Steroidogenesis: Unanswered Questions

The principal pathways of steroidogenesis, the identities of the principal steroidogenic enzymes, and genetic disorders of most of these enzymes have been elucidated. Nevertheless, new pathways, new enzymes, and new steroids have been discovered, and require further investigation. Much remains to be learned about the biochemistry and cell biology of several steroidogenic factors, notably StAR, 3βHSD, and P450c17. The cellular mechanisms of fetal adrenal involution, adrenarche, and adrenopause remain unknown. The roles of extraglandular steroidogenesis remain poorly understood. Despite decades of work, the genetics of these factors remain incompletely understood, and genetic disorders have not been found for many steroidogenic genes. Until the mid-1980s studies of steroidogenesis largely depended on identifying steroid structures and measuring steroid concentrations in body fluids. The molecular biology revolution radically revolutionized studies of steroidogenesis with the cloning of known steroidogenic enzymes, by identifying novel factors, and delineating the genetic basis of known and newly discovered diseases. Unfortunately, this dramatic success has led many young research-oriented endocrinologists to regard steroidogenesis as a ‘solved area’. However, many important and exciting questions remain, especially concerning the mechanisms of cholesterol delivery to the steroidogenic machinery, the biochemistry of androgen synthesis, the regulation and biological role of adrenarche, fetal adrenal development and involution, the roles of steroids made in ‘extraglandular’ cells, and the search for genetic disorders. This review outlines some of these questions, but this list is necessarily incomplete. Until the mid-1980s studies of steroidogenesis largely depended on identifying steroid structures and measuring steroid concentrations in body fluids. The molecular biology revolution radically revolutionized studies of steroidogenesis with the cloning of known steroidogenic enzymes, by identifying novel factors, and delineating the genetic basis of known and newly discovered diseases. Unfortunately, this dramatic success has led many young research-oriented endocrinologists to regard steroidogenesis as a ‘solved area’. However, many important and exciting questions remain, especially concerning the mechanisms of cholesterol delivery to the steroidogenic machinery, the biochemistry of androgen synthesis, the regulation and biological role of adrenarche, fetal adrenal development and involution, the roles of steroids made in ‘extraglandular’ cells, and the search for genetic disorders. This review outlines some of these questions, but this list is necessarily incomplete. the gonadotropin-independent increase in adrenal androgen production, marked by serum DHEAS. Adrenarche typically begins at least 1 year before the onset of puberty, but DHEAS levels do not reach maximal values until young adulthood. a subgroup of hydroxysteroid dehydrogenases. the enzyme that converts cholesterol to pregnenolone. It is encoded by the CYP11A1 gene and is associated with the matrix side of the inner mitochondrial membrane (IMM). a group of genetic disorders in adrenal cortisol synthesis that are caused by mutations of steroidogenic enzymes. When cortisol is low, the pituitary makes more ACTH (adrenocorticotropic hormone, corticotropin), resulting in adrenal growth. About 95% of CAH is caused by 21-hydroxylase deficiency. a small, 18 kDa heme-containing protein, encoded by the CYB5 gene, that serves diverse functions. a family of proteins encoded by CYP genes that include both microsomal and mitochondrial members acting as biosynthetic and xenobiotic-metabolizing enzymes. The name ‘P450’ refers to spectral characteristics of the proteins (absorption at 450 nm). The 57 human P450s are about 60 kDa and contain a heme group. Several steroidogenic enzymes are P450s. DHEA and its sulfate (DHEAS) are 19-carbon (C19) steroids that are abundantly produced by the adrenal. DHEA(S) designates either DHEA or DHEAS. any situation in which the external genitalia develop in a sex-atypical form (formerly termed ‘ambiguous genitalia’). a group of non-P450 steroidogenic enzymes that include the short-chain dehydrogenases and members of AKR family. the only currently available immortalized human adrenal cell line that expresses all the adrenal steroidogenic machinery and makes all the adrenal steroids. the microsomal P450 that sequentially catalyzes 17-hydroxylase activity and (in the presence of b5) 17,20 lyase activity. It is encoded by the CYP17A1 gene and is expressed in the adrenals and gonads, but not in placenta. a two-flavin protein that transfers electrons to microsomal (but not mitochondrial) P450s, and is required for their catalytic activity. a group of idiopathic, hyperandrogenic disorders of women characterized by increased ovarian and adrenal C19 steroid secretion, ovarian cysts, and mild virilism. the study of steroid hormone synthesis. Many cells and tissues (e.g., liver) can metabolize one steroid to another, but a cell is said to be ‘steroidogenic’ only if it can initiate the process by expressing P450scc, which initiates steroidogenesis. a rapidly induced, short-lived, 37 kDa protein that acts on the outer mitochondrial membrane (OMM) to stimulate the flow of cholesterol from the OMM to the IMM. At the IMM, cholesterol is taken up by P450scc and converted to cholesterol.