Jennifer Lee

All Publications

• Genetics of blood lipids among ~300,000 multi-ethnic participants of the Million Veteran Program. Nature genetics Klarin, D., Damrauer, S. M., Cho, K., Sun, Y. V., Teslovich, T. M., Honerlaw, J., Gagnon, D. R., DuVall, S. L., Li, J., Peloso, G. M., Chaffin, M., Small, A. M., Huang, J., Tang, H., Lynch, J. A., Ho, Y., Liu, D. J., Emdin, C. A., Li, A. H., Huffman, J. E., Lee, J. S., Natarajan, P., Chowdhury, R., Saleheen, D., Vujkovic, M., Baras, A., Pyarajan, S., Di Angelantonio, E., Neale, B. M., Naheed, A., Khera, A. V., Danesh, J., Chang, K., Abecasis, G., Willer, C., Dewey, F. E., Carey, D. J., Global Lipids Genetics Consortium, Myocardial Infarction Genetics (MIGen) Consortium, Geisinger-Regeneron DiscovEHR Collaboration, VA Million Veteran Program, Concato, J., Gaziano, J. M., O'Donnell, C. J., Tsao, P. S., Kathiresan, S., Rader, D. J., Wilson, P. W., Assimes, T. L. 2018

  Abstract

  The Million Veteran Program (MVP) was established in 2011 as a national research initiative to determine how genetic variation influences the health of US military veterans. Here we genotyped 312,571 MVP participants using a custom biobank array and linked the genetic data to laboratory and clinical phenotypes extracted from electronic health records covering a median of 10.0 years of follow-up. Among 297,626 veterans with at least one blood lipid measurement, including 57,332 black and 24,743 Hispanic participants, we tested up to around 32 million variants for association with lipid levels and identified 118 novel genome-wide significant loci after meta-analysis with data from the Global Lipids Genetics Consortium (total n>600,000). Through a focus on mutations predicted to result in a loss of gene function and a phenome-wide association study, we propose novel indications for pharmaceutical inhibitors targeting PCSK9 (abdominal aortic aneurysm), ANGPTL4 (type 2 diabetes) and PDE3B (triglycerides and coronary disease).

  View details for DOI 10.1038/s41588-018-0222-9

  View details for PubMedID 30275531

• 27-hydroxycholesterol, an endogenous SERM, and risk of fracture in postmenopausal women: A nested case-cohort study in the Women's Health Initiative. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research Chang, P., Feldman, D., Stefanick, M. L., McDonnell, D. P., Thompson, B. M., McDonald, J. G., Lee, J. S. 2018

  Abstract

  27-hydroxycholesterol (27HC) is a purported, novel endogenous SERM. In animal models, 27HC has an anti-estrogen effect in bone, and 17beta-estradiol mitigates this effect. 27HC in relation to fracture risk has not been investigated in humans. Depending on the level of bioavailable 17beta-estradiol (bioE2), 27HC may increase fracture risk in postmenopausal women and modify the fracture risk reduction from menopausal hormone therapy (MHT). To test these a priori hypotheses, we conducted a nested case-cohort study of 868 postmenopausal women within the Women's Health Initiative Hormone Therapy trials (WHI-HT). The WHI-HT tested conjugated equine estrogens versus placebo and separately conjugated equine estrogens plus progestin versus placebo. Fracture cases were 442 women who had an adjudicated incident hip or clinical vertebral fracture during the WHI-HT follow-up. The sub-cohort included 430 women randomly selected at WHI-HT baseline, 4 of whom had a subsequent fracture. Of 868 women, 266 cases and 219 non-cases were assigned to the placebo arms. Cox models estimated hazard ratios for incident fracture in relation to pre-randomization circulating levels of 27HC and 27HC/bioE2 molar ratio. Models adjusted for age, race/ethnicity, total cholesterol, bioE2, sex hormone-binding globulin, 25-hydroxyvitamin D, diabetes, osteoporosis, prior MHT use, BMI, falls history and prior fracture. In women assigned to placebo arms, those in the middle and the highest tertiles of 27HC/bioE2 had an up to 1.9-fold (95% confidence intervals: 1.25-2.99) greater risk of fracture than women in the lowest tertile. In women assigned to MHT arms, fracture risk increased with continuous 27HC/bioE2 levels but not with categorical levels. 27HC levels alone were not associated with fracture risk. 27HC and 27HC/bioE2 did not modify the fracture risk reduction from MHT. In postmenopausal women, circulating levels of 27HC relative to bioE2 may identify those at increased risk of fracture. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jbmr.3576

  View details for PubMedID 30138538

• Triglyceride and HDL-C Dyslipidemia and Risks of Coronary Heart Disease and Ischemic Stroke by Glycemic Dysregulation Status: The Strong Heart Study. Diabetes care Lee, J. S., Chang, P., Zhang, Y., Kizer, J. R., Best, L. G., Howard, B. V. 2017

  Abstract

  High triglyceride (TG) levels and low HDL cholesterol (HDL-C) levels are risk factors for cardiovascular disease. It is unclear whether this relationship depends on glycemic dysregulation, sex, or LDL cholesterol (LDL-C) level.We studied 3,216 participants (40% men, 41% with diabetes) who were free of cardiovascular disease at baseline in a community-based, prospective cohort of American Indians (median follow-up 17.7 years). Cox models estimated hazard ratios (HRs) and 95% CIs for incident ischemic stroke and coronary heart disease (CHD) in relation to combined TG and HDL-C status, where a fasting TG level ≥150 mg/dL was "high" and a fasting HDL-C level <40 mg/dL for men (<50 mg/dL for women) was "low." Models included age, sex, BMI, smoking, diabetes, fasting LDL-C level, antihypertensive medications, physical activity, estimated glomerular filtration rate, and urinary albumin-to-creatinine ratio.Participants with high TG and low HDL levels had a 1.32-fold greater HR (95% CI 1.06-1.64) for CHD than those with normal TG and normal HDL levels. It was observed in participants with diabetes, but not in those without diabetes, that high TG plus low HDL levels were associated with a 1.54-fold greater HR (95% CI 1.15-2.06) for CHD (P value for interaction = 0.003) and a 2.13-fold greater HR (95% CI 1.06-4.29) for stroke (P value for interaction = 0.060). High TG and low HDL level was associated with CHD risk in participants with an LDL-C level of ≥130 mg/dL, but this was not observed in those participants with lower LDL-C levels. Sex did not appear to modify these associations.Adults with both high TG and low HDL-C, particularly those with diabetes, have increased risks of incident CHD and stroke. In particular, those with an LDL-C level ≥130 mg/dL may have an increased risk of incident stroke.

  View details for DOI 10.2337/dc16-1958

  View details for PubMedID 28122840

  View details for PubMedCentralID PMC5360283

• Sex hormones and risk of estrogen receptor (ER)-negative and ER-positive breast cancer JOURNAL OF THE NATIONAL CANCER INSTITUTE Farhat, G., Cummings, S. R., Chlebowski, R. T., Parimi, N., Cauley, J. A., et al 2011; 103
• Prospective Study of Endogenous Circulating Estradiol and Risk of Stroke in Older Women ARCHIVES OF NEUROLOGY Lee, J. S., Yaffe, K., Lui, L., Cauley, J., Taylor, B., Browner, W., Cummings, S. 2010; 67 (2): 195-201

  Abstract

  To test the hypothesis that circulating endogenous estradiol is associated with stroke risk in older postmenopausal women. Stroke incidence increases after menopause, when endogenous estrogen levels fall, yet exogenous estrogen increases strokes in older postmenopausal women. The relation between endogenous estrogen and stroke is unclear.Prospective case-control study.Study of Osteoporotic Fractures.Women at least age 65 years (99% follow-up) who were not taking estrogen at baseline.Free estradiol index (FEI) was calculated by dividing total estradiol by sex hormone-binding globulin concentrations measured in banked baseline serum. Using logistic regression, odds ratios were estimated for a first-ever atherothrombotic stroke associated with endogenous FEI in 196 women who had a subsequent validated stroke (median follow-up, 8 years) compared with 219 randomly selected women who did not. Potential mediators were assessed in multivariable models.The age-adjusted odds of atherothrombotic stroke increased with increasing FEI quartiles (P(trend) = .007). Women in the highest FEI quartile had an age-adjusted 2.31-fold (odds ratio, 2.31; 95% confidence interval, 1.28-4.17) higher odds than women in the lowest quartile. Women with greater central adiposity had a suggestively stronger association (P = .08). Atherogenic dyslipidemia, type 2 diabetes mellitus, and C-reactive protein level were potential mediators of this relation.Endogenous estradiol level is an indicator of stroke risk in older postmenopausal women, especially in those with greater central adiposity. Potential mediators, including atherogenic dyslipidemia, insulin resistance, and inflammation, might underlie this association. Whether estradiol, independent of atherogenic adiposity, influences such mediators and stroke risk needs to be determined. Estrogen-altering agents might be harmful or beneficial depending on endogenous estradiol levels, especially in women with greater central adiposity.

  View details for Web of Science ID 000274374600009

  View details for PubMedID 20142527

• Subclinical thyroid dysfunction and risk of hip fracture in older adults ARCHIVES OF INTERNAL MEDICINE Lee, J. S., Buzkova, P., Fink, H., Carbone, L., Vu, J., et al 2010; 170
• Validation of Established Genetic Loci for Non-Alcoholic Fatty Liver Disease (NAFLD) and Their Contribution to NAFLD Phenotype in 194,457 Individuals Enrolled in the Million Veteran Program Serper, M., Vujkovic, M., Kaplan, D. E., Carr, R. M., Lee, K., Shao, Q., Miller, D., Huang, J., Reaven, P. D., Phillips, L. S., O'Donnell, C. J., Meigs, J. B., Wilson, P. F., Smith, R., Kranzler, H. R., Justice, A. C., Gaziano, J., Concato, J., Muralidhar, S., Cho, K., Assimes, T. L., Lee, J. S., Tsao, P., Damrauer, S. M., Rader, D. J., Lynch, J., Saleheen, D., Chang, K., DuVall, S. L., VA Million Veteran Program WILEY. 2018: 210A–211A

  View details for Web of Science ID 000446020500351

• A Temporal Examination of Platelet Counts as a Predictor of Prognosis in Lung, Prostate, and Colon Cancer Patients. Scientific reports Sylman, J. L., Boyce, H. B., Mitrugno, A., Tormoen, G. W., Thomas, I. C., Wagner, T. H., Lee, J. S., Leppert, J. T., McCarty, O. J., Mallick, P. 2018; 8 (1): 6564

  Abstract

  Platelets, components of hemostasis, when present in excess (>400 K/μL, thrombocytosis) have also been associated with worse outcomes in lung, ovarian, breast, renal, and colorectal cancer patients. Associations between thrombocytosis and cancer outcomes have been made mostly from single-time-point studies, often at the time of diagnosis. Using laboratory data from the Department of Veterans Affairs (VA), we examined the potential benefits of using longitudinal platelet counts in improving patient prognosis predictions. Ten features (summary statistics and engineered features) were derived to describe the platelet counts of 10,000+ VA lung, prostate, and colon cancer patients and incorporated into an age-adjusted LASSO regression analysis to determine feature importance, and predict overall or relapse-free survival, which was compared to the previously used approach of monitoring for thrombocytosis near diagnosis (Postdiag AG400 model). Temporal features describing acute platelet count increases/decreases were found to be important in cancer survival and relapse-survival that helped stratify good and bad outcomes of cancer patient groups. Predictions of overall and relapse-free survival were improved by up to 30% compared to the Postdiag AG400 model. Our study indicates the association of temporally derived platelet count features with a patients' prognosis predictions.

  View details for DOI 10.1038/s41598-018-25019-1

  View details for PubMedID 29700384

  View details for PubMedCentralID PMC5920102

• Incidence of Second Malignancy in Patients with Papillary Thyroid Cancer from Surveillance, Epidemiology, and End Results 13 Dataset JOURNAL OF THYROID RESEARCH Endo, M., Liu, J. B., Dougan, M., Lee, J. S. 2018

  View details for DOI 10.1155/2018/8765369

  View details for Web of Science ID 000438061600001

• Outdoor air pollution and mosaic loss of chromosome Y in older men from the Cardiovascular Health Study. Environment international Wong, J. Y., Margolis, H. G., Machiela, M., Zhou, W., Odden, M. C., Psaty, B. M., Robbins, J., Jones, R. R., Rotter, J. I., Chanock, S. J., Rothman, N., Lan, Q., Lee, J. S. 2018; 116: 239–47

  Abstract

  Mosaic loss of chromosome Y (mLOY) can occur in a fraction of cells as men age, which is potentially linked to increased mortality risk. Smoking is related to mLOY; however, the contribution of air pollution is unclear.We investigated whether exposure to outdoor air pollution, age, and smoking were associated with mLOY.We analyzed baseline (1989-1993) blood samples from 933 men ≥65 years of age from the prospective Cardiovascular Health Study. Particulate matter ≤10 μm (PM10), carbon monoxide, nitrogen dioxide, sulfur dioxide, and ozone data were obtained from the U.S. EPA Aerometric Information Retrieval System for the year prior to baseline. Inverse-distance weighted air monitor data were used to estimate each participants' monthly residential exposure. mLOY was detected with standard methods using signal intensity (median log-R ratio (mLRR)) of the male-specific chromosome Y regions from Illumina array data. Linear regression models were used to evaluate relations between mean exposure in the prior year, age, smoking and continuous mLRR.Increased PM10 was associated with mLOY, namely decreased mLRR (p-trend = 0.03). Compared with the lowest tertile (≤28.5 μg/m3), the middle (28.5-31.0 μg/m3; β = -0.0044, p = 0.09) and highest (≥31 μg/m3; β = -0.0054, p = 0.04) tertiles had decreased mLRR, adjusted for age, clinic, race/cohort, smoking status and pack-years. Additionally, increasing age (β = -0.00035, p = 0.06) and smoking pack-years (β = -0.00011, p = 1.4E-3) were associated with decreased mLRR, adjusted for each other and race/cohort. No significant associations were found for other pollutants.PM10 may increase leukocyte mLOY, a marker of genomic instability. The sample size was modest and replication is warranted.

  View details for DOI 10.1016/j.envint.2018.04.030

  View details for PubMedID 29698900

• Metabolic Obesity Phenotypes and Risk of Breast Cancer in Postmenopausal Women CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Kabat, G. C., Kim, M. Y., Lee, J. S., Ho, G. Y., Going, S. B., Beebe-Dimmer, J., Manson, J. E., Chlebowski, R. T., Rohan, T. E. 2017; 26 (12): 1730–35

  View details for DOI 10.1158/1055-9965.EPI-17-0495

  View details for Web of Science ID 000416858600006

• Older Men with Decreasing Hemoglobin Have a Higher Risk of Future Hip Fracture: The Cardiovascular Health Study Valderrabano, R. J., Buzkova, P., Chang, P., Zakai, N. A., Fink, H. A., Robbins, J. A., Wu, J. Y., Lee, J. S. WILEY. 2017: S98–S99

  View details for Web of Science ID 000418869201100

• Older Men with Anemia Have Increased Fracture Risk Independent of Bone Mineral Density. journal of clinical endocrinology and metabolism Valderrábano, R. J., Lee, J., Lui, L., Hoffman, A. R., Cummings, S. R., Orwoll, E. S., Wu, J. Y. 2017

  Abstract

  Extreme low hemoglobin values have been linked to increased risk of fracture at different sites in a small number of studies. However, careful assessment of a clinically relevant cutoff for anemia and cross sectional and longitudinal bone mineral density (BMD) measures is lacking.To determine whether men with anemia were at increased risk of fracture after accounting for bone density and bone loss.Cross-sectional analysis (at visit 3) and prospective analysis (from baseline to visit 3) in the Osteoporotic Fractures in Men (MrOS), a multi-site longitudinal cohort study.6 communities in the U.S.3632 community-dwelling men (>65 years) in MrOS at baseline (2000-2002) who were able to walk without assistance and did not have a hip replacement or fracture and had complete blood counts (CBCs) at visit 3 (2007-2009).Adjudicated spine and non-spine fractures during a median 7.2 years follow up.Analytic baseline characteristics associated with fractures or anemia (Hgb < 12g/dL) were included into multivariable models. Anemia was associated with increased risk of any (HR 1.67; 95% CI 1.26-2.21) and non-spine (HR 1.70; 95% CI 1.25-2.31) fractures. A model including change in BMD slightly attenuated the association with any (HR 1.60; 95% CI 1.20-2.13) and non-spine fractures (HR 1.57; 95% CI 1.14-2.15). Including absolute BMD did not significantly alter the anemia-fracture association. Anemia was not associated with spine fracture.Community-dwelling older men with anemia had a 57-72% increase in non-spine fracture risk independent of bone density and bone loss over time.

  View details for DOI 10.1210/jc.2017-00266

  View details for PubMedID 28368469

• Bone Density Loss Is Associated With Blood Cell Counts JOURNAL OF BONE AND MINERAL RESEARCH Valderrabano, R. J., Lui, L., Lee, J., Cummings, S. R., Orwoll, E. S., Hoffman, A. R., Wu, J. Y. 2017; 32 (2): 212-220

  Abstract

  Hematopoiesis depends on a supportive microenvironment. Preclinical studies in mice have demonstrated that osteoblasts influence the development of blood cells, particularly erythrocytes, B lymphocytes, and neutrophils. However, it is unknown whether osteoblast numbers or function impact blood cell counts in humans. We tested the hypothesis that men with low BMD or greater BMD loss have decreased circulating erythrocytes and lymphocytes and increased myeloid cells. We performed a cross-sectional analysis and prospective analysis in the Osteoporotic Fractures in Men (MrOS), a multi-site longitudinal cohort study. 2571 community-dwelling men (>65 years) who were able to walk without assistance, did not have a hip replacement or fracture and had complete blood counts (CBCs) at the third study visit were analyzed. Multivariable (MV)-adjusted logistic regression estimated odds of white blood cell subtypes (highest and lowest quintile vs middle), and anemia (clinically defined) associated with BMD by DXA scan (at visit 3), annualized percent BMD change (baseline to visit 3), and high BMD loss (>0.5%/year, from baseline to visit 3) at the femoral neck (FN) and total hip (TH). MV adjusted models included age, BMI, cancer history, smoking status, alcohol intake, corticosteroid use, self-reported health, thiazide use and physical activity. At visit 3 greater TH BMD loss (per standard deviation) was associated with increased odds of anemia, high neutrophils, and low lymphocytes. Annualized BMD loss of >0.5% was associated with increased odds of anemia, high neutrophils, and low lymphocytes. Similar results were observed for FN BMD regarding anemia and lymphocytes. We concluded that community-dwelling older men with declining hip BMD over about 7 years had increased risks of anemia, lower lymphocyte count, and higher neutrophil count, consistent with pre-clinical studies. Bone health and hematopoiesis may have greater interdependency than previously recognized. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jbmr.3000

  View details for Web of Science ID 000396935300004

• Evidence for use of Teriparatide in Spinal Fusion Surgery in Osteoporotic Patients. World neurosurgery Chaudhary, N., Lee, J. S., Wu, J. Y., Tharin, S. 2016

  Abstract

  Osteoporosis is defined as a bone mineral density (BMD) less than 2.5 standard deviations below the mean BMD at peak bone mass, or the presence of a fragility fracture. In the setting of osteoporosis, early hardware loosening is thought to cause decreased spinal fusion rates. The two mainstays of osteoporosis treatment are bisphosphonates and Teriparatide. Teriparatide, a form of synthetic parathyroid hormone (PTH), is an anabolic agent that increases osteoblast activity and, thereby, bone mass. Preclinical studies in animal models show that Teriparatide increases spinal fusion rates. Early clinical studies show that teriparatide both increases spinal fusion rates and decreases hardware loosening in the setting of postmenopausal osteoporosis. Ongoing additional trials will help formulate preoperative screening recommendations, determine the optimal duration of pre- and post-operative Teriparatide treatment, and investigate its utility in men.

  View details for DOI 10.1016/j.wneu.2016.11.135

  View details for PubMedID 27923758

• Prevalence and risk of fracture diagnoses in women across the adult life span: a national cross-sectional study. Osteoporosis international Chang, P. Y., Saechao, F. S., Lee, J., Haskell, S. G., Frayne, S. M., Lee, J. S. 2016; 27 (11): 3177-3186

  Abstract

  In a national sample of women veterans, the rate of lower limb fracture diagnosis was the highest across ages 18-74 years; rates of fracture diagnosis of other skeletal sites peaked in women aged 75+. Women with two or more primary care visits or mental healthcare visits had elevated odds of fracture diagnosis.We assessed the prevalence and healthcare utilization characteristics associated with a diagnosis of any fracture in women of all adult ages within the Veterans Health Administration.In 344,488 women during fiscal year 2012, logistic regression models for fracture diagnosis included age, race/ethnicity, residence, number of primary care visits, number of mental healthcare visits, and degree of service-connected disability.Lower limb fracture diagnosis was most prevalent across ages 18-74 years and peaked in women aged 55-64 years. In women aged 75+, the prevalence rates of fracture diagnosis at the hip (102, 95 % CI = 88-115 per 10,000 women), upper limb (100, 95 % CI = 87-114 per 10,000 women), and lower limb (84, 95 % CI = 72-97 per 10,000 women) were the highest. Fractures at other skeletal sites peaked in those aged 75+ years. Black women had the lowest odds of a fracture diagnosis, followed by Asian/Pacific Islander and Hispanic women compared to non-Hispanic White (by 25-51 %, P < 0.05). Having two or more primary care visits or any mental health visit was each associated with an increased risk. Women with five or more primary care visits had a 3.36-fold (95 % CI = 3.02-3.75) greater odds than those with no such visit, and separately, women with five or more mental health visits had a 1.51-fold (95 % CI = 1.43-1.60) greater odds. Women with a fracture diagnosis had higher overall healthcare costs than those without (P < 0.001).Prevalence of fracture diagnosis differed by age, race/ethnicity, and skeletal site of fracture. Fracture diagnosis may identify women veterans with greater overall healthcare needs.

  View details for PubMedID 27349559

• Environmental tobacco smoke and risk of late-diagnosis incident fibroids in the Study of Women's Health across the Nation (SWAN). Fertility and sterility Wong, J. Y., Chang, P., Gold, E. B., Johnson, W. O., Lee, J. S. 2016; 106 (5): 1157-1164

  Abstract

  To assess the longitudinal relationship of environmental tobacco smoke (ETS) exposure during midlife, and its interaction with active smoking, with the risk of late-diagnosis incident uterine fibroids during the menopausal transition.Thirteen-year prospective cohort study.Not applicable.Community-based, multiracial/ethnic cohort of 2,575 women aged 42 to 52 years at baseline, undergoing the menopausal transition.Questionnaire and blood draws.Discrete-time proportional odds models were used to estimate the conditional odds ratio (OR) and 95% confidence interval (CI) of incident fibroids, adjusted for menopausal status, race/ethnicity, study site, age, education, estradiol levels, sex hormone use, body mass index, timing of blood draw, age at menarche, alcohol use, and smoking status and pack-years.As part of SWAN, at each near-annual study visit, ETS exposure, smoking, and fibroid occurrence were self-reported via questionnaire, and blood draws were collected. Women who were exposed to ETS (≥1 person-hour/week) had 1.28 (95% CI, 1.03, 1.60) times the adjusted odds of incident fibroids in the ensuing year compared the unexposed. The odds were elevated in never smokers (adjusted OR 1.34; 95% CI, 1.06, 1.70) and former smokers (adjusted OR 2.57; 95% CI, 1.05, 7.23).In midlife, ETS exposure was associated with an increased risk of late-diagnosis incident fibroids in women undergoing the menopausal transition.

  View details for DOI 10.1016/j.fertnstert.2016.06.025

  View details for PubMedID 27445196

  View details for PubMedCentralID PMC5048612

• Bone Density Loss Is Associated With Blood Cell Counts. Journal of bone and mineral research Valderrábano, R. J., Lui, L., Lee, J., Cummings, S. R., Orwoll, E. S., Hoffman, A. R., Wu, J. Y. 2016

  Abstract

  Hematopoiesis depends on a supportive microenvironment. Preclinical studies in mice have demonstrated that osteoblasts influence the development of blood cells, particularly erythrocytes, B lymphocytes, and neutrophils. However, it is unknown whether osteoblast numbers or function impact blood cell counts in humans. We tested the hypothesis that men with low BMD or greater BMD loss have decreased circulating erythrocytes and lymphocytes and increased myeloid cells. We performed a cross-sectional analysis and prospective analysis in the Osteoporotic Fractures in Men (MrOS), a multi-site longitudinal cohort study. 2571 community-dwelling men (>65 years) who were able to walk without assistance, did not have a hip replacement or fracture and had complete blood counts (CBCs) at the third study visit were analyzed. Multivariable (MV)-adjusted logistic regression estimated odds of white blood cell subtypes (highest and lowest quintile vs middle), and anemia (clinically defined) associated with BMD by DXA scan (at visit 3), annualized percent BMD change (baseline to visit 3), and high BMD loss (>0.5%/year, from baseline to visit 3) at the femoral neck (FN) and total hip (TH). MV adjusted models included age, BMI, cancer history, smoking status, alcohol intake, corticosteroid use, self-reported health, thiazide use and physical activity. At visit 3 greater TH BMD loss (per standard deviation) was associated with increased odds of anemia, high neutrophils, and low lymphocytes. Annualized BMD loss of >0.5% was associated with increased odds of anemia, high neutrophils, and low lymphocytes. Similar results were observed for FN BMD regarding anemia and lymphocytes. We concluded that community-dwelling older men with declining hip BMD over about 7 years had increased risks of anemia, lower lymphocyte count, and higher neutrophil count, consistent with pre-clinical studies. Bone health and hematopoiesis may have greater interdependency than previously recognized. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jbmr.3000

  View details for PubMedID 27653240

• Triglyceride Levels and Fracture Risk in Midlife Women: Study of Women's Health Across the Nation Journal of Clinical Endocrinology and Metabolism Chang, P., Gold, E. B., Cauley, J., Johnson, W. O., Karvonen-Guitierrez, C., Jackson, E., Ruppert, K., Lee, J. S. 2016: 3297–3305

  Abstract

  Unfavorable lipid levels contribute to cardiovascular disease and may also harm bone health.Our objective was to investigate relationships between fasting plasma lipid levels and incident fracture in midlife women undergoing the menopausal transition.This was a 13-year prospective, longitudinal study of multiethnic women in five US communities, with near-annual assessments.At baseline, 2062 premenopausal or early perimenopausal women who had no history of fracture were included.Fasting plasma total cholesterol, triglycerides (TG), low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol at baseline and follow-up visits 1 and 3-7.Incident nontraumatic fractures 1) 2 or more years after baseline, in relation to a single baseline level of lipids; and 2) 2-5 years later, in relation to time-varying lipid levels. Cox proportional hazards modelings estimated hazard ratios and 95% confidence interval (CI).Among the lipids, TG levels changed the most, with median levels increased by 16% during follow-up. An increase of 50 mg/dl in baseline TG level was associated with a 1.1-fold increased hazards of fracture (adjusted hazard ratio, 1.11; 95% CI, 1.04-1.18). Women with baseline TG higher than 300 mg/dl had an adjusted 2.5-fold greater hazards for fractures (95% CI, 1.13-5.44) than women with baseline TG lower than 150 mg/dl. Time-varying analyses showed a comparable TG level-fracture risk relationship. Associations between total cholesterol, low-density lipoprotein cholesterol, or high-density lipoprotein cholesterol levels and fractures were not observed.Midlife women with high fasting plasma TG had an increased risk of incident nontraumatic fracture. Secondary Abstract: Midlife women with fasting plasma triglyceride (TG) of at least 300 mg/dl had 2.5-fold greater hazards of fracture in 2 years later and onward, compared to those with TG below 150 mg/dl, in a multiethnic cohort. Time-varying analyses revealed comparable results.

  View details for DOI 10.1210/jc.2016-1366

  View details for PubMedCentralID PMC5010577

• Subclinical Thyroid Dysfunction and Hip Fracture and Bone Mineral Density in Older Adults: The Cardiovascular Health Study JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Garin, M. C., Arnold, A. M., Lee, J. S., Robbins, J., Cappola, A. R. 2014; 99 (8): 2657-2664

  Abstract

  Subclinical thyroid dysfunction is common in the elderly, yet its relationship with hip fracture and bone mineral density (BMD) is unclear.We examined the association between endogenous subclinical hyper- and hypothyroidism and hip fracture and BMD in older adults.A total of 4936 US individuals 65 years old or older enrolled in the Cardiovascular Health Study and not taking thyroid preparations were included. Analyses of incident hip fracture were performed by thyroid status, over a median follow-up of 12 years. A cross-sectional analysis of thyroid status and BMD was performed in a subset of 1317 participants who had dual-energy x-ray absorptiometry scans. Models were adjusted for risk factors and stratified by sex.No association was found between subclinical hypothyroidism and incident hip fracture compared with euthyroidism, when assessed at a single time point or persisting at two time points, in either women [hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.69-1.20 for a single and HR 0.79, 95% CI 0.52-1.21 for two time points] or men (HR 1.27, 95% CI 0.82-1.95 for a single and HR 1.09, 95% CI 0.57-2.10 for two time points). Likewise, no association was found between subclinical hyperthyroidism and incident hip fracture in either sex (HR 1.11, 95% CI 0.55-2.25 in women and HR 1.78, 95% CI 0.56-5.66 in men). No association was found between subclinical thyroid dysfunction and BMD at the lumbar spine, total hip, or femoral neck sites.Our data suggest no association between subclinical hypothyroidism or subclinical hyperthyroidism and hip fracture risk or BMD in older men and women. Additional data are needed to improve the precision of estimates for subclinical hyperthyroidism and in men.

  View details for DOI 10.1210/jc.2014-1051

  View details for Web of Science ID 000342341200036

  View details for PubMedCentralID PMC4121038

• Subclinical Hypothyroidism, Weight Change, and Body Composition in the Elderly: The Cardiovascular Health Study JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Garin, M. C., Arnold, A. M., Lee, J. S., Tracy, R. P., Cappola, A. R. 2014; 99 (4): 1220-1226

  Abstract

  Subclinical hypothyroidism is common in the elderly, yet its relationship with weight and body composition is unclear.We examined the relationship between subclinical hypothyroidism and weight change and body composition in older adults.A total of 427 subclinically hypothyroid and 2864 euthyroid U.S. individuals ≥65 years old enrolled in the Cardiovascular Health Study and not taking thyroid preparations were included. Analyses of 6-year weight change were performed, compared by thyroid status. A cross-sectional analysis of thyroid status and body composition was performed in a subset of 1276 participants who had dual-energy x-ray absorptiometry scans. Models were risk factor-adjusted and stratified by sex.Overall, participants lost weight during follow-up (-0.38 kg/y in men, -0.37 kg/y in women). Subclinical hypothyroidism, when assessed at a single time point or persisting over 2 years, was not associated with a difference in weight change compared with euthyroidism. Subclinical hypothyroidism was also not associated with differences in lean mass, fat mass, or percent fat compared with euthyroidism. A TSH level 1 mU/L higher within the euthyroid or subclinical hypothyroid range was associated with a 0.51-kg higher baseline weight in women only (P < .001) but not with weight change in either sex. A 1 ng/dL higher free T4 level was associated with lower baseline weight and 0.32 kg/y greater weight loss in women only (P = .003). Baseline weight and weight change did not differ by T3 levels.Our data do not support a clinically significant impact of subclinical hypothyroidism on weight status in the elderly.

  View details for DOI 10.1210/jc.2013-3591

  View details for Web of Science ID 000342283500043

  View details for PubMedID 24432998

  View details for PubMedCentralID PMC3973778

• Age, body mass, usage of exogenous estrogen, and lifestyle factors in relation to circulating sex hormone-binding globulin concentrations in postmenopausal women. Clinical chemistry Goto, A., Chen, B. H., Song, Y., Cauley, J., Cummings, S. R., Farhat, G. N., Gunter, M., Van Horn, L., Howard, B. V., Jackson, R., Lee, J., Rexrode, K. M., Liu, S. 2014; 60 (1): 174-185

  Abstract

  Circulating concentrations of sex hormone-binding globulin (SHBG) have been associated with cardiovascular diseases, type 2 diabetes, metabolic syndrome, and hormone-dependent cancers; however, correlates of SHBG concentrations are not well understood.We comprehensively investigated correlates of SHBG concentrations among 13 547 women who participated in the Women's Health Initiative and who had SHBG measurements. We estimated study- and ethnicity-specific associations of age, reproductive history, usage of exogenous estrogen, body mass index (BMI), and lifestyle factors such as physical activity, smoking, alcohol consumption, coffee intake, and dietary factors with SHBG concentrations. These estimates were pooled using random-effects models. We also examined potential nonlinear associations using spline analyses.There was no significant ethnic difference in the age-adjusted mean concentrations of SHBG. Age, exogenous estrogen use, physical activity, and regular coffee intake were positively associated with SHBG concentrations, whereas BMI was inversely associated with SHBG concentrations after adjustment for potential confounding factors. Similar patterns were observed among both ever users and never users of exogenous estrogen. The spline analysis indicated nonlinear relations of regular intake of coffee, age, and BMI with SHBG concentrations. Two or more cups/day of regular coffee consumption and age of 60 years or older were associated with higher SHBG concentrations; the inverse BMI-SHBG relation was especially strong among women whose BMI was below 30.In this large sample of postmenopausal women, age, exogenous estrogen use, physical activity, regular coffee intake, and BMI were significant correlates of SHBG concentrations, presenting potential targets for interventions.

  View details for DOI 10.1373/clinchem.2013.207217

  View details for PubMedID 24048437

• Sex Hormone Levels and Risk of Breast Cancer With Estrogen Plus Progestin JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Farhat, G. N., Parimi, N., Chlebowski, R. T., Manson, J. E., Anderson, G., Huang, A. J., Vittinghoff, E., Lee, J. S., LaCroix, A. Z., Cauley, J. A., Jackson, R., Grady, D., Lane, D. S., Phillips, L., Simon, M. S., Cummings, S. R. 2013; 105 (19): 1496-1503

  Abstract

  Although high endogenous sex hormone levels and estrogen plus progestin (E+P) therapy are associated with increased breast cancer risk, it is unknown whether pretreatment levels of sex hormones modify E+P effect on breast cancer.We conducted a nested case-control study within the Women's Health Initiative randomized clinical trial of E+P. The trial enrolled 16608 postmenopausal women aged 50 to 79 years with intact uterus and no breast cancer history. During a mean of 5.6 years of follow-up, 348 incident breast cancer case subjects were identified and matched with 348 control subjects. Case and control subjects had their sex hormone levels measured at baseline (estrogens, testosterone, progesterone, and sex hormone-binding globulin [SHBG]) and year 1 (estrogens and SHBG) using sensitive assays. All statistical tests were two-sided.Statistically significant elevations in breast cancer risk were seen with greater pretreatment levels of total estradiol (P trend = .04), bioavailable estradiol (P trend = .03), estrone (P trend = .007), and estrone sulfate (P trend = .007). E+P increased all measured estrogens and SHGB at year 1 (all P < .001). The effect of E+P on breast cancer risk was strongest in women whose pretreatment levels of total estradiol, bioavailable estradiol, and estrone were in the lowest quartiles. For example, the odds ratio for E+P relative to placebo was 2.47 (95% confidence interval [CI] = 1.28 to 4.79) in the lowest total estradiol quartile, compared with 0.96 (95% CI = 0.44 to 2.09) in the highest total estradiol quartile; P interaction = .04).Women with lower pr-treatment endogenous estrogen levels were at greater risk of breast cancer during E+P therapy compared with those with higher levels. Further studies are warranted to confirm these findings.

  View details for DOI 10.1093/jnci/djt243

  View details for Web of Science ID 000325482100013

  View details for PubMedID 24041978

  View details for PubMedCentralID PMC3787910

• Fibroblast Growth Factor 23, Bone Mineral Density, and Risk of Hip Fracture Among Older Adults: The Cardiovascular Health Study JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Jovanovich, A., Buzkova, P., Chonchol, M., Robbins, J., Fink, H. A., de Boer, I. H., Kestenbaum, B., Katz, R., Carbone, L., Lee, J., Laughlin, G. A., Mukamal, K. J., Fried, L. F., Shlipak, M. G., Ix, J. H. 2013; 98 (8): 3323-3331

  Abstract

  Context: Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone that also inhibits calcitriol synthesis. Objective: Our objective was to evaluate the relationships of plasma FGF23 concentrations with bone mineral density (BMD) and hip fracture in community-dwelling older adults. Design and Setting: Linear regression and Cox proportional hazard models were used to examine the associations of plasma FGF23 concentrations with BMD and incident hip fracture, respectively. Analyses were also stratified by chronic kidney disease. Participants: Participants included 2008 women and 1329 men ≥65 years from the 1996 to 1997 Cardiovascular Health Study visit. Main Outcome Measures: Dual x-ray absorptiometry measured total hip (TH) and lumbar spine (LS) BMD in 1291 participants. Hip fracture incidence was assessed prospectively through June 30, 2008 by hospitalization records in all participants. Results: Women had higher plasma FGF23 concentrations than men (75 [56-107] vs 66 [interquartile range = 52-92] relative units/mL; P < .001). After adjustment, higher FGF23 concentrations were associated with greater total hip and lumbar spine BMD in men only (β per doubling of FGF23 = 0.02, with 95% confidence interval [CI] = 0.001-0.04 g/cm(2), and 0.03 with 95% CI = 0.01-0.06 g/cm(2)). During 9.6 ± 5.1-11.0 years of follow-up, 328 hip fractures occurred. Higher FGF23 concentrations were not associated with hip fracture risk in women or men (adjusted hazard ratio = 0.95, with 95% CI = 0.78-1.15, and 1.09 with 95% CI = 0.82-1.46 per doubling of FGF23). Results did not differ by chronic kidney disease status (P > .4 for interactions). Conclusions: In this large prospective cohort of community-dwelling older adults, higher FGF23 concentrations were weakly associated with greater lumbar spine and total hip BMD but not with hip fracture risk.

  View details for DOI 10.1210/jc.2013-1152

  View details for Web of Science ID 000322781300050

  View details for PubMedID 23771921

• Thyroid hormones and thyroid disease in relation to perchlorate dose and residence near a superfund site. Journal of exposure science and environmental epidemiology Gold, E. B., Blount, B. C., O'Neill Rasor, M., Lee, J. S., Alwis, U., Srivastav, A., Kim, K. 2013; 23 (4): 399-408

  Abstract

  Perchlorate is a widely occurring contaminant, which can competitively inhibit iodide uptake and thus thyroid hormone production. The health effects of chronic low dose perchlorate exposure are largely unknown. In a community-based study, we compared thyroid function and disease in women with differing likelihoods of prior and current perchlorate exposure. Residential blocks were randomly selected from areas: (1) with potential perchlorate exposure via drinking water; (2) with potential exposure to environmental contaminants; and (3) neighboring but without such exposures. Eligibility included having lived in the area for ≥6 months and aged 20-50 years during 1988-1996 (during documented drinking water well contamination). We interviewed 814 women and collected blood samples (assayed for thyroid stimulating hormone and free thyroxine) from 431 interviewed women. Daily urine samples were assayed for perchlorate and iodide for 178 premenopausal women with blood samples. We performed multivariable regression analyses comparing thyroid function and disease by residential area and by urinary perchlorate dose adjusted for urinary iodide levels. Residential location and current perchlorate dose were not associated with thyroid function or disease. No persistent effect of perchlorate on thyroid function or disease was found several years after contaminated wells were capped.

  View details for DOI 10.1038/jes.2012.90

  View details for PubMedID 22968349

• Factors Related to Age at Natural Menopause: Longitudinal Analyses From SWAN AMERICAN JOURNAL OF EPIDEMIOLOGY Gold, E. B., Crawford, S. L., Avis, N. E., Crandall, C. J., Matthews, K. A., Waetjen, L. E., Lee, J. S., Thurston, R., Vuga, M., Harlow, S. D. 2013; 178 (1): 70-83

  Abstract

  Early age at the natural final menstrual period (FMP) or menopause has been associated with numerous health outcomes and might be a marker of future ill health. However, potentially modifiable factors affecting age at menopause have not been examined longitudinally in large, diverse populations. The Study of Women's Health Across the Nation (SWAN) followed 3,302 initially premenopausal and early perimenopausal women from 7 US sites and 5 racial/ethnic groups, using annual data (1996-2007) and Cox proportional hazards models to assess the relation of time-invariant and time-varying sociodemographic, lifestyle, and health factors to age at natural FMP. Median age at the FMP was 52.54 years (n = 1,483 observed natural FMPs). Controlling for sociodemographic, lifestyle, and health factors, we found that racial/ethnic groups did not differ in age at the FMP. Higher educational level, prior oral contraceptive use, and higher weight at baseline, as well as being employed, not smoking, consuming alcohol, having less physical activity, and having better self-rated health over follow-up, were significantly associated with later age at the FMP. These results suggest that age at the natural FMP reflects a complex interrelation of health and socioeconomic factors, which could partially explain the relation of late age at FMP to reduced morbidity and mortality.

  View details for DOI 10.1093/aje/kws421

  View details for Web of Science ID 000321449400007

  View details for PubMedID 23788671

  View details for PubMedCentralID PMC3698989

• Persistent Subclinical Hypothyroidism and Cardiovascular Risk in the Elderly: The Cardiovascular Health Study JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Hyland, K. A., Arnold, A. M., Lee, J. S., Cappola, A. R. 2013; 98 (2): 533-540

  Abstract

  Use of a single set of thyroid function tests to define subclinical hypothyroidism may lead to misclassification over time and could influence findings from longitudinal studies. Objective: We assessed the risks of coronary heart disease (CHD), heart failure (HF), and cardiovascular (CV) death in older adults with persistent subclinical hypothyroidism.The study included 679 subclinically hypothyroid and 4184 euthyroid U.S. individuals at least 65 yr old enrolled in the Cardiovascular Health Study and not taking thyroid preparations.We measured the 10-yr risk of incident CHD, HF, and CV death from persistent subclinical hypothyroidism, overall and stratified by degree of TSH elevation (4.5-6.9, 7.0-9.9, and 10.0-19.9 mU/liter).There was no association between persistent subclinical hypothyroidism and incident CHD [hazard ratio (HR), 1.12; 95% confidence interval (CI), 0.93-1.36], HF (HR, 1.05; 95% CI, 0.97-1.27), or CV death (HR, 1.07; 95% CI, 0.87-1.31) in adjusted analyses in which subclinical hypothyroidism was modeled as a time-varying exposure using up to four serial thyroid function tests. When subclinical hypothyroidism was stratified by degree of TSH elevation, no significant associations were found in any stratum. Findings were similar in fixed exposure analyses in which only participants with testing 2 yr apart were considered, with no association between persistent or transient subclinical hypothyroidism and incident CHD, HF, or CV death.Our data do not support increased risk of CHD, HF, or CV death in older adults with persistent subclinical hypothyroidism.

  View details for Web of Science ID 000316270900047

  View details for PubMedID 23162099

• Sex hormone levels and risk of breast cancer with estrogen plus progestin Journal of the National Cancer Institute Farhat, G. N., Parimi, N., Chlebowski, R. T., Manson, J. E., Anderson, G., Huang, A. J., Vittinghoff, E., Lee, J. S., LaCroix, A. Z., Cauley, J. A., Jackson, R., Grady, D., Lane, D. S., Phillips, L., Simon, M. S., Cummings, S. R. 2013
• Quantifying Mediating Effects of Endogenous Estrogen and Insulin in the Relation between Obesity, Alcohol Consumption, and Breast Cancer CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Hvidtfeldt, U. A., Gunter, M. J., Lange, T., Chlebowski, R. T., Lane, D., Farhat, G. N., Freiberg, M. S., Keiding, N., Lee, J. S., Prentice, R., Tjonneland, A., Vitolins, M. Z., Wassertheil-Smoller, S., Strickler, H. D., Rod, N. H. 2012; 21 (7): 1203-1212

  Abstract

  Increased exposure to endogenous estrogen and/or insulin may partly explain the relationship of obesity, physical inactivity, and alcohol consumption and postmenopausal breast cancer. However, these potential mediating effects have not been formally quantified in a survival analysis setting.We combined data from two case-cohort studies based in the Women's Health Initiative-Observational Study with serum estradiol levels, one of which also had insulin levels. A total of 1,601 women (601 cases) aged 50 to 79 years who were not using hormone therapy at enrollment were included. Mediating effects were estimated by applying a new method based on the additive hazard model.A five-unit increase in body mass index (BMI) was associated with 50.0 [95% confidence interval (CI), 23.2-76.6] extra cases per 100,000 women at-risk per year. Of these, 23.8% (95% CI, 2.9-68.4) could be attributed to estradiol and 65.8% (95% CI, 13.6-273.3) through insulin pathways. The mediating effect of estradiol was greater (48.8%; 95% CI, 18.8-161.1) for BMI when restricted to estrogen receptor positive (ER(+)) cases. Consuming 7+ drinks/wk compared with abstinence was associated with 164.9 (95% CI, 45.8-284.9) breast cancer cases per 100,000, but no significant contribution from estradiol was found. The effect of alcohol on breast cancer was restricted to ER(+) breast cancers.The relation of BMI with breast cancer was partly mediated through estradiol and, to a greater extent, through insulin.The findings provide support for evaluation of interventions to lower insulin and estrogen levels in overweight and obese postmenopausal women to reduce breast cancer risk.

  View details for DOI 10.1158/1055-9965.EPI-12-0310

  View details for Web of Science ID 000306210100025

  View details for PubMedID 22564867

• Bone mineral density loss in relation to the final menstrual period in a multiethnic cohort: Results from the Study of Women's Health Across the Nation (SWAN) JOURNAL OF BONE AND MINERAL RESEARCH Greendale, G. A., Sowers, M., Han, W., Huang, M., Finkelstein, J. S., Crandall, C. J., Lee, J. S., Karlamangla, A. S. 2012; 27 (1): 111-118

  Abstract

  The objective of this study was to describe the time of onset and offset of bone mineral density (BMD) loss relative to the date of the final menstrual period (FMP); the rate and amount of BMD decline during the 5 years before and the 5 years after the FMP; and the independent associations between age at FMP, body mass index (BMI), and race/ethnicity with rates of BMD loss during this time interval. The sample included 242 African American, 384 white, 117 Chinese, and 119 Japanese women, pre- or early perimenopausal at baseline, who had experienced their FMP and for whom an FMP date could be determined. Loess-smoothed curves showed that BMD loss began 1 year before the FMP and decelerated (but did not cease) 2 years after the FMP, at both the lumbar spine (LS) and femoral neck (FN) sites. Piecewise, linear, mixed-effects regression models demonstrated that during the 10-year observation period, at each bone site, the rates and cumulative amounts of bone loss were greatest from 1 year before through 2 years after the FMP, termed the transmenopause. Postmenopausal loss rates, those occurring between 2 and 5 years after the FMP, were less than those observed during transmenopause. Cumulative, 10-year LS BMD loss was 10.6%; 7.38% was lost during the transmenopause. Cumulative FN loss was 9.1%; 5.8% was lost during the transmenopause. Greater BMI and African American heritage were related to slower loss rates, whereas the opposite was true of Japanese and Chinese ancestry.

  View details for DOI 10.1002/jbmr.534

  View details for Web of Science ID 000298479000011

  View details for PubMedID 21976317

• Sex Hormone Levels and Risks of Estrogen Receptor-Negative and Estrogen Receptor-Positive Breast Cancers JOURNAL OF THE NATIONAL CANCER INSTITUTE Farhat, G. N., Cummings, S. R., Chlebowski, R. T., Parimi, N., Cauley, J. A., Rohan, T. E., Huang, A. J., Vitolins, M., Hubbell, F. A., Manson, J. E., Cochrane, B. B., Lane, D. S., Lee, J. S. 2011; 103 (7): 562-570

  Abstract

  Endogenous sex hormone levels are associated with risks of breast cancer overall and estrogen receptor (ER)-positive breast tumors; however, their associations with ER-negative tumors remain unclear.In a case-cohort study within the Women's Health Initiative Observational Study among postmenopausal women aged 50-79 years, we examined associations between endogenous testosterone and estradiol levels and the risks of ER-negative and ER-positive breast cancers. Serum levels of bioavailable testosterone and estradiol were assessed at the baseline visit in 317 invasive breast cancer case subjects and in a subcohort of 594 women. Bioavailable sex hormone levels were calculated using the total hormone level and the sex hormone-binding globulin concentration (measured by radioimmunoassays and a chemiluminescent immunoassay, respectively). Cox proportional hazards regression was used for statistical analysis. All statistical tests were two-sided.The unadjusted absolute rates of ER-negative breast cancer for testosterone quartiles 1-4 were 0.34, 0.20, 0.23, and 0.21 per 10,000 person-years, respectively. Compared with women in the lowest quartile of testosterone level, those in quartile 2 had a 56% lower risk of ER-negative cancer (hazard ratio [HR] = 0.44, 95% confidence interval [CI] = 0.23 to 0.85), those in quartile 3 had a 45% lower risk (HR = 0.55, 95% CI = 0.30 to 1.01), and those in quartile 4 had a 49% lower risk (HR = 0.51, 95% CI = 0.28 to 0.94), independent of other risk factors. Estradiol level was not associated with ER-negative breast cancer. ER-positive breast cancer risk increased with higher testosterone levels (P(trend) = .04), but this trend was not statistically significant after adjustment for estradiol (P(trend) = .15). ER-positive cancer risk was approximately twofold higher in women with estradiol levels in quartiles 2-4 compared with women in quartile 1, independent of risk factors.Higher serum levels of bioavailable testosterone are associated with lower risks of ER-negative breast cancer in postmenopausal women.

  View details for DOI 10.1093/jnci/djr031

  View details for Web of Science ID 000289307800009

  View details for PubMedID 21330633

  View details for PubMedCentralID PMC3071353

• In PCOS, adrenal steroids are regulated differently in the morning versus in response to nutrient intake FERTILITY AND STERILITY Gurusinghe, D., Gill, S., Almario, R. U., Lee, J., Horn, W. F., et al 2010; 93 (4): 1192-99
• Cardiovascular Disease in Women-Challenges Deserving a Comprehensive Translational Approach JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH Lee, J. S., Bertakis, K., Meyers, F. J., Chedin, E., Tarantal, A., Anderson, K., Berglund, L. 2009; 2 (3): 251-255

  Abstract

  Heart disease in women is associated with high levels of morbidity and mortality. Although many of the underlying causes are similar for both genders, cardiovascular disease among women has some unique features, including higher coronary heart disease mortality, higher frequency of sudden cardiac death without previous symptoms, and increased mortality among older women compared to men following a myocardial infarction. During recent years, increasing efforts have been placed on identifying preventive measures, but translation of knowledge from epidemiological studies and clinical trials remain incomplete, particularly in women. The recent launch of the National Institutes of Health's Clinical and Translational Science Award program offers opportunities to address these gaps and represent a unique opportunity to foster a new generation of researchers familiar with important issues regarding women's cardiovascular health.

  View details for DOI 10.1007/s12265-009-9106-9

  View details for Web of Science ID 000284690600005

  View details for PubMedID 19655023

• Homocysteine levels and risk of hip fracture in postmenopausal women JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM LeBoff, M. S., Nerweker, R., LaCroix, A., Wu, L., Jackson, R., et al 2009; 9 (4): 1207-13
• Hip fractures and heart failure: Findings from the Cardiovascular Health Study EUROPEAN HEART JOURNAL Carbone, L., Buzkova, P., Fink, H., Lee, J. S., Chen, Z., et al 2009; 31 (1): 77-84
• Estrogen, aging and the cardiovascular system. Future cardiology Stice, J. P., Lee, J. S., Pechenino, A. S., Knowlton, A. A. 2009; 5 (1): 93-103

  Abstract

  Estrogen is a powerful hormone with pleiotropic effects. Estrogens have potent antioxidant effects and are able to reduce inflammation, induce vasorelaxation and alter gene expression in both the vasculature and the heart. Estrogen treatment of cultured cardiac myocytes and endothelial cells rapidly activates NFkappaB, induces heat-shock protein (HSP)-72, a potent intracellular protective protein, and protects cells from simulated ischemia. In in vivo models, estrogens protect against ischemia and trauma/hemorrhage. Estrogens may decrease the expression of soluble epoxide hydrolase, which has deleterious effects on the cardiovascular system through metabolism of epoxyeicosatrienoic acids. Natural (endogenous) estrogens in premenopausal women appear to protect against cardiovascular disease and yet controlled clinical trials have not indicated a benefit from estrogen replacement postmenopause. Much remains to be understood in regards to the many properties of this powerful hormone and how changes in this hormone interact with aging-associated changes. The unexpected negative results of trials of estrogen replacement postmenopause probably arise from our lack of understanding of the many effects of this hormone.

  View details for DOI 10.2217/14796678.5.1.93

  View details for PubMedID 19371207

• Genetic Variations in Sex Steroid-Related Genes as Predictors of Serum Estrogen Levels in Men. 30th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research ERIKSSON, A., Lorentzon, M., Vandenput, L., Labrie, F., Lindersson, M., Syvanen, A., Orwoll, E. S., Cummings, S. R., Lee, J. S., Zmuda, J. M., Ljunggren, O., Karlsson, M. K., Mellstrom, D., Ohlsson, C. WILEY-BLACKWELL. 2008: S285–S285

  View details for Web of Science ID 000259411001447

• Associations of serum sex hormone-binding globulin and sex hormone concentrations with hip fracture risk in postmenopausal women JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Lee, J. S., LaCroix, A. Z., Wu, L., Cauley, J. A., Jackson, R. D., Kooperberg, C., LeBoff, M. S., Robbins, J., Lewis, C. E., Bauer, D. C., Cummings, S. R. 2008; 93 (5): 1796-1803

  Abstract

  Endogenous estradiol, testosterone, and SHBG may influence the risk of hip fracture.From the Women's Health Initiative Observational Study, 39,793 eligible postmenopausal women did not have a previous hip fracture and were not using estrogen or other bone-active therapies. Of these, 400 who had a first-time nonpathological hip fracture (median follow-up, 7 yr) were matched to 400 controls by age, ethnicity, and baseline blood draw date. Estradiol, testosterone, and SHBG were measured in banked baseline serum.Compared with women in the lowest tertiles, those with bioavailable testosterone in the highest tertile had a lower risk [odds ratio (OR) = 0.62; 95% confidence interval (CI) = 0.44-0.88]; those with bioavailable estradiol in the highest tertile had a lower risk (OR = 0.44; 95% CI = 0.29-0.66), and those with SHBG in the highest tertile had a higher risk (OR = 1.90; 95% CI = 1.31-2.74) of hip fracture. In models with all three hormones and potential confounders, high SHBG remained a strong independent risk factor (OR = 1.76; 95% CI = 1.12-2.78), high bioavailable testosterone remained protective (OR = 0.64; 95% CI = 0.40-1.00), but estradiol no longer was associated (OR = 0.72; 95% CI = 0.42-1.23).High serum SHBG is associated with an increased risk of subsequent hip fracture and high endogenous testosterone with a decreased risk, independent of each other, serum estradiol concentration, and other putative risk factors. But endogenous estradiol has no independent association with hip fracture.

  View details for DOI 10.1210/jc.2007-2358

  View details for Web of Science ID 000255663100037

  View details for PubMedID 18334588

• Potential role of ultra-sensitive estradiol assays in estimating the risk of breast cancer and fractures STEROIDS Santen, R. J., Lee, J. S., Wang, S., Demers, L. S., Mauras, N., et al 2008; 73 (13): 1318-21
• Cystatin-c and incidence of hip fracture in postmenopausal women JOURNAL OF THE GERIATRICS SOCIETY LaCroix, A. Z., Lee, J. S., Wu, L., Cauley, J., Shilpak, M. G., et al 2008; 56 (8): 1434-41
• Exogenous hormone use, reproductive factors and risk of non-Hodgkin lymphoma AMERICAN JOURNAL OF EPIDEMIOLOGY Lee, J. S., Bracci, P., Holly, E. A. 2008; 168 (3): 278-88
• Serum 25 Hydroxyvitamin D concentrations and the risk of hip fractures: The Women's Health Initiative ANNALS OF INTERNAL MEDICINE Cauley, J. A., LaCroix, A. Z., Wu, L., Horwitz, M., Danielson, M. E., et al 2008; 149 (4): 242-250
• Standardization of steroid hormone assays: Why, how, and when? CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Stanczyk, F. Z., Lee, J. S., Santen, R. J. 2007; 16 (9): 1713-1719

  Abstract

  Lack of standardization of high-quality steroid hormone assays is a major deficiency in epidemiologic studies. In postmenopausal women, reported levels of serum 17beta-estradiol (E(2)) are highly variable and median normal values differ by approximately a 6-fold factor. A particular problem is the use of E(2) assays for prediction of breast cancer risk and osteoporotic fractures, where assay sensitivity may be the most important factor. Identification of women in the lowest categories of E(2) levels will likely provide prognostic information that would not be available in a large group of women in whom E(2) levels are undetectable by less sensitive assays. Detailed and costly methods involving extraction and chromatography in conjunction with RIA provide generally acceptable E(2) results in postmenopausal serum, whereas less tedious, direct immunoassays suffer from inadequate specificity and sensitivity. Studies comparing the two types of methods generally report higher E(2) values with the direct methods as a result of cross-reactivity with other steroids and reduced correlation with biological variables such as body mass index. Similar problems exist with measurements of E(2) and estrone in men, and estrone and testosterone in women. Interest in mass spectrometry-based assays is increasing as potential gold standard methods with enhanced sensitivity and specificity; however, these assays require costly instrumentation and highly trained personnel. Taking all of these issues into consideration, we propose establishment of standard pools of premenopausal, postmenopausal, and male serum, and utilization of these for cross-comparison of various methods on an international basis. An oversight group could then establish standards based on these comparisons and set agreed upon confidence limits of various hormones in the pools. These criteria would allow validation of sensitivity, specificity, precision, and accuracy of current steroid hormone assay methodology and provide surrogates until a true gold standard can be developed.

  View details for DOI 10.1158/1055-9965.EPI-06-0765

  View details for Web of Science ID 000249643600003

  View details for PubMedID 17855686

• Reproductive risk factors for cutaneous melanoma in women: A case-control study AMERICAN JOURNAL OF EPIDEMIOLOGY Lea, C. S., Holly, E. A., Hartge, P., Lee, J. S., Guerry, D., Elder, D. E., Halpern, A., Sagebiel, R. W., Tucker, M. A. 2007; 165 (5): 505-513

  Abstract

  Reproductive hormonal factors may have a potential role in cutaneous melanoma. This study estimated the risk of melanoma in women related to self-reported changes in nevi during pregnancy, while using oral contraceptives and/or hormone replacement therapy. Trained interviewers administered a questionnaire obtaining information about oral contraceptive use, hormone replacement therapy, reproductive history, sun exposure, occupation, and medical history from 318 Caucasian women newly diagnosed between 1991 and 1992 from two pigmented lesion clinics in San Francisco, California, and Philadelphia, Pennsylvania. A total of 395 frequency-matched control participants were recruited from hospital-affiliated outpatient clinics. Clinicians conducted skin examinations to assess the number and type of nevi, extent of freckling, solar damage, and skin type. For women aged less than 55 years, there was an association between a livebirth 5 years before diagnosis (odds ratio = 2.6, 95% confidence interval: 1.3, 5.3) and between number of births and melanoma risk (for > or = 3 births: odds ratio = 3.3, 95% confidence interval: 1.7, 6.5; ptrend < 0.001). Changes in nevi during recent pregnancies were a risk factor for melanoma, based upon small numbers (odds ratio = 2.9, 95% confidence interval: 1.1, 8.1). Oral contraceptive use and hormone replacement therapy were not associated with melanoma risk.

  View details for DOI 10.1093/aje/kwk040

  View details for Web of Science ID 000244427100004

  View details for PubMedID 17158470

• Comparison of methods to measure low serum estradiol levels in postmenopausal women JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Lee, J. S., Ettinger, B., Stanczyk, F. Z., Vittinghoff, E., Hanes, V., Cauley, J. A., Chandler, W., Settlage, J., Beattie, M. S., Folkerd, E., Dowsett, M., Grady, D., Cummings, S. R. 2006; 91 (10): 3791-3797

  Abstract

  Accurate measurement of low serum estradiol (E(2) < 30 pg/ml or < 110 pmol/liter) is needed to study relationships between endogenous E(2) and risks of diseases in older women.The objective of this study was to determine whether an extraction-based (indirect) assay or a non-extraction-based (direct) assay correlates better with mass spectrometry and body mass index (BMI).In a pilot study of 40 postmenopausal women, endogenous E(2) measurements from three indirect and four direct assay methods and gas chromatography-tandem mass spectrometry (GC-MS/MS) were compared. A confirmatory study compared an indirect and a direct assay, selected among those in the pilot study, to GC-MS/MS; this study was conducted in 374 postmenopausal women not taking hormone therapy from the Ultra Low-dose TRansdermal estrogen Assessment (ULTRA) trial.Pearson correlation coefficients among E(2) measurements by assay methods and BMI, and their confidence intervals, by bias-corrected bootstrap method, were used.In the pilot study, E(2) by three indirect assays correlated better (P < 0.03) with GC-MS/MS and with BMI than measurements by four direct assays. In the confirmatory study, the indirect assay correlated better (P < 0.01) with GC-MS/MS and BMI than the direct assay. Measurements by the indirect and direct assays were overestimated, but deviations in direct assay measurements were less precise. Mean E(2) by the indirect and direct assays were higher (by 14 and 68%, respectively) and less reproducible than by GC-MS/MS.Until mass spectrometry is practical for wide use, extraction-based indirect assays may be preferable for measuring low postmenopausal serum E(2).

  View details for DOI 10.1210/jc.2005-2378

  View details for Web of Science ID 000241100900015

  View details for PubMedID 16882749

• Making sense of puzzling genetic association studies: A team approach ANNALS OF INTERNAL MEDICINE Lee, J. S., Tucker, M. A. 2006; 145 (4): 302-304

  View details for Web of Science ID 000239858800009

  View details for PubMedID 16908922

• Breast and ovarian cancer in relatives of cancer patients, with and without BRCA mutations CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Lee, J. S., John, E. M., McGuire, V., Felberg, A., Ostrow, K. L., DiCioccio, R. A., Li, F. P., Miron, A., West, D. W., Whittemore, A. S. 2006; 15 (2): 359-363

  Abstract

  First-degree relatives of patients with breast or ovarian cancer have increased risks for these cancers. Little is known about how their risks vary with the patient's cancer site, carrier status for predisposing genetic mutations, or age at cancer diagnosis.We evaluated breast and ovarian cancer incidence in 2,935 female first-degree relatives of non-Hispanic White female patients with incident invasive cancers of the breast (n = 669) or ovary (n = 339) who were recruited from a population-based cancer registry in northern California. Breast cancer patients were tested for BRCA1 and BRCA2 mutations. Ovarian cancer patients were tested for BRCA1 mutations. We estimated standardized incidence ratios (SIR) and 95% confidence intervals (95% CI) for breast and ovarian cancer among the relatives according to the patient's mutation status, cancer site, and age at cancer diagnosis.In families of patients who were negative or untested for BRCA1 or BRCA2 mutations, risks were elevated only for the patient's cancer site. The breast cancer SIR was 1.5 (95% CI, 1.2-1.8) for relatives of breast cancer patients, compared with 1.1 (95% CI, 0.8-1.6) for relatives of ovarian cancer patients (P = 0.12 for difference by patient's cancer site). The ovarian cancer SIR was 0.9 (95% CI, 0.5-1.4) for relatives of breast cancer patients, compared with 1.9 (95% CI, 1.0-4.0) for relatives of ovarian cancer patients (P = 0.04 for difference by site). In families of BRCA1-positive patients, relatives' risks also correlated with the patient's cancer site. The breast cancer SIR was 10.6 (95% CI, 5.2-21.6) for relatives of breast cancer patients, compared with 3.3 (95% CI, 1.4-7.3) for relatives of ovarian cancer patients (two-sided P = 0.02 for difference by site). The ovarian cancer SIR was 7.9 (95% CI, 1.2-53.0) for relatives of breast cancer patients, compared with 11.3 (3.6-35.9) for relatives of ovarian cancer patients (two-sided P = 0.37 for difference by site). Relatives' risks were independent of patients' ages at diagnosis, with one exception: In families ascertained through a breast cancer patient without BRCA mutations, breast cancer risks were higher if the patient had been diagnosed before age 40 years.In families of patients with and without BRCA1 mutations, breast and ovarian cancer risks correlate with the patient's cancer site. Moreover, in families of breast cancer patients without BRCA mutations, breast cancer risk depends on the patient's age at diagnosis. These patterns support the presence of genes that modify risk specific to cancer site, in both carriers and noncarriers of BRCA1 and BRCA2 mutations.

  View details for DOI 10.1158/1055-9965.EPI-05-0687

  View details for Web of Science ID 000235587200026

  View details for PubMedID 16492929

• New physiologic approach to prevention of postmenopausal osteoporosis (book chapter) Postmenopausal Osteoporosis: Hormones and Other Therapies Ettinger, B., Lee, J. S. Taylor & Francis Medical Books. 2005
• Sex hormones and risk of breast cancer by estrogen receptor status in postmenopausal women CANCER EPIDEMIOLOGY BIOMARKERS AND PREVENTION Cummings, S. R., Lee, J. S., Lui, L., Cauley, J. A. 2005; 14 (5): 1047-51
• Histopathologic features of ovaries at increased risk for carcinoma - A case-control analysis 87th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Sherman, M. E., Lee, J. S., Burks, R. T., Struewing, J. P., Kurman, R. J., Hartge, P. LIPPINCOTT WILLIAMS & WILKINS. 1999: 151–57

  Abstract

  In this study, the pathogenesis of ovarian carcinoma was investigated by performing a masked histopathologic comparison of benign ovaries removed from 61 women predicted to be at increased risk for developing carcinoma (cases) with ovaries removed from 121 women without known predisposing conditions (controls). The cases included 26 women who had a unilateral invasive carcinoma and 35 women undergoing prophylactic oophorectomy for a family history of ovarian cancer. As predicted by previously developed models, epithelial inclusion cysts were identified more frequently with advancing age in both cases and controls. However, the mean and maximum number of cysts per slide in a woman were not increased among cases. Surface epithelial "atypia," a designation based on a composite impression of multiple features, was found in 13% of cases compared with 3% of controls (relative risk 7.1; 95% confidence interval, 1.9 to 26.1), but this result was based on small numbers. None of the other histologic features examined was found more often in cases following age-adjustment. Reexamination of sections with well-preserved surface epithelium or inclusion cysts under oil immersion demonstrated several differences in the detection of specific features between cases and controls and increased detection of "atypia" among cases, but none of these findings reached statistical significance. It is concluded that there may be subtle differences in the surface epithelium of ovaries predisposed to developing cancer as compared with controls, but these changes are difficult to identify reliably with light microscopy. Future etiologic studies should attempt to optimize specific handling and include molecular studies and epidemiologic analyses.

  View details for Web of Science ID 000079372000009

  View details for PubMedID 10202673

• Survival after breast cancer in BRCA1/2 Ashkenazi Jewish carriers JOURNAL OF THE NATIONAL CANCER INSTITUTE Lee, J. S., Struewing, J. P., Wacholder, S., McAdams, M., Pee, D., et al 1999; 91 (3): 259-63
• Diabetes susceptibility at IDDM2 cannot be positively mapped to the VNTR locus of the insulin gene DIABETOLOGIA DORIA, A., Lee, J., Warram, J. H., Krolewski, A. S. 1996; 39 (5): 594-599

  Abstract

  An inconsistency has come to light between the conclusion of Lucassen et al. that IDDM2 (11p15.5) must lie within a 4.1 kilobase (kb) segment at the insulin (INS) locus and their own data showing statistically significant associations between insulin-dependent diabetes mellitus (IDDM) and markers beyond the boundaries of that segment. We present data from an independent study of 201 IDDM patients and 107 non-diabetic control subjects that also show significant association with a marker 5' of the INS locus. Patients and control subjects were genotyped at INS/+ 1140 A/C (a surrogate for the variable number tandem repeat (VNTR) polymorphism in the regulatory part of the INS gene) and a marker 5' of the tyrosine hydroxylase (TH) gene, TH/pINS500-RsaI, making it 10 kb 5' of the VNTR. Homozygotes for INS/ + 1140 allele '+' were significantly more frequent among IDDM patients than among control subjects (73 vs 45%, p < 0.001) giving an odds ratio of 3.3 (95% confidence interval (CI): 2.0-5.3). A very similar association was found for homozygotes for the TH/RsaI allele '+' (53 vs 31%, p < 0.001) giving an odds ratio of 2.6 (95%CI 1.6-4.2). By multilocus analysis, the TH/RsaI allele '+' identified a subset of INS/ + 1140 alleles '+' haplotypes that are more specifically associated with IDDM (odds ratio = 5.4, 95%CI 2.9-10.4) than allele + 1140 '+' as a whole. In conclusion, the segment of chromosome 11 that is associated with IDDM spans, at least, the INS and TH loci. No legitimate claim can be made that IDDM2 corresponds to the VNTR polymorphism at the INS locus until the correct boundaries for IDDM2 have been defined and other loci within them have been excluded as determinants of IDDM.

  View details for Web of Science ID A1996UH67800012

  View details for PubMedID 8739920

• INCIDENCE OF RENAL-FAILURE IN NIDDM - THE OKLAHOMA INDIAN DIABETES STUDY DIABETES Lee, E. T., Lee, V. S., Lu, M., Lee, J. S., Russell, D., Yeh, J. L. 1994; 43 (4): 572-579

  Abstract

  The incidence of and risk factors for renal failure were determined in 912 Oklahoma Indians with non-insulin-dependent diabetes mellitus in a follow-up study conducted between 1987 and 1990. The incidence rate was 15.7/1,000 person-years after an average follow-up time of 10.2 years. Among those who had no qualitatively positive proteinuria at baseline, the incidence of renal failure was 10.3/1,000 person-years compared with 19.3- and 56.2/1,000 person-years, respectively, in those with slight and heavy proteinuria at baseline. Fasting plasma glucose (FPG) > or = 11.1 mM (200 mg/dl) increased the risk of renal failure to 2.9-fold (95% confidence interval [CI] = 1.9-4.6) higher than a level < 7.8 mM (140 mg/dl), and twofold (95% CI = 1.4-3.1) higher than a level between 7.8 (140 mg/dl) and 11.1 mM (200 mg/dl). The hypertensive patient had twice the incidence of renal failure than the normotensive subject (rate ratio = 2.1, 95% CI = 1.4-3.0). Patients with a lower blood pressure under antihypertensive medication had a lower incidence of renal failure than those whose hypertension remained uncontrolled with or without use of medication. Significant independent risk factors for renal failure, identified from Cox's proportional hazards model, were duration of diabetes, FPG, age, hypertension, and insulin use (P < 0.05). In patients without proteinuria at baseline, FPG and hypertension were significant predictors of renal failure as identified by multivariate analyses, whereas in patients who had proteinuria at baseline, insulin use was significant. Thus, hyperglycemic and hypertension control are suggested strongly for diabetic Oklahoma Indians as potential strategies to prevent the development of renal failure.

  View details for Web of Science ID A1994NC85900011

  View details for PubMedID 8138063

• Lower-extremity amputation: Incidence, risk factors, and mortality. The Oklahoma Diabetes Study DIABETES Lee, J. S., Lu, M., Lee, V. S., Russell, D., Bahr, C., et al 1993; 42: 876-82