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Background and Aims: Frailty is increasingly prevalent in people presenting with acute coronary syndrome (ACS). This high-risk group is typically excluded from trials of interventions in ACS, and there is uncertainty about the risks and benefits of invasive management., Methods: Patients with an ACS diagnosis between 2010 and 2015 in England were identified from Hospital Episode Statistics, with linked Office for National Statistics mortality data. Frailty was defined by the Hospital Frailty Risk Score. Causal inference analysis used regional variation in revascularization as an instrumental variable to estimate average treatment effects of revascularization on cardiovascular mortality up to 5 years in people presenting with ACS and low-, intermediate-, or high-risk frailty., Results: The analysis included 565 378 ACS patients, of whom 11.6% (n = 65 522) were at intermediate risk and 4.7% (n = 26 504) were at high risk of frailty. Intermediate and high frailty risks were associated with reduced likelihood of echocardiography, invasive angiography, or revascularization and increased likelihood of mortality and major adverse cardiovascular events compared with low frailty risk. Cardiovascular death at 5 years was 78.6%, 77.3%, and 75.7% in people at low, intermediate, and high frailty risk, respectively. Instrumental variable analysis suggested that revascularization resulted in a higher absolute reduction in cardiovascular mortality in high and intermediate frail risk patients compared with low risk at 1-year post-ACS., Conclusions: Frailty is common in people presenting with ACS, where cardiovascular causes are the principal mode of death. Revascularization is associated with short- and long-term survival benefits in people at intermediate and high risk of frailty after adjustment for measured and unmeasured confounders., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Context: Interpretation of thyroid function tests during pregnancy is limited by the generalizability of reference intervals between cohorts due to inconsistent methodology., Objective: (1) To provide an overview of published reference intervals for thyrotropin (TSH) and free thyroxine (FT4) in pregnancy, (2) to assess the consequences of common methodological between-study differences by combining raw data from different cohorts., Methods: (1) Ovid MEDLINE, EMBASE, and Web of Science were searched until December 12, 2021. Studies were assessed in duplicate. (2) The individual participant data (IPD) meta-analysis was performed in participating cohorts in the Consortium on Thyroid and Pregnancy., Results: (1) Large between-study methodological differences were identified, 11 of 102 included studies were in accordance with current guidelines; (2) 22 cohorts involving 63 198 participants were included in the meta-analysis. Not excluding thyroid peroxidase antibody-positive participants led to a rise in the upper limits of TSH in all cohorts, especially in the first (mean +17.4%; range +1.6 to +30.3%) and second trimester (mean +9.8%; range +0.6 to +32.3%). The use of the 95th percentile led to considerable changes in upper limits, varying from -10.8% to -21.8% for TSH and -1.2% to -13.2% for FT4. All other additional exclusion criteria changed reference interval cut-offs by a maximum of 3.5%. Applying these findings to the 102 studies included in the systematic review, 48 studies could be used in a clinical setting., Conclusion: We provide an overview of clinically relevant reference intervals for TSH and FT4 in pregnancy. The results of the meta-analysis indicate that future studies can adopt a simplified study setup without additional exclusion criteria., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Competing Interests: Conflict of interest: All authors report grants from the Health Research Council of New Zealand, and SW reports a grant from the Stevenson Foundation during the conduct of the study. KP and CG report grants from the Heart Foundation of New Zealand outside the submitted work.

Background: Machine learning-based risk prediction models may outperform traditional statistical models in large datasets with many variables, by identifying both novel predictors and the complex interactions between them. This study compared deep learning extensions of survival analysis models with Cox proportional hazards models for predicting cardiovascular disease (CVD) risk in national health administrative datasets., Methods: Using individual person linkage of administrative datasets, we constructed a cohort of all New Zealanders aged 30-74 who interacted with public health services during 2012. After excluding people with prior CVD, we developed sex-specific deep learning and Cox proportional hazards models to estimate the risk of CVD events within 5 years. Models were compared based on the proportion of explained variance, model calibration and discrimination, and hazard ratios for predictor variables., Results: First CVD events occurred in 61 927 of 2 164 872 people. Within the reference group, the largest hazard ratios estimated by the deep learning models were for tobacco use in women (2.04, 95% CI: 1.99, 2.10) and chronic obstructive pulmonary disease with acute lower respiratory infection in men (1.56, 95% CI: 1.50, 1.62). Other identified predictors (e.g. hypertension, chest pain, diabetes) aligned with current knowledge about CVD risk factors. Deep learning outperformed Cox proportional hazards models on the basis of proportion of explained variance (R2: 0.468 vs 0.425 in women and 0.383 vs 0.348 in men), calibration and discrimination (all P <0.0001)., Conclusions: Deep learning extensions of survival analysis models can be applied to large health administrative datasets to derive interpretable CVD risk prediction equations that are more accurate than traditional Cox proportional hazards models., (© The Author(s) 2021. Published by Oxford University Press on behalf of the International Epidemiological Association.)

We examined the importance of understanding and incorporating cultural context within Aotearoa/New Zealand when engaging in clinical research and practice. This paper reports on the qualitative findings of a mixed methods study aimed at determining what effect a cardiac risk reduction exercise and lifestyle management programme, embedded within a kaupapa Māori methodological approach, had on Māori participants. This methodology saw participants able to redevelop a western model cardiac risk reduction programme by introducing a Māori worldview. Our study revealed how the kaupapa Māori approach empowered participants to examine and evaluate not only their own health and lifestyle choices, but those of family and the wider community. Combining biomedical and kaupapa Māori components into the programme was found to benefit participants' mental, physical, spiritual and family well-being., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: Cardiovascular disease (CVD) risk management guided by predicted CVD risk is widely recommended internationally. This is the first study to examine CVD preventive pharmacotherapy in a whole-of-country primary prevention population, stratified by CVD risk., Methods and Results: Anonymized individual-level linkage of New Zealand administrative health and non-health data identified 2 250 201 individuals without atherosclerotic CVD, alive, and aged 30-74 years on 31 March 2013. We identified individuals with ≥1 dispensing by community pharmacies of blood pressure lowering (BPL) and/or lipid-lowering (LL) medications at baseline (1 October 2012-31 March 2013) and in 6-month periods between 1 April 2013 and 31 March 2016. Individuals were stratified using 5-year CVD risk equations specifically developed for application in administrative datasets. One-quarter of individuals had ≥5% 5-year risk (the current New Zealand guideline threshold for discussing preventive medications) and 5% met the ≥15% risk threshold for recommended dual therapy. By study end, dual therapy was dispensed to 2%, 18%, 34%, and 49% of individuals with <5%, 5-9%, 10-14%, and ≥15% 5-year risk, respectively. Among those dispensed baseline dual therapy, 83-89% across risk strata were still treated after 3 years. Dual therapy initiation during follow-up occurred among only 13% of high-risk individuals untreated at baseline. People without diabetes and those aged ≥65 years were more likely to remain untreated., Conclusion: Cardiovascular disease primary preventive pharmacotherapy was strongly associated with predicted CVD risk and, once commenced, was generally continued. However, only half of high-risk individuals received recommended dual therapy and treatment initiation was modest. Individually linked administrative datasets can identify clinically relevant quality improvement opportunities for entire populations., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Objective: To describe the dispensing of cardiovascular disease (CVD) preventive medications among older New Zealanders with and without prior CVD or diabetes., Methods: New Zealanders aged ≥65 years in 2013 were identified using anonymised linkage of national administrative health databases. Dispensing of blood pressure lowering (BPL), lipid lowering (LL) or antithrombotic (AT) medications, was documented, stratified by age and by history of CVD, diabetes, or neither., Results: Of the 593,549 people identified, 32% had prior CVD, 14% had diabetes (of whom half also had prior CVD) and 61% had neither diagnosis. For those with prior CVD, between 79-87% were dispensed BPL and 73-79% were dispensed AT medications, across all age groups. In contrast, LL dispensing was lower than either BPL or AT in every age group, falling from 75% at age 65-69 years to 43% at 85+ years. For people with diabetes, BPL and LL dispensing was similar to those with prior CVD, but AT dispensing was approximately 20% lower. Among people without prior CVD or diabetes, both BPL and AT dispensing increased with age (from 39% and 17% at age 65-69 years to 56% and 35% at 85+ years respectively), whereas LL dispensing was 26-31% across the 65-84 year age groups, falling to 17% at 85+ years., Conclusion: The much higher dispensing of BPL and AT compared to LL medications with increasing age suggests a preventive treatment paradox for older people, with the medications most likely to cause adverse effects being dispensed most often., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Severe thyroid dysfunction may lead to menstrual disorders and infertility via direct and indirect interactions with the hypothalamo-pituitary-ovarian axis and the reproductive organs. However, the exact prevalence of infertility in women with thyroid disorders remains unknown. Fertility problems may persist even after restoring normal thyroid function, and then surgery and/or an assisted reproductive technology (ART) may be necessary to obtain a pregnancy. The initial step in an ART treatment is the ovarian stimulation, putting strain on the thyroid gland, potentially leading to (permanent) hypothyroidism in women with thyroid autoimmunity (TAI) or when already treated with thyroid hormones (LT4). Moreover, women with ovarian and unexplained causes of infertility have a higher prevalence of TAI. In women treated with LT4, a serum TSH level <2.5 mIU/L should be targeted before ART. In women with TSH levels >4.0 mIU/L, fertilisation rates, embryo quality and live birth rates may be impaired but also improved with LT4 therapy. In euthyroid women with TAI, LT4 should not be given systematically, but on a case-by-case basis if serum TSH is >2.5 mIU/L. For all of the above reasons, women of infertile couples should be screened routinely for the presence of thyroid disorders. In this review, we will focus on the gaps in the current knowledge, the remaining questions on the associations between thyroid (disorders) and (assisted) reproduction and make proposals for future investigations that may lead to a better understanding and contribute to novel treatment options in the long term.

Context and Objective: Targeted screening is proposed for the detection of thyroid dysfunction in pregnant women rather than universal screening (US). We aimed to determine the detection rate of subclinical hypothyroidism (SCH) and overt hypothyroidism (OH) based on American Thyroid Association guidelines (ATA-GL) and whether it could be improved., Design, Setting, and Participants: Cross-sectional study of 1832 pregnant women in a single center. Thyroid function (TSH and free T4) and iron status were determined. The high-risk group (HRG) included women with one or more ATA-GL risk factors and the low-risk group (LRG) included women without. Participants with other risk factors [body mass index (BMI) 30 to 39.9 kg/m2, Caucasian background] were classified as HRG+ and those with iron deficiency as HRG++., Results: The HRG included 64% of women and the LRG included 36% (P < 0.001). Of all participants, 4.5% had SCH and 0.5% OH. The detection rate of SCH and OH was comparable between the LRG and HRG (46% vs 54% and 25% vs 75%; P = 0.560 and 0.157, respectively). In the HRG, the detection rate of SCH was lower than that of US (54% vs 100%; P < 0.001), but that of OH was comparable (75%; P = 0.596). The detection rate of SCH in the HRG+ and HRG++ was comparable to that in the US group (81% and 88% vs 100%; P = 0.220 and 0.439, respectively)., Conclusions: Targeted high-risk case finding screening was not effective for the detection of SCH but performed better for OH. When obesity in the range BMI 30 to 39.9 kg/m2 and a Caucasian background were included as risk factors, the detection rate of SCH became comparable with that of US., (Copyright © 2019 Endocrine Society.)

Background: Cardiovascular disease (CVD) risk prediction equations are primarily used in clinical settings to inform individual risk management decisions. We sought to develop and validate alternative equations derived solely from linked routinely collected national health data that could be applied countrywide to inform population health planning., Methods: Individual-level linkage of eight administrative health datasets identified all New Zealand residents aged 30-74 years in contact with publicly funded health services during 2006 with no previous hospitalizations for CVD or heart failure, and with complete data on eight pre-specified predictors. The linked health datasets encompassed demographic characteristics, hospitalizations, outpatient visits, primary care enrolment, primary care reimbursement, community laboratory requests, community pharmaceutical dispensing and mortality. Sex-specific Cox models were developed to estimate the risk of CVD death or hospitalization within 5 years and included sex, age, ethnicity, level of deprivation, diabetes, previous hospitalization for atrial fibrillation and baseline preventive pharmacotherapy (blood-pressure-lowering, lipid-lowering and antiplatelet/anticoagulant medications) as predictors. Calibration and discrimination were assessed in the whole cohort, in 15-year age bands, in different ethnic groups, in quintiles of deprivation, according to baseline dispensing of pharmacotherapy, and in regional sub-populations., Results: First CVD events occurred in 62 031 of the 1 746 695 people during 8 526 024 person-years of follow-up (mean = 4.8 years). Median 5-year CVD risk was 1.1% in women and 2.6% in men. In both sexes, the risk equations were well calibrated throughout the risk range and had good risk discrimination in the national, regional and ethnic populations, within 15-year age bands, in deprivation quintiles and according to baseline medication dispensing., Conclusions: Robust policy-focused CVD risk equations can be developed solely from administrative health data to inform population health planning, and will complement CVD primary prevention at the individual level using clinical risk tools. Similar policy-focused equations could be replicated in countries and regions with linked administrative health datasets.

Aims: Whether prevalence and mortality of patients with heart failure with preserved or mid-range (40-49%) ejection fraction (HFpEF and HFmREF) are similar to those of heart failure with reduced ejection fraction (HFrEF), as reported in some epidemiologic studies, remains highly controversial. We determined and compared characteristics and outcomes for patients with HFpEF, HFmREF, and HFrEF in a prospective, international, multi-ethnic population., Methods and Results: Prospective multi-centre longitudinal study in New Zealand (NZ) and Singapore. Patients with HF were assessed at baseline and followed over 2 years. The primary outcome was death from any cause. Secondary outcome was death and HF hospitalization. Cox proportional hazards models were used to compare outcomes for patients with HFpEF, HFmrEF, and HFrEF. Of 2039 patients enrolled, 28% had HFpEF, 13% HFmrEF, and 59% HFrEF. Compared with HFrEF, patients with HFpEF were older (62 vs. 72 years), more commonly female (17% vs. 48%), and more likely to have a history of hypertension (61% vs. 78%) but less likely to have coronary artery disease (55% vs. 41%). During 2 years of follow-up, 343 (17%) patients died. Adjusting for age, sex, and clinical risk factors, patients with HFpEF had a lower risk of death compared with those with HFrEF (hazard ratio 0.62, 95% confidence interval 0.46-0.85). Plasma (NT-proBNP) was similarly related to mortality in both HFpEF, HFmrEF, and HFrEF independent of the co-variates listed and of ejection fraction. Results were similar for the composite endpoint of death or HF and were consistent between Singapore and NZ., Conclusion: These prospective multinational data showed that the prevalence of HFpEF within the HF population was lower than HFrEF. Death rate was comparable in HFpEF and HFmrEF and lower than in HFrEF. Plasma levels of NT-proBNP were independently and similarly predictive of death in the three HF phenotypes., Trial Registration: Australian New Zealand Clinical Trial Registry (ACTRN12610000374066).

Background: Since 2010, three meta-analyses have been published on the impact of thyroid autoimmunity (TAI) on pregnancy outcomes in infertile women treated with assisted reproductive technology (ART). The initially observed high risk of miscarriage became very low in the most recent meta-analysis published in 2016., Objective: To investigate whether the lower risk of miscarriage in the latest meta-analysis was associated with the increased use of intracytoplasmic sperm injection (ICSI) in recent studies., Data Source: MEDLINE was searched from January, 1990, to May, 2017., Study Selection: Data from case-control and cohort studies, on ART (IVF/ICSI) pregnancy outcomes in women with and without TAI. Only studies were included in which women were treated with ICSI., Data Extraction and Synthesis: Four studies were retained including 1855 ICSI cycles (290 with and 1565 without TAI). In women with a clinical pregnancy (114 ICSI cycles with TAI and 651 without), there was no difference in miscarriage or live birth rates: respective combined OR 0.95 (95% CI, 0.48 to 1.87) and 1.12 (95% CI, 0.62 to 2.03). There was no difference in age in women with and without TAI: combined mean difference of 0.13 years (95% CI, -0.51 to 0.76), but serum TSH was higher in women with TAI: combined mean difference of 0.20 mIU/L (95% CI, 0.07 to 0.33)., Conclusion: Infertile women with TAI treated with ICSI had no increased risk of a first trimester miscarriage compared with women without TAI.

Objective: In the recently revised guidelines on the management of thyroid dysfunction during pregnancy, treatment with thyroid hormone (LT4) is not recommended in women without thyroid autoimmunity (TAI) and TSH levels in the range 2.5-4.0 mIU/L, and in a recent study in that particular group of pregnant women, more complications were observed when a treatment with LT4 was given. The objective of the study was therefore to investigate whether variation in thyroid function within the normal (non-pregnant) range in women free of thyroid disease was associated with altered pregnancy outcomes?, Design: Cross-sectional data analysis of 1321 pregnant women nested within an ongoing prospective collection of pregnant women's data in a single centre in Brussels, Belgium., Methods: Thyroid peroxidase antibodies (TPO-abs), thyroid-stimulating hormone (TSH), free T4 (FT4) and ferritin levels were measured and baseline characteristics were recorded. Women taking LT4, with TAI and thyroid function outside the normal non-pregnant range were excluded. Pregnancy outcomes and baseline characteristics were correlated with all TSH and FT4 levels within the normal range and compared between two groups (TSH cut-off < and ≥2.5 mIU/L)., Results: Tobacco use was associated with higher serum TSH levels (OR: 1.38; CI 95%: 1.08-1.74); P  = 0.009. FT4 levels were inversely correlated with age and BMI (rho = -0.096 and -0.089; P  < 0.001 and 0.001 respectively) and positively correlated with ferritin levels (rho = 0.097; P  < 0.001). Postpartum haemorrhage (>500 mL) was inversely associated with serum FT4 levels (OR: 0.35; CI 95%: 0.13-0.96); P  = 0.040. Also 10% of women free of thyroid disease had serum TSH levels ≥2.5 mIU/L., Conclusions: Variation in thyroid function during the first trimester within the normal (non-pregnant) range in women free of thyroid disease was not associated with altered pregnancy outcomes. These results add evidence to the recommendation against LT4 treatment in pregnant women with high normal TSH levels and without TPO antibodies., (© 2018 European Society of Endocrinology.)

Objective: Thyroid disorders and iron deficiency (ID) are associated with obstetrical and fetal complications. Iron is essential for the normal functioning of thyroid peroxidase (TPO-abs) and ID is frequent during pregnancy. The aim of this study was to compare the prevalence of thyroid autoimmunity (TAI) and dysfunction during the first trimester of pregnancy in women with and without ID., Design: Cross-sectional data analysis of 1900 pregnant women nested within an ongoing prospective collection of pregnant women's data., Method: The study was performed in a single, tertiary referral center. During the first antenatal visit, ferritin, TPO-abs, thyroid-stimulating hormone (TSH) and free T4 (FT4) were measured and age and BMI were recorded. ID was defined as ferritin <15µg/L, TAI when TPO-abs was >60kIU/L, and subclinical hypothyroidism (SCH) when TSH was >2.5mIU/L., Results: ID was present in 35% of women. Age and BMI were comparable between both groups. In the ID group, the prevalence of TAI and SCH was significantly higher, compared with that in the non-ID group (10% vs 6% and 20% vs 16%; P=0.011 and 0.049 respectively). Ferritin was inversely correlated with serum TSH (ρ=-0.076; P=0.001) and positive with FT4 levels (ρ=0.112; P<0.001). In the logistic regression model, ID remained associated with TAI after correction for confounding factors (P=0.017). The association with SCH was absent after correction for the confounders in the logistic regression model (P=0.082), but remained present in the linear regression model (P=0.035)., Conclusions: ID was frequent during the first trimester of pregnancy and was associated with a higher prevalence of TAI, higher serum TSH, and lower FT4 levels., (© 2016 European Society of Endocrinology.)

Study Question: Is there any association between thyroid autoimmunity (TAI) and diminished ovarian reserve (DOR)?, Summary Answer: TAI and hypothyroidism are not associated with low ovarian reserve., What Is Known Already: TAI is a common co-existent endocrinopathy in women with primary ovarian insufficiency. Several studies support a potential link between TAI and the reduction in ovarian reserve. However, robust evidence regarding its prevalence in women with DOR is lacking., Study Design, Size, Duration: This study is a large cross-sectional analysis of retrospective data from the Centre for Reproductive Medicine/University Hospital of Brussels. Serum measurements were taken for anti-Mullerian hormone (AMH), free thyroxine (FT4), thyroid-stimulating hormone (TSH) and anti-thyroperoxidase (anti-TPO)., Participants/materials, Setting, Methods: Among 5076 consecutive women, 4894 women had their AMH, FT4, TSH and anti-TPO levels measured on the same day. AMH levels were plotted in relation to age for the whole patients' cohort and age-specific AMH values (per year) were considered in order to categorize women according to the AMH levels of ovarian reserve. There were 3929 women who demonstrated normal reserve, 487 women who had low ovarian reserve and 478 women who demonstrated high ovarian reserve., Main Results and the Role of Chance: Serum FT4 and TSH levels were comparable between different ovarian reserve categories (P = 0.611 and 0.811, respectively). No significant differences were observed in the prevalence of positive anti-TPO antibodies among women with low (12.1%), normal (10.3%) and high (9.8%) ovarian reserve (P = 0.423). Finally, the prevalence of overt or subclinical hypothyroidism was comparable between the groups (4.1% in low, 4.6% in normal and 3.8% in high ovarian reserve women, P = 0.645).Analysis according to the exact cause of low ovarian reserve demonstrated that women with a genetic cause of low ovarian reserve had a significantly higher prevalence of overt hypothyroidism and subclinical hypothyroidism compared with women with unexplained low ovarian reserve for their age (25 versus 3.2%, P = 0.002 and 18.8 versus 1.6%, P = 0.004, respectively). On the contrary, no significant differences were observed in the prevalence of hypothyroidism between genetic causes and iatrogenic causes (P = 0.316) and between iatrogenic and unexplained causes (P = 0.219) of low ovarian reserve., Limitations, Reasons for Caution: This is a cross-sectional analysis based on retrospective data collection. Due to the retrospective design of this study, the presence of biases related to such a study design cannot be excluded. Furthermore, this study assessed only the association of TAI, and not autoimmunity in general, with ovarian reserve., Wider Implications of the Findings: TAI and hypothyroidism are not associated with low ovarian reserve. Future research should focus on examining underlying mechanisms, other than TAI, which may have an effect on ovarian reserve., Study Funding/competing Interests: No external funding was used for this study. No conflicts of interest are declared., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Maternal hypothyroidism in pregnancy is associated with several adverse outcomes. The Endocrine Society Guidelines for the management of thyroid diseases in pregnancy were published in 2007; however, impact of the guidelines in routine clinical practice is unknown. Therefore, we have carried out a survey of members of the European Thyroid Association (ETA) to study current practices relating to the management of hypothyroidism in pregnancy., Subjects and Methods: In December 2010, we emailed an electronic questionnaire survey based on clinical case scenarios to 605 members of the ETA. Responses from 190 clinician members (from 28 European countries) were analyzed., Results: For a pregnant woman with newly diagnosed overt hypothyroidism, most responders initiated a full dose of l-thyroxine (l-T(4)). For a woman with hypothyroidism planning pregnancy, 50% recommended increasing the dose of l-T(4) as soon as pregnancy is confirmed, whilst 43% favored testing thyroid function before adjusting the dose. Responders used diverse combinations of tests to monitor the dose of l-T(4). The target of thyroid function tests that responders aimed to achieve with l-T(4) was also inconsistent. Forty-two percent responders or their institutions screened all pregnant women for thyroid dysfunction, 43% performed targeted screening of only the high-risk group, whilst 17% did not carry out systemic screening. Timing of the screening, tests used, and criteria for starting treatment and monitoring were variable., Conclusions: There is wide variation in the clinical practice relating to the treatment and screening of hypothyroidism during pregnancy in Europe.

Via its interaction in several pathways, normal thyroid function is important to maintain normal reproduction. In both genders, changes in SHBG and sex steroids are a consistent feature associated with hyper- and hypothyroidism and were already reported many years ago. Male reproduction is adversely affected by both thyrotoxicosis and hypothyroidism. Erectile abnormalities have been reported. Thyrotoxicosis induces abnormalities in sperm motility, whereas hypothyroidism is associated with abnormalities in sperm morphology; the latter normalize when euthyroidism is reached. In females, thyrotoxicosis and hypothyroidism can cause menstrual disturbances. Thyrotoxicosis is associated mainly with hypomenorrhea and polymenorrhea, whereas hypothyroidism is associated mainly with oligomenorrhea. Thyroid dysfunction has also been linked to reduced fertility. Controlled ovarian hyperstimulation leads to important increases in estradiol, which in turn may have an adverse effect on thyroid hormones and TSH. When autoimmune thyroid disease is present, the impact of controlled ovarian hyperstimulation may become more severe, depending on preexisting thyroid abnormalities. Autoimmune thyroid disease is present in 5-20% of unselected pregnant women. Isolated hypothyroxinemia has been described in approximately 2% of pregnancies, without serum TSH elevation and in the absence of thyroid autoantibodies. Overt hypothyroidism has been associated with increased rates of spontaneous abortion, premature delivery and/or low birth weight, fetal distress in labor, and perhaps gestation-induced hypertension and placental abruption. The links between such obstetrical complications and subclinical hypothyroidism are less evident. Thyrotoxicosis during pregnancy is due to Graves' disease and gestational transient thyrotoxicosis. All antithyroid drugs cross the placenta and may potentially affect fetal thyroid function.

Objectives: To what extent persons with subclinical hyper- or hypothyroidism are more (or less) likely to die than euthyroid control subjects remains a matter of controversy., Methods: We searched electronic reference databases up to July 31, 2007. Three reviewers independently assessed eligibility. Cohort studies published in full that reported data on the hazard ratio (HR) for mortality from all causes in persons with subclinical thyroid dysfunction versus euthyroid controls were included., Results: Based on seven cohorts including 290 participants with subclinical hyperthyroidism, random-effects models estimated that the pooled HR for all-cause mortality was 1.41 (95% confidence interval (CI), 1.12-1.79; P=0.004). Using the pooled HR and standard life-table methods applied to a US reference population, we estimated that a white US woman, when diagnosed with subclinical hyperthyroidism at age of 70, has an excess mortality of 1.5, 4.0, and 8.7% at 2, 5, and 10 years respectively after diagnosis. Likewise, a white US man has an excess mortality of 2.3, 5.7, and 10.7%. For the nine cohorts including 1580 participants with subclinical hypothyroidism, observed heterogeneity (Q test P=0.006; I(2)=63%) disappeared after pooling cohorts in predefined subgroups according to the presence or absence of a comorbid condition. In doing so, the pooled HR for all-cause mortality was 1.03 (95% CI, 0.78-1.35; P=0.83) in cohorts from the community and 1.76 (95% CI, 1.36-2.30; P<0.001) in cohorts of participants with comorbidities (P=0.014 for heterogeneity among study groups)., Conclusions: Individuals with subclinical hyperthyroidism demonstrate a 41% increase in relative mortality from all causes versus euthyroid control subjects. Mathematical modeling suggests that absolute excess mortality after diagnosis might depend on age, with an increase beyond the age of 60, especially in aging men. For patients with subclinical hypothyroidism, the relative risk of all-cause mortality is increased only in patients with comorbid conditions.

Objective: To study the endogenous sex hormone levels in natural postmenopausal women and their association with the presence of internal carotid artery (ICA) atherosclerosis., Design: Case-control study, Methods: We compared 56 patients with severe ICA atherosclerosis referred for carotid artery endarterectomy (CEA) with 56 age-matched control subjects free of severe atherosclerotic disease. The presence of atherosclerosis was determined by high-resolution B-mode ultrasound. Metabolic parameters and sex hormones were measured or calculated: total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, glucose, insulin, quantitative insulin sensitivity check index, insulin resistance index, IGF-I, DHEA, DHEA sulfate (DHEA-S), free testosterone, total testosterone, estrone, estradiol, androstenedione, and sex hormone-binding globulin., Results: The cases had statistically significant lower levels of both total testosterone (0.23 +/- 0.12 vs 0.31 +/- 0.20 microg/l, P = 0.043) and free testosterone (3.42 +/- 1.94 vs 4.59 +/- 2.97 ng/l, P = 0.009) and significantly lower levels of androstenedione (625.3 +/- 168.7 vs 697.0 +/- 211.9 ng/l, P = 0.017) when compared with controls. Multivariate linear regression analysis, adjusted for traditional cardiovascular risk factors, baseline and physiologic characteristics, showed a significant inverse relationship between both serum free testosterone (beta = -0.234, P = 0.028) and androstenedione (beta = -0.241, P = 0.028) levels with the presence of severe atherosclerosis of ICA., Conclusions: The study provides evidence of a positive association between low serum androgen levels and severe ICA atherosclerosis in postmenopausal women. It suggests that higher, but physiological, levels of androgens in postmenopausal women have a protective role in the development of atherosclerosis of ICA.

Context: Data on the prevalence of thyroid disorders in male subfertility remain scarce., Objective: To investigate the prevalence of thyroid dysfunction and thyroid autoimmunity in men with normal and abnormal semen characteristics., Setting: Tertiary referral center for reproductive medicine of the University Hospital AZ-VUB, Brussels, Belgium., Patients and Design: Two hundred and ninety-two men were stratified according to the presence of normal (group 1; n = 39) or abnormal (group 2; n = 253) semen characteristics. Thyroid function was assessed by serum thyrotropin (TSH) and free thyroxine (FT4), and thyroid peroxidase antibodies (TPO-Ab) for thyroid autoimmunity (TAI or TPO-Ab > 34 kU/l); both were correlated with semen characteristics., Main Outcome Measures: Semen characteristics were determined by World Health Organisation criteria (rapid + slow motility > or = 50% and concentration > or = 20 x 10(6)) and Kruger criteria (morphology > or = 14% normal cells)., Results: In group 1, the mean (+/- s.d.) age was 33 +/- 4 years; serum TSH was 1.6 (0.3-29.6) mU/l (median (range)) and FT4 was 12.2 (8.8-15.6) ng/l. In group 2, the mean age was 33 +/- 5 years, serum TSH was 1.3 (0.3-5.2) mU/l and FT4 was 12.5 (8.4-17.5) ng/l; (compared with group 1 P = 0.008 for TSH and P = 0.037 for FT4). In both groups, one patient had increased TSH (2.6% and 0.4%; P = not significant (ns)). In group 1, one patient had TAI and in group 2 twelve patients had TAI (2.6% compared with 4.7%; P = ns). FT4 was an independent determinant for semen characteristics., Conclusions: The prevalence of thyroid dysfunction and autoimmunity is comparable between men with normal and abnormal semen characteristics. On the basis of these data, we do not advise systematic screening for thyroid disorders in subfertile men consulting a tertiary referral center for reproductive medicine.

Background: Patients with Cushing's disease have a high prevalence of atherosclerosis and maintain an increased cardiovascular risk even after cure of the disease. However, the impact of Cushing's disease on renal function remains to be quantified., Objectives: To evaluate glomerular filtration rate (GFR) and to identify predictors of GFR in patients with Cushing's disease., Design and Methods: We conducted a matched case-control study: 18 patients with active or cured Cushing's disease were compared with healthy population controls matched for age and sex. The main outcome measures were GFR and micro-albuminuria., Results: Patients with Cushing's disease had a lower GFR, as measured by 24-h creatinine clearance (79 versus 95 ml/min per 1.73 m2, P = 0.005) and estimated by the MDRD2 formula (75 versus 88 ml/min per 1.73 m2, P = 0.008). Multiple regression analyses indicated that disease duration was the strongest predictor for a worse GFR. The prevalence of micro-albuminuria was low (5.5% in both groups)., Conclusions: Patients with Cushing's disease have a decreased GFR. Even if they are cured, close follow-up with strict control of cardiovascular risk factors and monitoring of GFR seems mandatory. Furthermore, the dosage of certain drugs should be adapted to the individual GFR.

Objective: This open label, multicentre study was designed to evaluate the efficacy and tolerability of lanreotide Autogel (L-Autogel) in acromegalic patients over a 24-week period. The outcome of treatment with this new, long-acting, aqueous formulation of lanreotide was also compared with the patients' previous treatment with octreotide long acting repeatable (LAR)., Design and Methods: Twenty-five acromegalic patients (13 males, mean age 51+/-12 years) were switched from octreotide LAR (20-40 mg/4 weeks for at least 6 months) to L-Autogel, given deep subcutaneously at a fixed dose of 90 mg/4 weeks. After 12 weeks, the dose of L-Autogel was titrated according to patients' mean GH and IGF-I levels at week 8. It was increased to 120 mg/4 weeks if GH>2.5 microg/l or if IGF-I was above the age-adjusted normal range. It was reduced to 60 mg/4 weeks if mean GH<1 microg/l and IGF-I was within the normal range. If the values did not fall within these ranges, the dose remained unchanged at 90 mg., Results: After 24 weeks of treatment with L-Autogel (final doses 60 mg in 3 patients, 90 mg in 4 patients and 120 mg in 18 patients), mean serum GH (2.9+/-2.4 microg/l) and IGF-I concentrations (332+/-193 microg/l) remained statistically unchanged when compared with baseline values under octreotide LAR (GH 2.4+/-1.8 microg/l and IGF-I 337+/-201 microg/l, non significant (NS)). There was a significant improvement of the acromegalic symptom score over the study period, from 4.8+/-3.4 to 2.8+/-2.5 (P<0.001) and a small but significant reduction in the residual pituitary tumour volume (P<0.05). Local side-effects were observed less frequently and no technical problems were encountered with the L-Autogel injections, as opposed to treatment with octreotide LAR (60 difficult injections/150 (P<0.001))., Conclusions: L-Autogel appears to be as effective as octreotide LAR in lowering GH and IGF-I concentrations in acromegalic patients. This treatment was also well tolerated by the patients, giving fewer local side-effects and technical problems with injections. These advantages may improve the long-term acceptability of medical treatment in acromegaly.

Pregnancy is accompanied by changes in thyroid function, but limited data are available on these changes in the very first weeks of pregnancy. Yet, T(4) plays a major role in implantation and early fetal development. We sought to determine thyroid function during this period and during the first trimester, in pregnancies achieved by assisted reproductive technology. Furthermore, the thyroid hormone profile was compared between euthyroid women with (TAI+) and without (TAI-) thyroid autoimmunity. We prospectively analyzed data from 35 women who received ovarian hyperstimulation (OH) and presented clinical pregnancies. The mean age of the women was 32 +/- 5 yr. Thyroid function tests [serum TSH and free T(4) (FT(4))] and thyroid antibody status were determined before OH (baseline values) and every 20 d after ovulation induction during the first trimester of pregnancy. Serum TSH and FT(4) increased significantly at d 20, compared with baseline values (3.3 +/- 2.4 vs. 1.8 +/- 0.9 mU/liter; P < 0.0001 and 13.2 +/- 1.7 vs. 12.4 +/- 1.9 ng/liter; P = 0.005). During the first trimester of pregnancy, there was a significant change over time for TSH and FT(4) (P < 0.001 and P = 0.005, respectively). Nine women (27%) were TAI+. The TSH curve among these TAI+ women was significantly higher compared with TAI- women (P = 0.010). The opposite was observed for the FT(4) curve (P = 0.020). In conclusion, the present study showed a significant increase of serum TSH and FT(4) levels after OH in the very first period of pregnancy compared with pre-OH levels and a significant impact of TAI on the thyroid hormone profile during the first trimester. This provides evidence for an altered thyroid function in euthyroid TAI+ patients.

The association between positive thyroid antibodies and an increased miscarriage rate in pregnancies after assisted reproduction technology (ART) remains controversial. We wanted to clarify this issue by performing a prospective cohort study in 234 women by systematically screening for thyroid peroxidase antibodies (TPO-Ab), serum TSH, and free T(4)(FT(4)) before the first ART cycle. Women with overt thyroid dysfunction were excluded. Fourteen percent of the cohort had positive TPO-Ab. Baseline characteristics [age, 33 +/- 5 yr; TSH, 1.6 (0.02-4.1) mU/liter; and FT(4), 12.2 (9.1-18) ng/liter] were comparable to those of the 86% of women without antibodies [age, 32 +/- 5 yr; TSH, 1.3 (0.05-3.6) mU/liter; and FT(4), 11.7 (9.5-16.5) ng/liter]. In the antibody-positive group, the pregnancy rate was 53% vs. 43% in the antibody-negative group, with an odds ratio of 0.67 [95% confidence interval (CI) (0.32-1.41); P = not significant]; however within the group that was pregnant, the miscarriage rate was 53% and 23%, respectively, with an odds ratio of 3.77 [95% CI (1.29-11.05); P = 0.016]. The age of the women was an independent risk factor for miscarriage, odds ratio 1.08 [95% CI (1.03-1.15); P = 0.005]. We conclude that women with positive TPO-Ab before the first ART cycle have a significantly increased risk for miscarriage.

Objective: Slow-release (SR) lanreotide is a long-acting somatostatin analog that has been developed in order to overcome the inconvenience of multiple daily subcutaneous injections of octreotide, required for metabolic control in acromegaly. Lanreotide SR has been found to be well tolerated and effective in reducing GH and IGF-I levels but clinical data are still limited compared with those with subcutaneous octreotide treatment., Design: Sixty-six unselected patients with active acromegaly were therefore evaluated in a multi-center, prospective, open label study. Lanreotide SR was given at a dose of 30mg intramuscular every 7-14 days., Methods: At baseline and after 2, 4, 8, 12, 24, 36 and 48 weeks patients underwent a clinical examination with assessment of acromegaly related symptoms, and blood was sampled for serum GH, IGF-I, prolactin, glycosylated hemoglobin, fasting glucose, hematology, kidney function and liver function tests. Biliary ultrasonography and pituitary magnetic resonance imaging were performed at baseline and after one year., Results: Treatment resulted in a significant improvement in the symptom score from 2.69+/-0.27 to 1.06+/-0.17 (P<0.0001). Serum IGF-I levels fell from 699+/-38microg/l at baseline to 399+/-26microg/l (P<0.0001, n=60) after one month, after which levels remained stable: 480+/-37microg/l after 6 months (n=54) and 363+/-32microg/l after one year (n=46). GH levels dropped from 13.8+/-3.2microg/l to 4.3+/-0.7microg/l after one month (P<0.0001, n=60) and remained stable thereafter: 3.9+/-0.4microg/l (n=54) after 6 months and 3.5+/-1.1microg/l after one year (n=46). Twenty-nine out of 66 patients (44%) attained a normal age-corrected IGF-I level and 30 patients (45%) attained a GH level below 2.5microg/l. Pituitary adenoma shrinkage of at least 25% was found in 5 of 14 patients (36%) after one year. Side effects were mainly transient gastrointestinal symptoms and pain at the injection site, resulting in drug discontinuation in only 6 patients (9%). Two patients developed new gall stones. No difference was found between subcutaneous octreotide and lanreotide SR in efficacy and almost all patients preferred the easier dose administration of lanreotide SR., Conclusions: Long-term treatment of acromegaly with SR-lanreotide is effective in controlling GH and IGF-I levels and symptoms and is well tolerated in the majority of patients. Compared with subcutaneous octreotide, lanreotide SR considerably improves patient's acceptance of therapy while having the same overall efficacy.