madman
Super Moderator
CARDIOVASCULAR AND METABOLIC ACTIONS OF THE ANDROGENS: IS TESTOSTERONE A JANUS-FACED MOLECULE? (20220
John N. Stallone, Ahmed K. Oloyo
Abstract
Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide and in the Western world, one-third of all deaths are attributed to CVD. A conspicuous characteristic of this healthcare epidemic is that most CVD is higher in men than in age-matched premenopausal women, yet reasons for these obvious sex differences remain poorly understood. Driven by clinical case and epidemiological studies and supported by animal experiments, a strong dogma emerged early on that testosterone (TES) exerts deleterious effects on cardiovascular health and exacerbates the development of CVD and metabolic dysfunctions in men. In this review, earlier and more recent clinical and experimental animal evidence of cardiovascular and metabolic effects of androgens are discussed. The more recent evidence overwhelmingly suggests that it is progressive, age-dependent declines in TES levels in men that exacerbate CVD and metabolic dysfunctions, while TES exerts beneficial systemic hypotensive effects and protects against metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM). Recent findings reveal the existence of bi-directional modulation of glucose and fat homeostasis by TES in females vs. males, such that age-dependent declines in TES levels in males and abnormal increases in normally low TES levels in females both result in similar dysfunction in glucose and fat homeostasis, resulting in the development of MetS and T2DM, central risk factors for the development of CVD, in men as well as women. These findings suggest that the long-held view that TES is detrimental to male health should be discarded in favor of the view that, at least in men, TES is beneficial to cardiovascular and metabolic health.
1. Introduction
1.1. Androgen chemistry/structure-function
The sex steroid hormones are derived from the 27-carbon sterol precursor molecule cholesterol and are classified into one of three distinct families according to the number of carbon atoms contained; thus, there are the C18 estranes (estrogen derivatives), the C19 androstanes (androgen derivatives), and the C21 pregnanes (progesterone derivatives). The male sex steroid hormones (testosterone (TES) and related C19 androgens) are the molecules responsible for the differentiation, development, and maintenance of the male reproductive system and secondary sexual characteristics that are so strikingly different between males and females. In males, the biosynthesis of TES occurs in the Leydig (interstitial) cells beginning with the conversion of cholesterol to pregnenolone and then proceeding by one of two distinct routes, in which pregnenolone is first converted to the intermediate dehydroepiandrosterone (DHEA) and then to androstenediol via the 5 pathway (predominant in humans) or alternately, in which pregnenolone is first converted to progesterone and then to androstenedione via the 4 pathway (prevalent in other species). Both androstenediol and androstenedione then undergo direct conversion to TES, which may then be metabolized in some androgen target tissues to form the highly potent metabolite 5-dihydrotestosterone (5-DHT) or its largely inactive isomer 5-DHT, or in peripheral tissues such as adipose to form 17-estradiol (Fig. 1). In females, TES is produced in the theca cells of the ovarian follicles and is predominantly converted to 17-estradiol in the neighboring follicular granulosa cells. It is important to emphasize that both androgens and estrogens are synthesized in both sexes and circulate in the plasma, albeit at quite different levels. Plasma levels of TES in females are 5-10% of that in males, while levels of estrogen in males are 10-30% of that in females; thus, androgens and estrogens play unique roles in the regulation of reproductive, cardiovascular, metabolic, and other functions in females and males [1,2].
1.2. History of androgens
1.3. Mechanisms of androgen actions
1.4. The dogma of androgens in health and disease
The conundrum of dose- and sex-dependent effects of the androgens as beneficial vs. deleterious hormones important in the regulation of cardiovascular and metabolic function is reminiscent of the Roman God Janus who was the patron of doorways, beginnings and endings, passages, transitions, time, and duality, and was depicted as having two faces, symbolic of his ability to simultaneously look into the future and the past (Fig. 3). The two faces of Janus frequently symbolized change and transitions such as the progress of the past to the future, from one condition to another, from one vision to another, and represented time because he could see into both the past with one face and into the future with the other. The related term Janus-faced then, seems to be an appropriate moniker for our current level of understanding of the conundrum of cardiovascular and metabolic effects of TES; thus, the present article will review the literature on cardiovascular and metabolic effects of TES and related androgens in males vs. females with the goal of solving the conundrum of beneficial vs. deleterious effects of TES and thereby answer the question: is TES a Janus-faced molecule?
2. Cardiovascular effects of the androgens
2.1. Historical perspective of the androgens
2.2. The phases of androgen studies and clinical use in the cardiovascular system
2.3. Cardiovascular effects of the androgens
2.4. Sex differences in the cardiovascular effects of the androgens
2.5. Androgen chemical structure-function relationships
2.6. Significance of the cardiovascular effects of the androgens
3. Metabolic effects of androgens
3.1. Historical perspective of metabolic effects of the androgens
3.2. Role of androgens in regulation of metabolism in males in health and disease
3.3. Role of androgens in regulation of metabolism in females in health and disease
4. Summary and conclusions—where do we go from here?
It is increasingly apparent that endogenous TES and other androgens exert widespread beneficial effects on cardiovascular function. Recent experimental animal and human clinical trials over the last 10 years increasingly challenge the long-standing dogma that TES exerts detrimental effects on male cardiovascular health and is largely responsible for the greater incidence of CVD in men than in women. Instead, it is now becoming apparent that it is the gradual decline in circulating TES levels that are a normal part of the aging process that contributes to age-dependent increases in CVD and metabolic dysfunction. Indeed, the incidence of HT and CAD in men increases, while plasma TES level decreases, with age. The intersection of these two plots at middle age suggests (but does not establish causality) that age-dependent increases in HT and CVD are related to the progressive declines in TES with age (Fig. 6). In parallel, recent experimental animal studies reveal that castration of male rats results in the long-term development of HT that is completely reversed by TRT. Further, clinical hypogonadism in aging men is associated with both HT and MetS, which exacerbate the development of CVD. While the most recent human clinical trials overwhelmingly report that TRT does not increase cardiovascular risk or mortality in older hypogonadal men and that such therapy is associated with reductions in BP and improvement in the MetS (e.g., insulin resistance, serum lipids, diabetes, etc.), all of which are risk factors for CVD, clinical trials and observational studies of TRT do not provide unequivocal evidence that exogenous TRT is safe and does not increase the risk of CV events. However, it is also clear that at least some of the human studies suffer from poor experimental design and statistical analysis, and investigator bias. Thus, unequivocal proof that TRT is a safe and efficacious treatment for hypogonadism and associated cardiovascular and metabolic dysfunctions will require more better-designed clinical trials that avoid the shortcomings of previous studies. Nevertheless, the growing recognition of the roles of androgens and aging in the pathogenesis of HT is an emerging and important mechanism. Our understanding of the role of androgens in female health as well as CVD and metabolic dysfunction is still relatively limited and future studies are needed to increase the awareness of the mechanisms underlying the striking sexual dimorphism in the cardiovascular and metabolic effects of TES.
An important part of validating the value of TRT in the treatment of CVD and metabolic dysfunction is advancing the study of selective androgen receptor modulators (SARMs), which could provide for selective androgen treatment of cardiovascular or metabolic dysfunction, while avoiding detrimental effects of more conventional androgen analogs, such as the anabolic steroids. Another related topic of great importance is the study of novel endogenous metabolites of TES and other androgens. In particular, the TES metabolite 5-DHT, which is the genomically inactive stereoisomer of the most potent androgen 5-DHT, mediates many of the reproductive effects of TES. While genomicallty inactive as an androgen, 5-DHT is highly efficacious and potent as a vasodilator under both acute and chronic settings [41,44]. Recent preliminary studies suggest that chronic treatment of castrated male rats with 5-DHT exerts renal as well as vascular effects that completely reverse castration-induced hypertension after only one week of treatment, whereas treatment with TES requires 5 weeks [121]. Whether 5-DHT also exerts non-genomic metabolic effects is uncertain, but clearly additional study of this metabolite may be fruitful in the treatment of CVD and metabolic dysfunction related to hypogonadism in men.
Finally, let us address the conundrum of beneficial vs. deleterious effects of TES and thereby answer the question: is TES a Janus-faced molecule? Based on the accumulating recent evidence provided in this review, the long-held view that TES is detrimental to male health should likely be discarded in favor of the view that, at least in men, TES overall is beneficial to cardiovascular and metabolic health and that the apparent conundrum of androgen effects is the result of earlier dogmatic views combined with a limited number of earlier studies that suggested beneficial effects. With the rapidly accumulating beneficial effects of TES reported in the last 10- 15 years, it must be concluded that in men, TES is most definitely not a Janus-faced molecule, but rather one that looks only in one direction, that of promoting health. With regard to the role of androgens in women, the situation is quite different and at present, it would appear that TES is a Janus-faced molecule that mediates detrimental as well as beneficial effects in women.
John N. Stallone, Ahmed K. Oloyo
Abstract
Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide and in the Western world, one-third of all deaths are attributed to CVD. A conspicuous characteristic of this healthcare epidemic is that most CVD is higher in men than in age-matched premenopausal women, yet reasons for these obvious sex differences remain poorly understood. Driven by clinical case and epidemiological studies and supported by animal experiments, a strong dogma emerged early on that testosterone (TES) exerts deleterious effects on cardiovascular health and exacerbates the development of CVD and metabolic dysfunctions in men. In this review, earlier and more recent clinical and experimental animal evidence of cardiovascular and metabolic effects of androgens are discussed. The more recent evidence overwhelmingly suggests that it is progressive, age-dependent declines in TES levels in men that exacerbate CVD and metabolic dysfunctions, while TES exerts beneficial systemic hypotensive effects and protects against metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM). Recent findings reveal the existence of bi-directional modulation of glucose and fat homeostasis by TES in females vs. males, such that age-dependent declines in TES levels in males and abnormal increases in normally low TES levels in females both result in similar dysfunction in glucose and fat homeostasis, resulting in the development of MetS and T2DM, central risk factors for the development of CVD, in men as well as women. These findings suggest that the long-held view that TES is detrimental to male health should be discarded in favor of the view that, at least in men, TES is beneficial to cardiovascular and metabolic health.
1. Introduction
1.1. Androgen chemistry/structure-function
The sex steroid hormones are derived from the 27-carbon sterol precursor molecule cholesterol and are classified into one of three distinct families according to the number of carbon atoms contained; thus, there are the C18 estranes (estrogen derivatives), the C19 androstanes (androgen derivatives), and the C21 pregnanes (progesterone derivatives). The male sex steroid hormones (testosterone (TES) and related C19 androgens) are the molecules responsible for the differentiation, development, and maintenance of the male reproductive system and secondary sexual characteristics that are so strikingly different between males and females. In males, the biosynthesis of TES occurs in the Leydig (interstitial) cells beginning with the conversion of cholesterol to pregnenolone and then proceeding by one of two distinct routes, in which pregnenolone is first converted to the intermediate dehydroepiandrosterone (DHEA) and then to androstenediol via the 5 pathway (predominant in humans) or alternately, in which pregnenolone is first converted to progesterone and then to androstenedione via the 4 pathway (prevalent in other species). Both androstenediol and androstenedione then undergo direct conversion to TES, which may then be metabolized in some androgen target tissues to form the highly potent metabolite 5-dihydrotestosterone (5-DHT) or its largely inactive isomer 5-DHT, or in peripheral tissues such as adipose to form 17-estradiol (Fig. 1). In females, TES is produced in the theca cells of the ovarian follicles and is predominantly converted to 17-estradiol in the neighboring follicular granulosa cells. It is important to emphasize that both androgens and estrogens are synthesized in both sexes and circulate in the plasma, albeit at quite different levels. Plasma levels of TES in females are 5-10% of that in males, while levels of estrogen in males are 10-30% of that in females; thus, androgens and estrogens play unique roles in the regulation of reproductive, cardiovascular, metabolic, and other functions in females and males [1,2].
1.2. History of androgens
1.3. Mechanisms of androgen actions
1.4. The dogma of androgens in health and disease
The conundrum of dose- and sex-dependent effects of the androgens as beneficial vs. deleterious hormones important in the regulation of cardiovascular and metabolic function is reminiscent of the Roman God Janus who was the patron of doorways, beginnings and endings, passages, transitions, time, and duality, and was depicted as having two faces, symbolic of his ability to simultaneously look into the future and the past (Fig. 3). The two faces of Janus frequently symbolized change and transitions such as the progress of the past to the future, from one condition to another, from one vision to another, and represented time because he could see into both the past with one face and into the future with the other. The related term Janus-faced then, seems to be an appropriate moniker for our current level of understanding of the conundrum of cardiovascular and metabolic effects of TES; thus, the present article will review the literature on cardiovascular and metabolic effects of TES and related androgens in males vs. females with the goal of solving the conundrum of beneficial vs. deleterious effects of TES and thereby answer the question: is TES a Janus-faced molecule?
2. Cardiovascular effects of the androgens
2.1. Historical perspective of the androgens
2.2. The phases of androgen studies and clinical use in the cardiovascular system
2.3. Cardiovascular effects of the androgens
2.4. Sex differences in the cardiovascular effects of the androgens
2.5. Androgen chemical structure-function relationships
2.6. Significance of the cardiovascular effects of the androgens
3. Metabolic effects of androgens
3.1. Historical perspective of metabolic effects of the androgens
3.2. Role of androgens in regulation of metabolism in males in health and disease
3.3. Role of androgens in regulation of metabolism in females in health and disease
4. Summary and conclusions—where do we go from here?
It is increasingly apparent that endogenous TES and other androgens exert widespread beneficial effects on cardiovascular function. Recent experimental animal and human clinical trials over the last 10 years increasingly challenge the long-standing dogma that TES exerts detrimental effects on male cardiovascular health and is largely responsible for the greater incidence of CVD in men than in women. Instead, it is now becoming apparent that it is the gradual decline in circulating TES levels that are a normal part of the aging process that contributes to age-dependent increases in CVD and metabolic dysfunction. Indeed, the incidence of HT and CAD in men increases, while plasma TES level decreases, with age. The intersection of these two plots at middle age suggests (but does not establish causality) that age-dependent increases in HT and CVD are related to the progressive declines in TES with age (Fig. 6). In parallel, recent experimental animal studies reveal that castration of male rats results in the long-term development of HT that is completely reversed by TRT. Further, clinical hypogonadism in aging men is associated with both HT and MetS, which exacerbate the development of CVD. While the most recent human clinical trials overwhelmingly report that TRT does not increase cardiovascular risk or mortality in older hypogonadal men and that such therapy is associated with reductions in BP and improvement in the MetS (e.g., insulin resistance, serum lipids, diabetes, etc.), all of which are risk factors for CVD, clinical trials and observational studies of TRT do not provide unequivocal evidence that exogenous TRT is safe and does not increase the risk of CV events. However, it is also clear that at least some of the human studies suffer from poor experimental design and statistical analysis, and investigator bias. Thus, unequivocal proof that TRT is a safe and efficacious treatment for hypogonadism and associated cardiovascular and metabolic dysfunctions will require more better-designed clinical trials that avoid the shortcomings of previous studies. Nevertheless, the growing recognition of the roles of androgens and aging in the pathogenesis of HT is an emerging and important mechanism. Our understanding of the role of androgens in female health as well as CVD and metabolic dysfunction is still relatively limited and future studies are needed to increase the awareness of the mechanisms underlying the striking sexual dimorphism in the cardiovascular and metabolic effects of TES.
An important part of validating the value of TRT in the treatment of CVD and metabolic dysfunction is advancing the study of selective androgen receptor modulators (SARMs), which could provide for selective androgen treatment of cardiovascular or metabolic dysfunction, while avoiding detrimental effects of more conventional androgen analogs, such as the anabolic steroids. Another related topic of great importance is the study of novel endogenous metabolites of TES and other androgens. In particular, the TES metabolite 5-DHT, which is the genomically inactive stereoisomer of the most potent androgen 5-DHT, mediates many of the reproductive effects of TES. While genomicallty inactive as an androgen, 5-DHT is highly efficacious and potent as a vasodilator under both acute and chronic settings [41,44]. Recent preliminary studies suggest that chronic treatment of castrated male rats with 5-DHT exerts renal as well as vascular effects that completely reverse castration-induced hypertension after only one week of treatment, whereas treatment with TES requires 5 weeks [121]. Whether 5-DHT also exerts non-genomic metabolic effects is uncertain, but clearly additional study of this metabolite may be fruitful in the treatment of CVD and metabolic dysfunction related to hypogonadism in men.
Finally, let us address the conundrum of beneficial vs. deleterious effects of TES and thereby answer the question: is TES a Janus-faced molecule? Based on the accumulating recent evidence provided in this review, the long-held view that TES is detrimental to male health should likely be discarded in favor of the view that, at least in men, TES overall is beneficial to cardiovascular and metabolic health and that the apparent conundrum of androgen effects is the result of earlier dogmatic views combined with a limited number of earlier studies that suggested beneficial effects. With the rapidly accumulating beneficial effects of TES reported in the last 10- 15 years, it must be concluded that in men, TES is most definitely not a Janus-faced molecule, but rather one that looks only in one direction, that of promoting health. With regard to the role of androgens in women, the situation is quite different and at present, it would appear that TES is a Janus-faced molecule that mediates detrimental as well as beneficial effects in women.
