The Dynamics of Stress and Fatigue Across Menopause: Attractors, Coupling, and Resilience

Objective: The objective of this study was to evaluate the regulatory dynamics between stress and fatigue experienced by women during the menopausal transition (MT) and early postmenopause (EPM). Fatigue and perceived stress are commonly experienced by women during the MT and EPM. We sought to discover relationships between these symptoms and to employ these symptoms as possible markers for resilience. Methods: Participants were drawn from the longitudinal Seattle Midlife Women\u27s Health Study. Eligible women completed questionnaires on 60+ occasions (annual health reports and monthly health diaries) (n = 56 women). The total number of observations across the sample was 4,224. STRAW+10 criteria were used to stage women in either in late reproductive, early or late transition, or EPM stage. Change values were generated for fatigue and stress and analyzed with a multilevel structural equation model; slopes indicate how quickly a person returns to homeostasis after a perturbation. Coupling of stress and fatigue was modeled to evaluate resilience, the notion of maintaining stability during change. Results: Eligible women were on average 35 years old (SD = 4.71), well educated, employed, married or partnered, and white. Fit indices suggested the model depicts the relationships of stress and fatigue (χ2(9 df) = 7.638, P = 0.57, correction factor = 4.9244; root mean square error of approximation (RMSEA) 90% CI = 0.000 ≤ 0.000 ≤ 0.032; comparative fit index (CFI) = 1.00). A loss in model fit across stages suggests that the four stages differed in their dynamics (χ2Δ(12 df) = 21.181, P = .048). All stages showed fixed-point attractor dynamics: fatigue became less stable over time; stress generally became more stable over time. Coupling relationships of stress on fatigue show evidence for shifts in regulatory relationships with one another across the MT. Conclusions: Results are suggestive of general dysregulation via disruptions to coupling relationships of stress and fatigue across the MT. Findings support a holistic approach to understanding symptoms and supporting women during the MT

Contraceptive preferences and unmet need for contraception in midlife women: where are the data?

Abstract This commentary discusses the limited availability of information on contraceptive preferences and unmet need for contraception among midlife women in both high and low income countries. Given that risk of pregnancy continues until women reach menopause and given the increased risk of pregnancy complications, elective abortion, and maternal mortality in women aged 45 to 54 years old, increased focus on gathering basic data on midlife women’s preferences and unmet need is warranted.https://deepblue.lib.umich.edu/bitstream/2027.42/138119/1/40695_2017_Article_26.pd

Contraceptive preferences and unmet need for contraception in midlife women: where are the data?

Abstract This commentary discusses the limited availability of information on contraceptive preferences and unmet need for contraception among midlife women in both high and low income countries. Given that risk of pregnancy continues until women reach menopause and given the increased risk of pregnancy complications, elective abortion, and maternal mortality in women aged 45 to 54 years old, increased focus on gathering basic data on midlife women’s preferences and unmet need is warranted.https://deepblue.lib.umich.edu/bitstream/2027.42/138119/1/40695_2017_Article_26.pd

Racial/Ethnic Disparities in Alzheimer’s Disease Risk: Role of Exposure to Ambient Fine Particles

Background Whether racial/ethnic disparities in Alzheimer’s disease (AD) risk may be explained by ambient fine particles (PM2.5) has not been studied. Methods We conducted a prospective, population-based study on a cohort of Black (n=481) and White (n=6004) older women (aged 65-79) without dementia at enrollment (1995-98). Cox models accounting for competing risk were used to estimate the hazard ratio (HR) for racial/ethnic disparities in AD (1996-2010) defined by DSM-IV and the association with time-varying annual average PM2.5 (1999-2010) estimated by spatiotemporal model. Results Over an average follow-up of 8.3 (±3.5) years with 158 incident cases (21 in Black women), the racial disparities in AD risk (range of adjusted HRBlack women = 1.85-2.41) observed in various models could not be explained by geographic region, age, socioeconomic characteristics, lifestyle factors, cardiovascular risk factors, and hormone therapy assignment. Estimated PM2.5 exposure was higher in Black (14.38±2.21 µg/m 3) than in White (12.55±2.76 µg/m 3) women, and further adjustment for the association between PM2.5 and AD (adjusted HRPM2.5 = 1.18-1.28) slightly reduced the racial disparities by 2-6% (HRBlack women = 1.81-2.26). The observed association between PM2.5 and AD risk was ~2 times greater in Black (HRPM2.5 = 2.10-2.60) than in White (HRPM2.5 = 1.07-1.15) women (range of interaction Ps: Conclusions PM2.5 may contribute to racial/ethnic disparities in AD risk and its associated increase in AD risk was stronger amongst Black women

The InterLACE study: design, data harmonization and characteristics across 20 studies on women's health

The International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events (InterLACE) project is a global research collaboration that aims to advance understanding of women's reproductive health in relation to chronic disease risk by pooling individual participant data from several cohort and cross-sectional studies. The aim of this paper is to describe the characteristics of contributing studies and to present the distribution of demographic and reproductive factors and chronic disease outcomes in InterLACE

CNS Penetration of Intrathecal-Lumbar Idursulfase in the Monkey, Dog and Mouse: Implications for Neurological Outcomes of Lysosomal Storage Disorder

A major challenge for the treatment of many central nervous system (CNS) disorders is the lack of convenient and effective methods for delivering biological agents to the brain. Mucopolysaccharidosis II (Hunter syndrome) is a rare inherited lysosomal storage disorder resulting from a deficiency of iduronate-2-sulfatase (I2S). I2S is a large, highly glycosylated enzyme. Intravenous administration is not likely to be an effective therapy for disease-related neurological outcomes that require enzyme access to the brain cells, in particular neurons and oligodendrocytes. We demonstrate that intracerebroventricular and lumbar intrathecal administration of recombinant I2S in dogs and nonhuman primates resulted in widespread enzyme distribution in the brain parenchyma, including remarkable deposition in the lysosomes of both neurons and oligodendrocytes. Lumbar intrathecal administration also resulted in enzyme delivery to the spinal cord, whereas little enzyme was detected there after intraventricular administration. Mucopolysaccharidosis II model is available in mice. Lumbar administration of recombinant I2S to enzyme deficient animals reduced the storage of glycosaminoglycans in both superficial and deep brain tissues, with concurrent morphological improvements. The observed patterns of enzyme transport from cerebrospinal fluid to the CNS tissues and the resultant biological activity (a) warrant further investigation of intrathecal delivery of I2S via lumbar catheter as an experimental treatment for the neurological symptoms of Hunter syndrome and (b) may have broader implications for CNS treatment with biopharmaceuticals

Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression

The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research, and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 datasets containing 38 802 European-ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analyzed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis1) with qualifying unpublished data were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction, and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalizable, but must be of modest effect size and only observable in limited situations

Synaptic processes and immune-related pathways implicated in Tourette syndrome

Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS

Rare and low-frequency coding variants alter human adult height

Height is a highly heritable, classic polygenic trait with ~700 common associated variants identified so far through genome - wide association studies . Here , we report 83 height - associated coding variants with lower minor allele frequenc ies ( range of 0.1 - 4.8% ) and effects of up to 2 16 cm /allele ( e.g. in IHH , STC2 , AR and CRISPLD2 ) , >10 times the average effect of common variants . In functional follow - up studies, rare height - increasing alleles of STC2 (+1 - 2 cm/allele) compromise d proteolytic inhibition of PAPP - A and increased cleavage of IGFBP - 4 in vitro , resulting in higher bioavailability of insulin - like growth factors . The se 83 height - associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates ( e.g. ADAMTS3, IL11RA, NOX4 ) and pathways ( e.g . proteoglycan/ glycosaminoglycan synthesis ) involved in growth . Our results demonstrate that sufficiently large sample sizes can uncover rare and low - frequency variants of moderate to large effect associated with polygenic human phenotypes , and that these variants implicate relevant genes and pathways

Body mass index and age at natural menopause: an international pooled analysis of 11 prospective studies

Current evidence on the association between body mass index (BMI) and age at menopause remains unclear. We investigated the relationship between BMI and age at menopause using data from 11 prospective studies. A total of 24,196 women who experienced menopause after recruitment was included. Baseline BMI was categorised according to the WHO criteria. Age at menopause, confirmed by natural cessation of menses for ≥ 12 months, was categorised as < 45 years (early menopause), 45–49, 50–51 (reference category), 52–53, 54–55, and ≥ 56 years (late age at menopause). We used multinomial logistic regression models to estimate multivariable relative risk ratios (RRRs) and 95% confidence intervals (CI) for the associations between BMI and age at menopause. The mean (standard deviation) age at menopause was 51.4 (3.3) years, with 2.5% of the women having early and 8.1% late menopause. Compared with those with normal BMI (18.5–24.9 kg/m2), underweight women were at a higher risk of early menopause (RRR 2.15, 95% CI 1.50–3.06), while overweight (1.52, 1.31–1.77) and obese women (1.54, 1.18–2.01) were at increased risk of late menopause. Overweight and obesity were also significantly associated with around 20% increased risk of menopause at ages 52–53 and 54–55 years. We observed no association between underweight and late menopause. The risk of early menopause was higher among obese women albeit not significant (1.23, 0.89–1.71). Underweight women had over twice the risk of experiencing early menopause, while overweight and obese women had over 50% higher risk of experiencing late menopause