Of the Many Secrets of Steroidogenesis

Extract

So where is the excitement in the study of steroidogenesis? It is pretty well cut-and-dried; after all, 17β-estradiol is the same in mice, rats, cows, monkeys, and humans. The basic steroidogenic pathway of cholesterol to pregnenolone to progesterone and adrenal steroids, or to androgens and estrogens is the same in all mammalian taxa. The old debate about the “rate limiting step” in steroidogenesis has lost some traction as the role of the steroidogenic acute regulatory protein has gained clarification. Far and away most work in the field of steroidogenesis currently revolves around gene regulation of specific players in the pathway, to be sure, a critical and necessary aspect in understanding cell and tissue specificity. Finally, steroidogenesis does not pose a compelling clinical topic, as steroids are easy to measure and easy to manipulate. Despite all this, the immensely important role steroids play in nearly all aspects of vertebrate biology underlies both the true complexity and elegance of steroidogenesis. Species are in fact dramatically different in how they regulate the steroidogenic pathway. For example, 17α-hydroxyprogesterone (17OH-P) is a poor substrate for P450c17 (official symbol CYP17A1) in humans; because 17OH-P is a precursor for cortisol, this probably keeps substrate available for stress responses in the adrenal gland. In contrast, CYP17A1 efficiently metabolizes 17OH-P to androstenedione and, ultimately, to estrogen in species such as rats, perhaps allowing for a rapid resumption of follicle growth in species with short luteal phases [1]. Another example of species variability lies in the compartmentalization of steroidogenesis. While arguably all mammalian species have the same basic relationship in the ovary of androgen-producing theca cells and aromatizing granulosa cells, estrogen synthesis during pregnancy is divergent, for example, fetal adrenal-placenta in humans and placenta and maternal ovaries in rats. In this issue of Biology of Reproduction, Conley et al. [4] hypothesize that compartmentalization of steroidogenic enzymes represents a functional aspect of estrogen synthesis. Implicit in this hypothesis is the concept of optimization of the rate of steroidogenesis, while not necessarily maximizing estrogen production.