The Association of Inflammatory Factors With Peripheral Neuropathy: The Study of Women's Health Across the Nation.

PURPOSE: Previous work has focused on the role of diabetes in peripheral neuropathy (PN), but PN often occurs before, and independently from, diabetes. This study measures the association of cardiometabolic and inflammatory factor with PN, independent of diabetes. METHODS: Study of Women's Health Across the Nation participants (n = 1910), ages 60 to 73 (mean 65.6) were assessed for PN by symptom questionnaire and monofilament testing at the 15th follow-up visit (V15). Anthropometric measures and biomarkers were measured at study baseline approximately 20 years prior, and C-reactive protein (CRP) and fibrinogen were measured longitudinally. Log-binomial regression was used to model the association between metabolic syndrome (MetS), obesity (≥35 body mass index), CRP, and fibrinogen with PN, adjusting for sociodemographic and health behavior measures. RESULTS: Baseline MetS [prevalence ratio (PR) 1.79, 95% CI (1.45, 2.20)], obesity [PR 2.08 (1.65, 2.61)], median CRP [PR 1.32 per log(mg/dL), (1.20, 1.45)], and mean fibrinogen (PR 1.28 per 100 mg/dL, (1.09, 1.50)] were associated with PN symptoms at V15. After excluding participants with baseline diabetes or obesity, MetS [PR 1.59 (1.17, 2.14)] and CRP [PR 1.19 per log(mg/dL), (1.06, 1.35)] remained statistically significantly associated with PN. There was a negative interaction between MetS and obesity, and the association between these conditions and PN was mediated by CRP. CONCLUSIONS: Cardiometabolic factors and inflammation are significantly associated with PN, independent of diabetes and obesity. CRP mediates the relationship of both obesity and MetS with PN, suggesting an etiological role of inflammation in PN in this sample.

Genome-wide and transcriptome-wide association studies of mammographic density phenotypes reveal novel loci.

BACKGROUND: Mammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identified genetic variants. METHODS: We conducted a genome-wide association study, as well as a transcriptome-wide association study (TWAS), of age- and BMI-adjusted DA, NDA, and PMD in up to 27,900 European-ancestry women from the MODE/BCAC consortia. RESULTS: We identified 28 genome-wide significant loci for MD phenotypes, including nine novel signals (5q11.2, 5q14.1, 5q31.1, 5q33.3, 5q35.1, 7p11.2, 8q24.13, 12p11.2, 16q12.2). Further, 45% of all known breast cancer SNPs were associated with at least one MD phenotype at p < 0.05. TWAS further identified two novel genes (SHOX2 and CRISPLD2) whose genetically predicted expression was significantly associated with MD phenotypes. CONCLUSIONS: Our findings provided novel insight into the genetic background of MD phenotypes, and further demonstrated their shared genetic basis with breast cancer.

Lowered progesterone metabolite excretion and a variable LH excretion pattern are associated with vasomotor symptoms but not negative mood in the early perimenopausal transition: Study of Women's Health Across the Nation.

OBJECTIVE: The menopausal transition is characterized by progressive changes in ovarian function and increasing circulating levels of gonadotropins, with some women having irregular menstrual cycles well before their final menstrual period. These observations indicate a progressive breakdown of the hypothalamic-pituitary-ovarian axis often associated with an increase in menopausal symptoms. Relationships between vasomotor symptoms (VMS) and depressed mood and sleep as well as a bidirectional association between VMS and depressed mood in mid-life women have been reported, but the endocrine foundations and hormone profiles associated with these symptoms have not been well described. Our objective was to determine the relationship between daily urinary hormone profiles and daily logs of affect and VMS during the early perimenopausal transition. STUDY DESIGN: SWAN, the Study of Women's Health Across the Nation, is a large, mutli-ethnic, multisite cohort study of 3302 women aged 42-52 at baseline, designed to examine predictors of health and disease in women as they traversed the menopause. Inclusion criteria were: an intact uterus and at least one ovary present, at least one menstrual period in the previous three months, no use of sex steroid hormones in the previous three months, and not pregnant or lactating. A subset (n = 849) of women aged 43-53 years from all study sites in the first Daily Hormone Study collection were evaluated for this substudy. OUTCOME MEASURES: We measured daily VMS, and urinary hormones: follicle stimulating hormone (FSH), luteinizing hormone (LH), pregnanediol glucuronide (PdG) and estradiol (estrone conjugate, E1C). RESULTS: A variable pattern of LH and negative LH feedback were the hormone patterns most strongly associated with increased VMS. In contrast, no hormone pattern was significantly related to negative mood. CONCLUSION: Fluctuations of LH associated with low progesterone production were associated with VMS but not negative mood, suggesting different endocrine patterns may be related to increased negative mood than to the occurrence of VMS.

Vasomotor symptoms and lipids/lipoprotein subclass metrics in midlife women: Does level of endogenous estradiol matter? The SWAN HDL Ancillary Study.

BACKGROUND: A greater frequency of vasomotor symptoms (VMSs) has been associated with higher low-density lipoprotein cholesterol (LDL-C), but the association with high-density lipoprotein cholesterol (HDL-C) remains unclear. Endogenous estradiol (E2) levels are associated with both VMS and lipid levels and thus may confound such associations. OBJECTIVES: To assess the relationship of VMS frequency with HDL-C, LDL-C, and lipoprotein concentrations (HDL and LDL particles [HDL-P; LDL-P]) and lipoprotein sizes in midlife women and to evaluate whether these associations are explained by E2. METHODS: Participants were from the Study of Women's Health Across the Nation (SWAN) HDL ancillary study who had both nuclear magnetic resonance (NMR) spectroscopy lipoprotein subclass metrics and self-reported frequency of VMS measured 2-5 times over the menopause transition. VMS frequency was categorized into none, 1-5 days (infrequent), or ≥6 days (frequent) within the past 2 weeks. RESULTS: We evaluated 522 women [at baseline: mean age 50.3 (SD: 2.8) years; infrequent VMS: 29.8%, frequent VMS: 16.5%]. Adjusting for potential confounders except E2, frequent VMS was associated with smaller HDL size [ß(SE): -0.06 (0.03); P = .04] and higher concentrations of LDL-C [ß(SE): 3.58 (1.77); P = .04] and intermediate LDL-P [ß(SE): 0.09 (0.05); P = .04] than no VMS. These associations were largely explained by E2, all P's > .05. CONCLUSIONS: Frequent VMSs were associated with smaller HDL size and higher concentrations of LDL-C and intermediate LDL-P. These associations were explained by endogenous E2. Whether treating frequent VMS with exogenous E2 could simultaneously improve lipids/lipoproteins profile should be assessed in future studies.

Stressors, allostatic load, and health outcomes among women hotel housekeepers: A pilot study.

Hotel housekeepers are exposed to stressors at work and outside of work. A minimal amount is known about these workers' pathophysiological responses to those stressors. Allostatic load is a concept increasingly used to understand pathophysiologic manifestations of individuals' bodily response to stress. The purpose of this study was to examine the associations between work and nonwork stressors, allostatic load, and health outcomes among hotel housekeepers. Work and nonwork stressors (e.g., the number of traumatic events, everyday discrimination, and job strain) and health outcomes (e.g., general health status, physical and mental health, and chronic diseases) were measured. Biometric and anthropometric measures and fasting blood specimens were collected. Blood biomarkers included CRP, HbA1c, HDL, and cortisol. Descriptive analyses, correlations, regressions, and t-tests were conducted. Forty-nine women hotel housekeepers participated, with a mean age of 40 years. One-fifth reported high job strain and more than 40% had at least one traumatic event. Chronic conditions were commonly reported, with about 78%, 55%, and 35% reporting one, two, and three chronic conditions, respectively. Correlation analyses showed that reports of high job strain and everyday discrimination were significantly associated with high ALI quartile score (r = 0.39, p = 0.011; r = 0.41, p = 0.004). Job strain and everyday discrimination had medium to large effect sizes on ALI quartile scores. High ALI quartile score was significantly associated with having at least one chronic disease (r = 0.40, p = 0.005), and it had a large effect size on chronic diseases. To our knowledge, this is the first study to explore allostatic load among hotel housekeepers. Hotel housekeepers have high exposure to stressors within and outside of their work and experience poor chronic conditions. Allostatic load had strong associations with both stressors and health outcomes. Despite this worker group being a hard-to-reach worker group to participate in research studies, this study demonstrates the feasibility of accessing, recruiting and collecting survey data and blood samples among them to determine health risks and guide future targeted interventions.

Examining associations between action game play and motor control.

The effects of playing action video games have been investigated across a wide range of attentional and cognitive abilities. However, few studies have examined the association between motor control and action gaming experience. We report data from two discrete pointing tasks, manipulating the index of difficulty (ID) by movement distance and target size, respectively. Participants' gaming experience ranged from non-players to individuals who played several hours a night. Our results indicated greater experience playing action games, but not video games in general, was associated with shorter movement times (MT), higher velocities, and shallower ID-MT slopes when difficulty was manipulated across increasingly further distances and smaller target sizes. Additionally casual players, those who only play action games a couple times a week, were able to achieve a similar level of performance as more experienced players.

The role of individual differences on perceptions of wearable fitness device trust, usability, and motivational impact.

Lack of physical activity is a severe health concern in the United States with fewer than half of all Americans meeting the recommended weekly physical activity guidelines. Although wearable fitness devices can be effective in motivating people to be active, consumers are abandoning this technology soon after purchase. We examined the impact of several user (i.e. personality, age, computer self-efficacy, physical activity level) and device characteristics (trust, usability, and motivational affordances) on the behavioral intentions to use a wearable fitness device. Novice users completed a brief interaction with a fitness device similar to a first purchase experience before completing questionnaires about their interaction. We found computer self-efficacy, physical activity level, as well as personality traits indirectly increased the desire to use a fitness device and influenced the saliency of perceived motivational affordances. Additionally, trust, usability, and perceived motivational affordances were associated with increased intentions to use fitness devices.

Searching for Affective and Cognitive Restoration: Examining the Restorative Effects of Casual Video Game Play.

OBJECTIVE: We investigated the effects of a passive break, relaxation activity, and casual video game on affect, stress, engagement, and cognitive performance. BACKGROUND: Reducing stress and improving cognitive performance is critical across many domains. Previous studies investigated taking a break, relaxation techniques, or playing a game; however, these methods have not been compared within a single experiment. METHOD: Participants completed a baseline affective and cognitive assessment (ACA), which included the Positive and Negative Affect Schedule, shortened version of the Dundee Stress State Questionnaire, and backward digit-span. Next, participants completed a vigilance task, followed by another ACA. Participants were then assigned at random to complete a break or relaxation activity or play a casual video game, followed by a final ACA. RESULTS: Participants who played the casual video game exhibited greater engagement and affective restoration than the relaxation condition. The break condition slightly decreased affect and prevented cognitive restoration. CONCLUSION: Playing a casual video game even briefly can restore individuals' affective abilities, making it a suitable activity to restore mood in response to stress. However, future research is needed to find activities capable of cognitive restoration. APPLICATION: Many activities in life require sustained cognitive demand, which are stressful and decrease performance, especially for workers in performance-critical domains. Our research suggests some leisure activities are better than others for restoring fatigued affective processes.

Changes in androstenedione, dehydroepiandrosterone, testosterone, estradiol, and estrone over the menopausal transition.

BACKGROUND: Previous reports have noted that dehydroepiandrosterone-sulfate (DHEAS) increases prior to the final menstrual period (FMP) and remains stable beyond the FMP. How DHEAS concentrations correspond with other sex hormones across the menopausal transition (MT) including androstenedione (A4), testosterone (T), estrone (E1), and estradiol (E2) is not known. Our objective was to examine how DHEAS, A4, T, E1, and E2 changed across the MT by White vs. African-American (AA) race/ethnicity. METHODS: We conducted a longitudinal observational analysis of a subgroup of women from the Study of Women's Health Across the Nation observed over 4 visits prior to and 4 visits after the FMP (n = 110 women over 9 years for 990 observations). The main outcome measures were DHEAS, A4, T, E1, and E2. RESULTS: Compared to the decline in E2 concentrations, androgen concentrations declined minimally over the MT. T (ß 9.180, p < 0.0001) and E1 (ß 11.365, p < 0.0001) were higher in Whites than in AAs, while elevations in DHEAS (ß 28.80, p = 0.061) and A4 (ß 0.2556, p = 0.052) were borderline. Log-transformed E2 was similar between Whites and AAs (ß 0.0764, p = 0.272). Body mass index (BMI) was not significantly associated with concentrations of androgens or E1 over time. CONCLUSION: This report suggests that the declines in E2 during the 4 years before and after the FMP are accompanied by minimal changes in DHEAS, A4, T, and E1. There are modest differences between Whites and AAs and minimal differences by BMI.

Antimüllerian hormone among women with and without type 1 diabetes: the Epidemiology of Diabetes Interventions and Complications Study and the Michigan Bone Health and Metabolism Study.

OBJECTIVE: To compare concentrations of antimüllerian hormone (AMH) in women with and without type 1 diabetes. DESIGN: Cross-sectional analysis of longitudinal studies, adjusting for repeated measures. SETTING: Not applicable. PATIENT(S): Women aged 30-45 years who had not undergone oophorectomy, hysterectomy, or natural menopause at the time of AMH measurement were included (n = 376 in the Michigan Bone Health and Metabolism Study and n = 321 in the Epidemiology of Interventions and Complications Study). Linear mixed regression was used to evaluate whether AMH concentrations differed by diabetes status, adjusting for repeated measurements of AMH within individual women, body mass index, smoking status, and oral contraceptive use. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Concentrations of AMH. RESULT(S): In unadjusted comparisons, women with and without diabetes had similar median AMH values before 35 years of age, although women with type 1 diabetes had a lower proportion of women with elevated AMH concentrations (≥5.0 ng/dL). After adjustment for covariates and multiple observations per woman, log AMH concentrations were significantly lower among women with type 1 diabetes compared with women without diabetes (ß-coefficient -1.27, 95% confidence interval [-2.18, -0.36] in fully adjusted models) before 35 years of age. CONCLUSION(S): Before 35 years of age, women with type 1 diabetes have lower AMH levels than women without diabetes. Further investigation is needed to determine the etiologies of this difference and how it may contribute to reproductive disorders among women with type 1 diabetes.

Characterizing the trajectories of vasomotor symptoms across the menopausal transition.

OBJECTIVE: The aim of the study was to investigate the heterogeneity of temporal patterns of vasomotor symptoms (VMS) over the menopausal transition and identify factors associated with these patterns in a diverse sample of women. METHODS: The Study of Women's Health Across the Nation is a multisite longitudinal study of women from five racial/ethnic groups transitioning through the menopause. The analytic sample included 1,455 women with nonsurgical menopause and a median follow-up of 15.4 years. Temporal patterns of VMS and associations with serum estradiol and follicle-stimulating hormone, race/ethnicity, body mass index, and demographic and psychosocial factors were examined using group-based trajectory modeling. RESULTS: Four distinct trajectories of VMS were found: onset early (11 years before the final menstrual period) with decline after menopause (early onset, 18.4%), onset near the final menstrual period with later decline (late onset, 29.0%), onset early with persistently high frequency (high, 25.6%), and persistently low frequency (low, 27.0%). Relative to women with persistently low frequency of VMS, women with persistently high and early onset VMS had a more adverse psychosocial and health profile. Black women were overrepresented in the late onset and high VMS subgroups relative to white women. Obese women were underrepresented in the late onset subgroup. In multivariable models, the pattern of estradiol over the menopause was significantly associated with the VMS trajectory. CONCLUSIONS: These data distinctly demonstrate heterogeneous patterns of menopausal symptoms that are associated with race/ethnicity, reproductive hormones, premenopause body mass index, and psychosocial characteristics. Early targeted intervention may have a meaningful impact on long-term VMS.

Evaluating input device usability as a function of task difficulty in a tracking task.

Game controllers are emerging as a preferred choice for the manual control of unmanned vehicles, but an understanding of their usability characteristics has yet to emerge. We compared the usability of an Xbox 360 game controller in a dual task situation using MATB II to the traditional joystick and keyboard interface in two experiments. In the first experiment, performance with the game controller was associated with fewer tracking errors. In a second experiment, we trained users on the devices, and found that even after training the game controller was still associated with fewer tracking errors as well as higher usability and lower workload ratings. These results are consistent with the idea that game controllers are highly usable input devices and do not require high mental workload to operate, thus making them suitable for complex control tasks.

Milk immunity and reproductive status among Ariaal women of northern Kenya.

UNLABELLED: Abstract Background: The immune factors in human milk protect infants from infection and promote immune development. Evidence suggests that the production of milk-specific immunoproteins is energetically costly, making them a form of maternal investment in offspring health that is subject to life history trade-offs. AIM: This research tests the relationship between measures of reproductive effort and the production of milk immunoglobulin A (IgA) among Ariaal women, a settled northern Kenyan pastoralist population that experiences nutritional and disease stress. SUBJECTS AND METHODS: Two hundred and forty-three lactating Ariaal women participated in a questionnaire, anthropometric measurement and milk collection. Milk IgA was analysed using ELISA. RESULTS: There was a significant U-shaped relationship between post-partum months and milk IgA, reflecting decreasing investment in the current offspring over the early post-partum period and subsequent recovery of maternal energy status near the end. There was also a significant inverse U-shaped relationship between milk IgA and parity, with high parity women showing a drop in milk IgA. In contrast, anthropometric measures of energy status were not associated with the production of milk IgA. CONCLUSION: This research shows that patterns of reproductive investment can be demonstrated in milk IgA in the absence of measured energy changes.

Updated assays for inhibin B and AMH provide evidence for regular episodic secretion of inhibin B but not AMH in the follicular phase of the normal menstrual cycle.

STUDY QUESTION: What is the daily variation in serum inhibin B (InhB) and anti-Müllerian hormone (AMH) in relation to the LH surge in women of reproductive age. SUMMARY ANSWER: AMH is secreted in a biphasic follicular/luteal pattern in women with higher AMH secretion, while InhB secretion is episodic in the early to mid-follicular phase and immediately after the LH surge but not in the luteal phase. WHAT IS KNOWN ALREADY: In women of reproductive age with a mean serum AMH >1 ng/ml, levels are highest in Days 2-7 of the cycle. InhB concentrations are highest in the follicular phase of the cycle. STUDY DESIGN, SIZE, DURATION: In this cohort study conducted in an academic center, blood samples were collected daily from 20 women during one normal menstrual cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: Regularly menstruating 30- to 40-year-old women had daily serum InhB, AMH, LH and FSH levels measured. Intracycle variability of InhB and AMH were assessed after aligning to the LH surge. MAIN RESULTS AND THE ROLE OF CHANCE: When classified into quartiles of AMH concentration, the lowest AMH levels did not vary across the cycle; the highest AMH levels showed a mid-follicular increase, mid-cycle decrease and mid-luteal increase. A surge of InhB was noted following the LH surge in 16/20 cycles. Episodic increases in InhB occurred in 17/20 cycles prior to the LH surge. In the luteal phase, InhB decreased or became undetectable and did not demonstrate episodic secretion. Old and new assays for AMH and InhB were compared in all samples, with the AMH assays demonstrating good correlation (Rsq = 0.9625) but the InhB assays showing less correlation (Rsq = 0.4903). LIMITATIONS, REASONS FOR CAUTION: The study population is small and in the mid-to-late reproductive age group. Single daily sampling may not detect more frequent variability (i.e. pulses) in hormone levels. WIDER IMPLICATIONS OF THE FINDINGS: These data suggest different regulatory mechanisms for InhB and AMH secretion, and confirm an 'aging ovary' pattern of AMH and InhB secretion, which is consistent with decreased ovarian reserve. We also demonstrated comparability of the AMH Gen II assay with the previous version in standard usage but our data raised concerns about comparability of the InhB Gen II assay. STUDY FUNDING/COMPETING INTEREST(S): General Clinical Research Center for phlebotomy work has been supported in part by NIH grant UL1RR024986. Recruitment and data analyses were supported by the Center for Integrated Approaches to Complex Diseases (SD Harlow, Director). The authors report no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Prospects for direct social perception: a multi-theoretical integration to further the science of social cognition.

In this paper we suggest that differing approaches to the science of social cognition mirror the arguments between radical embodied and traditional approaches to cognition. We contrast the use in social cognition of theoretical inference and mental simulation mechanisms with approaches emphasizing a direct perception of others' mental states. We build from a recent integrative framework unifying these divergent perspectives through the use of dual-process theory and supporting social neuroscience research. Our elaboration considers two complementary notions of direct perception: one primarily stemming from ecological psychology and the other from enactive cognition theory. We use this as the foundation from which to offer an account of the informational basis for social information and assert a set of research propositions to further the science of social cognition. In doing so, we point out how perception of the minds of others can be supported in some cases by lawful information, supporting direct perception of social affordances and perhaps, mental states, and in other cases by cues that support indirect perceptual inference. Our goal is to extend accounts of social cognition by integrating advances across disciplines to provide a multi-level and multi-theoretic description that can advance this field and offer a means through which to reconcile radical embodied and traditional approaches to cognitive neuroscience.

Brief communication: chronic undernutrition is associated with higher mucosal antibody levels among Ariaal infants of northern Kenya.

The immune activation that occurs with infection diverts energy from growth and can contribute to poor nutritional outcomes in developing infants and children. This study investigates the association between salivary immunoglobulin A (IgA) levels and growth outcomes among Ariaal infants of northern Kenya. The Ariaal are a group of settled northern Kenyan pastoralists who are under considerable nutritional stress. Two hundred and thirty-nine breastfeeding Ariaal infants were recruited into the study and underwent anthropometric measurement and saliva collection, with mothers providing individual and household characteristics for them via questionnaire. Infant saliva samples were analyzed with an ELISA for IgA in the United States. Infant anthropometric measurements were converted to height-for-age z-scores (HAZ) using the WHO Child Growth Standards. Based on multivariate models performed in SAS 9.2 two main results emerge: 1) low HAZ, an indicator of chronic undernutrition, was significantly associated with higher IgA concentration (ß = -0.12, P = 0.050) and 2) boys had significantly higher IgA levels than girls (ß = 0.25, P = 0.039). Although there was not a significant interactive effect between HAZ and sex, the two variables confound each other, with boys having significantly lower HAZ values than girls do. In addition, maternal breastmilk IgA was significantly associated with infant salivary IgA, indicating that maternal effects play a role in infant IgA development. Future research will unravel the three-way association between sex, stunting, and immune function in the Ariaal community.

Trajectory clustering of estradiol and follicle-stimulating hormone during the menopausal transition among women in the Study of Women's Health across the Nation (SWAN).

CONTEXT: Variability in the pattern of change in estradiol (E2) and FSH levels over the menopause transition has not been well defined. OBJECTIVE: The current study aimed to determine whether different trajectories of E2 and FSH could be identified and whether race/ethnicity and body mass index were related to the different trajectories. DESIGN: The Study of Women's Health Across the Nation is a longitudinal observational study of the menopausal transition. SETTING: Women aged 42-52 yr from seven participating sites were recruited and underwent up to 11 annual visits. PARTICIPANTS: Postmenopausal women with 12 or more months of amenorrhea that was not due to hysterectomy/oophorectomy and who were not using hormone therapy before the final menstrual period participated in the study. MAIN OUTCOME MEASURES: Annual serum E2 and FSH levels anchored to final menstrual period were measured. RESULTS: Four distinct E2 trajectories and three distinct FSH trajectories were identified. The E2 trajectories were: slow decline (26.9%), flat (28.6%), rise/slow decline (13.1%), and rise/steep decline (31.5%). The FSH trajectories were: low (10.6%), medium (48.7%), and high (41.7%) rising patterns. Obesity increased the likelihood of a flat E2 and low FSH trajectory for all race/ethnic groups. Normal-weight Caucasian and African-American women tended to follow the rise/steep decline E2 and high FSH trajectories. Normal-weight Chinese/Japanese women tended to follow the slow decline E2 and the high/medium FSH trajectories. CONCLUSIONS: E2 and FSH trajectories over the menopausal transition are not uniform across the population of women. Race/ethnicity and body mass index affect the trajectory of both E2 and FSH change over the menopausal transition.

Androstenediol complements estrogenic bioactivity during the menopausal transition.

OBJECTIVE: The perimenopausal increase in circulating dehydroepiandrosterone sulfate (DHEAS) levels during the menopausal transition (MT) is accompanied by other adrenal steroids that have the potential to alter estrogen/androgen balance and explain the wide interwoman range of estrogen-related symptoms experienced during the MT. METHODS: Annual serum samples from the Study of Women's Health Across the Nation, which had previously been analyzed for immunoreactive estradiol (E2), testosterone, DHEAS, and sex hormone-binding globulin, were selected based on DHEAS concentration and analyzed for immunoreactive and bioactive estrogens and androgens, including immunoreactive androstenedione, dehydroepiandrosterone, and 5-androstene-3ß,17ß-diol (androstenediol [Adiol]). RESULTS: A two-fold increase in circulating androstenedione and testosterone was found to rise in parallel with the rise in circulating DHEAS, whereas dehydroepiandrosterone and Adiol concentrations rose seven- to eight-fold. Circulating Adiol, which has both androgenic and estrogenic biological activity, was significantly associated (P < 0.02) with circulating estrogen bioactivity only when E2 concentrations were low and Adiol levels were high. CONCLUSIONS: The wide range of circulating levels of Adiol and its contribution to total circulating estrogenicity during the MT is consistent with the observed interwoman difference in symptoms at this time. Therefore, we conclude that Adiol contributes to circulating estrogenicity when E2 production falls at menopause and may contribute significantly to the endocrine changes experienced by midlife women.

Menopausal transition stage-specific changes in circulating adrenal androgens.

OBJECTIVE: It is now recognized that mean circulating dehydroepiandrosterone sulfate (DHEAS) concentrations in most midlife women exhibit a positive inflection starting in early perimenopause, continuing through early postmenopause and returning to early perimenopausal levels by late postmenopause. This rise in mean DHEAS is accompanied by concomitant rises in testosterone (T), dehydroepiandrosteone (DHEA), and androstenedione (Adione) and an equal rise in androstenediol (Adiol). These observations suggest that there is a specific relationship between the circulating levels of steroids emanating from the adrenal glands, declining ovarian function, and the stages of the menopausal transition. This study was designed to test the hypothesis that the menopausal stage-specific change in circulating DHEAS is associated with concomitant changes in the circulating pattern of adrenal steroids and that some of these adrenal androgens could influence the circulating estrogen/androgen balance. METHODS: Stored annual serum samples (N = 120) were first selected to represent four longitudinal DHEAS profiles of individual women to assess and compare changes in the adrenal contribution to circulating steroids. RESULTS: Changes in mean circulating DHEAS levels in midlife women during the menopausal transition is associated with changes in mean circulating T, Adione, and Adiol. Mean Adione and T concentrations changed the least, whereas mean DHEAS and Adiol changed the most. CONCLUSIONS: Changes in circulating steroid hormone emanating from the adrenal during the menopausal transition may be more important than the decline in ovarian function in terms of altering the estrogen/androgen balance.

On using summary statistics from an external calibration sample to correct for covariate measurement error.

BACKGROUND: Covariate measurement error is common in epidemiologic studies. Current methods for correcting measurement error with information from external calibration samples are insufficient to provide valid adjusted inferences. We consider the problem of estimating the regression of an outcome Y on covariates X and Z, where Y and Z are observed, X is unobserved, but a variable W that measures X with error is observed. Information about measurement error is provided in an external calibration sample where data on X and W (but not Y and Z) are recorded. METHODS: We describe a method that uses summary statistics from the calibration sample to create multiple imputations of the missing values of X in the regression sample, so that the regression coefficients of Y on X and Z and associated standard errors can be estimated using simple multiple imputation combining rules, yielding valid statistical inferences under the assumption of a multivariate normal distribution. RESULTS: The proposed method is shown by simulation to provide better inferences than existing methods, namely the naive method, classical calibration, and regression calibration, particularly for correction for bias and achieving nominal confidence levels. We also illustrate our method with an example using linear regression to examine the relation between serum reproductive hormone concentrations and bone mineral density loss in midlife women in the Michigan Bone Health and Metabolism Study. CONCLUSIONS: Existing methods fail to adjust appropriately for bias due to measurement error in the regression setting, particularly when measurement error is substantial. The proposed method corrects this deficiency.