Steroid hormones

Cholesterol serves as a precursor steroid hormones that are synthesized in steroidogenic cells of the adrenals, gonads, placenta and brain and are essential for normal reproductive function and body homeostasis. In brain, steroid hormones regulate neuronal survival and differentiation, myelination, neurogenesis, plasticity and repair after injury (Sierra, 2004). There are several classes of steroid hormones and steroid hormone receptors. In the kidney mineralocorticoids mediate water and salt metabolism and regulate blood pressure. Glucocorticoids regulate stress and immune responses. Sex steroids: progestins, estrogens and androgens are involved in sex differentiation and reproduction. Steroidogenic cells do not store significant quantities of steroid hormones; hence steroid secretion is directly related to steroid synthesis. Steroid synthesis is regulated both acutely and chronically.

The first, rate-limiting and hormonally regulated step in the biosynthesis of all steroid hormones is the conversion of cholesterol to pregnenolone (Fig. 44) within the inner mitochondrial membrane by cytochrome P450scc (CYP11A1). The P450scc-linked monooxygenase system is located on the matrix side of the inner mitochondrial membrane. Various pathways regulate the level of P450scc and the amount of P450scc mRNA is correlated with steroid hormone production (DiBlasio et al. 1987). P450scc can function only within mitochondria (Black et al. 1994). The transfer of cholesterol to P450scc requires hormonal activation of cholesterol mobilization to the mitochondria. Transport of cholesterol from the outer to the inner mitochondrial membrane is the rate-limiting step in steroidogenesis, and the steroidogenic acute regulatory protein (StAR) has been demonstrated to mediate this process in steroidogenic cells (Stocco, 2001). Delivery of cholesterol to P450scc requires de novo synthesis of the protein (Kim et al. 2004). StAR was identified as a 30 kDa phosphoprotein associated with mitochondria (Kruger et al.1983) and it has been soon discovered that mutations in the StAR gene leads to congenital lipoid adrenal hyperplasia, a disease that is characterised by almost complete lack of steroid hormone synthesis (Lin et al 1995). The peripheral benzodiazepine receptor (PBR), located in the outer mitochondrial membranes, is another protein that allows cholesterol to cross the mitochondrial membrane in steroidogenesis (Lavaque et al. 2006). PBR is closely associated to StAR and it has been suggested it may function as a channel for cholesterol in steroid hormones synthesis (Papadopoulos 2004).