Activin Stimulates Follicle Formation and Activation and Modulates Steroidogenesis in Fetal Bovine Ovarian Tissue in Vitro 1

Abstract

The earliest stages of ovarian follicular development, follicle formation and development of the capacity to activate, are critical to the size of the ovarian reserve. In primates and most domestic animals, these stages occur during fetal life and thus, are difficult to study. Our laboratory has used cattle, an excellent model for human ovarian development, to elucidate the regulation of these early stages in fetal bovine ovarian tissue in vitro. The experiments described here were designed to determine if fetal bovine ovaries have activin A and its receptors and if activin A affects follicular formation and/or activation to begin growth. During the second trimester, when follicles first form, activin increased the total number follicles and the number of primary (activated) follicles in cultured ovarian cortical pieces, compared to control medium; its effects were similar to the positive control, insulin. During the second trimester, activin decreased primordial follicle numbers and increased primary and secondary follicles, again mimicking the positive control. Our previous experiments showed that fetal ovaries produce ovarian steroids, particularly during the second trimester, and that estradiol and progesterone inhibit follicle formation and activation. In control and gonadotropin-treated ovarian pieces, activin A increased progesterone, but decreased androstenedione and estradiol accumulation in the medium. Messenger RNA for activin and its type II receptors was detected in fetal bovine ovaries, with ACVR2A receptor mRNA more abundant than ACVR2B. Immunohistochemistry localized mRNA for activin A and ACVR2A to germ cells of all stages, granulosa cells, and theca cells of early secondary follicles. Staining for ACVR2B was weaker and mostly confined to germ calls. Taken together, these results strongly suggest that activin A of fetal ovarian origin 3 plays a role in ovarian development by promoting follicle formation and activation and modulating ovarian steroidogenesis.