Recent experimental data have revealed that activins and inhibins exert pivotal effects on development. As part of our studies on growth and differentiation of the human fetal adrenal gland, we examined the subunit localization, as well as the mitogenic and steroidogenic actions of activin and inhibin in human fetal and adult adrenals. All three activin and inhibin subunit proteins (a, ,A, and #B) were detected in the fetal and adult adre-

The actions, localization, and regulation of activin in the human ovary are unknown. Therefore, the aims of this study were (a) to define the effects of recombinant activin-A and its structural homologue, inhibin-A, on mitogenesis and steroidogenesis (progesterone secretion and aromatase activity) in human preovulatory follicular cells; (b) to localize the activin-A dimer in the human ovary by immunohistochemistry; and (c) to examine regulation of intracellular activin-A production in cultured human follicular cells. In addition to stimulating mitogenic activity, activin-A causes a dose-and time-dependent inhibition of basal and gonadotropin-stimulated progesterone secretion and aromatase activity in human luteinizing follicular cells on day 2 and day 4 of culture. Inhibin-A exerts no effects on mitogenesis, basal or gonadotropin-stimulated progesterone secretion and aromatase activity, and does not alter effects observed with activin-A alone. Immunostaining for dimeric activin-A occurs in granulosa and cumulus cells of human ovarian follicles and in granulosa-lutein cells of the human corpus luteum. cAMP, and to a lesser degree human chorionic gonadotropin and folliclestimulating hormone, but not inhibin-A, activin-A, or phorbol 12-myristate 13-acetate, increased the immunostaining for activin-A in cultured granulosa cells. These results indicate that activin-A may function as an autocrine or paracrine regulator of follicular function in the human ovary. (J. Clin. Invest. 1992.

Ovarian granulosa cells synthesize and secrete activin, a member of the transforming growth factor-beta (TGF-beta) peptide family, during the follicular phase of the menstrual cycle. We examined the growth-promoting activity of human recombinant activin-A on human luteinized preovulatory granulosa cells obtained from women undergoing in vitro fertilization. Activin-A induced proliferation of granulosa cells on day 5 of culture in a dose-dependent manner. Maximal effects were seen at concentrations greater than or equal to 100 ng/mL with an ED50 of 15 ng/mL. We suggest that activin-A is able to modulate growth of ovarian granulosa cells.

Activins and inhibins are dimeric peptides which are structurally and functionally related to transforming growth factor-beta (TGF-beta). The mRNA for the activin and inhibin subunits is expressed in the adrenal gland. Because members of the TGF-beta superfamily have effects on mitogenesis, we examined the effect of recombinant human activin-A (rh-activin-A) on proliferation of midgestation human fetal adrenal cells in vitro. Dose-dependent growth inhibition by rh-activin-A was obtained, with an ED50 of 1 ng/ml. Rh-activin-A inhibited basal and epidermal growth factor (EGF)-stimulated fetal zone cell proliferation, but did not alter basic fibroblast growth factor (bFGF)-stimulated growth. TGF-beta combined with rh-activin-A demonstrated additive inhibition of fetal adrenal growth. These findings suggest a potential autocrine or paracrine role for activin-A in modulating the growth and/or subsequent involution of the human fetal adrenal gland.

Throughout fetal and adult life, the balance of cell proliferation and cell death determines the size of cell populations in tissues throughout the body. Apoptosis, or programmed cell death, is the physiologic process of cell deletion. Cell death is critical in morphogenesis in the embryo and fetus as well as in maintaining tissue homeostasis in the adult. Throughout the menstrual cycle, cell death and renewal occur in the female reproductive tract in a highly regulated sequence. The process of follicular atresia and the cyclic shedding of the endometrium involve the process of apoptosis. In pathologic states, resistance to cell death by apoptosis may play a fundamental role in tumorigenesis. Because apoptosis is such a fundamental biologic process in a variety of physiologic and pathologic states, many unique to the female reproductive tract, it is imperative that clinicians be conversant with the rapidly expanding information in this area. Although apoptotic cell death has been recognized histologically for over 20 years (1), the molecular mechanisms that regulate apoptosis have only recently begun to be elucidated. The identification of some of these regulators, such as the p53 gene, has improved our understanding of the mechanisms of tumor response to chemotherapy. This review will summarize our current knowledge of the mechanisms of apoptosis in the ovary and endometrium, and in the normal development and malignant transformation of the breast.