Effects of pharmacologically induced Leydig cell testosterone production on intratesticular testosterone and spermatogenesis

• Published in: Biology of reproduction Vol. 102; no. 2; pp. 489 - 498
• Main Authors: Chung, Jin-Yong, Brown, Sean, Chen, Haolin, Liu, June, Papadopoulos, Vassilios, Zirkin, Barry
• Format: Journal Article
• Language: English
• Published: United States Society for the Study of Reproduction 14.02.2020; Oxford University Press
• Subjects: Leydig cells; Observations; Physiological aspects; Proteins; Reproductive health; RESEARCH ARTICLE; Sperm; Spermatogenesis; Testosterone; TSPO; United States; spermatogenesis; TSPO; testosterone; Leydig cells
• ISSN: 0006-3363; 1529-7268; 1529-7268
• DOI: 10.1093/biolre/ioz174

The Leydig cells of the mammalian testis produce testosterone (T) in response to luteinizing hormone (LH). In rats and men with reduced serum T levels, T replacement therapy (TRT) will raise T levels, but typically with suppressive effects on sperm formation. The rate-determining step in T formation is the translocation of cholesterol to the inner mitochondrial membrane, mediated by protein–protein interactions of cytosolic and outer mitochondrial membrane proteins. Among the involved proteins is cholesterol-binding translocator protein (TSPO) (18 kDa TSPO). We hypothesized that in contrast to TRT, the administration of the TSPO agonist N,N-dihexyl-2-(4-fluorophenyl)indole-3-acetamide (FGIN-1-27), by stimulating the ability of the Leydig cells to produce T, would result in the elevation of serum T levels while maintaining intratesticular T concentration and therefore without suppression of spermatogenesis. Age-related reductions in both serum and intratesticular T levels were seen in old Brown Norway rats. Both exogenous T and FGIN-1-27 increased serum T levels. With exogenous T, serum LH and Leydig cell T formation were suppressed, and intratesticular T was reduced to below the concentration required to maintain spermatogenesis quantitatively. In contrast, FGIN-1-27 stimulated Leydig cell T formation, resulting in increased serum T without reductions in intratesticular T concentrations or in testicular sperm numbers. FGIN-1-27 also significantly increased serum and intratesticular T levels in rats made LH-deficient by treatment with the gonadotropin-releasing hormone antagonist cetrorelix. These results point to a possible approach to increasing serum T without negative effects on spermatogenesis, based upon stimulating T production by the Leydig cells themselves rather than administering T exogenously. Summary Sentence The TSPO agonist FGIN-1-27 stimulates the ability of the Leydig cells producing testosterone and results in elevating serum and intratesticular testosterone without negative effect on spermatogenesis.