Congenital Adrenal Hyperplasia: Neuroendocrine, Behavioral and Cognitive Implications

Abstract

Congenital adrenal hyperplasia (CAH) is a group of disorders that disrupt the balance of adrenal cortical steroid hormone biosynthesis. Production of different classes of hormones is perturbed depending on the particular enzymatic defect. The most common form of CAH is steroid 21-hydroxylase deficiency, a recessively inherited trait that impedes the stepwise conversion of cholesterol to cortisol, the main human glucocorticoid, and in most cases, to aldosterone, the main mineralocorticoid. Absence of negative cortisol feedback to the hypothalamus and pituitary glands leads to over-secretion of corticotrophin releasing hormone (CRH) and adrenocorticotropic hormone (ACTH). These altered servo-control mechanisms drive excess secretion of adrenal sex hormones that do not require 21-hydroxylation. These are primarily androgen precursors and progestins, but secondarily estrogens, as well. The most visible effect is virilization of genetic females beginning prenatally in the first trimester, leading to genital ambiguity at birth. Thus, this form of CAH and other congenital virilizing disorders represent a human model for prenatal sex hormone effects not only on the reproductive organs but also on the brain. This chapter addresses what is known about behavior in CAH females in terms of gender identity, gender behavior, sexual orientation, career choices, and parenting. Discrete brain structural and cognitive changes are also described. Finally, the effects of prenatal glucocorticoid exposure will be summarized. In brief, affected girls generally have a core female gender identity but show more male-typical play and tomboyishness compared with sibs (Berenbaum et al. 2000; Meyer-Bahlburg et al. 2004a, b). Most patients display heterosexual orientation, but same sex attraction and sexual activity are reported more often than in the general population (Frisen et al. 2009; Meyer-Bahlburg et al. 2008). Career choice is skewed toward male-dominant occupations in severely affected women. Thus, in contrast to animal models of prenatal androgen exposure, human behavior is not dictated solely by hormones.