Mechanism of action: How enclomiphene works
Clinical efficacy of enclomiphene
Safety considerations and side effects
Who is a candidate for enclomiphene therapy?
Regulatory status and availability
Enclomiphene is one of the two stereoisomers of clomiphene citrate (CC), a non-steroidal selective estrogen receptor modulator (SERM). It acts as either an estrogen receptor agonist or antagonist, depending on the tissue involved.¹
Approved in 1976 for treating female infertility, CC comprises 62% enclomiphene (the trans isomer) and 38% zuclomiphene (the cis isomer). Both CC (used off-label) and enclomiphene have been used to treat male hypogonadism by raising testosterone levels while maintaining sperm production. However, the development of enclomiphene as a standalone treatment has since been discontinued.¹
The weak estrogen receptor agonist activity of CC—primarily due to zuclomiphene—can increase the risk of side effects, including low mood, decreased muscle strength, breast enlargement, mood swings, and restlessness.¹˒²
efficacy, and safety consideration" />Image Credit: LeviaUA/Shutterstock.com
Mechanism of action: How enclomiphene works
The hypothalamic-pituitary-gonadal (HPG) axis regulates gonadal function. The hypothalamus stimulates the pituitary gland to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH), both of which act on the testes. LH stimulates testosterone production, while FSH stimulates sperm production.³ Testosterone then provides negative feedback on the hypothalamus, suppressing further FSH and LH release.³
In secondary hypogonadism, dysfunction in the HPG axis leads to low testosterone levels accompanied by low or normal gonadotropins. Symptoms may include decreased libido, erectile dysfunction, muscle loss, fatigue, and depressive feelings.¹
Traditional testosterone replacement therapy (TRT) restores serum testosterone but suppresses FSH and LH, thereby inhibiting natural testosterone and sperm production.¹
Enclomiphene, like CC, blocks estrogen receptors in the hypothalamus, preventing negative feedback and stimulating the release of FSH and LH.³ This boosts testosterone production in the testes, which also supports sperm production.¹
Unlike zuclomiphene, enclomiphene acts as a pure estrogen antagonist, resulting in lower estrogen levels than CC but similar improvements in hypogonadal symptoms, with fewer estrogenic side effects.¹˒² In one study, enclomiphene use in secondary hypogonadism was associated with an 80% reduction in adverse effects compared to CC.¹
Clinical efficacy of enclomiphene
Enclomiphene addresses the two hallmarks of secondary hypogonadism: low serum testosterone and low or inappropriately normal LH levels. Compared to CC, enclomiphene leads to higher testosterone levels with a smaller increase in estrogen.¹
In men with chronic kidney disease and low testosterone, enclomiphene improved symptoms of testosterone deficiency.¹
While TRT also raises testosterone, it inhibits the HPG axis, decreasing FSH and LH and increasing the risk of oligospermia (low sperm count).¹˒³ Enclomiphene avoids this suppression, making it preferable for men concerned with fertility.
Importantly, enclomiphene does not induce supraphysiologic LH or testosterone levels, suggesting a plateau in its effect on Leydig cells. It also results in more stable serum testosterone compared to TRT.²
Since secondary hypogonadism often coexists with obesity and metabolic syndrome, enclomiphene’s ability to improve testosterone and glucose regulation adds clinical value.²
Another notable advantage is enclomiphene’s “legacy action”: elevated testosterone, LH, and FSH levels persist for at least one week after discontinuation, unlike TRT.³ This suggests potential for intermittent dosing, reducing the risk of tolerance and improving patient convenience.
hypothalamic-pituitary-gonadal (HPG) axis
Safety considerations and side effects
Enclomiphene may cause headaches, nausea, and mood changes. However, compared to CC, it is about 80% less likely to cause mood swings and fatigue, potentially improving adherence.¹ It may also benefit cardiometabolic markers, such as fasting blood glucose.²
By contrast, TRT can raise red blood cell counts, thicken the blood, alter cholesterol profiles, and may increase cardiovascular risk—though data is inconsistent.⁵ Short-term safety data for enclomiphene are similar to TRT, including risk of venous thromboembolism (VTE).²˒⁷ Long-term safety remains unestablished.
Enclomiphene has shown minimal impact on other endocrine or lipid markers. However, its effects on bone density, body composition, and sexual function require further study.
Who is a candidate for enclomiphene therapy?
Men with secondary hypogonadism due to reversible hypothalamic or pituitary dysfunction—often linked to obesity, type 2 diabetes, or metabolic syndrome—may benefit from enclomiphene.²˒⁵ It can be an alternative for those who cannot tolerate or are ineligible for TRT.⁸
It is also a suitable option for younger men who want to relieve hypogonadal symptoms while preserving fertility.²˒⁶ Exceptions include patients with pituitary tumors, craniopharyngiomas, or hemochromatosis.²
How Process Development Enhances Drug Discovery Outcomes
Regulatory status and availability
In 2007, the FDA declined to approve enclomiphene for secondary hypogonadism, citing insufficient evidence that it improved fertility—despite increases in testosterone. At the time, no high-level evidence demonstrated symptom improvement. A 2015 review was canceled, and the development of the drug was discontinued in 2021.⁶˒⁸
Enclomiphene remains a prescription-only medication. Although not FDA-approved, it can be compounded by specialty pharmacies when prescribed.⁹˒¹⁰ It is widely used off-label for managing male hypogonadism and infertility.⁹
References
- Saffati, G., Kassab, J., Rendon, D. O., et al. (2024). Safety and efficacy of enclomiphene and clomiphene for hypogonadal men. Translational Andrology And Urology. doi: 10.21037/tau-24-238.
- Wiehle, R., Cunningham, G. R., Pitteloud, N. et al. (2013). Testosterone restoration using enclomiphene citrate in men with secondary hypogonadism: a pharmacodynamic and pharmacokinetic study. BJU. doi: https://doi.org/10.1111/bju.12363.
- Wiehle, R. D., Fontenot, G. K., Wike, J., et al. (2014). ZA-203 Clinical Study Group. Enclomiphene citrate stimulates testosterone production while preventing oligospermia: a randomized phase II clinical trial comparing topical testosterone. Fertility & Sterility.
- Wexler, T. L., (2016). Enclomiphene citrate improves hormone levels while preserving sperm production in men with secondary hypogonadism. Available at: https://www.medcentral.com/endocrinology/hormones/enclomiphene-citrate-improves-hormone-levels-while-preserving. Accessed on February 25, 2025.
- Kassab, J., Saffati, G., Lipshultz, L., et al. (2024). Safety and efficacy of enclomiphene compared to clomiphene for hypogonadal men. The Journal of Sexual Medicine. doi: https://doi.org/10.1093/jsxmed/qdae001.090.
- Rodriguez, K. M., Pastuszak, A. W., and Lipshultz, L. I. (2016). Enclomiphene Citrate for the Treatment of Secondary Male Hypogonadism. Expert Opinion in Pharmacotherapy. doi: 10.1080/14656566.2016.1204294.
- EnCyzix (2018). Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/encyzix. Accessed on February 25, 2025.
- Enclomifene - Repros Therapeutics. (2021). Available from: https://adisinsight.springer.com/drugs/800019625. Accessed on March 4, 2025.
- A Deep Dive: The Science Behind Enclomiphene Therapy. Available from: https://conciergemdla.com/blog/enclomiphene-therapy-science/. Accessed on March 4, 2025.
- PCAC votes on substances nominated for inclusion on the final 503A Bulks List. Available from: https://www.reedsmith.com/en/perspectives/2022/07/pcac-votes-on-substances-nominated-for-inclusion. Accessed on March 4, 2025.
Further Reading