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Bestatin, an aminopeptidase inhibitor, promotes follicular growth and ovulation suppressed by stress in mice.

We previously reported that the intraperitoneal and intrabursal administration 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 conditions in which the ovarian response to gonadotropins was suppressed. Immature 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, bestatin (4 mg/ml, 100 microl) or PBS (100 microl) was administered ip. 4 times and pregnant mare serum gonadotropin (PMSG, 5 IU) and hCG (5 IU) were given on days 21 and 23, respectively. The numbers of ovulated oocytes per mice were significantly attenuated by both stresses. Bestatin significantly enhanced the numbers of ovulated oocytes under both lighting (49.5+/-7.0 vs. 28.0+/-5.5) and starvation (28.6+/-2.6 vs. 20.2+/-2.0) stresses (with vs. without bestatin, P<0.05). When follicular development was stimulated by PMSG (20 IU) on day 21, the serum estradiol concentration on day 23 was also suppressed by both stresses, 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 under starvation stress. These results indicated that stress inhibited the ovarian response to gonadotropins and that bestatin restored the response suppressed by stress.