Associate Professor of Medicine
Baylor College of Medicine
Dr. Villareal has established herself as a respected patient-oriented researcher studying the genetic determinants of estrogen metabolism and bone biology. She obtained RO3, R21, and VA Merit Award support for her research program, and published senior author papers in rigorously-reviewed journals that define fundamental genetic variants that affect estrogens and bone: Journal of Bone and Mineral Research, Journal of Clinical Endocrinology and Metabolism, and Bone. In addition, she has been co-investigator on several RO1 awards. She published in the New England Journal of Medicine a high impact paper on the effects of alendronate therapy on bone turnover and osteoporosis. In 2009, she left Washington University to become an Associate Professor of Medicine at the New Mexico VA Health Care System and the University of New Mexico School of Medicine. There, she served as the Chief of the Endocrinology Division. Recently, she joined the faculty at Baylor Medical College of Medicine as an Associate Professor of Medicine. She has a VA Merit Award to support work on the role of sex steroids to augment lifestyle in obese, elderly patients.
BIRCWH Scholar from 01/01/2003 until 12/31/2007
CYP Polymorphisms and Estrogen Status in Postmenopausal Women
Bone density varies between genders and across ethnic groups. The loss of estrogen in the postmenopausal period has been considered as the most important cause for bone loss in women. However, the correlation between bone loss and circulating estrogen levels is not very clear, in part because the estrogenic properties of the products resulting from the metabolism estradiol and estrone varies. We previously reported that the ratio of 2-hydroxyestrogen (inactive) / 16a-hydroxyestrogen (agonist) is an important determinant of bone loss in the postmenopausal period. Polymorphisms of the genes coding for Cytochrome p450 (CYP) enzymes involved in estrogen metabolism have been described in the context of other diseases, mainly breast cancer. Although very little information is available on the prevalence and the role of CYP genes polymorphism on bone mass, in vitro data indicate that allelic variants of these genes affect enzyme kinetics resulting in variable accumulation of different estrogen metabolites. We hypothesize that CYP genes polymorphism, by dictating the patterns of estrogen metabolism will result in specific profiles of estrogen activity. The balance between active and inactive estrogen metabolites will in turn account for racial differences in bone density. This proposed project will establish the biological significance of CYP gene polymorphism for an individual’s estrogen balance. To test the central hypothesis we propose to determine: 1) the prevalence of gene polymorphism of CYP1A1, CYP1B1, CYP1A2 and CYP3A4 among postmenopausal women of different ethnic groups, and 2) the functional correlates of these polymorphisms on estrogen status. We will genotypically and biochemically (by urine estrogen metabolites) characterize a cross-section of 300 postmenopausal women regardless of race. Although not the primary goal of this pilot project, we will also measure bone mineral density. These data will be used to develop a full-scale proposal and test the long-term hypothesis that CYP gene polymorphism is a critical determinant of bone mass accumulation, maintenance and loss.
Rates of bone loss in the postmenopausal period vary widely among individuals, even when controlled for age, years since menopause, and body mass index. Although estrogen exposure during the fertile period is important for the achievement and maintenance of peak bone mass, the role of postmenopausal estrogen levels remains controversial. Results from epidemiologic studies are conflicting about the correlation between bone loss and circulating estrogen levels (2-4). One reason for such discrepancies stems from the existence of many metabolic pathways that convert estradiol and estrone to metabolites with widely diverse estrogenic activity (5-8). We previously reported that the ratio of 2-hydroxyestrogen/16a-hydroxyestrogen, resulting from the oxidative metabolism of estrogen, is an important determinant of postmenopausal bone loss (9). Since 2-hydroxylated compounds are inactive or estrogen antagonists (10-12), whereas 16-hydroxylated estrogens are agonist (11), the rate of either metabolic pathway may dictate the overall estrogen “tone” after menopause.
There are four key CYP 450 enzymes involved in estrogen metabolism (5-8), namely, CYP1A1 (mainly C-2 and C-16 hydroxylation), CYP1B1 (mainly C-4 and C-16 hydroxylation), CYP1A2 (mainly C-2 hydroxylation) and CYP3A4 (mainly C-16 hydroxylations). Certain polymorphisms of these genes have been linked to the risk of hormone-related diseases as breast (13;14), ovarian (15) and prostate cancers (16;17). Some variants are believed to have altered catalytic activities, resulting in inter-individual and inter-racial differences in the risks of these diseases.
The objective of this proposal is to test the hypothesis that polymorphism of key Cytochrome P450 enzymes involved in estrogen metabolism (CYP1A1, CYP1B1, CYP1A2, and CYP3A4) determines estrogen activity in postmenopausal women. To test this hypothesis we propose the following
1. Determine the prevalence of CYP1A1, CYP1B1, CYP1A2 and CYP3A4 gene polymorphisms among women of different ethnic groups.
2. Evaluate the functional correlates of CYP1A1, CYP1B1, CYP1A2 and CYP3A4 gene polymorphisms on estrogen status and bone density.