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Exogenous testosterone: a preventable cause of male infertility
Lindsey E. Crosnoe1, Ethan Grober2, Dana Ohl3, Edward D. Kim1
1University of Tennessee Graduate School of Medicine, Knoxville, TN, USA; 2University of Toronto, Toronto, CA, Canada; 3University of Michigan, Ann Arbor, MI, USA
Correspondence to: Edward D. Kim, M.D. 1928 Alcoa Highway, Suite 222, Knoxville, TN 37920, USA. Email: ekim@utmck.edu.
Main problem: Testosterone replacement therapy inhibits spermatogenesis, representing a problem for hypogonadal men of reproductive age.
Methods: A literature review of PubMed from 1990-2013. Semen analysis and pregnancy outcomes, time to recovery of spermatogenesis, serum and intratesticular testosterone levels were examined.
Results: Exogenous testosterone suppresses intratesticular testosterone production, which is an absolute prerequisite for normal spermatogenesis. Therapies that protect the testis involve human chorionic gonadotropin (hCG) therapy or selective estrogen receptor modulators (SERMs), but may also include low dose hCG with exogenous testosterone. SERMs, such as clomiphene citrate, are effective for maintaining testosterone production and represent a well-tolerated, oral therapy. Routine use of aromatase inhibitors is not recommended based on a lack of long-term data.
Conclusions: Exogenous testosterone supplementation decreases sperm production. Studies of hormonal contraception indicate that most men have a return of normal sperm production within 1 year after discontinuation. Clomiphene citrate is a safe and effective therapy for men who desire to maintain future potential fertility. Although less frequently used in the general population, hCG therapy with or without testosterone supplementation represents an alternative treatment.
Keywords: Hypogonadism; selective estrogen receptor modulator; male fertility; testosterone; spermatogenesis
Submitted Jun 10, 2013. Accepted for publication Jun 20, 2013.
doi: 10.3978/j.issn.2223-4683.2013.06.01
Introduction
In a recent survey of U.S. urologists, Ko et al. (1) observed that approximately 25% have treated low testosterone levels associated with male infertility with exogenous testosterone. Many physicians are unaware that testosterone replacement therapies (TRT) adversely affect spermatogenesis. Increasingly, the diagnosis of hypogonadism is being made in younger men, many of whom are of reproductive age. In 1970, less than 15% of all men fathering children were over 35. Today, this percentage has risen to almost 25%. There has been a notable increase in fatherhood even among men in the 50 to 54 age group (2). However, there is a lack of expert recommendations regarding hormone replacement therapy in men of reproductive age.
Case presentationOther Section
A 30-year-old male presents with severe oligozoospermia (Figure 1). He has been on an intramuscular testosterone (IM-T) preparation for the treatment of symptomatic hypogonadism. He desires to have more children within in the next two years and has a normal exam. His baseline testosterone level was 200 ng/dL. The luteinizing hormone (LH) and follicular-stimulating hormone (FSH) levels were low. The pre-treatment semen analysis was normal. For potential treatment options, the physician could advise that (I) he switch to a topical testosterone; (II) stop testosterone therapy; (III) change to clomiphene citrate; or (IV) add human chorionic gonadotropin (hCG) to his IM-T.
Figure 1 Case presentation.
The best suggested answers are b and c (Figure 2). Option d may also be considered. Switching to a topical testosterone would still result in suppression of spermatogenesis. Similar effects on the HPG axis would be expected regardless of the route of administration. Stopping testosterone therapy is necessary to restore baseline HPG axis function and subsequent effects on spermatogenesis. Initiation of clomiphene citrate would address his symptomatic hypogonadism by increasing endogenous production of testosterone. Finally, there is a subset of men who do not want to consider cessation of testosterone therapy. For these men, addition of hCG to the IM-T has demonstrated beneficial effects on maintaining spermatogenesis.
Figure 2 Recommendations.
Regarding the treatment of similar hypogonadal men of reproductive age, this AUA Plenary Session Presentation will review (I) the extent of the problem; (II) the mechanisms by which testosterone therapy impairs spermatogenesis and (III) therapeutic approaches to protect the testis.
The extent of the problem
Symptomatic hypogonadism is not uncommon (3). It is estimated that more than 6.5 million men in the U.S. will have symptomatic androgen deficiency by 2025 (4). Between the ages of 20 and 30 years, men experience a decline in testosterone and free testosterone levels by 0.4% and 1.3% per year, respectively (5). Indeed, Mulligan et al. (6) observed that roughly 39% of men over the age of 45 had low serum testosterone levels, defined as less than 300 ng/dL.
Testosterone therapies have been increasingly utilized in aging men, as well as in men of reproductive age. Compared to the 1970s men are fathering children at an older age. Combined with the maturation of the Baby Boomer population, it is anticipated that there may be a significant increase in hypogonadal, aging men desiring to father children. The treatment of hypogonadism requires symptoms, as well as low serum testosterone levels. With the recent introduction of several newer commercial testosterone preparations and an increased public awareness of androgen deficiency syndromes, use of hormone replacement therapies (HRT) has been increasing. Over the past five years there has been an increase in testosterone prescriptions by 170% (7). However, men desiring to maintain their reproductive potential may not be fully aware of the risks of exogenous testosterone therapy.
Testosterone users and health care professionals are often unaware that exogenous testosterone suppresses the hypothalamic-pituitary-gonadal axis and may result in infertility. Physicians need to educate their patients about the potentially deleterious effects exogenous testosterone can have on spermatogenesis and on fertility. Indeed, use of intramuscular testosterone has been investigated as a male contraceptive agent (8).
How testosterone inhibits spermatogenesis and fertility
Mechanism of action
Testosterone inhibits both GnRH and gonadotropin secretion. Exogenous administration of synthetic testosterone results in negative feedback on the hypothalamic-pituitary axis, inhibiting GnRH, leading to inhibition of FSH and LH production. As a result, intratesticular testosterone levels (ITT) and overall testosterone production decrease. Exogenous testosterone therapies can suppress ITT production to such a degree that spermatogenesis can be dramatically compromised at ITT concentrations to less than 20 ng/mL, even resulting in azoospermia (9-11) (Figure 3).
Figure 3 How testosterone therapy affects spermatogenesis.
Spermatogenesis recovery after discontinuation of exogenous testosterone
Recovery of spermatogenesis after discontinuation exogenous testosterone is generally promising. First, the hypogonadal male interested in fathering children should attempt cessation of use of exogenous testosterone. A study by the WHO Task Force evaluated 271 men who received 200 mg of testosterone enanthate weekly (12). After 6 months, 157 (65%) of the men were azoospermic with the mean time to azoospermia at 120 days. After 6 months of treatment, the patients entered the recovery phase. While 84% of men were able to achieve a sperm density >20 million/mL after a median of 3.7 months, only 46% of patients were able to achieve their baseline sperm density.
Mills and associates evaluated the recovery of spermatogenesis after exogenous testosterone administration in of 26 men with a recent history of anabolic steroid use (13). All discontinued exogenous testosterone usage and were treated with hCG 3,000 units IM every other day for a minimum of 3 months. Of the two men who remained azoospermic, one had insufficient follow-up and the other was suspected of continued anabolic steroid use. Men using intramuscular testosterone at the time of presentation recovered spermatogenesis in an average of 3.1 months. However, men receiving transdermal testosterone supplementation at the time of presentation took an average of 7.4 months. The authors concluded that impairment of fertility following TRT suppression is reversible and that the rate of sperm may be related to the delivery system.
The published literature represents the best available evidence to date regarding the recovery of spermatogenesis after testosterone supplementation. A significant problem is that literature assesses the use of testosterone therapy as a male contraceptive agent. This situation may not reflect the hypogonadal male seen in clinical practice. However, most men who discontinue T supplementation have a return of normal sperm production within one year. The consistency of spermatogenesis recovery in clinical practice may not be as predictable as in contraceptive studies.
Testosterone as male contraceptive
Pharmaceutical companies have tried to develop hormonal male contraceptives with the intent of causing a withdrawal of the gonadotropin support to the testis with resultant suppression of spermatogenesis and ITT (14). Testosterone has been studied alone, as well as in combination with progestrogens (15). Testosterone used as a contraceptive agent may be used to determine the recovery of spermatogenesis after cessation of therapy. This analysis regarding the application of contraceptive studies to hypogonadal males is problematic. First, the men studied in contraceptive trials were not hypogonadal and did not have concerns about fertility. Many of these men had normal baseline testosterone levels, as well as sperm production. Additionally, different testosterone preparations and doses were used compared to clinical formulations.
Testosterone undecanoate was administered at a dose of 500 mg monthly for 30 months in a study of ethnic Chinese men (16). Over a 24-month efficacy phase (855 men), a cumulative contraceptive failure rate of 1.1% per 100 men was reported. Failure to achieve azoospermia or severe oligozoospermia (<1×106 sperm/mL) was seen in 4.8%. Median time to onset of azoospermia or severe oligozoospermia was 108 days. Spermatogenesis returned to the normal fertile reference range in all but two participants. The median time to recovery of spermatogenesis calculated from the beginning of the recovery phase was 196 days. Importantly, spermatogenesis recovered to normal reference levels (sperm concentration ranging from 0 to 19×106/mL) in all but 17 participants who completed the 12-month recovery period, and 15 of those returned to normal reference levels at an extra 3-month follow-up visit. No long term data are available after the 2.5 year follow-up period.
An integrated, multivariate analysis of 30 studies was published by Liu et al. (8). The primary outcome was the time for the sperm concentration to recover to a threshold of 20 million/mL. Healthy eugonadal men aged 18-51 years were treated with androgens or androgens plus proestrogens. The median times for sperm to recover to thresholds of 20, 10, and 3 million per mL were 3.4, 3.0, and 2.5 months, respectively. Older age, Asian origin, shorter treatment duration, shorter-acting testosterone preparations, higher sperm concentrations at baseline, faster suppression of spermatogenesis, and lower LH levels at baseline were associated with higher rates of recovery (Figure 4). The contraceptive trials were in men of Chinese ethnicity and that comparison of findings to men of non-Chinese ethnicities may not be reliable.
Figure 4 Cessation of testosterone therapy.
The typical probability of recovery to 20 million per mL was 67% within 6 months, 90% within 12 months, 96% within 16 months, and 100% within 24 months (Table 1). This observed time to recovery may be helpful for counseling patients, but it should be cautioned that return of spermatogenesis may be prolonged for a small number of men. This study concluded that hormonal male contraceptive regimens show full reversibility within a predictable time course. A significant limitation of the published literature is a lack of pregnancy outcome data. Also, semen analysis data do not correlate with pregnancy outcomes and that none of the present literature addresses time to fecundity.
Table 1 Model-based probability of spermatogenic recovery to various thresholds. Adapted from Liu PY et al. Lancet 2006;367:1412-20
Full table
Lindsey E. Crosnoe1, Ethan Grober2, Dana Ohl3, Edward D. Kim1
1University of Tennessee Graduate School of Medicine, Knoxville, TN, USA; 2University of Toronto, Toronto, CA, Canada; 3University of Michigan, Ann Arbor, MI, USA
Correspondence to: Edward D. Kim, M.D. 1928 Alcoa Highway, Suite 222, Knoxville, TN 37920, USA. Email: ekim@utmck.edu.
Main problem: Testosterone replacement therapy inhibits spermatogenesis, representing a problem for hypogonadal men of reproductive age.
Methods: A literature review of PubMed from 1990-2013. Semen analysis and pregnancy outcomes, time to recovery of spermatogenesis, serum and intratesticular testosterone levels were examined.
Results: Exogenous testosterone suppresses intratesticular testosterone production, which is an absolute prerequisite for normal spermatogenesis. Therapies that protect the testis involve human chorionic gonadotropin (hCG) therapy or selective estrogen receptor modulators (SERMs), but may also include low dose hCG with exogenous testosterone. SERMs, such as clomiphene citrate, are effective for maintaining testosterone production and represent a well-tolerated, oral therapy. Routine use of aromatase inhibitors is not recommended based on a lack of long-term data.
Conclusions: Exogenous testosterone supplementation decreases sperm production. Studies of hormonal contraception indicate that most men have a return of normal sperm production within 1 year after discontinuation. Clomiphene citrate is a safe and effective therapy for men who desire to maintain future potential fertility. Although less frequently used in the general population, hCG therapy with or without testosterone supplementation represents an alternative treatment.
Keywords: Hypogonadism; selective estrogen receptor modulator; male fertility; testosterone; spermatogenesis
Submitted Jun 10, 2013. Accepted for publication Jun 20, 2013.
doi: 10.3978/j.issn.2223-4683.2013.06.01
Introduction
In a recent survey of U.S. urologists, Ko et al. (1) observed that approximately 25% have treated low testosterone levels associated with male infertility with exogenous testosterone. Many physicians are unaware that testosterone replacement therapies (TRT) adversely affect spermatogenesis. Increasingly, the diagnosis of hypogonadism is being made in younger men, many of whom are of reproductive age. In 1970, less than 15% of all men fathering children were over 35. Today, this percentage has risen to almost 25%. There has been a notable increase in fatherhood even among men in the 50 to 54 age group (2). However, there is a lack of expert recommendations regarding hormone replacement therapy in men of reproductive age.
Case presentationOther Section
A 30-year-old male presents with severe oligozoospermia (Figure 1). He has been on an intramuscular testosterone (IM-T) preparation for the treatment of symptomatic hypogonadism. He desires to have more children within in the next two years and has a normal exam. His baseline testosterone level was 200 ng/dL. The luteinizing hormone (LH) and follicular-stimulating hormone (FSH) levels were low. The pre-treatment semen analysis was normal. For potential treatment options, the physician could advise that (I) he switch to a topical testosterone; (II) stop testosterone therapy; (III) change to clomiphene citrate; or (IV) add human chorionic gonadotropin (hCG) to his IM-T.
Figure 1 Case presentation.
The best suggested answers are b and c (Figure 2). Option d may also be considered. Switching to a topical testosterone would still result in suppression of spermatogenesis. Similar effects on the HPG axis would be expected regardless of the route of administration. Stopping testosterone therapy is necessary to restore baseline HPG axis function and subsequent effects on spermatogenesis. Initiation of clomiphene citrate would address his symptomatic hypogonadism by increasing endogenous production of testosterone. Finally, there is a subset of men who do not want to consider cessation of testosterone therapy. For these men, addition of hCG to the IM-T has demonstrated beneficial effects on maintaining spermatogenesis.
Figure 2 Recommendations.
Regarding the treatment of similar hypogonadal men of reproductive age, this AUA Plenary Session Presentation will review (I) the extent of the problem; (II) the mechanisms by which testosterone therapy impairs spermatogenesis and (III) therapeutic approaches to protect the testis.
The extent of the problem
Symptomatic hypogonadism is not uncommon (3). It is estimated that more than 6.5 million men in the U.S. will have symptomatic androgen deficiency by 2025 (4). Between the ages of 20 and 30 years, men experience a decline in testosterone and free testosterone levels by 0.4% and 1.3% per year, respectively (5). Indeed, Mulligan et al. (6) observed that roughly 39% of men over the age of 45 had low serum testosterone levels, defined as less than 300 ng/dL.
Testosterone therapies have been increasingly utilized in aging men, as well as in men of reproductive age. Compared to the 1970s men are fathering children at an older age. Combined with the maturation of the Baby Boomer population, it is anticipated that there may be a significant increase in hypogonadal, aging men desiring to father children. The treatment of hypogonadism requires symptoms, as well as low serum testosterone levels. With the recent introduction of several newer commercial testosterone preparations and an increased public awareness of androgen deficiency syndromes, use of hormone replacement therapies (HRT) has been increasing. Over the past five years there has been an increase in testosterone prescriptions by 170% (7). However, men desiring to maintain their reproductive potential may not be fully aware of the risks of exogenous testosterone therapy.
Testosterone users and health care professionals are often unaware that exogenous testosterone suppresses the hypothalamic-pituitary-gonadal axis and may result in infertility. Physicians need to educate their patients about the potentially deleterious effects exogenous testosterone can have on spermatogenesis and on fertility. Indeed, use of intramuscular testosterone has been investigated as a male contraceptive agent (8).
How testosterone inhibits spermatogenesis and fertility
Mechanism of action
Testosterone inhibits both GnRH and gonadotropin secretion. Exogenous administration of synthetic testosterone results in negative feedback on the hypothalamic-pituitary axis, inhibiting GnRH, leading to inhibition of FSH and LH production. As a result, intratesticular testosterone levels (ITT) and overall testosterone production decrease. Exogenous testosterone therapies can suppress ITT production to such a degree that spermatogenesis can be dramatically compromised at ITT concentrations to less than 20 ng/mL, even resulting in azoospermia (9-11) (Figure 3).
Figure 3 How testosterone therapy affects spermatogenesis.
Spermatogenesis recovery after discontinuation of exogenous testosterone
Recovery of spermatogenesis after discontinuation exogenous testosterone is generally promising. First, the hypogonadal male interested in fathering children should attempt cessation of use of exogenous testosterone. A study by the WHO Task Force evaluated 271 men who received 200 mg of testosterone enanthate weekly (12). After 6 months, 157 (65%) of the men were azoospermic with the mean time to azoospermia at 120 days. After 6 months of treatment, the patients entered the recovery phase. While 84% of men were able to achieve a sperm density >20 million/mL after a median of 3.7 months, only 46% of patients were able to achieve their baseline sperm density.
Mills and associates evaluated the recovery of spermatogenesis after exogenous testosterone administration in of 26 men with a recent history of anabolic steroid use (13). All discontinued exogenous testosterone usage and were treated with hCG 3,000 units IM every other day for a minimum of 3 months. Of the two men who remained azoospermic, one had insufficient follow-up and the other was suspected of continued anabolic steroid use. Men using intramuscular testosterone at the time of presentation recovered spermatogenesis in an average of 3.1 months. However, men receiving transdermal testosterone supplementation at the time of presentation took an average of 7.4 months. The authors concluded that impairment of fertility following TRT suppression is reversible and that the rate of sperm may be related to the delivery system.
The published literature represents the best available evidence to date regarding the recovery of spermatogenesis after testosterone supplementation. A significant problem is that literature assesses the use of testosterone therapy as a male contraceptive agent. This situation may not reflect the hypogonadal male seen in clinical practice. However, most men who discontinue T supplementation have a return of normal sperm production within one year. The consistency of spermatogenesis recovery in clinical practice may not be as predictable as in contraceptive studies.
Testosterone as male contraceptive
Pharmaceutical companies have tried to develop hormonal male contraceptives with the intent of causing a withdrawal of the gonadotropin support to the testis with resultant suppression of spermatogenesis and ITT (14). Testosterone has been studied alone, as well as in combination with progestrogens (15). Testosterone used as a contraceptive agent may be used to determine the recovery of spermatogenesis after cessation of therapy. This analysis regarding the application of contraceptive studies to hypogonadal males is problematic. First, the men studied in contraceptive trials were not hypogonadal and did not have concerns about fertility. Many of these men had normal baseline testosterone levels, as well as sperm production. Additionally, different testosterone preparations and doses were used compared to clinical formulations.
Testosterone undecanoate was administered at a dose of 500 mg monthly for 30 months in a study of ethnic Chinese men (16). Over a 24-month efficacy phase (855 men), a cumulative contraceptive failure rate of 1.1% per 100 men was reported. Failure to achieve azoospermia or severe oligozoospermia (<1×106 sperm/mL) was seen in 4.8%. Median time to onset of azoospermia or severe oligozoospermia was 108 days. Spermatogenesis returned to the normal fertile reference range in all but two participants. The median time to recovery of spermatogenesis calculated from the beginning of the recovery phase was 196 days. Importantly, spermatogenesis recovered to normal reference levels (sperm concentration ranging from 0 to 19×106/mL) in all but 17 participants who completed the 12-month recovery period, and 15 of those returned to normal reference levels at an extra 3-month follow-up visit. No long term data are available after the 2.5 year follow-up period.
An integrated, multivariate analysis of 30 studies was published by Liu et al. (8). The primary outcome was the time for the sperm concentration to recover to a threshold of 20 million/mL. Healthy eugonadal men aged 18-51 years were treated with androgens or androgens plus proestrogens. The median times for sperm to recover to thresholds of 20, 10, and 3 million per mL were 3.4, 3.0, and 2.5 months, respectively. Older age, Asian origin, shorter treatment duration, shorter-acting testosterone preparations, higher sperm concentrations at baseline, faster suppression of spermatogenesis, and lower LH levels at baseline were associated with higher rates of recovery (Figure 4). The contraceptive trials were in men of Chinese ethnicity and that comparison of findings to men of non-Chinese ethnicities may not be reliable.
Figure 4 Cessation of testosterone therapy.
The typical probability of recovery to 20 million per mL was 67% within 6 months, 90% within 12 months, 96% within 16 months, and 100% within 24 months (Table 1). This observed time to recovery may be helpful for counseling patients, but it should be cautioned that return of spermatogenesis may be prolonged for a small number of men. This study concluded that hormonal male contraceptive regimens show full reversibility within a predictable time course. A significant limitation of the published literature is a lack of pregnancy outcome data. Also, semen analysis data do not correlate with pregnancy outcomes and that none of the present literature addresses time to fecundity.
Table 1 Model-based probability of spermatogenic recovery to various thresholds. Adapted from Liu PY et al. Lancet 2006;367:1412-20
Full table
Last edited: