madman
Super Moderator
Testosterone versus hCG in Hypogonadotropic Hypogonadism – Comparing Clinical Effects and Evaluating Current Practice
Swashti Agarwal, MD , Duong D. Tu, MD, Paul F. Austin, MD, Michael E. Scheurer, PhD, and Lefkothea P Karaviti, MD, PhD
Abstract
Background. Gonadotropin therapy is not typically used for pubertal induction in hypogonadotropic hypogonadism (HH), however, represents a promising alternative to testosterone. It can potentially lead to the maintenance of future fertility in addition to testicular growth. We compared the pubertal effects of human chorionic gonadotropin (hCG) versus testosterone in adolescent males with HH. We evaluated the current practice, among pediatric endocrinologists, to identify barriers against gonadotropin use.
Methods. In this retrospective review, we compared the effect of testosterone versus hCG therapy on mean testicular volume (MTV), penile length, growth velocity, and testosterone levels. We surveyed pediatric endocrinologists at our center, using RedCap.
Results. Outcomes were assessed in 52 male patients with HH (hCG, n=4; T, n=48) after a mean treatment duration of 13.4 (testosterone) and 13.8 months (hCG; P=.79). Final MTV was higher with hCG (8.25mL) than testosterone (3.4mL; P<.001). The groups did not differ in penile length, growth velocity, or testosterone levels. Survey results showed that more than half the providers were aware of the benefits of gonadotropins, however, 91% were uncomfortable prescribing hCG. Commonly reported barriers to prescribing hCG were lack of experience (62%) and insurance coverage concerns (52%).
Conclusions. Larger testicular volume predicts faster induction of spermatogenesis. Since hCG promoted better testicular growth, compared to testosterone, it may potentially improve future fertility outcomes in HH patients. Our results identify an opportunity to improve current practice among pediatric endocrinologists worldwide and reduce barriers to prescribing gonadotropins in the adolescent population.
Introduction
Hypogonadotropic hypogonadism (HH) can be congenital or acquired. Congenital HH is more common in males, with an estimated prevalence of about 1 to 10 in 100,000 live births. About two-thirds of cases are caused by Kallman syndrome, and the other third are considered idiopathic.1 HH can also be acquired secondary to brain tumors, brain irradiation, or brain trauma. Males with HH have a defect in the hypothalamic-pituitary axis that leads to below-normal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, resulting in an absence of testicular maturation and testosterone production. Patients generally present with delayed puberty. For several decades, testosterone has been the primary agent used, worldwide, for pubertal induction in HH males, but this therapeutic strategy suppresses the hypothalamic-pituitary-gonadal axis, in turn suppressing FSH and LH. Although this exogenous treatment approach increases the testosterone levels, this treatment approach results in decreased secretion of endogenous testosterone and decreased testicular growth. Increased testicular growth and larger testicular size are predictive of rapid induction of spermatogenesis and unassisted conception,2, and therefore, considered a surrogate for fertility potential. This has created concerns that prolonged use of testosterone could potentially lead to decreased spermatogenesis and adversely affect fertility. The negative effects of prolonged androgen use on fertility were previously viewed as temporary and reversible with discontinuation of treatment. However, more recent studies demonstrate that prolonged androgen use is independently associated with a decreased likelihood of and longer time to achieving sperm output thresholds and successful conception.2-4
Gonadotropin therapy represents an alternative to androgen therapy for stimulation of pubertal changes in HH males. Several reports have described the induction of puberty with various gonadotropin regimens, including human chorionic gonadotropin (hCG) monotherapy, hCG + recombinant FSH (rFSH), human menotropic gonadotropin (HMG), and gonadotropin-releasing hormone. Previous studies on pubertal induction using hCG monotherapy and hCG + rFSH have each shown testicular growth and spermatogenesis in addition to adequate virilizing effects and better quality of life when compared to testosterone alone.5-9 In addition to larger testicular volumes, prior exposure to gonadotropins was also linked to a favorable response to fertility treatments in adulthood.4
Several guidelines recommend different gonadotropin regimens10-12 for pubertal induction. Results from comparison studies between these regimens have not favored or shown the superiority of any one regimen over another. For example, one study demonstrated that prepubescent adolescent males treated with hCG + rFSH had larger testicular volumes than those treated with hCG monotherapy,13 whereas another study showed no difference in post-treatment testicular growth between different gonadotropin treatment groups.14 Sperm counts, however, were significantly better with hCG + rFSH in the latter report.14 Until evidence suggests otherwise, hCG monotherapy may be reasonable to induce secondary sexual characteristics (when current fertility is not needed) and to simplify the regimen without compromising future fertility. Further advantages of hCG monotherapy in comparison to other gonadotropin regimens are that it is a simple regimen, is widely available, and potentially provides better future fertility outcomes compared to testosterone therapy. Multiple adult studies have shown the fertility benefits of gonadotropin therapy, but only a few pediatric studies have involved a direct comparison of therapeutic outcomes between testosterone and hCG therapies.15,16
Conclusion
This study highlights the benefits of gonadotropin use over testosterone in terms of testicular growth and, potentially, later fertility outcomes. However, practice gaps exist among pediatric endocrinologists. Testosterone therapy is still widely used for pubertal induction in adolescent males with HH, primarily because of inexperience with gonadotropin treatments and lack of guidelines.
Treatment of HH from the adolescent phase itself should be directed toward both androgenization and fertility. Testosterone therapy appears to fall short with regards to preserving fertility. In contrast, gonadotropin replacement not only promotes androgenization, but could potentially prevent infertility, oligo-spermatogenesis, and testicular atrophy from prolonged exogenous androgen exposure. The use of gonadotropins among pediatric endocrinologists is limited primarily because of inexperience with independently managing and monitoring hCG regimens. Establishing management strategies based on the available literature and expert recommendations will provide clinicians with guidance on gonadotropin use in adolescent males with HH. This will facilitate larger scale comparison studies to allow for more evidence-based guidelines for their use, potentially resulting in improved outcomes and improving the quality of care provided to these patients.
Swashti Agarwal, MD , Duong D. Tu, MD, Paul F. Austin, MD, Michael E. Scheurer, PhD, and Lefkothea P Karaviti, MD, PhD
Abstract
Background. Gonadotropin therapy is not typically used for pubertal induction in hypogonadotropic hypogonadism (HH), however, represents a promising alternative to testosterone. It can potentially lead to the maintenance of future fertility in addition to testicular growth. We compared the pubertal effects of human chorionic gonadotropin (hCG) versus testosterone in adolescent males with HH. We evaluated the current practice, among pediatric endocrinologists, to identify barriers against gonadotropin use.
Methods. In this retrospective review, we compared the effect of testosterone versus hCG therapy on mean testicular volume (MTV), penile length, growth velocity, and testosterone levels. We surveyed pediatric endocrinologists at our center, using RedCap.
Results. Outcomes were assessed in 52 male patients with HH (hCG, n=4; T, n=48) after a mean treatment duration of 13.4 (testosterone) and 13.8 months (hCG; P=.79). Final MTV was higher with hCG (8.25mL) than testosterone (3.4mL; P<.001). The groups did not differ in penile length, growth velocity, or testosterone levels. Survey results showed that more than half the providers were aware of the benefits of gonadotropins, however, 91% were uncomfortable prescribing hCG. Commonly reported barriers to prescribing hCG were lack of experience (62%) and insurance coverage concerns (52%).
Conclusions. Larger testicular volume predicts faster induction of spermatogenesis. Since hCG promoted better testicular growth, compared to testosterone, it may potentially improve future fertility outcomes in HH patients. Our results identify an opportunity to improve current practice among pediatric endocrinologists worldwide and reduce barriers to prescribing gonadotropins in the adolescent population.
Introduction
Hypogonadotropic hypogonadism (HH) can be congenital or acquired. Congenital HH is more common in males, with an estimated prevalence of about 1 to 10 in 100,000 live births. About two-thirds of cases are caused by Kallman syndrome, and the other third are considered idiopathic.1 HH can also be acquired secondary to brain tumors, brain irradiation, or brain trauma. Males with HH have a defect in the hypothalamic-pituitary axis that leads to below-normal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, resulting in an absence of testicular maturation and testosterone production. Patients generally present with delayed puberty. For several decades, testosterone has been the primary agent used, worldwide, for pubertal induction in HH males, but this therapeutic strategy suppresses the hypothalamic-pituitary-gonadal axis, in turn suppressing FSH and LH. Although this exogenous treatment approach increases the testosterone levels, this treatment approach results in decreased secretion of endogenous testosterone and decreased testicular growth. Increased testicular growth and larger testicular size are predictive of rapid induction of spermatogenesis and unassisted conception,2, and therefore, considered a surrogate for fertility potential. This has created concerns that prolonged use of testosterone could potentially lead to decreased spermatogenesis and adversely affect fertility. The negative effects of prolonged androgen use on fertility were previously viewed as temporary and reversible with discontinuation of treatment. However, more recent studies demonstrate that prolonged androgen use is independently associated with a decreased likelihood of and longer time to achieving sperm output thresholds and successful conception.2-4
Gonadotropin therapy represents an alternative to androgen therapy for stimulation of pubertal changes in HH males. Several reports have described the induction of puberty with various gonadotropin regimens, including human chorionic gonadotropin (hCG) monotherapy, hCG + recombinant FSH (rFSH), human menotropic gonadotropin (HMG), and gonadotropin-releasing hormone. Previous studies on pubertal induction using hCG monotherapy and hCG + rFSH have each shown testicular growth and spermatogenesis in addition to adequate virilizing effects and better quality of life when compared to testosterone alone.5-9 In addition to larger testicular volumes, prior exposure to gonadotropins was also linked to a favorable response to fertility treatments in adulthood.4
Several guidelines recommend different gonadotropin regimens10-12 for pubertal induction. Results from comparison studies between these regimens have not favored or shown the superiority of any one regimen over another. For example, one study demonstrated that prepubescent adolescent males treated with hCG + rFSH had larger testicular volumes than those treated with hCG monotherapy,13 whereas another study showed no difference in post-treatment testicular growth between different gonadotropin treatment groups.14 Sperm counts, however, were significantly better with hCG + rFSH in the latter report.14 Until evidence suggests otherwise, hCG monotherapy may be reasonable to induce secondary sexual characteristics (when current fertility is not needed) and to simplify the regimen without compromising future fertility. Further advantages of hCG monotherapy in comparison to other gonadotropin regimens are that it is a simple regimen, is widely available, and potentially provides better future fertility outcomes compared to testosterone therapy. Multiple adult studies have shown the fertility benefits of gonadotropin therapy, but only a few pediatric studies have involved a direct comparison of therapeutic outcomes between testosterone and hCG therapies.15,16
Conclusion
This study highlights the benefits of gonadotropin use over testosterone in terms of testicular growth and, potentially, later fertility outcomes. However, practice gaps exist among pediatric endocrinologists. Testosterone therapy is still widely used for pubertal induction in adolescent males with HH, primarily because of inexperience with gonadotropin treatments and lack of guidelines.
Treatment of HH from the adolescent phase itself should be directed toward both androgenization and fertility. Testosterone therapy appears to fall short with regards to preserving fertility. In contrast, gonadotropin replacement not only promotes androgenization, but could potentially prevent infertility, oligo-spermatogenesis, and testicular atrophy from prolonged exogenous androgen exposure. The use of gonadotropins among pediatric endocrinologists is limited primarily because of inexperience with independently managing and monitoring hCG regimens. Establishing management strategies based on the available literature and expert recommendations will provide clinicians with guidance on gonadotropin use in adolescent males with HH. This will facilitate larger scale comparison studies to allow for more evidence-based guidelines for their use, potentially resulting in improved outcomes and improving the quality of care provided to these patients.
