Divergent mechanisms regulate proliferation/survival and steroidogenesis of theca-interstitial cells.
Luteinizing hormone (LH) and insulin-like growth factor I (IGF-I) are recognized as major regulators of ovarian theca-interstitial (T-I) function. This study was designed to compare the effects of LH and IGF-I on T-I proliferation and steroidogenesis. Purified rat T-I cells were cultured in chemically-defined media. DNA synthesis was evaluated by a radiolabelled thymidine incorporation assay. The cells were also directly counted. Progesterone production was assessed using a specific radioimmunoassay. DNA synthesis of T-I cells was stimulated by IGF-I (10 nM) but modestly inhibited by LH (100 ng/ml). The inhibitory effect of LH was mimicked by 8Br-cAMP (10(-4) to 10(-3) M); forskolin (10(-5) M), cholera toxin (10 ng/ml) and 3-isobutyl-methylxanthine (10(-5) M). Stimulation of protein kinase C with phorbol 12-myristate 13-acetate (10(-7) M) had no significant effect on DNA synthesis. Furthermore, DNA synthesis was not affected by testosterone (10(-10) to 10(-9) M) or progesterone (10(-9) to 10(-8) M). Accumulation of progesterone was co-operatively stimulated by LH and IGF-I. These results suggest that LH-induced inhibition of T-I proliferation and/or survival is mediated via the cAMP system. IGF-I may be viewed as a co-gonadotrophin with respect to steroidogenesis but not with respect to proliferation/survival. The divergence of the effects on proliferation/survival versus steroidogenesis underscores the complexity of the interactions between LH and IGF-I signalling pathways.
Duleba
A J
AJ
Yale University School of Medicine, Department of Obstetrics and Gynecology, New Haven, CT 06520-8063, USA.
Spaczynski
R Z
RZ
Olive
D L
DL
Behrman
H R
HR
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015096:3-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D005260:Female; D006727:Hormone Antagonists / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology; D007986:Luteinizing Hormone / Q000494:pharmacology / Q000502:physiology*; D015735:Mifepristone / Q000494:pharmacology; D011374:Progesterone / Q000378:metabolism* / Q000494:pharmacology; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013799:Theca Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*
D006727:Hormone Antagonists; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D015735:Mifepristone; D013739:Testosterone; D011374:Progesterone; D007334:Insulin-Like Growth Factor I; D007986:Luteinizing Hormone; D004247:DNA; D000242:Cyclic AMP; D015096:3-Hydroxysteroid Dehydrogenases; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D015056:1-Methyl-3-isobutylxanthine