Molecular Human Reproduction, Vol. 5, No. 11, 1003-1010,
November 1999
© 1999 European Society of Human Reproduction and Embryology
Molecular endocrinology |
Insulin and insulin-like growth factor-I and- II modulate human granulosa–lutein cell steroidogenesis: enhancement of steroidogenic acute regulatory protein (StAR) expression
1 Center for Research on Reproduction and Women's Health, University of Pennsylvania, Philadelphia, PA, 19104, 2 Department of Cell and Molecular Physiology, Pennsylvania State University, Milton S .Hershey Medical Center, Hershey, PA 17033, USA
Abstract
Insulin and insulin-like growth factors (IGF)-I and -II stimulate granulosa cell steroidogenesis. Since steroidogenic acute regulatory protein (StAR) regulates the rate-limiting step in steroid hormone biosynthesis, the ability of insulin and IGF to modulate StAR protein and mRNA expression was examined in two human granulosa cell culture systems: (i) proliferating granulosa–lutein cells and (ii) luteinized-granulosa cells derived during in-vitro fertilization (IVF). In proliferating granulosa–lutein cells, IGF-I and IGF-II increased StAR protein ~4–5-fold, while insulin and 8-bromoadenosine 3',5'-cAMP (8-Br-cAMP) increased amounts of StAR protein 2.5- and 6-fold respectively. A combination of IGFs/insulin and 8-Br-cAMP increased StAR 7–9-fold. Luteinized granulosa cells also had increased StAR expression after treatment with IGF-I (2.8-fold), IGF-II (3-fold), insulin (2.5-fold) and 8-Br-cAMP (4.5-fold). Progesterone production generally followed a pattern similar to StAR protein in both cell systems. In proliferating granulosa–lutein cells, both IGF-I and insulin increased StAR mRNA (3-fold) and 8-Br-cAMP increased StAR mRNA 4-fold, whereas a combination of IGF-I and 8-Br-cAMP had an additive effect on StAR mRNA expression (7-fold). Transient transfection of proliferating granulosa–lutein cells with StAR promoter-luciferase reporter constructs demonstrated that IGF-I, IGF-II, and insulin had no effect on the StAR promoter activity, while 8-Br-cAMP stimulated StAR promoter function. The results indicate that: (i) IGFs and insulin stimulate StAR mRNA and protein expression in human granulosa–lutein cells; (ii) IGF-I and 8-Br-cAMP have an additive effect on StAR gene expression; and (iii) IGF-I increases StAR mRNA and protein by a mechanism that does not involve activation of the proximal StAR gene promoter.
granulosa cell/human steroidogenesis/insulin like growth factors/steroidogenic acute regulatory protein
Notes
3 To whom correspondence should be addressed at: 1354 BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104, USA
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