Estrogen Deficiency in Men Is a Challenge for Both the Hypothalamus and Pituitary

Extract

There is little doubt that androgens are crucial for phenotypic expression of gender differences. That men and women should be politically and socially equal despite small phenotypically differences due to separate hormones was once applauded in the French parliament as “vive la petite différence.” Indeed, androgens are not only the driving force for masculinization of both internal and external genitalia but are probably also responsible for sexual dimorphism of brain, bone, skin, hair, and lipid metabolism. Androgens and estrogens were, for a long time, considered as two opponents using two different receptors with mainly antagonistic effects. However, are these hormones so different from each other? Androgens, indeed, also have the puzzling feature of being prohormones for estrogens. The aromatase enzyme complex (CYP19) has the unique ability to convert androgens into estrogens via a multistep enzymatic process (1). Therefore, the relatively low serum concentration of estrogens in men may not accurately reflect their intracrine and paracrine actions of estrogens. Our understanding of the clinical implications of estrogen deficiency in men has recently been updated by the description of similar phenotypes of men suffering from mutations resulting in either loss of function of the estrogen receptor (ER) α or the cytochrome P450 aromatase enzyme (2). An important role of estrogen was revealed in skeletal development, male fertility, carbohydrate and lipid metabolism, and in regulation of gonadotropin secretion. Furthermore, the characterization of mice made deficient by targeted disruption of the ER (ER-α, β, or combined deficiency) or of the aromatase gene confirmed the crucial role of estrogens for male skeletal development, reproductive function, and gonadropin regulation by the hypothalamic-pituitary axis (3). The terminology “hypothalamic-pituitary axis,” however, often masks our poor understanding of the precise site and mode of action of gonadotropin regulation by sex steroids. The hypothalamic decapeptide GnRH was discovered more than 30 yr ago. Yet, the precise regulation of the oscillating GnRH pulse generator by sex steroids remains difficult to investigate because of the inability to directly measure GnRH in humans due to the poorly accessible sites of production and action and its short half-life.