Karen Held Hales, Ph.D.
Research Assistant Professor

Steroidogenesis in the Leydig cells of the testis and in the cortex of the adrenal depend on many of the same enzymes. Both rely on the ongoing synthesis of Steroidogenic Acute Regulatory (StAR) protein to move cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane where it is converted to pregnenolone by the action of P450scc. Within two hours after injection of lipopolysaccharide (LPS) to induce experimental endotoxemia in mice, the production of glucocorticoids by the adrenals is stimulated whereas serum testosterone levels drop to less than 80% of control animals. We have found that the rapid inhibition of testosterone synthesis by the Leydig cell is due to a post-transcriptional block in StAR protein function. Simultaneously and conversely, StAR synthesis is enhanced in the adrenals, at both the transcriptional and translational levels, aiding in the increased production of glucocorticoids. In the later phases of endotoxemia, we have observed that the transcription of several of the steroidogenic genes is reduced. In vitro, we have reproduced this inibition of transcription by treating primary Leydig cells with cytokines such as IL-1 and TNFa . The Cyp17 gene is the most sensitive to cytokine inhibition and using the Cyp17 promoter to drive expression of a reporter gene in MA-10 tumor Leydig cells, we obtain inhibition of cAMP-induced expression by TNFa . To date, the cAMP-regulatory factor(s) mediating mouse Cyp17 expression have not been identified. We are addressing the regulation of this promoter from both positive (cAMP) and negative (cytokine repression) perspectives.

• Bosmann, H.B., Hales, K.H., Li, X., Liu, Z., Stocco, D.M. and Hales, D.B. Acute in vivo inhibition of testosterone by endotoxin parallels loss of steroidogenic acute regulatory (StAR) protein in Leydig cells. Endocrinology, 137, 4522-4525, 1996.
• Li, X., Held Hales, K., Watanabe, G., Lee, R.J., Pestell, R.G., Hales, D.B. "The effect of tumor necrosis factor-a and cAMP on induction of AP-1 activation in MA10 tumor Leydig cells." Endocrine, 6, 317-324, 1997.
• Clark, B.J., Combs, R., Held Hales, K., Hales, D.B., and Stocco, D.M. Inhibition of transcription affects the synthesis of the steroidogenic acute regulatiory protein (StAR) and steroidogenesis in MA-10 mouse Leydig tumor cells. Endocrinology, 138, 4893-4901, 1997.
• Ronen-Fuhrmann, T., Timberg, R., King, S.R., Hales, K.H., Hales, D.B., Stocco, D.M., and Orly, J. Spatio-temporal expression patterns of steroidogenic acute regulatory protein (StAR) during follicular development in the rat ovary. Endocrinology, 139, 303-315, 1997.
• Sandoff, T.W., Hales, D.B., Held Hales, K., McLean, M.P. "Transcriptional regulation of the rat Steroidogenic Acute Regulatory (StAR) Protein gene by Steroidogenic Factor-1." Endocrinology 139:4820-4831 (1998).
• Oglivie, K.M., Held Hales, K., Roberts, M., Hales, D.B., Rivier, C. "The inhibitory effects of intracerbroventricularly injected IL-1b on testosterone secretion in the rat: role of Steroidogenic Acute Regulatory (StAR) Protein." Biology of Reproduction 60:527-533 (1999).
• Fiedler, E.P., Plouffe, L., Hales, D.B., Held Hales, K., Khan, I. "Prostaglandin F2? induces a rapid decline in progesterone production and Steroidogenic Acute Regulatory Protein expression in isolated rat corpus luteum without altering transcription." Biology of Reproduction 61:643-650 (1999).
• Hales D.B., Diemer T., Held Hales K. "Review: The Role of Cytokines in Testicular Function" Endocrine 10:201-217 (1999)

Research in the Hales Laboratory

Department of Physiology and Biophysics at UIC