Over the last two decades, work using transgenic mouse models revealed that estrogens are critical for normal development and function of male reproductive and nonreproductive organs.

Despite these data, roles for estrogen signaling in the normal male were difficult to determine for years, due both to a lack of good experimental systems to address this question and a paucity of clear end points for estrogen action. Furthermore, estrogen receptors (ER) were present in males during development and adulthood, and exposure to exogenous estrogens, especially developmentally, had deleterious effects on the male reproductive tract. Although estrogens were first detected in stallions in the 1930s ( 769), by the 1960s and 1970s, it became clear that males produced significant quantities of estrogens and men and males of other species had measureable circulating E2 concentrations. HISTORICAL PERSPECTIVES ON ESTROGEN FUNCTIONS IN MALESġ7β-Estradiol (E2) and other estrogens regulate many aspects of female reproductive development and function. Thus estrogens are important physiological regulators in males, and future studies may reveal additional roles for estrogen signaling in various target tissues. Recent evidence also indicates that membrane ESR1 has critical roles in male reproduction. Expression of GPER is extensive in male tracts, suggesting a possible role for E2 signaling through this receptor in male reproduction. Loss of ESR1 or aromatase also produces effects on nonreproductive targets such as brain, adipose, skeletal muscle, bone, cardiovascular, and immune tissues. Efferent ductules and epididymal functions are dependent on estrogen signaling through ESR1, whose loss impaired ion transport and water reabsorption, resulting in abnormal sperm. Exogenous estrogen treatment produced male reproductive pathologies in laboratory animals and men, especially during development, and studies with transgenic mice with compromised estrogen signaling demonstrated an E2 role in normal male physiology. Early studies showed E2 binding in numerous male tissues, and ESR1 and ESR2 each show unique distributions and actions in males. Aromatase, which converts androgens to estrogens, is expressed in Leydig cells, seminiferous epithelium, and other male organs. 17β-Estradiol (E2) is measureable in blood of men and males of other species, but in rete testis fluids, E2 reaches concentrations normally found only in females and in some species nanomolar concentrations of estrone sulfate are found in semen. Estrogens have historically been associated with female reproduction, but work over the last two decades established that estrogens and their main nuclear receptors (ESR1 and ESR2) and G protein-coupled estrogen receptor (GPER) also regulate male reproductive and nonreproductive organs.

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