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Development and Function of the Adult Generation of Leydig Cells in Mice with Sertoli Cell-Selective or Total Ablation of the Androgen Receptor

Laboratory for Experimental Medicine and Endocrinology, Department of Developmental Biology, Catholic University of Leuven (K.D.G., E.D., G.V.), B-3000 Leuven, Belgium; Medical Research Council Human Reproductive Sciences Unit, Center for Reproductive Biology (N.A., K.A.L.T., C.M., R.M.S., P.T.K.S.), and Division of Reproductive and Developmental Science, University of Edinburgh (J.I.M.), Edinburgh, Scotland, EH16 4SB United Kingdom; Institute of Experimental Morphology and Anthropology, Bulgarian Academy of Science (N.A.), 1113 Sofia, Bulgaria; Laboratory of Cellular Biology, Department of Morphology, Instituto de Ciências Biológicas/Federal University of Minas Gerais (L.R.d.F., G.G.P.), Belo Horizonte-MG, Brazil; Institute for Hormone and Fertility Research, University of Hamburg (S.H.), D-20251 Hamburg, Germany; and School of Molecular and Biomedical Sciences, University of Adelaide (R.I.), Adelaide 5005, Australia

Address all correspondence and requests for reprints to: Dr. R. M. Sharpe, Medical Research Council Human Reproductive Sciences Unit, Center for Reproductive Biology, Chancellors Building, 49 Little France Crescent, Edinburgh, Scotland EH16 4SB, United Kingdom. E-mail: r.sharpe{at}hrsu.mrc.ac.uk.

It is established that androgens and unidentified Sertoli cell (SC)-derived factors can influence the development of adult Leydig cells (LC) in rodents, but the mechanisms are unclear. We evaluated adult LC development and function in SC-selective androgen receptor (AR) knockout (SCARKO) and complete AR knockout (ARKO) mice. In controls, LC number increased 26-fold and LC size increased by approximately 2-fold between 12 and 140 d of age. LC number in SCARKOs was normal on d 12, but was reduced by more than 40% at later ages, although LC were larger and contained more lipid droplets and mitochondria than control LC by adulthood. ARKO LC number was reduced by up to 83% at all ages compared with controls, and LC size did not increase beyond d 12. Serum LH and testosterone levels and seminal vesicle weights were comparable in adult SCARKOs and controls, whereas LH levels were elevated 8-fold in ARKOs, although testosterone levels appeared normal. Immunohistochemistry and quantitative PCR for LC-specific markers indicated steroidogenic function per LC was probably increased in SCARKOs and reduced in ARKOs. In SCARKOs, insulin-like factor-3 and estrogen sulfotransferase (EST) mRNA expression were unchanged and increased 3-fold, respectively, compared with controls, whereas the expression of both was reduced more than 90% in ARKOs. Changes in EST expression, coupled with reduced platelet-derived growth factor-A expression, are potential causes of altered LC number and function in SCARKOs. These results show that loss of androgen action on SC has major consequences for LC development, and this could be mediated indirectly via platelet-derived growth factor-A and/or estrogens/EST.

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