Estrogen Sulfotransferase: Intracrinology Meets Metabolic Diseases

Over the past two decades, the female hormone 17β-estradiol (estrogen) has emerged as an important contributor to energy homeostasis in both males and females. Early clinical evidence involved the observation that men lacking estrogen synthesis secondary to mutations in aromatase—the enzyme that converts androgen to estrogen—or men harboring estrogen resistance secondary to mutation of the estrogen receptor (ER)α, develop visceral obesity, insulin resistance, and/or glucose intolerance (1,2). As an experimental confirmation, it was observed that elimination of the aromatase or ERα genes in male and female mice produced the same metabolic syndrome as in humans (3,4). Thus, it is reasonable to assume that although men have lower circulating estrogen concentrations than premenopausal women, aromatization of circulating androgen to estrogen in target metabolic tissues equilibrates cellular estrogen concentrations, and ER activation is critical in both sexes in promoting fuel homeostasis (5). This is consistent with the paradigm that estrogen functions as a circulating hormone in premenopausal women. Conversely, in men and in postmenopausal women—in whom estrogen concentrations are low—estradiol does not function as a hormone; instead, it is synthesized in extragonadal sites such as breast, brain, bone, and fat where it acts locally as a paracrine or intracrine factor (6). Thus, in men and in postmenopausal women, the driver of estrogen action is not circulating estrogens; rather, it depends on estrogen biosynthesis from a circulating source of androgenic precursors such as testosterone. A logical consequence …