Testosterone Replacement and Hypogonadism: A Brief Review of APIs

Sarah Taylor, PharmD
Academy Director
June 22, 2022

Testosterone Replacement and Hypogonadism: A Brief Review of APIs that Modify Testosterone’s Metabolism in the Body

Testosterone replacement therapy is currently the standard of treatment for hypogonadism, however, testosterone replacement alone is not always sufficient due to the multiple metabolic pathways involved in the transformation or breakdown of testosterone.1

Testosterone is converted to estradiol via aromatase. Estrogens such as estradiol generate negative feedback to the hypothalamus and pituitary gland reducing the amount of follicle stimulating hormone (FSH) and luteinizing hormone (LH) secreted. This negative feedback loop resulting in reduction of FSH and LH (gonadotropins) decreases testosterone production which can compromise the utility of testosterone therapy alone for hypogonadism.1

Adjunct therapies such as aromatase inhibitors (anastrozole, letrozole etc.) or estrogen receptor antagonists (clomiphene, enclomiphene, tamoxifen, etc.), or GNRH antagonists such as sermorelin are sometimes used instead of or in combination with testosterone supplementation to prevent the negative feedback loop associated with estradiol.1,2

One study evaluating combination treatments with anastrozole and testosterone, concluded that anastrozole given in conjunction with testosterone replacement therapy kept estrogen levels low and attenuated adverse effects typically associated with elevated estrogen levels that can occur with testosterone replacement therapy alone.3

Other studies evaluating clomiphene citrate versus testosterone replacement therapy have noted the benefit of clomiphene for raising testosterone levels and combating hypogonadism.4 Though testosterone is necessary for spermatogenesis, exogenously administered testosterone, in the form of testosterone replacement therapy, can inhibit FSH and LH secretion by the pituitary gland, resulting in decreased spermatogenesis.2

Studies evaluating ingredients that work to prevent this adverse effect on spermatogenesis, including anastrozole and clomiphene among others, have demonstrated efficacy for increasing FSH or LH and improvements in spermatogenesis.4,5,6 To learn more about these active pharmaceutical ingredients (APIs) as well as others used for this purpose, check out a summary table of the listed APIs and the studied dosages and routes for each of these ingredients on our Fagron Academy site!

The topics and descriptions discussed within this presentation are not intended and should not be interpreted to make recommendations or claims regarding the use, efficacy, or safety of products, formulas, or vehicles. Only a physician or other appropriately licensed professional, as a learned intermediary, can determine if a formula, product or service is appropriate for a patient


1.        Ide V, Vanderschueren D, Antonio L. Treatment of Men with Central Hypogonadism: Alternatives for Testosterone Replacement Therapy. Int J Mol Sci. 2020;22(1):21. Published 2020 Dec 22. doi:10.3390/ijms22010021

2.       Rambhatla A, Mills JN, Rajfer J. The Role of Estrogen Modulators in Male Hypogonadism and Infertility. Rev Urol. 2016;18(2):66-72. doi:10.3909/riu0711

3.      Glaser RL, York AE. Subcutaneous Testosterone Anastrozole Therapy in Men: Rationale, Dosing, and Levels on Therapy. Int J Pharm Compd. 2019;23(4):325-339.

4.      Dadhich P, Ramasamy R, Scovell J, Wilken N, Lipshultz L. Testosterone versus clomiphene citrate in managing symptoms of hypogonadism in men. Indian J Urol. 2017;33(3):236-240. doi:10.4103/iju.IJU_372_16

5.      Shoshany O, Abhyankar N, Mufarreh N, Daniel G, Niederberger C. Outcomes of anastrozole in oligozoospermic hypoandrogenic subfertile men. Fertil Steril. 2017;107(3):589-594. doi:10.1016/j.fertnstert.2016.11.021

6.      Taylor F, Levine L. Clomiphene citrate and testosterone gel replacement therapy for male hypogonadism: efficacy and treatment cost. J Sex Med. 2010 Jan;7(1 Pt 1):269-76. doi: 10.1111/j.1743-6109.2009.01454.x. Epub 2009 Aug 17.

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Sarah Taylor, PharmD
Academy Director

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