Understanding the Role of Enclomiphene for Hypogonadism

Hypogonadism is a common condition, with studies reporting approximately 40% of men older than 45 and 50% of men in their 80s suffer from hypogonadism. Hypogonadism may be diagnosed as primary or secondary hypogonadism, with primary hypogonadism being caused by testicular failure and secondary hypogonadism being the result of pituitary failure. Both primary and secondary hypogonadism present with persistent low levels of testosterone, but primary hypogonadism is also associated with elevated luteinizing hormone (LH) while secondary hypogonadism may present with low or normal LH. Both types of hypogonadism can impact sperm count and cause other abnormalities in semen resulting in compromised fertility.¹

Pharmacotherapy for Hypogonadism

Patients with symptoms of low testosterone associated with hypogonadism, or who struggle with fertility as a result of hypogonadism, are candidates for pharmacotherapy. Testosterone supplementation by a variety of routes of administration is a first line treatment for hypogonadism.² However, testosterone supplementation alone is not always sufficient to manage symptoms of hypogonadism.

Testosterone may be aromatized to estradiol in adipocytes and a negative feedback loop wherein exogenously administered testosterone results in decreased spermatogenesis via inhibition of follicle-stimulating hormone (FSH) and LH can occur. Active pharmaceutical ingredients such as anastrozole (an aromatase inhibitor) or clomiphene citrate (a selective estrogen receptor modulator (SERM)) are sometimes used in male patients to manage secondary hypogonadism while preserving fertility.^3,4 Clomiphene Citrate is typically dosed at 25-50mg daily to every other day.

Studies have shown that clomiphene citrate can increase testosterone levels and improve symptomatology associated with hypogonadism while preserving fertility. Some studies have also shown improvements in libido and mood associated with clomiphene supplementation in hypogonadal patients.^4,5 Though clomiphene citrate is typically well tolerated, it can be associated with adverse effects including hot flashes, headache, or gynecomastia among others.⁴

Clomiphene Citrate vs Enclomiphene Citrate

Clomiphene citrate is a mixture of two diastereoisomers, (cis)zuclomiphene citrate (38%) and (trans)enclomiphene citrate (62%). It is hypothesized by some that the zuclomiphene is responsible for some adverse effects associated with clomiphene citrate and that enclomiphene citrate is primarily responsible for the beneficial effects on hypogonadism by increasing FSH and LH.⁶ Zuclomiphene also has a longer half like than enclomiphene and may linger longer in the body, with some data suggesting zuclomiphene may remain detectable for more than a month after administration in subjects given clomiphene citrate.¹¹

One recent analysis of 66 patients who had originally been prescribed clomiphene citrate prior to being switched to enclomiphene citrate did note significantly more reported adverse effects while the patients were on clomiphene citrate. Men on clomiphene citrate reported adverse events (depressive thoughts, weak muscle strength, gynecomastia, mood changes, agitation, or changes in estradiol or hematocrit levels) 18.18% of the time compared to just 3.45% of the time for patients on enclomiphene.

After switching to enclomiphene, significantly fewer patients reported decreased libido, decreased energy, and mood changes specifically. Numerically fewer patients reported adverse events such as gynecomastia or agitation, though the differences failed to reach statistical significance, likely in part due to small sample size. These differences in adverse event profile may be in part driven by a differing impact on estradiol. The study noted that there was a statistically significant increase in estradiol levels in patients on clomiphene citrate that was not observed with enclomiphene citrate.⁷

Enclomiphene Citrate Dosing

One dose- finding study evaluated dosing at 6.25mg, 12.5mg, and 25mg of enclomiphene citrate daily vs. transdermal testosterone. The study found that, after six weeks of treatment, all doses of enclomiphene citrate increased LH levels compared to the testosterone supplementation arm, which reported suppressed LH levels. All doses of enclomiphene citrate also increased total testosterone and FSH levels as well as sperm count. The impact of enclomiphene citrate was dose-dependent, with the greatest increase in LH being observed in the 12.5mg and 25mg groups. Patients on enclomiphene citate 25mg had total testosterone levels above those reported in the transdermal testosterone supplementation group.^6,8 Studies looking at higher doses, such as one comparing 12.5mg, 25mg, and 50mg, found a non-dose-dependent steady-state level maximum at the 25mg dose.¹⁰

Enclomiphene Citrate Route of Administration

Studies on enclomiphene citrate for hypogonadism have focused on the oral route of administration and absorption via the oral route is rapid.¹⁰ Though specific bioavailability data is not currently available on enclomiphene citrate, it is a component of clomiphene citrate, which is readily absorbed orally in humans.¹¹ At this time neither clomiphene citrate nor enclomiphene citrate have been studied via alternative routes of administration such as the transdermal or sublingual route.

Regulatory Status

As of the posting of this blog there is no USP drug monograph for enclomiphene citrate. As of the most recent update on September 27th, 2024, enclomiphene citrate is category 1 on the Bulk Drug Substances Nominated for Use in Compounding Under Section 503A of the Federal Food, Drug, and Cosmetic Act. In July 2022, the FDA’s Pharmacy Compounding Advisory Committee (PCAC) voted against inclusion of enclomiphene citrate on the final 503A bulks list, though the material remains listed as category 1 on the most recent iteration of the 503A bulk drugs list.

Eager to Learn More?

If you are interested in learning more about management of hypogonadism, head to our Video Platform to watch our webinar Beyond Testosterone Replacement Therapy. In this webinar, Briana Cain, NMD discusses pharmacotherapy for hypogonadism and alternatives to testosterone replacement therapy.

References:

1.       Sizar O, Leslie S, Schwartz J. “MaleHypogonadism.” National Library ofMedicine. Male Hypogonadism -StatPearls - NCBI Bookshelf. Updated February 25^th 2024.Accessed April 16^th 2025.

2.       Bhasin S, Brito J, Cunningham G et al. “Testosteronetherapy for hypogonadism guideline resources.” JCEM.2018; TestosteroneTherapy for Hypogonadism Guideline Resources | Endocrine SocietyAccessed April 16^th 2025.

3.       Rambhatla A, Mills JN, Rajfer J. “TheRole of Estrogen Modulators in Male Hypogonadism and Infertility.”RevUrol. 2016, ;18(2):66-72.doi: 10.3909/riu0711. PMID: 27601965; PMCID: PMC5010627.

4.       Da RosCT, Da Ros LU, Da Ros JPU. “Therole of clomiphene citrate in late onset male hypogonadism.” IntBraz J Urol.,2022 Sep-Oct;48(5):850-856. doi: 10.1590/S1677-5538.IBJU.2021.0724. PMID:35168314; PMCID: PMC9388170.

5.       Taylor F, Levine L. “Clomiphenecitrate and testosterone gel replacement therapy for male hypogonadism:efficacy and treatment cost.” JSex Med.,2010 Jan;7(1 Pt 1):269-76. doi: 10.1111/j.1743-6109.2009.01454.x. Epub 2009 Aug17.

6.       Wiehle R, Cunningham GR, Pitteloud N, et al. “TestosteroneRestoration by Enclomiphene Citrate in Men with Secondary Hypogonadism: Pharmacodynamicsand Pharmacokinetics.” [published online ahead of print,2013 Jul 12]. BJU Int. 2013;112(8):1188-1200.doi:10.1111/bju.12363

7.       J Kassab, G Saffati, L Lipshultz, M Khera,, (094) “Safetyand Efficacy of Enclomiphene Compared to Clomiphene for Hypogonadal Men,”, TheJournal of Sexual Medicine, Volume 21, Issue Supplement_1, February 2024,qdae001.090, https://doi.org/10.1093/jsxmed/qdae001.090

8.       Manov A, Benge E. “Treatmentof male hypogonadism with clomiphene citrate: review article.”WorldJournal of Advanced Research and Reviews,2022, 14(03), 128–135.

9.       Rodriguez KM, Pastuszak AW, Lipshultz LI. “Enclomiphenecitrate for the treatment of secondary male hypogonadism.” ExpertOpin Pharmacother. 2016;17(11):1561-1567.doi:10.1080/14656566.2016.1204294

10.   Wiehle R, Fontenot G, Willet M et al. “EnclomipheneCitrate Stimulates Serum Testosterone in Men With Low Testosterone Within 14Days.” Journal of Men’sHealth.,2014; 11(4): https://doi.org/10.1089/jomh.2014.0006

11.   Clomiphene Citrate[package insert]. Spring Valley, NY. Par Pharmaceutical Companies Inc. UpdatedSeptember 23^rd 2010. Accessed April 16^th 2025.