Gabriela Guercio

Mutation of HSD3B2 Gene and Fate of Dehydroepiandrosterone

3βHSD2 enzyme is crucial for adrenal and gonad steroid biosynthesis. In enzyme deficiency states, due to recessive loss-of-function HSD3B2 mutations, steroid flux is altered and clinical manifestations result. Deficiency of 3βHSD2 activity in the adrenals precludes normal aldosterone and cortisol synthesis and the alternative backdoor and 11-oxygenated C19 steroid pathways and the flooding of cortisol precursors along the Δ5 pathway with a marked rise in DHEA and DHEAS production. In gonads, it precludes normal T and estrogen synthesis. Here, we review androgen-dependent male differentiation of the external genitalia in humans and link this to female development and steroidogenesis in the developing adrenal cortex. The molecular mechanisms governing postnatal adrenal cortex zonation and ZR development were also revised. This chapter will review relevant clinical, hormonal, and genetic aspects of 3βHSD2 deficiency with emphasis on the significance of alternate fates encountered by steroid hormone precursors in the adrenal gland and gonads. Our current knowledge of the process of steroidogenesis and steroid action is derived from pathological conditions. In humans the 3βHSD2 deficiency represents a model of nature that reinforces our knowledge about the role of the steroidogenic alternative pathway in sex differentiation in both sexes. However, the physiological role of the high serum DHEAS levels in fetal life as well as after adrenarche remains to be elucidated.

Human Aromatase Deficiency

cP450 aromatase deficiency is a rare autosomal recessive disorder that impairs androgen conversion to estrogens. New knowledge on cP450 aromatase deficiency has contributed to the understanding of the role of estrogens in human health and disease. Currently, 37 cases of aromatase deficiency (26 46,XX) have been published. In affected subjects, the clinical phenotype depends on sex, age, and genotype. In affected 46,XX newborns a broad variability in clinical virilization of the external genitalia is observed; however, aromatase deficiency should be considered in the etiology of 46,XX DSD, after ruling out congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency. After birth, in both sexes, the phenotype reflects the effects of estrogen insufficiency on the skeleton, hypothalamic–pituitary–gonadal function, the gonads and the reproductive system, and on glucose and lipid metabolism. Variable or nonclassic forms of the disease have expanded the phenotypic variability in aromatase insufficiency in humans. The long-term follow-up of patients with aromatase deficiency is important to increase our knowledge on the clinical course of the disease and to establish an appropriate therapeutic strategy to prevent the devastating consequences of prolonged estrogen deficiency.