Inhibition of Follicle-Stimulating Hormone-Induced Ovulation by Indomethacin in the Perfused Rat Ovary1

Abstract

In isolated, perfused ovaries of rats treated with pregnant mare's serum gonadotropin (PMSG), purified preparations of ovine follicle-stimulating hormone (FSH) (oFSH-211B) and rat FSH (rFSH-I-6), 100 ng/ml, were found to induce ovulations (4.8 +/- 0.9, n = 4, and 6.4 +/- 2.0, n = 5, ovulations per ovary, respectively). Indomethacin (5 micrograms/ml) added to the perfusate inhibited this ovulatory effect and exogenous prostaglandin F2 alpha (PGF2 alpha) (1 microgram/ml), or prostaglandin E2 (PGE2) (0.5 microgram/ml), reversed the blockade. Ovine FSH and rFSH had only a weak stimulatory effect on estradiol release, and only rFSH caused a significant increase in progesterone accumulation. Indomethacin reduced the stimulatory effect of rFSH on progesterone release, and this effect was reversed by PGE2 but not by PGF2 alpha. In a 6-h incubation experiment with preovulatory rat follicles, we tested the biological activity of gonadotropins used to induce oocyte maturation. The concentration of FSH used in the perfusion experiments induced oocyte maturation in more than 88% of the oocytes studied. The data confirm earlier findings that FSH can induce ovulations and show that prostaglandins are involved in this process. The data also indicate that prostaglandins might be involved in the FSH-induced increase of progesterone levels.

Effect of intrafollicular indomethacin injection on gonadotropin surge-induced expression of select extracellular matrix degrading enzymes and their inhibitors in bovine preovulatory follicles

“…The cyclooxygenase (COX)-2 enzyme, which catalyzes the rate-limiting step in intrafollicular prostanoid synthesis, is induced within the granulosal layer of rat (Sirois et al 1992), equine (Sirois & Dore 1997) and bovine preovulatory follicles (Sirois 1994, Tsai et al 1996 in response to the LH surge. Indomethacin (INDO), an inhibitor of the COX pathway, is a potent inhibitor of ovulation in numerous species (Tsafriri et al 1972, Murdoch et al 1986, Sogn et al 1987, including cattle (De Silva & Reeves 1985). Mice with a targeted mutation in the COX-2 gene are infertile (Dinchuk et al 1995) and anovulatory (Davis et al 1999), potentially due to a proteoglycan synthesisrelated alteration in cumulus expansion and impaired follicle rupture.…”

Effects of selective inhibition of cyclooxygenase and lipooxygenase pathways in follicle rupture and ovulation in the rat

“…In the first approach, classical non-steroidal anti-inflammatory drugs (NSAIDs), inhibiting both COX-1 and COX-2 activity, as well as the more recently developed selective COX-2 inhibitors, have been repeatedly reported to inhibit ovulation in all mammalian species investigated so far (reviewed by Brännströ m & Janson 1991, Tsafriri et al 1993, Espey & Lipner 1994. Furthermore, exogenous prostaglandin supplementation restored ovulation in NSAID-treated animals, at least under some experimental conditions (Holmes et al 1983, Sogn et al 1987, Gaytán et al 2002a). More recently, genetic studies in mice (Lim et al 1997, Matsumoto et al 2000 have confirmed the obligatory role of COX-2/ prostaglandins in ovulation.…”

Two pathways for prostaglandin F2α synthesis by the primate periovulatory follicle

“…However, it is important to note that the presence of functional FP receptors has never been reported for follicular granulosa cells of any mammalian species. Disruption of the PGE2 receptor EP2 reduces the efficiency of ovulation in mice (Hizaki et al 1999), and previous studies support a role for PGE2 to regulate periovulatory events in mammals (Sogn et al 1987, Peters et al 2004, including primates (Duffy & Stouffer 2002). It remains possible that either or both PGE2 and PGF2a may be able to initiate ovulatory events in the follicles of primates and domestic animals.…”

“…Administration of PGF2a to PG-synthesis inhibitor-treated animals can restore ovulation in rodents, domestic animals, and primates (Wallach et al 1975, Murdoch et al 1986, Sogn et al 1987, Janson et al 1988. However, disruption of FP receptor expression did not prevent ovulation in mice (Sugimoto et al 1997), arguing against receptormediated action of PGF2a to initiate ovulatory events in this species.…”

“…While studies with PGF2a receptor knockout mice suggest that PGF2a is not required for ovulation (Sugimoto et al 1997), subfertility in mice lacking expression of the PGE2 receptor EP2 focused attention on PGE2 as the key ovulatory PG (Hizaki et al 1999). Blockade of PG production within the follicle prevented cumulus expansion, follicle rupture, and oocyte release; restoration of periovulatory events with coadministration of the PG synthesis inhibitor and PGE2 identified PGE2 as a key mediator of ovulation in mammals (Sogn et al 1987, Peters et al 2004, including primates (Duffy & Stouffer 2002). However, additional studies have demonstrated restoration of ovulation with PGF2a administration (Wallach et al 1975, Murdoch et al 1986, Sogn et al 1987, Janson et al 1988, suggesting that PGF2a may also play a role in ovulatory processes.…”