EFFECTS OF INSULIN AND INSULIN-LIKE GROWTH-FACTORS ON PROLIFERATION OF RAT OVARIAN THECA-INTERSTITIAL CELLS

Hyperplasia of the theca-interstitial (T-l) compartment, such as obser ved in polycystic ovary syndrome, is associated with ovarian dysfuncti on. Yet the mechanisms regulating proliferation of T-l cells are virtu ally unknown. This study was an investigation of the effects of insuli n and insulin-like growth factors (IGF-I and IGF-II) on proliferation of rat T-l cells. Purified T-l cells were incubated in chemically defi ned media. Insulin (1-100 nM) and both IGFs (0.3-30 nM) dose-dependent ly stimulated DNA synthesis as determined by radiolabeled thymidine in corporation assay. ICF-I was most potent with EC(50) = 1.4 +/- 0.4 nM, while IGF-II had EC(50) = 4.3 +/- 0.18 nM and insulin had EC(50) = 8. 4 +/- 3.9 nM. The maximal effects of all three treatments were compara ble. A combination of IGF-I at 10 nM (a concentration producing a near -maximal effect) with insulin or ICF-II resulted in DNA synthesis comp arable to that achieved by IGF-l alone. ICF-I mutants with decreased a ffinity to IGF-binding proteins (IGFBPs)-long R(3)-IGF-I and des(1-3)I GF-I-produced greater effects on DNA synthesis than did IGF-I. The eff ects of insulin and IGFs on cell proliferation were confirmed by count ing the steroidogenically active cells (stained positive for 3 beta-hy droxysteroid dehydrogenase [3 beta-HSD]) and steroidogenically inactiv e cells (3 beta-HSD negative). The number of steroidogenically active T-l cells was increased by insulin (by 3.7-fold, p < 0.001), ICF-I (by 3.2-fold, p < 0.001), and IGF-II (by 2.1-fold, p < 0.001). The number of steroidogenically inactive cells was not significantly altered. Th ese findings indicate that 1) insulin- and IGF-dependent synthesis of DNA by T-I cells is stimulated via a common pathway, probably via type I IGF receptors; 2) endogenous IGFBPs may modify the effects of ICF-I ; and 3) the increased DNA synthesis is reflected by an increase in th e number of steroidogenically active cells. Insulin and the IGFs may p lay a role in the regulation of proliferation and differentiation of T -I cells under physiological and pathological conditions. In particula r, the present observations may explain thecal and stromal hyperplasia accompanying hyperinsulinemic conditions such as polycystic ovary syn drome or hyperthecosis.