Abstract
BackgroundThe present study was designed to examine the effect of chronic treatment with rosiglitazone - thiazolidinedione used in the treatment of type 2 diabetes mellitus for its insulin sensitizing effects - on the Leydig cell steroidogenic capacity and expression of the steroidogenic acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (P450scc) in normal adult rats.MethodsTwelve adult male Wistar rats were treated with rosiglitazone (5 mg/kg) administered by gavage for 15 days. Twelve control animals were treated with the vehicle. The ability of rosiglitazone to directly affect the production of testosterone by Leydig cells ex vivo was evaluated using isolated Leydig cells from rosiglitazone-treated rats. Testosterone production was induced either by activators of the cAMP/PKA pathway (hCG and dbcAMP) or substrates of steroidogenesis [22(R)-hydroxy-cholesterol (22(R)-OH-C), which is a substrate for the P450scc enzyme, and pregnenolone, which is the product of the P450scc-catalyzed step]. Testosterone in plasma and in incubation medium was measured by radioimmunoassay. The StAR and P450scc expression was detected by immunocytochemistry.ResultsThe levels of total circulating testosterone were not altered by rosiglitazone treatment. A decrease in basal or induced testosterone production occurred in the Leydig cells of rosiglitazone-treated rats. The ultrastructural and immunocytochemical analysis of Leydig cells from rosiglitazone-treated rats revealed cells with characteristics of increased activity as well as increased StAR and P450scc expression, which are key proteins in androgen biosynthesis. However, a number of rosiglitazone-treated cells exhibited significant mitochondrial damage.ConclusionThe results revealed that the Leydig cells from rosiglitazone-treated rats showed significant reduction in testosterone production under basal, hCG/dbcAMP- or 22 (R)-OH-C/pregnenolone-induced conditions, although increased labeling of StAR and P450scc was detected in these cells by immunocytochemistry. The ultrastructural study suggested that the lower levels of testosterone produced by these cells could be due to mitochondrial damage induced by rosiglitazone.
Highlights
The present study was designed to examine the effect of chronic treatment with rosiglitazone thiazolidinedione used in the treatment of type 2 diabetes mellitus for its insulin sensitizing effects - on the Leydig cell steroidogenic capacity and expression of the steroidogenic acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (P450scc) in normal adult rats
Ex vivo testosterone secretion These experiments examined the impact of chronic treatment with rosiglitazone on the steroidogenic response of Leydig cells to direct induction by activators of the cAMP/PKA pathway, which is the major signaling pathway regulating steroidogenesis [26], and by substrates of steroidogenesis (22-OH-C and pregnenolone)
The objective of the use of these substrates was to determine whether the limiting-steps of steroidogenesis - the transportation of cholesterol from outer to inner mitochondrial membrane by the StAR protein and the cleavage of the cholesterol side chain by mitochondrial P450scc to yield pregnenolone - were affected by rosiglitazone treatment
Summary
The present study was designed to examine the effect of chronic treatment with rosiglitazone thiazolidinedione used in the treatment of type 2 diabetes mellitus for its insulin sensitizing effects - on the Leydig cell steroidogenic capacity and expression of the steroidogenic acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (P450scc) in normal adult rats. Activation of PPARg by TZDs improves insulin sensitivity and, rosiglitazone on the production of testosterone has been demonstrated in healthy men [11], while in obese male Zucker rats [19] plasma testosterone was not affected by this TZD. The aim of the present study was to determine whether oral rosiglitazone treatment influences testicular production of testosterone using an ex-vivo model of Leydig cells isolated from rosiglitazone-treated adult male rats. Ultrastructural and immunocytochemical analysis of Leydig cell was performed to assess the cellular integrity and the expression of StAR and P450scc, which are key proteins in androgen biosynthesis
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