Non-testosterone management of male hypogonadism: an examination of the existing literature

Abstract

Testosterone deficiency is defined as a total testosterone level <300 ng/dL confirmed on two early morning lab draws. Testosterone therapy has historically been offered to men with symptomatic testosterone deficiency in the form of injections, gels, or pellets. However, these treatments are invasive or have undesirable effects including the risk of drug transference. Additionally, testosterone therapy has been associated with increases in hematocrit and controversy remains regarding the risk of cardiovascular and thromboembolic events while on testosterone therapy. As such, much interest has recently been focused on alternative treatment options for testosterone deficiency in the form of orally-administered medications with more favorable side effect profiles. Lifestyle modifications and varicocelectomy have been shown to raise endogenous testosterone production. Similarly, SERMs and aromatase inhibitors (AIs) have been shown to raise testosterone levels safely and effectively. Human chorionic gonadotropin (hCG) remains the only FDA-approved non-testosterone treatment option for testosterone deficiency in men. However, this medication is expensive and requires patient-administered injections. Over the counter herbal supplements and designer steroids remain available though they are poorly studied and are associated with the potential for abuse as well as increased hepatic and cardiovascular risks. This review aims to discuss the existing treatment alternatives to traditional testosterone therapy, including efficacy, safety, and side effects of these options. The authors suggest that the SERM clomiphene citrate (CC) holds the greatest promise as a non-testosterone treatment option for testosterone deficiency.

Keywords: Aromatase inhibitors (AIs); gonadotropins; hypogonadism; selective estrogen receptor modulators (SERMs); testosterone.

Figure 1

Hypothalamus-pituitary-gonadal axis. The hypothalamus releases GnRH in a pulsatile fashion, which stimulates the anterior pituitary to release LH and FSH to stimulate testosterone production and spermatogenesis in the testis. Testosterone negatively feeds back on the pituitary to suppress LH release. GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; FSH, follicle stimulating hormone.

Figure 2

The effect of exogenous testosterone on the HPG axis. Exogenous testosterone suppresses the release of GnRH and LH, resulting in testicular atrophy and suppression of spermatogenesis. HPG, hypothalamic-pituitary-gonadal; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; FSH, follicle stimulating hormone.

Figure 3

Steroid regulation pathway. Adapted from Kovac JR, Pan M, Arent S, et al. Dietary Adjuncts for Improving Testosterone Levels in Hypogonadal Males. Am J Mens Health 2016;10:NP109-17. copyright © 2016 by © SAGE Publications; Reprinted by Permission of SAGE Publications, Inc.

Figure 4

Sites of action of SERMs, aromatase inhibitors, and hCG in the HPG axis. SERMs, selective estrogen receptor modulators; hCG, human chorionic gonadotropin; HPG, hypothalamic-pituitary-gonadal; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; FSH, follicle stimulating hormone.