madman
Super Moderator
Summary: Chronic kidney disease (CKD) causes substantial alterations in the male endocrine system, which affect puberty, libido, and sexual function. A major effect of CKD is a reduction in testosterone levels because of both primary and hypogonadotropic hypogonadism. In addition to impairment of pubertal growth and sexual maturation in children with CKD, clinical evidence suggests that uremic hypogonadism strongly contributes to several CKD complications, including erectile dysfunction, muscle wasting, frailty, anemia, decreased bone mineralization, depression, and cognitive impairment. This review focuses on a reappraisal of the physiologic role of testosterone, with an emphasis on the hypogonadal condition linked to CKD and its complications.
Testosterone deficiency or hypogonadism is a common finding in men with chronic kidney disease (CKD), owing to decreased function of the hypothalamic−pituitary−gonadal axis and reduced androgen synthesis.1 In addition to impairment of pubertal growth and sexual maturation in children with CKD, clinical evidence in adults suggests that uremic hypogonadism strongly contributes to several common complications, including erectile dysfunction, muscle wasting, and frailty, anemia, decreased bone mineralization, depression, and cognitive impairment.1-3 In addition, hypogonadism might contribute to all-cause and cardiovascular disease mortality.1-3 There currently is little consideration of hypogonadism among nephrologists, therefore it often is overlooked. This review focuses on a reappraisal of the physiologic role of testosterone with emphasis on the hypogonadal condition linked to CKD and its complications.
PHYSIOLOGY OF TESTOSTERONE ACTION
Testosterone is released from the testis and to some extent from the adrenal medulla. Testosterone regulates lipid, carbohydrate, and protein metabolism, and modulates the function of different cells and tissues, including hematopoietic cells, muscle, fat, bone, heart, and kidney.4 In the kidney, testosterone promotes fluid retention by acting on aquaporin 1 and the Na+ /K+ exchanger.4 In vessels, testosterone favors vascular relaxation but promotes thrombocytosis and erythrocytosis.4 Based on various studies, testosterone has vasorelaxant, anti-atherosclerotic, antihyperlipidemic, and anti-inflammatory actions. In addition, in the heart, testosterone therapy exerts inotropic effects, T-wave prolongation, and reduction in the Q-T interval.
Testosterone circulates in plasma with 2% unbound free hormone, 40% bound to sex hormone-binding globulin (SHBG), and 58% more loosely bound to albumin. Guidelines suggest that hypogonadism should be diagnosed with total testosterone less than 350 ng/dL or free testosterone less than 80 ng/dL in the presence of symptoms.5 However, it still is unclear whether the biological actions of testosterone are best represented by the total, bioavailable, or unbound forms. The biologically active hormone is contained in the unbound and nonspecifically bound fractions. Circulating concentrations are approximately 15 to 25 times higher in adult men compared with women. With aging, men have gradual declines in average serum testosterone levels, with a 1% per year decrease in testosterone and a parallel increase in SHBG.6 The age-related decrease in circulating testosterone is associated with decreases in sexual function, bone mass, muscle mass, and strength, and increases in body fat, depression, and fatigue.7,8 In aging men, free testosterone appears to be a better predictor of arm and leg strength than total testosterone.9
African American ethnicity and a higher estimated glomerular filtration rate (GFR) are related to lower odds of having hypogonadism, while diabetes, higher body mass index, and visceral adiposity are associated with higher odds.8,9Therefore, hypogonadism is more frequent among menwithobesityandtype2diabetes (Fig.1).
*TESTOSTERONE AND SEXUAL DIMORPHISM OF KIDNEY DISEASES
*EFFECTS OF HYPOGONADISM
*DERANGEMENTS IN THE HYPOTHALAMIC −PITUITARY−GONADAL AXIS IN CKD
*TESTOSTERONE DEFICIENCY IN CKD: PREVALENCE AND ASSOCIATIONS
*CLINICAL PRESENTATION OF HYPOGONADISM IN CKD
*LATE-OCCURRING PUBERTY AND REDUCED PUBERTAL GROWTH IN CHILDREN WITH CKD
*SEXUAL DYSFUNCTION
*ANEMIA
*BONE FRAGILITY
*INFECTIONS
*MUSCLE WASTING
*FRAILTY
*TESTOSTERONE DEFICIENCY AND MORTALITY RISK IN THE GENERAL POPULATION AND IN DIALYSIS PATIENTS: CAUSAL EFFECT OR REVERSE CAUSALITY?
*HOW TO CORRECT MALE HYPOGONADISM IN CKD?
-Effects of Drugs and Different Dialysis Treatments
*TESTOSTERONE REPLACEMENT THERAPY IN HYPOGONADAL UREMIC MEN
*TESTOSTERONE TREATMENT, PROSTATE CANCER, AND CARDIOVASCULAR RISKS
Even if testosterone supplementation in hypogonadism has well-defined favorable effects,74-79 its inherent risks are undefined. Androgen deficiency in young men resulting from organic disease of the hypothalamus, pituitary gland, or testes has been treated with testosterone replacement for many years without evidence of increased cardiovascular events. In contrast to these cohort studies, some retrospective studies have shown an increased number of cardiovascular events in men who received testosterone replacement therapy, whereas other studies found either neutral or beneficial effects.69,70 Moreover, observational studies have shown that testosterone replacement therapy might increase susceptibility to future prostate cancer.86
These findings, together with results of a recent study on testosterone replacement in older men with hypogonadism that was terminated early because of an excess of cardiovascular events in the testosterone group,87 led the Food and Drug Administration to release a warning statement about the potential cardiovascular risks of testosterone replacement therapy and kindled the discussion on the cardiovascular safety of testosterone replacement.88 However, a recent meta-analysis of 39 randomized controlled trials and 10 observational studies86 concluded that there is no statistically significant increased risk of testosterone treatment on a composite outcome of myocardial infarction, stroke, and mortality. As a matter of fact, no trials of testosterone replacement therapy published to date were designed or adequately powered to assess prostate cancer and cardiovascular events87,88; therefore, the safety of long-term testosterone therapy has not been established.
*The Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy ResponSE in Hypogonadal Men trial (NCT03518034) design is a trial of testosterone therapy that is adequately powered to assess cardiovascular events and the incidence of prostate cancer, but its results will take several years to become available.88 Unfortunately, the Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy ResponSE in Hypogonadal Men trial excludes subjects at advanced (stages 4-5) CKD stages.
SUMMARY
A major effect of CKD is a reduction in testosterone levels because of both primary and hypogonadotropic hypogonadism. In addition to impairment of pubertal growth and sexual maturation in children with CKD, uremic hypogonadism contributes to several CKD complications, including erectile dysfunction, wasting and frailty, anemia, decreased bone mineralization, depression, and cognitive impairment. In addition, hypogonadism may contribute to all-cause and cardiovascular disease mortality and the progression to ESRD. It is interesting that testosterone supplementation has the potential to reverse or attenuate CKD complications. In particular, upon binding to androgen receptors, the testosterone downward signal is positioned to counterbalance the catabolic pathways that are primed by the uremic state. In muscle, testosterone increases protein synthesis through stimulation of androgen receptors and activation of the insulin-like growth factor-1 pathway; in addition, it promotes myonuclear accretion and satellite cell recruitment. Testosterone replacement for androgen deficient male CKD patients has some support from available studies on muscle mass and function, but lacks a robust evidence base and carries hypothetical risks. The safety of long-term testosterone therapy has not been established in the general population. Similarly, there is a need for clinical trials to evaluate the impact of testosterone treatment on musculoskeletal tissue, frailty, cardiovascular, and overall safety. Until the results of the ongoing long-term large trial are available, nephrologists need to individualize testosterone treatment after having an informed discussion with their patients about the risks and benefits of testosterone replacement therapy.
Testosterone deficiency or hypogonadism is a common finding in men with chronic kidney disease (CKD), owing to decreased function of the hypothalamic−pituitary−gonadal axis and reduced androgen synthesis.1 In addition to impairment of pubertal growth and sexual maturation in children with CKD, clinical evidence in adults suggests that uremic hypogonadism strongly contributes to several common complications, including erectile dysfunction, muscle wasting, and frailty, anemia, decreased bone mineralization, depression, and cognitive impairment.1-3 In addition, hypogonadism might contribute to all-cause and cardiovascular disease mortality.1-3 There currently is little consideration of hypogonadism among nephrologists, therefore it often is overlooked. This review focuses on a reappraisal of the physiologic role of testosterone with emphasis on the hypogonadal condition linked to CKD and its complications.
PHYSIOLOGY OF TESTOSTERONE ACTION
Testosterone is released from the testis and to some extent from the adrenal medulla. Testosterone regulates lipid, carbohydrate, and protein metabolism, and modulates the function of different cells and tissues, including hematopoietic cells, muscle, fat, bone, heart, and kidney.4 In the kidney, testosterone promotes fluid retention by acting on aquaporin 1 and the Na+ /K+ exchanger.4 In vessels, testosterone favors vascular relaxation but promotes thrombocytosis and erythrocytosis.4 Based on various studies, testosterone has vasorelaxant, anti-atherosclerotic, antihyperlipidemic, and anti-inflammatory actions. In addition, in the heart, testosterone therapy exerts inotropic effects, T-wave prolongation, and reduction in the Q-T interval.
Testosterone circulates in plasma with 2% unbound free hormone, 40% bound to sex hormone-binding globulin (SHBG), and 58% more loosely bound to albumin. Guidelines suggest that hypogonadism should be diagnosed with total testosterone less than 350 ng/dL or free testosterone less than 80 ng/dL in the presence of symptoms.5 However, it still is unclear whether the biological actions of testosterone are best represented by the total, bioavailable, or unbound forms. The biologically active hormone is contained in the unbound and nonspecifically bound fractions. Circulating concentrations are approximately 15 to 25 times higher in adult men compared with women. With aging, men have gradual declines in average serum testosterone levels, with a 1% per year decrease in testosterone and a parallel increase in SHBG.6 The age-related decrease in circulating testosterone is associated with decreases in sexual function, bone mass, muscle mass, and strength, and increases in body fat, depression, and fatigue.7,8 In aging men, free testosterone appears to be a better predictor of arm and leg strength than total testosterone.9
African American ethnicity and a higher estimated glomerular filtration rate (GFR) are related to lower odds of having hypogonadism, while diabetes, higher body mass index, and visceral adiposity are associated with higher odds.8,9Therefore, hypogonadism is more frequent among menwithobesityandtype2diabetes (Fig.1).
*TESTOSTERONE AND SEXUAL DIMORPHISM OF KIDNEY DISEASES
*EFFECTS OF HYPOGONADISM
*DERANGEMENTS IN THE HYPOTHALAMIC −PITUITARY−GONADAL AXIS IN CKD
*TESTOSTERONE DEFICIENCY IN CKD: PREVALENCE AND ASSOCIATIONS
*CLINICAL PRESENTATION OF HYPOGONADISM IN CKD
*LATE-OCCURRING PUBERTY AND REDUCED PUBERTAL GROWTH IN CHILDREN WITH CKD
*SEXUAL DYSFUNCTION
*ANEMIA
*BONE FRAGILITY
*INFECTIONS
*MUSCLE WASTING
*FRAILTY
*TESTOSTERONE DEFICIENCY AND MORTALITY RISK IN THE GENERAL POPULATION AND IN DIALYSIS PATIENTS: CAUSAL EFFECT OR REVERSE CAUSALITY?
*HOW TO CORRECT MALE HYPOGONADISM IN CKD?
-Effects of Drugs and Different Dialysis Treatments
*TESTOSTERONE REPLACEMENT THERAPY IN HYPOGONADAL UREMIC MEN
*TESTOSTERONE TREATMENT, PROSTATE CANCER, AND CARDIOVASCULAR RISKS
Even if testosterone supplementation in hypogonadism has well-defined favorable effects,74-79 its inherent risks are undefined. Androgen deficiency in young men resulting from organic disease of the hypothalamus, pituitary gland, or testes has been treated with testosterone replacement for many years without evidence of increased cardiovascular events. In contrast to these cohort studies, some retrospective studies have shown an increased number of cardiovascular events in men who received testosterone replacement therapy, whereas other studies found either neutral or beneficial effects.69,70 Moreover, observational studies have shown that testosterone replacement therapy might increase susceptibility to future prostate cancer.86
These findings, together with results of a recent study on testosterone replacement in older men with hypogonadism that was terminated early because of an excess of cardiovascular events in the testosterone group,87 led the Food and Drug Administration to release a warning statement about the potential cardiovascular risks of testosterone replacement therapy and kindled the discussion on the cardiovascular safety of testosterone replacement.88 However, a recent meta-analysis of 39 randomized controlled trials and 10 observational studies86 concluded that there is no statistically significant increased risk of testosterone treatment on a composite outcome of myocardial infarction, stroke, and mortality. As a matter of fact, no trials of testosterone replacement therapy published to date were designed or adequately powered to assess prostate cancer and cardiovascular events87,88; therefore, the safety of long-term testosterone therapy has not been established.
*The Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy ResponSE in Hypogonadal Men trial (NCT03518034) design is a trial of testosterone therapy that is adequately powered to assess cardiovascular events and the incidence of prostate cancer, but its results will take several years to become available.88 Unfortunately, the Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy ResponSE in Hypogonadal Men trial excludes subjects at advanced (stages 4-5) CKD stages.
SUMMARY
A major effect of CKD is a reduction in testosterone levels because of both primary and hypogonadotropic hypogonadism. In addition to impairment of pubertal growth and sexual maturation in children with CKD, uremic hypogonadism contributes to several CKD complications, including erectile dysfunction, wasting and frailty, anemia, decreased bone mineralization, depression, and cognitive impairment. In addition, hypogonadism may contribute to all-cause and cardiovascular disease mortality and the progression to ESRD. It is interesting that testosterone supplementation has the potential to reverse or attenuate CKD complications. In particular, upon binding to androgen receptors, the testosterone downward signal is positioned to counterbalance the catabolic pathways that are primed by the uremic state. In muscle, testosterone increases protein synthesis through stimulation of androgen receptors and activation of the insulin-like growth factor-1 pathway; in addition, it promotes myonuclear accretion and satellite cell recruitment. Testosterone replacement for androgen deficient male CKD patients has some support from available studies on muscle mass and function, but lacks a robust evidence base and carries hypothetical risks. The safety of long-term testosterone therapy has not been established in the general population. Similarly, there is a need for clinical trials to evaluate the impact of testosterone treatment on musculoskeletal tissue, frailty, cardiovascular, and overall safety. Until the results of the ongoing long-term large trial are available, nephrologists need to individualize testosterone treatment after having an informed discussion with their patients about the risks and benefits of testosterone replacement therapy.
