The Goldilocks Principle and Developmental Androgens in Males, What Is “Just Right”?

Abstract

Goldilocks famously rejected items that did not fit her criteria of “just right.” In the endocrinology of reproductive development, appropriate feedback along the hypothalamo-pituitary-gonad axis, and indeed the other axes (thyroid, adrenal, etc), is essential in humans and other species in which the fetal hypothalamo-pituitarygonad axis is active during gestation (1). This complicates our understanding of appropriate levels of developmentally important hormones because feedback effects actively modulate the endocrine system, even in utero. Androgens, principally secreted from the developing fetal testes, are a classic example of critical endocrine signaling during development (2) and are the subject of an important new study in this volume by Connolly et al (25). It is well known that in mammals the establishment of the male phenotype and development of a functionally healthy male adult, is androgen dependent. This is clearly seen when there is disruption of androgen signaling (eg, reviewed in Ref. 3) leading to a gradient of impaired masculinization that, at the extreme of complete androgen insensitivity syndrome, leaves the individual with an apparent normal female phenotype, although infertile (4). Less extreme versions, partial and moderate androgen insensitivity syndrome, are characterized by greater degrees of masculinization of the individual and are associated with less severe androgen receptor mutations. Therefore, in general the availability of inadequate androgen or inadequate androgen signaling is associated with a clear spectrum of disorders of male reproductive development. From the other perspective, in the XX fetus developmental excess of androgen has serious consequences leading to masculinization of the external genitalia (virilization). In humans the most common problems arise from congenital adrenal hyperplasia (CAH), which leads to excess androgen production by the adrenal gland. In addition to virilization of the female fetus (although there is no evidence for retention of the Wolffian ducts, and the Mullerian ducts develop normally), individuals of both sexes with CAH are more likely to show increased blood pressure, obesity, and poor hormone control (5, 6). In addition, adult men with CAH have impaired fertility and lower testosterone to estradiol ratios (7), although it remains uncertain by exactly how much the total androgen tone was raised in these males in utero (Figure 1). Another example of abnormally raised gestational androgens is polycystic ovarian syndrome (PCOS). Maternal androgen levels are thought to be a prime driver of PCOS in female offpsring, but in a recent study (8) female neonates had very high levels of testosterone (similar to unaffected male neonate levels) if their mother had PCOS. In contrast, in male neonates from women with PCOS, testosterone was at levels similar to unaffected males. This is likely to be due to the fact that normal endogenous fetal androgen levels are high and, in the human, approach adult male levels (9). The developmental trajectory programmed by in utero androgen action is important for more than just male reproductive competence. In a number of studies, men with lower testosterone have health deficits such as metabolic syndrome, including increased incidence of obesity, diabetes, and cardiovascular disease (10–12). Therefore, from both a reproductive and a health and well-being point of view, it is very important that the developing male