. Author manuscript; available in PMC: 2021 Feb 19.

Published in final edited form as: F S Rev. 2020 Nov 17;2(1):32–42. doi: 10.1016/j.xfnr.2020.11.001

Table 3.

Therapies that increase endogenous testosterone

Class	Mechanism of Action	Strengths	Limitations	References
Selective Estrogen Receptor Modulators (SERMs)	- Mixed estrogen agonist/antagonist properties in different tissues - In the pituitary gland, acts as an antagonist, thus stimulating the release of LH and FSH, which drive both testosterone production and spermatogenesis	- Successful in treatment of azoospermia, oligospermia, male hypogonadism, and unexplained male infertility	- Increased risk of thromboembolic events and carcinogenesis	El Meliegy et al. 2018 (56), Chehab et al. 2015 (57), Moein et al. 2012 (58), Martinkovich et al. 2014 (59), Pickar et al. 2010 (60)
Gonadotropins	- Mimics effects of endogenous gonadotropins and is particularly useful in the treatment of hypogonadotropic hypogonadism - Like endogenous gonadotropins, stimulates testosterone production and spermatogenesis	- Successful in treatment of hypogonadal men, while maintaining semen parameters, intratesticular testosterone, and fertility - Useful for preserving spermatogenesis in men undergoing exogenous TRT by maintaining intratesticular testosterone levels	- Side effects of gynecomastia, headache, fatigue, and mood changes	Pasqualotto et al. 2004 (38), Lee & Ramasamy 2018 (44), El Meliegy et al. 2018 (56), Dohle et al. 2016 (61), Crosnoe-Shipley et al. 2015 (62), Hsieh et al. 2013 (63), Coviello et al. 2005 (64)
Aromatase Inhibitors	- Blocks aromatase conversion of testosterone to estradiol, thereby increasing testosterone levels and normalizing the testosterone/estradiol ratio	- Useful in treating infertility in obese men with hypogonadotropic hypogonadism	- Potential increase in PSA level in elderly men with low or borderline hypogonadism - Limited long-term data to assess efficacy and adverse effects	Crosnoe et al. 2013 (55), El Meliegy et al. 2018 (56), Ribeiro et al. 2016 (65), Zumoff et al. 2003 (66), Leder et al. 2004 (67)
Selective Androgen Receptor Modulators (SARMs)	- Selective agonist of tissue-specific androgen receptors, mimicking the effect of testosterone in certain tissues	- Potential use in the treatment of male hypogonadism and infertility	- Currently in investigational phase; further studies are required to assess safety and efficacy	Bassil et al. 2009 (6), Narayanan et al. 2018 (68), Solomon et al. 2018 (69), Miner et al. 2007 (70), Bhasin & Jasuja 2009 (71)
Leydig Stem Cell Transplantation	- Leydig stem cells can differentiate into adult Leydig cells, which produce intratesticular testosterone under stimulation of LH	- Successful studies showing increased testosterone production in various animal models	- Further studies are required to prove effectiveness and safety in humans	Zang et al. 2017 (72), Beattie et al. 2015 (75), Mendis-Handagama & Ariyaratne 2001 (77), Chen et al. 2009 (78), Chen et al. 2010 (79), Jiang et al. 2014 (80), Zhang et al. 2017 (81), Arora et al. 2019 (82)