211 COMMENTARY Possible new mechanism of cortisol action in female reproductive organs: physiological implications of the free hormone hypothesis C Yding Andersen Laboratory of Reproductive Biology, Section 5712, University Hospital of Copenhagen, DK-2100 Copenhagen, Denmark (Requests for offprints should be addressed to C Yding Andersen; Email: [email protected]) Abstract The so-called free hormone hypothesis predicts that the cortisol to cortisone, while 11-HSD type 1 reverses this biological activity of a given steroid correlates with the free reaction. As a result, a high concentration of cortisol protein-unbound concentration rather than with the total available for biological action is present in the preovulatory concentration (i.e. free plus protein-bound). Cortisol is a follicle just prior to ovulation and it has been suggested that glucocorticoid with many diverse functions and the free cortisol may function to reduce the inflammatory-like hormone hypothesis seems to apply well to the observed reactions occurring in connection with ovulation. effects of cortisol. The ovaries express glucocorticoid This paper suggests (1) that the function of the oviduct receptors and are affected by cortisol, but lack the neces- is also affected by the high levels of free cortisol released in sary enzymes for cortisol synthesis. Ovarian follicles modu- preovulatory follicular fluid at ovulation and (2) that late the biological activity of cortisol by (1) follicular formation and function of the corpus luteum benefits from production of especially progesterone and 17-hydroxy- a high local concentration of free cortisol, whereas the progesterone which, within the follicle, reach levels that surrounding developing follicles may experience negative displace cortisol from its binding proteins, in particular, effects. If this hypothesis proves correct it may describe a cortisol-binding protein, making it available for biological new physiological mechanism by which cortisol interacts action and (2) a developmental regulated expression of two with the female reproductive organs, showing that the types of 11-hydroxysteroid dehydrogenase (i.e. 11- biologically active concentration of a steroid locally can be HSD type 1 and type 2), which oppose the action of one regulated to serve specific functions. another, the 11-HSD type 2 predominantly inactivating Journal of Endocrinology (2002) 173, 211–217 Cortisol and the ovaries fraction is free and unbound. The principal binding Glucocorticoids exert their effects in all parts of the body protein in the circulation is cortisol-binding protein and are involved in a number of physiological processes. (CBP). One molecule of CBP binds one molecule of The ovary is also susceptible to the action of glucocorti- cortisol with high affinity. Also albumin binds cortisol but coids; receptors for glucocorticoids are present and it is with low affinity (Table 1). The third major protein well known that the reproductive function may be transporting steroids is sex-hormone-binding globulin impaired during periods of adrenal hyperactivity. In (SHBG) which, however, only binds cortisol with low addition to a direct effect on the ovaries, glucocorticoids affinity and is without physiological significance with also affect ovarian function indirectly via the adrenal– regard to glucocorticoids (Dunn et al. 1981). hypothalamo–pituitary axis. One of the prominent gluco- The biological activity of cortisol seems to be confined corticoids affecting ovarian function is cortisol. Cortisol is to the free unbound fraction, which is available for not produced de novo by the ovaries (Omura & Morohashi movement out of the capillaries and into cells, where it 1995) but transport takes place from the adrenal glands may either initiate a biological response or be cleared from through the circulation. the circulation in a variety of metabolic pathways (Rosner 1990). The free hormone hypothesis predicts that the Cortisol and the free hormone hypothesis biological activity of cortisol is proportional to the concen- Cortisol reaches the ovaries in one of two forms, the tration of free hormone and not to the total concentration majority is bound to plasma proteins and only a small including the protein-bound fraction. Although this Journal of Endocrinology (2002) 173, 211–217 Online version via http://www.endocrinology.org 0022–0795/02/0173–211 2002 Society for Endocrinology Printed in Great Britain Downloaded from Bioscientifica.com at 10/02/2021 02:46:35PM via free access 212 C YDING ANDERSEN · Cortisol action in female reproductive organs Table 1 Binding affinities of steroids for cortisol-binding protein 1981) and this small concentration available for biological (CBP), sex-hormone-binding globulin (SHBG) and albumin action therefore undertakes the normal physiological CBP SHBG Albumin functions of cortisol. (k106/M) (k106/M) (k106/M) Cortisol 76 1·6 0·003 Modulation of cortisol levels within the ovaries Cortisone 7·8 2·7 0·005 Oestradiol 0·06 680 0·060 Pregnenolone 0·18 14 0·060 The 11-hydroxysteroid dehydrogenase (11-HSD) fam- Progesterone 24 8·8 0·060 ily of enzymes plays an important role in controlling the 17-OH-progesterone 55 9·9 0·040 local tissue concentration of cortisol. Two distinct isoforms Testosterone 5·3 1600 0·040 of 11-HSD exist (i.e. 11-HSD type 1 and type 2) (Michael et al. 1997, Tetsuka et al. 1997), 11-HSD type Values obtained from Dunn et al. (1981). 2 predominantly inactivates cortisol to cortisone, while 11-HSD type 1 reverses this reaction predominantly converting cortisone to cortisol (Fig. 1) (Monder & hypothesis may not be valid for all steroid hormones in Lakshmi 1989, Mercer et al. 1993, Michael et al. 1997). every organ, there seems to be good evidence to suggest The relative expression of the two types of 11-HSD in that it accounts for cortisol action in most situations (for specific organs modifies cortisol exposure by interconver- review see Orth & Kovacs 1998) as supported by the sion between active and inactive glucocorticoids as seen in following studies: (1) A reduced in vivo activity of CBP- the kidney, liver, bone and adipose tissue. In the human, bound cortisol (Slaunwhite et al. 1962), (2) a reduced ovary expression of 11-HSD types 1 and 2 is also well suppressive effect of cortisol on mononuclear cell DNA documented (Tetsuka et al. 1997, Smith et al. 2000, Yong synthesis in vitro in the presence of CBP (Ogawa et al. et al. 2000). However, expression of 11-HSD type 2 (i.e. 1983), (3) cortisol bound to CBP avoids metabolic degra- inactivation of cortisol) is most abundant during the luteal dation (Bright 1995), (4) the mechanism that regulates phase in the corpus luteum (CL), and in non-luteinized cortisol production correlates with the free rather than the granulosa cells from follicles before the mid-cycle surge of total concentration and (5) the concentration of free gonadotrophins. In contrast, expression of 11-HSD type cortisol in the circulation is usually normal in the presence 1 (i.e. formation of cortisol from cortisone) is only seen in of abnormal CBP levels (Mendel 1989). granulosa cells from preovulatory follicles in response to The function of steroid-binding proteins, therefore, is to the mid-cycle surge of gonadotrophins (Tetsuka et al. act as a buffer reservoir of steroids present throughout the 1997, Smith et al. 2000, Yong et al. 2000). As observed in body that can readily be made available to the pool of other organs (Escher et al. 1997), it has been suggested that free hormone by simple dissociation (Rosner 1990). The release of cytokines like interleukin-1 and tumour necro- steroid-binding proteins reduce alterations in the free sis factor- regulates the expression of 11-HSD in rat steroid level and maintain the level of free biologically granulosa cells and that these factors, in connection with active cortisol at a relative constant level. CBP is present in the mid-cycle surge of gonadotrophins, up-regulates 11- a relative constant concentration of around 700 nmol/l, HSD type 1 expression (Hillier & Tetsuka 1998). The and exceeds the upper limit of the normal concentration expression of 11-HSD types 1 and 2 actually fits well range of cortisol (i.e. 550 nmol/l). Consequently, in both with the observed levels of total cortisol and cortisone in normal men and women only a few percent of the total follicular fluid (FF), where cortisone seems to predominate concentration of cortisol is free and unbound (Dunn et al. before the mid-cycle surge of gonadotrophins, whereas Figure 1 In the ovary, cortisol is inactivated through the action of 11-hydroxysteroid dehydrogenase (HSD) type 2, which predominantly favours the formation of cortisone, whereas 11-HSD type 1 reverses this process, predominantly catalysing the formation of cortisol from cortisone. Journal of Endocrinology (2002) 173, 211–217 www.endocrinology.org Downloaded from Bioscientifica.com at 10/02/2021 02:46:35PM via free access Cortisol action in female reproductive organs · C YDING ANDERSEN 213 Table 2 Average total and free concentrations (in nmol/l) of steroids in serum and preovulatory follicular fluid (FF) obtained from women undergoing in vitro fertilization (IVF) with exogenous gonadotrophins Progesterone 17-OH-progesterone Cortisol Oestradiol Testosterone Androstenedione Total Serum 18 14 286 4·2 3·9 8·4 FF 29 700 6490 254 2480 8·3 58 Free Serum 0·4 0·24 5·7 0·026 0·032 0·56 (2·2%) (1·7%) (2·0%) (1·1%) (0·8%) (6·7%) FF 985 310 69 83 0·4 5·6 (3·3%) (4·8%) (27%) (3·3%) (4·8%) (9·6%) Percentages given in parentheses for the free concentrations indicate concentrations of free steroid in relation to the total concentration. Concentrations of free steroids were calculated using the computer simulation program Transport as described (Dunn et al. 1981), based on respective association constants between the steroids and binding proteins, and the total molar concentration of each of the steroid–protein complexes.