Untargeted serum metabolomic profiles and breast density in young women.

PURPOSE OF THE STUDY: Breast density is an established risk factor for breast cancer. However, little is known about metabolic influences on breast density phenotypes. We conducted untargeted serum metabolomics analyses to identify metabolic signatures associated with breast density phenotypes among young women. METHODS: In a cross-sectional study of 173 young women aged 25-29 who participated in the Dietary Intervention Study in Children 2006 Follow-up Study, 449 metabolites were measured in fasting serum samples using ultra-high-performance liquid chromatography-tandem mass spectrometry. Multivariable-adjusted mixed-effects linear regression identified metabolites associated with magnetic resonance imaging measured breast density phenotypes: percent dense breast volume (%DBV), absolute dense breast volume (ADBV), and absolute non-dense breast volume (ANDBV). Metabolite results were corrected for multiple comparisons using a false discovery rate adjusted p-value (q). RESULTS: The amino acids valine and leucine were significantly inversely associated with %DBV. For each 1 SD increase in valine and leucine, %DBV decreased by 20.9% (q = 0.02) and 18.4% (q = 0.04), respectively. ANDBV was significantly positively associated with 16 lipid and one amino acid metabolites, whereas no metabolites were associated with ADBV. Metabolite set enrichment analysis also revealed associations of distinct metabolic signatures with %DBV, ADBV, and ANDBV; branched chain amino acids had the strongest inverse association with %DBV (p = 0.002); whereas, diacylglycerols and phospholipids were positively associated with ANDBV (p ≤ 0.002), no significant associations were observed for ADBV. CONCLUSION: Our results suggest an inverse association of branched chain amino acids with %DBV. Larger studies in diverse populations are needed.

The risk of drug overdose death among adults with select types of disabilities in the United States - A longitudinal study using nationally representative data.

BACKGROUND: Disability is associated with increased risk of drug overdose mortality, but previous studies use coarse and inconsistent methods to identify adults with disabilities. This investigation makes use of the U.S. Department of Health and Human Services disability questions to estimate the risk of drug overdose death among U.S. adults using seven established disability categories. METHODS: The longitudinal Mortality Disparities in American Communities study was used to determine disability status among a nationally representative sample of adults age ≥18 in 2008 (n = 3,324,000). Through linkage to the National Death Index, drug overdose deaths were identified through 2019. Adults in mutually-exclusive disability categories (hearing, vision, cognitive, mobility, complex activity, ≥2 limitations) were compared to adults with no reported disabilities using adjusted hazard ratios (aHRs) and controlling for demographic and socioeconomic covariates. RESULTS: The risk of drug overdose death varied considerably by disability type, as adults in some disability categories displayed only marginally significant risk, while adults in other disability categories displayed substantially elevated risk. Compared to non-disabled adults, the risk of drug overdose death was highest among adults with ≥2 limitations (aHR = 3.0, 95% CI = 2.8-3.3), cognitive limitation (aHR = 2.6, 95% CI = 2.3-2.9), mobility limitation (aHR = 2.6, 95% CI = 2.3-2.9), complex activity limitation (aHR = 2.3, 95% CI = 1.8-2.9), hearing limitation (aHR = 1.6, 95% CI = 1.3-1.9), and vision limitation (aHR = 1.3, 95% CI = 1.0-1.7). CONCLUSIONS: The examination of specific disability categories revealed unique associations that were not apparent in previous research. These findings can be used to focus overdose prevention efforts on the populations at greatest risk for drug-related mortality.

Self-Reported Disability Type and Risk of Alcohol-Induced Death - A Longitudinal Study Using Nationally Representative Data.

BACKGROUND: Disability is associated with alcohol misuse and drug overdose death, however, its association with alcohol-induced death remains understudied. OBJECTIVE: To quantify the risk of alcohol-induced death among adults with different types of disabilities in a nationally representative longitudinal sample of US adults. METHODS: Persons with disabilities were identified among participants ages 18 or older in the Mortality Disparities in American Communities (MDAC) study (n = 3,324,000). Baseline data were collected in 2008 and mortality outcomes were ascertained through 2019 using the National Death Index. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were estimated for the association between disability type and alcohol-induced death, controlling for demographic and socioeconomic covariates. RESULTS: During a maximum of 12 years of follow-up, 4000 alcohol-induced deaths occurred in the study population. In descending order, the following disability types displayed the greatest risk of alcohol-induced death (compared to adults without disability): complex activity limitation (aHR = 1.7; 95% CI = 1.3-2.3), vision limitation (aHR = 1.6; 95% CI = 1.2-2.0), mobility limitation (aHR = 1.4; 95% CI = 1.3-1.7), ≥2 limitations (aHR = 1.4; 95% CI = 1.3-1.6), cognitive limitation (aHR = 1.2; 95% CI = 1.0-1.4), and hearing limitation (aHR = 1.0; 95% CI = 0.9-1.3). CONCLUSIONS: The risk of alcohol-induced death varies considerably by disability type. Efforts to prevent alcohol-induced deaths should be tailored to meet the needs of the highest-risk groups, including adults with complex activity (i.e., activities of daily living - "ALDs"), vision, mobility, and ≥2 limitations. Early diagnosis and treatment of alcohol use disorder within these populations, and improved access to educational and occupational opportunities, should be considered as prevention strategies for alcohol-induced deaths.

Alcohol consumption and serum metabolite concentrations in young women.

PURPOSE: Alcohol consumption is an established breast cancer risk factor, though further research is needed to advance our understanding of the mechanism underlying the association. We used global metabolomics profiling to identify serum metabolites and metabolic pathways that could potentially mediate the alcohol-breast cancer association. METHODS: A cross-sectional analysis of reported alcohol consumption and serum metabolite concentrations was conducted among 211 healthy women 25-29 years old who participated in the Dietary Intervention Study in Children 2006 Follow-Up Study (DISC06). Alcohol-metabolite associations were evaluated using multivariable linear mixed-effects regression. RESULTS: Alcohol was significantly (FDR p < 0.05) associated with several serum metabolites after adjustment for diet composition and other potential confounders. The amino acid sarcosine, the omega-3 fatty acid eicosapentaenoate, and the steroid 4-androsten-3beta,17beta-diol monosulfate were positively associated with alcohol intake, while the gamma-tocopherol metabolite gamma-carboxyethyl hydroxychroman (CEHC) was inversely associated. Positive associations of alcohol with 2-methylcitrate and 4-androsten-3beta,17beta-diol disulfate were borderline significant (FDR p < 0.10). Metabolite set enrichment analysis identified steroids and the glycine pathway as having more members associated with alcohol consumption than expected by chance. CONCLUSIONS: Most of the metabolites associated with alcohol in the current analysis participate in pathways hypothesized to mediate the alcohol-breast cancer association including hormonal, one-carbon metabolism, and oxidative stress pathways, but they could also affect risk via alternative pathways. Independent replication of alcohol-metabolite associations and prospective evaluation of confirmed associations with breast cancer risk are needed.

The Association Between Perceived Stress and Hypertension Among Asian Americans: Does Social Support and Social Network Make a Difference?

Prior research suggests that stress plays role in the etiology and progression of hypertension. To lend a more accurate depiction of the underlying mechanisms between stress and hypertension, this study aims to assess the associations between perceived stress and hypertension across varying levels of social support and social network among Asian Americans. We conducted a cross-sectional study using data on 530 Chinese, Korean and Vietnamese Americans recruited from a liver cancer prevention program in the Washington D.C.-Baltimore metropolitan area. Hypertension prevalence was 29.1%. Individuals with high perceived stress were 61% more likely to have hypertension compared to those with low levels of perceived stress (odds ratio 1.61, 95% confidence interval 1.15, 2.46). There was no evidence that social support and social network acted as effect modifiers. Social support had a direct beneficial effect on hypertension, irrespective of whether individuals were under stress. The relationship between perceived stress and hypertension was modified by gender and ethnicity whereby a significant positive association was only observed among male or Chinese participants. Our study highlights the importance of understanding the associations between stress, social support, and hypertension among Asian American subgroups. Findings from the study can be used to develop future stress management interventions, and incorporate culturally and linguistically appropriate strategies into community outreach and education to decrease hypertension risk within the Asian population.

Validation of a Human Papillomavirus (HPV) DNA Cervical Screening Test That Provides Expanded HPV Typing.

As cervical cancer screening shifts from cytology to human papillomavirus (HPV) testing, a major question is the clinical value of identifying individual HPV types. We aimed to validate Onclarity (Becton Dickinson Diagnostics, Sparks, MD), a nine-channel HPV test recently approved by the FDA, by assessing (i) the association of Onclarity types/channels with precancer/cancer; (ii) HPV type/channel agreement between the results of Onclarity and cobas (Roche Molecular Systems, Pleasanton, CA), another FDA-approved test; and (iii) Onclarity typing for all types/channels compared to typing results from a research assay (linear array [LA]; Roche). We compared Onclarity to histopathology, cobas, and LA. We tested a stratified random sample (n = 9,701) of discarded routine clinical specimens that had tested positive by Hybrid Capture 2 (HC2; Qiagen, Germantown, MD). A subset had already been tested by cobas and LA (n = 1,965). Cervical histopathology was ascertained from electronic health records. Hierarchical Onclarity channels showed a significant linear association with histological severity. Onclarity and cobas had excellent agreement on partial typing of HPV16, HPV18, and the other 12 types as a pool (sample-weighted kappa value of 0.83); cobas was slightly more sensitive for HPV18 and slightly less sensitive for the pooled high-risk types. Typing by Onclarity showed excellent agreement with types and groups of types identified by LA (kappa values from 0.80 for HPV39/68/35 to 0.97 for HPV16). Onclarity typing results corresponded well to histopathology and to an already validated HPV DNA test and could provide additional clinical typing if such discrimination is determined to be clinically desirable.

Epidemiologic Risk Factors for In Situ and Invasive Breast Cancers Among Postmenopausal Women in the National Institutes of Health-AARP Diet and Health Study.

Comparing risk factor associations between invasive breast cancers and possible precursors may further our understanding of factors related to initiation versus progression. Accordingly, among 190,325 postmenopausal participants in the National Institutes of Health-AARP Diet and Health Study (1995-2011), we compared the association between risk factors and incident ductal carcinoma in situ (DCIS; n = 1,453) with that of risk factors and invasive ductal carcinomas (n = 7,525); in addition, we compared the association between risk factors and lobular carcinoma in situ (LCIS; n = 186) with that of risk factors and invasive lobular carcinomas (n = 1,191). Hazard ratios and 95% confidence intervals were estimated from multivariable Cox proportional hazards regression models. We used case-only multivariable logistic regression to test for heterogeneity in associations. Younger age at menopause was associated with a higher risk of DCIS but lower risks of LCIS and invasive ductal carcinomas (P for heterogeneity < 0.01). Prior breast biopsy was more strongly associated with the risk of LCIS than the risk of DCIS (P for heterogeneity = 0.04). Increased risks associated with use of menopausal hormone therapy were stronger for LCIS than DCIS (P for heterogeneity = 0.03) and invasive lobular carcinomas (P for heterogeneity < 0.01). Associations were similar for race, age at menarche, age at first birth, family history, alcohol consumption, and smoking status, which suggests that most risk factor associations are similar for in situ and invasive cancers and may influence early stages of tumorigenesis. The differential associations observed for various factors may provide important clues for understanding the etiology of certain breast cancers.

Estrogen metabolism and breast cancer risk among postmenopausal women: a case-cohort study within B~FIT.

Although elevated circulating estrogens are associated with increased postmenopausal breast cancer risk, less is known regarding the role of estrogen metabolism in breast carcinogenesis. We conducted a case-cohort study within the Breast and Bone Follow-up to the Fracture Intervention Trial to assess serum estrogens and estrogen metabolites (EMs) in 407 incident breast cancer cases diagnosed during follow-up and a subcohort of 496 women. In 1992-93, women completed a baseline questionnaire and provided blood samples. Hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for geography and trial participation status, were estimated using Cox proportional hazard regression. Serum concentrations of EMs were measured by liquid chromatography-tandem mass spectrometry. EMs (quintiles, Q) were analyzed individually, as metabolic pathways (C-2, -4 or -16) and as ratios. Elevated circulating estradiol was associated with increased breast cancer risk (HRQ5vsQ1 = 1.86; 95% CI: 1.19-2.90; P trend = 0.04). An elevated ratio of the 2-hydroxylation pathway (HRQ5vsQ1 = 0.69; 95% CI: 0.46-1.05; P trend = 0.01) and 4-hydroxylation pathway (HRQ5vsQ1 = 0.61; 95% CI: 0.40-0.93; P trend = 0.004) to parent estrogens (estradiol and estrone) was inversely associated with risk. A higher ratio of the 2/16-hydroxylation pathways was associated with reduced risk (HRQ5vsQ1 = 0.60; 95% CI: 0.40-0.90; P trend = 0.002). Increased 2- or 4-hydroxylation of parent estrogens may lower risk of postmenopausal breast cancer. Analyses of metabolic pathways may help elucidate the role of estrogen metabolism in breast carcinogenesis.

Breast cancer risk in older women: results from the NIH-AARP Diet and Health Study.

BACKGROUND: Divergent risk factors exist for premenopausal and postmenopausal breast cancers, but it is unclear whether differences by age exist among postmenopausal women. METHODS: We examined relationships among 190,872 postmenopausal women, ages 50-71 years recruited during 1995-1996 for the NIH-AARP Diet and Health Study, in whom 7,384 incident invasive breast carcinomas were identified through 2006. Multivariable Cox regression hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for breast cancer risk factors by age (50-59, 60-69, ≥70 years). RESULTS: The only factor showing significant statistical heterogeneity by age (p(het) = 0.001) was menopausal hormone therapy duration, but trends were apparent across all ages and the strongest association prevailed among women 60-69 years. Although other risk factors did not show statistically significant heterogeneity by age, we did observe attenuated relations for parity and late age at first birth among older women [e.g., HR for age at first birth ≥30 vs. 20-24 = 1.62 (95% CI 1.23-2.14) for women 50-59 years vs. 1.12 (0.96-1.31) for ≥70 years]. In contrast, risk estimates associated with alcohol consumption and BMI tended to be slightly stronger among the oldest subjects [e.g., HR for BMI ≥35 vs. 18.5-24.9 = 1.24 (95% CI 0.97-1.58) for 50-59 years vs. 1.46 (1.26-1.70) for ≥70 years]. These differences were somewhat more pronounced for estrogen receptor positive and ductal cancers, tumors predominating among older women. Breast cancer family history, physical activity, and previous breast biopsies did not show divergent associations by age. CONCLUSION: Although breast cancer risk factor differences among older women were not large, they may merit further consideration with respect to individualized risk prediction.

Risk factors for specific histopathological types of postmenopausal breast cancer in the NIH-AARP Diet and Health Study.

Risk factor associations for rare breast cancer variants are often imprecise, obscuring differences between tumor types. To clarify differences, we examined risk factors for 5 histological types of breast cancer in the National Institutes of Health-AARP Diet and Health Study. Risk factor information was self-reported. We followed 192,076 postmenopausal women aged 50-71 years from 1995-1996 through 2006. During that time period, 5,334 ductal, 836 lobular, 639 mixed ductal-lobular, 216 mucinous, and 132 tubular breast cancers were diagnosed. Hazard ratios and 95% confidence intervals were estimated using Cox proportional hazards regression. Heterogeneity was evaluated using case-only logistic regression. The strongest differences were for menopausal hormone therapy (Pheterogeneity < 0.01) and age at first birth (Pheterogeneity < 0.01). Risk of tubular cancer in relation to current menopausal hormone therapy (for current use vs. never use, hazard ratio (HR) = 4.39, 95% confidence interval (CI): 2.77, 6.96) was several times stronger than risk of other histological types (range of HRs, 1.39-1.75). Older age at first birth was unassociated with risk of mucinous (for ≥30 years vs. 20-24 years, HR = 0.62, 95% CI: 0.27, 1.42) or tubular (HR = 1.08, 95% CI: 0.51, 2.29) tumors, in contrast to clear positive associations with lobular (HR = 1.82, 95% CI: 1.39, 2.37) and mixed ductal-lobular (HR = 1.87, 95% CI: 1.39, 2.51) tumors. Differing associations for hormonal factors and mucinous and tubular cancers suggest etiologies distinct from those of common breast cancers.

Drug and alcohol use disorders among adults with select disabilities: The national survey on drug use and health.

BACKGROUND: Deaths caused by drugs and alcohol have reached high levels in the US, and prior research shows a consistent association between disability status and substance misuse. OBJECTIVE: Using national data, this study quantifies the association between disability status and drug and alcohol use disorders among US adults. METHODS: The most recent pre-pandemic years (2018-2019) of the cross-sectional National Survey on Drug Use and Health (n = 83,439) were used to examine how the presence of any disability, and specific disabilities, were associated with past year drug and alcohol use disorders. Logistic regression was used to estimate adjusted odds ratios (aORs) controlling for potential sociodemographic confounders. RESULTS: Adults with any disability had increased odds of drug (aOR = 2.7; 95% CI = 2.5-3.0), and alcohol use disorder (aOR = 1.8; 95% CI = 1.6-2.0), compared to adults without disability. Examining specific types of disabilities, adults with cognitive limitations only had increased odds of drug (aOR = 3.1; 95% CI = 2.6-3.6), and alcohol use disorders (aOR = 2.2; 95% CI = 1.9-2.5), compared to adults without disability. Smaller associations were observed between vision and complex activity limitations and drug use disorder. Adults with two or more types of limitations had increased odds of drug (aOR = 3.7; 95% CI = 3.3-4.3), and alcohol use disorders (aOR = 2.3; 95% CI = 2.0-2.6). CONCLUSIONS: The presence of disability, especially cognitive limitation only, or two or more types of limitations, is associated with elevated odds of drug and alcohol use disorder among US adults. Additional research should examine the temporal relationship between and mechanisms linking disability and substance misuse.

A comparison of associations of body mass index and dual-energy x-ray absorptiometry measured percentage fat and total fat with global serum metabolites in young women.

OBJECTIVE: Body mass index (BMI) does not directly measure adiposity, whereas dual-energy x-ray absorptiometry (DXA) provides valid direct estimates of adiposity. Therefore, this study evaluated usefulness of BMI as a measure of adiposity in serum metabolomics studies. METHODS: A cross-sectional analysis was conducted of 202 women aged 25 to 29 years in the Dietary Intervention Study in Children Follow-Up Study. Heights and weights were measured, and body composition was quantified using clinical DXA protocols. Serum metabolomic profiling was performed by liquid chromatography-tandem mass spectrometry. Partial correlations of BMI, percentage fat (%FAT), and total fat (TOTFAT) with log transformed serum metabolites were calculated. RESULTS: There was significant overlap in the 93 metabolites that correlated with BMI, %FAT, and/or TOTFAT; 9 differently correlated with BMI and %FAT, whereas 15 differently correlated with BMI and TOTFAT. Even for these metabolites, absolute differences were modest. Metabolite set enrichment analysis identified diacylglycerol and sphingolipid metabolism as overrepresented among metabolites significantly correlated with all three measures of adiposity. CONCLUSIONS: BMI can be a good proxy for DXA measured %FAT and TOTFAT in descriptive metabolomic studies of healthy, young White women. Larger studies in more diverse populations are needed to endorse more generalized conclusions.

Accelerometer-based measures of active and sedentary behavior in relation to breast cancer risk.

Epidemiologic studies suggest that physical activity reduces breast cancer risk by 20-40 %. However, prior studies have relied on measures of self-report. In a population-based case-control study, we evaluated accelerometer measures of active and sedentary behavior in relation to breast cancer among 996 incident cases and 1,164 controls, residents of Warsaw, Poland (2000-2003), who were asked to wear an accelerometer for 7 days. Accelerometer values were averaged across valid wear days and summarized as overall activity (counts [ct]/min/day); in minutes spent in sedentary behavior (0-99 ct/min); and light (100-759 ct/min) and moderate-to-vigorous (760+ ct/min) activity. Odds ratios (OR) and 95 % confidence intervals (CI) were estimated using unconditional logistic regression. Comparing women in the highest quartile (Q4) of activity to those in the lowest (Q1), time spent in moderate-to-vigorous activity was inversely associated with breast cancer odds after adjustment for known risk factors, sedentary behavior and wear time (OR(Q4vsQ1) 0.39, 95 % CI 0.27-0.56; P-trend < .0001). Sedentary time was positively associated with breast cancer, independent of moderate-to-vigorous activity (OR(Q4vsQ1) 1.81, 95 % CI 1.26-2.60; P-trend = 0.001). Light activity was not associated with breast cancer in multivariable models including both moderate-to-vigorous activity and sedentary behavior. Our findings support an inverse association between accelerometer-based measures of moderate-to-vigorous physical activity and breast cancer while also suggesting potential increases in risk with sedentary time.

Racial and Sex Differences between Urinary Phthalates and Metabolic Syndrome among U.S. Adults: NHANES 2005-2014.

Phthalates, plasticizers ubiquitous in household and personal care products, have been associated with metabolic disturbances. Despite the noted racial differences in phthalate exposure and the prevalence of metabolic syndrome (MetS), it remains unclear whether associations between phthalate metabolites and MetS vary by race and sex. A cross-sectional analysis was conducted among 10,017 adults from the National Health and Nutritional Examination Survey (2005-2014). Prevalence odds ratios (POR) and 95% confidence intervals (CIs) were estimated for the association between 11 urinary phthalate metabolites and MetS using weighted sex and race stratified multivariable logistic regression. Higher MCOP levels were significantly associated with increased odds of MetS among women but not men, and only remained significant among White women (POR Q4 vs. Q1 = 1.68, 95% CI: 1.24, 2.29; p-trend = 0.001). Similarly, the inverse association observed with MEHP among women, persisted among White women only (POR Q4 vs. Q1 = 0.53, 95% CI: 0.35, 0.80; p-trend = 0.003). However, ΣDEHP metabolites were associated with increased odds of MetS only among men, and this finding was limited to White men (POR Q4 vs. Q1 = 1.54, 95% CI: 1.01, 2.35; p-trend = 0.06). Among Black men, an inverse association was observed with higher MEP levels (POR Q4 vs. Q1 = 0.43, 95% CI: 0.24, 0.77; p-trend = 0.01). The findings suggest differential associations between phthalate metabolites and MetS by sex and race/ethnicity.

A Longitudinal Assessment of Parental Caregiving and Blood Pressure Trajectories: Findings from the China Health and Nutrition Survey for Women 2000-2011.

BACKGROUND: Few studies have investigated the consequences of caregiving on the objectively measured physiological health outcomes in China. This study used population-based longitudinal data to examine the association between parental caregiving and blood pressure among Chinese women. METHOD: This is a retrospective analysis of 2586 women using five waves of data from the Ever-Married Women Survey component of the China Health and Nutrition Survey (2000, 2004, 2006, 2009, and 2011). We applied growth curve models to examine trajectories of systolic blood pressure (SBP) and diastolic blood pressure (DBP) associated with parental caregiving among women in China. RESULTS: In multivariable analyses of blood pressure trajectories adjusting for potential confounders, parental caregivers had higher systolic (ß-coefficient (ß) = 1.16; p ≤ 0.01) and diastolic blood pressure (ß = 0.75; p ≤ 0.01) compared with non-caregivers across multiple waves. Caregivers and non-caregivers had similar levels of systolic blood pressure at baseline, but caregivers exhibited relatively higher growth rate over time. Diastolic blood pressure was much higher among caregivers at the baseline measure, and across time relative to non-caregivers. Moreover, low-intensity but not high-intensity caregivers showed higher growth rate compared with non-caregivers for both SBP and DBP. DISCUSSION: Our results demonstrate the negative cardiovascular consequences of parental caregiving among Chinese women. Findings from the study can be used to develop future stress management interventions to decrease hypertension risk within women who provide care to their parents.

Endogenous Progestogens and Colorectal Cancer Risk among Postmenopausal Women.

BACKGROUND: The role of progestogens in colorectal cancer development is poorly characterized. To address this, our group developed a highly sensitive assay to measure concentrations of seven markers of endogenous progestogen metabolism among postmenopausal women. METHODS: The markers were measured in baseline serum collected from postmenopausal women in a case-cohort study within the breast and bone follow-up to the fracture intervention trial (B∼FIT). We followed women not using exogenous hormones at baseline (1992-1993) for up to 12 years: 187 women with incident colorectal cancer diagnosed during follow-up and a subcohort of 495 women selected on strata of age and clinical center. We used adjusted Cox regression models with robust variance to estimate risk for colorectal cancer [hazard ratios (HR), 95% confidence intervals (CI)]. RESULTS: High concentrations of pregnenolone and progesterone were not associated with colorectal cancer [quintile(Q)5 versus Q1: pregnenolone HR, 0.71, 95% CI, 0.40-1.25; progesterone HR, 1.25; 95% CI, 0.71-2.22]. A trend of increasing risk was suggested, but statistically imprecise across quintiles of 17-hydroxypregnenolone (Q2 to Q5 HRs, 0.75-1.44; P trend, 0.06). CONCLUSIONS: We used sensitive and reliable assays to measure multiple circulating markers of progestogen metabolism. Progestogens were generally unassociated with colorectal cancer risk in postmenopausal women. IMPACT: Our findings are consistent with most prior research on circulating endogenous sex hormones, which taken together suggest that sex hormones may not be major drivers of colorectal carcinogenesis in postmenopausal women.

Association of Endogenous Pregnenolone, Progesterone, and Related Metabolites with Risk of Endometrial and Ovarian Cancers in Postmenopausal Women: The B∼FIT Cohort.

BACKGROUND: Postmenopausal pregnenolone and/or progesterone levels in relation to endometrial and ovarian cancer risks have been infrequently evaluated. To address this, we utilized a sensitive and reliable assay to quantify prediagnostic levels of seven markers related to endogenous hormone metabolism. METHODS: Hormones were quantified in baseline serum collected from postmenopausal women in a cohort study nested within the Breast and Bone Follow-up to the Fracture Intervention Trial (B∼FIT). Women using exogenous hormones at baseline (1992-1993) were excluded. Incident endometrial (n = 65) and ovarian (n = 67) cancers were diagnosed during 12 follow-up years and compared with a subcohort of 345 women (no hysterectomy) and 413 women (no oophorectomy), respectively. Cox models with robust variance were used to estimate cancer risk. RESULTS: Circulating progesterone levels were not associated with endometrial [tertile (T)3 vs. T1 HR (95% confidence interval): 1.87 (0.85-4.11); P trend = 0.17] or ovarian cancer risk [1.16 (0.58-2.33); 0.73]. Increasing levels of the progesterone-to-estradiol ratio were inversely associated with endometrial cancer risk [T3 vs. T1: 0.29 (0.09-0.95); 0.03]. Increasing levels of 17-hydroxypregnenolone were inversely associated with endometrial cancer risk [0.40 (0.18-0.91); 0.03] and positively associated with ovarian cancer risk [3.11 (1.39-6.93); 0.01]. CONCLUSIONS: Using sensitive and reliable assays, this study provides novel data that endogenous progesterone levels are not strongly associated with incident endometrial or ovarian cancer risks. 17-hydroxypregnenolone was positively associated with ovarian cancer and inversely associated with endometrial cancer. IMPACT: While our results require replication in large studies, they provide further support of the hormonal etiology of endometrial and ovarian cancers.

Social Relationships and Functional Impairment in Aging Cancer Survivors: A Longitudinal Social Network Study.

BACKGROUND AND OBJECTIVES: The intersection of cancer, treatment, and aging accelerates functional decline. Social networks, through the provision of social support and resources, may slow the progression of functional deterioration. Socioemotional selectivity theory posits that aging and major life events, like cancer, cause an intentional social network pruning to procure and maintain emotionally fulfilling bonds, while shedding weaker, less supportive relationships. However, it is relatively unknown if such network changes impact functional impairment in cancer survivors. This study examined the relationships between changes in the egocentric social network and functional impairment in older adult cancer survivors and a similarly aged group without cancer (older adults). RESEARCH DESIGN AND METHODS: Data were analyzed from 1,481 community dwelling older adults (n = 201 cancer survivors) aged 57-85 years, from Waves 1 and 2 (2005-2006 and 2010-2011) of the National Social Life, Health and Aging Project. Associations were analyzed with multiple logistic regression. RESULTS: Cancer survivors and older adults reported similar levels of functional impairment and social network change. Adding 2 new relationships exhibited protective effects against functional impairment, irrespective of cancer status (odds ratio [OR]: 0.64, 95% confidence interval [CI]: 0.41-0.99). Declines in frequent contact were associated with higher odds of functional impairment among cancer survivors (OR: 1.92, 95% CI: 1.15-3.20). Social network components were not significantly associated with functional impairment in older adults. DISCUSSION AND IMPLICATIONS: Adding new relationships may reduce disability in older adults and increasing network contact may help cancer survivors remain independent. Social network interventions may improve quality of life for older adults.

Association of Circulating Progesterone With Breast Cancer Risk Among Postmenopausal Women.

Importance: The role of endogenous progesterone in the development of breast cancer remains largely unexplored to date, primarily owing to assay sensitivity limitations and low progesterone concentrations in postmenopausal women. Recently identified progesterone metabolites may provide insights as experimental data suggest that 5α-dihydroprogesterone (5αP) concentrations reflect cancer-promoting properties and 3α-dihydroprogesterone (3αHP) concentrations reflect cancer-inhibiting properties. Objective: To evaluate the association between circulating progesterone and progesterone metabolite levels and breast cancer risk. Design, Setting, and Participants: Using a sensitive liquid chromatography-tandem mass spectrometry assay, prediagnostic serum levels of progesterone and progesterone metabolites were quantified in a case-cohort study nested within the Breast and Bone Follow-up to the Fracture Intervention Trial (n = 15 595). Participation was limited to women not receiving exogenous hormone therapy at the time of blood sampling (1992-1993). Incident breast cancer cases (n = 405) were diagnosed during 12 follow-up years and a subcohort of 495 postmenopausal women were randomly selected within 10-year age and clinical center strata. Progesterone assays were completed in July 2017; subsequent data analyses were conducted between July 15, 2017, and December 20, 2018. Exposures: Circulating concentrations of pregnenolone, progesterone, and their major metabolites. Main Outcomes and Measures: Development of breast cancer, with hazard ratios (HRs) and 95% CIs was estimated using Cox proportional hazards regression adjusted for key confounders, including estradiol. Evaluation of hormone ratios and effect modification were planned a priori. Results: The present study included 405 incident breast cancer cases and a subcohort of 495 postmenopausal women; the mean (SD) age at the time of the blood draw was 67.2 (6.2) years. Progesterone concentrations were a mean (SD) of 4.6 (1.7) ng/dL. Women with higher circulating progesterone levels were at an increased risk for breast cancer per SD increase in progesterone levels (HR, 1.16; 95% CI, 1.00-1.35; P = .048). The association with progesterone was linear in a 5-knot spline and stronger for invasive breast cancers (n = 267) (HR, 1.24; 95% CI, 1.07-1.43; P = .004). Among women in the lowest quintile (Q1) of circulating estradiol (<6.30 pg/mL) elevated progesterone concentrations were associated with reduced breast cancer risk per SD increase in progesterone levels (HR, 0.38; 95% CI, 0.15-0.95; P = .04) and increased risk among women in higher quintiles of estradiol (Q2-Q5; ≥6.30 pg/mL) (HR, 1.18; 95% CI, 1.04-1.35; P = .01; P = .04 for interaction). Conclusions and Relevance: In this case-cohort study of postmenopausal women, elevated circulating progesterone levels were associated with a 16% increase in the risk of breast cancer. Additional research should be undertaken to assess how postmenopausal breast cancer risk is associated with both endogenous progesterone and progesterone metabolites and their interactions with estradiol.

Parental caregiving trajectories and Metabolic Syndrome: A longitudinal study among Chinese women.

Caregiving stress may play a role in the pathogenesis of Metabolic Syndrome (MetS). However, few studies have investigated the consequences of caregiving on this objectively measured health outcome. This study used population based longitudinal data to examine the causal relationship between caregiving trajectory and MetS among Chinese women. This is a retrospective analysis of 741 women using three waves of data from the Ever-Married Women Survey component of the China Health and Nutrition Survey (2004, 2006, and 2009). Group-based trajectory analysis was used to examine the caregiving trajectories among women in China. Three caregiving trajectories were identified. In multivariate analyses adjusting for potential covariates, 'rising to high-intense' caregivers (Odds Ratio (OR) = 3.78; 95% Confidence Interval (CI): 1.10, 12.93) and 'stable low-intense' caregivers (OR = 2.07; 95% CI: 1.09, 3.92) were associated with higher risk of MetS compared with non-caregivers. Moreover, caregivers who provided 'stable low-intense' parental care were found to be associated with hypertension, high glucose and high triglycerides than those awho did not provide caregiving for their parents. Our results demonstrate that the caregiving trajectories were significantly associated with the risk of MetS. Findings from the study can be used to develop future stress management interventions to decrease MetS risk among women who provide care to their parents.