Enclomiphene vs Clomid: What Research Says About Raising Testosterone

When a man is diagnosed with low testosterone, the conversation often jumps straight to testosterone replacement therapy (TRT). Because TRT supplies testosterone from outside the body, it suppresses the signals that drive the testes. For men who want to preserve fertility, doctors sometimes consider selective estrogen receptor modulators (SERMs) instead. Two names come up most: clomiphene citrate, sold as Clomid, and its isolated isomer, enclomiphene. They are related but not equivalent, and the regulatory and safety picture differs.

How SERMs Work on the HPG Axis

Testosterone production is controlled by the hypothalamic-pituitary-gonadal (HPG) axis. The hypothalamus signals the pituitary to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH tells the testes to make testosterone, and FSH supports sperm production. Estrogen feeds back on the brain to limit this signal.

Enclomiphene citrate is a SERM: it is thought to compete with estrogen for receptor binding sites in the brain, limiting estrogen's suppression of FSH and LH release and so increasing testosterone. In other words, instead of supplying testosterone from outside the body, it aims to raise the body's own production. That only works if the testes can respond. These drugs are studied in men with secondary hypogonadism, where the problem lies in the signal from the brain, not in men whose testes themselves are not working. For a broader comparison with other approaches, see our TRT vs natural testosterone optimization guide.

Clomid: A Mixture of Two Isomers

Clomiphene citrate is FDA-approved for the treatment of ovulatory dysfunction in women. Its use in men is off-label. It is a mixture of two isomers, enclomiphene (the trans isomer) and zuclomiphene (the cis isomer). A review of the literature concluded that most of the beneficial effects of clomiphene are due to enclomiphene, and that zuclomiphene contributes little to the intended outcomes.^[1]

Zuclomiphene is also the isomer that researchers worry about. In a study of 15 men with hypogonadism on long-term clomiphene citrate therapy (median duration about 26 months), zuclomiphene was the predominant isomer in the blood. The authors noted the "vastly different biochemical and toxicological properties" of the two isomers and concluded that their data supported developing a pure selective estrogen receptor antagonist for treating men with hypogonadism.^[6] That small study does not by itself show that zuclomiphene causes specific side effects, but it explains the interest in enclomiphene.

What the Research Says About Clomiphene in Men

A systematic review and meta-analysis of clomiphene citrate for men with hypogonadism included 19 studies (4 randomized controlled trials and 15 observational studies) covering 1,642 patients. Total testosterone rose during treatment, as did free testosterone, LH, FSH, SHBG and estradiol. Side effects were reported in under 10 percent of the study populations, and no serious adverse events were reported. The authors concluded clomiphene is effective with few reported side effects, but they also noted that follow-up and symptom scoring methods varied between studies.^[4]

A retrospective review of 400 men treated at two institutions, 120 of them for more than 3 years, reported that 8 percent of the long-term group reported side effects, the most common being mood changes, blurred vision and breast tenderness, with no significant adverse events recorded. The authors noted clomiphene is not typically offered as primary treatment to men who do not want to preserve fertility.^[7] Because visual changes are a known concern with this class of drug, anyone who notices blurred vision or other visual symptoms should tell their prescriber promptly.

Enclomiphene: What the Trials Show

Enclomiphene citrate is the isolated trans isomer of clomiphene. It was developed under the name Androxal for secondary hypogonadism in overweight men. In two parallel randomized, double-blind, placebo- and gel-controlled Phase 3 studies (ZA-304 and ZA-305) in overweight men aged 18 to 60 with secondary hypogonadism, total testosterone increased from baseline to week 16 in all treatment groups. LH and FSH increased with enclomiphene and decreased with testosterone gel, and enclomiphene maintained sperm concentration in the normal range while the gel group showed a marked reduction in sperm production.^[5]

A smaller earlier Phase 2 trial found a similar pattern: enclomiphene increased morning testosterone and LH to a degree comparable to topical testosterone gel in men with secondary hypogonadism, and sperm counts were conserved.^[8]

There is no published head-to-head trial in this article's sources comparing enclomiphene directly with clomiphene in men, so claims that one is clearly "better" or has fewer side effects are, at this point, mostly extrapolated from the isomer chemistry and separate studies.

Fertility and Testosterone Therapy

TRT can reduce sperm production because the testes lose their LH and FSH drive. The Endocrine Society guideline recommends against starting testosterone therapy in men who are planning fertility in the near term, and recommends it only for men with symptoms and signs of testosterone deficiency and consistently low serum testosterone.^[9] That is why some doctors consider SERMs for younger men who want to keep options open. The evidence above shows that sperm concentration was maintained with enclomiphene in trials, and clomiphene is used off-label with the same aim.^[4] These findings do not guarantee fertility, and anyone planning to have children should be guided by a urologist, andrologist or endocrinologist.

Regulatory Status and Access

Enclomiphene is not FDA-approved. In December 2015 the FDA issued a complete response letter to the developer, Repros Therapeutics, stating that the design of the enclomiphene Phase 3 studies was no longer adequate to demonstrate clinical benefit and recommending additional Phase 3 studies; the letter also raised issues about study entry criteria, titration and bioanalytical method validation.^[2]In June 2022 the FDA's Pharmacy Compounding Advisory Committee voted 8 to 4 against placing enclomiphene citrate on the 503A bulks list; several members who voted no cited a lack of clinical efficacy evidence.^[3]

What this means in practice: enclomiphene is not an approved product, and products sold online or by some clinics may be unapproved, of uncertain quality or sold as "research chemicals." Clomiphene is an approved drug, but its use in men is off-label. Because of these gaps, any decision should involve a licensed doctor who can assess the cause of low testosterone, discuss risks and alternatives, and monitor you. Do not source these drugs from unverified websites or supplement sellers.

What a Doctor-Led Process Looks Like

Dosing and monitoring decisions belong to the prescriber, not to an article. In general, the pathway looks like this:

The Bottom Line

Clomiphene and enclomiphene both aim to raise testosterone by stimulating the body's own signaling rather than replacing the hormone. Trial data are encouraging for specific groups (men with secondary hypogonadism), but enclomiphene is not FDA-approved, long-term safety is not established, and clomiphene is used off-label in men. These are prescription medicines for diagnosed medical conditions, not performance or wellness supplements.

If you have symptoms such as persistent fatigue, low sex drive or low mood, the right first step is an appointment with a doctor for proper testing. In the meantime, the foundations covered in our daily habits guide support overall health. For other pharmaceutical-adjacent topics, see our guide to peptides for men's health.

How Thrive Helps

Thrive is a wellness app that helps you build and track daily habits such as sleep, training and nutrition. It does not diagnose or treat low testosterone and is not a substitute for medical care. Try Thrive free to build the foundations, and see a doctor if you have symptoms or concerns about your hormones.