Steroidogenesis: Unanswered Questions

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 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.