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PurposeOsteoblasts and their precursors support hematopoiesis in the bone marrow. We hypothesized that declines in Hgb levels are associated with bone mineral density (BMD).MethodsThe Cardiovascular Health Study is a prospective longitudinal study that enrolled 5888 community-dwelling adults aged >65 years and measured hemoglobin twice, in 1989-90 and 1992-93, as well as BMD by dual-energy X-ray absorptiometry (DXA) in 1994-95. In a subset of 1513 men and women with a Hgb in 1992-93 and BMD, we used linear regression to estimate associations of Hgb (per standard deviation (SD)) with total hip (TH), lumbar spine (LS) and total body (TB) BMD, and used Poisson regression to estimate associations of anemia (in 1992-93; Hgb

ObjectiveTo evaluate factors associated with incident self-reported vaginal dryness and the consequences of this symptom across the menopausal transition in a multiracial/ethnic cohort of community-dwelling women.MethodsWe analyzed questionnaire and biomarker data from baseline and 13 approximately annual visits over 17 years (1996-2013) from 2,435 participants in the Study of Women's Health Across the Nation, a prospective cohort study. We used discrete-time Cox proportional-hazards regression to identify predictors of incident vaginal dryness and to evaluate vaginal dryness as a predictor of pain during intercourse and changes in sexual intercourse frequency.ResultsThe prevalence of vaginal dryness increased from 19.4% among all women at baseline (ages 42-53 years) to 34.0% at the 13th visit (ages 57-69 years). Advancing menopausal stage, surgical menopause, anxiety, and being married were positively associated with developing vaginal dryness, regardless of partnered sexual activity. For women not using hormone therapy, higher concurrent levels of endogenous estradiol were inversely associated (multivariable-adjusted hazard ratio: 0.94 per 0.5 standard deviation increase, 95% confidence interval: 0.91-0.98). Concurrent testosterone levels, concurrent dehydroepiandrosterone sulfate levels, and longitudinal change in any reproductive hormone were not associated with developing vaginal dryness. Both vaginal dryness and lubricant use were associated with subsequent reporting of pain during intercourse, but not with a decline in intercourse frequency.ConclusionIn these longitudinal analyses, our data support many clinical observations about the relationship between vaginal dryness, menopause, and pain during intercourse, and suggest that reporting of vaginal dryness is not related to androgen level or sexual intercourse frequency.

The development of comprehensive measures for tobacco exposure is crucial to specify effects on disease and inform public health policy. In this population-based case-control study, we evaluated the associations between cumulative lifetime cigarette tar exposure and cancers of the lung and upper aerodigestive tract (UADT). The study included 611 incident cases of lung cancer; 601 cases of UADT cancers (oropharyngeal, laryngeal and esophageal cancers); and 1,040 cancer-free controls. We estimated lifetime exposure to cigarette tar based on tar concentrations abstracted from government cigarette records and self-reported smoking histories derived from a standardized questionnaire. We analyzed the associations for cumulative tar exposure with lung and UADT cancer, overall and according to histological subtype. Cumulative tar exposure was highly correlated with pack-years among ever smoking controls (Pearson coefficient = 0.90). The adjusted odds ratio (95% confidence limits) for the estimated effect of about 1 kg increase in tar exposure (approximately the interquartile range in all controls) was 1.61 (1.50, 1.73) for lung cancer and 1.21 (1.13, 1.29) for UADT cancers. In general, tar exposure was more highly associated with small, squamous and large cell lung cancer than adenocarcinoma. With additional adjustment for pack-years, positive associations between tar and lung cancer were evident, particularly for small cell and large cell subtypes. Therefore, incorporating the composition of tobacco carcinogens in lifetime smoking exposure may improve lung cancer risk estimation. This study does not support the claim of a null or inverse association between "low exposure" to tobacco smoke and risk of these cancer types.

BackgroundPeroxisome proliferator-activated receptors (PPARs) are transcriptional factors involved in several biological processes such as inflammation, cancer growth, progression and apoptosis that are important in lung and upper aero-digestive tract (UADT) cancer outcomes. Nonetheless, there are no published studies of the relationship between PPARs gene polymorphisms and survival of patients with lung cancer or UADT cancers.Methods1212 cancer patients (611 lung, 303 oral, 100 pharyngeal, 90 laryngeal, and 108 esophageal) were followed for a median duration of 11 years. We genotyped three potentially functional single nucleotide polymorphisms (SNPs) using Taqman - rs3734254 of the gene PPARD and rs10865710 and rs1801282 of the gene PPARG - and investigated their associations with lung and UADT cancer survival using Cox regression. A semi-Bayesian shrinkage approach was used to reduce the potential for false positive findings when examining multiple associations.ResultsThe variant homozygote CC (vs. TT) of PPARD rs3734254 was inversely associated with mortality of both lung cancer (adjusted hazard ratio [aHR]=0.63, 95% confidence interval [CI]=0.42, 0.96) and UADT cancers (aHR=0.51, 95% CI=0.27, 0.99). Use of the semi-Bayesian shrinkage approach yielded a posterior aHR for lung cancer of 0.66 (95% posterior limits=0.44, 0.98) and a posterior aHR for UADT cancers of 0.58 (95% posterior limits=0.33, 1.03).ConclusionOur findings suggest that lung-cancer patients with the CC variant of PPARD rs3734254 may have a survival advantage over lung-cancer patients with other gene variants.

PurposeAlthough single nucleotide polymorphisms (SNPs) of NBS1 have been associated with susceptibility to lung and upper aerodigestive tract (UADT) cancers, their relations to cancer survival and measures of effect are largely unknown.MethodsUsing follow-up data from 611 lung cancer cases and 601 UADT cancer cases from a population-based case-control study in Los Angeles, we prospectively evaluated associations of tobacco smoking and 5 NBS1 SNPs with all-cause mortality. Mortality data were obtained from the Social Security Death Index. We used Cox regression to estimate adjusted hazard ratios (HR) for main effects and ratios of hazard ratios (RHR) derived from product terms to assess hazard ratio variations by each SNP. Bayesian methods were used to account for multiple comparisons.ResultsWe observed 406 (66 %) deaths in lung cancer cases and 247 (41 %) deaths in UADT cancer cases with median survival of 1.43 and 1.72 years, respectively. Ever tobacco smoking was positively associated with mortality for both cancers. We observed an upward dose-response association between smoking pack-years and mortality in UADT squamous cell carcinoma. The adjusted HR relating smoking to mortality in non-small cell lung cancer (NSCLC) was greater for cases with the GG genotype of NBS1 rs1061302 than for cases with AA/AG genotypes (semi-Bayes adjusted RHR = 1.97; 95 % limits = 1.14, 3.41).ConclusionsA history of tobacco smoking at cancer diagnosis was associated with mortality among patients with lung cancer or UADT squamous cell carcinoma. The HR relating smoking to mortality appeared to vary with the NBS1 rs1061302 genotype among NSCLC cases.

One-carbon metabolism (folate metabolism) is considered important in carcinogenesis because of its involvement in DNA synthesis and biological methylation reactions. We investigated the associations of single nucleotide polymorphisms (SNPs) in folate metabolic pathway and the risk of three GI cancers in a population-based case-control study in Taixing City, China, with 218 esophageal cancer cases, 206 stomach cancer cases, 204 liver cancer cases, and 415 healthy population controls. Study participants were interviewed with a standardized questionnaire, and blood samples were collected after the interviews. We genotyped SNPs of the MTHFR, MTR, MTRR, DNMT1, and ALDH2 genes, using PCR-RFLP, SNPlex, or TaqMan assays. To account for multiple comparisons and reduce the chances of false reports, we employed semi-Bayes (SB) shrinkage analysis. After shrinkage and adjusting for potential confounding factors, we found positive associations between MTHFR rs1801133 and stomach cancer (any T versus C/C, SB odds-ratio [SBOR]: 1.79, 95% posterior limits: 1.18, 2.71) and liver cancer (SBOR: 1.51, 95% posterior limits: 0.98, 2.32). There was an inverse association between DNMT1 rs2228612 and esophageal cancer (any G versus A/A, SBOR: 0.60, 95% posterior limits: 0.39, 0.94). In addition, we detected potential heterogeneity across alcohol drinking status for ORs relating MTRR rs1801394 to esophageal (posterior homogeneity P = 0.005) and stomach cancer (posterior homogeneity P = 0.004), and ORs relating MTR rs1805087 to liver cancer (posterior homogeneity P = 0.021). Among non-alcohol drinkers, the variant allele (allele G) of these two SNPs was inversely associated with the risk of these cancers; while a positive association was observed among ever-alcohol drinkers. Our results suggest that genetic polymorphisms related to one-carbon metabolism may be associated with cancers of the esophagus, stomach, and liver. Heterogeneity across alcohol consumption status of the associations between MTR/MTRR polymorphisms and these cancers indicates potential interactions between alcohol drinking and one-carbon metabolic pathway.

27‐Hydroxycholesterol (27HC) is a purported, novel endogenous SERM. In animal models, 27HC has an anti‐estrogen effect in bone, and 17β‐estradiol mitigates this effect. 27HC in relation to fracture risk has not been investigated in humans. Depending on the level of bioavailable 17β‐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 (WHI‐HT) trials. 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 subcohort included 430 women randomly selected at WHI‐HT baseline, four of whom had a subsequent fracture. Of the 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 to 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. © 2018 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Low circulating levels of sex hormone-binding globulin (SHBG), a putative marker of androgenicity, have been associated with poor glucose control in studies conducted primarily among post-menopausal women. However, the relation of long-term changes in endogenous SHBG to risk of type 2 diabetes (T2DM) in women during and after the menopause transition is unclear. We aimed to assess the longitudinal associations between SHBG levels and risk of developing T2DM among such women. We included 3,060 participants in the Study of Women's Health Across the Nation (SWAN) who were free of diabetes at baseline. SWAN is a longitudinal cohort study with up to 17 years of follow-up. SHBG levels were measured at 13 visits. Participants reported diagnosed diabetes status at all visits, and fasting glucose was measured at 8 follow-up visits. T2DM was defined based on self-report or fasting glucose levels. Women averaged 46 (SD=3) years of age at baseline. 311 women developed T2DM during follow-up. We used complementary log-log-based discrete time survival models anchored at baseline to estimate associations of longitudinal SHBG with incident T2DM. A 5-unit (nM) increase in time-varying SHBG was associated with a hazard ratio (HR) of 0.86 (95% CI 0.82, 0.90), for T2DM, after controlling for race-ethnicity, age, cycle day of blood draw, site, time-varying body mass index (BMI), testosterone, and baseline SHBG level. After adjusting for covariates, women in the lowest ((-92.0 - -1.1 nM/year) vs. highest quartile (0.7 - 42.1 nM/year) for time-invariant average rate of change per year in SHBG levels) had a HR of 5.18 (95% CI: 3.55,7.56). No association was observed for other quartiles in rate of change of SHBG with developing T2DM. Women with low levels of SHBG and/or decreases in SHBG levels were at increased risk to develop T2DM. Clinicians should be aware that declining levels of SHBG in mid-life women is strongly associated with developing T2DM, independent known T2DM risk factors. Disclosure: M.M. Hedderson: None. C. Lee: None. A. Capra: None. J. Lee: None. P. Chang: None. E. Gold: None. E. Waetjen: None. L.A. Habel: None. S.R. El Khoudary: None. Funding: National Institutes of Health [ABSTRACT FROM AUTHOR]