BESTATIN, AN AMINOPEPTIDASE INHIBITOR, PROMOTES FOLLICULAR-GROWTH ANDOVULATION SUPPRESSED BY STRESS IN MICE

We previously reported that the intraperitoneal and intrabursal admini stration of bestatin, an aminopeptidase inhibitor, enhanced follicular growth and ovulation in immature mice. In this study, we examined the effect of bestatin on follicular growth and ovulation under the condi tions in which the ovarian response to gonadotropins was suppressed. I mmature female mice were exposed to 72-h continuous lighting (on days 20-22 of life), or to 24-h starvation (on day 20). On days 20-22, best atin (4 mg/ml, 100 mu l) or PBS (100 mu l) was administered ip. 4 time s and pregnant mare serum gonadotropin (PMSG, 5 IU) and hCG (5 IU) wer e given on days 21 and 23, respectively. The numbers of ovulated oocyt es per mice were significantly attenuated by both stresses. Bestatin s ignificantly enhanced the numbers of ovulated oocytes under both light ing (49.5 +/- 7.0 vs. 28.0 +/- 5.5) and starvation (28.6 +/- 2.6 vs. 2 0.2 +/- 2.0) stresses (with vs. without bestatin, P < 0.05). When foll icular development was stimulated by PMSG (20 IU) on day 21, the serum estradiol concentration on day 23 was also suppressed by both stresse s, but enhanced by bestatin under lighting (231.3 +/- 36.0 vs. 111.0 /- 23.0 pg/ml) and starvation (151.9 +/- 8.8 vs. 90.7 +/- 15.4 pg/ml) stresses (with vs. without bestatin, P < 0.01). Northern blot analysis revealed that the expression of P450arom-mRNA in the ovaries induced by PMSG (20 IU) was increased on day 23 by treatment with bestatin und er starvation stress. These results indicated that stress inhibited th e ovarian response to gonadotropins and that bestatin restored the res ponse suppressed by stress.