Possible new mechanism of cortisol action in female reproductive organs: physiological implications of the free hormone hypothesis

The so-called free hormone hypothesis predicts that the biological activity of a given steroid correlates with the free protein-unbound concentration rather than with the total concentration (i.e. free plus protein-bound). Cortisol is a glucocorticoid with many diverse functions and the free hormone hypothesis seems to apply well to the observed effects of cortisol. The ovaries express glucocorticoid receptors and are affected by cortisol, but lack the necessary enzymes for cortisol synthesis. Ovarian follicles modulate the biological activity of cortisol by (1) follicular production of especially progesterone and 17 alpha-hydroxy-progesterone which, within the follicle, reach levels that displace cortisol from its binding proteins, in particular, cortisol-binding protein, making it available for biological action and (2) a developmental regulated expression of two types of 11 beta-hydroxysteroid dehydrogenase (i.e. 11 beta-HSD type 1 and type 2), which oppose the action of one another, the 11 beta-HSD type 2 predominantly inactivating cortisol to cortisone, while 11 beta-HSD type 1 reverses this reaction. As a result, a high concentration of cortisol available for biological action is present in the preovulatory follicle just prior to ovulation and it has been suggested that cortisol may function to reduce the inflammatory-like reactions occurring in connection with ovulation. This paper suggests (1) that the function of the oviduct is also affected by the high levels of free cortisol released in preovulatory follicular fluid at ovulation and (2) that formation and function of the corpus luteum benefits from a high local concentration of free cortisol, whereas the surrounding developing follicles may experience negative effects. If this hypothesis proves correct it may describe a new physiological mechanism by which cortisol interacts with the female reproductive organs, showing that the biologically active concentration of a steroid locally can be regulated to serve specific functions.