madman
Super Moderator
Treatment of Men with Central Hypogonadism: Alternatives for Testosterone Replacement Therapy
Abstract: Central hypogonadism is a clinical condition, characterized by sexual symptoms and low serum testosterone levels, due to an impaired function of the hypothalamus or pituitary gland. Testosterone replacement therapy (TRT) is the standard treatment for hypogonadism, but it has some disadvantages. TRT is not a good option in men wishing to preserve fertility, nor in men with (high risk of) prostate cancer, polycythemia, thrombophilia, and severe cardiovascular disease. In this review, we discuss alternative treatments for central hypogonadism. If reversible causes are present, non-pharmacological interventions can be therapeutic. Gonadotropins are a good alternative to TRT when fertility is desired in the near future though they require frequent injections. Clomiphene citrate and tamoxifen seem to be a safe alternative for the treatment of functional central hypogonadism in men, as several studies reported a significant increase in testosterone levels with these drugs. However, their use is off-label and data supporting the efficacy of clomiphene citrate and tamoxifen on hypogonadal symptoms are insufficient. For this reason, clomiphene citrate and tamoxifen should not be used in routine clinical practice to treat sexual symptoms in men with central hypogonadism.
1. Introduction
The production of testosterone is driven by the hypothalamic-pituitary-gonadal (HPG)- axis. Hypothalamic gonadotropin-releasing hormone (GnRH) stimulates the secretion of gonadotropins by the pituitary gland, namely luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH regulates the secretion of testosterone by the Leydig cells, whereas FSH supports spermatogenesis [1].
Testosterone deficiency can be asymptomatic or lead to a broad spectrum of symptoms ranging from sexual symptoms (reduced libido and morning erections, erectile dysfunction) to nonspecific symptoms, such as fatigue, depression, poor concentration, altered body composition with more body fat and decreased muscle mass, and lower bone mineral density [2,3].
Hypogonadism is a clinical condition characterized by hypogonadal signs and symptoms, together with low serum testosterone levels due to an impaired function of the HPG axis [1,4]. According to the Endocrine Society and European Academy of Andrology guidelines, only men with symptoms or signs of testosterone deficiency and repeatedly low serum testosterone concentrations on morning blood samples, taken in standardized conditions should be diagnosed with hypogonadism [2,3]
In primary hypogonadism, impaired androgen production is caused by a testicular problem, such as Klinefelter syndrome or testicular injury, resulting in high gonadotropin levels (hypergonadotropic hypogonadism). Central hypogonadism, on the other hand, is caused by impaired function of the hypothalamus or pituitary gland and characterized by low or inappropriately normal gonadotropin levels (hypogonadotropic hypogonadism) [3]
Underlying organic causes of central hypogonadism consist of congenital and acquired conditions (Figure 1). Congenital hypogonadotropic hypogonadism (CHH) is characterized by isolated central hypogonadism, due to the deficient secretion or action of GnRH. In around 50% of patients, CHH is associated with hypo- or anosmia (Kallmann syndrome), whereas in the other half, the olfactory function is preserved (normosmic CHH) [5–7]. Up to date, a genetic cause can be identified in almost 50% of people with CHH. Some of these genes are associated with both normosmic CHH and Kallman syndrome [7]. Hereditary hemochromatosis is an autosomal recessive disorder that disrupts the regulation of iron in the body. Iron overload can lead to organ damage and hypogonadism in later life [8]. Acquired organic central hypogonadism includes neoplasm, injury, and infiltrative disorders of the hypothalamus or pituitary [1,3].
In functional central hypogonadism, the HPG axis is structurally intact, but gonadotropin production is suppressed. Frequent causes are Cushing syndrome, hyperprolactinemia, obesity, and comorbidities. Drugs associated with central hypogonadism include opioids, glucocorticoids, and withdrawal of anabolic-androgenic steroids [1,3,9]
Late-onset hypogonadism is a condition in aging men that is characterized by low serum testosterone levels and sexual signs or symptoms. Testosterone levels gradually decline with age. This can become symptomatic in some men, although there is only a weak association between sexual symptoms and testosterone levels in aging men. Therefore, the European Male Aging Study (EMAS) group suggests that only aging men with concomitantly low total and free serum testosterone levels and at least three sexual symptoms should be diagnosed with late-onset hypogonadism [10,11]. This clinical syndrome is associated with obesity, metabolic syndrome, and chronic diseases [12,13]. However, recent evidence suggests that genes causing CHH can also predispose to mild late-onset hypogonadism [14,15].
Testosterone replacement therapy (TRT) is the standard treatment for hypogonadism. It is available in different formulations, such as transdermal patches or gels, intramuscular injections, subcutaneous pellets, nasal gels, and capsules [3].
TRT has some disadvantages. It may result in gynecomastia, acne, testicular atrophy, and erythrocytosis. It suppresses spermatogenesis, and thus, cannot be used in patients with a desire to have children in the near future. TRT is also contraindicated in people with (high risk of) prostate cancer, a history of breast cancer, thrombophilia, elevated hematocrit, untreated severe obstructive sleep apnea, uncontrolled heart failure, and myocardial infarction or stroke within the last 6 months [3].
Moreover, the role of TRT to treat men with functional or late-onset hypogonadism remains controversial because of unclear indications and potential side effects [1,9]. Recently, the Testosterone Trials learned that treating men with late-onset hypogonadism with TRT resulted in a moderate improvement of sexual function, hemoglobin levels, and bone mineral density, and had slightly positive effects on mood, depressive symptoms, and walking distance [16]
*In this review, we will discuss alternative treatments for central hypogonadism (summarized in Table 1). These treatments aim to increase endogenous testosterone production instead of administering exogenous testosterone by means of TRT [17]. The choice of treatment depends on different questions, as visualized in Figure 2.
2. Non-Pharmacological Treatment
3. Gonadotropins
3.1. Mechanism of Action
In central hypogonadism, gonadotropin levels are low or inappropriately normal due to an impaired function of the hypothalamus or pituitary gland. Exogenous gonadotropins can be administered to replace endogenous gonadotropin secretion. Recombinant or urinary human chorionic gonadotropin (hCG) functions as an LH analog stimulating the production of testosterone by the Leydig cells. Human menopausal gonadotropin (hMG) is extracted from human urine and contains both FSH and LH [31]. FSH is available as a urinary derivative (highly purified FSH (hpFSH)), synthetic recombinant human FSH (rhFSH), and as corifollitropin alfa, a long-acting FSH-analog [17,31–33]. The urinary derivates are cheaper than the others [31]. Advantages of the recombinant forms of FSH comparing to the urinary derivatives include the limitless availability, the absence of contaminating urinary compounds, the greater stability of concentration, and the greater efficacy in restoring fertility in men with hypogonadism [34]. rhFSH has a short half-life which means it has to be injected 3 times a week. Corifollitropin alfa is an FSH-analog with a similar pharmacodynamic profile as rhFSH but a longer half-life. Therefore, the frequency of corifollitropin alfa injections can be diminished to once every week [33].
3.2. Indications
3.3. Treatment Regimens
3.4. Results
3.5. Adverse Effects and Monitoring of Therapy
4. Pulsatile GnRH Therapy
Pulsatile GnRH treatment has been used to restore fertility in patients with central hypogonadism with intact pituitary function. [1]. As the physiological secretion of GnRH is episodic, continuous administration of GnRH leads to desensitization of the pituitary and suppression of gonadotropin secretion. GnRH therapy must thus be administered in a pulsatile manner by a subcutaneous pump [42,46]. Pulsatile GnRH therapy succeeds to induce spermatogenesis in 80% of men. This means the outcome of GnRH therapy and therapy with gonadotropins is similar [40]. Pulsatile GnRH therapy is expensive and requires experience and specific pump material [1,35,40] and it is no longer used in routine clinical practice.
Take-home points for the uninformed:
*As the physiological secretion of GnRH is episodic, continuous administration of GnRH leads to desensitization of the pituitary and suppression of gonadotropin secretion.
* GnRH therapy must thus be administered in a pulsatile manner by a subcutaneous pump [42,46].
*Pulsatile GnRH is a less attractive option because of the cost and the need for expertise and specific pump material.
5. Clomiphene Citrate and Tamoxifen
5.1. Mechanism of Action
Selective estrogen receptor modulators (SERMs) selectively modulate the estrogen receptor leading to variable effects in different tissues. In the central nervous system, some SERMs, namely clomiphene citrate and tamoxifen, function as antagonists to the estrogen receptor, thereby, inhibiting the negative feedback of estrogen to the hypothalamus and pituitary gland. This results in increased endogenous gonadotropin levels which stimulate testosterone production [4,17,47].
5.2. Off-Label Use and Treatment Regimens
5.3. Results
5.4. Adverse Effects
6. Aromatase Inhibitors
6.1. Mechanism of Action and Off-Label Use
Aromatase inhibitors (AIs) inhibit the conversion of androgens to estrogens [1]. Like SERMs, AIs inhibit the negative feedback mechanism on gonadotropin secretion, leading to increased production of testosterone [4]. Unlike the SERMs clomiphene citrate and tamoxifen, AIs reduce estrogen levels [47].
AIs are not approved to treat men with functional central hypogonadism, but anastrozole and letrozole are sometimes used as an off-label treatment [4,17].
6.2. Results
6.3. Adverse Effects
7. Conclusions
Testosterone replacement therapy is considered standard therapy for male hypogonadism. However, TRT is not a good option in men wishing to preserve fertility nor in men with (high risk of) prostate cancer, polycythemia, thrombophilia, and severe cardiovascular disease. Different alternative treatment options for central hypogonadism are available.
First, it is important to keep in mind that non-pharmacological interventions can be therapeutic in men with functional central hypogonadism. In particular, in obese men, lifestyle modifications are of primary importance in an attempt to restore gonadal function. Drugs negatively interfering with the HPG axis should be avoided.
Gonadotropins are a good alternative to TRT when fertility is desired in the near future though they require frequent injections. Pulsatile GnRH is a less attractive option because of the cost and the need for expertise and specific pump material.
Clomiphene citrate, tamoxifen, and AIs are used off-label in men with functional central hypogonadism. Multiple studies reported a significant increase in testosterone levels with these drugs in this study population. As AIs have a negative impact on bone mineral density, their use is not recommended. Furthermore, the clear clinical benefit of treatment with AIs is lacking. The SERMs clomiphene citrate and tamoxifen seem to be a safe off-label alternative for TRT for the treatment of functional central hypogonadism in men, especially in younger men who wish to maintain their fertility. However, up until now, data supporting the efficacy of clomiphene citrate and tamoxifen on hypogonadal symptoms are insufficient. Larger RCTs with a clearer definition of the study population and long-time follow-up are necessary to determine the effect of these SERMs on several outcome parameters. Until then, clomiphene citrate and tamoxifen should not be used to treat sexual symptoms in men with central hypogonadism.
Abstract: Central hypogonadism is a clinical condition, characterized by sexual symptoms and low serum testosterone levels, due to an impaired function of the hypothalamus or pituitary gland. Testosterone replacement therapy (TRT) is the standard treatment for hypogonadism, but it has some disadvantages. TRT is not a good option in men wishing to preserve fertility, nor in men with (high risk of) prostate cancer, polycythemia, thrombophilia, and severe cardiovascular disease. In this review, we discuss alternative treatments for central hypogonadism. If reversible causes are present, non-pharmacological interventions can be therapeutic. Gonadotropins are a good alternative to TRT when fertility is desired in the near future though they require frequent injections. Clomiphene citrate and tamoxifen seem to be a safe alternative for the treatment of functional central hypogonadism in men, as several studies reported a significant increase in testosterone levels with these drugs. However, their use is off-label and data supporting the efficacy of clomiphene citrate and tamoxifen on hypogonadal symptoms are insufficient. For this reason, clomiphene citrate and tamoxifen should not be used in routine clinical practice to treat sexual symptoms in men with central hypogonadism.
1. Introduction
The production of testosterone is driven by the hypothalamic-pituitary-gonadal (HPG)- axis. Hypothalamic gonadotropin-releasing hormone (GnRH) stimulates the secretion of gonadotropins by the pituitary gland, namely luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH regulates the secretion of testosterone by the Leydig cells, whereas FSH supports spermatogenesis [1].
Testosterone deficiency can be asymptomatic or lead to a broad spectrum of symptoms ranging from sexual symptoms (reduced libido and morning erections, erectile dysfunction) to nonspecific symptoms, such as fatigue, depression, poor concentration, altered body composition with more body fat and decreased muscle mass, and lower bone mineral density [2,3].
Hypogonadism is a clinical condition characterized by hypogonadal signs and symptoms, together with low serum testosterone levels due to an impaired function of the HPG axis [1,4]. According to the Endocrine Society and European Academy of Andrology guidelines, only men with symptoms or signs of testosterone deficiency and repeatedly low serum testosterone concentrations on morning blood samples, taken in standardized conditions should be diagnosed with hypogonadism [2,3]
In primary hypogonadism, impaired androgen production is caused by a testicular problem, such as Klinefelter syndrome or testicular injury, resulting in high gonadotropin levels (hypergonadotropic hypogonadism). Central hypogonadism, on the other hand, is caused by impaired function of the hypothalamus or pituitary gland and characterized by low or inappropriately normal gonadotropin levels (hypogonadotropic hypogonadism) [3]
Underlying organic causes of central hypogonadism consist of congenital and acquired conditions (Figure 1). Congenital hypogonadotropic hypogonadism (CHH) is characterized by isolated central hypogonadism, due to the deficient secretion or action of GnRH. In around 50% of patients, CHH is associated with hypo- or anosmia (Kallmann syndrome), whereas in the other half, the olfactory function is preserved (normosmic CHH) [5–7]. Up to date, a genetic cause can be identified in almost 50% of people with CHH. Some of these genes are associated with both normosmic CHH and Kallman syndrome [7]. Hereditary hemochromatosis is an autosomal recessive disorder that disrupts the regulation of iron in the body. Iron overload can lead to organ damage and hypogonadism in later life [8]. Acquired organic central hypogonadism includes neoplasm, injury, and infiltrative disorders of the hypothalamus or pituitary [1,3].
In functional central hypogonadism, the HPG axis is structurally intact, but gonadotropin production is suppressed. Frequent causes are Cushing syndrome, hyperprolactinemia, obesity, and comorbidities. Drugs associated with central hypogonadism include opioids, glucocorticoids, and withdrawal of anabolic-androgenic steroids [1,3,9]
Late-onset hypogonadism is a condition in aging men that is characterized by low serum testosterone levels and sexual signs or symptoms. Testosterone levels gradually decline with age. This can become symptomatic in some men, although there is only a weak association between sexual symptoms and testosterone levels in aging men. Therefore, the European Male Aging Study (EMAS) group suggests that only aging men with concomitantly low total and free serum testosterone levels and at least three sexual symptoms should be diagnosed with late-onset hypogonadism [10,11]. This clinical syndrome is associated with obesity, metabolic syndrome, and chronic diseases [12,13]. However, recent evidence suggests that genes causing CHH can also predispose to mild late-onset hypogonadism [14,15].
Testosterone replacement therapy (TRT) is the standard treatment for hypogonadism. It is available in different formulations, such as transdermal patches or gels, intramuscular injections, subcutaneous pellets, nasal gels, and capsules [3].
TRT has some disadvantages. It may result in gynecomastia, acne, testicular atrophy, and erythrocytosis. It suppresses spermatogenesis, and thus, cannot be used in patients with a desire to have children in the near future. TRT is also contraindicated in people with (high risk of) prostate cancer, a history of breast cancer, thrombophilia, elevated hematocrit, untreated severe obstructive sleep apnea, uncontrolled heart failure, and myocardial infarction or stroke within the last 6 months [3].
Moreover, the role of TRT to treat men with functional or late-onset hypogonadism remains controversial because of unclear indications and potential side effects [1,9]. Recently, the Testosterone Trials learned that treating men with late-onset hypogonadism with TRT resulted in a moderate improvement of sexual function, hemoglobin levels, and bone mineral density, and had slightly positive effects on mood, depressive symptoms, and walking distance [16]
*In this review, we will discuss alternative treatments for central hypogonadism (summarized in Table 1). These treatments aim to increase endogenous testosterone production instead of administering exogenous testosterone by means of TRT [17]. The choice of treatment depends on different questions, as visualized in Figure 2.
2. Non-Pharmacological Treatment
3. Gonadotropins
3.1. Mechanism of Action
In central hypogonadism, gonadotropin levels are low or inappropriately normal due to an impaired function of the hypothalamus or pituitary gland. Exogenous gonadotropins can be administered to replace endogenous gonadotropin secretion. Recombinant or urinary human chorionic gonadotropin (hCG) functions as an LH analog stimulating the production of testosterone by the Leydig cells. Human menopausal gonadotropin (hMG) is extracted from human urine and contains both FSH and LH [31]. FSH is available as a urinary derivative (highly purified FSH (hpFSH)), synthetic recombinant human FSH (rhFSH), and as corifollitropin alfa, a long-acting FSH-analog [17,31–33]. The urinary derivates are cheaper than the others [31]. Advantages of the recombinant forms of FSH comparing to the urinary derivatives include the limitless availability, the absence of contaminating urinary compounds, the greater stability of concentration, and the greater efficacy in restoring fertility in men with hypogonadism [34]. rhFSH has a short half-life which means it has to be injected 3 times a week. Corifollitropin alfa is an FSH-analog with a similar pharmacodynamic profile as rhFSH but a longer half-life. Therefore, the frequency of corifollitropin alfa injections can be diminished to once every week [33].
3.2. Indications
3.3. Treatment Regimens
3.4. Results
3.5. Adverse Effects and Monitoring of Therapy
4. Pulsatile GnRH Therapy
Pulsatile GnRH treatment has been used to restore fertility in patients with central hypogonadism with intact pituitary function. [1]. As the physiological secretion of GnRH is episodic, continuous administration of GnRH leads to desensitization of the pituitary and suppression of gonadotropin secretion. GnRH therapy must thus be administered in a pulsatile manner by a subcutaneous pump [42,46]. Pulsatile GnRH therapy succeeds to induce spermatogenesis in 80% of men. This means the outcome of GnRH therapy and therapy with gonadotropins is similar [40]. Pulsatile GnRH therapy is expensive and requires experience and specific pump material [1,35,40] and it is no longer used in routine clinical practice.
Take-home points for the uninformed:
*As the physiological secretion of GnRH is episodic, continuous administration of GnRH leads to desensitization of the pituitary and suppression of gonadotropin secretion.
* GnRH therapy must thus be administered in a pulsatile manner by a subcutaneous pump [42,46].
*Pulsatile GnRH is a less attractive option because of the cost and the need for expertise and specific pump material.
5. Clomiphene Citrate and Tamoxifen
5.1. Mechanism of Action
Selective estrogen receptor modulators (SERMs) selectively modulate the estrogen receptor leading to variable effects in different tissues. In the central nervous system, some SERMs, namely clomiphene citrate and tamoxifen, function as antagonists to the estrogen receptor, thereby, inhibiting the negative feedback of estrogen to the hypothalamus and pituitary gland. This results in increased endogenous gonadotropin levels which stimulate testosterone production [4,17,47].
5.2. Off-Label Use and Treatment Regimens
5.3. Results
5.4. Adverse Effects
6. Aromatase Inhibitors
6.1. Mechanism of Action and Off-Label Use
Aromatase inhibitors (AIs) inhibit the conversion of androgens to estrogens [1]. Like SERMs, AIs inhibit the negative feedback mechanism on gonadotropin secretion, leading to increased production of testosterone [4]. Unlike the SERMs clomiphene citrate and tamoxifen, AIs reduce estrogen levels [47].
AIs are not approved to treat men with functional central hypogonadism, but anastrozole and letrozole are sometimes used as an off-label treatment [4,17].
6.2. Results
6.3. Adverse Effects
7. Conclusions
Testosterone replacement therapy is considered standard therapy for male hypogonadism. However, TRT is not a good option in men wishing to preserve fertility nor in men with (high risk of) prostate cancer, polycythemia, thrombophilia, and severe cardiovascular disease. Different alternative treatment options for central hypogonadism are available.
First, it is important to keep in mind that non-pharmacological interventions can be therapeutic in men with functional central hypogonadism. In particular, in obese men, lifestyle modifications are of primary importance in an attempt to restore gonadal function. Drugs negatively interfering with the HPG axis should be avoided.
Gonadotropins are a good alternative to TRT when fertility is desired in the near future though they require frequent injections. Pulsatile GnRH is a less attractive option because of the cost and the need for expertise and specific pump material.
Clomiphene citrate, tamoxifen, and AIs are used off-label in men with functional central hypogonadism. Multiple studies reported a significant increase in testosterone levels with these drugs in this study population. As AIs have a negative impact on bone mineral density, their use is not recommended. Furthermore, the clear clinical benefit of treatment with AIs is lacking. The SERMs clomiphene citrate and tamoxifen seem to be a safe off-label alternative for TRT for the treatment of functional central hypogonadism in men, especially in younger men who wish to maintain their fertility. However, up until now, data supporting the efficacy of clomiphene citrate and tamoxifen on hypogonadal symptoms are insufficient. Larger RCTs with a clearer definition of the study population and long-time follow-up are necessary to determine the effect of these SERMs on several outcome parameters. Until then, clomiphene citrate and tamoxifen should not be used to treat sexual symptoms in men with central hypogonadism.
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