Hypothyroxinaemia during gestation is associated with low ferritin and increased levels of inflammatory markers.

Objective: Pregnancy is a state of physiological inflammation facilitating implantation. Early isolated hypothyroxinaemia (IH) and increased inflammation (including obesity) have been associated with severe obstetric complications. The current study evaluated the association between IH, low ferritin and inflammation parameters (interleukin 6 (IL-6), C-reactive protein (CRP), human chorionic gonadotrophin (hCG) and obesity. Moreover, the course of these parameters throughout pregnancy was evaluated in relation to IH. Methods: In the cross-sectional study (A) at 12 weeks, 2759 women participated and 2433 participated in the longitudinal study (B) with assessments at 12, 20 and 28 weeks gestation. At the first trimester, 122 (4.4%) IH women (free thyroxine (FT4) <5th percentile, normal TSH levels) were compared with 2114 (76.6%) reference women (FT4 between tenth and 90th percentiles, normal thyrotrophin (TSH) levels), in study B these figures were 99 (4.1%) and 1847 (75.9%), respectively. Results: Cross-sectionally, compared to reference women, IH was independently associated with low ferritin (<5th percentile, OR: 2.6, 95% CI: 1.4-4.9), high CRP (>95th percentile: OR: 1.9, 95% CI: 1.04-3.7), low hCG ( 30, OR: 1.7, 95% CI: 1.12.9) and higher age (OR: 1.1, 95% CI: 1.04-1.15). Longitudinally, compared to reference women, women with IH at 12 weeks gestation showed persistently and significantly lower ferritin and hCG levels, and persistently higher CRP and IL-6 levels throughout gestation. Conclusion: Gestational IH could be viewed as a condition of increased inflammation, as reported in non-thyroidal illness syndrome. Less favourable inflammation parameters and low iron status during early gestation in IH women seem to persist throughout gestation.

Association between maternal thyroid function and risk of gestational hypertension and pre-eclampsia: a systematic review and individual-participant data meta-analysis.

BACKGROUND: Adequate maternal thyroid function is important for an uncomplicated pregnancy. Although multiple observational studies have evaluated the association between thyroid dysfunction and hypertensive disorders of pregnancy, the methods and definitions of abnormalities in thyroid function tests were heterogeneous, and the results were conflicting. We aimed to examine the association between abnormalities in thyroid function tests and risk of gestational hypertension and pre-eclampsia. METHODS: In this systematic review and meta-analysis of individual-participant data, we searched MEDLINE (Ovid), Embase, Scopus, and the Cochrane Database of Systematic Reviews from date of inception to Dec 27, 2019, for prospective cohort studies with data on maternal concentrations of thyroid-stimulating hormone (TSH), free thyroxine (FT4), thyroid peroxidase (TPO) antibodies, individually or in combination, as well as on gestational hypertension, pre-eclampsia, or both. We issued open invitations to study authors to participate in the Consortium on Thyroid and Pregnancy and to share the individual-participant data. We excluded participants who had pre-existing thyroid disease or multifetal pregnancy, or were taking medications that affect thyroid function. The primary outcomes were documented gestational hypertension and pre-eclampsia. Individual-participant data were analysed using logistic mixed-effects regression models adjusting for maternal age, BMI, smoking, parity, ethnicity, and gestational age at blood sampling. The study protocol was registered with PROSPERO, CRD42019128585. FINDINGS: We identified 1539 published studies, of which 33 cohorts met the inclusion criteria and 19 cohorts were included after the authors agreed to participate. Our study population comprised 46 528 pregnant women, of whom 39 826 (85·6%) women had sufficient data (TSH and FT4 concentrations and TPO antibody status) to be classified according to their thyroid function status. Of these women, 1275 (3·2%) had subclinical hypothyroidism, 933 (2·3%) had isolated hypothyroxinaemia, 619 (1·6%) had subclinical hyperthyroidism, and 337 (0·8%) had overt hyperthyroidism. Compared with euthyroidism, subclinical hypothyroidism was associated with a higher risk of pre-eclampsia (2·1% vs 3·6%; OR 1·53 [95% CI 1·09-2·15]). Subclinical hyperthyroidism, isolated hypothyroxinaemia, or TPO antibody positivity were not associated with gestational hypertension or pre-eclampsia. In continuous analyses, both a higher and a lower TSH concentration were associated with a higher risk of pre-eclampsia (p=0·0001). FT4 concentrations were not associated with the outcomes measured. INTERPRETATION: Compared with euthyroidism, subclinical hypothyroidism during pregnancy was associated with a higher risk of pre-eclampsia. There was a U-shaped association of TSH with pre-eclampsia. These results quantify the risks of gestational hypertension or pre-eclampsia in women with thyroid function test abnormalities, adding to the total body of evidence on the risk of adverse maternal and fetal outcomes of thyroid dysfunction during pregnancy. These findings have potential implications for defining the optimal treatment target in women treated with levothyroxine during pregnancy, which needs to be assessed in future interventional studies. FUNDING: Arkansas Biosciences Institute and Netherlands Organization for Scientific Research.

Long-Term Follow-Up Results of Mechanical Wrist Traction as Non-Invasive Treatment for Carpal Tunnel Syndrome.

Background: For patients with carpal tunnel syndrome (CTS), the only long-term effective treatment option is carpal tunnel release surgery. Up to one-third report recurrent symptoms, and 12% needs repeated surgery. This study aimed to evaluate the long-term effects of mechanical traction as a non-invasive treatment option for CTS compared to care as usual. Methods: Patients with electrodiagnostically confirmed CTS [N = 181; mean age, 58.1 (13.0) years; 67% women] were recruited from an outpatient neurology clinic in the Netherlands. Patients completed baseline questionnaires and randomized to the intervention group (12 treatments with mechanical traction, twice a week for 6 weeks) or care as usual. The primary clinical outcome measure was surgery during the 12-month follow-up. Secondly, we assessed symptom severity with the Boston Carpal Tunnel Questionnaire (BCTQ) at baseline and at the 12-month follow-up. Changes in CTS symptom severity between baseline and the 12-month follow-up were analyzed between groups using t-tests and a multiple linear regression analyses, adjusting for duration of complaints, age, gender, and symptom severity at baseline. Results: At the 12-month follow-up, 35 of 94 (37%) patients in the intervention group had surgery, compared to 38 of 87 (44%) in the care-as-usual group ( χ 1 2 = 0.78, p = 0.377). Symptom severity and functional status scores did not significantly differ between the intervention (n = 81) and care-as-usual group (n = 55) at follow-up. For patients who did not have surgery, BCTQ scores decreased significantly more from baseline to the 12-month follow-up in the intervention group (n = 53) compared to patients in the care-as-usual group (n = 25). For patients who did not have surgery, belonging to the intervention group and a higher BCTQ score at baseline were related to a greater decrease in BCTQ scores from baseline to the 12-month follow-up, as well as symptom severity and functional status. Conclusions: Mechanical traction is effective in reducing symptom severity compared to current conservative treatment options in standard care and can therefore benefit the large number of patients that prefer conservative treatment for CTS. Clinical Trial Registration: Clinical Trials NL44692.008.13. Registered 19 September 2013, https://clinicaltrials.gov/ct2/show/NCT01949493.

Association of maternal thyroid function with birthweight: a systematic review and individual-participant data meta-analysis.

BACKGROUND: Adequate transplacental passage of maternal thyroid hormone is important for normal fetal growth and development. Maternal overt hypothyroidism and hyperthyroidism are associated with low birthweight, but important knowledge gaps remain regarding the effect of subclinical thyroid function test abnormalities on birthweight-both in general and during the late second and third trimester of pregnancy. The aim of this study was to examine associations of maternal thyroid function with birthweight. METHODS: In this systematic review and individual-participant data meta-analysis, we searched MEDLINE (Ovid), Embase, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar from inception to Oct 15, 2019, for prospective cohort studies with data on maternal thyroid function during pregnancy and birthweight, and we issued open invitations to identify study authors to join the Consortium on Thyroid and Pregnancy. We excluded participants with multiple pregnancies, in-vitro fertilisation, pre-existing thyroid disease or thyroid medication usage, miscarriages, and stillbirths. The main outcomes assessed were small for gestational age (SGA) neonates, large for gestational age neonates, and newborn birthweight. We analysed individual-participant data using mixed-effects regression models adjusting for maternal age, BMI, ethnicity, smoking, parity, gestational age at blood sampling, fetal sex, and gestational age at birth. The study protocol was pre-registered at the International Prospective Register of Systematic Reviews, CRD42016043496. FINDINGS: We identified 2526 published reports, from which 36 cohorts met the inclusion criteria. The study authors for 15 of these cohorts agreed to participate, and five more unpublished datasets were added, giving a study population of 48 145 mother-child pairs after exclusions, of whom 1275 (3·1%) had subclinical hypothyroidism (increased thyroid stimulating hormone [TSH] with normal free thyroxine [FT4]) and 929 (2·2%) had isolated hypothyroxinaemia (decreased FT4 with normal TSH). Maternal subclinical hypothyroidism was associated with a higher risk of SGA than was euthyroidism (11·8% vs 10·0%; adjusted risk difference 2·43%, 95% CI 0·43 to 4·81; odds ratio [OR] 1·24, 1·04 to 1·48; p=0·015) and lower mean birthweight (mean difference -38 g, -61 to -15; p=0·0015), with a higher effect estimate for measurement in the third trimester than in the first or second. Isolated hypothyroxinaemia was associated with a lower risk of SGA than was euthyroidism (7·3% vs 10·0%, adjusted risk difference -2·91, -4·49 to -0·88; OR 0·70, 0·55 to 0·91; p=0·0073) and higher mean birthweight (mean difference 45 g, 18 to 73; p=0·0012). Each 1 SD increase in maternal TSH concentration was associated with a 6 g lower birthweight (-10 to -2; p=0·0030), with higher effect estimates in women who were thyroid peroxidase antibody positive than for women who were negative (pinteraction=0·10). Each 1 SD increase in FT4 concentration was associated with a 21 g lower birthweight (-25 to -17; p<0·0001), with a higher effect estimate for measurement in the third trimester than the first or second. INTERPRETATION: Maternal subclinical hypothyroidism in pregnancy is associated with a higher risk of SGA and lower birthweight, whereas isolated hypothyroxinaemia is associated with lower risk of SGA and higher birthweight. There was an inverse, dose-response association of maternal TSH and FT4 (even within the normal range) with birthweight. These results advance our understanding of the complex relationships between maternal thyroid function and fetal outcomes, and they should prompt careful consideration of potential risks and benefits of levothyroxine therapy during pregnancy. FUNDING: Netherlands Organization for Scientific Research (grant 401.16.020).

Hormonal and psychological factors in nausea and vomiting during pregnancy.

BACKGROUND: The aetiology of nausea and vomiting during pregnancy (NVP) is multifactorial, but the relative contribution of biological and psychological determinants is insufficiently understood. We examined the association of human chorionic gonadotropin (hCG), thyroid hormones (thyroid-stimulating hormone and thyroxin) and psychological factors with NVP. METHODS: Blood chemistry and psychological measures were obtained in 1682 pregnant women participating in the Holistic Approach to Pregnancy and the first Postpartum Year (HAPPY) study between 12 and 14 weeks of gestation. The presence of NVP was measured using the Pregnancy-Unique Quantification of Emesis scale. Depressive symptoms were assessed using the Edinburgh Depression Scale. Multivariable logistic regression analyses were used to investigate the independent role of hCG, thyroid hormones and depression as related to NVP, adjusting for age, body mass index, education, parity, smoking status, unplanned pregnancy and history of depression. RESULTS: Elevated levels of NVP were observed in 318 (18.9%) participants. High hCG levels [odds ratio (OR) = 1.47, 95% confidence interval (CI) = 1.11-1.95], elevated depressive symptoms in the first trimester (OR = 1.67, 95% CI = 1.15-2.43) and a history of depression (OR = 1.53, 95% CI = 1.11-2.11) were independently related to high NVP. Multiparity (OR = 1.47, 95% CI = 1.12-1.92) and younger age (OR = 0.91, 95% CI = 0.87-0.94) were also associated with high NVP, whereas (sub)clinical hyperthyroidism was not related to high NVP. CONCLUSIONS: The current study is the first to demonstrate that a combination of hCG hormone and psychological factors are independently related to nausea and vomiting during early pregnancy.

Development of the Patient's Experience and Attitude Colposcopy Eindhoven Questionnaire (PEACE-q).

BACKGROUND: No validated instruments for the evaluation of patient satisfaction in colposcopy do exist. Therefore, this study reports on the development of a Patient's Experience and Attitude to Colposcopy questionnaire. METHODS: Patients who recently received colposcopy participated in a focus group. A panel of experts evaluated the transcriptions and agreed on a 15-item draft questionnaire. The draft questionnaire was completed by 68 women who subsequently came for a colposcopy. For construct validation, Exploratory Factor Analysis (EFA) and Confirmatory Factor Analysis (CFA) were performed as well as reliability analysis. Concurrent validity was assessed with the 4-item Patient Health questionnaire (PHQ-4). RESULTS: Construct validation resulted in an 8-item patient perception scale with good psychometric properties (Cronbach's alpha: 0.76) and excellent model fit. Two subscales could be discriminated: patient procedure perception scale (alpha: 0.89) and caregiver attitude perception scale (alpha: 0.71). Both subscales intercorrelated moderately (r = 0.28, p = 0.045). The subscale patient perception correlated significantly with the PHQ-4 scale and its anxiety subscale, not with the depression subscale. CONCLUSIONS: We developed a Patient's Experience and Attitude to Colposcopy questionnaire with adequate psychometric properties. Future application in out-patient clinics should further evaluate its clinical relevance.

Mechanical wrist traction as a non-invasive treatment for carpal tunnel syndrome: a randomized controlled trial.

BACKGROUND: Carpal tunnel syndrome (CTS) is a common, compressive nerve-entrapment disorder with symptoms of numbness, paresthesia, and pain. Carpal tunnel release surgery is the only known long-term effective treatment. However, surgery is invasive and up to 30% of patients report recurrence or persistence of symptoms or suffer from post-surgical complications. A promising non-surgical treatment for CTS is mechanical wrist traction. The purpose of this study was to evaluate clinical outcomes following mechanical traction in patients with CTS compared to care as usual. METHODS: Adult patients (N = 181, mean age 58.1 (13.0) years, 67% women) with electrodiagnostically confirmed CTS were recruited from an outpatient neurology clinic in the Netherlands between October 2013 and April 2015. After baseline assessments, patients were randomized to either the intervention group (12 treatments with mechanical traction, twice a week for a period of 6 weeks) or "care as usual". The main clinical outcome measure was surgery during 6 months' follow-up. In addition, symptom severity was measured using the Boston Carpal Tunnel Questionnaire (BCTQ) at baseline, 3, and 6 months' follow-up. Baseline characteristics and severity of CTS symptoms at follow-up were compared between the intervention and care-as-usual groups using a t test and χ 2 tests. Time to event (surgery) between the groups was analyzed using Kaplan-Meier survival analysis and Cox proportional hazards analysis. RESULTS: The intervention group had fewer surgeries (28%) compared to the care-as-usual group (43%) during follow-up (χ21 = 4.40, p = .036). Analyses of the survival curves revealed a statistically significant difference between the groups over time (log-rank test χ 21 = 6.94, p = .008). At 6 months' follow-up, symptom severity and functional status scores had significantly decreased from baseline in both groups (p < .001) and the improvements did not differ between the two groups. CONCLUSIONS: Mechanical traction is associated with fewer surgical interventions compared to care as usual in CTS patients. Reductions in patient-reported symptoms at 6 months' follow-up was similar in both groups. The long-term effects of mechanical traction require further evaluation. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NL44692.008.13 . Registered on 19 September 2013.

Different patterns of depressive symptoms during pregnancy.

Recently, the US Preventive Services Task Force has advocated to screen pregnant and postpartum women for depression. However, we questioned the meaning of a single elevated depression score: does it represent just one episode of depression or do these symptoms persist throughout the entire pregnancy? This study assessed depressive symptoms at each trimester in a cohort of 1813 pregnant women and evaluated whether women with different patterns of depressive symptoms showed other characteristics. Depending on the trimester, elevated depression scores were prevalent in 10-15% of the pregnant women. Up to 4% reported persistent symptoms of depression throughout pregnancy. Different patterns of depressive symptoms were observed, for which persistent symptoms were related to other characteristics than incidentally elevated symptoms. Besides a previous history of mental health problems as best overall predictor, incidentally elevated depression scores were related to major life events. Furthermore, persistently depressive symptoms were related to unplanned pregnancy and multiparity. An EDS assessment at 12 weeks of gestation including three additional items (history of mental health problems, unplanned pregnancy and multiparity) enabled us to identify 83% of the women with persistent depressive symptoms. A depression screening strategy in pregnant women should take into account the potential chronicity of depressive symptoms by repeated assessments in order to offer an intervention to the most vulnerable women.

Beta-blockers and depression in elderly hypertension patients in primary care.

BACKGROUND AND OBJECTIVES: Previous findings regarding a possible association between beta-blocker use and depression are mixed. To our knowledge there have been no studies investigating the association of beta-blockers with depression in primary care hypertension patients without previous myocardial infarction. The aim of this study was to determine the relation between lipophilic beta-blocker use and depression in elderly primary care patients with hypertension. METHODS: This was a cross-sectional study in primary care practices located in the South of The Netherlands. Primary care hypertension patients without previous myocardial infarction or heart failure (n=573), aged between 60 and 85 years (mean age=70±6.6), were included. All patients underwent a structured interview that included a self-report questionnaire to assess depression (PHQ-9), which was divided in four groups (PHQ-9 score of 0, 1--3, 4--8, 9 or higher). RESULTS: A PHQ-9 score of 0 was more prevalent in non-beta-blocker users versus lipophilic beta-blocker users (46% versus 35%), a PHQ-9 score of 4--8 was less prevalent in non-beta-blocker users as compared with lipophilic beta-blocker users (14% versus 25%). A chi-squared test showed that lipophilic beta-blocker users as compared to non-beta-blockers users were more likely to be in a higher depression category. Ordinal regression showed a significant relationship between use of lipophilic beta-blockers and depression (OR=1.60, 95% CI=1.08--2.36) when adjusting for potential confounders. CONCLUSIONS: Our findings show that primary care hypertension patients who use a lipophilic beta-blocker are more likely to have higher depression scores than those who do not use a lipophilic beta-blocker.

Screening for anxiety disorders in patients with coronary artery disease.

BACKGROUND: Anxiety disorders are prevalent and associated with poor prognosis in patients with coronary artery disease (CAD). However, studies examining screening of anxiety disorders in CAD patients are lacking. In the present study we evaluated the prevalence of anxiety disorders in patients with CAD and diagnostic utility of self-rating scales for screening of anxiety disorders. METHODS: Five-hundred and twenty-three CAD patients not receiving psychotropic treatments at initiation of rehabilitation program completed self-rating scales (Hospital Anxiety and Depression Scale or HADS; Spielberger State-Anxiety Inventory or SSAI; and Spielberger Trait-Anxiety Inventory or STAI) and were interviewed for generalized anxiety disorder (GAD), social phobia, panic disorder and agoraphobia (Mini-International Neuropsychiatric Interview or MINI). RESULTS: Thirty-eight (7%) patients were diagnosed with anxiety disorder(s), including GAD (5%), social phobia (2%), agoraphobia (1%) and panic disorder (1%). Areas under the ROC curve of the HADS Anxiety subscale (HADS-A), STAI and SSAI for screening of any anxiety disorder were .81, .80 and .72, respectively. Optimal cut-off values for screening of any anxiety disorders were ≥ 8 for the HADS-A (sensitivity = 82%; specificity = 76%; and positive predictive value (PPV) = 21%); ≥ 45 for the STAI (sensitivity = 89%; specificity = 56%; and PPV = 14%); and ≥ 40 for the SSAI (sensitivity = 84%; specificity = 55%; PPV = 13%). In a subgroup of patients (n = 340) scoring below the optimal major depressive disorder screening cut-off value of HADS-Depression subscale (score <5), the HADS-A, STAI and SSAI had moderate-high sensitivity (range from 69% to 89%) and low PPVs (≤ 22%) for GAD and any anxiety disorders. CONCLUSIONS: Anxiety disorders are prevalent in CAD patients but can be reliably identified using self-rating scales. Anxiety self-rating scales had comparable sensitivities but the HADS-A had greater specificity and PPV when compared to the STAI and SSAI for screening of anxiety disorders. However, false positive rates were high, suggesting that patients with positive screening results should undergo psychiatric interview prior to initiating treatment for anxiety disorders and that routine use of anxiety self-rating scales for screening purposes can increase healthcare costs. Anxiety screening has incremental value to depression screening for identifying anxiety disorders.

Managing co-morbid depression and anxiety in primary care patients with asthma and/or chronic obstructive pulmonary disease: study protocol for a randomized controlled trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and asthma are common chronic diseases that are frequently accompanied by depression and/or anxiety. However, symptoms of depression and anxiety are often not recognized and therefore not treated. Currently, only a few studies have tested new clinical approaches that could improve the treatment of co-morbid depression and anxiety in these groups of patients. METHODS/DESIGN: The present randomized controlled study will be conducted within the framework of PoZoB (Praktijk Ondersteuning Zuid-Oost Brabant), a large primary care organization in the Netherlands. Patients with asthma/COPD and co-morbid anxiety/depression will be included in order to test the effectiveness of a disease management approach to treat these co-morbid disorders. Important elements of this approach are: 1) systematic screening to improve detection of anxiety and depression 2) treatment in case of positive screening 3) monitoring of anxiety and depression 4) intensified treatment in case of non-remission (stepped care). DISCUSSION: The present study is a large primary care study on the treatment of co-morbid depression and anxiety in patients with asthma and COPD. Strengths of this study are its randomized design, the focus on implementation in primary care and the fact that it applies the latest findings on the treatment of depression and anxiety. First results are expected in 2012/2013.

Hormone therapy and coronary heart disease risk by vasomotor menopausal symptoms.

OBJECTIVES: We examined whether the association between hormone therapy (HT) use and coronary heart disease (CHD) risk differed between women with and without vasomotor symptoms (VMS). STUDY DESIGN: We used data from a Dutch (EPOS) and Swedish (WHILA) population-based sample of 8865 women, aged 46-64 years, and free of CHD, stroke, venous thrombosis/pulmonary embolism or cancer at baseline. Data on HT use, VMS and potential confounders were collected by questionnaires. MAIN OUTCOME MEASURES: CHD endpoints, obtained via registries. RESULTS: 252 CHD cases occurred during 10.3 years of follow-up. Neither for women with nor for women without flushing or (night) sweats ever HT use was associated with CHD risk, compared with never HT use. Among women with intense VMS, ever HT use borderline significantly decreased CHD risk compared with never HT use (HR 0.48 [95% CI 0.20-1.03]). Among women without intense VMS, ever HT use was associated with a borderline significant increased CHD risk (HR 1.28 [95% CI 0.96-1.70]; P for interaction=0.02). However, after multivariate adjustment, as compared to never HT use, ever HT use was not associated with risk of CHD among women with or without intense VMS. CONCLUSIONS: In both groups of women with and without VMS, HT use does not seem to be associated with the risk of CHD. Hence, our findings do not support the view that HT use increases the CHD risk among women with an indication, i.e. VMS, but this needs to be confirmed in specifically designed studies.

Depressive disorder and thyroid axis functioning during pregnancy.

BACKGROUND: Depression and thyroid dysfunction are prevalent in women, including pregnant women. The aim of this study was to assess the relationship between depression and thyroid function during pregnancy. METHODS: One hundred and ninety-nine pregnant women three times during pregnancy were assessed for depressive disorder and for thyroid stimulating hormone (TSH) and free thyroxine (FT(4)) concentrations. RESULTS: Prevalence of depressive disorder was 6.5% in early pregnancy, 3.0% in middle pregnancy and 3.5% in late pregnancy. There were no women with overt thyroid dysfunction. Subclinical hyperthyroidism was found in 23% of women in early pregnancy, in 5% of women in middle pregnancy and in 6% of women in late of pregnancy. In late pregnancy depressed women compared to non-depressed women had significantly higher FT(4) concentrations and a strong trend towards lower TSH concentrations as well as higher prevalence of subclinical hyperthyroidism. CONCLUSIONS: These findings show an association between thyroid dysfunction and depression in late pregnancy. Because gestational depression might interfere with pregnancy outcome, evaluation of thyroid function during gestation is warranted.

Loci at chromosomes 13, 19 and 20 influence age at natural menopause.

We conducted a genome-wide association study for age at natural menopause in 2,979 European women and identified six SNPs in three loci associated with age at natural menopause: chromosome 19q13.4 (rs1172822; -0.4 year per T allele (39%); P = 6.3 × 10(-11)), chromosome 20p12.3 (rs236114; +0.5 year per A allele (21%); P = 9.7 × 10(-11)) and chromosome 13q34 (rs7333181; +0.5 year per A allele (12%); P = 2.5 × 10(-8)). These common genetic variants regulate timing of ovarian aging, an important risk factor for breast cancer, osteoporosis and cardiovascular disease.

Vasomotor symptoms are associated with a lower bone mineral density.

OBJECTIVE: The severity of vasomotor symptoms has been hypothesized to be linked to a lower bone mineral density (BMD). We examined whether women with vasomotor symptoms are different from women without symptoms with regard to BMD. METHODS: We used data from a population-based sample of 5,600 women, aged 46 to 57 years and free from bone diseases, who participated in the first cross-sectional part of the Eindhoven Perimenopausal Osteoporosis Study between 1994 and 1995. Questionnaires at baseline were used to collect data on vasomotor symptoms and potential confounders. At baseline, BMD of the lumbar spine was measured using dual energy x-ray absorptiometry. Linear regression analysis was used to analyze the data. RESULTS: Flushing was reported by 39% of all women, and night sweats, by 38% of all women. The average BMD was 1.01 +/- 0.14 g/cm and decreased with increasing frequency of flushing (P for trend < 0.0001) and night sweats (P for trend = 0.03). After multivariate adjustments for age, body mass index, menopause status, smoking, education, exercise, and hormone use, women with the highest frequency of symptoms had a 0.022 g/cm (95% CI, -0.03 to -0.01) lower BMD compared with asymptomatic women. Women who reported having the highest frequency of night sweats had a 0.011 g/cm (95% CI, -0.02 to -0.001) lower BMD compared with women with no symptoms of night sweats. CONCLUSIONS: Our findings show that vasomotor symptoms are associated with reduced bone density. It could be hypothesized that women with vasomotor symptoms might be more susceptible to the beneficial effects of estrogens, possibly by neutralizing the effect of estrogen fluctuations. Further research is needed to extend these findings to other estrogen-sensitive end organs.

Hypothyroidism might be related to breast cancer in post-menopausal women.

An association between breast cancer and thyroid (autoimmune) diseases or the presence of thyroid peroxidase antibodies (TPOAb; a marker of thyroid autoimmune disease) has been suggested. However, little is known about whether women with thyroid (autoimmune) diseases are at increased risk for developing breast cancer. This cross-sectional and prospective cohort study investigated whether the presence of TPOAb or thyroid dysfunction is related to the presence or development of breast cancer. An unselected cohort of 2,775 women around menopause was screened for the thyroid parameters thyrotropin (TSH), free thyroxine (FT(4)), and TPOAb during 1994. Detailed information on previous or actual thyroid disorders and breast cancer, and on putative factors related to breast cancer and thyroid disorders, was obtained. Clinical thyroid dysfunction was defined by both abnormal FT4 and TSH, and subclinical thyroid dysfunction by abnormal TSH (with normal FT4). A TPOAb concentration >or= 100 U/ml was defined as positive (TPOAb(+)). The study group was linked with the Eindhoven Cancer Registry to detect all women with (in situ) breast cancer (ICD-O code 174) diagnosed between 1958 and 1994. Subsequently, in the prospective study, all women who did not have breast cancer in 1994 (n = 2,738) were followed up to July, 2003, and all new cases of (in situ) breast cancer and all cancer-related deaths were registered. Of the 2,775 women, 278 (10.0%) were TPOAb(+). At the 1994 screening, 37 women (1.3%) had breast cancer. TPOAbs were (independently) related to a current diagnosis of breast cancer (OR = 3.3; 95% CI 1.3-8.5). Of the remaining women, 61 (2.2%) developed breast cancer. New breast cancer was related to: (1) an earlier diagnosis of hypothyroidism (OR = 3.8; 95% CI 1.3-10.9); (2) the use of thyroid medication (OR = 3.2; 95% CI 1.0-10.7); and (3) low FT4 (lowest tenth percentile: OR = 2.3; 95% CI 1.2-4.6). In the first 3 years follow up, the relationship between FT4 and log-TSH was disturbed in women with a new breast cancer diagnosis. The presence of TPOAb was not related to breast cancer during follow-up. A direct relationship between thyroid autoimmunity and breast cancer is unlikely. Hypothyroidism and low-normal FT4 are related with an increased risk of breast cancer in post-menopausal women. Studies are needed to clarify the origins of this possible association.

Indicators for the total duration of premenopausal endogenous estrogen exposure in relation to BMD.

BACKGROUND: Previous studies have shown that age at menopause is an important indicator of duration of endogenous estrogen exposure. The present study investigates whether combining more information on reproductive factors is useful in estimating individual total duration of exposure to endogenous estrogens. METHODS: Bone mineral density (BMD) was used as operational outcome. The study population consisted of 3476 white women living in Eindhoven, The Netherlands, aged 46-57 years, either pre- (n = 2420) or postmenopausal (n = 1056). BMD of the lumbar spine was measured by dual X-ray absorptiometry. Information on reproductive factors was obtained with questionnaires. RESULTS: The number of reproductive years explained 4.8% of the variance in BMD, while age at menopause alone accounted for 3.6%. Duration of lactation or oral contraceptive use did not add to the proportion of variance explained. The effect of reproductive years on BMD was stronger in older women. No significant associations with BMD were found for other reproductive variables. The number of miscarriages in premenopausal women (beta = 0.00760, SE = 0.00357, P = 0.03) explained only 0.16% of the variance in BMD. CONCLUSIONS: We conclude that it is not necessary to use more reproductive factors besides age at menopause and menarche in determining total duration of endogenous estrogen exposure.