CYCLOOXYGENASE EXPRESS & PROSTAGLANDIN PRODUCT BY PRIMAT PERIOVULATORY FOLLICLES

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Production of prostaglandins (PGs) by granulosa cells of periovulatory follicles increases rapidly following the ovulatory gonadotropin surge in nonprimates, but this relationship has not been examined in monkeys or women. To examine PG production by primate periovulatory follicles, adult female rhesus monkeys received gonadotropins to promote multiple follicular development. Granulosa cells and follicular fluid were obtained before (0 h) and 12, 24, or 36 hours after administration of an ovulatory bolus of gonadotropin (hCG). Granulosa cells were analyzed for content of mRNAs for the cyclooxygenase (COX) isoforms COX-1 and COX-2, which catalyze the rate limiting step in PG production. While granulosa cell COX-1 mRNA levels did not change during the periovulatory interval, COX-2 mRNA expression was low at 0 h, rose 40-fold by 12 h, and remained elevated through 36 h. Follicular fluid PGE2 and PGF2? levels were also low at 0 h and remained low through 24 h. How ever , PGE2 and PGF2? concentrations were elevated at 36 h, representing a 100-fold increase in follicular fluid levels between 24 and 36 h. These data suggest that the ovulatory gonadotropin surge increases primate granulosa cell PG production by enhancing COX-2 expression, resulting in elevated follicular PG levels 4-16 hours before the expected time of ovulation. To determine if the ovulatory gonadotropin surge acts directly at granulosa cells to stimulate COX-2 expression and PG synthesis, granulosa cells obtained before administration of the ovulatory dose of hCG were cultured without or with ovulatory concentrations of gonadotropin for 36 hours. Gonadotropin did not enhance PG production or COX-2 mRNA levels above that in control cultures, though low levels of COX-1 expression were maintained. Thus, the timing of the periovulatory rise in follicular fluid PGs in monkeys supports the unifying hypothesis that elevated PG levels about 10 hours before ovulation are critical for follic le rupture and release of the oocyte in primate as well as non-primate species. However, gonadotropin may not act directly at granulosa cells to stimulate PG production in response to the ovulatory surge. These studies are applicable to both the treatment of conditions contributing to infertility as well as the development of novel contraceptives that block ovulation. FUNDING Medical Research Foundation of Oregon, HD20869, HD18185 PUBLICATIONS Duffy DM, Stouffer RL. Cyclooxygenase expression and prostaglandin production during the periovulatory interval Control of the ovulatory clock in primates. In International Symposium on Ovulation Evolving and Clinical Concepts (held in Salt Lake City, UT, September 24-27, 1998), p 33 (abstract #2). Duffy DM, Stouffer RL. Expression of cyclooxygenase-1 and -2 genes in granulosa cells of primate follicles in response to the ovulatory gonadotropin surge. In Endocrine Society Program and Abstracts 80th Annual Meeting (held in New Orleans, LA, June 24-27, 1998), p 184 (abstract #P1-305).