madman
Super Moderator
Testosterone has a variety of functions and is commonly used in older men to treat symptoms of hypogonadism, such as decreased libido, decreased mood and erectile dysfunction. Despite its positive effects on sexual function, it has a negative effect on fertility. Exogenous testosterone therapy can negatively affect the hypothalamic-pituitary gonadal axis and inhibit the production of follicle stimulating hormone and luteinizing hormone. The purpose of this review is to discuss the contraceptive properties of testosterone therapy and to discuss strategies to increase testosterone in men with the desire to preserve fertility.
INTRODUCTION
Testosterone is a pleiotropic hormone that plays various physiological roles in the development of male genitalia in utero and during puberty. Classically, testosterone is a hormone associated with masculinity. Testosterone is used as treatment for males with late onset hypogonadism, a condition in men who experience symptoms caused by a decrease in serum testosterone. Symptoms associated with low testosterone can include decreased libido, decreased muscle mass, depressed mood and/or erectile dysfunction. The use of testosterone replacement therapy (TRT) among men over the age of 40 years has increased more than 3-fold over the last decade [1].
Exogenous testosterone comes in various preparations and each form carries various risks. Along with an increase in hematocrit, a major adverse effect of TRT is the diminished sperm production because of the decreased intra-testicular concentration of testosterone and suppression of the hypothalamic-pituitary-gonadal (HPG) axis [2-4]. Suppression of follicle stimulating hormone (FSH) release from the pituitary gland impairs sperm production and suppression of luteinizing hormone (LH) release inhibits intra-testicular testosterone production.
The purpose of this review is to evaluate the contraceptive effect of testosterone, discuss how the use of exogenous testosterone can negatively impact a man’s fecundity and identify the importance of family planning in men who are planning to receive TRT.
PHYSIOLOGY OF TESTOSTERONE
In healthy adult men, testosterone production is precisely regulated by the HPG axis. Higher cortical centers in the brain signal the hypothalamus to secrete gonadotropin-releasing hormone (GnRH) in a pulsatile fashion. GnRH in turn stimulates the release of LH and FSH from the anterior pituitary which modulates testosterone production from the Leydig cells and spermatogenesis by the Sertoli cells, respectively. As testosterone levels increase, negative feedback suppression is exerted on the androgen receptors in the hypothalamic neurons and pituitary gland, thereby inhibiting the release of GnRH, FSH and LH [5].
The Endocrine Society and American Urological Association (AUA) recommends treating symptomatic men with low testosterone documented on two morning fasting serum total testosterone concentrations. Both organizations recommend against the use of testosterone for treatment of hypogonadism in men who desire fertility in the next 6 to 12 months [3,4].
The exogenous administration of testosterone suppresses the release of gonadotropins (FSH and LH) to levels below that required for spermatogenesis. Spermatogenesis is largely dependent on the action of FSH on Sertoli cells coupled with high intra-testicular testosterone concentrations. Within the seminiferous tubules, only Sertoli cells possess receptors for both FSH and testosterone. Numerous signaling pathways are activated when FSH binds to FSH receptors on these cells. It acts synergistically with testosterone to increase fertility and the efficiency of spermatogenesis [6]. The inhibition of LH release by exogenous testosterone leads to the suppression of endogenous testosterone production by the Leydig cells. The decreased intra-testicular testosterone combined with the suppression of FSH leads to decreased germ cell survival and maturation (Fig. 1).
Intra-testicular testosterone is required in spermatogenesis for the formation of the blood-testis barrier (BTB). The BTB is a series of tight and adherens junctions between the Sertoli cells that separates postmeiotic germ cells in the adluminal compartment of the seminiferous tubules from the basal compartment containing the blood supply. During spermatogenesis, the BTB is disrupted and reformed as preleptotene spermatocytes pass through this barrier. In the absence of testosterone stimulation, spermatogenesis can only proceed as far as the prophase 1-leptotene stage of meiosis [7].
Testosterone is also required in maintaining connections between Sertoli cells and the haploid spermatid germ cells. Round spermatids are initially connected to Sertoli cells via desmosomes. As the spermatids mature and elongate, the desmosomes are replaced with stronger, specialized adherens junctions called ectoplasmic specializations, which are maintained until the release of mature sperm. Testosterone aids in this process and increases the efficiency of germ cell attachment to Sertoli cells. Testosterone is also essential for the release of mature spermatozoa from Sertoli cells. It has been shown that in the absence of testosterone stimulation, sperm are not released but are instead phagocytized by Sertoli cells [7].
Ultimately, the low intra-testicular testosterone results in decreased proliferation of spermatogonia, defects in spermiation of mature spermatozoa by Sertoli cells and accelerated apoptosis of spermatozoa [811]. Since 80% of testicular volume consists of germinal epithelium and seminiferous tubules, a reduction in these cells is usually manifested by testicular atrophy and this reflects the loss of both spermatogenesis and Leydig cell function [12,13].
Testosterone as a contraceptive can suppress spermatogenesis and lead to azoospermia in 65% of normospermic men within 4 months of use [14]. Cessation of exogenous testosterone will lead to the reversal of hormonally-induced azoospermia in 64% to 84% of men with a median time of about 110 days [13-15]. All men in these studies recovered to baseline levels after cessation of therapy; however, it took up to 2 years for some men to recover. These studies were performed in a controlled setting for a clinical trial, with a limited duration of testosterone use. In actual practice, recovery may not be as pronounced. Kohn et al [16] studied spermatogenesis recovery with human chorionic gonadotropin (hCG) and selective estrogen receptor modulators (SERM) in men with infertility associated with testosterone use. Thirty percent of the 66 men were not able to achieve a total motile sperm count of more than 5 million after 12 months in the study. They found that the failure of recovery is associated with older patients and longer TRT duration.
If fertility is affected because of TRT, couples may require the use of in vitro fertilization or intra-cytoplasmic sperm injection for future conception. These assistive reproductive technologies are expensive and are not always successful [17,18].
In summary, despite the androgenic effects of testosterone on sexual function, libido and mood; its effect on gonadotropins leads to the inhibition of sperm production [13]. This effect may diminish with the cessation of testosterone intake, but the extent of recovery is not clear for chronic users [16,19].
INTRODUCTION
Testosterone is a pleiotropic hormone that plays various physiological roles in the development of male genitalia in utero and during puberty. Classically, testosterone is a hormone associated with masculinity. Testosterone is used as treatment for males with late onset hypogonadism, a condition in men who experience symptoms caused by a decrease in serum testosterone. Symptoms associated with low testosterone can include decreased libido, decreased muscle mass, depressed mood and/or erectile dysfunction. The use of testosterone replacement therapy (TRT) among men over the age of 40 years has increased more than 3-fold over the last decade [1].
Exogenous testosterone comes in various preparations and each form carries various risks. Along with an increase in hematocrit, a major adverse effect of TRT is the diminished sperm production because of the decreased intra-testicular concentration of testosterone and suppression of the hypothalamic-pituitary-gonadal (HPG) axis [2-4]. Suppression of follicle stimulating hormone (FSH) release from the pituitary gland impairs sperm production and suppression of luteinizing hormone (LH) release inhibits intra-testicular testosterone production.
The purpose of this review is to evaluate the contraceptive effect of testosterone, discuss how the use of exogenous testosterone can negatively impact a man’s fecundity and identify the importance of family planning in men who are planning to receive TRT.
PHYSIOLOGY OF TESTOSTERONE
In healthy adult men, testosterone production is precisely regulated by the HPG axis. Higher cortical centers in the brain signal the hypothalamus to secrete gonadotropin-releasing hormone (GnRH) in a pulsatile fashion. GnRH in turn stimulates the release of LH and FSH from the anterior pituitary which modulates testosterone production from the Leydig cells and spermatogenesis by the Sertoli cells, respectively. As testosterone levels increase, negative feedback suppression is exerted on the androgen receptors in the hypothalamic neurons and pituitary gland, thereby inhibiting the release of GnRH, FSH and LH [5].
The Endocrine Society and American Urological Association (AUA) recommends treating symptomatic men with low testosterone documented on two morning fasting serum total testosterone concentrations. Both organizations recommend against the use of testosterone for treatment of hypogonadism in men who desire fertility in the next 6 to 12 months [3,4].
The exogenous administration of testosterone suppresses the release of gonadotropins (FSH and LH) to levels below that required for spermatogenesis. Spermatogenesis is largely dependent on the action of FSH on Sertoli cells coupled with high intra-testicular testosterone concentrations. Within the seminiferous tubules, only Sertoli cells possess receptors for both FSH and testosterone. Numerous signaling pathways are activated when FSH binds to FSH receptors on these cells. It acts synergistically with testosterone to increase fertility and the efficiency of spermatogenesis [6]. The inhibition of LH release by exogenous testosterone leads to the suppression of endogenous testosterone production by the Leydig cells. The decreased intra-testicular testosterone combined with the suppression of FSH leads to decreased germ cell survival and maturation (Fig. 1).
Intra-testicular testosterone is required in spermatogenesis for the formation of the blood-testis barrier (BTB). The BTB is a series of tight and adherens junctions between the Sertoli cells that separates postmeiotic germ cells in the adluminal compartment of the seminiferous tubules from the basal compartment containing the blood supply. During spermatogenesis, the BTB is disrupted and reformed as preleptotene spermatocytes pass through this barrier. In the absence of testosterone stimulation, spermatogenesis can only proceed as far as the prophase 1-leptotene stage of meiosis [7].
Testosterone is also required in maintaining connections between Sertoli cells and the haploid spermatid germ cells. Round spermatids are initially connected to Sertoli cells via desmosomes. As the spermatids mature and elongate, the desmosomes are replaced with stronger, specialized adherens junctions called ectoplasmic specializations, which are maintained until the release of mature sperm. Testosterone aids in this process and increases the efficiency of germ cell attachment to Sertoli cells. Testosterone is also essential for the release of mature spermatozoa from Sertoli cells. It has been shown that in the absence of testosterone stimulation, sperm are not released but are instead phagocytized by Sertoli cells [7].
Ultimately, the low intra-testicular testosterone results in decreased proliferation of spermatogonia, defects in spermiation of mature spermatozoa by Sertoli cells and accelerated apoptosis of spermatozoa [811]. Since 80% of testicular volume consists of germinal epithelium and seminiferous tubules, a reduction in these cells is usually manifested by testicular atrophy and this reflects the loss of both spermatogenesis and Leydig cell function [12,13].
Testosterone as a contraceptive can suppress spermatogenesis and lead to azoospermia in 65% of normospermic men within 4 months of use [14]. Cessation of exogenous testosterone will lead to the reversal of hormonally-induced azoospermia in 64% to 84% of men with a median time of about 110 days [13-15]. All men in these studies recovered to baseline levels after cessation of therapy; however, it took up to 2 years for some men to recover. These studies were performed in a controlled setting for a clinical trial, with a limited duration of testosterone use. In actual practice, recovery may not be as pronounced. Kohn et al [16] studied spermatogenesis recovery with human chorionic gonadotropin (hCG) and selective estrogen receptor modulators (SERM) in men with infertility associated with testosterone use. Thirty percent of the 66 men were not able to achieve a total motile sperm count of more than 5 million after 12 months in the study. They found that the failure of recovery is associated with older patients and longer TRT duration.
If fertility is affected because of TRT, couples may require the use of in vitro fertilization or intra-cytoplasmic sperm injection for future conception. These assistive reproductive technologies are expensive and are not always successful [17,18].
In summary, despite the androgenic effects of testosterone on sexual function, libido and mood; its effect on gonadotropins leads to the inhibition of sperm production [13]. This effect may diminish with the cessation of testosterone intake, but the extent of recovery is not clear for chronic users [16,19].
