
Weakness | 1.7% | 6.1% | Hypogonadism alone can cause problems with fatigue and energy |
Enlarged breast tissue | 0% | 3% | Due to increase in estrogen |
Mood changes | 0% | 9.1% | May signal low estrogen levels |
Agitation | 1.7% | 6.1% | May signal low estrogen levels |
Drug Interactions to Know
When it comes to enclomiphene drug interactions, the best course of action is to talk to your clinician about your individual health risks, as well as medications and supplements you are taking. For example, if you have a risk of blood clots and are taking anticoagulants, you should discuss if it is safe for you to use both.
The metabolism of clomiphene is reliant on liver enzymes CYP3A4 and CYP2D6, notes research in Pharmaceutics, possibly giving way to potential interactions among many drugs (including anti-fungals and depression medications) that can speed up or slow down its metabolism. In addition, enclomiphene is a medication that affects your hormones — if you are taking other medications that alter your hormones, including DHT-blocking treatments, let your clinician know.
Long-Term Safety: What We Know (and Don't)
Research published by the British Society for Sexual Medicine noted that because there isn’t a lot of enclomiphene long-term safety data, this medication should only be prescribed by clinicians who specialize in treating secondary hypogonadism in men — and patients should have regular check-ups during treatment. This is where Mochi’s care model excels compared to other telehealth options, as your Mochi Health membership plan includes unlimited provider visits and monitoring so you can feel confident you’re on the right track.
That’s the same thing Dr. Kansal stresses: Although clomiphene has a rich set of data to show its safety and efficacy (including rigorous studies to get to FDA-approval) — and the two medications are similar — data is limited for enclomiphene. “Enclomiphene does not have the same scrutiny, FDA-approval, and it is used off-label,” he says.
Many of the side effects clinicians watch for are extrapolated from clomiphene data. Given the drug affects your hormones, Dr. Kansal recommends seeing a clinician at least once or twice a year to monitor your hormone levels. This might include testosterone, estradiol, LH/FSH, PSA, blood counts, and lipid levels.
And finally, enclomiphene may not be the best medication for you long-term. “Efficacy can go down over time, as testosterone levels will follow the natural things the body goes through,” says Dr. Kansal. Since enclomiphene stimulates the body to produce testosterone, as you age those signals may become too weak to stimulate adequate T, necessitating a switch to another treatment like TRT.
The Bottom Line
Enclomiphene is generally well-tolerated, according to short-term trials, but specific health risks warrant monitoring. Long-term data is available for clomiphene but is still developing with enclomiphene, especially given that this medication is not FDA-approved and needs to be made by a compounding pharmacy, where product quality can vary.
If you experience side effects from enclomiphene, you may not have to stop it altogether. “If you’re on enclomiphene and feel worse instead of better, don’t assume the medication failed,” says Dr. Houman. “Ask your provider to check estradiol along with your testosterone. Dose adjustments or a different strategy often solve it,” he says, noting that while testosterone levels can jump up relatively quickly — within a few weeks — symptom improvement can take two to three months.
If you’re considering treatment for hypogonadism, enclomiphene may be an option for you, but there are benefits, risks, and side effects to talk through. If you’re interested in starting or have questions about continuing enclomiphene treatment, you can talk to a physician in the Mochi Health network for more personal guidelines catering to your health and your goals.
FAQs
Is enclomiphene FDA-approved?
No, enclomiphene is not FDA-approved. It is used off-label to treat secondary hypogonadism in males and clinicians must order the medication through a compounding pharmacy with a prescription.
Does enclomiphene affect fertility?
One of the reported benefits to enclomiphene is the elevation of testosterone levels while preserving fertility in males. It’s a good potential option for men who are looking to raise their testosterone and want to remain fertile. TRT, on the other hand, can impair sperm production.
What happens when you stop enclomiphene?
Enclomiphene works by stimulating your own body to produce more testosterone. If you have seen improvement in your T levels and symptoms when taking it but then stop treatment, your levels will return to baseline and your symptoms may return.
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