Inhibition of 11beta-hydroxysteroid dehydrogenase enzymatic activities by glycyrrhetinic acid in vivo supports direct glucocorticoid-mediated suppression of steroidogenesis in Leydig cells.
Previous studies have suggested that glucocorticoid (GC) can directly affect testicular testosterone (T) biosynthesis by Leydig cells through a receptor-mediated mechanism. Interconversion of corticosterone (CORT), the active form in rodents, and 11-dehydroCORT, the biologically inert 11-keto form, is catalyzed by 11betaHSD1. This enzyme thus controls the intracellular concentration of active GC. We have postulated that elevated CORT levels resulting from stress exceed the Leydig cell's capacity for metabolic inactivation of CORT, resulting in suppressed T production. The present study tested whether inhibition of 11betaHSD1 in vivo, by the administration of glycyrrhetinic acid (GA), increases intracellular active GC concentration and thereby affects serum T concentration and Leydig cell T production. Adult Sprague-Dawley rats were treated with vehicle (corn oil), CORT, GA, or GA + CORT. Serum luteinizing hormone (LH), CORT, and T levels were measured, as were the steroidogenic capacities of purified Leydig cells. Twofold elevations of CORT were achieved by the administration of either CORT or GA alone, but in both cases there was no effect on serum T levels. However, when CORT and GA were administered in combination, serum CORT levels increased 3.5-fold (to 420 +/- 34 ng/mL) and serum T levels were reduced significantly (to 0.72 +/- 0.07 ng/mL; control, 2.12 +/- 0.23 ng/mL). Serum levels of LH were not affected by CORT, GA, or GA + CORT. Consistent with the reduced serum T levels following GA + CORT, steroidogenic enzyme expression and capacities were significantly reduced compared to control. These data support a role for 11betaHSD1 in modulating intracellular CORT concentrations and, in turn, for a direct effect of GC on Leydig cells in response to stress.
Hu
Guo-Xin
GX
Institute of Molecular Toxicology and Pharmacology, School of Pharmacy, 2nd Affiliated Hospital, Wenzhou Medical College, Wenzhou, Zhejiang, People's Republic of China.
Lin
Han
H
Sottas
Chantal M
CM
Morris
David J
DJ
Hardy
Matthew P
MP
Ge
Ren-Shan
RS
D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D000818:Animals; D003345:Corticosterone / Q000097:blood / Q000494:pharmacology*; D005938:Glucocorticoids / Q000378:metabolism*; D006034:Glycyrrhetinic Acid / Q000494:pharmacology*; D007985:Leydig Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000096:biosynthesis* / Q000097:blood
D005938:Glucocorticoids; D013739:Testosterone; D007986:Luteinizing Hormone; D042842:11-beta-Hydroxysteroid Dehydrogenases; D006034:Glycyrrhetinic Acid; D003345:Corticosterone