Sex Hormone Receptors and Regulation of Gene Expression Tissue Specificity of Traditional and Alternative Hormone Replacement Therapies
Sex hormones (estrogens, progestogens, and androgens) exert their effects on target tissues through specific hormone receptors. Alterations in the levels of these hormones through aging, menopause, or pharmacologic interventions have diverse effects on different target tissues, sometimes promoting health in one tissue and disease in another. Our previous work demonstrated that reproductive and non-reproductive tissues from non-human primates express both the classical ER (ERa) and a newly discovered estrogen receptor (ERb). Coronary arteries from females as well as males were found to express relatively high levels of ERb mRNA compared to ERa, suggesting this receptor could play a role in the protective effects of estrogens against atherosclerosis. ERb/ERa mRNA ratios were found to be highest in hippocampus and hypothalamus, intermediate in ovary, artery and uterus, and low in mammary and hepatic tissues. Since these receptors have unique properties, their absolute and relative expression may be important factors in tissue-specific responses to estrogen(s) and other hormones. Some phytoestrogens, for example, have a higher affinity for ERb.
My primary research interest relates to the effects of estrogen and estrogen-like compounds on gene expression in traditional and non-traditional target tissues and the role of the estrogen receptors, ERa and ERb. We have several projects underway: the first involves a set of archived non-human primate target tissues in which we are determining of the effects of estrogen(s) and other hormone replacement therapies on 1) expression of estrogen, androgen, and progesterone receptors and 2) global mRNA expression. This project will allow us to determine relationships between effects of various hormones, individual receptor levels, and gene expression in reproductive and non-reproductive target tissues. A second project is designed to determine the direct effects of estrogens on mRNA expression in human vascular smooth muscle and endothelial cells, and the relative importance of ERa vs. ERb in those effects. Both of the above studies are employing functional genomics and the emerging cDNA microarray technologies to explore hormone effects on global gene expression. A third project is designed to determine the role that androgens play in the effects of oral contraceptives on skeletal and reproductive tissues. Overall this work will provide valuable information regarding tissue-specific effects of hormone therapies and the importance of sex hormone receptor expression in site -specific responses to these therapies. |
Recent Publications (selected):
Stavisky RC, Register TC, Watson SL, Weaver DS, Kaplan JR.: Behavioral responses to ovariectomy and chronic anabolic steroid treatment in female cynomolgus macaques. Physiol. Behav. 66:95-100 (1999).
Lees CJ, Jerome CP, Register TC, Carlson CS.: Changes in bone mass and bone biomarkers of cynomolgus monkeys during pregnancy and lactation. J. Clin. Endocrinol. Metab. 83:4298-302 (1998).
Jayo MJ, Register TC, Carlson CS.: Effects on bone of oral hormone replacement therapy initiated 2 years after ovariectomy in young adult monkeys. Bone 23:361-6 (1998).
Register TC, Adams MR, Golden DL, Clarkson TB.: Conjugated equine estrogens alone, but not in combination with medroxyprogesterone acetate, inhibit aortic connective tissue remodeling after plasma lipid lowering in female monkeys. Arterioscler. Thromb. Vasc. Biol. 18:1164-71 (1998).
Register TC, Adams MR.: Coronary artery and cultured aortic smooth muscle cells express mRNA for both the classical estrogen receptor and the newly described estrogen receptor beta. J. Steroid Biochem. Mol. Biol. 64:187-91 (1998).
Register TC, Shively CA, Lewis CE. Expression of estrogen receptor a and b transcripts in female monkey hippocampus and hypothalamus. Brain Res 788:320-322 (1998).
Robinson D, Register TC, Carter LR. The effects of delayed hormone replacement therapy on estrogen receptors of cynomolgus monkey bladder and vagina. Neurourol Urodynam 17:241-247 (1998).
Register TC, Jayo MJ, Jerome CP. Oral contraceptive treatment inhibits the normal acquisition of bone mineral in skeletally immature young adult female monkeys. Osteoporos Int 7:348-353 (1997). |