This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pradeep, P. K. Articles by Menon, K. M. J. Search for Related Content PubMed PubMed Citation Articles by Pradeep, P. K. Articles by Menon, K. M. J.

Dihydrotestosterone Inhibits Granulosa Cell Proliferation by Decreasing the Cyclin D2 mRNA Expression and Cell Cycle Arrest at G1 Phase

Departments of Obstetrics and Gynecology and Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: Dr. K. M. J. Menon, 6428 Medical Science I, 1150 West Medical Center Drive, University of Michigan, Ann Arbor, Michigan 48109. E-mail: .

Hyperandrogenism is known to perturb ovarian physiology resulting in anovulatory conditions. In the ovary, androgens produced by theca-interstitial cells are converted to estrogens in granulosa cells under the influence of FSH and LH. In some of the target organs, including the ovary, androgens are also converted into their 5 reduced metabolites. In the present study, we examined the molecular mechanism by which dihydrotestosterone (DHT), a 5 reduced metabolite of testosterone, mediates the inhibition of granulosa cell proliferation, using a rat model. Immature female rats were primed with estradiol, followed by DHT administration for 2 d and granulosa cells were cultured in the presence or absence of forskolin. Granulosa cells from the DHT-treated rats showed reduced [³H]thymidine incorporation into DNA and reduced cell number in response to forskolin stimulation, compared with control. The decreased responsiveness of DHT-treated granulosa cells to forskolin was not due to increased apoptosis because the expression of cleaved caspase 3 remained the same in both control and DHT-exposed granulosa cells stimulated with forskolin. Forskolin treatment stimulated the expression of cyclin D2 mRNA in control granulosa cells, whereas DHT treatment abolished this response. In vitro DHT treatment of granulosa cells for 48 h resulted in a cell cycle arrest with 70% of cells at G1 phase and 26% at S phase, and control cells exhibited a distribution of 42% and 55% at G1 and S phase, respectively. In conclusion, the present study shows that DHT inhibits the granulosa cell proliferation through a decrease in cyclin D2 mRNA expression, which leads to cell cycle arrest at the G1 phase.

This article has been cited by other articles:

				P. P. Kayampilly and K. M. J. Menon Follicle-Stimulating Hormone Increases Tuberin Phosphorylation and Mammalian Target of Rapamycin Signaling through an Extracellular Signal-Regulated Kinase-Dependent Pathway in Rat Granulosa Cells Endocrinology, August 1, 2007; 148(8): 3950 - 3957. [Abstract] [Full Text] [PDF]

				M. Orisaka, S. Orisaka, J.-Y. Jiang, J. Craig, Y. Wang, F. Kotsuji, and B. K. Tsang Growth Differentiation Factor 9 Is Antiapoptotic during Follicular Development from Preantral to Early Antral Stage Mol. Endocrinol., October 1, 2006; 20(10): 2456 - 2468. [Abstract] [Full Text] [PDF]

				S. C. Foong, D. H. Abbott, M. A. Zschunke, T. G. Lesnick, J. L. Phy, and D. A. Dumesic Follicle Luteinization in Hyperandrogenic Follicles of Polycystic Ovary Syndrome Patients Undergoing Gonadotropin Therapy for in Vitro Fertilization J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2327 - 2333. [Abstract] [Full Text] [PDF]

				P. P. Kayampilly and K. M. J. Menon Dihydrotestosterone Inhibits Insulin-Stimulated Cyclin D2 Messenger Ribonucleic Acid Expression in Rat Ovarian Granulosa Cells by Reducing the Phosphorylation of Insulin Receptor Substrate-1 Endocrinology, January 1, 2006; 147(1): 464 - 471. [Abstract] [Full Text] [PDF]

				T.E. Hickey, D.L. Marrocco, F. Amato, L.J. Ritter, R.J. Norman, R.B. Gilchrist, and D.T. Armstrong Androgens Augment the Mitogenic Effects of Oocyte-Secreted Factors and Growth Differentiation Factor 9 on Porcine Granulosa Cells Biol Reprod, October 1, 2005; 73(4): 825 - 832. [Abstract] [Full Text] [PDF]

				T.E. Hickey, D.L. Marrocco, R.B. Gilchrist, R.J. Norman, and D.T. Armstrong Interactions Between Androgen and Growth Factors in Granulosa Cell Subtypes of Porcine Antral Follicles Biol Reprod, July 1, 2004; 71(1): 45 - 52. [Abstract] [Full Text] [PDF]

				P. P. Kayampilly and K. M. J. Menon Inhibition of Extracellular Signal-Regulated Protein Kinase-2 Phosphorylation by Dihydrotestosterone Reduces Follicle-Stimulating Hormone-Mediated Cyclin D2 Messenger Ribonucleic Acid Expression in Rat Granulosa Cells Endocrinology, April 1, 2004; 145(4): 1786 - 1793. [Abstract] [Full Text] [PDF]

				A. J. Zeleznik, L. Little-Ihrig, and S. Ramasawamy Administration of Dihydrotestosterone to Rhesus Monkeys Inhibits Gonadotropin-Stimulated Ovarian Steroidogenesis J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 860 - 866. [Abstract] [Full Text] [PDF]

				P. Yang and S. K. Roy Follicle Stimulating Hormone-Induced DNA Synthesis in the Granulosa Cells of Hamster Preantral Follicles Involves Activation of Cyclin-Dependent Kinase-4 Rather Than Cyclin D2 Synthesis Biol Reprod, February 1, 2004; 70(2): 509 - 517. [Abstract] [Full Text] [PDF]

				J. R. Wood, V. L. Nelson, C. Ho, E. Jansen, C. Y. Wang, M. Urbanek, J. M. McAllister, S. Mosselman, and J. F. Strauss III The Molecular Phenotype of Polycystic Ovary Syndrome (PCOS) Theca Cells and New Candidate PCOS Genes Defined by Microarray Analysis J. Biol. Chem., July 11, 2003; 278(29): 26380 - 26390. [Abstract] [Full Text] [PDF]