Understanding and managing the suppression of spermatogenesis caused by testosterone replacement therapy (TRT) and anabolic-androgenic steroids (AAS)

Abstract

Use of testosterone replacement therapy (TRT) and anabolic-androgenic steroids (AAS) has increased over the last 20 years, coinciding with an increase in men presenting with infertility and hypogonadism. Both agents have a detrimental effect on spermatogenesis and pose a clinical challenge in the setting of hypogonadism and infertility. Adding to this challenge is the paucity of data describing recovery of spermatogenesis on stopping such agents. The unwanted systemic side effects of these agents have driven the development of novel agents such as selective androgen receptor modulators (SARMs). Data showing natural recovery of spermatogenesis following cessation of TRT are limited to observational studies. Largely, these have shown spontaneous recovery of spermatogenesis after cessation. Contemporary literature suggests the time frame for this recovery is highly variable and dependent on several factors including baseline testicular function, duration of drug use and age at cessation. In some men, drug cessation alone may not achieve spontaneous recovery, necessitating hormonal stimulation with selective oestrogen receptor modulators (SERMs)/gonadotropin therapy or even the need for assisted reproductive techniques. However, there are limited prospective randomized data on the role of hormonal stimulation in this clinical setting. The use of hormonal stimulation with agents such as gonadotropins, SERMs, aromatase inhibitors and assisted reproductive techniques should form part of the counselling process in this cohort of hypogonadal infertile men. Moreover, counselling men regarding the detrimental effects of TRT/AAS on fertility is very important, as is the need for robust randomized studies assessing the long-term effects of novel agents such as SARMs and the true efficacy of gonadotropins in promoting recovery of spermatogenesis.

Keywords: anabolic–androgenic steroids (AAS); dihydrotestosterone (DHT); follicle-stimulating hormone (FSH); gonadotropins; hypogonadism; hypothalamic-pituitary-gonadal (HPG) axis; intratesticular testosterone (ITT); luteinizing hormone (LH); male infertility; selective androgen receptor modulators (SARMs); selective oestrogen receptor modulators (SERMs); spermatogenesis; testosterone; testosterone replacement therapy (TRT).

Figure 1.

Hypothalamic–pituitary–gonadal axis. Source: Adapted from Dorota J. Hawksworth, Burnett AL. Other hormonal therapies and men’s health.ABP, androgen-binding protein; E2, estradiol; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; SERM, selective oestrogen receptor modulator; T, testosterone.

Figure 2.

Classical pathway (left) and nonclassical pathway (right) of testosterone and other androgenic steroids acting on somatic cells. Source: Adapted from Walker. AR, androgen receptor; ARE, androgen response elements; CREB, cAMP(cyclic adenosine monophosphate) responsive element binding protein; EGFR, Epidermal growth factor receptor; HSP, heat-shock protein; P, Phosphate; T, testosterone.

Figure 3.

Cellular infrastructure of the seminiferous tubule and role of testosterone in spermatogenesis. Source: Adapted from Nishimura and L’Hernault. BTB, blood–testis barrier; LH, luteinizing hormone.

Figure 4.

Mechanism of action of SARMs. Source: Adapted from Solomon et al. AR, androgen receptor; ARE: androgen response element; HSP, heat-shock protein; SARMs, selective androgen receptor modulators.

Figure 5.

Molecular structure of LH, HCG and FSH – all have an identical alpha subunit with similarities in the beta-subunit between LH and HCG. All beta-subunits have varying degrees of N-linked glycosylations. Source: Adapted from Esteves, with permission granted via Creative Commons Attribution non-commercial 4.0 copyright public licence. FSH, follicle-stimulating hormone; HCG, human chorionic gonadotropin; LH, luteinizing hormone.