Activin Stimulates Follicle Formation and Activation and Modulates Steroidogenesis in Fetal Bovine Ovarian Tissue in Vitro1
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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 developed methods in vitro to elucidate the regulation of these early stages in fetal ovarian tissue of cattle, an excellent model for human ovarian development. The current experiments were designed to determine if fetal bovine ovaries have activin A and its receptors and if activin A regulates follicular formation and/or follicle activation to begin growth in pieces of fetal ovarian cortex. During early to mid-gestation follicles first form in the ovarian cortex when oocytes are enclosed in a single layer of flattened granulosa cells. Activin increased the total number of follicles by 2-fold and the number of primary (activated) follicles by 5-fold in cultured ovarian cortical pieces, compared to control medium. During mid to late gestation, after follicles have formed, activin decreased primordial follicle numbers and increased primary follicles about 4-fold, indicating that activin stimulated primordial follicles to become growing, primary follicles. Our previous experiments showed that fetal ovaries produce ovarian steroids, especially just before and during early to mid-gestation (when follicles are forming), 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 culture medium, suggesting that the effects of activin A are achieved, at least in part, by its modulating effects on ovarian steroidogenesis. 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 and granulosa cells at all stages and to 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 plays a role in the establishment of the follicular reserve that is so important for normal female fertility.
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