Enclomiphene, an isomer of the medication clomid, has recently picked up steam as an alternative to testosterone replacement therapy.
For background, testosterone production occurs at the end of a chain of biological processes. The hypothalamus, a gland in the center of the brain, secretes something called gonadotropin-releasing hormone (GnRH). GnRH then signals for the pituitary, another gland in the brain, to release, wait for it… gonadotropins. The gonadotropins in men are luteinizing hormone (LH) and follicle stimulating hormone (FSH). FSH stimulates sperm production by acting upon sertoli cells, while LH acts on leydig cells and stimulates testosterone production. Both types of these cells are found in the testicles. Testosterone is converted into both estrogen through aromatase, and DHT through 5 alpha-reductase. Testosterone and estrogen, as well inhibin from Sertoli cells, provide negative feedback to the hypothalamus and pituitary. Selective estrogen receptor modulators (SERMs) prevent estrogen from binding to the pituitary and hypothalamus, resulting in an increase of GnRH, LH and FSH secretion and raise testosterone levels. They’ve been in those with type two hypogonadism for a while [1].
Clomid is a SERM that was introduced in the 60s as a treatment for female infertility. It’s been used off label to treat hypogonadal men as far back as the late 70s [2]. It’s also commonly been used as a part of post cycle therapies (use of medication to restore function after steroid use) by bodybuilders and powerlifters [3]. It’s composed of the two isomers (compounds of the same molecular composition but different arrangement), enclomiphene and zuclomiphene.
The primary issue with Clomid itself is that it both antagonizes and agonizes the estrogen receptor, due to its isomer zuchlomiphene [4]. It’s also been shown that zuclomiphene has a significantly longer half life than enclomiphene, these being 14* days and 10 hours [5]. While the ratio of zuclomiphene to enclomiphene in clomid is roughly 38% to 62%, the differences in half lives can lead to higher amounts of zuclomiphene building up in serum and tissue[6], which has been shown to have undesirable effects according to a 2015 study[7]. In this study researchers gave high and low doses of clomid’s two isomers to male mice. The group receiving high dose zuclomiphene saw severe testicular degradation, as well as a lack of sperm in the epididymis [7]. Given zuclomiphene’s ability to accumulate in the body as well it’s negative side effects at high dosages, it would appear that clomid is not a good TRT alternative. This leads to the conclusion that enclomiphene alone would be better suited towards this use.
There are some key points to keep in mind with using enclomiphene as an alternative to testosterone replacement, however. In the states enclomiphene isn’t an FDA approved medication and is prescribed off-label, as it’s a derivative. Although medications not being FDA approved doesn’t necessarily mean there is a lack of research into their efficacy. “Off-label” prescription also isn’t as uncommon as the term might make it sound. Even so, I haven’t come across any long term data on enclomiphene being used for any purpose. In my opinion, this should lead to some reluctance to use it long term. That being said, I think enclomiphene can have a place in short term hormone and fertility optimization, such as improving fertility while on TRT, or immediately after a cycle. Another use case could potentially be in obese men looking to optimize their hormone levels to aid in weight loss and increase overall health.
[1] Krzastek SC, Smith RP. Non-testosterone management of male hypogonadism: an examination of the existing literature. Transl Androl Urol. 2020 Mar;9(Suppl 2):S160-S170. doi: 10.21037/tau.2019.11.16. PMID: 32257856; PMCID: PMC7108991.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108991/
[2] Paulson DF, Wacksman J. Clomiphene citrate in the management of male infertility. J Urol. 1976 Jan;115(1):73-6. doi: 10.1016/s0022-5347(17)59072-2. PMID: 1246117.https://pubmed.ncbi.nlm.nih.gov/1246117/
[3] Tan RS, Vasudevan D. Use of clomiphene citrate to reverse premature andropause secondary to steroid abuse. Fertil Steril. 2003 Jan;79(1):203-5. doi: 10.1016/s0015-0282(02)04550-8. PMID: 12524089.https://pubmed.ncbi.nlm.nih.gov/12524089/
[4] Fitzpatrick SL, Berrodin TJ, Jenkins SF, Sindoni DM, Deecher DC, Frail DE. Effect of estrogen agonists and antagonists on induction of progesterone receptor in a rat hypothalamic cell line. Endocrinology. 1999 Sep;140(9):3928-37. doi: 10.1210/endo.140.9.7006. PMID: 10465261.]https://academic.oup.com/endo/article/140/9/3928/2990493?login=false
[5] Fontenot GK, Wiehle RD, Hsu K, et al. The Isomers of Clomiphene Citrate have Dissimilar Dispositions Once Ingested: Results of a Mouse ADME Study. Adv Tech Clin Microbiol. 2017, 1:1.https://www.imedpub.com/articles/the-isomers-of-clomiphene-citrate-have-dissimilar-dispositions-once-ingestedresults-of-a-mouse-adme-study.php?aid=18622
[6] Mikkelson TJ, Kroboth PD, Cameron WJ, Dittert LW, Chungi V, Manberg PJ. Single-dose pharmacokinetics of clomiphene citrate in normal volunteers. Fertil Steril. 1986 Sep;46(3):392-6. doi: 10.1016/s0015-0282(16)49574-9. PMID: 3091405.https://pubmed.ncbi.nlm.nih.gov/3091405/
[7] Fontenot GK, Wiehle RD, Podolski JS. Differential effects of isomers of clomiphene citrate on reproductive tissues in male mice. BJU Int. 2016 Feb;117(2):344-50. doi: 10.1111/bju.13244. Epub 2015 Sep 7. PMID: 26220499.https://pubmed.ncbi.nlm.nih.gov/26220499/
Leave a Reply