Aging and the Male Reproductive System
Essential points
· In aging men there is a mild to moderate decline of gamete quality and fertility, which is accompanied by relative increase of the risk of adverse offspring outcome, but absolute risk remains low.
· Hormonal changes in aging men are individually variable with mean levels in the population showing mild decline of total T, increase of SHBG, more pronounced decline of free T, and moderate increase of LH.
· Comorbidities and in particular the increased prevalence of obesity play an important contributory role in the hormonal changes in aging men.
· Hypogonadism related to comorbidities tends to be of the secondary type, whereas changes related to aging appear to be primarily testicular.
· In a majority of cases, hypogonadism in aging men is linked to obesity and other comorbidities rather than to chronological age. Therefore, the frequently used term ‘late-onset hypogonadism’ is in fact a misnomer.
· Among the most consistent associations with low T in elderly men are the occurrence of sexual symptoms and lower hematocrit, and both seem at least partly responsive to T therapy.
· The relationship in aging men of body composition and metabolic health with serum T is complex and bidirectional. T therapy in older men with low T has limited beneficial effects on body composition, which translate in only marginal effects on metabolic health and physical function, of doubtful clinical significance.
· Association in aging men of sex steroids with altered bone metabolism and increased fracture risk is primarily with low E2 and high SHBG. Modest favorable effects on the maintenance of skeletal integrity may be an added benefice of T treatment initiated for another indication in older men with low serum T, but osteoporosis is not an indication for T therapy.
· Cognitive decline is not consistently associated with low T and T therapy has no beneficial effects on cognition in elderly men.
· There is little evidence for a role of moderate androgen decline in the occurrence of depressive symptoms, but T therapy has small beneficial effects on mood, depressive symptoms and vitality.
· Increased risk of stroke, but not of ischemic heart disease or myocardial infarction, has been associated with not optimal T (and/or DHT) serum levels.
· Association of low T with mortality reflects most likely reverse causality with low T a marker of poorer health status.
· The term ‘ T replacement therapy’ is a misnomer and should be avoided in the context of newly initiated T therapy in older men because we do not really know what the physiological-, desired- or ideal serum T levels are in older men. Desirability of (a particular modality of) T therapy in aging men depends primarily on the benefit-risk for meaningful clinical endpoints.
· Overall, neither the severity of clinical adverse effects attributable to low T, nor the nature and magnitude of beneficial treatment effects justify the concept of a broadly applied ‘T replacement therapy’ in older men with low T.
· Long-term (cardiovascular and prostate) safety of T therapy has not been established.
This narrative review presents an overview of present knowledge on fertility and reproductive hormones changes in aging men, the factors driving and modulating these changes, their clinical consequences, and benefits and risks of testosterone (T) therapy.
Aging is accompanied by moderate decline of gamete quality and fertility. Population mean levels show mild total T decline, SHBG increase, steeper free T decline, and moderate LH increase with important contribution of comorbidities (e.g. obesity) to these changes. Sexual symptoms and lower hematocrit are associated with low T and partly responsive to T therapy.
Relationship of serum T with body composition and metabolic health is bidirectional; limited beneficial effects of T therapy on body composition have only marginal effects on metabolic health and physical function. Skeletal changes are associated primarily with estradiol and SHBG. Cognitive decline is not consistently linked to low T and not improved by T therapy.
Although limited evidence links moderate androgen decline with depressive symptoms, T therapy has small beneficial effects on mood, depressive symptoms and vitality in elderly with low T. Not optimal T (and/or DHT) has been associated with increased risk of stroke, but not of ischemic heart disease, whereas association with mortality probably reflects that low T is a marker of poor health.
Globally, neither severity of clinical consequences attributable to low T, nor nature and magnitude of beneficial treatment effects justify the concept of some broadly applied ‘T replacement therapy’ in older men with low T. Moreover, long-term safety of T therapy is not established.
Mahmoud A, Lapauw B, T’Sjoen G, Kaufman JM, Huhtaniemi IT. Aging and the Male Reproductive System. 2019. Aging and the Male Reproductive System
Essential points
· In aging men there is a mild to moderate decline of gamete quality and fertility, which is accompanied by relative increase of the risk of adverse offspring outcome, but absolute risk remains low.
· Hormonal changes in aging men are individually variable with mean levels in the population showing mild decline of total T, increase of SHBG, more pronounced decline of free T, and moderate increase of LH.
· Comorbidities and in particular the increased prevalence of obesity play an important contributory role in the hormonal changes in aging men.
· Hypogonadism related to comorbidities tends to be of the secondary type, whereas changes related to aging appear to be primarily testicular.
· In a majority of cases, hypogonadism in aging men is linked to obesity and other comorbidities rather than to chronological age. Therefore, the frequently used term ‘late-onset hypogonadism’ is in fact a misnomer.
· Among the most consistent associations with low T in elderly men are the occurrence of sexual symptoms and lower hematocrit, and both seem at least partly responsive to T therapy.
· The relationship in aging men of body composition and metabolic health with serum T is complex and bidirectional. T therapy in older men with low T has limited beneficial effects on body composition, which translate in only marginal effects on metabolic health and physical function, of doubtful clinical significance.
· Association in aging men of sex steroids with altered bone metabolism and increased fracture risk is primarily with low E2 and high SHBG. Modest favorable effects on the maintenance of skeletal integrity may be an added benefice of T treatment initiated for another indication in older men with low serum T, but osteoporosis is not an indication for T therapy.
· Cognitive decline is not consistently associated with low T and T therapy has no beneficial effects on cognition in elderly men.
· There is little evidence for a role of moderate androgen decline in the occurrence of depressive symptoms, but T therapy has small beneficial effects on mood, depressive symptoms and vitality.
· Increased risk of stroke, but not of ischemic heart disease or myocardial infarction, has been associated with not optimal T (and/or DHT) serum levels.
· Association of low T with mortality reflects most likely reverse causality with low T a marker of poorer health status.
· The term ‘ T replacement therapy’ is a misnomer and should be avoided in the context of newly initiated T therapy in older men because we do not really know what the physiological-, desired- or ideal serum T levels are in older men. Desirability of (a particular modality of) T therapy in aging men depends primarily on the benefit-risk for meaningful clinical endpoints.
· Overall, neither the severity of clinical adverse effects attributable to low T, nor the nature and magnitude of beneficial treatment effects justify the concept of a broadly applied ‘T replacement therapy’ in older men with low T.
· Long-term (cardiovascular and prostate) safety of T therapy has not been established.
This narrative review presents an overview of present knowledge on fertility and reproductive hormones changes in aging men, the factors driving and modulating these changes, their clinical consequences, and benefits and risks of testosterone (T) therapy.
Aging is accompanied by moderate decline of gamete quality and fertility. Population mean levels show mild total T decline, SHBG increase, steeper free T decline, and moderate LH increase with important contribution of comorbidities (e.g. obesity) to these changes. Sexual symptoms and lower hematocrit are associated with low T and partly responsive to T therapy.
Relationship of serum T with body composition and metabolic health is bidirectional; limited beneficial effects of T therapy on body composition have only marginal effects on metabolic health and physical function. Skeletal changes are associated primarily with estradiol and SHBG. Cognitive decline is not consistently linked to low T and not improved by T therapy.
Although limited evidence links moderate androgen decline with depressive symptoms, T therapy has small beneficial effects on mood, depressive symptoms and vitality in elderly with low T. Not optimal T (and/or DHT) has been associated with increased risk of stroke, but not of ischemic heart disease, whereas association with mortality probably reflects that low T is a marker of poor health.
Globally, neither severity of clinical consequences attributable to low T, nor nature and magnitude of beneficial treatment effects justify the concept of some broadly applied ‘T replacement therapy’ in older men with low T. Moreover, long-term safety of T therapy is not established.
Mahmoud A, Lapauw B, T’Sjoen G, Kaufman JM, Huhtaniemi IT. Aging and the Male Reproductive System. 2019. Aging and the Male Reproductive System
