Physiological roles of activins in the human ovary

Abstract Initially discovered in the pituitary as stimulators of follicle stimulating hormone, activins are homo- or heterodimers of inhibin subunits, which belong to the transforming growth factor-&bgr; superfamily. Subsequent studies have demonstrated that these growth factors play multifaceted roles in regulating various functions in multiple organs, including the ovary. The spatial and temporal expression of inhibin subunits (&agr;, &bgr;A, &bgr;B, and &bgr;C), their cognate receptors, and activin-binding proteins (inhibins and follistatins) in the principal cells of growing follicles in human ovaries indicates that these activin isoforms are involved in ovarian biology. Information collected from animal studies and clinical samples suggests that these locally produced growth factors are crucial modulators of various ovarian functions, including primordial germ cell development, follicular growth and development, ovarian steroidogenesis, extracellular matrix remodeling, oocyte maturation, ovulation, and luteal function. Along with gonadotropins, intrafollicular activins exert synergistic and complementary effects on growing follicles to help them develop a mature, competent oocyte that is prepared for fertilization. Abnormal activin expression, an imbalanced activin/follistatin ratio, and the dysregulation of the activin signaling pathway have been observed in several ovarian pathologies, such as reproductive aging, polycystic ovary syndrome, and ovarian cancers. Recent advancements in our understanding of the molecular interactions and mechanisms that underlie activins and the development of related ovarian abnormalities have provided insights into disease pathogenesis and increased opportunities to achieve efficient and safe therapies.