Estrogens and Body Weight Regulation in Men

Abstract

Our understanding of the metabolic roles of sex steroids in men has evolved substantially over recent decades. Whereas testosterone once was believed to contribute to metabolic risk in men, the importance of adequate androgen exposure for the maintenance of metabolic health has been demonstrated unequivocally. A growing body of evidence now also supports a critical role for estrogens in metabolic regulation in men. Recent data from clinical intervention studies indicate that estradiol may be a stronger determinant of adiposity than testosterone in men, and even short-term estradiol deprivation contributes to fat mass accrual. The following chapter will outline findings to date regarding the mechanisms whereby estrogens contribute to the regulation of body weight and adiposity in men. It will present emergent clinical data as well as preclinical findings that reveal mechanistic insights into estrogen-mediated regulation of body composition. Findings in both males and females will be reviewed, to draw comparisons and to highlight knowledge gaps regarding estrogen action specifically in males. Finally, the clinical relevance of estrogen exposure in men will be discussed, particularly in the context of a rising global prevalence of obesity and expanding clinical use of sex steroid-based therapies in men.

Obesity and male hypogonadism: Tales of a vicious cycle

“…The higher estradiol levels observed in men with obesity were attributed to increased testosterone conversion into estradiol by aromatase in peripheral tissues . Aromatase is expressed in adipocytes and due to the increased adipocyte mass, aromatase expression is also increased, thus explaining the higher rate of peripheral conversion of testosterone and thus the higher estradiol levels observed in men with obesity . Then, high estradiol levels would potentially exert a negative feedback on the hypothalamic secretion of GnRH, consequently suppressing the HPT axis and ultimately limiting testosterone secretion in the testis.…”

“…Taken together, the role of estradiol might be more complex than initially hypothesized. Currently, estradiol levels are described as an adaptative and tissue‐specific response to obesity . In another words, estradiol levels may reflect an adaptative response to the metabolic state of the individual, regulating lipid metabolism and adipocytes differentiation and function in order to preserve the adipose tissue homeostasis.…”

Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α

“…17α-E2 is known to be a mild 5α-reductase inhibitor that is prescribed as a topical treatment for androgenetic alopecia [90]. Moreover, 5α-reductase inhibition could conceivably elicit beneficial metabolic effects by either reducing the concentration of DHT, which could decrease adiposity [91,92], or by promoting greater aromatization of testosterone to 17β-E2 [93], which has been linked to improvements in metabolic parameters [94]. If true, this would imply that the benefits of 17α-E2 are occurring in an indirect manner.…”

Drug‐drug interactions between feminizing hormone therapy and pre‐exposure prophylaxis among transgender women: the iFACT study

“…Eligibility criteria included being of Thai nationality, aged 18‐40 years, with body mass index (BMI) of 18.5‐24.9 kg/m 2 , were ARV‐naïve had calculated creatinine clearance (CrCl) ≥ 60 mL/min using Cockcroft‐Gault equation, and had alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal. Despite that there are no previous studies among TGW, associations between sex hormones and BMI in non‐TGW population have been reported . To eliminate potential confounders in the setting of this intensive pharmacokinetic (PK) study, BMI was included in the inclusion criteria recruiting only those in the normal range (18.5‐24.9 kg/m 2 ), according to the World Health Organization.…”