Leydig cells contain glucocorticoid receptors and respond to glucocorticoid by decreasing their rate of testosterone production. Serum levels of glucocorticoid are increased during stress caused by a wide variety of conditions, including disease, exercise and psychosocial interaction. Based upon these facts, the applicant and other investigators hypothesize that declines in male reproductive function associated with stress are due in part to the direct inhibition of Leydig cells by glucocorticoid. Therefore, the applicant will test the hypothesis that rapid declines in testosterone occurring within two hours of acute stress are independent of luteinizing hormone and are directly mediated by glucocorticoid acting on Leydig cells. He will also investigate the physiological role of 11beta-hydroxysteroid dehydrogenase (11betaHSD) because this enzyme is abundantly expressed in Leydig cells and metabolizes glucocorticoid.
Three Specific Aims are proposed.
Aim (1) is to test for effects of glucocorticoid mediated by glucocorticoid receptors (GR) in Leydig cells, using both adrenalectomized rats and mice with a Leydig-cell-specific knockout of GR.
Specific Aim (2) will define the consequences of stress for the Leydig cell.
Aim (3) is intended to identify sustained effects of high glucocorticoid concentrations on Leydig cell steroidogenesis after exposure to stress in utero, perinatally or during adulthood. These studies would be the first to establish the extent of direct, GR-mediated glucocorticoid action on Leydig cells during stress. Other stress-induced factors such as nitric oxide and beta-endorphin will be monitored at the testis level because they may affect Leydig cell function independently and/or in addition to glucocorticoid. The hypothesis that 11betaHSD in Leydig cells is a key determinant of stress effects is supported by the fact that 11beta oxidation is the usual mode of 11betaHSD catalysis in Leydig cells from adults. The reverse is true of immature Leydig cells where the 11beta-reductase predominates. The balance of oxidative and reductive catalytic activity displayed by the type 1 isoform of the enzyme in Leydig cells may be adjustable by intracellular conditions, fine-tuning of glucocorticoid effects, affected by stress. Therefore, the applicant will also test for the existence of endogenous inhibitors in the testis that selectively modulate these opposing activities of 11betaHSD. Anticipated results would show that 11betaHSD is a critical intracellular regulator of testosterone production in Leydig cells.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD033000-08
Application #
6687706
Study Section
Reproductive Biology Study Section (REB)
Program Officer
Rankin, Tracy L
Project Start
1996-05-01
Project End
2006-12-31
Budget Start
2004-01-01
Budget End
2006-12-31
Support Year
8
Fiscal Year
2004
Total Cost
$331,732
Indirect Cost
Name
Population Council
Department
Type
DUNS #
071050090
City
New York
State
NY
Country
United States
Zip Code
10017
Latif, Syed A; Shen, Mae; Ge, Ren-Shan et al. (2011) Role of 11*-OH-C(19) and C(21) steroids in the coupling of 11*-HSD1 and 17*-HSD3 in regulation of testosterone biosynthesis in rat Leydig cells. Steroids 76:682-9
Zheng, Rong; Horiguchi, Akio; Iida, Katsuyuki et al. (2010) Neutral endopeptidase is a myristoylated protein. Mol Cell Biochem 335:173-80
Lee, June G; Zheng, Rong; McCafferty-Cepero, Jennifer M et al. (2009) Endothelin-1 enhances the expression of the androgen receptor via activation of the c-myc pathway in prostate cancer cells. Mol Carcinog 48:141-9
Ge, Renshan; Chen, Guorong; Hardy, Matthew P (2008) The role of the Leydig cell in spermatogenic function. Adv Exp Med Biol 636:255-69
Hu, Guo-Xin; Lian, Qing-Quan; Lin, Han et al. (2008) Rapid mechanisms of glucocorticoid signaling in the Leydig cell. Steroids 73:1018-24
Lee, J G; Ge, R; Hardy, D O et al. (2008) Modulation of 11beta-hydroxysteroid dehydrogenase expression by bombesin: a possible mechanism for glucocorticoid resistance in androgen independent prostate cancer. Horm Metab Res 40:772-8
Hu, Guo-Xin; Lin, Han; Sottas, Chantal M et al. (2008) Inhibition of 11beta-hydroxysteroid dehydrogenase enzymatic activities by glycyrrhetinic acid in vivo supports direct glucocorticoid-mediated suppression of steroidogenesis in Leydig cells. J Androl 29:345-51
Chen, Guo-Rong; Ge, Ren-Shan; Lin, Han et al. (2007) Development of a cryopreservation protocol for Leydig cells. Hum Reprod 22:2160-8
Morris, D J; Latif, S A; Hardy, M P et al. (2007) Endogenous inhibitors (GALFs) of 11beta-hydroxysteroid dehydrogenase isoforms 1 and 2: derivatives of adrenally produced corticosterone and cortisol. J Steroid Biochem Mol Biol 104:161-8
Weissman, Ben A; Sottas, Chantal M; Zhou, Ping et al. (2007) Testosterone production in mice lacking inducible nitric oxide synthase expression is sensitive to restraint stress. Am J Physiol Endocrinol Metab 292:E615-20

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