Obesity in men: The hypogonadal–estrogen receptor relationship and its effect on glucose homeostasis

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Summary

Aromatase is important in men’s health, obesity, the metabolic syndrome, type 2 diabetes and aging. In males with increasing obesity there is increased aromatase activity, which irreversibly converts testosterone to estradiol resulting in decreased testosterone and elevated estrogen levels. Since androgens reduce the expression of ERbeta activity, decreased testosterone levels release the normally suppressed ERbeta expression and results in the down regulation of GLUT4 with resultant insulin resistance. The increased estradiol concentrations influence both of the estrogen receptors, but specifically intensify the metabolic effects of ERbeta because of its released suppression, a consequence of diminished testosterone concentrations. These dual actions then combine to amplify the mechanisms that lead to disordered glucose homeostasis and insulin resistance under these conditions.

An appreciation of the relationships between the hormonal products of aromatase activity and their direct effects on the estrogen receptors focuses on potential innovative therapeutic interventions. These include aromatase inhibitors, which correct the dual consequences of hypotestosteronemia and hyperestrogenemia and eventually ERbeta antagonists when they become available.

Introduction

Aromatase is important in men’s health, obesity, the metabolic syndrome, type 2 diabetes and aging. Since estradiol is the major sex hormone produced by the ovary and because of breast cancer being so prevalent, a great deal of the research emphasis on aromatase has been in females [1]. In recent years, this focus has been extended to men because of the increasing awareness of the peripheral conversion of C19 androgen precursors to C18 estrogens by aromatase located in fat tissue [2]. In postmenopausal females testosterone as well as the less potent adrenal products DHEA and DHEAS function as prohormones for aromatization into the estrogens: estradiol, estrone and estriol. The resultant estrogen concentrations are low because of diminished androgenic precursor levels. In males, the concentrations of these same precursors are much greater and therefore increased estrogen production results in higher estrogenic product levels.

Section snippets

Aromatase

Aromatase is a dual-component cytochrome P450 enzyme complex located in the endoplasmic reticulum. In males, it irreversibly converts testosterone to estradiol resulting in decreased testosterone and elevated estrogen levels. In this circumstance, continued positive energy balance results in the accumulation of adipose tissue and increased aromatase activity. This may lead to a chronic hypogonadal state-the hypogonadal–obesity cycle [3], whereby 3′ hypotestosteronemia facilitates the

The hypogonadal-obesity–estrogen receptor-connection in males

Continued energy retention in males may give rise to a spectrum of diseases ranging from obesity to the metabolic syndrome and type 2 diabetes. Early observations by Hemsell et al. noted that human adipose tissue was a major source of estrogen production in both men and women [4]. Subsequently, others found that obese males produced increased amounts of estrogen [5]. The recognition that increasing fat mass was associated with increased aromatase activity and estrogen production also focused on

Glucose homeostasis

Both estrogens and androgens exert powerful metabolic effects in muscle and adipose tissue. Since increased aromatase activity depresses testosterone and increases estradiol concentrations, the respective receptors respond directly to these changes. Recent studies have shown that androgens reduce the expression of ERbeta activity. Furthermore, both of the estrogen receptors affect glucose homeostasis [7]. This was clearly demonstrated in a case report of a male (human) with ERalpha mutations

Discussion

The importance of increased aromatase activity in the hypogonadal–obesity cycle goes beyond the pathogenetic effects of diminished testosterone and increased estradiol concentrations in obesity, the metabolic syndrome, type 2 diabetes and aging in males. An appreciation of the relationships between the aromatase activity and its effects on the estrogen receptors focuses on potential innovative therapeutic interventions at several levels. Aromatase inhibition has been shown to normalize both

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