Pharmacological doses of testosterone upregulated androgen receptor and 3-Beta-hydroxysteroid dehydrogenase/delta-5-delta-4 isomerase and impaired leydig cells steroidogenesis in adult rats

• Published in: Toxicological sciences Vol. 121; no. 2; pp. 397 - 407
• Main Authors: Kostic, Tatjana S, Stojkov, Natasa J, Bjelic, Maja M, Mihajlovic, Aleksandar I, Janjic, Marija M, Andric, Silvana A
• Format: Journal Article
• Language: English
• Published: United States 01-06-2011
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - genetics; 3',5'-Cyclic-AMP Phosphodiesterases - metabolism; Animals; Aromatase - metabolism; Blotting, Western; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cholesterol Side-Chain Cleavage Enzyme - genetics; Cholesterol Side-Chain Cleavage Enzyme - metabolism; Cyclic Nucleotide Phosphodiesterases, Type 4 - genetics; Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism; Dose-Response Relationship, Drug; Leydig Cells - drug effects; Leydig Cells - metabolism; Male; Models, Animal; Multienzyme Complexes - genetics; Multienzyme Complexes - metabolism; Phosphoproteins - genetics; Phosphoproteins - metabolism; Progesterone Reductase - genetics; Progesterone Reductase - metabolism; Rats; Rats, Wistar; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Receptors, GABA-A - genetics; Receptors, GABA-A - metabolism; Scavenger Receptors, Class B - genetics; Scavenger Receptors, Class B - metabolism; Steroid 17-alpha-Hydroxylase - genetics; Steroid 17-alpha-Hydroxylase - metabolism; Steroid Isomerases - genetics; Steroid Isomerases - metabolism; Testosterone - administration & dosage; Testosterone - pharmacology; Time Factors; Up-Regulation
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfr063

Anabolic androgenic steroids (AAS) are testosterone derivatives originally designed to enhance muscular mass and used for the treatment of many clinical conditions as well as in contraception. Despite popular interest and abuse, we still lack a broad understanding of effects of AAS on synthesis of steroid hormones on the molecular level. This study was designed to systematically analyze the effects of pharmacological/high doses of testosterone on steroidogenic machinery in Leydig cells. Two different experimental approaches were used: (1) In vivo experiment on groups of adult male rats treated with testosterone for 1 day, 2 weeks, and 2 months; (2) Direct in vitro testosterone treatment of Leydig cells isolated from intact rats. Result showed that prolonged in vivo treatment with testosterone decreased the expression of Scarb1 (scavenger receptor class B type 1), Tspo (translocator protein), Star (steroidogenic acute regulatory protein), Cyp11a1 (cholesterol side-chain cleavage enzyme), and Cyp17a1 (17α-hydroxylase/17, 20 lyase) in Leydig cells. Oppositely, the expression of Hsd3b (3-beta-hydroxysteroid dehydrogenase/delta-5-delta-4 isomerase), Ar (androgen receptor), and Pde4a/b (cyclic adenosine monophosphate-dependent phosphodiesterases) was increased. Androgenization for 2 weeks inhibited Cyp19 (aromatase) transcription, whereas 2-month exposure caused the opposite effect. Direct in vitro testosterone treatment also decreased the expression of Cyp11a1, Cyp17a1, and Cyp19a1, whereas Hsd3b was upregulated. The results of expression analysis were supported by declined steroidogenic capacity and activity of Leydig cells, although conversion of pregnenolone to progesterone was stimulated. The upregulation of AR and 3βHSD in testosterone-impaired Leydig cells steroidogenesis could be the possible mechanism that maintain and prevent loss of steroidogenic function.