madman
Super Moderator
Understanding and managing the suppression of spermatogenesis caused by testosterone replacement therapy (TRT) and anabolic–androgenic steroids (AAS) (2022)
Ankit Desai , Musaab Yassin, Axel Cayetano, Tharu Tharakan, Channa N. Jayasena and Suks Minhas
Abstract
The 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 the 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.
Introduction
The prevalence of male hypogonadism is increasing,1 and it is projected that as many as 6.5 million men in the United States will have symptomatic hypogonadism by 2025.2 This has led to a rise in the use of testosterone replacement therapy (TRT), with a 12-fold increase in worldwide sales of testosterone replacement preparations between 2000 and 2011,3 with approximately 12% of men seeking TRT during their prime reproductive years.4 Reflecting this trend, the expenditure on TRT in the United States quadrupled between 2007 (from $108 million) and 2016 (to over $400 million),5 despite a slight reduction in TRT prescriptions in 2014 due to the U.S. Food and Drug Agency (FDA) issuing a safety communication regarding the use of TRT in men with cardiovascular disease.6 Overall, this trend has coincided with more men presenting with infertility with a prior history of TRT use. A UK study showed that 7% of men with a current or prior history of TRT use were requesting treatment for infertility.6 In addition to this, the use of anabolic-androgenic steroids (AAS) has increased over the last 20–30 years largely among young men for muscle building and physique.7,8 While the detrimental impact of TRT and AAS on spermatogenesis is well recognized,7,9 awareness of these adverse effects among clinicians and patients is variable. Indeed, a survey of American urologists reported that 25% of participants would administer exogenous testosterone in cases of idiopathic male infertility.10 Although this is a survey from 2012 and may not accurately reflect the contemporary practice of urologists, it is important to note such a perception has featured among trained urologists within the past decade. Hence, a closer evaluation of the potential adverse effects on male fertility along with better awareness of the effects of these agents and the search for more novel therapies for treating male hypogonadism are needed.
Conversely, it is also important to appreciate the rationale behind the treatment of male hypogonadism and the proposed benefits TRT portends in men suffering from this condition. In this article, we will review the contemporary data for the pharmacotherapy of male hypogonadism, largely TRT and gonadotropins, and their effects on spermatogenesis. Moreover, we will describe the pharmacological and assisted reproductive strategies employed to address cases where there is a significant delay or failure of spermatogenesis to recover.
Background
To appreciate the rationale of the pharmacotherapy for male hypogonadism, it is important to understand the role of testosterone and other androgens in the maintenance of male reproductive physiology.
Physiological importance of androgens
-The hypothalamic-pituitary-gonadal (HPG) axis
-Mechanism of action of steroidal androgens
-Androgens and spermatogenesis
Suppression and recovery of spermatogenesis
*Recovery of spermatogenesis after TRT
*Anabolic-androgenic steroids
*Selective androgen receptor modulators (SARMs)
*Factors affecting rate of recovery
*Agents used to aid recovery of spermatogenesis
-Gonadotropins: HCG and FSH
-Selective oestrogen receptor modulators
-Aromatase inhibitors
Discussion
The growing prevalence of symptomatic male hypogonadism104 and the increasing number of prescriptions for TRT4 have raised concerns for male fertility.7,9 Despite the well-documented detrimental impact of these drugs on fertility, there seems to be a lack of awareness of this effect among those using them and, in some cases, clinicians with the ability to prescribe them.10 Alongside this, there is increasing use of AAS among young men seeking to improve muscle build and perceived physique.
Despite the relatively scant literature, natural recovery of spermatogenesis after TRT and AAS has been shown to occur in the vast majority of cases.7 However, as a general rule men seeking conception should avoid TRT/AAS, or if they are taking such agents, they must be discontinued immediately. Following this, the recovery of spermatogenesis may be a slow process, particularly in previously hypogonadal men with poor baseline testicular function, long history of TRT use or older age at cessation.7,40,57 This cohort of men or those with older female partners wanting to conceive as soon as possible will be suitable candidates for hormonal stimulation to speed up the recovery of spermatogenesis. HCG, being an analogue of LH, has the theoretical benefit of directly stimulating the testicle to raise ITT and hence sperm maturation. Whereas SERMs largely rely on inhibition of the negative feedback effect of circulating oestrogen on the anterior pituitary and hence stimulating gonadotropin release. CC is the most widely prescribed agent for this use.39 While the use of agents such as HCG and SERMs like CC has been well established to promote ovulation in women, their use in men to promote spermatogenesis is an off-licence treatment. Although there is some evidence demonstrating their efficacy in men, this largely stems from case series and non-randomized data.
While these agents have been used to aid recovery of spermatogenesis in men taking TRT or those previously having taken TRT/AAS, their use in this context is empirical. Although the theoretical basis is convincing, the data suggesting some efficacy of these agents in infertile men are mostly anecdotal and based on small retrospective series. There has yet to be a prospective randomized placebo-controlled trial that addresses the question of whether HCG ± rFSH or SERMs can effectively stimulate the recovery of spermatogenesis in this setting. Nevertheless, with the growing proportion of men who may not achieve spontaneous recovery after cessation of TRT/ASS, it is important for urologists and andrologists to counsel men thoroughly at the outset when contemplating TRT and be aware of these therapies, albeit with a limited evidence base. Other strategies for those wishing to preserve fertility may be discussed and should include treatment with HCG ± rFSH in hypogonadal men (instead of TRT) or sperm cryopreservation in those with viable sperm in the ejaculate. Those who remain azoospermic after cessation of TRT/AAS and have older female partners with a limited ovarian reserve may not be agreeable to initiating/completing a long trial of hormonal stimulation due to the limited time available for such couples to conceive. In such cases, consideration must be given to offering surgical sperm retrieval (SSR) with a view to assisted reproductive techniques such as in-vitro fertilization and intra-cytoplasmic sperm injection (IVF/ICSI).
Conclusion
The majority of men with a previous history of TRT and AAS use presenting with infertility will achieve recovery of spermatogenesis; however, this is not guaranteed and successful recovery after discontinuation of TRT/AAS is dependent on a number of patient-specific and treatment-specific factors. In those who do not achieve recovery of their fertility on cessation, additional agents such as HCG ± rFSH, SERMs or AIs can be trialled. These men must be counselled that should this fail to yield sperm in the ejaculate, they may need to proceed with SSR. Thus, there is some merit in discussing cryopreservation of sperm from the ejaculate before embarking on TRT/AAS, which may later preclude the need for SSR. In cases where patients have not had sperm cryopreserved previously and become azoospermic following TRT/AAS, they would require attempts at SSR with a view to implementing assisted reproductive techniques (e.g. IVF/ICSI) and hence should also form a key part of the informed counselling process. Furthermore, more robust randomized placebo-controlled data are needed to ascertain the true efficacy of hormonal agents in aiding the recovery of spermatogenesis after TRT/AAS as well as more novel agents such as SARMs.
Ankit Desai , Musaab Yassin, Axel Cayetano, Tharu Tharakan, Channa N. Jayasena and Suks Minhas
Abstract
The 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 the 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.
Introduction
The prevalence of male hypogonadism is increasing,1 and it is projected that as many as 6.5 million men in the United States will have symptomatic hypogonadism by 2025.2 This has led to a rise in the use of testosterone replacement therapy (TRT), with a 12-fold increase in worldwide sales of testosterone replacement preparations between 2000 and 2011,3 with approximately 12% of men seeking TRT during their prime reproductive years.4 Reflecting this trend, the expenditure on TRT in the United States quadrupled between 2007 (from $108 million) and 2016 (to over $400 million),5 despite a slight reduction in TRT prescriptions in 2014 due to the U.S. Food and Drug Agency (FDA) issuing a safety communication regarding the use of TRT in men with cardiovascular disease.6 Overall, this trend has coincided with more men presenting with infertility with a prior history of TRT use. A UK study showed that 7% of men with a current or prior history of TRT use were requesting treatment for infertility.6 In addition to this, the use of anabolic-androgenic steroids (AAS) has increased over the last 20–30 years largely among young men for muscle building and physique.7,8 While the detrimental impact of TRT and AAS on spermatogenesis is well recognized,7,9 awareness of these adverse effects among clinicians and patients is variable. Indeed, a survey of American urologists reported that 25% of participants would administer exogenous testosterone in cases of idiopathic male infertility.10 Although this is a survey from 2012 and may not accurately reflect the contemporary practice of urologists, it is important to note such a perception has featured among trained urologists within the past decade. Hence, a closer evaluation of the potential adverse effects on male fertility along with better awareness of the effects of these agents and the search for more novel therapies for treating male hypogonadism are needed.
Conversely, it is also important to appreciate the rationale behind the treatment of male hypogonadism and the proposed benefits TRT portends in men suffering from this condition. In this article, we will review the contemporary data for the pharmacotherapy of male hypogonadism, largely TRT and gonadotropins, and their effects on spermatogenesis. Moreover, we will describe the pharmacological and assisted reproductive strategies employed to address cases where there is a significant delay or failure of spermatogenesis to recover.
Background
To appreciate the rationale of the pharmacotherapy for male hypogonadism, it is important to understand the role of testosterone and other androgens in the maintenance of male reproductive physiology.
Physiological importance of androgens
-The hypothalamic-pituitary-gonadal (HPG) axis
-Mechanism of action of steroidal androgens
-Androgens and spermatogenesis
Suppression and recovery of spermatogenesis
*Recovery of spermatogenesis after TRT
*Anabolic-androgenic steroids
*Selective androgen receptor modulators (SARMs)
*Factors affecting rate of recovery
*Agents used to aid recovery of spermatogenesis
-Gonadotropins: HCG and FSH
-Selective oestrogen receptor modulators
-Aromatase inhibitors
Discussion
The growing prevalence of symptomatic male hypogonadism104 and the increasing number of prescriptions for TRT4 have raised concerns for male fertility.7,9 Despite the well-documented detrimental impact of these drugs on fertility, there seems to be a lack of awareness of this effect among those using them and, in some cases, clinicians with the ability to prescribe them.10 Alongside this, there is increasing use of AAS among young men seeking to improve muscle build and perceived physique.
Despite the relatively scant literature, natural recovery of spermatogenesis after TRT and AAS has been shown to occur in the vast majority of cases.7 However, as a general rule men seeking conception should avoid TRT/AAS, or if they are taking such agents, they must be discontinued immediately. Following this, the recovery of spermatogenesis may be a slow process, particularly in previously hypogonadal men with poor baseline testicular function, long history of TRT use or older age at cessation.7,40,57 This cohort of men or those with older female partners wanting to conceive as soon as possible will be suitable candidates for hormonal stimulation to speed up the recovery of spermatogenesis. HCG, being an analogue of LH, has the theoretical benefit of directly stimulating the testicle to raise ITT and hence sperm maturation. Whereas SERMs largely rely on inhibition of the negative feedback effect of circulating oestrogen on the anterior pituitary and hence stimulating gonadotropin release. CC is the most widely prescribed agent for this use.39 While the use of agents such as HCG and SERMs like CC has been well established to promote ovulation in women, their use in men to promote spermatogenesis is an off-licence treatment. Although there is some evidence demonstrating their efficacy in men, this largely stems from case series and non-randomized data.
While these agents have been used to aid recovery of spermatogenesis in men taking TRT or those previously having taken TRT/AAS, their use in this context is empirical. Although the theoretical basis is convincing, the data suggesting some efficacy of these agents in infertile men are mostly anecdotal and based on small retrospective series. There has yet to be a prospective randomized placebo-controlled trial that addresses the question of whether HCG ± rFSH or SERMs can effectively stimulate the recovery of spermatogenesis in this setting. Nevertheless, with the growing proportion of men who may not achieve spontaneous recovery after cessation of TRT/ASS, it is important for urologists and andrologists to counsel men thoroughly at the outset when contemplating TRT and be aware of these therapies, albeit with a limited evidence base. Other strategies for those wishing to preserve fertility may be discussed and should include treatment with HCG ± rFSH in hypogonadal men (instead of TRT) or sperm cryopreservation in those with viable sperm in the ejaculate. Those who remain azoospermic after cessation of TRT/AAS and have older female partners with a limited ovarian reserve may not be agreeable to initiating/completing a long trial of hormonal stimulation due to the limited time available for such couples to conceive. In such cases, consideration must be given to offering surgical sperm retrieval (SSR) with a view to assisted reproductive techniques such as in-vitro fertilization and intra-cytoplasmic sperm injection (IVF/ICSI).
Conclusion
The majority of men with a previous history of TRT and AAS use presenting with infertility will achieve recovery of spermatogenesis; however, this is not guaranteed and successful recovery after discontinuation of TRT/AAS is dependent on a number of patient-specific and treatment-specific factors. In those who do not achieve recovery of their fertility on cessation, additional agents such as HCG ± rFSH, SERMs or AIs can be trialled. These men must be counselled that should this fail to yield sperm in the ejaculate, they may need to proceed with SSR. Thus, there is some merit in discussing cryopreservation of sperm from the ejaculate before embarking on TRT/AAS, which may later preclude the need for SSR. In cases where patients have not had sperm cryopreserved previously and become azoospermic following TRT/AAS, they would require attempts at SSR with a view to implementing assisted reproductive techniques (e.g. IVF/ICSI) and hence should also form a key part of the informed counselling process. Furthermore, more robust randomized placebo-controlled data are needed to ascertain the true efficacy of hormonal agents in aiding the recovery of spermatogenesis after TRT/AAS as well as more novel agents such as SARMs.
