Preconceptional maternal hyperandrogenism and metabolic syndrome risk in male offspring: a long-term population-based study.

PURPOSE: There is limited research on the effects of maternal hyperandrogenism (MHA) on cardiometabolic risk factors in male offspring. We aimed to compare the risk of metabolic syndrome (MetS) in sons of women with preconceptional hyperandrogenism (HA) to those of non-HA women in later life. METHODS: Using data obtained from the Tehran Lipid and Glucose Cohort Study, with an average of 20 years follow-up, 1913 sons were divided into two groups based on their MHA status, sons with MHA (n = 523) and sons without MHA (controls n = 1390). The study groups were monitored from the baseline until either the incidence of events, censoring, or the end of the study period, depending on which occurred first. Age-scaled unadjusted and adjusted Cox regression models were utilized to evaluate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between MHA and MetS in their sons. RESULTS: There was no significant association between MHA and HR of MetS in sons with MHA compared to controls, even after adjustment (unadjusted HR (95% CI) 0.94 (0.80-1.11), P = 0.5) and (adjusted HR (95% CI) 0.98 (0.81-1.18), P = 0.8). Sons with MHA showed a HR of 1.35 for developing high fasting blood sugar compared to controls (unadjusted HR (95% CI) 1.35 (1.01-1.81), P = 0.04), however, after adjustment this association did not remain significant (adjusted HR (95% CI) 1.25 (0.90-1.74), P = 0.1). CONCLUSION: The results suggest that preconceptional MHA doesn't increase the risk of developing MetS in sons in later life. According to this suggestion, preconceptional MHA may not have long-term metabolic consequences in male offspring.

Maternal androgen excess increases the risk of pre-diabetes mellitus in male offspring in later life: a long-term population-based follow-up study.

PURPOSE: Prenatal androgen exposure could be a source of early programming, leading to the development of cardiometabolic diseases in later life. In this study, we aimed to examine cardiometabolic disturbances in males exposed to maternal androgen excess during their prenatal life. METHODS: In this prospective population-based study, 409 male offspring with maternal hyperandrogenism (MHA), and 954 male offspring without MHA, as controls, were included. Both groups of male offspring were followed from the baseline to the date of the incidence of events, censoring, or end of the study period, whichever came first. Age-scaled unadjusted and adjusted Cox regression models were applied to assess the hazard ratios (HR) and 95% confidence intervals (CIs) for the association between MHA with pre-diabetes mellitus (Pre-DM), type 2 diabetes mellitus (T2DM), pre-hypertension (Pre-HTN), hypertension (HTN), dyslipidemia, overweight, and obesity in the offspring of both groups. Statistical analysis was performed using the STATA software package; the significance level was set at P < 0.05. RESULTS: A higher risk of Pre-DM (adjusted HR: 1.46 (1.20, 1.78)) was observed in male offspring with MHA after adjustment for potential confounders, including body mass index, education, and physical activity. However, no significant differences were observed in the risk of T2DM, Pre-HTN, HTN, dyslipidemia, overweight, and obesity in males with MHA compared to controls in both the unadjusted and adjusted models. CONCLUSION: Maternal androgen excess increases the risk of Pre-DM in male offspring in later life. More longitudinal studies with long enough follow-up are needed to clarify the effects of MHA on the cardiometabolic risk factors of male offspring in later life.

Weight fluctuation, mortality, and cardiovascular disease in adults in 18 years of follow-up: Tehran Lipid and Glucose Study.

PURPOSE: Controversies exist in the effect of body weight loss and fluctuation on cardiovascular disease (CVD) and mortality. This study aims to assess the effect of weight variability on CVD and all-cause and cardiovascular mortality in the Tehran Lipid and Glucose Study (TLGS) cohort. METHOD: Participants aged ≥ 40 year at the baseline period with at least 3 BMI measurements were included in this study. After excluding individuals with cancer, CVD, end-stage renal disease, systemic use of glucocorticoids, pregnancy, and missing covariates at the baseline, a total of 3461 participants were enrolled and followed for 18 years. BMI variability was defined using root mean squared error (RMSE) and average successive variability (ASV). In the RMSE method, BMI variability was calculated using the best-fitting model for BMI trend of each subject. Multivariate Cox proportional hazard models were applied to assess BMI variability's effect on CVD and mortality. RESULTS: Among the 3461 participants in this study, the group with the highest weight variability had an increased risk of death for all-cause (HR 1.65; 95% CI 1.21-2.25), non-cardiovascular (HR 1.77; 95% CI 1.24-2.53), and non-cancer (HR 1.77; 95% CI 1.25-2.50) mortality. However, BMI variability showed to be protective against CVD (HR 0.76; 95% CI 0.6-0.97). These findings were significant in males, non-smokers, participants with age ≤ 60 year, BMI < 30, negative BMI slope, and both diabetic and non-diabetic subjects. CONCLUSION: High BMI variability is associated with increased risk of all-cause, non-CVD, and non-cancer mortality, although protective for the CVD event. Appropriate strategies for body weight maintenance after weight loss could be adopted to avoid weight variability, particularly in non-obese subjects.

Natural history of subclinical hypothyroidism and prognostic factors for the development of overt hypothyroidism: Tehran Thyroid Study (TTS).

OBJECTIVE: The significance of subclinical hypothyroidism (SCH) is largely due to its potential risk for developing overt hypothyroidism (OH). Investigations are still exploring predictive factors contributing to the progression of SCH to OH, particularly in patients with mildly elevated serum thyrotropin (TSH). We aimed to clarify the natural history of SCH and the predictive factors of its progression, based on the grade of SCH severity. METHODS: This study was conducted within the framework of the Tehran Thyroid Study (TTS), in which 5783 individuals aged ≥ 20 years were followed. After applying exclusion criteria, data of 270 SCH subjects remained for the analysis. Thyroid function tests were assessed at baseline and every 3 years. RESULTS: Of 270 participants with SCH, 239 (88.5%) had TSH level between 5.06 and 10 mU/L, and 31 (11.4%) had TSH ≥ 10 mU/L. During a median follow-up of 10 years, 40% had TSH within the reference range, 44% maintained elevated TSH, and 16% had added low T4 to the elevated TSH. The annual incidence rate of progression to OH was 22.3 (16.5-101.9) per 1000 person-years [18 (12.6-25.6) for those with TSH 5.07-9.9 mU/L and 57.8 (22.8-101.9) for patients with TSH ≥ 10 mU/L per 1000 person-years (P = 0.001)]. After adjusting age, sex, body mass index (BMI), thyroid peroxidase antibody (TPOAb), and serum TSH, only TPOAb positivity (HR: 2.31; 95% CI 1.10-4.83, P = 0.026) and baseline TSH level ≥ 10 mU/L (HR: 5.14; 95% CI 2.14-12.3, P < 0.001) remained as predictors for development of OH. In patients with TSH 5.07-9.9 mU/L, TPOAb positivity was associated with an increased risk of OH (HR: 2.41; 95% CI 1.10-5.30, P = 0.027). However, in patients with TSH ≥ 10 mU/L, TPOAb positivity was not a predictor (P = 0.49). CONCLUSION: TPOAb and not TSH are associated with the development of OH in individuals with serum TSH below 10 mU/L, and follow-up at regular intervals is recommended in TPOAb-positive individuals with TSH between 5 and 10 mU/L.

Treatment of post-radioactive iodine relapse of hyperthyroidism: comparison of long-term methimazole and radioactive iodine treatment.

BACKGROUND: This study aimed to compare the time to achieve euthyroidism and sustained control of hyperthyroidism after treatment with radioactive iodine (RAI) or long-term methimazole (LT-MMI) in patients with post-RAI relapsed hyperthyroidism. METHODS: Sixty four patients with recurrence of hyperthyroidism after RAI treatment were randomly assigned to either RAI or LT-MMI treatment. Both groups were followed every 1-3 months in the first year and then every 6 months for a total of 60 months. RESULTS: In RAI and LT-MMI groups, mean age was 49.0 ± 12.1 and 50.1 ± 14.6 years and time of relapse of hyperthyroidism after previous RAI treatment was 23.2 ± 18.8 and 20.8 ± 17.1 months, respectively. At the end of study, in the LT-MMI group, 31 (97%) and 1 (3%) were euthyroid and hypothyroid, respectively; in the RAI group, 8 (25%) patients were euthyroid, whereas 18 (56%), 3 (9.5%) and 3 (9.5%) had overt hypothyroidism, subclinical hypothyroidism and hyperthyroidism, respectively. Mean time to euthyroidism was 9.4 ± 5.0 months in the RAI group and 3.5 ± 2.8 months in the LT-MMI group (p < 0.001). Patients in the RAI group spent 77.7 ± 14.0 percent and those in the LT-MMI group spent 95.2 ± 5.9 percent of 60 months in the euthyroid state (p < 0.001). CONCLUSION: In patients with post-RAI relapse of hyperthyroidism, LT-MMI treatment was superior to radioiodine because of faster achievement of euthyroidism and more sustained control of hyperthyroidism during 60 months of follow-up.

The targeted high-risk case-finding approach versus universal screening for thyroid dysfunction during pregnancy: thyroid-stimulating hormone (TSH) and/or thyroid peroxidase antibody (TPOAb) test?

PURPOSE: To compare the effects of different thyroid screening scenarios, using the universal and targeted high-risk case-finding approaches with different diagnostic tests on the prevalence of subclinical hypothyroidism (SCH), thyroid autoimmunity, and pregnancy outcomes after adjustments for the intervention. METHODS: During a secondary analysis of data collected in Tehran Thyroid and Pregnancy Study, a total of 2277 women from the total population, including 1303 high-risk individuals for thyroid dysfunction. The Cochran-Mantel-Haenszel method, adjusted for the intervention, was also used to evaluate the relationships between different screening scenarios [i.e., universal approach using thyroid-stimulating hormone (TSH) and/or thyroid peroxidase antibody (TPOAb) tests and targeted high-risk case-finding approach using TSH and/or TPOAb tests] and pregnancy outcomes (i.e., preterm delivery and NICU admission). The universal approach using both TSH and TPOAb measurements was considered as the reference scenario. We analyzed outcomes of different screening methods in individuals treated with LT4, compared to those individuals who were not treated. RESULTS: Compared to the universal screening approach with both TSH and TPOAb measurements, the targeted high-risk case-finding approach overlooked approximately 42%, 62%, and 74% of women with elevated TSH (> 4 µlU/mL) when using both TSH and TPOAb tests, TSH alone, and TPO alone, respectively. After adjusting for the missed cases, 2.86% of women with preterm delivery and 2.76% of women with NICU admission were missed when they were screened using the targeted high-risk case-finding approach by measuring both TSH and TPOAb. The percentage of missed cases increased when applying the targeted approach with the TSH test alone, without measuring TPOAb. Overall, 4.16% and 4.02% of women with preterm delivery and NICU admission were overlooked in this scenario, respectively. After adjustments for the intervention, the probability of NICU admission in neonates of mothers, who were screened using the targeted high-risk case-finding approach with TPOAb measurement, was 2.31 folds higher than those screened by the reference scenario. CONCLUSION: This study suggests that although the targeted high-risk case-finding approach including both TSH and TPOAb tests, may overlook some women with SCH, it is a reasonable option since it is not associated with a higher risk of adverse pregnancy outcomes.

Association of different lipid measures with incident bone fractures: Tehran lipid and glucose study.

OBJECTIVE: To investigate the association between different lipid measures and long-term hospitalization-required incident fracture among Iranian men and women. METHODS: A total of 3309 individuals aged ≥50 years (men = 1598) were included in the study. Multivariate Cox proportional hazard analyses were performed to assess the risk of incident fracture across quintiles, considering first quintile as reference, as well as for 1-standard deviation (SD) increase in each lipid measure, i.e. total cholesterol (TC), triglycerides (TG), low- and high-density lipoprotein cholesterol (LDL-C and HDL-C, respectively), non-HDL-C, and related indices (TG/HDL-C and TC/HDL-C). Covariates included age, body mass index, current smoking, type 2 diabetes mellitus, hypertension, lipid lowering-drugs, and steroid medications (for women). RESULTS: During a median follow-up of 18 years, incident fracture was observed in 201 cases (men = 87). In both gender, no linear association was found between different lipid measures and incident fracture. Among men, only the fourth quartile of TG was associated with lower risk of fracture in the age-adjusted analysis with the hazard ratio (HR) and 95% confidence interval (CI) of [0.45 (0.21-0.95)]. Among women, the age-adjusted HRs and 95% CIs for the second, third, fourth, and fifth quintiles of non-HDL-C were [0.46 (0.25-0.87)], [0.73 (0.42-1.25)], [0.90 (0.54-1.51)], and [0.52 (0.29-0.95)], respectively; the corresponding values in the multivariate model were [0.48 (0.26-0.90)], [0.76 (0.4-1.32)], [0.94 (0.56-1.58)], and [0.52 (0.28-0.95)], respectively. The second quintile of LDL-C was also associated with lower risk for incident fracture in the multivariate analysis [0.53 (0.29-0.98)]. CONCLUSIONS: Among Iranian women, a nonlinear association between non-HDL-C and LDL-C and incident fracture was found as the second and fifth quintile of the former and the second quintile of the latter were associated with about 50% lower risk of fracture. Generally, our findings did not support harmful impact of these lipid measures on incident fracture.

Appropriate duration of antithyroid drug treatment as a predictor for relapse of Graves' disease: a systematic scoping review.

BACKGROUND: Following the conventional 12-18 month antithyroid drug (ATD) treatment in Graves' disease (GD), 50% of patients experience relapse of hyperthyroidism. OBJECTIVE: The aim of this systematic scoping review was critical appraisal of duration of ATD therapy in the last 80 years. METHODS: Articles were identified through the search of PubMed from January 1, 1941 to April 30, 2021. All study types were included. Articles were eligible if they reported data on the length of ATD treatment, particularly thyroid hormones and TSH receptor antibodies (TRAb) concentrations and specifically those with data on the remission and/or relapse rates. RESULTS: We described major progress regarding the duration of ATD therapy and related outcomes at every 20 years. Articles of 1941-1960 were mainly concerned with determination of favorable treatment, minimal effective dose, side effects and rate of remission after < 12-month ATD therapy. Studies with larger number of patients and longer follow-ups appeared in 1961-1980; higher remission rate after 18-24 months versus 6 months of ATD therapy was reported. Articles of 1981-2000 focused on identification of factors associated with high relapse rates after discontinuation of ATD. In 2001-2021, ATD became the first choice of treatment in many countries. However, 12-18 months of ATD therapy was arbitrarily chosen as the appropriate option. According to recent studies, persistent normalization of TRAb occurs after 5 years of methimazole therapy and ATD treatment of > 60 months could offer a 4-year remission rate of 85%. CONCLUSION: Long-term ATD treatment for more than 60 months is safe and effective, has the highest remission rate and cures most patients with GD; hence, it should be considered as the most appropriate duration for ATD therapy in these patients.

Effectiveness of Decision Aid in Men with Localized Prostate Cancer: a Multicenter Randomized Controlled Trial at Tertiary Referral Hospitals in an Asia Pacific Country.

There are several treatment options for localized prostate cancer with very similar outcome but vary in terms of technique and side effect profiles and risks. Considering the potential difficulty in choosing the best treatment, a patient decision aid (PDA) is used to help patients in their decision-making process. However, the use and applicability of PDA in a country in Asia Pacific region like Malaysia is still unknown. This study aims to evaluate the effectiveness of a PDA modified to the local context in improving patients' knowledge, decisional conflict, and preparation for decision making among men with localized prostate cancer. Sixty patients with localized prostate cancer were randomly assigned to control and intervention groups. A self-administered questionnaire, which evaluate the knowledge on prostate cancer (23 items), decisional conflict (10 items) and preparation for decision-making (10 items), was given to all participants at pre- and post-intervention. Data were analyzed using independent T test and paired T test. The intervention group showed significant improvement in knowledge (p = 0.02) and decisional conflict (p = 0.01) from baseline. However, when compared between the control and intervention groups, there were no significant differences at baseline and post-intervention on knowledge, decisional conflict and preparation for decision-making. A PDA on treatment options of localized prostate cancer modified to the local context in an Asia Pacific country improved patients' knowledge and decisional conflict but did not have significant impact on the preparation for decision-making. The study was also registered under the Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12614000668606 registered on 25/06/2014.

TPO antibody in euthyroid pregnant women and cognitive ability in the offspring: a focused review.

PURPOSE: A link between maternal thyroid dysfunction during pregnancy and the risk of cognitive and behavioral problems in the offspring has previously been established; however, the potential effects of maternal thyroid autoimmunity on neurodevelopment in the absence of maternal hypothyroidism are less clear. The present review aims to highlight the gaps in knowledge in this regard and provide a thorough assessment of relevant literature. METHOD: Related keywords searched in MEDLINE, Web of Science, and Scopus till January 2021. RESULTS: There is some evidence that neuropsychological and intellectual developments of offspring are adversely affected by maternal thyroid autoimmunity, although the results of available studies are not concordant. The tools and measurements that have been applied in different studies to assess neurodevelopment or IQ vary widely and the children born to mothers with thyroid autoimmunity have been assessed at different chronological stages of life. Such variations may explain some of the differences across studies. In addition, the definition of thyroid autoimmunity has been based on TPOAb cut points provided by manufacturers in most cases, but it is preferable to define these values based on age, trimester, and method-specific reference ranges. CONCLUSION: Well-designed studies are needed to assess verbal and non-verbal neurocognition of offspring born to mothers with autoimmune thyroid disease before or during pregnancy.

Aging and changes in adiposity indices: the impact of menopause.

PURPOSE: Aging is associated with significant changes in fat distribution and menopause may alter this process. This study aimed to investigate the longitudinal effect of menopause on changes in adiposity indices (AI). METHODS: A total number of 3876 non-menopausal women, aged > 20 years, who participated in the Tehran Lipid and Glucose study, were selected for the present study. They were followed from 1998 to 2018 at a 3-year interval and their adiposity indices were measured. Throughout the study, participants were categorized into two groups according to their menopausal status as group 1): women who reached menopause and group 2): women who did not reach menopause. The generalized estimation equation (GEE) models were used to compare the trend of changes in AIs between these two groups. RESULTS: At the end of the study, a total number of 1479 (38.2%) participants reached menopause. The odds of general obesity decreased by 5% (OR: 0.95, 95% CI: 0.90-0.99), and the odds of central obesity increased by 6% in group1 compared to group2 (OR: 1.06, 95% CI: 1.01-1.12). CONCLUSIONS: Menopause alters the impact of aging on central fat distribution. Increasing awareness of the related risk in menopausal women and their healthcare professional may prevent adverse related outcomes.

Impact of educational level on incident chronic kidney disease during 13 years of follow-up: a prospective cohort study.

OBJECTIVES: To examine the association between educational level and chronic kidney disease (CKD) among the Iranian population. STUDY DESIGN: This is a prospective cohort study conducted in the framework of the Tehran Lipid and Glucose Study. METHODS: A total of 8173 Iranians (men = 3659) aged ≥20 years were included in the study. CKD was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. The association between educational status and CKD was explored using multivariate Cox proportional regression analyses, adjusted for age, gender, current smoking, marital status, body mass index, waist circumference, baseline eGFR, diabetes, hypertension, physical activity, history of cardiovascular diseases and dyslipidaemia. RESULTS: During a median follow-up of 13.14 years, 2609 cases of incident CKD were identified; the corresponding incidence rate was 26.35 (range 25.39-27.34) per 1000 person-years. Compared to low educational level, middle and high educational levels showed lower risks for incident CKD in the crude model [hazard ratio (HR) 0.37 (95% confidence interval {CI} 0.34-0.40) and HR 0.40 (95% CI 0.35-0.45), respectively]; however, these HRs changed direction after further adjustment for age and gender [HR 1.26 (95% CI 1.14-1.39) and HR 1.40 (95% CI 1.22-1.61), respectively]. The increased risk of incident CKD for those at higher educational levels remained significant in the fully adjusted model. In addition, results from the gender stratified analyses were in the same direction as those found among the whole study population (P-value for interaction of gender and education >0.8). CONCLUSIONS: Higher educational levels were associated with incident CKD during more than a decade of follow-up; this finding may be attributed to unhealthy lifestyle behaviours among this population group.

Iodine supplementation for pregnant women: a cross-sectional national interventional study.

BACKGROUND: Although Iran has been considered iodine replete since 2000, the first national survey of iodine intake among Iranian pregnant women in 2014 indicated that despite the adequate intake of iodine by the general population, this vulnerable group has moderate iodine deficiency. Therefore, in this national cross-sectional interventional study, we aimed to assess the iodine intake and thyroid function of Iranian pregnant women 2 years after implementing national iodine supplementation for this vulnerable group. MATERIALS AND METHODS: In this cross-sectional study, we conducted a national interventional survey of pregnant women. A total of 1200 pregnant women (400 women from each trimester) from 12 provinces of Iran were recruited from the antenatal care clinics from October 2018 to March 2019. The median urinary iodine concentration (MUIC), as an indicator of iodine status in three spot urine samples, was measured, along with the serum total T4 (TT4), thyrotropin (TSH), thyroglobulin (Tg), thyroid peroxidase antibody (TPO-Ab), and iodine content of household salt. RESULTS: The mean age of the cohort was 28 ± 6.2 years, with the mean gestational age of 22.7 ± 13.0 weeks. The overall MUIC (IQR) of pregnant women was 188 µg/L (124.2-263 µg/L). Also, the MUICs in the three trimesters of pregnancy were 174 µg/L (110-254), 175 µg/L (116-251), and 165 µg/L (114-235), respectively. The MUICs ≥ 150, 100-149, and < 100 µg/L were found in 63, 19.8, and 16.2% of the subjects, respectively. The mean TT4 level was 12 ± 4.5 µg/dL, and the median (IQR) level of TSH was 2.37 mIU/L (1.66-3.18 mIU/L). According to our local reference range, 118 (10.5%) pregnant women had subclinical hypothyroidism, 6 (0.53%) women had isolated hypothyroxinemia, and 65 (5.7%) women were TPO-Ab positive. Also, the median (IQR) level of Tg was 10.08 µg/dL (5.7-20.4 µg/dL), and the median iodine content of household salt was 29.6 µg/g; the iodine content was ≥ 30 µg/g in 85% of household salt. The results showed that more than 95% of households were under iodized salt coverage. CONCLUSION: The results of this study indicated that iodine supplementation with at least 150 µg of iodine per day improved the iodine intake of pregnant women. Except for subclinical hypothyroidism, the prevalence of clinical hypothyroidism, clinical/subclinical thyrotoxicosis, TPO-Ab positivity, and isolated hypothyroxinemia decreased significantly, which emphasizes the importance of iodine supplementation during pregnancy.

All-cancer incidence in Tehranian adults: more than a decade of follow-up-results from the Tehran Lipid and Glucose Study.

OBJECTIVES: To investigate the incidence rates for different malignancies and assess the risk factors for all-cancer incidence in Tehran. STUDY DESIGN: Cohort study. METHODS: This study consists of 8599 participants aged ≥ 30 years who were free of cancer (3935 men). Cancer diagnosis was based on pathology reports. Sex-stratified crude incidence rates and age-standardized incidence rates (ASRs) using Segi's method were calculated for all-cancers. Multivariate Poisson regression models were used to evaluate associations of potential risk factors, including sex, age, obesity status (body mass index [BMI]: 25-30 kg/m2 as reference), education, smoking status, and diabetes mellitus with the incidence of cancers among the population. Incidence rate ratios (IRRs) with 95% confidence interval (CI) were also reported. RESULTS: During a median follow-up of 13.9 years, there were 130 and 129 incident cancers for men and women, respectively; the corresponding ASRs were 356.1 and 243.6 per 100,000 person-years, respectively. The three most incident cancers among men were gastrointestinal (GI) (ASR = 127.5), hematopoietic (ASR = 99.5), and reproductive system malignancies (ASR = 46.3). The most common incident cancers in women were breast cancer (ASR = 92.1), GI (ASR = 65.4), and reproductive system malignancies (ASR = 16.8). Among risk factors for cancer incidence, age (IRR [95% CI]: 1.05 [1.03-1.06]) and having a BMI < 25 kg/m2 (IRR [95% CI]: 1.38 [1.01-1.90]) had a statistically significant association with incident cancer. CONCLUSIONS: The high rates of cancers in Tehran during more than a decade of follow-up calls for a need to define risk factors as well as to implement programs for early screening.

Safety of long-term antithyroid drug treatment? A systematic review.

Continued low-dose MMI treatment for longer than 12-18 months may be considered in patients not in remission. However, ATDs are not free from adverse effects. We undertook a systematic review to clarify safety of long-term ATD treatment. Medline and the Cochrane Library for trials published between 1950 and Nov 2018 were systematically searched. We included original studies containing data for long-term (> 18 months) ATD treatment. Two reviewers independently extracted data from included trials and any disagreement was adjudicated by consensus. Of 615 related articles found, 12 fulfilled the criteria. Six articles had data for adults, five for non-adults and one article had data for both groups. The sample sizes ranged between 20 and 249 individuals, and the mean duration of ATD treatment ranged between 2.1 and 14.2 years. Considering all data from 1660 patients treated with ATD for a mean duration of 5.8 years (around 10,000 patient-years), major complications occurred only in 14 patients: 7 severe agranulocytosis, 5 severe liver damage, one ANCA-associated glomerulonephritis and one vasculitis with small cutaneous ulcerations. Minor complications rates were between 2 and 36%, while more complications were in higher doses and in the children. The most reported AE was cutaneous reaction; the other adverse events were elevated liver enzymes, leukocytopenia, arthritis, arthralgia, myalgia, thrombocytopenia, fever, nausea and oral aphthous. Long-term ATD treatment is safe, especially in low dose and in adults, indicating that it should be considered as an earnest alternative treatment for GD.

Evaluating the interaction of common FTO genetic variants, added sugar, and trans-fatty acid intakes in altering obesity phenotypes.

BACKGROUND AND AIMS: The results of studies on the effect of trans-fatty acids (TFAs) and added sugars on obesity are not consistent. This study aimed to investigate whether the association of changes in general and central obesity with added sugar and TFA intakes is modified by common fat mass and obesity-associated gene (FTO) polymorphisms, in isolation or in a combined-form genetic risk score (GRS). METHODS AND RESULTS: Subjects of this cohort study were selected from among adult participants of the Tehran Lipid and Glucose Study (n = 4292, 43.2% male). Dietary data were collected using a valid and reliable food frequency questionnaire. The genotypes of selected polymorphisms (rs1421085, rs1121980, and rs8050136) were determined. Genetic risk score (GRS) was calculated using the dominant weighted method. The mean age of participants was 42.6 ± 14 and 40.4 ± 13 years in men and women, respectively. FTO rs8050136 polymorphisms and TFAs have a significant interaction in changing body mass index (BMI) (P interaction = 0.01). There were no changes in waist circumference (WC) and BMI among FTO risk allele carriers, across quartiles of added sugar intake. GRS and TFA intakes significantly interacted in altering the BMI and WC; thus, a higher intake of TFAs was associated with higher changes of BMI and WC in subjects with high GRS (P trend<0.05) compared to individuals with low GRS. CONCLUSION: Our findings suggest that TFA intake can increase the genetic susceptibility of FTO SNPs to BMI or WC change.

The association between serum total testosterone and progression of hyperglycemia: a 15-year prospective cohort study.

BACKGROUND: The association between low testosterone concentration and increased risk of hyperglycemia in men has been demonstrated in observational and interventional studies. However, considering a variety of confounding factors, limited population-based studies have so far been conducted. Also, no information is available regarding the effect of testosterone on progressive development of dysglycemia. OBJECTIVE: To examine the effect of total testosterone on development of pre-diabetes/diabetes in normoglycemic middle-aged and older men. MATERIALS AND METHODS: Data were obtained from the Tehran Lipid and Glucose Study, a community-based prospective cohort of an Iranian population. Analyses were conducted on 903 normoglycemic eligible men aged 30-70 years. An illness-death model was applied to estimate the probabilities of three transitional phases of normoglycemia→diabetes, normoglycemia→pre-diabetes, and pre-diabetes→diabetes. RESULTS: Over a median follow-up of 12 years, 0.9% individuals developed diabetes. Per unit increase (ng/mL) in testosterone concentration, the transition rate from normoglycemia to pre-diabetes decreased by 6% [hazard ratios (HRs): 0.94 (95% confidence interval (CI): 0.90, 0.99)]. However, no effect for testosterone on the progression of diabetes from normoglycemia or pre-diabetes was observed [HRs: 0.79 (95% CI: 0.44, 1.41) and 0.98 (95% CI: 0.84, 1.16), respectively]. High body mass index was a strong predictor of hyperglycemia within all transitions. DISCUSSION: Independent of major confounding factors, low testosterone was associated with normoglycemia progression to pre-diabetes, but not with pre-diabetes to diabetes, which might indirectly highlight the stronger impact of other risk factors after occurrence of pre-diabetes. CONCLUSION: Low testosterone concentrations in men are associated with progression from normoglycemia to pre-diabetes, but not from pre-diabetes to diabetes.

Long-term effects of coffee and caffeine intake on the risk of pre-diabetes and type 2 diabetes: Findings from a population with low coffee consumption.

BACKGROUND AND AIM: Here, we examined the potential effect of coffee consumption and total caffeine intake on the occurrence of pre-diabetes and T2D, in a population with low coffee consumption. METHODS AND RESULTS: Adults men and women, aged 20-70 years, were followed for a median of 5.8 y. Dietary intakes of coffee and caffeine were estimated using a 168-food items validate semi-quantitative food frequency questionnaire, at baseline. Cox proportional hazards regression models, adjusted for potential cofounders, were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between coffee and caffeine intakes and incidence of pre-diabetes and T2D. The total population was 1878 adults (844 men, 1034 women) and 2139 adults (971 men, 1168 women) for analysis of pre-diabetes and T2D, respectively. During the follow-up period the incidence of pre-diabetes and T2D was 30.8% and 6.6%, respectively. Forty-three percent of our subjects were no coffee drinker whereas 51.4% consumed 1 cup of coffee/week and 6.0% consumed more than 1 cup of coffee/week. A lower risk of pre-diabetes (HR = 0.73, 95% CI = 0.62-0.86) and T2D (HR = 0.66, 95% CI = 0.44-1.00) was observed in coffee drinkers compared to non-drinkers, in the fully adjusted models. Higher dietary intake of caffeine (≥152 vs. <65 mg/d) was accompanied with a borderline (P = 0.053) reduced risk of pre-diabetes (HR = 0.45, 95% CI = 0.19-1.00). CONCLUSION: Our findings indicated that coffee drinking may have favorable effect in prevention of pre-diabetes and T2D.

Does AMH relate to timing of menopause? Results of an Individual Patient Data meta- analysis.

CONTEXT: Anti-Müllerian hormone based (AMH) age at menopause predictions remain cumbersome due to predictive inaccuracy. OBJECTIVE: To perform an Individual Patient Data (IPD) meta-analysis, regarding AMH based menopause prediction. DATA SOURCES: A systematic literature search was performed using PubMed, Embase and Cochrane databases. STUDY SELECTION: Prospective cohort studies regarding menopause prediction using serum AMH levels were selected by consensus discussion. DATA SELECTION: Individual cases were included if experiencing a regular cycle at baseline. Exclusion criteria were hormone use and gynecological surgery. DATA SYNTHESIS: 2596 women were included, 1077 experienced menopause. A multivariable Cox regression analysis assessed time to menopause (TTM) using age and AMH. AMH predicted TTM, however, added value on top of age was poor (age alone C-statistic 84%; age + AMH HR 0.66 95% CI 0.61-0.71, C-statistic 86%). Moreover, the capacity of AMH to predict early (≤45 years) and late menopause (≥55 years) was assessed. An added effect of AMH was demonstrated for early menopause (age alone C-statistic 52%; age + AMH HR 0.33, 95% CI 0.24-0.45, C-statistic 80%). A Weibull regression model calculating individual age at menopause revealed that predictive inaccuracy remained present and increased with decreasing age at menopause. Lastly, a check of non-proportionality of the predictive effect of AMH demonstrated a reduced predictive effect with increasing age. CONCLUSION: AMH was a significant predictor of TTM and especially of time to early menopause. However, individual predictions of age at menopause demonstrated a limited precision, particularly when concerning early age at menopause, making clinical application troublesome.