Bothersome symptoms at midlife in relation to body fat percentage.

OBJECTIVES: Increasing obesity has been associated with a higher frequency of symptoms at midlife. Bothersomeness represents an important measure of perceived symptom severity, but has received relatively little consideration, and relationships between symptom bothersomeness and obesity are not known. We evaluated the association between body fat percentage (%BF) and the bothersomeness of symptoms at midlife. METHODS: This cross-sectional study included women aged 40-60 in Qatar (n = 841). Participants reported frequency and bothersomeness of midlife symptoms hypothesized to be related to body composition. Initially, we characterized the relationship between continuous %BF and presence (yes/no) and bothersomeness (yes/no) for each symptom using restricted cubic spline (RCS) models to test nonlinearity. Subsequently, we used multinomial logistic regressions to evaluate associations between %BF and multilevel symptom outcomes, where categories were: (a) no symptoms or bother, (b) symptoms without bothersomeness, and (c) symptoms with bothersomeness. RESULTS: The highest frequency of bothersomeness was reported for aches/stiffness in joints (51%), followed by trouble sleeping (34%), night sweats (21%), urinary incontinence (18%), hot flashes (16%), and shortness of breath (15%). In unadjusted multinomial logistic regressions, aches/stiffness in joints with and without bothersomeness had the same significant relationship with %BF. Bothersome night sweats, urinary incontinence, and hot flashes were significantly associated with %BF (p < .05), but those same symptoms without bothersomeness were not significantly associated with %BF. CONCLUSIONS: Our findings suggest that bothersomeness is an important variable that tracks with body fat and gives different information than report of the presence/absence of a symptom alone.

Association of oral contraceptives and tubal ligation with risk of early natural menopause.

STUDY QUESTION: What is the association of oral contraceptives (OCs) and tubal ligation (TL) with early natural menopause? SUMMARY ANSWER: We did not observe an association of OC use with risk of early natural menopause; however, TL was associated with a modestly higher risk. WHAT IS KNOWN ALREADY: OCs manipulate hormone levels, prevent ovulation, and may modify the rate of follicular atresia, while TL may disrupt the blood supply to the ovaries. These mechanisms may be associated with risk of early menopause, a condition associated with increased risk of cardiovascular disease and other adverse health outcomes. STUDY DESIGN, SIZE, DURATION: We examined the association of OC use and TL with natural menopause before the age of 45 years in a population-based study within the prospective Nurses' Health Study II (NHSII) cohort. Participants were followed from 1989 to 2017 and response rates were 85-90% for each cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants included 106 633 NHSII members who were premenopausal and aged 25-42 years at baseline. Use, duration and type of OC, and TL were measured at baseline and every 2 years. Menopause status and age were assessed every 2 years. Follow-up continued until early menopause, age 45 years, hysterectomy, oophorectomy, death, cancer diagnosis, or loss to follow-up. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CIs adjusted for lifestyle, dietary, and reproductive factors. MAIN RESULTS AND THE ROLE OF CHANCE: Over 1.6 million person-years, 2579 members of the analytic cohort experienced early natural menopause. In multivariable models, the duration, timing, and type of OC use were not associated with risk of early menopause. For example, compared with women who never used OCs, those reporting 120+ months of OC use had an HR for early menopause of 1.01 (95% CI, 0.87-1.17; P for trend=0.71). TL was associated with increased risk of early menopause (HR = 1.17, 95% CI, 1.06-1.28). LIMITATIONS, REASONS FOR CAUTION: Our study population is homogenous with respect to race and ethnicity. Additional evaluation of these relations in more diverse populations is important. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is the largest study examining the association of OC use and TL with early natural menopause to date. While TL was associated with a modest higher risk of early menopause, our findings do not support any material hazard or benefit for the use of OCs. STUDY FUNDING/COMPETING INTEREST(S): The study was sponsored by UO1CA176726 and R01HD078517 from the National Institutes of Health and Department of Health and Human Services. The work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors have no competing interests to report. TRIAL REGISTRATION NUMBER: N/A.

Male birthweight, semen quality and birth outcomes.

STUDY QUESTION: What are the relations among birthweight (BW), semen parameters and birth outcomes in a population-based sample? SUMMARY ANSWER: BW is unrelated to semen parameters, which are in turn unrelated to birth outcomes. WHAT IS KNOWN ALREADY: In clinical settings, there has been suggestion that semen parameters are related to BW when comparing fertile and infertile men; however, findings have been less clear in more general populations. STUDY DESIGN, SIZE, DURATION: Questionnaire data and semen samples were collected at baseline from 427 male participants of the population-based Longitudinal Investigation of Fertility and the Environment (LIFE) prospective cohort study from 2005 to 2009, who were followed prospectively to assess pregnancy outcomes among 226 singleton births. PARTICIPANTS/MATERIALS, SETTING, METHODS: Men of at least 18 years of age who were married or in a committed relationship and trying to conceive were eligible for participation; physician-diagnosed infertility was an exclusion criterion. Participants were recruited from two geographic areas and semen samples were analyzed for 34 quality parameters categorized as general, motility, morphology, sperm head and sperm chromatin structure using methods including computer-aided semen analysis integrated visual optical system and sperm chromatin structure assay. Linear and mixed models were used for statistical analysis of the relations between men's BW, semen parameters, and BW, gestational age at delivery, birth length, head circumference and ponderal index of singleton births. MAIN RESULTS AND THE ROLE OF CHANCE: No association was observed between male BW and semen parameters or birth outcomes. Few associations were observed between semen parameters and birth outcomes, and the observed statistically significant associations were isolated and without a consistent pattern that would suggest an association between BW and birth outcomes. LIMITATIONS, REASONS FOR CAUTION: Men's BW was self-reported and may be subject to some imprecision. Semen analysis was performed the day after collection, an approach that impacts the assessment of motility and that may limit inference from our analyses of motility measures. In addition, inclusion criteria for selection into the cohort limits generalizability to generally healthy couples trying to conceive and without known subfertility. WIDER IMPLICATIONS OF THE FINDINGS: Despite suggestions from prior studies of male in utero exposures impacting BW and male reproductive health, there appears to be little support for such relations in this generally healthy population. STUDY FUNDING/COMPETING INTEREST(S): Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (N01-HD-3-3355, N01-HD-3-3356 and NOH-HD-3-3358). The authors report no competing interests, and a Memo of Understanding with the National Institute of Occupational Safety and Health (NIOSH) for semen analysis. TRIAL REGISTRATION NUMBER: Not applicable.

Adult adiposity and risk of early menopause.

STUDY QUESTION: Is adult adiposity associated with early menopause? SUMMARY ANSWER: Overall and abdominal adiposity were non-linearly associated with odds for early natural menopause with elevated odds observed among women who were underweight in early or mid-adulthood compared to lean-normal weight women. WHAT IS KNOWN ALREADY: High and low adiposity have been associated with reproductive function and may potentially impact timing of menopause. It is unclear whether various aspects of adiposity are associated with risk of early menopause. STUDY DESIGN, SIZE, DURATION: Prospective cohort study that examined data from 78 759 premenopausal women from the Nurses' Health Study II who were followed from 1989 to 2011 for incidence of early natural menopause. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were aged 25-42 years and premenopausal at baseline in 1989, when information on menopausal status, height and weight was reported via questionnaire. Information on menopausal status, type of menopause (natural, surgical, radiation/chemotherapy), hormone therapy use and weight was updated every two years along with information on smoking, physical activity and other behavioral and health-related factors. Multivariable logistic regression was used to estimate odds ratios for early menopause, defined as natural menopause before age 45 years, by aspects of adiposity. MAIN RESULTS AND THE ROLE OF CHANCE: Early natural menopause was reported by 2804 participants. Body mass index (BMI) was non-linearly associated with risk for early menopause. Compared to women with BMI = 18.5-22.4 kg/m2, those with BMI < 18.5 kg/m2 had a significant 30% higher odds of early menopause (95% confidence interval (CI) = 1.08, 1.57), while women with BMIs between 25.0-29.9 kg/m2 had significant 21-30% lower odds. Odds were not higher in women with BMI ≥ 35.0 kg/m2 in fully adjusted analysis. Non-linear associations with higher odds in underweight women were also observed for age 18 and age 35 BMI, though lower odds for overweight women was only observed for age 35 BMI. Odds were highest among women with age 18 BMI < 18.5 kg/m2 reporting severe weight cycling. LIMITATIONS, REASONS FOR CAUTION: Though weight and early menopause status were self-reported, validation studies conducted among Nurses' Health Study participants suggest that self-reported weight is highly correlated with directly measured weight, and prospective self-reported menopausal status is highly reproducible. It is possible that underweight women may have been misclassified with an earlier age at menopause if being underweight led to amenorrhea. WIDER IMPLICATIONS OF THE FINDINGS: In one of the few studies to prospectively examine a variety of adiposity measures and risk for early menopause, our findings that women who were underweight in early or mid-adulthood had elevated risk for early menopause can assist in efforts to better understand the etiology of early menopause. Additional prospective research is needed to understand how low adiposity may physiologically impact timing of menopause. STUDY FUNDING/COMPETING INTEREST(S): This study was conducted with funding from NIH UM1CA176726 and R01HD078517. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: Not applicable.

Self-collected dried blood spots as a tool for measuring ovarian reserve in young female cancer survivors.

STUDY QUESTION: Are female young cancer survivors (YCS) able to self-collect high-quality dried blood spots (DBSs) at home to provide biospecimens for studying ovarian reserve? SUMMARY ANSWER: YCS can self-collect high-quality DBS specimens in non-clinical settings, and anti-Mullerian hormone (AMH) levels can be assayed in such specimens. WHAT IS KNOWN ALREADY: Large-scale biosample collection is a barrier to studying ovarian reserve in YCS. DBS collected by research personnel has high acceptability. AMH levels measured in DBS are highly correlated with those measured by serum-based methods. STUDY DESIGN, SIZE, DURATION: In a prospective cohort study, YCS were recruited to self-collect DBS samples. AMH levels were assayed in 112 samples. PARTICIPANTS/MATERIALS, SETTING, METHODS: YCS participants, ages 18-44, were recruited from a nationwide longitudinal cohort and DBS collection materials were posted to them. AMH levels were assayed by the Ansh DBS AMH ELISA and compared according to participant characteristics. MAIN RESULTS AND THE ROLE OF CHANCE: Among 163 potential participants, 123 (75%) were enrolled. Of those enrolled, 112 (91%) were able to complete DBS self-collection and submit mailed samples adequate for measuring AMH. Participants (mean age 31.6 [SD 5.5]) were 85% white, 87% college graduates and 46% reported higher income. Common cancer types were lymphoma and leukemia (34%), breast cancer (30%) and thyroid or skin cancer (8%). The geometric mean (95% confidence interval) AMH level in DBS samples was 0.24 ng/ml (0.16-0.36). In adjusted analysis, AMH levels for survivors of breast cancer (0.02 ng/ml [0.01-0.07]) or leukemia/lymphoma (0.03 ng/ml [0.01-0.08]) were lower than the levels in thyroid or skin cancer survivors (0.12 ng/ml [0.03-0.44]). Pelvic radiation remained associated with lower AMH levels (0.20 ng/ml [0.10-0.40] in unexposed versus 0.02 ng/ml [0.01-0.06] in exposed). Amenorrheic survivors had AMH levels (0.02 ng/ml [0.01-0.06]) that were lower than those of YCS with 7-9 (0.09 ng/ml [0.03-0.32]) or ≥10 (0.17 ng/ml [0.08-0.37]) menstrual periods in the past year. LIMITATIONS, REASONS FOR CAUTION: The results are generalizable to a population of highly educated, higher income YCS. It is unclear how generalizable the results are to other populations. WIDER IMPLICATIONS OF THE FINDINGS: Self-collected DBS is a patient-friendly and minimally invasive tool for studying ovarian reserve in geographically diverse populations. STUDY FUNDING/COMPETING INTERESTS: Research related to the development of this paper was supported by the National Institutes of Health, grants UL1 RR024926 pilot and HD080952-02, and by the American Cancer Society MRSG-08-110-01-CCE. The authors report no competing interests.

Hot flash report and measurement among Bangladeshi migrants, their London neighbors, and their community of origin.

OBJECTIVES: To examine hot flashes in relation to climate and activity patterns, and to compare subjective and objective hot flashes among Bangladeshi immigrants to London, their white London neighbors, and women still living in their community of origin, Sylhet, Bangladesh ("sedentees"). METHODS: Ninety-five women, aged 40-55, wore the Biolog ambulatory hot flash monitor. Objective measurements and subjective hot flash reports were examined in relation to demographic, reproductive, anthropometric, and lifestyle variables; temperature and humidity at 12:00 and 18:00; and time spent on housework and cooking. Concordance of objective and subjective hot flashes was assessed by Kappa statistics and by sensitivity of hot flash classification. RESULTS: During the study period, Bangladeshi sedentees reported more subjective hot flashes (p < .05), but there was no difference in number of objective hot flashes. White Londoners were more likely to describe hot flashes on their face and neck compared to Bangladeshis (p < .05). Sedentees were more likely to describe hot flashes on their feet (p < .05). Postmenopausal status, increasing parity, and high levels of housework were significant determinants of subjective hot flashes, while ambient temperature and humidity were not. Measures of subjective/objective concordance were low but similar across groups (10-20%). The proportion of objective hot flashes that were also self-reported was lowest among immigrants. DISCUSSION: Hot flashes were not associated with warmer temperatures, but were associated with housework and with site-specific patterns of cooking. The number of objective hot flash measures did not differ, but differences in subjective experience suggest the influence of culture.

Associations between urinary phthalate concentrations and semen quality parameters in a general population.

STUDY QUESTION: Are urinary phthalate concentrations associated with altered semen quality parameters among males recruited from the general population? SUMMARY ANSWER: Urinary levels of metabolites of phthalate diesters are associated with lower total sperm counts, larger sperm head sizes, and higher percentages of morphologically abnormal sperm. WHAT IS KNOWN ALREADY: High dose experiments in rats implicate phthalates as anti-androgens. Studies involving infertile men seeking care suggest that phthalates influence measures of semen quality raising concern about the implications for men in the general population. STUDY DESIGN, SIZE, DURATION: This prospective cohort study comprised 501 male partners in couples discontinuing contraception to become pregnant, who were recruited from 16 US counties using population-based sampling frameworks from 2005 to 2009. PARTICIPANTS/MATERIALS, SETTING, METHODS: Urine and semen samples were obtained at baseline from 473 (94%) men, of whom 378 (80%) men provided a second sample the following month. Urine was analyzed for 14 monoester metabolites of phthalate diesters by high-performance liquid chromatography coupled to tandem mass spectrometry. Semen samples were analyzed for 34 quality parameters categorized as general, motility, morphology, sperm head and sperm chromatin structure. MAIN RESULTS AND THE ROLE OF CHANCE: Urinary mono-[2-(carboxymethyl) hexyl] phthalate (MCMHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-benzyl phthalate (MBzP), and mono-isononyl phthalate (MNP) were significantly associated with lower total sperm counts and concentrations, larger sperm head sizes, higher proportions of megalo head sperm morphology, and/or other morphological changes. Urinary mono-methyl phthalate (MMP) and mono-cyclohexyl phthalate (MCPP) were significantly associated with lower sperm motility, and urine mono-2-ethylhexyl phthalate (MEHP) was significantly associated with higher sperm motility. LIMITATIONS, REASONS FOR CAUTION: While adverse associations were observed, the implications of the findings for couple fecundity and fertility remain to be established. Cautious interpretation is needed in light of reliance on a single measurement of phthalate measure and no correction for multiple comparisons.

Association of inflammation markers with menstrual symptom severity and premenstrual syndrome in young women.

STUDY QUESTION: Are markers of chronic inflammation associated with menstrual symptom severity and premenstrual syndrome (PMS)? SUMMARY ANSWER: Serum levels of inflammatory markers, including interleukin (IL)-2, IL-4, IL-10, IL-12 and interferon (IFN)-γ were positively associated with menstrual symptom severity and/or PMS in young women. WHAT IS KNOWN ALREADY: Chronic inflammation has been implicated in the etiology of depression and other disorders that share common features with PMS, but whether inflammation contributes to menstrual symptom severity and PMS is unknown. STUDY DESIGN, SIZE, DURATION: Cross-sectional study of 277 women aged 18-30 years, conducted in 2006-2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants provided information on menstrual symptoms, lifestyle, diet, anthropometry and other factors by questionnaire and/or direct measurement, and a mid-luteal phase fasting blood sample was taken between 7 a.m. and 12 p.m. Total, physical and affective menstrual symptom scores were calculated for all participants, of whom 13% (n = 37) met criteria for moderate-to-severe PMS and 24% (n = 67) met PMS control criteria. Inflammatory factors assayed in serum included IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, tumor necrosis factor-α, granulocyte macrophage colony stimulating factor, IFN-γ and C-reactive protein. MAIN RESULTS AND THE ROLE OF CHANCE: After adjustment for age, smoking status and BMI, total menstrual symptom score was positively associated with levels of IL-2 (percentage difference in women at the 75th percentile of total symptom score versus at the 25th percentile = 24.7%; P = 0.04), IL-4 (21.5%; P = 0.04), IL-10 (28.0%; P < 0.01) and IL-12 (42.0%; P = 0.02) in analyses including all participants. Affective menstrual symptom score was linearly related to levels of IL-2 (percentage difference at 75th percentile versus 25th percentile = 31.0%; P = 0.02), while physical/behavioral symptom score was linearly related to levels of IL-4 (19.1%; P = 0.03) and IL-12 (33.2%; P = 0.03). Additionally, mean levels of several factors were significantly higher in women meeting PMS criteria compared with women meeting control criteria, including IL-4 (92% higher in cases versus controls; P = 0.01); IL-10 (87%; P = 0.03); IL-12 (170%; P = 0.04) and IFN-γ (158%; P = 0.01). LIMITATIONS, REASONS FOR CAUTION: Our study has several limitations. While a single blood sample may not perfectly capture long-term levels of inflammation, ample data suggest that levels of cytokines are stable over time. Although we did not base our assessment of PMS on prospective symptom diaries, we used validated criteria to define PMS cases and controls, and excluded women with evidence of comorbid mood disorders. Furthermore, because of the cross-sectional design of the study, the temporal relation of inflammatory factors and menstrual symptoms is unclear. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is among the first studies to suggest that inflammatory factors may be elevated in women experiencing menstrual symptoms and PMS. Additional studies are needed to determine whether inflammation plays an etiologic role in PMS. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Departments of Public Health and Nutrition and by a Faculty Research Grant, University of Massachusetts Amherst. No conflicts declared. TRIAL REGISTRATION NUMBER: N/A.

Improper adjustment for baseline in genetic association studies of change in phenotype.

OBJECTIVE: In studies of associations between genetic factors and outcomes where change in phenotype is of interest, proper modeling of the data, particularly the treatment of baseline trait values, is required to draw valid conclusions. METHODS: The authors compared models of blood pressure response to a cold pressor test with and without inclusion of baseline blood pressure as a regressor and evaluate the resultant biases. RESULTS: Adjustment for baseline presents a potential source of bias for assessment of genotype-phenotype associations. This bias was observed to occur both under the absence of a true effect, as well when a relation between genotype and change in phenotype was simulated. In simulations that incorporated measurement error, estimates were as great as two fold the true parameter values when unmeasured confounding was a factor. CONCLUSIONS: Adjusting for baseline introduces bias in genetic association studies when change in phenotype is the outcome of interest. Model misspecification bias may impact inference and provide one possible source of non-replication of findings in the literature.

Perceived psychosocial stress and glucose intolerance among pregnant Hispanic women.

AIM: Prior literature suggests a positive association between psychosocial stress and the risk of diabetes in non-pregnant populations, but studies during pregnancy are sparse. We evaluated the relationship between stress and glucose intolerance among 1115 Hispanic (predominantly Puerto Rican) prenatal care patients in Proyecto Buena Salud, a prospective cohort study in Western Massachusetts (2006-2011). METHODS: Cohen's Perceived Stress Scale (PSS-14) was administered in early (mean = 12.3 weeks gestation; range 4.1-18 weeks) and mid- (mean = 21.3 weeks gestation; range 18.1-26 weeks) pregnancy. Participants were classified as having a pregnancy complicated by gestational diabetes mellitus, impaired glucose tolerance, and abnormal glucose tolerance, based on the degree of abnormality on glucose tolerance testing between 24 and 28 weeks of gestation. RESULTS: The prevalence of gestational diabetes mellitus, impaired glucose tolerance, and abnormal glucose tolerance was 4.1%, 7.2%, and 14.5%, respectively. Absolute levels of early or mid-pregnancy stress were not significantly associated with glucose intolerance. However, participants with an increase in stress from early to mid-pregnancy had a 2.6-fold increased odds of gestational diabetes mellitus (95% confidence intervals: 1.0-6.9) as compared to those with no change or a decrease in stress after adjusting for age and pre-pregnancy body mass index. In addition, every one-point increase in stress scores was associated with a 5.5mg/dL increase in screening glucose level (ß=5.5; standard deviation=2.8; P=0.05), after adjusting for the same variables. CONCLUSION: In this population of predominantly Puerto Rican women, stress patterns during pregnancy may influence the risk of glucose intolerance.

Environmental PCB exposure and risk of endometriosis.

BACKGROUND: Hormonally active environmental agents have recently been associated with the development of endometriosis. METHODS: We undertook a study to assess the relationship between endometriosis, an estrogen-dependent gynaecological disease, and 62 individual polychlorinated biphenyl (PCBs) congeners. We enrolled 84 eligible women aged 18-40 years undergoing laparoscopy for study, which included an interview and blood specimen (n=79; 94%). Thirty-two women had visually confirmed endometriosis at laparoscopy while 52 did not. Blood specimens were run in batches of 14 including four quality control samples for toxicological analysis. Each PCB congener was adjusted for recovery; batch-specific reagent blanks were subtracted. All PCB concentrations were log transformed and expressed in ng/g serum first as a sum and then as tertiles by purported estrogenic or anti-estrogenic activity of PCB congeners. RESULTS: Using unconditional logistic regression analysis, a significantly elevated odds ratio (OR) was observed for women in the third tertile of anti-estrogenic PCBs [OR 3.77; 95% confidence interval (CI) 1.12-12.68]. Risk remained elevated after controlling for gravidity, current cigarette smoking and serum lipids (OR 3.30; 95% CI 0.87-12.46). CONCLUSIONS: These data suggest that anti-estrogenic PCBs may be associated with the development of endometriosis.