Adrenal Hyperandrogenism in Children

Abstract

HYPERANDROGENISM of a mild-to-moderate degree is probably the most common abnormality in normoestrogenic menstrual disturbances. Androgen excess arises from abnormal ovarian or adrenal sources. The adrenal androgens, normally secreted by the fetal adrenal zone or the zona reticularis, are steroid hormones with weak androgen activity. Although adrenal androgens do not seem to play a major role in the fully androgenized adult men, they seem to play a role in the adult woman and in both sexes before puberty. Girls, women, as well as prepubertal boys may be negatively affected by adrenal androgen hypersecretion in contrast to adult men. In this review, we examine the roles and effects of adrenal androgens and analyze the clinical significance of their hypersecretion during childhood. The adrenal cortex is divided into three histological and functional zones: the outer, aldosterone-secreting zona glomerulosa; the intermediate, cortisol-secreting, zona fasciculata; and the inner, androgen-secreting, zona reticularis. In the fetus, the adrenal cortex consists of the two adult adrenal zonae glomerulosa and fasciculata and an inner large fetal adrenal zone, which virtually disappears within weeks after birth. Remaining cell foci from the fetal adrenal zone presumably give rise to the adrenal zona reticularis starting at the age of 4–5 yr in both sexes. This zone continues to grow until young adulthood (20–25 yr), remains at a plateau for 5–10 yr, and regresses gradually after the age of 35 yr. The major androgens secreted by the adrenals are dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S), and androstenedione (Δ4-A). Production of testosterone (T) by these glands is minimal (1). DHEA and DHEA-S are mainly the products of zona reticularis, Δ4-A and testosterone T are secreted by both zona reticularis and zona fasciculata (2, 3). Adrenal androgens are secreted in small amounts during infancy and early childhood, and their secretion gradually increases with age, paralleling the growth of the zona reticularis (4). The mechanism(s) by which this zone develops with age and the regulation of its secretion are not fully known. During this process, plasma concentrations of the adrenal androgens increase, whereas those of cortisol remain stable, suggesting that factors other than corticotropin are involved. These may include the elusive androgen-stimulating factor (AASF) (Fig. 1), the existence of which has been repeatedly questioned (5, 6). A programmed shift in production of intradrenal regulatory factors associated with differentiation of adrenal cells and changes in steroid biosynthesis might also take place independently of circulating factors. Schematic representation of the causes of adrenal hyperandrogenism in children. Adrenal androgens are secreted by the adrenal glands in response to their tropic hormone ACTH (2) (Fig. 1). This is a 39-amino acid peptide synthesized and secreted by the anterior pituitary under the regulatory control of CRH and arginine-vasopressin (7, 8). Under ACTH regulation, adrenal androgens are secreted synchronously with cortisol, in both the secretory episodes and the circadian pattern (9, 10). Corticotropin-stimulated cortisol exerts major feedback inhibitory influences at the level of both the hypothalamus and the anterior pituitary by suppressing CRH, arginine-vasopressin, and ACTH synthesis and secretion. Furthermore, the hypothalamic-pituitary-adrenal (HPA) axis exerts both negative and positive influences on GH secretion (11), as well as a primarily negative influence on the secretion of TSH (12). Under physiological conditions, the HPA axis has also a prevailing inhibitory effect on leptin secretion (Ghizzoni, L., personal communication). Steroid precursors and the adrenal androgens themselves may be respectively converted to androgens or more potent androgens in peripheral tissues, such as hair follicles, sebaceous glands, prostate, and external genitalia (13). Major conversions are those of Δ4-A to T and T to dihydrotestosterone by the enzymes 17-ketosteroid reductase and 5α-reductase, respectively. Active uptake of androgens and in situ estrogen synthesis occur in peripheral adipose tissue, where the aromatization of Δ4-A and T to estrone and estradiol, respectively, occurs. The adrenal androgens and their metabolites are inactivated at various tissues, including the liver and kidney (14). Etiology of adrenal androgen hypersecretion in children Boldface indicates the topics examined in this review. Etiology of adrenal androgen hypersecretion in children Boldface indicates the topics examined in this review. Premature pubarche.Premature pubarche refers to the appearance of pubic hair before age 8 yr in girls and 9 yr in boys, without other signs of puberty or virilization (15). Axillary hair, apocrine odor, and acne may or may not be present. Growth velocity may be increased, and slightly advanced bone maturation is often present and is usually well correlated with the height a