madman
Super Moderator
Kevin J Campbell, John F. Sullivan, Larry I. Lipshultz
Abstract
The prevalence of hypogonadism is an increasing problem that affects increasingly more men of reproductive age. With the mainstay of hypogonadal treatment involving testosterone therapy (TTh), the fertility potential of many of these men must be investigated and considered accordingly. There exist multiple treatments for the recovery of anabolic steroid-induced hypogonadism, including gonadotropin replacement therapy to induce both spermatogeneses as well as intratesticular testosterone production. The use of follicular stimulating hormone (FSH) has been reported to decrease the time to recovery of spermatogenesis in anabolic steroid-induced azoospermia. A new formulation of testosterone in the form of tri-daily applied intranasal testicular gel mimics gonadotropin-releasing hormone (GnRH) pulsatile release of luteinizing hormone (LH) to promote the production of testosterone and decreases feedback inhibition of spermatogenesis. Additionally, immature testicular tissue transplant may aid in fertility preservation for patients anticipating significant suppression of spermatogenesis.
Introduction
Hypogonadism is a clinical condition characterized by low serum testosterone levels in addition to global symptoms which include malaise, fatigue, decreased libido, erectile dysfunction, and mood changes. Hypogonadism has also been linked to osteoporosis, cardiovascular disease, and early-onset diabetes [1].
As has been previously discussed, testosterone therapy (TTh) may be initiated in the male for a myriad of reasons, including but not limited to, primary and secondary hypogonadism, testosterone deficiency in the aging male, and to optimize body musculature [2]. The use of TTh for hypogonadism continues to grow and more younger men are now receiving treatment; as many as 12.4% of all testosterone prescriptions are written for men <39 years of age [3]. Anabolic steroid-induced infertility is a commonly seen diagnosis in the male of reproductive age who presents to a men’s health clinic. An estimated 3 million men are on TTh; however, exogenous testosterone use can disrupt the hypothalamus-pituitary-gonadal (HPG) axis and markedly impair spermatogenesis [4].
With the use of exogenous TTh, the HPG axis becomes quiescent and endogenous testosterone production ceases. In addition, in most men, there is the cessation of sperm production within the testes due to decreased gonadotropin secretion [5]. In men who have previously taken TTh and now desire fertility, various pharmacological agents are employed to stimulate endogenous testosterone production and restore spermatogenesis [2]. It has previously been reported that the use of human chorionic gonadotropin (hCG) in addition to selective estrogen receptor modulators (SERMs) such as clomiphene citrate has been shown to result in the return of sperm to the ejaculate in testosterone-induced azoospermia [6] (Figure 1).
The spontaneous recovery of spermatogenesis after cessation of TTh is possible but may take months to years and the associated hypogonadal symptoms can be devastating. HCG is a naturally occurring protein that mimics LH and may be used as a therapy to support the return of spermatogenesis quickly with minimal side effects [6]. Studies have shown that testosterone-induced infertile patients can recover sperm in the ejaculate when treated with HCG combined with clomiphene citrate, tamoxifen, anastrozole, or FSH [2,6].
Follicle Stimulating Hormone
Testosterone is synthesized and secreted by the testicular interstitial Leydig cells. The process of spermatogenesis takes 72- 74 days and is dependent on high concentrations of intratesticular testosterone of approximately 40-fold higher than the serum testosterone levels [7]. Follicular stimulating hormone (FSH) greatly enhances spermatogenesis by stimulating the functions of Sertoli cells and increasing mitoses of spermatogonia. Once mitosis has been initiated in spermatogonia, testosterone alone can maintain spermatogenesis.
Enclomiphene
Clomiphene citrate has been used as an agent to increase sex hormones LH and FSH and intratesticular testosterone in hypogonadal men. In the anabolic-steroid induced hypogonadal male, gonadotropins are routinely low due to negative feedback from elevated levels of exogenous androgens. Enclomiphene citrate is a transisomer of clomiphene citrate that has been proposed as a treatment in men with secondary hypogonadism. The single isomer of enclomiphene demonstrates pure estrogen antagonism and has improved activity compared to a mixture of isomers found in clomiphene in both antagonism and agonism activities.
Intranasal Testosterone
The use of TTh in a dose-dependent and pulsatile-mimicking application cycle is a current area of focus for researchers seeking to combat hypogonadal symptoms in men trying to recover spermatogenesis following the withdrawal of conventional TTh. With the cessation of TTh, these patients are often rendered symptomatically hypogonadal. Recent preliminary results show the potential to offset hypogonadism symptoms that accompany exogenous testosterone cessation through the administration of intranasal testosterone gel [8,11].
Natesto is a nasal administered exogenous 4.5% testosterone gel, administered from a non-pressurized, manual pump dispenser with a specialized nasal applicator that administers 125 uL (5.5mg of testosterone). Previous studies have shown that a single nasal dose has a rapid absorption with a Tmax at 60 minutes, a half-life that ranged between 10-100 minutes [12]. Three to four daily doses achieve eugonadal levels of circulating testosterone comparable to the normal pulsatile regulated release of testosterone. It has also been suggested that men on Natesto maintain FSH and LH levels as well as total motile sperm counts with a normal range [8,11].
Additional Therapies
The pathology in anabolic steroid-induced azoospermia begins its reversal with the removal of the offending agent and the induction of spermatogenesis is then augmented with supplemental agents. Though the removal of the steroids may be all that is needed for the recovery of spermatogenesis, there are other factors to consider which may be contributors to the azoospermia.
Varicocele
A varicocele is present in 15% of the male population and may be found in 19-40% of men as a citing factor in men who present to an infertility clinic [13]. Varicoceles are dilations of the veins of the pampiniform plexus thought to be caused by increases in vascular pressure from anatomical variants or abnormalities in the normal anti-reflux venous system. The vascular dilation leads to the pooling of blood in close proximity to the testicle. The temperature of the testicle increases and may lead to decreases in spermatogenesis as well as testosterone production [13]. Varicoceles may be the contributing factor in approximately 5% of males with azoospermia [14].
Stem cell transplants
Immature testicular tissue transplant may aid in fertility preservation for patients anticipating suppression of spermatogenesis.
Conclusion
There exist multiple strategies in the andrologist’s armamentarium to aid in the recovery or maintenance of spermatogenesis following impairment from anabolic steroids, anatomical variants, or gonadotoxic onco-therapeutics. Sperm cryopreservation is the best pre-treatment for future fertility, as in the case of patients anticipating suppression of spermatogenesis. However, many patients present post-therapy with a desire to restore spermatogenesis after the initial insult has occurred. The recovery of spermatogenesis in these patients is linked with the interplay between hormones within the HPG. HCG, SERMs, and FSH offer direct and indirect testicular signaling to induce spermatogenesis and the recovery or maintenance of fertility. In these cases, cessation of testosterone often renders the patient hypogonadal. Novel therapies as with FSH, enclomiphene citrate, and intranasal testosterone offer exciting strategies to combat hypogonadal symptoms while enhancing spermatogenic potential.
Abstract
The prevalence of hypogonadism is an increasing problem that affects increasingly more men of reproductive age. With the mainstay of hypogonadal treatment involving testosterone therapy (TTh), the fertility potential of many of these men must be investigated and considered accordingly. There exist multiple treatments for the recovery of anabolic steroid-induced hypogonadism, including gonadotropin replacement therapy to induce both spermatogeneses as well as intratesticular testosterone production. The use of follicular stimulating hormone (FSH) has been reported to decrease the time to recovery of spermatogenesis in anabolic steroid-induced azoospermia. A new formulation of testosterone in the form of tri-daily applied intranasal testicular gel mimics gonadotropin-releasing hormone (GnRH) pulsatile release of luteinizing hormone (LH) to promote the production of testosterone and decreases feedback inhibition of spermatogenesis. Additionally, immature testicular tissue transplant may aid in fertility preservation for patients anticipating significant suppression of spermatogenesis.
Introduction
Hypogonadism is a clinical condition characterized by low serum testosterone levels in addition to global symptoms which include malaise, fatigue, decreased libido, erectile dysfunction, and mood changes. Hypogonadism has also been linked to osteoporosis, cardiovascular disease, and early-onset diabetes [1].
As has been previously discussed, testosterone therapy (TTh) may be initiated in the male for a myriad of reasons, including but not limited to, primary and secondary hypogonadism, testosterone deficiency in the aging male, and to optimize body musculature [2]. The use of TTh for hypogonadism continues to grow and more younger men are now receiving treatment; as many as 12.4% of all testosterone prescriptions are written for men <39 years of age [3]. Anabolic steroid-induced infertility is a commonly seen diagnosis in the male of reproductive age who presents to a men’s health clinic. An estimated 3 million men are on TTh; however, exogenous testosterone use can disrupt the hypothalamus-pituitary-gonadal (HPG) axis and markedly impair spermatogenesis [4].
With the use of exogenous TTh, the HPG axis becomes quiescent and endogenous testosterone production ceases. In addition, in most men, there is the cessation of sperm production within the testes due to decreased gonadotropin secretion [5]. In men who have previously taken TTh and now desire fertility, various pharmacological agents are employed to stimulate endogenous testosterone production and restore spermatogenesis [2]. It has previously been reported that the use of human chorionic gonadotropin (hCG) in addition to selective estrogen receptor modulators (SERMs) such as clomiphene citrate has been shown to result in the return of sperm to the ejaculate in testosterone-induced azoospermia [6] (Figure 1).
The spontaneous recovery of spermatogenesis after cessation of TTh is possible but may take months to years and the associated hypogonadal symptoms can be devastating. HCG is a naturally occurring protein that mimics LH and may be used as a therapy to support the return of spermatogenesis quickly with minimal side effects [6]. Studies have shown that testosterone-induced infertile patients can recover sperm in the ejaculate when treated with HCG combined with clomiphene citrate, tamoxifen, anastrozole, or FSH [2,6].
Follicle Stimulating Hormone
Testosterone is synthesized and secreted by the testicular interstitial Leydig cells. The process of spermatogenesis takes 72- 74 days and is dependent on high concentrations of intratesticular testosterone of approximately 40-fold higher than the serum testosterone levels [7]. Follicular stimulating hormone (FSH) greatly enhances spermatogenesis by stimulating the functions of Sertoli cells and increasing mitoses of spermatogonia. Once mitosis has been initiated in spermatogonia, testosterone alone can maintain spermatogenesis.
Enclomiphene
Clomiphene citrate has been used as an agent to increase sex hormones LH and FSH and intratesticular testosterone in hypogonadal men. In the anabolic-steroid induced hypogonadal male, gonadotropins are routinely low due to negative feedback from elevated levels of exogenous androgens. Enclomiphene citrate is a transisomer of clomiphene citrate that has been proposed as a treatment in men with secondary hypogonadism. The single isomer of enclomiphene demonstrates pure estrogen antagonism and has improved activity compared to a mixture of isomers found in clomiphene in both antagonism and agonism activities.
Intranasal Testosterone
The use of TTh in a dose-dependent and pulsatile-mimicking application cycle is a current area of focus for researchers seeking to combat hypogonadal symptoms in men trying to recover spermatogenesis following the withdrawal of conventional TTh. With the cessation of TTh, these patients are often rendered symptomatically hypogonadal. Recent preliminary results show the potential to offset hypogonadism symptoms that accompany exogenous testosterone cessation through the administration of intranasal testosterone gel [8,11].
Natesto is a nasal administered exogenous 4.5% testosterone gel, administered from a non-pressurized, manual pump dispenser with a specialized nasal applicator that administers 125 uL (5.5mg of testosterone). Previous studies have shown that a single nasal dose has a rapid absorption with a Tmax at 60 minutes, a half-life that ranged between 10-100 minutes [12]. Three to four daily doses achieve eugonadal levels of circulating testosterone comparable to the normal pulsatile regulated release of testosterone. It has also been suggested that men on Natesto maintain FSH and LH levels as well as total motile sperm counts with a normal range [8,11].
Additional Therapies
The pathology in anabolic steroid-induced azoospermia begins its reversal with the removal of the offending agent and the induction of spermatogenesis is then augmented with supplemental agents. Though the removal of the steroids may be all that is needed for the recovery of spermatogenesis, there are other factors to consider which may be contributors to the azoospermia.
Varicocele
A varicocele is present in 15% of the male population and may be found in 19-40% of men as a citing factor in men who present to an infertility clinic [13]. Varicoceles are dilations of the veins of the pampiniform plexus thought to be caused by increases in vascular pressure from anatomical variants or abnormalities in the normal anti-reflux venous system. The vascular dilation leads to the pooling of blood in close proximity to the testicle. The temperature of the testicle increases and may lead to decreases in spermatogenesis as well as testosterone production [13]. Varicoceles may be the contributing factor in approximately 5% of males with azoospermia [14].
Stem cell transplants
Immature testicular tissue transplant may aid in fertility preservation for patients anticipating suppression of spermatogenesis.
Conclusion
There exist multiple strategies in the andrologist’s armamentarium to aid in the recovery or maintenance of spermatogenesis following impairment from anabolic steroids, anatomical variants, or gonadotoxic onco-therapeutics. Sperm cryopreservation is the best pre-treatment for future fertility, as in the case of patients anticipating suppression of spermatogenesis. However, many patients present post-therapy with a desire to restore spermatogenesis after the initial insult has occurred. The recovery of spermatogenesis in these patients is linked with the interplay between hormones within the HPG. HCG, SERMs, and FSH offer direct and indirect testicular signaling to induce spermatogenesis and the recovery or maintenance of fertility. In these cases, cessation of testosterone often renders the patient hypogonadal. Novel therapies as with FSH, enclomiphene citrate, and intranasal testosterone offer exciting strategies to combat hypogonadal symptoms while enhancing spermatogenic potential.
