Disorders of Adrenals and Gonads

Abstract

Defects in steroid biosynthesis in adrenals and gonads lead to complex and profound clinical consequences that can be grouped in four categories: (1) defects of salt–water homeostasis and sexual development (DSD), (2) defects of salt–water homeostasis, (3) defects of sexual development, and (4) end-organ steroid hormone resistance. Among the members of the first group, lipoid adrenal hyperplasia is characterized by lack of all steroid hormones, with consequent 46, XY DSD and salt loss in the first weeks of life. 17a-Hydroxylase deficiency leads also to 46, XY DSD associated with hypertension and hypokalemia. 3b-Hydroxysteroid dehydrogenase deficiency causes incomplete virilization in male fetuses, together with salt loss. 21-Hydroxylase deficiency, whose nonclassic form is one of the most common autosomal recessive diseases in humans, is responsible for female ambiguous genitalia at birth and salt loss. 11b-Hydroxylase deficiency differs from 21-hydroxylase deficiency for the absence of salt wasting and later presence of hypertension and hypokalemia. Defects of P450 oxidoreductase, a cofactor common to 21-hydroxylase, 17a-hydroxylase, and aromatase, lead to a complex combined defect of all three enzymes.

Enzymatic defects of the second group cause either salt-wasting symptoms in the neonatal period, spontaneously resolving in adulthood, as in the case of corticosterone methyl oxidase II deficiency, or hypertension and hypokalemia as in the cases of glucocorticoid-suppressible hyperaldosteronism and apparent mineralocorticoid excess. The third group of defects includes enzymatic blocks of the last steps of sex hormones biosynthesis. 17,20-Lyase, 17b-hydroxysteroid dehydrogenase, 5a-reductase, and aldo-keto reductase deficiencies determine incomplete virilization of the male fetus. In 17,20-lyase deficiency, there is no spontaneous puberty in males and females; in the latter two male puberty occurs. Aromatase deficiency is a cause of nonadrenal 46, XX DSD. The end-organ resistance syndromes, which are still an exclusion diagnosis, represent a further challenge for future diagnostic and therapeutic applications. The treatment of these defects is based on exogenous administration of the deficient hormones and corrective surgery in intersexuality. Given the rarity of most of these diseases, prenatal diagnosis is possible only in a family at risk. In the case of 21-hydroxylase deficiency, however, advances in prenatal diagnosis allowed in utero treatment. Progress in molecular analysis of steroid biosynthesis and action defects will allow a better prenatal diagnosis and treatment of such diseases.