madman
Super Moderator
ABSTRACT
Introduction: Although testosterone replacement therapy is an effective treatment for hypogonadism, there are safety concerns regarding potential cardiovascular risks and fertility preservation.
Objective: To assess the effect of selective estrogen receptor modulator (SERM), an aromatase inhibitor, and human chorionic gonadotropin (hCG) on total testosterone (TT) levels and hypogonadism.
Methods: We performed a systematic literature review from 1987 to 2019 via PubMed, Cochrane review, and Web of Science. Terms used were infertility, hypogonadism, an alternative to testosterone therapy, selective estrogen receptor modulator, an aromatase inhibitor, and human chorionic gonadotropin. Studies that reported an effect of TT and hypogonadism after the treatment of each medication were selected. Hypogonadal symptoms were assessed by the Androgen Deficiency of The Aging Male (ADAM) questionnaire. Aggregated data were analyzed via Chi-squared analysis.
Results: From literature, 25 studies were selected; of which, 12 evaluated efficacy of aromatase inhibitor, 8 evaluated SERMs, and 5 evaluated hCG effects. For SERMs, 512 patients with mean age 42.3 ± 1.94 years showed mean TT before treatment vs after treatment (167.9 ± 202.8 [ng/dl] vs 366.2 ± 32.3 [ng/dl], P < .0001 [180.5-216.1 95% confidence interval {CI}]). For aromatase inhibitor, 375 patients with mean age 54.1 ± 0.67 years showed mean TT before treatment vs after treatment (167.9 ± 202.8 [ng/dl] vs 366.2 ± 32.3 [ng/dl], P < .0001 [180.5-216.1 95% CI]). SERMs also showed ADAM before treatment vs after treatment (4.95 ± 0.28 vs 5.50 ± 0.19, P < .0001 [0.523-0.581 95% CI]). For hCG, 196 patients with mean age 41.7 ± 1.5 years showed mean TT before treatment vs after treatment (284.5 ± 13.6 [ng/dl] vs 565.6 ± 39.7 [ng/dl], P < .0001 [275.2-287.0 95% CI]). In addition, hCG also showed ADAM before treatment vs after treatment (28.1 ± 2.0 vs 30.9 ± 2.3, P < .0001 [2.313 95% CI]).
Conclusions: Non-testosterone therapies are efficacious in hypogonadal men. Our results show statistically significant improvement in TT and ADAM scores in all 3 medications after treatment. Future studies are warranted to elucidate the relationship between improved hypogonadism and erectile function in the setting of non-testosterone-based treatment.
INTRODUCTION
Male hypogonadism is characterized by low serum testosterone and associated with symptoms such as decreased libido, erectile dysfunction (ED), loss of vitality, loss of lean muscle mass, fatigue, and depression.1,2 The etiology of hypogonadism in the aging male is a combination of hypothalamic-pituitary-gonadal (HPG) axis dysfunction and primary testicular failure due to decreased production of testosterone by Leydig cells.3 The incidence of hypogonadism in men aged 40-79 years varies from 2.1% to 5.7%.4 The overall prevalence of male hypogonadism is reported to be 37% in the United States.5,6 Criteria for a diagnosis of hypogonadism include the presence of abnormal sexual symptoms, total testosterone (TT) levels, and free testosterone levels.7,8 Several societies used these 3 indicators to define male hypogonadism. The American Urological Association (AUA) guidelines suggest TT levels lower than 300 ng/dL on 2 independent tests with supported symptoms.8 In addition, the Endocrine Society also defines male hypogonadism as a patient presenting with signs of testosterone deficiency and low serum TT and/or free testosterone laboratory values.9
Moreover, male hypogonadism can be subtyped into several different forms: primary, secondary, hypogonadotropic, and hypergonadotropic. Primary testosterone deficiency has been shown to be linked to testicular dysfunction. Associated disease states are Klinefelter syndrome, undescended testicles, mumps orchitis, and hemochromatosis. This is contrasted with secondary hypogonadism, which is linked to an issue with the pituitary or hypothalamus and is largely associated with Kallmann’s syndrome. In addition, hypogonadism can be either hypogonadotropic or hypergonadotropic. Hypogonadotropic exhibits decreased follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels; hypergonadotropic disorder is when a patient presents with increased FSH and LH levels. In the clinical setting, it is important to identify the presenting patient’s hypogonatic subtyped to offer the optimal treatment.8,9
Treatment for hypogonadism typically includes testosterone replacement therapy (TRT), which results in satisfactory amelioration of disease-specific symptoms and normalization of serum testosterone.2 TRT improves sexual function, muscle strength, bone density, mood, and cognition of the patient. Improved symptoms depend on the pretreatment presentation, and results between patients can vary.10 Although these benefits can significantly improve the quality of life for hypogonadal men, TRT can affect spermatogenesis in some but not all men.11 Sperm production depends on a functionally intact HPG axis with the normal pituitary secretion of LH and FSH to support testicular testosterone production and spermatogenesis. Exogenous testosterone suppresses the HPG axis and testicular testosterone production.12 A study by the World Health Organization found that 65% of men became azoospermic by 6 months, with an average time to azoospermia of 120 days.13 Although 84% achieved normal sperm density after a median of 3.7 months after cessation of exogenous testosterone, only 46% of men recovered their pre-TRT baseline sperm density.13 Notably, a 2010 survey of AUA member urologists found that 25% of patients believed that TRT would improve a man’s fertility.14 Patients’ lack of awareness regarding potential reproductive risks of exogenous testosterone use and some physicians’ inappropriate overprescription expose a need for improved education regarding medical management of male factor infertility.
The European Association of Urology and AUA guidelines have addressed the issue of fertility preservation in patients who present with hypogonadism.2,11 The European Association of Urology guidelines support the use of human chorionic gonadotropin (hCG) in men with secondary hypogonadism who desire future fertility.2 The AUA guidelines conditionally support the use of aromatase inhibitors (AIs), hCG, and selective estrogen receptor modulators (SERMs) for these men.10 In addition, the 2018 Endocrine Society Clinical Practice Guidelines recommend against the use of exogenous testosterone in patients who desire fertility in the near term.9 In accordance with the AUA guideline, hCG is the only drug that has been approved by the Food and Drug Administration specifically to treat males with hypogonadotropic hypogonadism.10 The overall quantity and quality of studies investigating the use of these non-testosterone agents in men are limited. However, several studies provide important insight into the impact that SERMs, AIs, and hCG can have on the hypogonadal men’s serum testosterone level, libido, and erectile function. Therefore, this study serves to highlight current data regarding alternative treatment options for men with hypogonadism who wish to preserve their fertility.
EVIDENCE SYNTHESIS OF THIS REVIEW
Selective Estrogen Receptor Modulators
SERMs are compounds that exhibit tissue-specific estrogen receptor (ER) agonist or antagonist activity. The functional diversity of SERMs reflects the molecular and functional complexity of the ER.15 Four compounds make up the SERMs presently in clinical use in the United States: clomiphene citrate (CC), tamoxifen, toremifene, and raloxifene.15 Each compound demonstrates a specific profile for its target tissue effects.15 CC, now one of the most widely used drugs in the management of infertility, was approved by the Food and Drug Administration in 1967 for the treatment of ovulatory dysfunction in women desiring pregnancy (Clomid; Hoechst Marion Roussel or Serophene; Serono).15 It is a triphenylethylene that is structurally related to tamoxifen and toremifene.15 Notably, CC has been prescribed for more than 30 years off-label, primarily by reproductive urologists, for men with idiopathic infertility and hypogonadism.16 The AUA guidelines conditionally support the use of CC for hypogonadal men who desire to maintain fertility.10 This section will review the biologic mechanism of action and relevant literature regarding the effects of CC on testosterone and hypogonadal function.
Biopharmacology and Mechanism of Action
CC binds to nuclear ER for prolonged periods of time and leads to a reduction in ER concentration by inhibiting normal ER replacement.17 It blocks the normal negative feedback of circulating estradiol on the hypothalamus, preventing estrogen from lowering the output of gonadotropin-releasing hormone (Figure 1). During CC therapy, the frequency and amplitude of gonadotropin-releasing hormone pulses increase, stimulating the pituitary gland to release more FSH and LH. Consequently, sperm and testicular testosterone productions are increased.15,17 CC is readily absorbed orally in humans and reaches peak plasma concentrations within 6 hours. The half-life of its oral dose is approximately 5 days, but trace amounts of the drug have been found for at least 6 weeks after dosing.17 CC is metabolized by the liver and is contraindicated in patients with liver dysfunction. However, little data exist on the exact pathways involved in CC metabolism.17 5 days after a single oral dose, approximately 50% of CC is excreted (42% by fecal excretion and 8% by urinary excretion).16
*Effects on Testosterone
*Effect on Symptoms Associated with Hypogonadism
*Potential Side Effects
Aromatase Inhibitors
An alternative option for non-testosterone-based hormonal therapy is the AIs. Drugs within this class such as anastrozole and letrozole have been established as the standard of care for ER-positive breast cancer in postmenopausal women.30,31 Off-label use of AIs has increased by male patients seeking alternatives to exogenous testosterone for conditions such as hypogonadism and male infertility. AI use stimulates gonadotropin release by inhibiting the synthesis of estradiol, which itself is a potent inhibitor of the HPG axis.31 This section will review the biologic mechanism of action and relevant literature regarding the effects of AIs on testosterone and hypogonadic function.
Biopharmacology and Mechanism of Action
Cytochrome P450 aromatase is an enzyme that is present in the male brain, adipose tissue, and testis, and female reproductive organs. Aromatase converts androstenedione to estrone and testosterone to estradiol (Figure 3). AIs inhibit this pathway, thereby preserving testosterone levels and limiting estrogen production. The first discovered member in this class was testolactone, which is an irreversible, non-specific steroidal inhibitor of aromatase.32 Letrozole and anastrozole are third- and fourth-generation specific non-steroidal competitive antagonists of aromatase, respectively.30,31
*Effects on Testosterone
*Effect on Hypogonadal Symptoms
*Potential Side Effects
Human Chorionic Gonadotropin
hCG was discovered in 1927 when blood and urine from pregnant women were shown to have gonad-stimulating effects on immature female mice.41 Within 4 years, the hormone was able to be purified and made commercially available in 1931 under the brand name Pregnon, renamed to Pregnyl in 1932. The majority of currently available hCG products are still obtained from highly purified pregnant female urine, with the exception of Ovidrel that is manufactured using recombinant DNA. hCG is currently the Food and Drug Administration approved for the treatment of prepubertal cryptorchidism not because of anatomic obstruction, selected cases of hypogonadotropic hypogonadism, and induction of ovulation in female infertility.41 Within the field of andrology and infertility, hCG is used in the treatment of men with azoospermia or oligospermia resulting from exogenous TRT. This section will review the biological mechanism of action and relevant literature regarding the effects of hCG on testosterone and hypogonadal function.
Biopharmacology and Mechanism of Action
hCG is a glycoprotein hormone made of 237 amino acids with a molecular mass of 36.7 and is composed of an alpha and beta subunit. The alpha subunit is structurally identical to that of the glycoprotein hormones thyroid-stimulating hormone, LH, and FSH. The beta subunit of hCG has a series of 121 amino acids that are identical to the biologically active 121 amino acids of the LH beta subunit responsible for interactions with the LH receptor.41 Owing to these structural similarities, hCG is used to stimulate testosterone production by the Leydig cells while not suppressing the HPG axis.
*Effects on Testosterone
*Effect on Hypogonadal Symptoms
*Potential Side Effects
*Length of Treatment
CONCLUSIONS
CC, AI, and hCG have demonstrated their ability to raise testosterone while preserving spermatogenesis. This makes them prime agents to treat hypogonadism in men wanting to preserve fertility. Our results show statistically significant improvement in TT in all 3 medications after treatment. Although CC and hCG also demonstrated the ability to ameliorate hypogonadal-related symptoms, there is no current evidence that AI does to a significant degree. Future studies are warranted to elucidate the relationship between improved hypogonadism and erectile function in the setting of non-testosterone-based treatment.
Introduction: Although testosterone replacement therapy is an effective treatment for hypogonadism, there are safety concerns regarding potential cardiovascular risks and fertility preservation.
Objective: To assess the effect of selective estrogen receptor modulator (SERM), an aromatase inhibitor, and human chorionic gonadotropin (hCG) on total testosterone (TT) levels and hypogonadism.
Methods: We performed a systematic literature review from 1987 to 2019 via PubMed, Cochrane review, and Web of Science. Terms used were infertility, hypogonadism, an alternative to testosterone therapy, selective estrogen receptor modulator, an aromatase inhibitor, and human chorionic gonadotropin. Studies that reported an effect of TT and hypogonadism after the treatment of each medication were selected. Hypogonadal symptoms were assessed by the Androgen Deficiency of The Aging Male (ADAM) questionnaire. Aggregated data were analyzed via Chi-squared analysis.
Results: From literature, 25 studies were selected; of which, 12 evaluated efficacy of aromatase inhibitor, 8 evaluated SERMs, and 5 evaluated hCG effects. For SERMs, 512 patients with mean age 42.3 ± 1.94 years showed mean TT before treatment vs after treatment (167.9 ± 202.8 [ng/dl] vs 366.2 ± 32.3 [ng/dl], P < .0001 [180.5-216.1 95% confidence interval {CI}]). For aromatase inhibitor, 375 patients with mean age 54.1 ± 0.67 years showed mean TT before treatment vs after treatment (167.9 ± 202.8 [ng/dl] vs 366.2 ± 32.3 [ng/dl], P < .0001 [180.5-216.1 95% CI]). SERMs also showed ADAM before treatment vs after treatment (4.95 ± 0.28 vs 5.50 ± 0.19, P < .0001 [0.523-0.581 95% CI]). For hCG, 196 patients with mean age 41.7 ± 1.5 years showed mean TT before treatment vs after treatment (284.5 ± 13.6 [ng/dl] vs 565.6 ± 39.7 [ng/dl], P < .0001 [275.2-287.0 95% CI]). In addition, hCG also showed ADAM before treatment vs after treatment (28.1 ± 2.0 vs 30.9 ± 2.3, P < .0001 [2.313 95% CI]).
Conclusions: Non-testosterone therapies are efficacious in hypogonadal men. Our results show statistically significant improvement in TT and ADAM scores in all 3 medications after treatment. Future studies are warranted to elucidate the relationship between improved hypogonadism and erectile function in the setting of non-testosterone-based treatment.
INTRODUCTION
Male hypogonadism is characterized by low serum testosterone and associated with symptoms such as decreased libido, erectile dysfunction (ED), loss of vitality, loss of lean muscle mass, fatigue, and depression.1,2 The etiology of hypogonadism in the aging male is a combination of hypothalamic-pituitary-gonadal (HPG) axis dysfunction and primary testicular failure due to decreased production of testosterone by Leydig cells.3 The incidence of hypogonadism in men aged 40-79 years varies from 2.1% to 5.7%.4 The overall prevalence of male hypogonadism is reported to be 37% in the United States.5,6 Criteria for a diagnosis of hypogonadism include the presence of abnormal sexual symptoms, total testosterone (TT) levels, and free testosterone levels.7,8 Several societies used these 3 indicators to define male hypogonadism. The American Urological Association (AUA) guidelines suggest TT levels lower than 300 ng/dL on 2 independent tests with supported symptoms.8 In addition, the Endocrine Society also defines male hypogonadism as a patient presenting with signs of testosterone deficiency and low serum TT and/or free testosterone laboratory values.9
Moreover, male hypogonadism can be subtyped into several different forms: primary, secondary, hypogonadotropic, and hypergonadotropic. Primary testosterone deficiency has been shown to be linked to testicular dysfunction. Associated disease states are Klinefelter syndrome, undescended testicles, mumps orchitis, and hemochromatosis. This is contrasted with secondary hypogonadism, which is linked to an issue with the pituitary or hypothalamus and is largely associated with Kallmann’s syndrome. In addition, hypogonadism can be either hypogonadotropic or hypergonadotropic. Hypogonadotropic exhibits decreased follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels; hypergonadotropic disorder is when a patient presents with increased FSH and LH levels. In the clinical setting, it is important to identify the presenting patient’s hypogonatic subtyped to offer the optimal treatment.8,9
Treatment for hypogonadism typically includes testosterone replacement therapy (TRT), which results in satisfactory amelioration of disease-specific symptoms and normalization of serum testosterone.2 TRT improves sexual function, muscle strength, bone density, mood, and cognition of the patient. Improved symptoms depend on the pretreatment presentation, and results between patients can vary.10 Although these benefits can significantly improve the quality of life for hypogonadal men, TRT can affect spermatogenesis in some but not all men.11 Sperm production depends on a functionally intact HPG axis with the normal pituitary secretion of LH and FSH to support testicular testosterone production and spermatogenesis. Exogenous testosterone suppresses the HPG axis and testicular testosterone production.12 A study by the World Health Organization found that 65% of men became azoospermic by 6 months, with an average time to azoospermia of 120 days.13 Although 84% achieved normal sperm density after a median of 3.7 months after cessation of exogenous testosterone, only 46% of men recovered their pre-TRT baseline sperm density.13 Notably, a 2010 survey of AUA member urologists found that 25% of patients believed that TRT would improve a man’s fertility.14 Patients’ lack of awareness regarding potential reproductive risks of exogenous testosterone use and some physicians’ inappropriate overprescription expose a need for improved education regarding medical management of male factor infertility.
The European Association of Urology and AUA guidelines have addressed the issue of fertility preservation in patients who present with hypogonadism.2,11 The European Association of Urology guidelines support the use of human chorionic gonadotropin (hCG) in men with secondary hypogonadism who desire future fertility.2 The AUA guidelines conditionally support the use of aromatase inhibitors (AIs), hCG, and selective estrogen receptor modulators (SERMs) for these men.10 In addition, the 2018 Endocrine Society Clinical Practice Guidelines recommend against the use of exogenous testosterone in patients who desire fertility in the near term.9 In accordance with the AUA guideline, hCG is the only drug that has been approved by the Food and Drug Administration specifically to treat males with hypogonadotropic hypogonadism.10 The overall quantity and quality of studies investigating the use of these non-testosterone agents in men are limited. However, several studies provide important insight into the impact that SERMs, AIs, and hCG can have on the hypogonadal men’s serum testosterone level, libido, and erectile function. Therefore, this study serves to highlight current data regarding alternative treatment options for men with hypogonadism who wish to preserve their fertility.
EVIDENCE SYNTHESIS OF THIS REVIEW
Selective Estrogen Receptor Modulators
SERMs are compounds that exhibit tissue-specific estrogen receptor (ER) agonist or antagonist activity. The functional diversity of SERMs reflects the molecular and functional complexity of the ER.15 Four compounds make up the SERMs presently in clinical use in the United States: clomiphene citrate (CC), tamoxifen, toremifene, and raloxifene.15 Each compound demonstrates a specific profile for its target tissue effects.15 CC, now one of the most widely used drugs in the management of infertility, was approved by the Food and Drug Administration in 1967 for the treatment of ovulatory dysfunction in women desiring pregnancy (Clomid; Hoechst Marion Roussel or Serophene; Serono).15 It is a triphenylethylene that is structurally related to tamoxifen and toremifene.15 Notably, CC has been prescribed for more than 30 years off-label, primarily by reproductive urologists, for men with idiopathic infertility and hypogonadism.16 The AUA guidelines conditionally support the use of CC for hypogonadal men who desire to maintain fertility.10 This section will review the biologic mechanism of action and relevant literature regarding the effects of CC on testosterone and hypogonadal function.
Biopharmacology and Mechanism of Action
CC binds to nuclear ER for prolonged periods of time and leads to a reduction in ER concentration by inhibiting normal ER replacement.17 It blocks the normal negative feedback of circulating estradiol on the hypothalamus, preventing estrogen from lowering the output of gonadotropin-releasing hormone (Figure 1). During CC therapy, the frequency and amplitude of gonadotropin-releasing hormone pulses increase, stimulating the pituitary gland to release more FSH and LH. Consequently, sperm and testicular testosterone productions are increased.15,17 CC is readily absorbed orally in humans and reaches peak plasma concentrations within 6 hours. The half-life of its oral dose is approximately 5 days, but trace amounts of the drug have been found for at least 6 weeks after dosing.17 CC is metabolized by the liver and is contraindicated in patients with liver dysfunction. However, little data exist on the exact pathways involved in CC metabolism.17 5 days after a single oral dose, approximately 50% of CC is excreted (42% by fecal excretion and 8% by urinary excretion).16
*Effects on Testosterone
*Effect on Symptoms Associated with Hypogonadism
*Potential Side Effects
Aromatase Inhibitors
An alternative option for non-testosterone-based hormonal therapy is the AIs. Drugs within this class such as anastrozole and letrozole have been established as the standard of care for ER-positive breast cancer in postmenopausal women.30,31 Off-label use of AIs has increased by male patients seeking alternatives to exogenous testosterone for conditions such as hypogonadism and male infertility. AI use stimulates gonadotropin release by inhibiting the synthesis of estradiol, which itself is a potent inhibitor of the HPG axis.31 This section will review the biologic mechanism of action and relevant literature regarding the effects of AIs on testosterone and hypogonadic function.
Biopharmacology and Mechanism of Action
Cytochrome P450 aromatase is an enzyme that is present in the male brain, adipose tissue, and testis, and female reproductive organs. Aromatase converts androstenedione to estrone and testosterone to estradiol (Figure 3). AIs inhibit this pathway, thereby preserving testosterone levels and limiting estrogen production. The first discovered member in this class was testolactone, which is an irreversible, non-specific steroidal inhibitor of aromatase.32 Letrozole and anastrozole are third- and fourth-generation specific non-steroidal competitive antagonists of aromatase, respectively.30,31
*Effects on Testosterone
*Effect on Hypogonadal Symptoms
*Potential Side Effects
Human Chorionic Gonadotropin
hCG was discovered in 1927 when blood and urine from pregnant women were shown to have gonad-stimulating effects on immature female mice.41 Within 4 years, the hormone was able to be purified and made commercially available in 1931 under the brand name Pregnon, renamed to Pregnyl in 1932. The majority of currently available hCG products are still obtained from highly purified pregnant female urine, with the exception of Ovidrel that is manufactured using recombinant DNA. hCG is currently the Food and Drug Administration approved for the treatment of prepubertal cryptorchidism not because of anatomic obstruction, selected cases of hypogonadotropic hypogonadism, and induction of ovulation in female infertility.41 Within the field of andrology and infertility, hCG is used in the treatment of men with azoospermia or oligospermia resulting from exogenous TRT. This section will review the biological mechanism of action and relevant literature regarding the effects of hCG on testosterone and hypogonadal function.
Biopharmacology and Mechanism of Action
hCG is a glycoprotein hormone made of 237 amino acids with a molecular mass of 36.7 and is composed of an alpha and beta subunit. The alpha subunit is structurally identical to that of the glycoprotein hormones thyroid-stimulating hormone, LH, and FSH. The beta subunit of hCG has a series of 121 amino acids that are identical to the biologically active 121 amino acids of the LH beta subunit responsible for interactions with the LH receptor.41 Owing to these structural similarities, hCG is used to stimulate testosterone production by the Leydig cells while not suppressing the HPG axis.
*Effects on Testosterone
*Effect on Hypogonadal Symptoms
*Potential Side Effects
*Length of Treatment
CONCLUSIONS
CC, AI, and hCG have demonstrated their ability to raise testosterone while preserving spermatogenesis. This makes them prime agents to treat hypogonadism in men wanting to preserve fertility. Our results show statistically significant improvement in TT in all 3 medications after treatment. Although CC and hCG also demonstrated the ability to ameliorate hypogonadal-related symptoms, there is no current evidence that AI does to a significant degree. Future studies are warranted to elucidate the relationship between improved hypogonadism and erectile function in the setting of non-testosterone-based treatment.
