Strategies to increase testosterone in men seeking fertility
Kevin Y. Chu , Justin K. Achua , Ranjith Ramasamy
ABSTRACT
The prevalence of testosterone deficiency is increasing in the adolescent and young adult male population. As the average paternal age rises, there is a significant population of men with hypogonadism seeking testosterone therapy wishing to achieve or maintain fertility potential. Identification of potential lifestyle modifications that may improve testosterone deficiency is one of the initial interventions of the holistic strategy in treatment. This is followed by drug therapy; however, traditional testosterone therapy acts as a contraceptive by suppressing the hypothalamus-pituitary-gonadal (HPG) axis and therefore cannot be used as a treatment strategy. A solution has been the off-label use of selective estrogen receptor modulators, human chorionic gonadotropin (hCG), and anastrozole inhibitors to treat hypogonadal symptoms while increasing intratesticular testosterone, a necessity for spermatogenesis. Recently, a novel therapy, Natesto intranasal testosterone gel, has been shown to increase serum testosterone levels while maintaining semen parameters. This is hypothesized to be because of its short-acting properties having a lesser effect on the HPG axis, in contrast to the long-acting properties of traditional testosterone therapy. It is important to differentiate hypogonadal men between those seeking to achieve or maintain fertility status because the drug therapy of choice differs. This can be accomplished by determining the levels of 17-hydroxyprogesterone (17-OHP) because it is a biomarker for intratesticular testosterone. Those with low 17-OHP may wish to initiate treatment with alternative therapies, whereas those with high 17-OHP may trial short-acting testosterone therapies. As the urologist’s armamentarium continues to increase, better strategies to increase testosterone levels in men seeking fertility can be achieved.
Introduction
Male hypogonadism is estimated to have a prevalence of 2.1% and 5.6% by the Massachusetts Male Aging Study and the European Male Aging Study, respectively.[1,2] A diagnosis of male hypogonadism is defined as a state of low serum testosterone (>300 ng/dL) and concurrent clinical symptoms that impact physical and mental health.[3] The symptoms are broad and vary depending on the age of onset and severity of testosterone deficiency. These symptoms include decreased libido, erectile dysfunction, infertility, low energy, low mood, depression, gynecomastia, decreased lean muscle mass, increased body fat gain, and osteoporosis.[3,4] Low serum testosterone has also been shown to have potential long-term negative effects on cardiovascular health, metabolism, and longevity.[5] Because the average paternal age has increased over time, and hypogonadism rates increase with age, the challenge of treating low testosterone while maintaining fertility status has become paramount.[6] Although testosterone deficiency was commonly thought to be a diagnosis in only older men, recent studies have started to show an increase in prevalence in younger men too.[7] This impacts the potential testosterone therapy plan because the patient’s desire for conception needs to be considered.
Testosterone deficiency in adolescents and young adult (AYA) men, defined as those between the ages of 15-39, has a prevalence of approximately 20%. In addition, studies have shown that total testosterone levels among AYA men have been declining over the past few decades. Although increasing obesity rates have shown to be an independent predictor of declining testosterone levels, Lokeshwar et al.[7] demonstrated a decline in total testosterone among AYA males despite controlling for confounders. AYA men diagnosed with hypogonadism present with initial symptoms of low energy and fatigue, in contrast to the complaints of decreased libido or erectile dysfunction in older men.[8] Among this patient population, strategies to increase testosterone levels to address hypogonadal symptoms must be well thought out to maintain fertility status.
In this review, we have summarized the various therapies available for increasing testosterone levels in men seeking fertility. These therapies include selective estrogen receptor modulators, gonadotropins, aromatase inhibitors, and testosterone therapy. In addition, it is important to consider non-drug approaches to increase testosterone levels. This allows for a holistic approach to treating hypogonadism. Treating hypogonadism can be difficult for physicians, because inappropriate therapies, such as exogenous testosterone, will suppress spermatogenesis and impact future fertility. The physician and the patient must have a thoughtful discussion before initiating the treatment.
Drug Therapies for Testosterone Deficiency
Testosterone therapy (TT)
Alternative therapy: selective estrogen receptor modulators (SERMs)
Alternative therapy: gonadotropins
Alternative therapy: aromatase inhibitors (AIs)
Differentiating Treatment with Alternative Therapies versus Novel Testosterone Therapy
Non-drug Strategies for Testosterone Deficiency
Conclusion
Testosterone deficiency is a clinical problem that is increasing in prevalence among AYA. As the average paternal age increases, the hypogonadal population seeking to improve or maintain fertility gets larger. A holistic approach with counseling on lifestyle modifications is a must. Alternative therapies such as SERMs, hCG, or anastrozole inhibitors have been used off-label for treatment. Recent drug development of a short-acting testosterone formulation, Natesto, has been approved for testosterone therapy, and studies have shown maintenance of semen parameters with it. In addition, 17-OHP has been identified as a potential biomarker for intratesticular testosterone levels, which will allow for better counseling of patients on the appropriate treatment strategy. As the urologist’s armamentarium continues to increase, better strategies to increase testosterone levels in men seeking fertility can be achieved.
Kevin Y. Chu , Justin K. Achua , Ranjith Ramasamy
ABSTRACT
The prevalence of testosterone deficiency is increasing in the adolescent and young adult male population. As the average paternal age rises, there is a significant population of men with hypogonadism seeking testosterone therapy wishing to achieve or maintain fertility potential. Identification of potential lifestyle modifications that may improve testosterone deficiency is one of the initial interventions of the holistic strategy in treatment. This is followed by drug therapy; however, traditional testosterone therapy acts as a contraceptive by suppressing the hypothalamus-pituitary-gonadal (HPG) axis and therefore cannot be used as a treatment strategy. A solution has been the off-label use of selective estrogen receptor modulators, human chorionic gonadotropin (hCG), and anastrozole inhibitors to treat hypogonadal symptoms while increasing intratesticular testosterone, a necessity for spermatogenesis. Recently, a novel therapy, Natesto intranasal testosterone gel, has been shown to increase serum testosterone levels while maintaining semen parameters. This is hypothesized to be because of its short-acting properties having a lesser effect on the HPG axis, in contrast to the long-acting properties of traditional testosterone therapy. It is important to differentiate hypogonadal men between those seeking to achieve or maintain fertility status because the drug therapy of choice differs. This can be accomplished by determining the levels of 17-hydroxyprogesterone (17-OHP) because it is a biomarker for intratesticular testosterone. Those with low 17-OHP may wish to initiate treatment with alternative therapies, whereas those with high 17-OHP may trial short-acting testosterone therapies. As the urologist’s armamentarium continues to increase, better strategies to increase testosterone levels in men seeking fertility can be achieved.
Introduction
Male hypogonadism is estimated to have a prevalence of 2.1% and 5.6% by the Massachusetts Male Aging Study and the European Male Aging Study, respectively.[1,2] A diagnosis of male hypogonadism is defined as a state of low serum testosterone (>300 ng/dL) and concurrent clinical symptoms that impact physical and mental health.[3] The symptoms are broad and vary depending on the age of onset and severity of testosterone deficiency. These symptoms include decreased libido, erectile dysfunction, infertility, low energy, low mood, depression, gynecomastia, decreased lean muscle mass, increased body fat gain, and osteoporosis.[3,4] Low serum testosterone has also been shown to have potential long-term negative effects on cardiovascular health, metabolism, and longevity.[5] Because the average paternal age has increased over time, and hypogonadism rates increase with age, the challenge of treating low testosterone while maintaining fertility status has become paramount.[6] Although testosterone deficiency was commonly thought to be a diagnosis in only older men, recent studies have started to show an increase in prevalence in younger men too.[7] This impacts the potential testosterone therapy plan because the patient’s desire for conception needs to be considered.
Testosterone deficiency in adolescents and young adult (AYA) men, defined as those between the ages of 15-39, has a prevalence of approximately 20%. In addition, studies have shown that total testosterone levels among AYA men have been declining over the past few decades. Although increasing obesity rates have shown to be an independent predictor of declining testosterone levels, Lokeshwar et al.[7] demonstrated a decline in total testosterone among AYA males despite controlling for confounders. AYA men diagnosed with hypogonadism present with initial symptoms of low energy and fatigue, in contrast to the complaints of decreased libido or erectile dysfunction in older men.[8] Among this patient population, strategies to increase testosterone levels to address hypogonadal symptoms must be well thought out to maintain fertility status.
In this review, we have summarized the various therapies available for increasing testosterone levels in men seeking fertility. These therapies include selective estrogen receptor modulators, gonadotropins, aromatase inhibitors, and testosterone therapy. In addition, it is important to consider non-drug approaches to increase testosterone levels. This allows for a holistic approach to treating hypogonadism. Treating hypogonadism can be difficult for physicians, because inappropriate therapies, such as exogenous testosterone, will suppress spermatogenesis and impact future fertility. The physician and the patient must have a thoughtful discussion before initiating the treatment.
Drug Therapies for Testosterone Deficiency
Testosterone therapy (TT)
Alternative therapy: selective estrogen receptor modulators (SERMs)
Alternative therapy: gonadotropins
Alternative therapy: aromatase inhibitors (AIs)
Differentiating Treatment with Alternative Therapies versus Novel Testosterone Therapy
Non-drug Strategies for Testosterone Deficiency
Conclusion
Testosterone deficiency is a clinical problem that is increasing in prevalence among AYA. As the average paternal age increases, the hypogonadal population seeking to improve or maintain fertility gets larger. A holistic approach with counseling on lifestyle modifications is a must. Alternative therapies such as SERMs, hCG, or anastrozole inhibitors have been used off-label for treatment. Recent drug development of a short-acting testosterone formulation, Natesto, has been approved for testosterone therapy, and studies have shown maintenance of semen parameters with it. In addition, 17-OHP has been identified as a potential biomarker for intratesticular testosterone levels, which will allow for better counseling of patients on the appropriate treatment strategy. As the urologist’s armamentarium continues to increase, better strategies to increase testosterone levels in men seeking fertility can be achieved.
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