Effects of insulin and insulin-like growth factors on proliferation of rat ovarian theca-interstitial cells

• Published in: Biology of reproduction Vol. 56; no. 4; pp. 891 - 897
• Main Authors: DULEBA, A. J, SPACZYNSKI, R. Z, OLIVE, D. L, BEHRMAN, H. R
• Format: Journal Article
• Language: English
• Published: Madison, WI Society for the Study of Reproduction 01.04.1997
• Subjects: 3-Hydroxysteroid Dehydrogenases - metabolism; Analysis of Variance; Animals; Biological and medical sciences; Cell Division - drug effects; Cells, Cultured; DNA - biosynthesis; Female; Fundamental and applied biological sciences. Psychology; Hormone metabolism and regulation; Insulin - pharmacology; Insulin-Like Growth Factor Binding Proteins - metabolism; Insulin-Like Growth Factor I - pharmacology; Insulin-Like Growth Factor II - pharmacology; Mammalian female genital system; Ovary - cytology; Ovary - drug effects; Ovary - metabolism; Rats; Rats, Sprague-Dawley; Sexual Maturation; Theca Cells - cytology; Theca Cells - drug effects; Theca Cells - metabolism; Thymidine - metabolism; Tritium; Vertebrates: reproduction; Cell proliferation; Pancreatic hormone; Theca folliculi; Rat; Rodentia; Insulin like growth factor 1; Insulin like growth factor 2; In vitro; Insulin; Ovary; Interstitial cell; Vertebrata; Mammalia; Female genital system; Female; Differentiation; Ovarian follicle
• ISSN: 0006-3363; 1529-7268
• DOI: 10.1095/biolreprod56.4.891

Hyperplasia of the theca-interstitial (T-I) compartment, such as observed in polycystic ovary syndrome, is associated with ovarian dysfunction. Yet the mechanisms regulating proliferation of T-I cells are virtually unknown. This study was an investigation of the effects of insulin and insulin-like growth factors (IGF-I and IGF-II) on proliferation of rat T-I cells. Purified T-I cells were incubated in chemically defined media. Insulin (1-100 nM) and both IGFs (0.3-30 nM) dose-dependently stimulated DNA synthesis as determined by radiolabeled thymidine incorporation assay. IGF-I was most potent with EC50 = 1.4 +/- 0.4 nM, while IGF-II had EC50 = 4.3 +/- 0.18 nM and insulin had EC50 = 8.4 +/- 3.9 nM. The maximal effects of all three treatments were comparable. A combination of IGF-I at 10 nM (a concentration producing a near-maximal effect) with insulin or IGF-II resulted in DNA synthesis comparable to that achieved by IGF-I alone. IGF-I mutants with decreased affinity to IGF-binding proteins (IGFBPs)-long R3-IGF-I and des(1-3)IGF-I-produced greater effects on DNA synthesis than did IGF-I. The effects of insulin and IGFs on cell proliferation were confirmed by counting the steroidogenically active cells (stained positive for 3 beta-hydroxysteroid dehydrogenase [3 beta-HSD]) and steroidogenically inactive cells (3 beta-HSD negative). The number of steroidogenically active T-I cells was increased by insulin (by 3.7-fold, p < 0.001), IGF-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. These 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 IGF-I; and 3) the increased DNA synthesis is reflected by an increase in the number of steroidogenically active cells. Insulin and the IGFs may play a role in the regulation of proliferation and differentiation of T-I cells under physiological and pathological conditions. In particular, the present observations may explain thecal and stromal hyperplasia accompanying hyperinsulinemic conditions such as polycystic ovary syndrome or hyperthecosis.