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Aging and androgens: Physiology and clinical implications (2022)
Bradley D. Anawalt · Alvin M. Matsumoto
Abstract
In men> ~35 years, aging is associated with perturbations in the hypothalamus-pituitary–testicular axis and declining serum testosterone concentrations. The major changes are decreased gonadotropin-releasing hormone (GnRH) outflow and decreased Leydig cell responsivity to stimulation by luteinizing hormone (LH). These physiologic changes increase the prevalence of biochemical secondary hypogonadism—a low serum testosterone concentration without an elevated serum LH concentration. Obesity, medications such as opioids or corticosteroids, and systemic disease further reduce GnRH and LH secretion and might result in biochemical or clinical secondary hypogonadism. Biochemical secondary hypogonadism related to aging often remits with weight reduction and avoidance or treatment of other factors that suppress GnRH and LH secretion. Starting at age ~65–70, progressive Leydig cell dysfunction increases the prevalence of biochemical primary hypogonadism—a low serum testosterone concentration with an elevated serum LH concentration. Unlike biochemical secondary hypogonadism in older men, biochemical primary hypogonadism is generally irreversible. The evaluation of low serum testosterone concentrations in older men requires a careful assessment of symptoms, signs, and causes of male hypogonadism. In older men with a body mass index (BMI)≥30, biochemical secondary hypogonadism and without an identifiable cause of hypothalamus or pituitary pathology, weight reduction and improvement of overall health might reverse biochemical hypogonadism. For older men with biochemical primary hypogonadism, testosterone replacement therapy might be beneficial. Because aging is associated with decreased metabolism of testosterone and increased tissue-specific androgen sensitivity, lower dosages of testosterone replacement therapy are often effective and safer in older men.
1 Introduction
Serum total and free testosterone concentrations decline in aging men, and this decline typically begins by their 4th decade. This decline tends to be gradual and progressive and is due to perturbations primarily at the levels of the hypothalamus and testes. The focus of this review is to describe the physiological mechanisms of the aging-related decline of serum testosterone concentrations, the health and lifestyle factors that contribute to this aging-related decline, and the aging-related changes in testosterone metabolism and androgen sensitivity that potentially attenuate the effects of this decline. We also discuss whether the aging-related decline in serum testosterone is a cause or a marker of poor health and whether aging-related male hypogonadism exists. Finally, we integrate the evidence for the pathophysiology of these aging-related changes in testosterone concentrations, testosterone metabolism, and androgen sensitivity into a rational clinical approach for the assessment and management of an older man with a low serum testosterone concentration.
2 Physiological changes of the hypothalamus‑pituitary–testicular axis that affect serum testosterone concentrations associated with aging in men: an overview
The entire male hypothalamus-pituitary–testicular axis is directly or indirectly affected by aging with a net effect of decreased testosterone and sperm production in most older men. With aging, there is impaired hypothalamic secretion of gonadotropin-releasing hormone (GnRH) that results in decreased pituitary gonadotropin secretion of luteinizing hormone (LH), and Leydig cells become less responsive to LH stimulation compared to young men (Fig. 1)
2.1 Aging‑related perturbations of hypothalamic secretion of gonadotropin‑releasing hormone concentrations associated with aging in men
2.2 Aging‑related perturbations of pituitary secretion of luteinizing hormone concentrations associated with aging in men
2.3 Aging‑related perturbations of Leydig cell secretion of testosterone concentrations associated with aging in men
2.4 Aging‑related changes in testosterone metabolism and androgen sensitivity associated with aging in men
2.5 Summary of aging‑related changes of hypothalamus‑pituitary gonadal axis and clinical implications
In healthy aging men, there is decreased and less orderly hypothalamic GnRH outflow that results in decreased LH secretion from pituitary gonadotropes. There is also decreased Leydig cell secretion of testosterone in response to LH stimulation. These effects of aging might be attenuated or absent in very healthy older men. Furthermore, these aging-related physiologic changes in the hypothalamus-pituitary–testicular axis likely vary between individuals, and deficits might be variably expressed within individuals. Overall, there is a declining function in the hypothalamic GnRH neurons and testicular Leydig cells in aging men. This decline of hypothalamic-pituitary–testicular axis function is partially mitigated by decreased metabolic clearance of testosterone and possibly by increased organ-specific androgen sensitivity. Although there are limited data, there do not appear to be clinically important differences in these aging-related changes of the hypothalamus-pituitary–gonadal axis in men of different races [35, 39, 40, 46, 47].
3 Epidemiology of serum testosterone concentrations associated with aging in men
Several studies have demonstrated a gradual longitudinal decline in serum total and free testosterone concentration in men that begins (at least by) age 35 and is followed by a sharper decline starting at age~65 [3, 48–54]. The decline has been observed in most studies using immunoassays or mass spectrometry assays, but the measured decline is greater in the studies that have used the more accurate mass spectrometry assays [47]
3.1 Epidemiological studies of the relationship between aging, obesity, co‑morbidities, and lifestyle
3.1.1 Obesity, serum testosterone, and SHBG concentrations and aging‑related changes in aging men
3.1.2 Overall health, co‑morbidities, lifestyle factor, and aging‑related changes in serum testosterone
3.2 Summary of obesity, co‑morbidities, lifestyle factors, and aging‑related changes in testosterone
Although it has been tempting to invoke a causal relationship between declining serum testosterone concentrations in the decline of androgen-responsive endpoints such as strength, bone density, and sexual function, epidemiology studies suggest that low serum testosterone concentrations are more likely to be a marker of poor health, obesity, and co-morbidities than caused by aging per se. Although obesity and co-morbidities might contribute significantly to the aging-related decline of serum testosterone, there is an independent effect of aging on the hypothalamus-pituitary–testicular axis. The physiology studies demonstrating decreased hypothalamic GnRH outflow and Leydig cell secretion of testosterone were in healthy, non-obese young and older men [6–9, 21, 22, 25, 26, 69]. Because aging is associated with decreased overall function of the hypothalamus-pituitary–testicular axis, men become more vulnerable to factors that further suppress testosterone production and serum testosterone concentrations.
4 Epidemiology of serum dihydrotestosterone and estradiol concentrations associated with aging in men
Based on a small number of studies using accurate assay methods, there seems to be a decline in serum dihydrotestosterone concentrations that is similar to the decline in serum total testosterone (0.5–1.2% per year in mass spectrometry studies) in men starting at~35 years and that decreases more rapidly in the middle of the 7th decade of life. Serum estradiol concentrations, on the other hand, tend to remain relatively stable and begin to increase in the middle of the 7th decade of life.
5 The epidemiology of biochemical primary and secondary hypogonadism in aging men
5.1 Biochemical primary hypogonadism associated with aging in men
5.1.1 Compensated biochemical primary hypogonadism associated with aging in men
5.2 Secondary hypogonadism associated with aging in men
6 Does late‑onset male hypogonadism exist?
The largest evidence gaps about the clinical implications of aging-related hypogonadism are the following: 1) the lack of prospective longitudinal epidemiological studies of healthy, racially and geographically diverse men with baseline data on symptoms, signs, and outcomes of hypogonadism (e.g., bone density) and serum testosterone (measured on at least two occasions by a validated, harmonized assay) [73], and serum gonadotropins with a long-term followup of these metrics; and 2) placebo-controlled studies of the effects of testosterone therapy in healthy, racially and geographically diverse men with repeatedly and consistently low serum testosterone concentrations (measured in a validated, harmonized assay), no identifiable cause of hypogonadism and a broad range of ages and BMIs.
7 Summary of clinical implications of aging‑related changes of the hypothalamus‑pituitary–testicular axis
The clinical implications of the aging-related changes are summarized in Table 1. The clinical implications include the following: 1) decreased hypothalamic outflow of GnRH leads to greater vulnerability to the development of biochemical secondary hypogonadism due to medications, obesity, and systemic disease; 2) progressive Leydig cell dysfunction results in a higher incidence and prevalence of persistent primary biochemical hypogonadism in men over age 65; 3) and because there is decreased metabolism of testosterone and increased tissue-specific androgen sensitivity associated with aging, older men with hypogonadism often require lower testosterone replacement therapy dosages.
The largest evidence gaps about the clinical implications of aging-related hypogonadism are the following: 1) the lack of prospective longitudinal epidemiological studies of healthy, racially and geographically diverse men with baseline data on symptoms, signs, and outcomes of hypogonadism (e.g., bone density) and serum testosterone (measured on at least two occasions by a validated, harmonized assay) [73], and serum gonadotropins with the long-term follow-up of these metrics; and 2) placebo-controlled studies of the effects of testosterone therapy in healthy, racially and geographically diverse men with repeatedly and consistently low serum testosterone concentrations (measured in a validated, harmonized assay), no identifiable cause of hypogonadism and a broad range of ages and BMIs.
8 Conclusions and clinical guidance
Aging is associated with decreased function of the hypothalamus-pituitary–testicular axis that leads to increased incidence and prevalence of biochemical secondary hypogonadism in men 35–65 years old and increased incidence and prevalence of biochemical primary hypogonadism in men>65 years old. Biochemical secondary hypogonadism occurs predominantly in men with higher BMIs and is likely to remit with weight loss or interventions that improve overall health. Clinicians should be cautious about the initiation of testosterone therapy for older men with biochemical secondary hypogonadism and should focus on interventions to improve overall health including increased exercise and lifestyle changes (Fig. 3a). Biochemical primary hypogonadism is more likely to persist in men>65 years old. Because Klinefelter syndrome is the most common cause of primary hypogonadism and it is commonly underdiagnosed, serum karyotyping should be considered in all older men with biochemical primary hypogonadism [79]. Testosterone therapy should be initiated in older men with primary hypogonadism due to Klinefelter syndrome. There are no clinical trials of testosterone therapy in older men with biochemical primary hypogonadism. Based on the benefit-to-detriment ratio observed in younger with primary hypogonadism and the likelihood that biochemical primary hypogonadism is a permanent condition in men>65 years, testosterone therapy is reasonable to consider in older men with persistently low serum testosterone concentrations and high serum gonadotropin concentrations (Fig. 3b)
Compensated biochemical primary hypogonadism may persist indefinitely in older men.
Because the benefits of testosterone are not proven and the risks are unknown for older men with compensated primary hypogonadism, the clinician should manage compensated primary hypogonadism similarly to biochemical secondary hypogonadism in older men by promoting healthy lifestyle choices and limiting or avoiding causes of decreased hypothalamus-pituitary–testicular function such as glucocorticoids, opioids, drugs that induce hyperprolactinemia or anti-androgens such as spironolactone. Because many older men with compensated hypogonadism maintain normal serum testosterone concentrations for many years, testosterone therapy generally should be withheld until serum testosterone concentrations have declined below normal (unless there is a high degree of suspicion for hypogonadism).
Understanding the physiological changes of aging in the male hypothalamus-pituitary–testicular axis is essential for the management of low serum testosterone concentrations in aging men. There is a spectrum in the pathophysiologic effects of aging on a given individual man’s gonadal axis that depends on the man’s baseline hypothalamic-pituitary–testicular reserve function, differential rates of physiologic aging, and co-morbidities including obesity and systemic disease. On one end of the spectrum, some very healthy aging men with baseline normal hypothalamus-pituitary–testicular axis function might experience little or no change in serum testosterone concentrations into their 8th, 9th, or 10th decade. In contrast to these rare men, many more aging men with baseline normal hypothalamus-pituitary–testicular axis function might experience declining serum testosterone concentrations as their BMI rises and systemic diseases (and their therapies that might affect GnRH outflow) accrue. These men may eventually develop biochemical secondary hypogonadism that might remit with the treatment of obesity or systemic disease and avoidance of drugs that affect the hypothalamus-pituitary axis. On the other hand, aging may unmask a baseline compromised hypothalamus or pituitary dysfunction (e.g., a patient with radiotherapy of head neck cancer who suffers some hypothalamic-pituitary injury due to radiation scatter to the sellar region) might develop irreversible secondary hypogonadism with aging. Finally, a significant minority of aging men>65 years seem to develop irreversible primary hypogonadism due to progressive aging-related decline in overall Leydig cell function; again, a decreased baseline reserve of Leydig cell function might contribute to or accelerate the onset of aging-related primary hypogonadism. Based on the physiology of aging, it is best for the clinician to consider advancing age and obesity as potential contributors as opposed to the sole causes of the increasing incidence of low serum testosterone concentrations in aging men. Because obesity is potentially treatable, lifestyle measures represent a sensible preventive and therapeutic intervention for most aging men that present with biochemical secondary hypogonadism and no identifiable pathology of the hypothalamus-pituitary–testicular axis.
Knowledge of the physiological changes of the hypothalamus-pituitary–testicular axis is important for the evaluation and management of aging men with low serum testosterone concentrations. It is essential to base the diagnosis of clinical hypogonadism on symptoms, signs, and biochemical evidence of androgen deficiency and to restrict testosterone therapy to men who are most likely to benefit. At any age, the men most likely to benefit from testosterone therapy are those who have symptoms, signs, or outcomes of androgen deficiency and who have consistently low to very low serum testosterone concentrations.
Bradley D. Anawalt · Alvin M. Matsumoto
Abstract
In men> ~35 years, aging is associated with perturbations in the hypothalamus-pituitary–testicular axis and declining serum testosterone concentrations. The major changes are decreased gonadotropin-releasing hormone (GnRH) outflow and decreased Leydig cell responsivity to stimulation by luteinizing hormone (LH). These physiologic changes increase the prevalence of biochemical secondary hypogonadism—a low serum testosterone concentration without an elevated serum LH concentration. Obesity, medications such as opioids or corticosteroids, and systemic disease further reduce GnRH and LH secretion and might result in biochemical or clinical secondary hypogonadism. Biochemical secondary hypogonadism related to aging often remits with weight reduction and avoidance or treatment of other factors that suppress GnRH and LH secretion. Starting at age ~65–70, progressive Leydig cell dysfunction increases the prevalence of biochemical primary hypogonadism—a low serum testosterone concentration with an elevated serum LH concentration. Unlike biochemical secondary hypogonadism in older men, biochemical primary hypogonadism is generally irreversible. The evaluation of low serum testosterone concentrations in older men requires a careful assessment of symptoms, signs, and causes of male hypogonadism. In older men with a body mass index (BMI)≥30, biochemical secondary hypogonadism and without an identifiable cause of hypothalamus or pituitary pathology, weight reduction and improvement of overall health might reverse biochemical hypogonadism. For older men with biochemical primary hypogonadism, testosterone replacement therapy might be beneficial. Because aging is associated with decreased metabolism of testosterone and increased tissue-specific androgen sensitivity, lower dosages of testosterone replacement therapy are often effective and safer in older men.
1 Introduction
Serum total and free testosterone concentrations decline in aging men, and this decline typically begins by their 4th decade. This decline tends to be gradual and progressive and is due to perturbations primarily at the levels of the hypothalamus and testes. The focus of this review is to describe the physiological mechanisms of the aging-related decline of serum testosterone concentrations, the health and lifestyle factors that contribute to this aging-related decline, and the aging-related changes in testosterone metabolism and androgen sensitivity that potentially attenuate the effects of this decline. We also discuss whether the aging-related decline in serum testosterone is a cause or a marker of poor health and whether aging-related male hypogonadism exists. Finally, we integrate the evidence for the pathophysiology of these aging-related changes in testosterone concentrations, testosterone metabolism, and androgen sensitivity into a rational clinical approach for the assessment and management of an older man with a low serum testosterone concentration.
2 Physiological changes of the hypothalamus‑pituitary–testicular axis that affect serum testosterone concentrations associated with aging in men: an overview
The entire male hypothalamus-pituitary–testicular axis is directly or indirectly affected by aging with a net effect of decreased testosterone and sperm production in most older men. With aging, there is impaired hypothalamic secretion of gonadotropin-releasing hormone (GnRH) that results in decreased pituitary gonadotropin secretion of luteinizing hormone (LH), and Leydig cells become less responsive to LH stimulation compared to young men (Fig. 1)
2.1 Aging‑related perturbations of hypothalamic secretion of gonadotropin‑releasing hormone concentrations associated with aging in men
2.2 Aging‑related perturbations of pituitary secretion of luteinizing hormone concentrations associated with aging in men
2.3 Aging‑related perturbations of Leydig cell secretion of testosterone concentrations associated with aging in men
2.4 Aging‑related changes in testosterone metabolism and androgen sensitivity associated with aging in men
2.5 Summary of aging‑related changes of hypothalamus‑pituitary gonadal axis and clinical implications
In healthy aging men, there is decreased and less orderly hypothalamic GnRH outflow that results in decreased LH secretion from pituitary gonadotropes. There is also decreased Leydig cell secretion of testosterone in response to LH stimulation. These effects of aging might be attenuated or absent in very healthy older men. Furthermore, these aging-related physiologic changes in the hypothalamus-pituitary–testicular axis likely vary between individuals, and deficits might be variably expressed within individuals. Overall, there is a declining function in the hypothalamic GnRH neurons and testicular Leydig cells in aging men. This decline of hypothalamic-pituitary–testicular axis function is partially mitigated by decreased metabolic clearance of testosterone and possibly by increased organ-specific androgen sensitivity. Although there are limited data, there do not appear to be clinically important differences in these aging-related changes of the hypothalamus-pituitary–gonadal axis in men of different races [35, 39, 40, 46, 47].
3 Epidemiology of serum testosterone concentrations associated with aging in men
Several studies have demonstrated a gradual longitudinal decline in serum total and free testosterone concentration in men that begins (at least by) age 35 and is followed by a sharper decline starting at age~65 [3, 48–54]. The decline has been observed in most studies using immunoassays or mass spectrometry assays, but the measured decline is greater in the studies that have used the more accurate mass spectrometry assays [47]
3.1 Epidemiological studies of the relationship between aging, obesity, co‑morbidities, and lifestyle
3.1.1 Obesity, serum testosterone, and SHBG concentrations and aging‑related changes in aging men
3.1.2 Overall health, co‑morbidities, lifestyle factor, and aging‑related changes in serum testosterone
3.2 Summary of obesity, co‑morbidities, lifestyle factors, and aging‑related changes in testosterone
Although it has been tempting to invoke a causal relationship between declining serum testosterone concentrations in the decline of androgen-responsive endpoints such as strength, bone density, and sexual function, epidemiology studies suggest that low serum testosterone concentrations are more likely to be a marker of poor health, obesity, and co-morbidities than caused by aging per se. Although obesity and co-morbidities might contribute significantly to the aging-related decline of serum testosterone, there is an independent effect of aging on the hypothalamus-pituitary–testicular axis. The physiology studies demonstrating decreased hypothalamic GnRH outflow and Leydig cell secretion of testosterone were in healthy, non-obese young and older men [6–9, 21, 22, 25, 26, 69]. Because aging is associated with decreased overall function of the hypothalamus-pituitary–testicular axis, men become more vulnerable to factors that further suppress testosterone production and serum testosterone concentrations.
4 Epidemiology of serum dihydrotestosterone and estradiol concentrations associated with aging in men
Based on a small number of studies using accurate assay methods, there seems to be a decline in serum dihydrotestosterone concentrations that is similar to the decline in serum total testosterone (0.5–1.2% per year in mass spectrometry studies) in men starting at~35 years and that decreases more rapidly in the middle of the 7th decade of life. Serum estradiol concentrations, on the other hand, tend to remain relatively stable and begin to increase in the middle of the 7th decade of life.
5 The epidemiology of biochemical primary and secondary hypogonadism in aging men
5.1 Biochemical primary hypogonadism associated with aging in men
5.1.1 Compensated biochemical primary hypogonadism associated with aging in men
5.2 Secondary hypogonadism associated with aging in men
6 Does late‑onset male hypogonadism exist?
The largest evidence gaps about the clinical implications of aging-related hypogonadism are the following: 1) the lack of prospective longitudinal epidemiological studies of healthy, racially and geographically diverse men with baseline data on symptoms, signs, and outcomes of hypogonadism (e.g., bone density) and serum testosterone (measured on at least two occasions by a validated, harmonized assay) [73], and serum gonadotropins with a long-term followup of these metrics; and 2) placebo-controlled studies of the effects of testosterone therapy in healthy, racially and geographically diverse men with repeatedly and consistently low serum testosterone concentrations (measured in a validated, harmonized assay), no identifiable cause of hypogonadism and a broad range of ages and BMIs.
7 Summary of clinical implications of aging‑related changes of the hypothalamus‑pituitary–testicular axis
The clinical implications of the aging-related changes are summarized in Table 1. The clinical implications include the following: 1) decreased hypothalamic outflow of GnRH leads to greater vulnerability to the development of biochemical secondary hypogonadism due to medications, obesity, and systemic disease; 2) progressive Leydig cell dysfunction results in a higher incidence and prevalence of persistent primary biochemical hypogonadism in men over age 65; 3) and because there is decreased metabolism of testosterone and increased tissue-specific androgen sensitivity associated with aging, older men with hypogonadism often require lower testosterone replacement therapy dosages.
The largest evidence gaps about the clinical implications of aging-related hypogonadism are the following: 1) the lack of prospective longitudinal epidemiological studies of healthy, racially and geographically diverse men with baseline data on symptoms, signs, and outcomes of hypogonadism (e.g., bone density) and serum testosterone (measured on at least two occasions by a validated, harmonized assay) [73], and serum gonadotropins with the long-term follow-up of these metrics; and 2) placebo-controlled studies of the effects of testosterone therapy in healthy, racially and geographically diverse men with repeatedly and consistently low serum testosterone concentrations (measured in a validated, harmonized assay), no identifiable cause of hypogonadism and a broad range of ages and BMIs.
8 Conclusions and clinical guidance
Aging is associated with decreased function of the hypothalamus-pituitary–testicular axis that leads to increased incidence and prevalence of biochemical secondary hypogonadism in men 35–65 years old and increased incidence and prevalence of biochemical primary hypogonadism in men>65 years old. Biochemical secondary hypogonadism occurs predominantly in men with higher BMIs and is likely to remit with weight loss or interventions that improve overall health. Clinicians should be cautious about the initiation of testosterone therapy for older men with biochemical secondary hypogonadism and should focus on interventions to improve overall health including increased exercise and lifestyle changes (Fig. 3a). Biochemical primary hypogonadism is more likely to persist in men>65 years old. Because Klinefelter syndrome is the most common cause of primary hypogonadism and it is commonly underdiagnosed, serum karyotyping should be considered in all older men with biochemical primary hypogonadism [79]. Testosterone therapy should be initiated in older men with primary hypogonadism due to Klinefelter syndrome. There are no clinical trials of testosterone therapy in older men with biochemical primary hypogonadism. Based on the benefit-to-detriment ratio observed in younger with primary hypogonadism and the likelihood that biochemical primary hypogonadism is a permanent condition in men>65 years, testosterone therapy is reasonable to consider in older men with persistently low serum testosterone concentrations and high serum gonadotropin concentrations (Fig. 3b)
Compensated biochemical primary hypogonadism may persist indefinitely in older men.
Because the benefits of testosterone are not proven and the risks are unknown for older men with compensated primary hypogonadism, the clinician should manage compensated primary hypogonadism similarly to biochemical secondary hypogonadism in older men by promoting healthy lifestyle choices and limiting or avoiding causes of decreased hypothalamus-pituitary–testicular function such as glucocorticoids, opioids, drugs that induce hyperprolactinemia or anti-androgens such as spironolactone. Because many older men with compensated hypogonadism maintain normal serum testosterone concentrations for many years, testosterone therapy generally should be withheld until serum testosterone concentrations have declined below normal (unless there is a high degree of suspicion for hypogonadism).
Understanding the physiological changes of aging in the male hypothalamus-pituitary–testicular axis is essential for the management of low serum testosterone concentrations in aging men. There is a spectrum in the pathophysiologic effects of aging on a given individual man’s gonadal axis that depends on the man’s baseline hypothalamic-pituitary–testicular reserve function, differential rates of physiologic aging, and co-morbidities including obesity and systemic disease. On one end of the spectrum, some very healthy aging men with baseline normal hypothalamus-pituitary–testicular axis function might experience little or no change in serum testosterone concentrations into their 8th, 9th, or 10th decade. In contrast to these rare men, many more aging men with baseline normal hypothalamus-pituitary–testicular axis function might experience declining serum testosterone concentrations as their BMI rises and systemic diseases (and their therapies that might affect GnRH outflow) accrue. These men may eventually develop biochemical secondary hypogonadism that might remit with the treatment of obesity or systemic disease and avoidance of drugs that affect the hypothalamus-pituitary axis. On the other hand, aging may unmask a baseline compromised hypothalamus or pituitary dysfunction (e.g., a patient with radiotherapy of head neck cancer who suffers some hypothalamic-pituitary injury due to radiation scatter to the sellar region) might develop irreversible secondary hypogonadism with aging. Finally, a significant minority of aging men>65 years seem to develop irreversible primary hypogonadism due to progressive aging-related decline in overall Leydig cell function; again, a decreased baseline reserve of Leydig cell function might contribute to or accelerate the onset of aging-related primary hypogonadism. Based on the physiology of aging, it is best for the clinician to consider advancing age and obesity as potential contributors as opposed to the sole causes of the increasing incidence of low serum testosterone concentrations in aging men. Because obesity is potentially treatable, lifestyle measures represent a sensible preventive and therapeutic intervention for most aging men that present with biochemical secondary hypogonadism and no identifiable pathology of the hypothalamus-pituitary–testicular axis.
Knowledge of the physiological changes of the hypothalamus-pituitary–testicular axis is important for the evaluation and management of aging men with low serum testosterone concentrations. It is essential to base the diagnosis of clinical hypogonadism on symptoms, signs, and biochemical evidence of androgen deficiency and to restrict testosterone therapy to men who are most likely to benefit. At any age, the men most likely to benefit from testosterone therapy are those who have symptoms, signs, or outcomes of androgen deficiency and who have consistently low to very low serum testosterone concentrations.
