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1.  Periodontal disease and breast cancer: Prospective cohort study of postmenopausal women 
Periodontal disease (PD) has been consistently associated with chronic disease; there are no large studies of breast cancer although oral-associated microbes are present in breast tumors.
In the Women’s Health Initiative Observational Study, a prospective cohort of postmenopausal women, 73,737 women without previous breast cancer were followed. Incident, primary, invasive breast tumors were verified by physician adjudication. PD was by self-report. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated by Cox proportional hazards, adjusted for breast cancer risk factors. Because the oral microbiome of those with PD differs with smoking status, we examined associations stratified by smoking.
2,124 incident, invasive breast cancer cases were identified after mean follow-up of 6.7 years. PD, reported by 26.1% of women, was associated with increased breast cancer risk (HR 1.14, 95% CI 1.03 to 1.26), particularly among former smokers who quit within 20 years (HR 1.36; 95% CI 1.05 to 1.77). Among current smokers, the trend was similar (HR 1.32; 95% CI 0.83 to 2.11); there were few cases (n=74) and the CI included the null. The population attributable fraction was 12.06% (95% CI 1.12 to 21.79) and 10.90% (95% CI 10.31 to 28.94) for PD among former smokers quitting within 20 years and current smokers, respectively.
PD, a common chronic inflammatory disorder, was associated with increased risk of postmenopausal breast cancer, particularly among former smokers who quit in the past 20 years.
Understanding a possible role of the oral microbiome in breast carcinogenesis could impact prevention.
PMCID: PMC4713270  PMID: 26689418
Breast neoplasms; periodontal disease; postmenopausal women; inflammation; microbiome; epidemiology
2.  Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women 
JAMA  2010;304(15):1684-1692.
In the Women's Health Initiative estrogen plus progestin trial, after mean (SD) intervention of 5.6 (1.3) years (range 3.7 to 8.6 years) and mean follow-up of 7.9 (1.4) years, breast cancer incidence was increased by combined hormone therapy. However, breast cancer mortality results have not been previously reported.
To determine estrogen plus progestin effects on cumulative breast cancer incidence and mortality after a total mean follow-up of 11.0 (2.7) years thru August 14, 2009.
Design, Setting, and Participants
16,608 postmenopausal women, aged 50-79 years with no prior hysterectomy, were randomly assigned to combined conjugated equine estrogens (0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d) or placebo. After the original trial completion date (March 31, 2005) re-consent was required for continued follow-up for breast cancer incidence and was obtained in 83%.
Main outcome measures
Invasive breast cancer incidence and breast cancer mortality.
In intent-to-treat analyses including all randomized participants, censoring those on March 31, 2005 not-consenting for additional follow-up, estrogen plus progestin increased invasive breast cancers compared with placebo (385 [0.42%/yr] vs 293 [0.34%/yr] cases; hazard ratio [HR] 1.25, 95% confidence interval (CI) 1.07-1.46; P=.004). The breast cancers in the estrogen plus progestin group were similar in histology and grade but were more likely to be node positive (81 [23.7%] vs 43 [16.2%], respectively; P=0.03). Deaths directly attributed to breast cancer were greater in the estrogen plus progestin group (25 [0.03%/yr] vs 12 [0.01%/yr] deaths; HR, 1.96; 95% CI 1.00-4.04, P=.049) as were deaths from all causes occurring after a breast cancer diagnosis (51 [0.05%/yr] vs 31 [0.03%/yr] deaths; HR 1.57, 95% CI 1.01-2.48; P=.045).
Estrogen plus progestin increases breast cancer incidence with cancers more commonly node positive. Breast cancer mortality also appears to be increased with combined estrogen plus progestin use.
PMCID: PMC5142300  PMID: 20959578
3.  NSAID use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: The Liver Cancer Pooling Project 
Chronic inflammation plays a pivotal role in the pathogenesis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), the two most common types of liver cancer. A number of prior experimental studies have suggested that non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin and ibuprofen, may potentially protect against liver cancer. However, no observational study has examined the association between aspirin duration and dose or other over-the-counter non-aspirin NSAIDs, such as ibuprofen, and liver cancer incidence. Furthermore, the association between NSAID use and risk of ICC is unclear. As part of the Liver Cancer Pooling Project, we harmonized data on 1,084,133 individuals (HCC=679, ICC=225) from ten US-based prospective cohort studies. Cox proportional hazards regression models were used to evaluate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Current aspirin use, versus nonuse, was inversely associated with HCC (HR=0.68, 95% CI=0.57-0.81), which persisted when restricted to individuals not using non-aspirin NSAIDs and in a 5 and 10-year lag analysis. The association between aspirin use and HCC risk was stronger for users who reported daily use, longer duration use, and lower dosage. Ibuprofen use was not associated with HCC risk. Aspirin use was associated with a reduced ICC risk in men (HR=0.64, 95% CI=0.42-0.98) but not women (HR=1.34, 95% CI=0.89-2.01, pinteraction=0.01). The observed inverse association between aspirin use and liver cancer in our study, together with previous data, suggest the merit of future intervention studies of aspirin and other agents that affect chronic inflammatory pathways for HCC and possibly ICC.
PMCID: PMC4704448  PMID: 26391917
4.  Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types 
Sampson, Joshua N. | Wheeler, William A. | Yeager, Meredith | Panagiotou, Orestis | Wang, Zhaoming | Berndt, Sonja I. | Lan, Qing | Abnet, Christian C. | Amundadottir, Laufey T. | Figueroa, Jonine D. | Landi, Maria Teresa | Mirabello, Lisa | Savage, Sharon A. | Taylor, Philip R. | Vivo, Immaculata De | McGlynn, Katherine A. | Purdue, Mark P. | Rajaraman, Preetha | Adami, Hans-Olov | Ahlbom, Anders | Albanes, Demetrius | Amary, Maria Fernanda | An, She-Juan | Andersson, Ulrika | Andriole, Gerald | Andrulis, Irene L. | Angelucci, Emanuele | Ansell, Stephen M. | Arici, Cecilia | Armstrong, Bruce K. | Arslan, Alan A. | Austin, Melissa A. | Baris, Dalsu | Barkauskas, Donald A. | Bassig, Bryan A. | Becker, Nikolaus | Benavente, Yolanda | Benhamou, Simone | Berg, Christine | Van Den Berg, David | Bernstein, Leslie | Bertrand, Kimberly A. | Birmann, Brenda M. | Black, Amanda | Boeing, Heiner | Boffetta, Paolo | Boutron-Ruault, Marie-Christine | Bracci, Paige M. | Brinton, Louise | Brooks-Wilson, Angela R. | Bueno-de-Mesquita, H. Bas | Burdett, Laurie | Buring, Julie | Butler, Mary Ann | Cai, Qiuyin | Cancel-Tassin, Geraldine | Canzian, Federico | Carrato, Alfredo | Carreon, Tania | Carta, Angela | Chan, John K. C. | Chang, Ellen T. | Chang, Gee-Chen | Chang, I-Shou | Chang, Jiang | Chang-Claude, Jenny | Chen, Chien-Jen | Chen, Chih-Yi | Chen, Chu | Chen, Chung-Hsing | Chen, Constance | Chen, Hongyan | Chen, Kexin | Chen, Kuan-Yu | Chen, Kun-Chieh | Chen, Ying | Chen, Ying-Hsiang | Chen, Yi-Song | Chen, Yuh-Min | Chien, Li-Hsin | Chirlaque, María-Dolores | Choi, Jin Eun | Choi, Yi Young | Chow, Wong-Ho | Chung, Charles C. | Clavel, Jacqueline | Clavel-Chapelon, Françoise | Cocco, Pierluigi | Colt, Joanne S. | Comperat, Eva | Conde, Lucia | Connors, Joseph M. | Conti, David | Cortessis, Victoria K. | Cotterchio, Michelle | Cozen, Wendy | Crouch, Simon | Crous-Bou, Marta | Cussenot, Olivier | Davis, Faith G. | Ding, Ti | Diver, W. Ryan | Dorronsoro, Miren | Dossus, Laure | Duell, Eric J. | Ennas, Maria Grazia | Erickson, Ralph L. | Feychting, Maria | Flanagan, Adrienne M. | Foretova, Lenka | Fraumeni, Joseph F. | Freedman, Neal D. | Beane Freeman, Laura E. | Fuchs, Charles | Gago-Dominguez, Manuela | Gallinger, Steven | Gao, Yu-Tang | Gapstur, Susan M. | Garcia-Closas, Montserrat | García-Closas, Reina | Gascoyne, Randy D. | Gastier-Foster, Julie | Gaudet, Mia M. | Gaziano, J. Michael | Giffen, Carol | Giles, Graham G. | Giovannucci, Edward | Glimelius, Bengt | Goggins, Michael | Gokgoz, Nalan | Goldstein, Alisa M. | Gorlick, Richard | Gross, Myron | Grubb, Robert | Gu, Jian | Guan, Peng | Gunter, Marc | Guo, Huan | Habermann, Thomas M. | Haiman, Christopher A. | Halai, Dina | Hallmans, Goran | Hassan, Manal | Hattinger, Claudia | He, Qincheng | He, Xingzhou | Helzlsouer, Kathy | Henderson, Brian | Henriksson, Roger | Hjalgrim, Henrik | Hoffman-Bolton, Judith | Hohensee, Chancellor | Holford, Theodore R. | Holly, Elizabeth A. | Hong, Yun-Chul | Hoover, Robert N. | Horn-Ross, Pamela L. | Hosain, G. M. Monawar | Hosgood, H. Dean | Hsiao, Chin-Fu | Hu, Nan | Hu, Wei | Hu, Zhibin | Huang, Ming-Shyan | Huerta, Jose-Maria | Hung, Jen-Yu | Hutchinson, Amy | Inskip, Peter D. | Jackson, Rebecca D. | Jacobs, Eric J. | Jenab, Mazda | Jeon, Hyo-Sung | Ji, Bu-Tian | Jin, Guangfu | Jin, Li | Johansen, Christoffer | Johnson, Alison | Jung, Yoo Jin | Kaaks, Rudolph | Kamineni, Aruna | Kane, Eleanor | Kang, Chang Hyun | Karagas, Margaret R. | Kelly, Rachel S. | Khaw, Kay-Tee | Kim, Christopher | Kim, Hee Nam | Kim, Jin Hee | Kim, Jun Suk | Kim, Yeul Hong | Kim, Young Tae | Kim, Young-Chul | Kitahara, Cari M. | Klein, Alison P. | Klein, Robert J. | Kogevinas, Manolis | Kohno, Takashi | Kolonel, Laurence N. | Kooperberg, Charles | Kricker, Anne | Krogh, Vittorio | Kunitoh, Hideo | Kurtz, Robert C. | Kweon, Sun-Seog | LaCroix, Andrea | Lawrence, Charles | Lecanda, Fernando | Lee, Victor Ho Fun | Li, Donghui | Li, Haixin | Li, Jihua | Li, Yao-Jen | Li, Yuqing | Liao, Linda M. | Liebow, Mark | Lightfoot, Tracy | Lim, Wei-Yen | Lin, Chien-Chung | Lin, Dongxin | Lindstrom, Sara | Linet, Martha S. | Link, Brian K. | Liu, Chenwei | Liu, Jianjun | Liu, Li | Ljungberg, Börje | Lloreta, Josep | Lollo, Simonetta Di | Lu, Daru | Lund, Eiluv | Malats, Nuria | Mannisto, Satu | Marchand, Loic Le | Marina, Neyssa | Masala, Giovanna | Mastrangelo, Giuseppe | Matsuo, Keitaro | Maynadie, Marc | McKay, James | McKean-Cowdin, Roberta | Melbye, Mads | Melin, Beatrice S. | Michaud, Dominique S. | Mitsudomi, Tetsuya | Monnereau, Alain | Montalvan, Rebecca | Moore, Lee E. | Mortensen, Lotte Maxild | Nieters, Alexandra | North, Kari E. | Novak, Anne J. | Oberg, Ann L. | Offit, Kenneth | Oh, In-Jae | Olson, Sara H. | Palli, Domenico | Pao, William | Park, In Kyu | Park, Jae Yong | Park, Kyong Hwa | Patiño-Garcia, Ana | Pavanello, Sofia | Peeters, Petra H. M. | Perng, Reury-Perng | Peters, Ulrike | Petersen, Gloria M. | Picci, Piero | Pike, Malcolm C. | Porru, Stefano | Prescott, Jennifer | Prokunina-Olsson, Ludmila | Qian, Biyun | Qiao, You-Lin | Rais, Marco | Riboli, Elio | Riby, Jacques | Risch, Harvey A. | Rizzato, Cosmeri | Rodabough, Rebecca | Roman, Eve | Roupret, Morgan | Ruder, Avima M. | de Sanjose, Silvia | Scelo, Ghislaine | Schned, Alan | Schumacher, Fredrick | Schwartz, Kendra | Schwenn, Molly | Scotlandi, Katia | Seow, Adeline | Serra, Consol | Serra, Massimo | Sesso, Howard D. | Setiawan, Veronica Wendy | Severi, Gianluca | Severson, Richard K. | Shanafelt, Tait D. | Shen, Hongbing | Shen, Wei | Shin, Min-Ho | Shiraishi, Kouya | Shu, Xiao-Ou | Siddiq, Afshan | Sierrasesúmaga, Luis | Sihoe, Alan Dart Loon | Skibola, Christine F. | Smith, Alex | Smith, Martyn T. | Southey, Melissa C. | Spinelli, John J. | Staines, Anthony | Stampfer, Meir | Stern, Marianna C. | Stevens, Victoria L. | Stolzenberg-Solomon, Rachael S. | Su, Jian | Su, Wu-Chou | Sund, Malin | Sung, Jae Sook | Sung, Sook Whan | Tan, Wen | Tang, Wei | Tardón, Adonina | Thomas, David | Thompson, Carrie A. | Tinker, Lesley F. | Tirabosco, Roberto | Tjønneland, Anne | Travis, Ruth C. | Trichopoulos, Dimitrios | Tsai, Fang-Yu | Tsai, Ying-Huang | Tucker, Margaret | Turner, Jenny | Vajdic, Claire M. | Vermeulen, Roel C. H. | Villano, Danylo J. | Vineis, Paolo | Virtamo, Jarmo | Visvanathan, Kala | Wactawski-Wende, Jean | Wang, Chaoyu | Wang, Chih-Liang | Wang, Jiu-Cun | Wang, Junwen | Wei, Fusheng | Weiderpass, Elisabete | Weiner, George J. | Weinstein, Stephanie | Wentzensen, Nicolas | White, Emily | Witzig, Thomas E. | Wolpin, Brian M. | Wong, Maria Pik | Wu, Chen | Wu, Guoping | Wu, Junjie | Wu, Tangchun | Wu, Wei | Wu, Xifeng | Wu, Yi-Long | Wunder, Jay S. | Xiang, Yong-Bing | Xu, Jun | Xu, Ping | Yang, Pan-Chyr | Yang, Tsung-Ying | Ye, Yuanqing | Yin, Zhihua | Yokota, Jun | Yoon, Ho-Il | Yu, Chong-Jen | Yu, Herbert | Yu, Kai | Yuan, Jian-Min | Zelenetz, Andrew | Zeleniuch-Jacquotte, Anne | Zhang, Xu-Chao | Zhang, Yawei | Zhao, Xueying | Zhao, Zhenhong | Zheng, Hong | Zheng, Tongzhang | Zheng, Wei | Zhou, Baosen | Zhu, Meng | Zucca, Mariagrazia | Boca, Simina M. | Cerhan, James R. | Ferri, Giovanni M. | Hartge, Patricia | Hsiung, Chao Agnes | Magnani, Corrado | Miligi, Lucia | Morton, Lindsay M. | Smedby, Karin E. | Teras, Lauren R. | Vijai, Joseph | Wang, Sophia S. | Brennan, Paul | Caporaso, Neil E. | Hunter, David J. | Kraft, Peter | Rothman, Nathaniel | Silverman, Debra T. | Slager, Susan L. | Chanock, Stephen J. | Chatterjee, Nilanjan
Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites.
Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers.
GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl 2, on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures.
Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
PMCID: PMC4806328  PMID: 26464424
5.  Wrist Fracture and Risk of Subsequent Fracture: Findings from the Women’s Health Initiative Study 
Wrist fractures are common in postmenopausal women and are associated with functional decline. Fracture patterns after wrist fracture are unclear. The goal of this study was to determine the frequency and types of fractures that occur after a wrist fracture among postmenopausal women. We carried out a post-hoc analysis of data from the Women’s Health Initiative Observational Study and Clinical Trials (1993–2010) carried out at 40 U.S. clinical centers. Participants were postmenopausal women aged 50–79 at baseline. Mean follow-up duration was 11.8 years. Main measures included incident wrist, clinical spine, humerus, upper extremity, lower extremity, hip, and total non-wrist fractures and bone mineral density (BMD) in a subset. Among women who experienced wrist fracture, 15.5% subsequently experienced non-wrist fracture. The hazard for non-wrist fractures was higher among women who had experienced previous wrist fracture than among women who had not experienced wrist fracture: non-wrist fracture overall (hazard ratio [HR] 1.40, 95% confidence interval [CI] 1.33–1.48), spine (HR 1.48, 95% CI 1.32–1.66), humerus (HR 1.78, 95% CI 1.57–2.02), upper extremity (non-wrist) (HR 1.88, 95% CI 1.70–2.07), lower extremity (non-hip) (HR 1.36, 95% CI 1.26–1.48), and hip (HR 1.50, 95% CI 1.32–1.71) fracture. Associations persisted after adjustment for BMD, physical activity, and other risk factors. Risk of non-wrist fracture was higher in women who were younger when they experienced wrist fracture (interaction p-value 0.02). Associations between incident wrist fracture and subsequent non-wrist fracture did not vary by baseline BMD category (normal, low bone density, osteoporosis). A wrist fracture is associated with increased risk of subsequent hip, vertebral, upper extremity, and lower extremity fractures. There may be substantial missed opportunity for intervention in the large number of women who present with wrist fractures.
PMCID: PMC4615529  PMID: 25990562
Fracture; osteoporosis
6.  Identifying post-menopausal women at elevated risk for epithelial ovarian cancer 
Gynecologic oncology  2015;139(2):253-260.
We developed and validated a hybrid risk classifier combining serum markers and epidemiologic risk factors to identify post-menopausal women at elevated risk for invasive fallopian tube, primary peritoneal, and ovarian epithelial carcinoma.
To select epidemiologic risk factors for use in the classifier, Cox proportional hazards analyses were conducted using 74,786 Women’s Health Initiative (WHI) Observational Study (OS) participants. To construct a combination classifier, 210 WHI OS cases and 536 matched controls with serum marker measurements were analyzed; validation employed 143 cases and 725 matched controls from the WHI Clinical Trial (CT) with similar data.
Analyses identified a combination risk classifier composed of two elevated-risk groups: 1) women with CA125 or HE4 exceeding a 98% specificity threshold; and 2) women with intact fallopian tubes, prior use of menopausal hormone therapy for at least two years, and either a first degree relative with breast or ovarian cancer or a personal history of breast cancer. In the WHI OS population, it classified 13% of women as elevated risk, identifying 30% of ovarian cancers diagnosed up to 7.8 years post-enrollment (Hazard Ratio [HR]=2.6, p<0.001). In the WHI CT validation population, it classified 8% of women as elevated risk, identifying 31% of cancers diagnosed within 7 years of enrollment (HR=4.6, p<0.001).
CA125 and HE4 contributed significantly to a risk prediction classifier combining serum markers with epidemiologic risk factors. The hybrid risk classifier may be useful to identify post-menopausal women who would benefit from timely surgical intervention to prevent epithelial ovarian cancer.
PMCID: PMC4664187  PMID: 26343159
ovarian cancer; risk prediction; CA125; HE4
7.  Effect of Age of Self-Reported, Non-Surgical Menopause on Time to First Fracture and Bone Mineral Density in the Women’s Health Initiative Observational Study 
Menopause (New York, N.Y.)  2015;22(10):1035-1044.
Menopause is a risk factor for fracture, thus menopause age may affect bone mass and fracture rates. We compared Bone Mineral Density (BMD) and fracture rates among healthy postmenopausal women with varying ages of self-reported non-surgical menopause.
Hazard ratios for fracture and differences in BMD among 21,711 postmenopausal women from the Women’s Health Initiative Observational cohort without prior hysterectomy, oophorectomy, or hormone therapy, who reported age of menopause of <40, 40–49, or ≥50 years, were compared.
Prior to multivariable adjustments, we found no differences in absolute fracture risk among menopausal age groups. After multivariable adjustments for known risk factors for fracture, women undergoing menopause <40 had a higher fracture risk at any site compared to women undergoing menopause ≥50 years (HR=1.21, 95% CI: 1.02, 1.44; p=0.03). In a subset with BMD measurements (n=1,351), whole body BMD was lower in women who reported menopause <40 compared to 40–49 years (estimated difference= −0.034 g/cm2; 95% CI: −0.07, −0.004; p=0.03) and compared to ≥50 years (estimated difference= −0.05 g/cm2; 95% CI; −0.08, −0.02; p<0.01). Left hip BMD was lower in women with menopause <40 compared to ≥50 years (estimated difference= −0.05 g/cm2; 95% CI: −0.08, −0.01; p=0.01), and total spine BMD was lower in women with menopause <40 compared to ≥50 and 40–49 years (estimated differences= −0.11 g/cm2; 95% CI; −0.16, −0.06; p<0.01 and −0.09 g/cm2; 95% CI; −0.15, −0.04; p<0.01, respectively).
In the absence of hormone therapy, earlier menopause age may be a risk factor contributing to decreased BMD and increased fracture risk in healthy postmenopausal women. Our data suggest that menopause age should be taken into consideration, along with other osteoporotic risk factors, when estimating fracture risk in postmenopausal women.
PMCID: PMC4580482  PMID: 25803670
fracture; menopause; premature menopause; bone mineral density
8.  Coffee consumption and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma by sex: The Liver Cancer Pooling Project 
Coffee consumption has been reported to be inversely associated with hepatocellular carcinoma (HCC), the most common type of liver cancer. Caffeine has chemopreventive properties, but whether caffeine is responsible for the coffee-HCC association is not well studied. In addition, few studies have examined the relationship by sex, and no studies have examined whether there is an association between coffee and intrahepatic cholangiocarcinoma (ICC), the second most common type of liver cancer.
In the Liver Cancer Pooling Project, a consortium of U.S.-based cohort studies, data from 1,212,893 individuals (HCC n=860, ICC n=260) in nine cohorts were pooled. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression.
Higher coffee consumption was associated with lower risk of HCC (HR>3 cups/day vs. non-drinker, 0.73; 95% CI, 0.53-0.99; ptrend cups/day=<0.0001). More notable reduced risk was seen among women than men (pinteraction=0.07). Women who consumed more than three cups of coffee per day were at a 54% lower risk of HCC (HR, 0.46; 95% CI, 0.26-0.81), whereas men had more modest reduced risk of HCC (HR, 0.93; 95% CI, 0.63-1.37). The associations were stronger for caffeinated coffee (HR>3 cups/day vs. non-drinker, 0.71, 95% CI, 0.50-1.01) than decaffeinated coffee (HR, 0.92; 95% CI, 0.55-1.54). There was no relationship between coffee consumption and ICC.
These findings suggest that, in a U.S. population, coffee consumption is associated with reduced risk of HCC.
Further research into specific coffee compounds and mechanisms that may account for these associations is needed.
PMCID: PMC4576990  PMID: 26126626
coffee; diet; epidemiology; hepatocellular carcinoma; intrahepatic cholangiocarcinoma
9.  Identification of a common variant with potential pleiotropic effect on risk of inflammatory bowel disease and colorectal cancer 
Carcinogenesis  2015;36(9):999-1007.
We identified the minor allele (T) in SNP rs11676348 to have pleiotropic effect on risk of UC and CRC, particularly in tumors with an inflammatory component. Our findings offer the promise of risk stratification of UC patients for developing CRC.
Although genome-wide association studies (GWAS) have separately identified many genetic susceptibility loci for ulcerative colitis (UC), Crohn’s disease (CD) and colorectal cancer (CRC), there has been no large-scale examination for pleiotropy, or shared genetic susceptibility, for these conditions. We used logistic regression modeling to examine the associations of 181 UC and CD susceptibility variants previously identified by GWAS with risk of CRC using data from the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. We also examined associations of significant variants with clinical and molecular characteristics in a subset of the studies. Among 11794 CRC cases and 14190 controls, rs11676348, the susceptibility single nucleotide polymorphism (SNP) for UC, was significantly associated with reduced risk of CRC (P = 7E−05). The multivariate-adjusted odds ratio of CRC with each copy of the T allele was 0.93 (95% CI 0.89–0.96). The association of the SNP with risk of CRC differed according to mucinous histological features (P heterogeneity = 0.008). In addition, the (T) allele was associated with lower risk of tumors with Crohn’s-like reaction but not tumors without such immune infiltrate (P heterogeneity = 0.02) and microsatellite instability-high (MSI-high) but not microsatellite stable or MSI-low tumors (P heterogeneity = 0.03). The minor allele (T) in SNP rs11676348, located downstream from CXCR2 that has been implicated in CRC progression, is associated with a lower risk of CRC, particularly tumors with a mucinous component, Crohn’s-like reaction and MSI-high. Our findings offer the promise of risk stratification of inflammatory bowel disease patients for complications such as CRC.
PMCID: PMC4573660  PMID: 26071399
10.  Dietary factors and luteal phase deficiency in healthy eumenorrheic women 
Human Reproduction (Oxford, England)  2015;30(8):1942-1951.
Are prospectively assessed dietary factors, including overall diet quality, macronutrients and micronutrients, associated with luteal phase deficiency (LPD) in healthy reproductive aged women with regular menstrual cycles?
Mediterranean Diet Score (MDS), fiber and isoflavone intake were positively associated with LPD while selenium was negatively associated with LPD after adjusting for age, percentage body fat and total energy intake.
LPD may increase the risk of infertility and early miscarriage. Prior research has shown positive associations between LPD and low energy availability, either through high dietary restraint alone or in conjunction with high energy expenditure via exercise, but few studies with adequate sample sizes have been conducted investigating dietary factors and LPD among healthy, eumenorrheic women.
The BioCycle Study (2005–2007) prospectively enrolled 259 women from Western New York state, USA, and followed them for one (n = 9) or two (n = 250) menstrual cycles.
Women aged 18–44 years, with self-reported BMI between 18 and 35 kg/m2 and cycle lengths between 21 and 35 days, were included in the study. Participants completed baseline questionnaires, four 24-h dietary recalls per cycle and daily diaries capturing vigorous exercise, perceived stress and sleep; they also provided up to eight fasting serum samples during clinic visits timed to specific phases of the menstrual cycle using a fertility monitor. Cycles were included for this analysis if the peak serum luteal progesterone was >1 ng/ml and a urine or serum LH surge was detected. Associations between prospectively assessed diet quality, macronutrients and micronutrients and LPD (defined as luteal duration <10 days) were evaluated using generalized linear models adjusting for age, percentage body fat and total energy intake.
LPD occurred in 41 (8.9%) of the 463 cycles from 246 women in the final analysis. After adjusting for age, percentage body fat and total energy intake, LPD was positively associated with MDS, adjusted odds ratio (aOR): 1.70 (95% confidence interval [CI]: 1.17, 2.48), P = 0.01. In separate macro- and micronutrient adjusted models, increased fiber and isoflavone intake showed modest positive associations with LPD: fiber (per g), aOR: 1.10 (95% CI: 0.99, 1.23), P = 0.07; and isoflavones (per 10 mg), aOR: 1.38 (95% CI: 0.99, 1.92), P = 0.06. In contrast, selenium (per 10 mcg) was inversely associated with LPD, aOR: 0.80 (95% CI: 0.65, 0.97), P = 0.03. Additional adjustments for relevant lifestyle factors including vigorous exercise, perceived stress and sleep did not appreciably alter estimates.
The number of LPD cycles was limited, and thus these findings are exploratory. We relied on participant self-report of their medical history to apply exclusion criteria; it is possible that we admitted to the study women with a gynecologic or medical disease who were unaware of their diagnosis.
Our study suggests that diet quality may be associated with LPD among healthy eumenorrheic women. As LPD may contribute to infertility and early miscarriage, further research is warranted to elucidate how dietary factors, such as MDS, may influence LPD. The inverse association we found with selenium is supported by previous research and deserves further investigation to determine whether this finding has pathophysiologic and therapeutic implications.
This work was supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. No competing interests declared.
PMCID: PMC4507331  PMID: 26082480
luteal phase deficiency; menstrual cycle; Mediterranean diet; fiber; selenium
11.  Calcium and Vitamin D supplementation do not influence menopause-related symptoms: Results of the Women’s Health Initiative Trial 
Maturitas  2015;81(3):377-383.
It is unknown whether supplementation with calcium and vitamin D has an impact on menopause-related symptoms.
As part of the Women’s Health Initiative Calcium/Vitamin D Supplementation Trial (CaD), women were randomized at 40 clinical sites to elemental calcium carbonate 1,000 mg with vitamin D 400 IU daily or placebo. At the CaD baseline visit (year 1 or year 2) and during a mean follow-up of 5.7 years, participants provided data on menopause-related symptoms via questionnaires. Generalized linear mixed effects techniques were used to address research questions.
After excluding participants with missing data (N=2,125), we compared menopause-related symptoms at follow-up visits of 11,584 women randomized to CaD with those of 11,436 women given the placebo. Women in the CaD arm did not have a different number of symptoms at follow-up compared to women taking the placebo (p=0.702). Similarly, there was no difference between sleep disturbance, emotional well-being, or energy/fatigue at follow-up in those who were randomized to CaD supplementation compared to those taking the placebo.
Our data suggest that supplementation with 1000 mg of calcium plus 400 IU of vitamin D does not influence menopause-related symptoms over an average of 5.7 years of follow-up among postmenopausal women with an average age of 64 at the WHI baseline visit.
PMCID: PMC4469550  PMID: 26044075
Vitamin D; calcium; menopause; hot flashes; mood; sleep
Results from the Women's Health Initiative (WHI) clinical trials (CT) demonstrated no increase in the risk of lung cancer in postmenopausal women treated with hormone therapy. We conducted a joint analysis of the WHI observational study data and CT data to further explore the association between estrogen and estrogen-related reproductive factors and lung cancer risk.
Reproductive history, oral contraceptive (OC) use, and postmenopausal hormone therapy (HT) was evaluated in 160,855 women with known HT exposures. Follow-up for lung cancer was through September 17, 2012; 2,467 incident lung cancer cases were ascertained, with median follow-up of 14 years.
For all lung cancers, women with previous use of estrogen plus progestin of < 5 years (HR=0.84; 95% CI 0.71-0.99) were at reduced risk. A limited number of reproductive factors demonstrated associations with risk. There was a trend towards decreased risk with increasing age at menopause (ptrend=0.04) and a trend towards increased risk with increasing number of live births (ptrend=0.03). Reduced risk of non-small cell lung cancer was associated with age 20-29 at first live birth. Risk estimates varied with smoking history, years of HT use and previous bilateral oophorectomy.
Indirect measures of estrogen exposure to lung tissue, as used in this study, provide only weak evidence for an association between reproductive history or HT use and risk of lung cancer. More detailed mechanistic studies and evaluation of risk factors in conjunction with ER expression in the lung should continue as a role for estrogen can't be ruled out and may hold potential for prevention and treatment strategies.
PMCID: PMC4627490  PMID: 25852020
Lung Cancer; Hormone Therapy; Reproductive History
13.  Vitamin D Status and Five Year Changes in Periodontal Disease Measures among Postmenopausal Women: The Buffalo OsteoPerio Study 
Journal of periodontology  2014;85(10):1321-1332.
Vitamin D is hypothesized to prevent periodontal disease progression through its immune modulating properties and its role in maintaining systemic calcium concentrations. We investigated associations between plasma 25(OH)D (collected 1997–2000) and the five-year change in periodontal disease measures from baseline (1997–2000) to follow-up (2002–2005) among 655 postmenopausal women in a Women’s Health Initiative Observational Study ancillary study. Exploratory analyses were conducted in 628 women who also had 25(OH)D measures at follow-up.
Four continuous measures of five-year change in periodontal disease were assessed using alveolar crestal height (ACH), clinical attachment level (CAL), probing pocket depth (PD), and percent of gingival sites that bled upon assessment. Linear regression was used to estimate beta-coefficients (β), standard errors (SE), and p-values corresponding to change in periodontal disease (either a 1 mm change in ACH, CAL or PD, or 1 unit change in the percent of gingival sites that bled) for a 10 nmol/L difference in 25(OH)D. Models were adjusted for age, education, dental visit frequency, smoking, diabetes status, current medications affecting bone health, baseline measures of periodontal disease, body mass index, and recreational physical activity.
No statistically significant associations were observed between baseline 25(OH)D and change in periodontal disease measures, overall or in a subset (n=442) of women with stable 25(OH)D concentrations (women whose 25(OH)D changed less than ± 20 nmol/L from baseline to follow-up). Results also did not vary significantly in analyses that were stratified by baseline periodontal disease status.
No association between baseline 25(OH)D and the subsequent five-year change in periodontal disease measures was observed. Vitamin D status may not influence periodontal disease progression. More studies are needed to confirm these results.
Study summary
In our prospective study in postmenopausal women, baseline vitamin D status, assessed using 25-hydroxyvitamin D concentrations, was not associated with the five-year progression of periodontal disease defined as changes in alveolar bone, clinical attachment, probing pocket depth, or gingival bleeding.
PMCID: PMC4861231  PMID: 24794688
vitamin D; periodontal diseases; postmenopausal period; epidemiology; alveolar bone loss
14.  Non-steroidal anti-inflammatory drug and aspirin use in relation to lung cancer risk among postmenopausal women 
Results from prospective studies suggest that non-steroidal anti-inflammatory drugs (NSAID) may decrease lung cancer risk; however, any protective effect appears to be most evident in men.
We evaluated the associations between NSAID use and lung cancer incidence in postmenopausal women in the Women’s Health Initiative (WHI) adjusting for female specific potential confounders such as hormone therapy in addition to smoking histories and other potential confounders. We identified 143,841 women from ages 50 to 79 and 1,902 centrally confirmed lung cancer cases were included in the analysis. We used Cox regression models to estimate hazard ratios and their 95% confidence intervals.
Compared to non-use, regular NSAID use was not associated with overall lung cancer incidence (NSAID use >10 years HR 0.87, 95% CI 0.71–1.08, p-trend =0.13). No statistically significant associations were found when examined by histological subtypes and although there was a trend of decreased risk with longer duration of NSAID use in the adenocarcinoma subtype, this was not statistically significant (NSAID use >10 years HR 0.80, 95% CI 0.58–1.10, p trend = 0.07).
Our study did not show that NSAID use is associated with lung cancer risk in women even after adjusting for female-specific confounders. There was a trend of decreased risk in the adenocarcinoma subtype; however, this was not statistically significant.
Future studies will need to take in account the various molecular subtypes of non-small cell lung cancer to further elucidate the role of NSAIDS in lung cancer, especially for the adenocarcinoma subtype.
PMCID: PMC4578149  PMID: 25670808
15.  Diabetes, metformin and incidence of and death from invasive cancer in postmenopausal women: Results from the women’s health initiative 
International journal of cancer  2015;138(8):1915-1927.
Findings from studies of metformin use with risk of cancer incidence and outcome provide mixed results; with few studies examined associations by recency of diabetes diagnosis or duration of medication use. Thus, in the Women’s Health Initiative, we examined these associations and further explored whether associations differ by recency of diabetes and duration of metformin use. Cox regression models were used to estimate hazard ratios (HR) and their 95% confidence intervals. Diabetes was associated with higher risk of total invasive cancer (HR, 1.13; p < 0.001) and of several site-specific cancers (HR, 1.2–1.4, and up to over twofold). Diabetes was also associated with higher risk of death from cancer (HR, 1.46; p < 0.001). There was no overall difference in cancer incidence by diabetes therapy (p = 0.66). However, there was a lower risk of death from cancer for metformin users, compared to users of other medications, relative to women without diabetes, overall (HRs, 1.08 vs. 1.45; p = 0.007) and for breast cancer (HRs, 0.50 vs. 1.29; p = 0.05). Results also suggested that lower cancer risk associated with metformin may be evident only for a longer duration of use in certain cancer sites or subgroup populations. We provide further evidence that postmenopausal women with diabetes are at higher risk of invasive cancer and cancer death. Metformin users, particularly long-term users, may be at lower risk of developing certain cancers and dying from cancer, compared to users of other anti-diabetes medications. Future studies are needed to determine the long-term effect of metformin in cancer risk and survival from cancer.
PMCID: PMC4830266  PMID: 26616262
diabetes; metformin; invasive cancer; incidence; mortality
16.  Association of Serum 17β-Estradiol Concentration, Hormone Therapy, and Alveolar Crest Height in Postmenopausal Women 
Journal of periodontology  2015;86(4):595-605.
Declines in endogenous estrogen levels after menopause can lead to systemic bone loss, including loss of oral bone and alveolar crest height (ACH). However, few studies have assessed both serum 17β-estradiol (E2) and exogenous hormone therapy (HT) use in relation to oral bone loss.
This study examines the associations among serum E2, HT use, and ACH in 613 postmenopausal women from the Buffalo OsteoPerio study. Baseline ACH levels and 5-year ACH were assessed for groups according to E2 level (undetectable, >5.00 to ≤18.00, >18.00 to ≤46.07, and >46.07 pg/mL) and among HT use (never, ever) using analysis of variance and analysis of covariance. Logistic regression was used to analyze the association of ACH loss with serum E2 and HT use.
In cross-sectional analyses, no association was found of serum E2 with whole-mouth mean or worst-site ACH. However, history of HT use was associated with ACH. Women who had never used HT had more ACH loss assessed as a whole-mouth mean ACH (P = 0.01) and as worst-site ACH loss (P = 0.03). In logistic regression analyses of baseline ACH loss severity, HT never-users had two-fold higher odds of being in the severe ACH loss category compared to ever-users (odds ratio, 2.00; 95% confidence interval, 1.11 to 3.62). No association was observed of 5-year change in ACH with baseline serum E2 or HT use.
Although this study did not detect an association with current serum E2 level and ACH, HT use was found to be associated with less ACH loss in postmenopausal women.
PMCID: PMC4469131  PMID: 25594424
Epidemiology; osteoporosis; periodontitis; women's health
17.  Oral Bisphosphonate Use and Risk of Postmenopausal Endometrial Cancer 
Journal of Clinical Oncology  2015;33(10):1186-1190.
Bisphosphonates are common medications used for the treatment of osteoporosis and are also used to reduce metastases to bone in patients with cancer. Several studies, including the Women's Health Initiative (WHI), have found that use of bisphosphonates is associated with reduced risk of developing breast cancer, but less is known about associations with other common malignancies. This study was aimed at examining the effects of bisphosphonates on the risk of endometrial cancer.
We evaluated the relationship between use of oral bisphosphonates and endometrial cancer risk in a cohort of 89,918 postmenopausal women participating in the WHI. A detailed health interview was conducted at baseline, and bisphosphonate use was ascertained from an inventory of regularly used medications at baseline and over follow-up. All women had an intact uterus at the time of study entry.
During a median follow-up of 12.5 years, 1,123 women were diagnosed with incident invasive endometrial cancer. Ever use of bisphosphonates was associated with reduced endometrial cancer risk (adjusted hazard ratio, 0.80; 95% CI, 0.64 to 1.00; P = .05), with no interactions observed with age, body mass index, or indication for use.
In this large prospective cohort of postmenopausal women, bisphosphonate use was associated with a statistically significant reduction in endometrial cancer risk.
PMCID: PMC4372855  PMID: 25713431
18.  Perceived stress, reproductive hormones, and ovulatory function: a prospective cohort study 
Epidemiology (Cambridge, Mass.)  2015;26(2):177-184.
Stress has been shown to suppress ovulation in experimental models, but its effect on human reproduction at the population level is unclear.
Healthy women (n=259), aged 18–44 years from Western New York, were followed for two menstrual cycles (2005–2007). Women completed daily perceived stress assessments, a 4-item Perceived Stress Scale (PSS-4) up to four times each cycle, and a 14-item PSS at baseline. Mixed model analyses were used to assess effects of stress on log reproductive hormone concentrations and sporadic anovulation.
High versus low daily stress was associated with lower estradiol (-9.5%; 95% confidence interval (CI)= -15.6% to -3.0%), free estradiol (-10.4% [-16.5% to -3.9%]), and LH (-14.8% = [-21.3% to -7.7%]), and higher FSH (6.2% [2.0% to 10.5%]) after adjusting for age, race, percent body fat, depression score, and time-varying hormones and vigorous exercise. High versus low daily stress was also associated with lower luteal progesterone (-10.4% [-19.7% to -0.10%]) and higher odds of anovulation (adjusted OR = 2.2 [95% CI=1.0 to 4.7]). For each unit increase in daily stress level, women had a 70% higher odds of an anovulatory episode (OR=1.7 [1.1 to 2.4]). Similar but attenuated results were found for the association between the PSS-4 and reproductive hormones, while null findings were found for the baseline PSS.
Daily perceived stress does appear to interfere with menstrual cycle function among women with no known reproductive disorders, warranting further research to explore potential population-level impacts and causal biologic mechanisms.
PMCID: PMC4315337  PMID: 25643098
19.  The effect of a very short interpregnancy interval and pregnancy outcomes following a previous pregnancy loss 
American journal of obstetrics and gynecology  2014;212(3):375.e1-375.e11.
We sought to assess the relationship between a short interpregnancy interval (IPI) following a pregnancy loss and subsequent live birth and pregnancy outcomes.
Study Design
A secondary analysis of women enrolled in the Effects of Aspirin in Gestation and Reproduction trial with an hCG-positive pregnancy test and whose last reproductive outcome was a loss were included in this analysis (n=677). IPI was defined as the time between last pregnancy loss and last menstrual period of the current pregnancy and categorized by 3-month intervals. Pregnancy outcomes include live birth, pregnancy loss, and any pregnancy complications. These were compared between IPI groups using multivariate relative risk estimation by Poisson regression.
Demographic characteristics were similar between IPI groups. The mean gestational age of prior pregnancy loss was 8.6 ± 2.8 weeks. The overall live birth rate was 76.5%, with similar live birth rates between those with IPI ≤ 3 months as compared to IPI > 3 months, aRR=1.07 (95% CI 0.98–1.16). Rates were also similar for peri-implantation loss (aRR=0.95; 95% CI 0.51–1.80), clinically confirmed loss, (aRR=0.75; 95% CI 0.51–1.10), and any pregnancy complication (aRR=0.88; 95% CI 0.71–1.09) for those with IPI ≤ 3 months as compared to IPI > 3 months.
Live birth rates and adverse pregnancy outcomes, including pregnancy loss, were not associated with a very short IPI after a prior pregnancy loss. The traditional recommendation to wait at least 3 months after a pregnancy loss before attempting a new pregnancy may not be warranted.
PMCID: PMC4346440  PMID: 25246378
interpregnancy interval; miscarriage; pregnancy loss; pregnancy outcomes; spontaneous abortion
20.  The Association between Dietary Inflammatory Index and Risk of Colorectal Cancer among Postmenopausal Women: Results from the Women’s Health Initiative 
Cancer causes & control : CCC  2014;26(3):399-408.
Inflammation is a process central to carcinogenesis, and in particular to colorectal cancer (CRC). Previously, we developed a dietary inflammatory index (DII) from extensive literature review to assess the inflammatory potential of diet. In the current study, we utilized this novel index in the Women’s Health Initiative (WHI) to prospectively evaluate its association with risk of CRC in postmenopausal women.
The DII was calculated from baseline food frequency questionnaires administered to 152,536 women aged 50–79 years without CRC at baseline between 1993 and 1998 and followed through September 30, 2010. Incident CRC cases were ascertained through a central physician adjudication process. Multiple covariate-adjusted Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) for colorectal, colon (proximal/distal locations), and rectal cancer risk, by DII quintiles(Q).
During an average 11.3 years of follow-up, a total of 1,920 cases of colorectal cancer (1,559 colon and 361 rectal) were identified. Higher DII scores (representing a more pro-inflammatory diet) were associated with an increased incidence of colorectal cancer (HRQ5-Q1, 1.22; 95% CI, 1.05, 1.43; Ptrend=0.02) and colon cancer, specifically proximal colon cancer (HRQ5-Q1, 1.35; 95% CI, 1.05, 1.67; Ptrend=0.01) but not distal colon cancer (HRQ5-Q1, 0.84; 95% CI, 0.61, 1.18; Ptrend=0.63) or rectal cancer (HRQ5-Q1, 1.20; 95% CI, 0.84, 1.72; Ptrend=0.65).
Consumption of pro-inflammatory diets is associated with an increased risk of CRC, especially cancers located in the proximal colon. The absence of a significant association for distal colon cancer and rectal cancer may be due to the small number of incident cases for these sites. Interventions that may reduce the inflammatory potential of the diet are warranted to test our findings, thus provide more information for colon cancer prevention.
PMCID: PMC4334706  PMID: 25549833
dietary inflammatory index; colorectal cancer; Women’s Health Initiative
21.  Vitamin D levels and menopause-related symptoms 
Menopause (New York, N.Y.)  2014;21(11):1197-1203.
To determine whether vitamin D levels are associated with menopause-related symptoms in older women.
A randomly selected subset of 1,407 women, among 26,104 potentially eligible participants of the Women’s Health Initiative Calcium and Vitamin D (CaD) trial of postmenopausal women aged 51-80 years, had 25-hydroxyvitamin D [25(OH)D] levels measured at the CaD trial baseline visit. Information about menopause-related symptoms at baseline was obtained by questionnaire and included overall number of symptoms and composite measures of sleep disturbance, emotional well-being, and energy/fatigue, as well as individual symptoms. After exclusions for missing data, 530 women [mean age 66.2 years (SD 6.8)] were included in these analyses.
There were borderline significant associations between 25(OH)D levels and total number of menopausal symptoms (p values ranging from 0.05 to 0.06 for fully adjusted models); however, the effect was clinically insignificant and disappeared with correction for multiple testing. There were no associations between 25(OH)D levels and composite measures of sleep disturbance, emotional well-being, or energy/fatigue (p’s > 0.10 for fully adjusted models).
There was no evidence of a clinically important association between serum 25(OH)D levels and menopause-related symptoms in postmenopausal women.
PMCID: PMC4764124  PMID: 24736200
Vitamin D; menopause; hot flashes; mood; sleep
22.  Kidney biomarkers associated with blood lead, mercury, and cadmium in premenopausal women: a prospective cohort study 
Certain metals are harmful to the kidney and liver at high levels but associations with functional biomarkers at low exposure levels among premenopausal women has not apparently been evaluated. Healthy, regularly menstruating women (n=259) were followed for up to two menstrual cycles with up to 16 visits. Renal and liver biomarkers were measured in serum at each clinic visit. Cadmium (Cd), lead (Pb), and mercury (Hg) were measured in whole blood at baseline. Linear mixed models were adjusted for age, body mass index (BMI), race, average calories, alcohol intake, smoking, and cycle day. Median levels of Cd, Pb, and Hg were 0.31 μg/l, 0.88 μg/dl, and 1.1 μg/l, respectively. One-third of women had diminished glomerular filtration rate (eGFR) (<90 ml/min/1.73m2). Each 2-fold increase in Cd was associated with a negative 4.9% change in blood urea nitrogen (BUN) and bilirubin. Each 2-fold rise in Pb was associated with decreased eGFR and increased creatinine. A 2-fold elevation in Hg was associated with higher protein and reduced alkaline phosphatase. In healthy, predominantly nonsmoking women, low levels of Cd, Pb, and Hg were associated with changes in select biomarkers of kidney and liver function.
PMCID: PMC4246415  PMID: 25424620
cadmium; lead; mercury; liver; kidney; renal; hepatic; women
23.  Depressive Symptoms and Bone Mineral Density among Police Officers in a Northeastern US City 
The purpose of this study was to examine the association between depressive symptoms and bone mineral density (BMD).
Depressive symptoms were measured using the Center for Epidemiologic Studies Depression (CES-D) scale. BMD of total hip, femoral neck, anterio-posterior (AP) spine, wrist, and total body were measured by DXA using standardized procedures. Mean levels of BMD across gender-specific tertiles of CES-D score were obtained using ANOVA and ANCOVA.
Participants included 97 police officers (41 women; 29–64 years). Depressive symptoms were not associated with BMD at any site among men. However among women, mean BMD values decreased across increasing (worsening) tertiles of CES-D for the AP spine (low CES-D=1.22 ± 0.04; medium CES-D=1.05±0.04; high CES-D=1.03±0.04 g/cm2; p=0.035) and for the whole body (low=1.26±0.03; medium=1.20±0.03; high=1.11±0.03 g/cm2; p=0.018) after adjustment.
Higher depressive symptoms were associated with lower BMD among female but not male officers.
PMCID: PMC4681287  PMID: 22980231
depression; bone mineral density; osteoporosis; police officers; CES-D; gender
24.  Depressive symptoms and their relationship with endogenous reproductive hormones and sporadic anovulation in premenopausal women 
Annals of epidemiology  2014;24(12):920-924.
To determine whether depressive symptoms are associated with ovulation or reproductive hormone concentrations in eumenorrheic women without a reported diagnosis of clinical depression.
A prospective cohort of 248 regularly-menstruating women, aged 18–44 years (27.3± 8.2) were evaluated for depressive symptoms at baseline using the 20-item Center for Epidemiological Studies Depression (CES-D) scale and categorized dichotomously (< 16, no depressive symptoms [92%] vs. ≥16, depressive symptoms [8%]). Serum concentrations of estradiol, progesterone, luteinizing hormone, and follicle-stimulating hormone were measured up to 8 times/cycle for up to two menstrual cycles. Linear mixed models estimated associations between depressive symptoms and hormone concentrations while generalized linear mixed models assessed their relationship with sporadic anovulation.
No significant associations were identified between depressive symptoms and reproductive hormone levels (all P > 0.05) or the odds of sporadic anovulation (adjusted OR: 1.1, 95% confidence interval [0.02, 5.0]), after adjusting for age, race, body mass index, perceived stress level, and alcohol consumption.
Despite reported associations between mental health and menstrual cycle dysfunction, depressive symptoms were not associated with reproductive hormone concentrations or sporadic anovulation in this cohort of regularly-menstruating women with no recent (within one year) self-reported history of clinical depression.
PMCID: PMC4355057  PMID: 25453349
depression; depressive symptoms; menstrual cycle; ovulation; reproductive hormones; mental health; women’s health
25.  Sex ratio following preconception low-dose aspirin in women with prior pregnancy loss 
The Journal of Clinical Investigation  2015;125(9):3619-3626.
BACKGROUND. Several lines of evidence suggest that male embryos may have greater vulnerability than female embryos to disordered inflammation; therefore, antiinflammatory drugs, such as low-dose aspirin (LDA), may alter the sex ratio. Here, we assessed the effect of LDA on male live birth and male offspring, incorporating pregnancy losses (n = 56) via genetic assessment, as part of a parallel-design, block-randomized, placebo-controlled trial of preconception LDA.
METHODS. Participants (615 treated with LDA, 613 treated with placebo) ranged in age from 18 to 40 years of age, with 1 to 2 prior pregnancy losses. We estimated the intention-to-treat (ITT) risk ratio (RR) and 95% CI and assessed interaction with baseline high-sensitivity C-reactive protein (hsCRP) serum concentration — a marker of systemic inflammation.
RESULTS. Among the 1,078 women who completed follow-up (535 treated with LDA, 543 treated with placebo), the male live birth ITT RR equaled 1.31 (95% CI: 1.07–1.59). With increasing tertile of hsCRP, the proportion of males at birth decreased in the placebo group, and the effect of LDA on male live birth increased (first tertile: 48% male in LDA vs. 52% in placebo, ITT RR = 0.97, 95% CI: 0.70–1.35; second tertile: 57% male in LDA vs. 43% in placebo, ITT RR = 1.36, 95% CI: 0.98–1.90; third tertile: 53% male in LDA vs. 35% in placebo, ITT RR = 1.70, 95% CI: 1.13–2.57; P interaction = 0.03). Analysis of pregnancy with male offspring yielded similar results.
CONCLUSION. Initiation of LDA prior to conception restored numbers of male live births and pregnancy with male offspring among women with 1 to 2 prior pregnancy losses. Moreover, our data suggest that LDA modulates inflammation that would otherwise reduce the conception or survival of male embryos.
FUNDING. Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health.
PMCID: PMC4588294  PMID: 26280577

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