Activin stimulates proliferation of rat ovarian thecal-interstitial cells

There is growing evidence that the function of ovarian theca-interstitial ( T-I) cells may be modulated by paracrine actions of activin, inhibin, and f ollistatin. Furthermore, either dysregulation, dysfunction, or both, of the se peptides may play a role in conditions associated with T-I hyperplasia, such as polycystic ovary syndrome (PCOS) and hyperthecosis. This study was designed to evaluate the role of activin, inhibin, and follistatin in the m odulation of T-I cell proliferation. Interaction of these peptides with ins ulin-like growth factor-I (IGF-I), a known stimulator of T-I cell prolifera tion, was also assessed. Purified rat T-I cells were cultured for 48 h in c hemically defined media and with or without activin (3-30 ng/ml), inhibin ( 3-30 ng/ml), follistatin (100 ng/ml), and/or IGF-I (10 nM). T-I cell prolif eration was assessed using radiolabeled thymidine incorporation assay. Acti vin alone stimulated proliferation of T-I cells in a dose-dependent fashion (by up to 320% above control; P < 0.001), whereas inhibin alone or follist atin alone had no significant effect. Inhibin had also no effect on activin -induced proliferation. Follistatin significantly reduced the stimulatory e ffects of activin and decreased proliferation by up to 46% (P < 0.01) below the level attained in the presence of activin alone. IGF-I (10 nM), at a d ose producing a near-maximal effect, increased proliferation by 175% above control (P < 0.001); insulin (10 nM) increased proliferation by 52% above c ontrol (P < 0.03). A combination of IGF-I (10 nM) and activin (30 ng/ml) re sulted in a 1090% increase of proliferation above control (P < 0.001); this stimulatory effect was significantly greater than that achieved in the pre sence of either activin alone or IGF-I alone (P < 0.001). Similarly, a comb ination of insulin (10 nM) and activin (30 ng/ml) increased proliferation b y 506% above control levels. Flow cytometry evaluation revealed that activi n increased the proportion of actively dividing cells (in S or G2/M phase o f the cell cycle) by 42% (P < 0.02), whereas IGF-I had no effect on the pro portion of actively dividing cells. The present findings indicate that an a ctivin-follistatin system may be involved in the regulation of the size of ovarian thecal-stromal compartment. In view of the synergy between activin and IGF-I, and the difference in the effects on the cell cycle distribution , stimulation of T-I proliferation by these agents is likely to be mediated via separate transduction pathways. Excess activin or insufficient follist atin may contribute to T-I hyperplasia.