madman
Super Moderator
Abstract: Strategies exist that can mitigate the risk of causing iatrogenic infertility when men require testosterone replacement therapy (TRT). This article reviews the current medical therapies that preserve spermatogenesis when TRT is indicated. Furthermore, we highlight the re-emerging concept of hypothalamic-pituitary-gonadal (HPG) axis reset in hypergonadotrophic, hypogonadal infertile men who are planning sperm retrieval procedures. Finally, we present our hypothesis for a novel protocol to optimize hypergonadotrophic hypogonadal men before sperm extraction surgeries hormonally.
Physiology of the HPG axis
Male fertility and proper functioning of the HPG axis are closely intertwined. Spermatogenesis depends on the pulsatile release of gonadotropins, follicle stimulating hormone (FSH), and luteinizing hormone (LH), from the pituitary, and their action on their cells in the testis. FSH signals to FSH receptors (FSHR) on Sertoli cells to initiate spermatogenesis, whereas LH signals to LH receptors (LHR) on Leydig cells to produce intratesticular testosterone (2). The qualitative and quantitative integrity of these receptors plays an equally significant role in the regulation of spermatogenesis. Unsurprisingly, inactivating mutations of the FSHR and LHR results in impaired fertility (3,4). However, gonadotrophic overstimulation can also have a detrimental effect on spermatogenesis by downregulating the expression of LHR and FSHR (5). This effect may explain the clinical observations of Ross et al., who observed a reversible decline in sperm motility following high dose administration of selective estrogen receptor modulators (SERMs), which function by increasing the gonadotropin levels (6).
High intratesticular testosterone (ITT) levels maintain the spermatogenic process and prevent germ cell death (7). Low ITT levels result in an impaired blood-testis barrier permitting immune cells to enter the seminiferous tubules and attack autoantigenic germ cells [reviewed by Walker (8)]. Low intratesticular testosterone levels also block the conversion of round spermatids to elongating spermatogonia and prevent spermiation, leading to phagocytosis of spermatids by Sertoli cells (8,9).
It is well established that exogenous testosterone therapy causes azoospermia in the majority of men (10). Exogenous testosterone’s contraceptive effect occurs through its suppression of the HPG axis, preventing LH and FSH release and their respective gonadal functions (11). Studies examining the reproductive outcomes and rates of azoospermia development of various testosterone treatment modalities show less detrimental effects with testosterone patches [24% rate of azoospermia (12)] compared to intramuscular injections of testosterone enanthate, which result in up to an 98% rate of combined azoospermia and oligozoospermia (≤3 million/cc) after 1 year of therapy (13).
In a male contraceptive study, Coviello et al. followed seven healthy men with serum hormone assessments and percutaneous testicular aspirates to assess intratesticular hormone levels (14). They showed a 98% suppression of LH, 97% suppression of FSH, and 93% suppression of intratesticular androgenic bioactivity levels following weekly administrations of intramuscular testosterone enanthate (TE) 100 mg with levonorgestrel over a 6-month treatment period compared to baseline. Levonorgestrel was administered to suppress the HPG axis further. One subject failed to suppress spermatogenesis with a nadir sperm count of 3.4 mill/mL despite a reduction in his ITT level from 1,607 to 29 nmol/L (98% reduction). This study demonstrates the heterogeneity in TRT’s contraceptive effect and the variability in intratesticular testosterone levels necessary for spermatogenesis to occur. Conversely, recovery of the HPG axis function following testosterone therapy cessation is possible but can take between 110 days and 2 years (15,16).
*Strategies to preserve fertility when testosterone therapy cannot be stopped
-HCG
-Selective estrogen receptor modulators and aromatase inhibitors
-Nasal testosterone
*HPG axis reset—a new tool in our armamentarium?
*Additional evidence for HPG axis reset: an independent case series
Conclusions
Keeping men on TRT fertile has proven to be difficult for male fertility specialists. When the option of avoiding testosterone with alternative therapies, such as clomiphene citrate, aromatase inhibitors, and human chorionic gonadotropin, is not possible, some strategies can mitigate the negative impact of TRT on spermatogenesis. It is important to note that these therapies are not well established, possess limitations in their applicability, and carry side effects.
Novel methods of treating hypogonadal symptoms and keeping men fertile include the use of nasal testosterone and resetting the HPG axis with TRT and controlled administration of HCG. While preliminary results suggest that these methods may increase success for fertility treatments, more extensive research is needed to demonstrate the efficacy and safety of these therapies. The most recent evidence provides hope for the future of male fertility in patients that require TRT.
Physiology of the HPG axis
Male fertility and proper functioning of the HPG axis are closely intertwined. Spermatogenesis depends on the pulsatile release of gonadotropins, follicle stimulating hormone (FSH), and luteinizing hormone (LH), from the pituitary, and their action on their cells in the testis. FSH signals to FSH receptors (FSHR) on Sertoli cells to initiate spermatogenesis, whereas LH signals to LH receptors (LHR) on Leydig cells to produce intratesticular testosterone (2). The qualitative and quantitative integrity of these receptors plays an equally significant role in the regulation of spermatogenesis. Unsurprisingly, inactivating mutations of the FSHR and LHR results in impaired fertility (3,4). However, gonadotrophic overstimulation can also have a detrimental effect on spermatogenesis by downregulating the expression of LHR and FSHR (5). This effect may explain the clinical observations of Ross et al., who observed a reversible decline in sperm motility following high dose administration of selective estrogen receptor modulators (SERMs), which function by increasing the gonadotropin levels (6).
High intratesticular testosterone (ITT) levels maintain the spermatogenic process and prevent germ cell death (7). Low ITT levels result in an impaired blood-testis barrier permitting immune cells to enter the seminiferous tubules and attack autoantigenic germ cells [reviewed by Walker (8)]. Low intratesticular testosterone levels also block the conversion of round spermatids to elongating spermatogonia and prevent spermiation, leading to phagocytosis of spermatids by Sertoli cells (8,9).
It is well established that exogenous testosterone therapy causes azoospermia in the majority of men (10). Exogenous testosterone’s contraceptive effect occurs through its suppression of the HPG axis, preventing LH and FSH release and their respective gonadal functions (11). Studies examining the reproductive outcomes and rates of azoospermia development of various testosterone treatment modalities show less detrimental effects with testosterone patches [24% rate of azoospermia (12)] compared to intramuscular injections of testosterone enanthate, which result in up to an 98% rate of combined azoospermia and oligozoospermia (≤3 million/cc) after 1 year of therapy (13).
In a male contraceptive study, Coviello et al. followed seven healthy men with serum hormone assessments and percutaneous testicular aspirates to assess intratesticular hormone levels (14). They showed a 98% suppression of LH, 97% suppression of FSH, and 93% suppression of intratesticular androgenic bioactivity levels following weekly administrations of intramuscular testosterone enanthate (TE) 100 mg with levonorgestrel over a 6-month treatment period compared to baseline. Levonorgestrel was administered to suppress the HPG axis further. One subject failed to suppress spermatogenesis with a nadir sperm count of 3.4 mill/mL despite a reduction in his ITT level from 1,607 to 29 nmol/L (98% reduction). This study demonstrates the heterogeneity in TRT’s contraceptive effect and the variability in intratesticular testosterone levels necessary for spermatogenesis to occur. Conversely, recovery of the HPG axis function following testosterone therapy cessation is possible but can take between 110 days and 2 years (15,16).
*Strategies to preserve fertility when testosterone therapy cannot be stopped
-HCG
-Selective estrogen receptor modulators and aromatase inhibitors
-Nasal testosterone
*HPG axis reset—a new tool in our armamentarium?
*Additional evidence for HPG axis reset: an independent case series
Conclusions
Keeping men on TRT fertile has proven to be difficult for male fertility specialists. When the option of avoiding testosterone with alternative therapies, such as clomiphene citrate, aromatase inhibitors, and human chorionic gonadotropin, is not possible, some strategies can mitigate the negative impact of TRT on spermatogenesis. It is important to note that these therapies are not well established, possess limitations in their applicability, and carry side effects.
Novel methods of treating hypogonadal symptoms and keeping men fertile include the use of nasal testosterone and resetting the HPG axis with TRT and controlled administration of HCG. While preliminary results suggest that these methods may increase success for fertility treatments, more extensive research is needed to demonstrate the efficacy and safety of these therapies. The most recent evidence provides hope for the future of male fertility in patients that require TRT.
