Dr. Richard Harris
Enclomiphene is not a new therapy, but it has recently garnered a fair amount of attention. Some individuals and companies are saying that enclomiphene is superior to clomiphene. Do human clinical studies support these statements? Let’s dive in and answer that question.
Clomiphene is a selective estrogen receptor modulator (SERM) that is used off-label (not an FDA-approved indication) for male hypogonadism, also known as low testosterone or low T. Clomiphene is 68% enclomiphene and 38% zuclomiphene. 1 The theory is that zuclomiphene is responsible for the estrogenic adverse effects that may occur with clomiphene. Zuclomiphene may also be the part that is responsible for increasing LH and FSH levels, which are essential hormones for testosterone synthesis and sperm production. Zuclomiphene remains in the body for less time than enclomiphene. 2 These differences are the mechanisms behind why using purified enclomiphene might have better outcomes than the mixture of enclomiphene and zuclomiphene. Outcomes are the keyword because we are unaware of any head-to-head trials comparing the safety and efficacy of enclomiphene vs clomiphene.
We have covered clomiphene before and outlined its efficacy and safety profile in our FAQ. Evidence supports enclomiphene in treating low testosterone levels. A randomized trial using enclomiphene found that enclomiphene effectively restored normal-range testosterone levels. An interesting finding is that in these study participants, enclomiphene raised testosterone levels but also maintained the normal circadian fluctuations in testosterone levels not seen in using transdermal testosterone. 3
Robust evidence on the safety and tolerability of enclomiphene is somewhat lacking. In the clinical trials utilizing enclomiphene, adverse effects included elevated estradiol levels (which goes against one of the supposed benefits of enclomiphene), headache, and abdominal discomfort 4. Other reported adverse effects were in low frequency and included nausea, diarrhea, hot flashes, dizziness, elevated triglycerides, and joint pains 5. Enclomiphene also does not have an FDA-approved indication.
As mentioned earlier, we are unaware of head-to-head trials comparing enclomiphene to clomiphene. In July of 2023, a retrospective trial was published that compared clomiphene to enclomiphene as treatments for male infertility. They reviewed charts in men over 18 who presented to a clinic with primary infertility, abnormal semen studies, or hypogonadism who had received enclomiphene or clomiphene. They found no difference in the ability of clomiphene and enclomiphene to raise testosterone levels. Enclomiphene improved motility and total sperm count, whereas clomiphene only improved motility. An interesting finding was that enclomiphene decreased the total testosterone to estradiol (T/E) ratio while clomiphene increased the T/E ratio. 6
It’s difficult to draw firm conclusions from a retrospective single-center study, and it doesn’t answer the question of superiority. Further research is needed to determine if enclomiphene is more efficacious or has a better safety and tolerability profile than clomiphene. We eagerly await a head-to-head trial that seeks to answer these questions. We don’t believe enclomiphene would be inferior to clomiphene based on the weight of current evidence, nor is it superior to clomiphene based on current evidence.
1 Wiehle R, Cunningham GR, Pitteloud N, et al. Testosterone Restoration by Enclomiphene Citrate in Men with Secondary Hypogonadism: Pharmacodynamics and Pharmacokinetics [published online ahead of print, 2013 Jul 12]. BJU Int. 2013;112(8):1188-1200. doi:10.1111/bju.12363
2 Rodriguez KM, Pastuszak AW, Lipshultz LI. Enclomiphene citrate for the treatment of secondary male hypogonadism. Expert Opin Pharmacother. 2016;17(11):1561-1567. doi:10.1080/14656566.2016.1204294
3 Wiehle R, Cunningham GR, Pitteloud N, et al. Testosterone Restoration by Enclomiphene Citrate in Men with Secondary Hypogonadism: Pharmacodynamics and Pharmacokinetics [published online ahead of print, 2013 Jul 12]. BJU Int. 2013;112(8):1188-1200. doi:10.1111/bju.12363
4 Rodriguez KM, Pastuszak AW, Lipshultz LI. Enclomiphene citrate for the treatment of secondary male hypogonadism. Expert Opin Pharmacother. 2016;17(11):1561-1567. doi:10.1080/14656566.2016.1204294
5 Rodriguez KM, Pastuszak AW, Lipshultz LI. Enclomiphene citrate for the treatment of secondary male hypogonadism. Expert Opin Pharmacother. 2016;17(11):1561-1567. doi:10.1080/14656566.2016.1204294
6 Thomas J, Suarez Arbelaez MC, Narasimman M, et al. Efficacy of Clomiphene Citrate Versus Enclomiphene Citrate for Male Infertility Treatment: A Retrospective Study. Cureus. 2023;15(7):e41476. Published 2023 Jul 6. doi:10.7759/cureus.41476
