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As we very well know T s metabolites estradiol and DHT are needed in order to reap full beneficial effects of testosterone.
Ts metabolites estradiol and DHT are needed in healthy amounts to experience the full spectrum of testosterones beneficial effects on (cardiovascular health, brain health, libido, erectile function, bone health, tendon health, immune system, lipids, and body composition).
*Anecdotally, male patients on TRT often enquire about their E2 levels due to fear of “too much female hormone.” Men s’ health clinics even prescribe aromatase inhibitors to suppress E2 production while raising T concentrations. However, we discussed the essential role of T’s conversion to E2 in male bone and vascular health, as well as glucose and lipid homeostasis (not to mention libido and erectile function). Thus, it is our view that E2 should not be suppressed in men, and in fact clinical trials of E2 supplementation should be considered in some men on TRT to decrease LDL cholesterol and improve endothelial function.
*Finally, current laboratory measurements of serum T and E2 levels (total or free) poorly reflect tissue and cellular T and E2 concentrations, catabolism, and elimination. Novel assays that provide accurate measures of cellular T and E2 outputs will be informative in clinical studies and are desperately needed.
Metabolic benefits afforded by estradiol and testosterone in both sexes: clinical considerations
Franck Mauvais-Jarvis, Sarah H. Lindsey
Testosterone (T) and 17β-estradiol (E2) are produced in male and female humans and are potent metabolic regulators in both sexes. When E2 and T production stops or decreases during aging, metabolic dysfunction develops and promotes degenerative metabolic and vascular disease. Here, we discuss the shared benefits afforded by E2 and T for metabolic function human females and males. In females, E2 is central to bone and vascular health, subcutaneous adipose tissue distribution, skeletal muscle insulin sensitivity, anti inflammatory immune function, and mitochondrial health. However, T also plays a role in female skeletal, vascular, and metabolic health. In males, T’s conversion to E2 is fundamental to bone and vascular health, as well as prevention of excess visceral adiposity and the promotion of insulin sensitivity via activation of the estrogen receptors. However, T and its metabolite dihydrotestosterone also prevent excess visceral adiposity and promote skeletal muscle growth and insulin sensitivity via activation of the androgen receptor. In conclusion, T and E2 are produced in both sexes at sex-specific concentrations and provide similar and potent metabolic benefits. Optimizing levels of both hormones may be beneficial to protect patients from cardiometabolic disease and frailty during aging, which requires further study.
Introduction
Testosterone (T) and 17β-estradiol (E2) are considered male and female sex hormones, respectively, because they are secreted by gonads in the circulation at sex-specific concentrations and are involved in sexual differentiation and reproduction. E2, however, is not exclusively a female hormone since, for example, itis essential for erection and libido in male individuals (1). Likewise, T is not exclusively a male hormone, as it is essential forl ibido in female individuals (2). Most importantly, E2 and T are central to metabolic homeostasis of most cells and in both sexes.When E2 and T production stops or decreases during aging, metabolic dysfunction develops and promotes degenerative metabolic and vascular disease. Understanding the sex-specific and shared benefits of E2 and T in metabolic function in both sexes is critical to medicine and healthy aging. Here, we analyze sex differences and similarities in E2 and T benefits for metabolic homeostasis in male and female humans, including glucose and lipid metabolism, bone, vascular, adipose, muscle, and immune functions, and the prevention of metabolic dysfunction leading to cardiometabolic disease. We use the terms male and femalet o describe the biological sex of human subjects through the paper and we specify when animal studies are discussed. For details on mechanisms of E2 and T’s actions, we will refer to recent and landmark reviews.
Origin of T and E2 in both sexes
In males, all T is produced by Leydig cells of the testis. T behaves as a hormone by binding the androgen receptor (AR), and also behaves as a prohormone that is converted in peripheral tissues to E2 or dihydrotestosterone (DHT), a pure AR agonist that cannot be converted to E2. In males, most E2 (80%) is formed via aromatization of circulating T in the periphery. The testes directly produce approximately20% of circulating E2 (3) (Figure 1A). Circulating concentrations of E2 in males are half of those of females and are essential to metabolic homeostasis, as we will discuss. In females of reproductive age,the granulosa cells of the ovaries produce E2, the major circulating estrogen (Figure 1B). After menopause, estrone (E1) becomes the major circulating estrogen (4). E1 is produced by aromatization from the adrenal androgen androstenedione in adipose tissue (5) (Figure1C). E1 is a weak estrogen and should be considered a reservoir of the more potent E2 in postmenopausal females. E2 is produced locally in extra-ovarian tissues and acts locally as a paracrine and intracrine factor (Figure 1). In females, T is the most abundant circulating active sex steroid throughout the life span (Figure 2). In females of reproductive age, T is produced by the ovary (25%), the adrenal gland (25%), and in peripheral tissues (50%), following conversion from circulating androstenedione (equally produced by the ovaryand the adrenal gland) (6–9) (Figure 1B). After natural menopause, ovarian T production decreases slowly. T is mainly produced by the ovaries (50%) and via peripheral conversion from androstenedione(40%) mainly of adrenal origin (6–9). Direct adrenal production of T is minor (around 10%) (Figure 1C). Although T is ten times less abundant in the blood of females than males, in females across the life span, circulating T is 5–50 times more abundant than E2 (Figure2), the implications of which we will discuss below.
E2 promotes metabolic homeostasis in females
In females of reproductive age, E2 is instrumental to skeletal, vascular, and energy homeostasis. The central role of E2 in maintenance of bone metabolism, the detrimental effect of postmenopausal E2 deficiency on osteopenia and osteoporosis, and their prevention by estrogen therapy in postmenopausal females is evidence-based medicine (10, 11) and will not be discussed here.
*E2 promotes female vascular function and health
*E2 promotes subcutaneous lipid storage in females
*E2 promotes glucose and lipid homeostasis in females
*E2 promotes mitochondrial fitness in females
The importance of T in female metabolic homeostasis
*T production favors healthy body composition in females
*Physiological T production protects female vascular health
T promotes metabolic homeostasis in males
In males, T is a hormone that binds the AR and a prohormone that provides a circulating reservoir of E2 and DHT. T deficiency in males leads to sexual dysfunction, depressed mood, anemia, osteoporosis, metabolic syndrome and T2D, and CVD. In the following section, we discuss the effect of T on metabolic homeostasis separated into the effects induced by E2 versus T/DHT
*T-to-E2 conversion maintains bone mass in males
*T is an anti-obesity hormone in males
*T prevents T2D in males
*Endogenous T promotes cardiovascular health in males
Conclusions and clinical implications
T and E2 are produced in both sexes at sex-specific concentrations and share similar and potent metabolic functions. The loss of E2 after menopause in females and the decrease in T in aging males both produce metabolic dysfunction and are serious health threats leading to cardiometabolic disease and frailty. The reason that these important metabolic mediators are not prescribed more often relates to myths about the danger of hormones. In particular, there are persistent misconceptions about the risks of estrogen-based therapies in females (148–154). Apart from the purported risk of breast cancer, which has been attributed to synthetic progestins, confusion about the risks of estrogens lies in the too often ignored biological difference between synthetic hormones like CEE, which is associated with CVD, and endogenous and bioidentical E2, which is not associated with negative CVD outcomes. In the case of males and T, myths about risk of prostate cancer and CVD along with its cultural associations with illegally enhancing athletic performance and toxic masculinity has created resistance to consider aging as a treatable condition of T deficiency (155).
It is not known what the role of T in female metabolism is. Is it mediated via T or DHT acting on AR, as animal studies suggest, or is T an additional reservoir for local E2 synthesis in tissues? Clinical trials assessing the effect of T supplementation in postmenopausal women to achieve serum concentrations in the upper limit of female physiology should be considered to ascertain its ability to improve muscle and metabolic function along with its beneficial effects on libido.
Anecdotally, male patients on TRT often enquire about their E2 levels due to fear of “too much female hormone.” Men s’ health clinics even prescribe aromatase inhibitors to suppress E2 production while raising T concentrations. However, we discussed the essential role of T’s conversion to E2 in male bone and vascular health, as well as glucose and lipid homeostasis (not to mention libido and erectile function). Thus, it is our view that E2 should not be suppressed in men, and in fact clinical trials of E2 supplementation should be considered in some men on TRT to decrease LDL cholesterol and improve endothelial function.
Finally, current laboratory measurements of serum T and E2 levels (total or free) poorly reflect tissue and cellular T and E2 concentrations, catabolism, and elimination. Novel assays that provide accurate measures of cellular T and E2 outputs will be informative in clinical studies and are desperately needed.
As we very well know T s metabolites estradiol and DHT are needed in order to reap full beneficial effects of testosterone.
Ts metabolites estradiol and DHT are needed in healthy amounts to experience the full spectrum of testosterones beneficial effects on (cardiovascular health, brain health, libido, erectile function, bone health, tendon health, immune system, lipids, and body composition).
*Anecdotally, male patients on TRT often enquire about their E2 levels due to fear of “too much female hormone.” Men s’ health clinics even prescribe aromatase inhibitors to suppress E2 production while raising T concentrations. However, we discussed the essential role of T’s conversion to E2 in male bone and vascular health, as well as glucose and lipid homeostasis (not to mention libido and erectile function). Thus, it is our view that E2 should not be suppressed in men, and in fact clinical trials of E2 supplementation should be considered in some men on TRT to decrease LDL cholesterol and improve endothelial function.
*Finally, current laboratory measurements of serum T and E2 levels (total or free) poorly reflect tissue and cellular T and E2 concentrations, catabolism, and elimination. Novel assays that provide accurate measures of cellular T and E2 outputs will be informative in clinical studies and are desperately needed.
Metabolic benefits afforded by estradiol and testosterone in both sexes: clinical considerations
Franck Mauvais-Jarvis, Sarah H. Lindsey
Testosterone (T) and 17β-estradiol (E2) are produced in male and female humans and are potent metabolic regulators in both sexes. When E2 and T production stops or decreases during aging, metabolic dysfunction develops and promotes degenerative metabolic and vascular disease. Here, we discuss the shared benefits afforded by E2 and T for metabolic function human females and males. In females, E2 is central to bone and vascular health, subcutaneous adipose tissue distribution, skeletal muscle insulin sensitivity, anti inflammatory immune function, and mitochondrial health. However, T also plays a role in female skeletal, vascular, and metabolic health. In males, T’s conversion to E2 is fundamental to bone and vascular health, as well as prevention of excess visceral adiposity and the promotion of insulin sensitivity via activation of the estrogen receptors. However, T and its metabolite dihydrotestosterone also prevent excess visceral adiposity and promote skeletal muscle growth and insulin sensitivity via activation of the androgen receptor. In conclusion, T and E2 are produced in both sexes at sex-specific concentrations and provide similar and potent metabolic benefits. Optimizing levels of both hormones may be beneficial to protect patients from cardiometabolic disease and frailty during aging, which requires further study.
Introduction
Testosterone (T) and 17β-estradiol (E2) are considered male and female sex hormones, respectively, because they are secreted by gonads in the circulation at sex-specific concentrations and are involved in sexual differentiation and reproduction. E2, however, is not exclusively a female hormone since, for example, itis essential for erection and libido in male individuals (1). Likewise, T is not exclusively a male hormone, as it is essential forl ibido in female individuals (2). Most importantly, E2 and T are central to metabolic homeostasis of most cells and in both sexes.When E2 and T production stops or decreases during aging, metabolic dysfunction develops and promotes degenerative metabolic and vascular disease. Understanding the sex-specific and shared benefits of E2 and T in metabolic function in both sexes is critical to medicine and healthy aging. Here, we analyze sex differences and similarities in E2 and T benefits for metabolic homeostasis in male and female humans, including glucose and lipid metabolism, bone, vascular, adipose, muscle, and immune functions, and the prevention of metabolic dysfunction leading to cardiometabolic disease. We use the terms male and femalet o describe the biological sex of human subjects through the paper and we specify when animal studies are discussed. For details on mechanisms of E2 and T’s actions, we will refer to recent and landmark reviews.
Origin of T and E2 in both sexes
In males, all T is produced by Leydig cells of the testis. T behaves as a hormone by binding the androgen receptor (AR), and also behaves as a prohormone that is converted in peripheral tissues to E2 or dihydrotestosterone (DHT), a pure AR agonist that cannot be converted to E2. In males, most E2 (80%) is formed via aromatization of circulating T in the periphery. The testes directly produce approximately20% of circulating E2 (3) (Figure 1A). Circulating concentrations of E2 in males are half of those of females and are essential to metabolic homeostasis, as we will discuss. In females of reproductive age,the granulosa cells of the ovaries produce E2, the major circulating estrogen (Figure 1B). After menopause, estrone (E1) becomes the major circulating estrogen (4). E1 is produced by aromatization from the adrenal androgen androstenedione in adipose tissue (5) (Figure1C). E1 is a weak estrogen and should be considered a reservoir of the more potent E2 in postmenopausal females. E2 is produced locally in extra-ovarian tissues and acts locally as a paracrine and intracrine factor (Figure 1). In females, T is the most abundant circulating active sex steroid throughout the life span (Figure 2). In females of reproductive age, T is produced by the ovary (25%), the adrenal gland (25%), and in peripheral tissues (50%), following conversion from circulating androstenedione (equally produced by the ovaryand the adrenal gland) (6–9) (Figure 1B). After natural menopause, ovarian T production decreases slowly. T is mainly produced by the ovaries (50%) and via peripheral conversion from androstenedione(40%) mainly of adrenal origin (6–9). Direct adrenal production of T is minor (around 10%) (Figure 1C). Although T is ten times less abundant in the blood of females than males, in females across the life span, circulating T is 5–50 times more abundant than E2 (Figure2), the implications of which we will discuss below.
E2 promotes metabolic homeostasis in females
In females of reproductive age, E2 is instrumental to skeletal, vascular, and energy homeostasis. The central role of E2 in maintenance of bone metabolism, the detrimental effect of postmenopausal E2 deficiency on osteopenia and osteoporosis, and their prevention by estrogen therapy in postmenopausal females is evidence-based medicine (10, 11) and will not be discussed here.
*E2 promotes female vascular function and health
*E2 promotes subcutaneous lipid storage in females
*E2 promotes glucose and lipid homeostasis in females
*E2 promotes mitochondrial fitness in females
The importance of T in female metabolic homeostasis
*T production favors healthy body composition in females
*Physiological T production protects female vascular health
T promotes metabolic homeostasis in males
In males, T is a hormone that binds the AR and a prohormone that provides a circulating reservoir of E2 and DHT. T deficiency in males leads to sexual dysfunction, depressed mood, anemia, osteoporosis, metabolic syndrome and T2D, and CVD. In the following section, we discuss the effect of T on metabolic homeostasis separated into the effects induced by E2 versus T/DHT
*T-to-E2 conversion maintains bone mass in males
*T is an anti-obesity hormone in males
*T prevents T2D in males
*Endogenous T promotes cardiovascular health in males
Conclusions and clinical implications
T and E2 are produced in both sexes at sex-specific concentrations and share similar and potent metabolic functions. The loss of E2 after menopause in females and the decrease in T in aging males both produce metabolic dysfunction and are serious health threats leading to cardiometabolic disease and frailty. The reason that these important metabolic mediators are not prescribed more often relates to myths about the danger of hormones. In particular, there are persistent misconceptions about the risks of estrogen-based therapies in females (148–154). Apart from the purported risk of breast cancer, which has been attributed to synthetic progestins, confusion about the risks of estrogens lies in the too often ignored biological difference between synthetic hormones like CEE, which is associated with CVD, and endogenous and bioidentical E2, which is not associated with negative CVD outcomes. In the case of males and T, myths about risk of prostate cancer and CVD along with its cultural associations with illegally enhancing athletic performance and toxic masculinity has created resistance to consider aging as a treatable condition of T deficiency (155).
It is not known what the role of T in female metabolism is. Is it mediated via T or DHT acting on AR, as animal studies suggest, or is T an additional reservoir for local E2 synthesis in tissues? Clinical trials assessing the effect of T supplementation in postmenopausal women to achieve serum concentrations in the upper limit of female physiology should be considered to ascertain its ability to improve muscle and metabolic function along with its beneficial effects on libido.
Anecdotally, male patients on TRT often enquire about their E2 levels due to fear of “too much female hormone.” Men s’ health clinics even prescribe aromatase inhibitors to suppress E2 production while raising T concentrations. However, we discussed the essential role of T’s conversion to E2 in male bone and vascular health, as well as glucose and lipid homeostasis (not to mention libido and erectile function). Thus, it is our view that E2 should not be suppressed in men, and in fact clinical trials of E2 supplementation should be considered in some men on TRT to decrease LDL cholesterol and improve endothelial function.
Finally, current laboratory measurements of serum T and E2 levels (total or free) poorly reflect tissue and cellular T and E2 concentrations, catabolism, and elimination. Novel assays that provide accurate measures of cellular T and E2 outputs will be informative in clinical studies and are desperately needed.
