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Development-Related Increase in Cortisol Biosynthesis by Human Granulosa Cells¹

Assisted Conception Unit (P.Y.K.Y., K.J.T.), Royal Infirmary of Edinburgh, Edinburgh EH3 9EF; Department of Medical Sciences (R.A., B.R.W.), University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU; and Department of Reproductive and Developmental Sciences (S.G.H.), University of Edinburgh, Centre for Reproductive Biology, Edinburgh EH3 9EW, Scotland, United Kingdom

Address all correspondence and requests for reprints to: Dr. Stephen G. Hillier, University of Edinburgh, Centre for Reproductive Biology, 37 Chalmers Street, Edinburgh EH3 9EW, Scotland, United Kingdom.

Antiinflammatory mechanisms are important in ovulation and may be regulated by cortisol (F). We previously showed that after administration of human (h)CG for ovulation induction, luteinized granulosa cells (LGC) abundantly express 11ß-hydroxysteroid dehydrogenase type 1 (11ßHSD1) messenger RNA but not 11ßHSD type 2 (11ßHSD2) messenger RNA. 11ßHSD1 is responsible for the reversible formation of antiinflammatory F from its inactive precursor cortisone (E), whereas 11ßHSD2 unidirectionally converts F to E through 11-oxidation. This pattern of gene expression predicts that LGC from periovulatory follicles would show increased activation of E to F, compared with granulosa cells from immature follicles (IGC), and that follicular fluid concentrations of E and F would alter accordingly. To test this hypothesis, we isolated IGC, thecal cells (TC), and follicular fluid, from ovaries of cyclic women, removed during surgery for benign gynecological disease. LGC and follicular fluid were aspirated from periovulatory follicles, 35 h after hCG injection, in patients undergoing in vitro fertilization treatment. In an 11ßHSD assay based on interconversion of tritiated E and F by cell suspensions in vitro, IGC (% conversion, 0.6 ± 0.4, mean ± SEM) and collagenase-dispersed TC (0.2 ± 0.1%) were unable to convert E to F, whereas LGC (36.3 ± 3.7%) were highly efficient at this reaction. Immature granulosa cells, LGC, and (to a lesser extent) TC were all able to convert F to E. Correspondingly, follicular fluid concentrations of total F and F:E ratios were significantly higher in periovulatory follicles, compared with immature follicles. Culturing IGC for 48 h in the presence of hFSH resulted in increased 11ßHSD1 reductase activity, paralleling stimulation of estrogen (aromatase activity) and progesterone biosynthesis. Similar treatment with hLH did not influence 11ßHSD1 reductase activity, except in a patient with more mature IGC, which also showed a significant increase in E-to-F conversion, as well as progesterone synthesis in response to hLH. These data confirm that 11ßHSD activity in the human ovary is developmentally regulated and gonadotropin responsive, favoring metabolism of F to E in immature follicles and E to F in periovulatory follicles. Increased formation of F by LGC in periovulatory follicles is consistent with an antiinflammatory function for this glucocorticoid at ovulation.

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