Matheos Yosef

Anti-Mullerian Hormone and Inhibin B in the Definition of Ovarian Aging and the Menopause Transition

CONTEXT/OBJECTIVE The objective of the study was to determine whether anti-Mullerian hormone (AMH) and inhibin B are viable endocrine biomarkers for framing the menopause transition from initiation to the final menstrual period (FMP). DESIGN We assayed AMH, inhibin B, and FSH in 300 archival follicular phase specimens from 50 women with six consecutive annual visits commencing in 1993 when all women were in the pre- and perimenopausal menopause stages. Subsequently each woman had a documented FMP. The assay results were fitted as individual-woman profiles and then related to time to FMP and age at FMP as outcomes. RESULTS Based on annual values from six time points prior to the FMP, (log)AMH longitudinal profiles declined and were highly associated with a time point 5 yr prior to FMP [including both observed and values below detection (P < 0.0001 and P = 0.0001, respectively)]. Baseline AMH profiles were also associated with age at FMP (P = 0.035). Models of declining (log)inhibin B profiles (including both observed and values below detection) were associated with time to FMP (P < 0.0001 and P = 0.0003, respectively). There was no significant association of (log)inhibin B profiles with age at FMP. CONCLUSIONS AMH, an endocrine marker that reflects the transition of resting primordial follicles to growing follicles, declined to a time point 5 yr prior to the FMP; this may represent a critical biological juncture in the menopause transition. Low and nondetectable levels inhibin B levels also were observed 4-5 yr prior to the FMP but were less predictive of time to FMP or age at FMP.

Associations of Anatomical Measures from MRI with Radiographically Defined Knee Osteoarthritis Score, Pain, and Physical Functioning

BACKGROUND The prevalence of knee osteoarthritis is traditionally based on radiographic findings, but magnetic resonance imaging is now being used to provide better visualization of bone, cartilage, and soft tissues as well as the patellar compartment. The goal of this study was to estimate the prevalences of knee features defined on magnetic resonance imaging in a population and to relate these abnormalities to knee osteoarthritis severity scores based on radiographic findings, physical functioning, and reported knee pain in middle-aged women. METHODS Magnetic resonance images of the knee were evaluated for the location and severity of cartilage defects, bone marrow lesions, osteophytes, subchondral cysts, meniscal and/or ligamentous tears, effusion, and synovitis among 363 middle-aged women (724 knees) from the Michigan Study of Womens Health Across the Nation. These findings were related to Kellgren-Lawrence osteoarthritis severity scores from radiographs, self-reported knee pain, self-reported knee injury, perception of physical functioning, and physical performance measures to assess mobility. Radiographs, physical performance assessment, and interviews were undertaken at the 1996 study baseline and again (with the addition of magnetic resonance imaging assessment) at the follow-up visit during 2007 to 2008. RESULTS The prevalence of moderate-to-severe knee osteoarthritis changed from 3.7% at the baseline assessment to 26.7% at the follow-up visit eleven years later. Full-thickness cartilage defects of the medial, lateral, and patellofemoral compartments were present in 14.5% (105 knees), 4.6% (thirty-three knees), and 26.2% (190 knees), respectively. Synovitis was identified in 24.7% (179) of the knees, and joint effusions were observed in 70% (507 knees); 21.7% (157) of the knees had complex or macerated meniscal tears. Large osteophytes, marked synovitis, macerated meniscal tears, and full-thickness tibial cartilage defects were associated with increased odds of knee pain and with 30% to 40% slower walking and stair-climbing times. CONCLUSIONS Middle-aged women have a high prevalence of moderate-to-severe knee osteoarthritis corroborated by strong associations with cartilage defects, complex and macerated meniscal tears, osteophytes and synovitis, knee pain, and lower mobility levels.

Longitudinal changes of serum COMP and urinary CTX-II predict X-ray defined knee osteoarthritis severity and stiffness in women

OBJECTIVE To ascertain the predictive role of longitudinally acquired biochemical measures of cartilage turnover in relation to X-ray defined knee osteoarthritis (OAK), knee pain and functioning. METHODS This is a feasibility study based on 72 enrollees of the Michigan site of Study of Womens Health Across the Nation (SWAN), a longitudinal, population-based cohort study with 11 annual visits to characterize health at the mid-life. At visits in 1996, 1998 and 2007, radiographs were evaluated for the presence of OAK [>or=2 on the Kellgren and Lawrence (K-L) scale]. Knee pain and stiffness were assessed by interview. Functioning was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Cartilage oligomeric matrix protein (COMP) and Type II collagen telopeptides (CTX-II) were assayed in serum and urine samples collected on alternate years from 1997 to 2006. We related trajectories of the cartilage biochemical markers from these five time points to OAK severity (no OAK, K-L score<2; mild OAK, K-L score=2; moderate/severe OAK, K-L score=3 or 4), pain, stiffness, or functioning, using longitudinal non-linear mixed modeling. RESULTS The 2007 prevalence of X-ray defined OAK was 50% in these 72 women. Upward trajectories of COMP (P=0.02) and CTX-II (P=0.006) were associated with increased OAK severity and body size. COMP trajectories were associated with pain and stiffness, but not functioning. CTX-II trajectories were associated with stiffness scores, but not knee pain or functioning scores. CONCLUSION Multiple, biennial measures of COMP or CTX-II taken over a 10-year period were predictive of subsequent OAK and knee stiffness.

Relating smoking, obesity, insulin resistance, and ovarian biomarker changes to the final menstrual period

To determine if smoking, obesity, and insulin resistance mediated age at final menstrual period (FMP), we examined anti‐Müllerian hormone (AMH), inhibin B, and follicle‐stimulating hormone (FSH) as biomarkers of changing follicle status and ovarian aging. We performed a longitudinal data analysis from a cohort of premenopausal women followed to their FMP. Our results found that smokers had an earlier age at FMP (P < 0.003) and a more rapid decline in their AMH slope relative to age at FMP (P < 0.002). Smokers had a lower baseline inhibin B level relative to age at the FMP than nonsmokers (P= 0.002). Increasing insulin resistance was associated with a shorter time to FMP (P < 0.003) and associations of obesity and time to FMP were observed (P= 0.004, in model with FSH). Change in ovarian biomarkers did not mediate the time to FMP. We found that smoking was associated with age at FMP and modified associations of AMH and inhibin B with age at FMP. Insulin resistance was associated with shorter time to FMP independent of the biomarkers. Interventions targeting smoking and insulin resistance could curtail the undue advancement of reproductive aging.

Dietary Intake Related to Prevalent Functional Limitations in Midlife Women

Physical functioning measures are considered integrated markers of the aging process. This prospective investigation examined relations between dietary intake of women at midlife in 1996-1997 and prevalence of physical functioning limitations 4 years later, defined by the Medical Outcomes Study Short-Form 36. The sample included 2,160 multiethnic women, aged 42-52 years, from six geographic areas participating in the Study of Womens Health Across the Nation (SWAN). Associations between measures of diet quality and number of fruit and vegetable servings and prevalent physical functional limitations (no, moderate, or substantial limitations) were tested by logistic regression. The prevalence of moderate and substantial functional limitations was 31% and 10%, respectively. Women in the highest quartile of cholesterol intake had 40% greater odds (odds ratio = 1.4, 95% confidence interval: 1.1, 1.8) of being more limited versus those in the lowest quartile. Women in the highest quartile of fat and saturated fat intakes were 50% and 60% more likely to be more limited, with respective odds ratios of 1.5 and 1.6 (95% confidence intervals: 1.2, 2.0 and 1.2, 2.1) versus those in the lowest quartiles. Lower fruit, vegetable, and fiber intakes were related to reporting greater functional limitations. Modifying dietary practices could be important in minimizing physical limitations.

Associations between depression and all-cause and cause-specific risk of death: a retrospective cohort study in the Veterans Health Administration

OBJECTIVE Depression may be associated with increased mortality risk, but there are substantial limitations to existing studies assessing this relationship. We sought to overcome limitations of existing studies by conducting a large, national, longitudinal study to assess the impact of depression on all-cause and cause-specific risk of death. METHODS We used Cox regression models to estimate hazard ratios associated with baseline depression diagnosis (N=849,474) and three-year mortality among 5,078,082 patients treated in Veterans Health Administration (VHA) settings in fiscal year (FY) 2006. Cause of death was obtained from the National Death Index (NDI). RESULTS Baseline depression was associated with 17% greater hazard of all-cause three-year mortality (95% CI hazard ratio [HR]: 1.15, 1.18) after adjusting for baseline patient demographic and clinical characteristics and VHA facility characteristics. Depression was associated with a higher hazard of three-year mortality from heart disease, respiratory illness, cerebrovascular disease, accidents, diabetes, nephritis, influenza, Alzheimers disease, septicemia, suicide, Parkinsons disease, and hypertension. Depression was associated with a lower hazard of death from malignant neoplasm and liver disease. Depression was not associated with mortality due to assault. CONCLUSIONS In addition to being associated with suicide and injury-related causes of death, depression is associated with increased risk of death from nearly all major medical causes, independent of multiple major risk factors. Findings highlight the need to better understand and prevent mortality seen with multiple medical disorders associated with depression.

Receipt of employment services among Veterans Health Administration users with psychiatric diagnoses

This study examined the population-based reach of Veterans Health Administration (VHA) employment services to VHA patients with psychiatric diagnoses. Reach of services includes the percentage and characteristics of people who accessed services compared with those who did not. Using clinical administrative data, we identified patients with a psychiatric diagnosis among a random sample of all patients who received VHA services in 1 yr. Among VHA patients with psychiatric diagnoses, we examined their likelihood of receiving any VHA employment services and specific types of employment services, including supported employment, transitional work, incentive therapy, and vocational assistance. We identified clinical and demographic characteristics associated with receiving employment services. Results indicated that 4.2% of VHA patients with a psychiatric diagnosis received employment services. After adjusting for clinical and demographic characteristics, VHA patients with schizophrenia and bipolar disorder were more likely to receive any employment services and to receive supported employment than were patients with depression, PTSD, or other anxiety disorders. VHA patients with depression and PTSD were more likely to receive transitional work and vocational assistance than patients with schizophrenia. Future studies should examine system-level barriers to receiving employment services and identify types of employment services most appropriate for Veterans with different psychiatric diagnoses.

Employment status, employment functioning, and barriers to employment among VA primary care patients

BACKGROUND Prior research found lower employment rates among working-aged patients who use the VA than among non-Veterans or Veterans who do not use the VA, with the lowest reported employment rates among VA patients with mental disorders. This study assessed employment status, employment functioning, and barriers to employment among VA patients treated in primary care settings, and examined how depression and anxiety were associated with these outcomes. METHODS The sample included 287 VA patients treated in primary care in a large Midwestern VA Medical Center. Bivariate and multivariable analyses were conducted examining associations between socio-demographic and clinical predictors of six employment domains, including: employment status, job search self-efficacy, work performance, concerns about job loss among employed Veterans, and employment barriers and likelihood of job seeking among not employed Veterans. RESULTS 54% of respondents were employed, 36% were not employed, and 10% were economically inactive. In adjusted analyses, participants with depression or anxiety (43%) were less likely to be employed, had lower job search self-efficacy, had lower levels of work performance, and reported more employment barriers. Depression and anxiety were not associated with perceived likelihood of job loss among employed or likelihood of job seeking among not employed. LIMITATIONS Single VA primary care clinic; cross-sectional study. DISCUSSION Employment rates are low among working-aged VA primary care patients, particularly those with mental health conditions. Offering primary care interventions to patients that address mental health issues, job search self-efficacy, and work performance may be important in improving health, work, and economic outcomes.

Mobile health monitoring to characterize depression symptom trajectories in primary care

BACKGROUND Classification of depression severity can guide treatment decisions. This study examined whether using repeated mobile health assessments to determine symptom trajectories is a potentially useful method for classifying depression severity. METHODS 344 primary care patients with depression were identified and recruited as part of a program of mobile health symptom monitoring and self-management support. Depression symptoms were measured weekly via interactive voice response (IVR) calls using the Patient Health Questionnaire (PHQ-9). Trajectory analysis of weekly IVR PHQ-9 scores from baseline through week 6 was used to subgroup patients according to similar trajectories. Multivariable linear regression was used to determine whether the trajectories predicted 12-week PHQ-9 scores after adjusting for baseline and 6-week PHQ-9 scores. RESULTS The optimal trajectory analysis model included 5 non-intersecting trajectories. The subgroups of patients assigned to each trajectory had mean baseline PHQ-9s of 19.7, 14.5, 9.5, 5.0, and 2.0, and respective mean decreases in PHQ-9s over six weeks of .3, 2.0, 3.6, 2.3, and 1.9. In regression analyses, each trajectory significantly predicted 12-week PHQ-9 scores (using the modal trajectory as a reference) after adjusting for both baseline and 6-week PHQ-9 scores. LIMITATIONS Treatment history was unknown, findings may not be generalizable to new episodes of treatment. CONCLUSIONS Depression symptom trajectories based on mobile health assessments are predictive of future depression outcomes, even after accounting for typical assessments at baseline and a single follow-up time point. Approaches to classify patients׳ disease status that involve multiple repeated assessments may provide more accurate and useful information for depression management compared to lower frequency monitoring.

Influence of race/ethnicity, body mass index, and proximity of menopause on menstrual cycle patterns in the menopausal transition: the Study of Women's Health Across the Nation

ObjectiveFew studies have evaluated factors that influence menstrual cycle length (MCL) during the menopausal transition (MT), a life stage during which very long cycles become more likely to occur. The objective of this article was to assess how body mass index and race/ethnicity—factors associated with MCL in young women—influence MCL during the MT. MethodsStudy of Women’s Health Across the Nation menstrual calendar substudy data of African-American, white, Chinese, and Japanese women were available for three sites (southeastern Michigan, Los Angeles, and northern California). Self-recorded monthly menstrual calendars with end-of-the-month questions on hormone therapy use and smoking were collected from 1996 to 2006. Height and weight were measured at annual study visits. We used quantile regression to model MCL at the 25th, 50th, 75th, and 90th percentiles with bootstrap sampling to construct 95% CIs. Models evaluated MCL with time indexed to the start of the MT (n = 963) and to the final menstrual period (n = 431). ResultsDuring the MT, increases in MCL occurred mostly at the right tail of the distribution, reflecting a lengthening of long menstrual cycles, not of the median MCL. After adjustment for smoking, education, physical activity, and time, Chinese and Japanese women had 1 day to 6 days longer MCLs compared with white women. Obese women had 1 day to 5 days longer MCLs compared with nonobese women. ConclusionsAs occurs in younger women, menstrual characteristics during the MT are influenced by race/ethnicity and obesity. The long menstrual cycles characteristic of the MT are longer in obese women and in Chinese and Japanese women.