Cohort profile update: Tehran cardiometabolic genetic study.

The Tehran cardiometabolic genetic study (TCGS) is a large population-based cohort study that conducts periodic follow-ups. TCGS has created a comprehensive database comprising 20,367 participants born between 1911 and 2015 selected from four main ongoing studies in a family-based longitudinal framework. The study's primary goal is to identify the potential targets for prevention and intervention for non-communicable diseases that may develop in mid-life and late life. TCGS cohort focuses on cardiovascular, endocrine, metabolic abnormalities, cancers, and some inherited diseases. Since 2017, the TCGS cohort has augmented by encoding all health-related complications, including hospitalization outcomes and self-reports according to ICD11 coding, and verifying consanguineous marriage using genetic markers. This research provides an update on the rationale and design of the study, summarizes its findings, and outlines the objectives for precision medicine.

Diagnostic dilemma in a patient with history of medullary thyroid carcinoma and abnormal serum liver enzymes; a case report with six years follow up.

BACKGROUND: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor that originates from parafollicular C-cells. Calcitonin (Ctn) and carcinoembryonic antigen (CEA) are useful biomarkers for monitoring MTC cases. CASE PRESENTATION: Here, we describe a 48-year-old woman, who presented in 2014 with bilateral thyroid nodules. Report of fine needle aspiration was suspicious for MTC; initial laboratory evaluation showed serum Ctn level of 1567 pg/mL. After excluding type 2 multiple endocrine neoplasia syndrome clinically, total thyroidectomy and neck lymph node dissection were performed. The final histopathological diagnosis was right lobe MTC with neither vascular invasion nor lymph node involvement. On regular follow-up visits, Ctn and CEA levels have been undetectable, and repeated cervical ultrasonographic exams were unremarkable from 2014 to 2021. As liver enzymes became elevated in 2016, the patient was further evaluated by a gastroenterologist. Abdominopelvic ultrasonography revealed a coarse echo pattern of the liver parenchyma with normal bile ducts. A liver fibroscan showed a low fibrosis score (7kPa). The patient was recommended to use ursodeoxycholic acid. According to the progressive rise of liver enzymes with a cholestatic pattern in October 2020, a liver biopsy was performed that showed tiny nests of neuroendocrine-like cells with a background of primary biliary cholangitis (PBC). Immunohistochemical stainings were positive for chromogranin A (CgA), and synaptophysin and negative for Ctn, CEA, and thyroglobulin. Further imaging investigations did not reveal any site of a neuroendocrine tumor in the body. Considering normal physical exam, imaging findings, as well as normal serum levels of Ctn, CEA, CgA, and procalcitonin, the patient was managed as a PBC. CONCLUSION: In follow-up of a patient with MTC, we reported progressively increased liver enzymes with a cholestatic pattern. Liver biopsy revealed nests of neuroendocrine-like cells with a background of PBC, the findings that might suggest acquiring neuroendocrine phenotype by proliferating cholangiocytes.

Are HOMA-IR and HOMA-B good predictors for diabetes and pre-diabetes subtypes?

BACKGROUND: To investigate the association between the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and Homeostasis Model Assessment of Beta-cell function (HOMA-B) with the incidence of diabetes and pre-diabetes subtypes. METHODS: A total of 3101 normoglycemic people aged 20-70 years were included in the 6-year follow-up study. Multinomial logistic regression was used to calculate the incidence possibility of isolated Impaired Fasting Glucose (iIFG), isolated Impaired Glucose Tolerance (iIGT), Combined impaired fasting glucose & impaired glucose tolerance (CGI), and Diabetes Mellitus (DM) per standard deviation (SD) increment in HOMA-IR and HOMA-B in the crude and multivariable model. RESULTS: In the multivariate model, an increase in one SD change in HOMA-IR was associated with a 43, 42, 75, and 92% increased risk of iIFG, iIGT, CGI, and DM, respectively. There was a positive correlation between the increase in HOMA-B and the incidence of iIGT; however, after adjusting the results for metabolic syndrome components, it was inversely correlated with the incidence of iIFG [Odds Ratio = 0.86(0.75-0.99)]. CONCLUSIONS: HOMA-IR is positively correlated with diabetes and pre-diabetes subtypes' incidence, and HOMA-B is inversely correlated with the incidence of iIFG but positively correlated with iIGT incidence. However, none of these alone is a good criterion for predicting diabetes and pre-diabetes.

Pharmacodynamic and pharmacokinetic properties of the combined preparation of levothyroxine plus sustained- release liothyronine; a randomized controlled clinical trial.

BACKGROUND: Understanding pharmacokinetics (PK) and pharmacodynamics (PD) of the sustained-release liothyronine (SR-T3) is of paramount importance to design therapeutic regimens that are able to simulate normal thyroid hormone secretion while avoiding excursions in the T3 serum concentration. Here, we designed a parallel randomized clinical trial to characterize the PK and PD of the combined preparations of LT4 + SR-T3 in hypothyroid patients. METHODS: Radioiodine-treated hypothyroid patients over 20 years of age, who attained euthyroidism with LT4 monotherapy were recruited from the Endocrine Clinic in Tehran. The patients were allocated to two intervention groups of group A: 9 µg SR-T3 plus 68.5 µg LT4 (ratio 1:7.5) and group B: 12 µg SR-T3 plus 60 µg LT4 (ratio 1:5), and a control group with LT4 monotherapy. For PD study, thyroid hormone profile was evaluated at 8 and 12 weeks intervals after intervention. To assess PK properties of SR-T3, T3-Cmax, T3-Tmax and AUC0 - 24 were calculated at the last visit. RESULTS: Serum T4 and FT4 concentrations decreased in the intervention groups after 3 months. No significant difference was observed in serum T3 and FT3 concentrations before and after intervention. Serum T3/T4 ratio increased significantly in the intervention groups after intervention, with the highest increase in group B from 8.6 ± 2.03 at baseline to 12.2 ± 1.6. Comparison of trial groups at follow-up showed no differences in serum TSH, T4, T3 and T3/T4 concentrations among different groups. During 24 h, minimal variation in serum T3 concentration was observed in group B with mean ∆T3 of 15.4 ± 10.5 ng/dl. T3-Tmax, T3-Cmax and AUC0 - 24 in the combined sustained-release preparation were 4.38 ± 1.1 h., 101.0 ± 5.7 ng/dl and 2257 ± 110 ng.h/L, respectively which were significantly different from the control group. CONCLUSION: Combined treatment with a single dose of SR-T3 plus LT4 is associated with increased serum T3/T4 ratio and minimal excursions in serum T3 concentration during 24 h; however, it was not significantly different from the control group. To incorporate sustained-release T3 in the management of hypothyroidism, a higher ratio of SR-T3 to LT4 than that of the previously recommended by the international organizations is suggested. IRCT REGISTRATION NUMBER: IRCT20100922004794N13. https://www.irct.ir/search/result?query=IRCT20100922004794N13 . Registration date: 08/12/2021.

Association of LDL-cholesterol subfractions with cardiovascular disorders: a systematic review.

BACKGROUND: Cardiovascular disorders (CVDs) are the leading cause of death worldwide. This study aimed to evaluate the association between low-density lipoprotein (LDL) subfractions and cardiovascular disorders. METHODS: To ensure the rigor of the systematic review, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used. For this systematic review, a comprehensive search strategy was performed in important databases including PubMed, Scopus, Embase, International Statistical Institute (ISI) Web of Science, and google scholar from 2009 to February 2021. The following terms were used for systematic search: low-density lipoprotein, LDL, subfractions, subclasses, nuclear magnetic resonance, NMR, chromatography, high-pressure liquid, HPLC, cardiovascular disease, cerebrovascular, and peripheral vascular disease. Also, for evaluating the risk of bias, the Newcastle-Ottawa scale was employed. RESULTS: At the end of the search process, 33 articles were included in this study. The results of most of the evaluated studies revealed that a higher LDL particle number was consistently associated with increased risk for cardiovascular disease, independent of other lipid measurements. Also, small dense LDL was associated with an increased risk of CVDs. There was no association between LDL subfraction and CVDs in a small number of studies. CONCLUSIONS: Overall, it seems that the evaluation of LDL subclasses can be used as a very suitable biomarker for the assessment and diagnosis of cardiovascular diseases. However, further studies are required to identify the mechanisms involved.

Prevalence and metabolic determinants of abnormal alanine aminotransferase: A cross-sectional study of Iranian adults, 2018-2022.

BACKGROUND: Alanine aminotransferase (ALT) is an enzyme whose activity became the principal biomarker for liver disease. In the current study, we aimed to determine the prevalence of abnormal ALT, as a surrogate of nonalcoholic fatty liver disease (NAFLD) and its associated determinants using different criteria among Tehranian subjects between 2018 and 2022. METHODS: This is a cross-sectional study on 5676 Tehranian individuals aged 20-70 years. The weighted prevalence of abnormal ALT was calculated using both the National Health and Nutrition Examination Survey in the United States (US-NHANCE; ALT ≥30 U/L for females and ≥40 U/L for males) and the American College of Gastroenterology (ACG) guideline (ALT >25 U/L for females, and >33 U/L for males) thresholds. Moreover, uni/multivariable logistic regression analysis was performed to find the determinants of abnormal ALT. RESULTS: The weighted prevalence of abnormal ALT was 12.8% (7.6% females and 18% males) and 22.5% (17.7% females and 27.3% males) based on US-NHANCE and ACG criteria, respectively. Our results showed every decade increase in age decreased the risk of abnormal ALT by 32%. We also found that generally male gender, being overweight/obese, central adiposity, TG ≥6.9 mmol/L, non-HDL-C ≥3.37 mmol/L, lipid-lowering medications, pre-diabetes/T2DM were associated with abnormal ALT using different cutoff points. Moreover, among men resting tachycardia (≥90 beats per min), hypertension, and females past-smoker were also found as other determinants of abnormal ALT. CONCLUSION: High prevalence of abnormal ALT among non-elderly Iranian adults, especially among men, necessitates immediate multifaceted strategies by policymakers to prevent potential complications caused by NAFLD.

Cumulative Effects of Thyroid Hormones Over 10 Years and Risk of General and Abdominal Obesity.

We aimed to assess if changes in thyrotropin (TSH) and free thyroxine (FT4) over 10 years of follow-up would be associated with changes in body mass index (BMI) and waist circumference (WC) or risk of obesity. We enrolled 2317 out of 4179 participants in Tehran Thyroid Study with serum TSH between 0.1-10 mU/l and without history of thyroid medication or surgery. Serum concentrations of FT4 and TSH were measured at baseline and three follow-ups (1999-2011). To account for within-subject correlation, the generalized estimating equation was used to assess the association between one standard deviation(SD) change in the main exposures [cumulative excess (CE)TSH and CEFT4] and changes in BMI and WC; calculated scores of CETSH and CEFT4 were included in models as time-varying exposures. Cumulative excess of TSH or FT4 was not associated with increased incidence of general or abdominal obesity. However, CEFT4 was negatively associated with BMI only in overweight and obese subjects. In GEE analysis, one unit increase in TSH was associated with 0.02 kg/m2 increase in BMI (95% CI: 0.01, 0.03), which remained significant only in women; although the association was not significant after adding FT4 to model. One unit increase in FT4 was associated with 1.5 kg/m2 decrease in BMI (95% CI:-1.8,-1.2) and 4.1 cm decrease in WC (95% CI:-5.1,-3.1) in both sexes independent of TSH and other confounders. Cumulative excess of TSH or FT4 indicated no risk for general or abdominal obesity. However, FT4 was negatively associated with BMI and WC independent of TSH.

The role of different lipid measures for incident hypertension during more than 12-year follow-up: Tehran Lipid and Glucose Study.

The associations of different lipid measures and related indices with incident hypertension during a median follow-up of 12·89 years were examined. Fasting levels of total cholesterol (TC), TAG, HDL-cholesterol and LDL-cholesterol, and related indices (TC/HDL-cholesterol and TAG/HDL-cholesterol) were determined in 7335 Iranian adults (men = 3270) free of hypertension, aged 39·0 (sd 13·2) years. Multivariate Cox proportional hazard regression was applied and lipid parameters were considered either as categorical or continuous variables. During follow-up, 2413 (men = 1126) participants experienced hypertension. Using the first quartile as reference, significant trends were found between quartiles of TAG, HDL-cholesterol, TC/HDL-cholesterol and TAG/HDL-cholesterol in multivariate models; moreover considering these measures as continuous variables, a 1 sd increase in each of these parameters was significantly associated with the risk of incident hypertension; the corresponding hazard ratios and CI were 1·06 (95 % CI 1·02, 1·10), 0·94 (95 % CI 0·89, 0·98), 1·04 (95 % CI 1·01, 1·09) and 1·04 (95 % CI 1·01, 1·07), respectively. The associations between lipid measures and incident hypertension did not change after excluding lipid lowering drug users and those with type 2 diabetes mellitus and these associations were independent of the categories of baseline blood pressure (P for interaction > 0·08). These findings indicate that TAG, TAG/HDL-cholesterol and TC/HDL-cholesterol were independently associated with higher risk, while HDL-cholesterol was associated with lower risk of incident hypertension.

Recurrence of a neuroendocrine tumor of adrenal origin: a case report with more than a decade follow-up.

BACKGROUND: Neuroendocrine tumor (NET) with adrenocorticotropic hormone (ACTH) secretion are very rare. To our knowledge, no follow-up study is published for ACTH-secreting NET, regardless of the primary site, to show second occurrence of tumor after a long follow-up, following resection of primary tumor. CASE PRESENTATION: Here, we describe a 49-year-old-man with cushingoid feature, drowsiness and quadriparesis came to emergency department at December 2005. Laboratory tests revealed hyperglycemia, metabolic alkalosis, severe hypokalemia, and chemical evidence of an ACTH-dependent hypercortisolism as morning serum cortisol of 57 µg /dL without suppression after 8 mg dexamethasone suppression test, serum ACTH level of 256 pg/mL, and urine free cortisol of > 1000 µg /24 h. Imaging showed only bilateral adrenal hyperplasia, without evidence of pituitary adenoma or ectopic ACTH producing tumors. Importantly, other diagnostic tests for differentiating Cushing disease (CD) from ectopic ACTH producing tumor, such as inferior petrosal sinus sampling (IPSS), corticotropin releasing hormone (CRH) stimulation test, octreotide scan or fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan were not available in our country at that time. Therefore, bilateral adrenalectomy was performed that led to clinical and biochemical remission of hypercortisolism and decreased ACTH level to < 50 pg/mL, findings suggestive of a primary focus of NET in adrenal glands. After 11 years uncomplicated follow up, the ACTH level elevated up to 341 pg/mL and re-evaluation showed a 2 cm nodule in the middle lobe of the right lung. Surgical excision of the pulmonary nodule yielded a carcinoid tumor with positive immunostaining for ACTH; leading to decrease in serum ACTH level to 98 pg/mL. Subsequently after 7 months, serum ACHT levels rose again. More investigation showed multiple lung nodules with metastatic bone lesions accompanied by high serum chromogranin level (2062 ng/mL), and the patient managed as a metastatic NET, with bisphosphonate and somatostatin receptor analogues. CONCLUSION: This case of surgically-treated NET showing a secondary focus of carcinoid tumor after one decade of disease-free follow-up emphasizes on the importance of long-term follow-up of ACTH-secreting adrenal NET.

Investigating the prevalence of primary thyroid dysfunction in obese and overweight individuals: Tehran thyroid study.

BACKGROUND: Due to the increasing worldwide prevalence of obesity, it is essential to determine the prevalence of obesity-related thyroid dysfunctions. The purpose of this study was to investigate the prevalence of thyroid dysfunctions, namely hypothyroidism and hyperthyroidism, and their association with BMI among adult Iranian overweight and obese individuals. METHOD: This cross-sectional study was carried out within the framework of the Tehran Thyroid Study (TTS); 5353 participants (57.5% female) entered our study. Anthropometric measurements were performed. Serum levels of thyroid-stimulating hormone (TSH), free thyroxine (FT4), and thyroid peroxidase antibody (TPOAb) were assayed. We categorized individuals into 3 BMI groups (normal-weight, overweight and obese), then calculated prevalence rate, odds ratio (OR), and 95% confidence interval (CI) for outcomes in overweight and obese groups. The normal-weight group was used as the control group. RESULTS: We found a higher prevalence of hypothyroidism (11.6% vs 8.2% Total, 4.0% vs 1.1% overt and 7.6% vs 7.1% subclinical, P < 0.001) and TPOAb positivity (17.3% vs 11.6%, P < 0.001) in obese participants compared with normal-weight participants. Hyperthyroidism's overall prevalence was 4.2, 5.7, and 4.9% in obese, overweight, and normal-weight groups, respectively. Obesity was associated with higher odds of overt hypothyroidism (OR: 2.0, 95% CI: 1.15-3.49, P < 0.05) and TPOAb positivity (OR: 1.29, 95% CI: 1.04-1.60, P < 0.05) after adjusting for confounding variables. In contrast, no association was observed between the overweight group and the odds of hypothyroidism and TPOAb positivity in the adjusted results. CONCLUSIONS: Obesity was associated with an increased risk of overt hypothyroidism and TPOAb positivity.

The association between subclinical hypothyroidism and TPOAb positivity with infertility in a population-based study: Tehran thyroid study (TTS).

BACKGROUND: Thyroid autoimmunity(TAI) is the most prevalent autoimmune condition in women of fertile age. There are increasing data regarding the association of thyroid dysfunction and thyroid autoimmunity with adverse pregnancy outcomes but there is no consensus regarding infertility and TPOAb positivity; thus we aimed to evaluate the association between thyroid TPOAb positivity and infertility in females and males in a population-based study (TTS). METHODS: Cross-sectional study of 3197 female and male participants in Tehran Thyroid Study (TTS) at the framework of the Tehran Lipid and Glucose Study (TLGS). Data included biochemical measurements and a self-administered questionnaire. RESULTS: A total of 12,823 cases in phase 4, 3719 cases (2108 female and 1611 male) were analyzed. The mean TSH of the infertile female and male was 2.52 ± 2.68 µIU/ml and 3.24 ± 10.26 µIU/ml respectively. The TPO median(IQR) of women with and without a history of infertility were 6.05 (3.30-13.96)and 6.04 (3.17-11.15);(P = 0.613), they were 5.08 (3.20-125.68) and 5.31 (3.93-125.68);(P = 0.490) in male participants, respectively. Results of crude and adjusted logistic regression analysis of the development of infertility by thyroid function and TPOAb, except for fT4 in male subjects, depicted no association between infertility and other variables in both crude and adjusted models. CONCLUSION: Based on the result, thyroid autoimmunity was not associated with infertility in both females and males.

Macrosomia is a risk factor for incident maternal chronic kidney disease.

BACKGROUND: Gestational diabetes mellitus (GDM) and macrosomia are associated with several adverse outcomes including diabetes mellitus and cardiovascular diseases, however, the relationship between GDM/macrosomia with incident chronic kidney disease (CKD) is a matter of debate. The purpose of this study was to examine the association between the history of macrosomia with or without GDM and incident maternal CKD. METHODS: The study population includes 2669 women aged 18-50 years without known diabetes mellitus and CKD from participants of the Tehran Lipid and Glucose Study. The study population was categorized into 3 groups; group 1: GDM/macrosomia and without diabetes mellitus (n = 204), group 2: newly diagnosed incident diabetes mellitus (NDM) in the presence or abcence of GDM/Macrosomia (n = 113), and, group 3: the reference group including women without prior history of GDM/macrosomia and free of NDM (n = 2352). CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2. Multivariable Cox proportional hazard regression adjusted for baseline values of age, body mass index, waist circumference, parity numbers, smoking, educational level, gestational hypertension, eGFR, systolic and diastolic blood pressures (SBP and DBP, respectively), anti-hypertensive medication, and family history of diabetes mellitus was applied for data analyses. RESULTS: During a median follow-up of 11.9 years, 613 incident CKD cases were identified. The multivariable hazard ratio (HR) and 95% confidence interval (CI) on GDM/macrosomia group was [1.32 (1.02-1.72)]; the risk was more prominent among non-hypertensive women [1.41 (1.07-1.85); P for interaction: 0.046]. Moreover, the history of macrosomia alone also showed a significant risk [1.36 (1.04-1.78)]; however, history of GDM alone did not have a significant risk [0.92 (0.34-2.46)]. Age, current smoking, eGFR, and SBP remained as independent risk factors for incident CKD. CONCLUSIONS: A history of GDM/macrosomia or macrosomia alone, independent of subsequent diabetes mellitus was associated with significant risk for incident maternal CKD. Pregnancy may provide a unique situation to identify high-risk women at risk for CKD that could benefit from regular monitoring of kidney function and providing risk modifying strategies.

Determination of age and sex specific TSH and FT4 reference limits in overweight and obese individuals in an iodine-replete region: Tehran Thyroid Study (TTS).

Introduction: To determine age and sex-specific thyrotropin (TSH) and free thyroxine (FT4) reference ranges according to body mass index (BMI) categories. Methods: With regards to the National Academy of Clinical Biochemistry (NACB) criteria, a total of 2818 individuals from the Tehran Thyroid Study population was selected and categorized in three BMI groups. Results: TSH levels did not differ significantly between BMI groups (p = .054). Females had statistically higher TSH levels than males in all BMI categories (p < .001). According to age-specific analyses, the youngest category (20-29 years) had the highest median values of serum TSH in all BMI groups. With increasing BMI, the 2.5th percentile of TSH remained approximately unchanged and the 97.5th percentile showed an increasing pattern. FT4 level was significantly higher in the normal weight group compared to obese individuals (p < .001); females had significantly lower FT4 levels than males in normal weight and obese groups (p < .001). According to age categories, the youngest group (20-29 years) had higher levels of FT4 than the elderly group in all BMI categories. A decreasing pattern in both 2.5th and 97.5th percentiles of FT4 was observed along with increasing BMI. Conclusions: Compared to the normal weight population, obese individuals have slightly lower FT4 concentrations accompanied by similar TSH levels. With increasing BMI, upper limits of TSH and FT4 show increasing and decreasing patterns, respectively.

The impact of triglyceride-glucose index on incident cardiovascular events during 16 years of follow-up: Tehran Lipid and Glucose Study.

BACKGROUND: To investigate whether the Triglyceride-Glucose index (TyG-index) is associated with increased risk of cardiovascular diseases (CVD)/coronary heart disease (CHD). METHODS: A total of 7521 Iranians aged ≥ 30 years (male = 3367) were included in the study. Multivariate Cox regression analyses (adjusted for age, gender, waist circumference, body mass index, educational level, smoking status, physical activity, family history of CVD, type 2 diabetes, hypertension, low and high density lipoprotein cholesterol, and lipid lowering drugs) were used to assess the risk of incident CVD/CHD across quintiles and for 1-standard deviation (SD) increase in the TyG-index. The cut off point for TyG-index was assessed by the minimum value of [Formula: see text]. We also examined the added value of the TyG-index in addition to the Framingham risk score when predicting CVD. RESULTS: During follow-up, 1084 cases of CVD (male = 634) were recorded. We found a significant trend of TyG-index for incident CVD/CHD in multivariate analysis (both Ps for tend ≤ 0.002). Moreover, a 1-SD increase in TyG-index was associated with significant risk of CVD/CHD in multivariate analysis [1.16 (1.07-1.25) and 1.19 (1.10-1.29), respectively]. The cut-off value of TyG-index for incident CVD was 9.03 (59.2% sensitivity and 63.2% specificity); the corresponding value of TyG-index for incident CHD was 9.03 (60.0% sensitivity and 62.8% specificity), respectively. Although no interaction was found between gender and TyG-index for CVD/CHD in multivariate analysis (both Ps for interaction > 0.085), the significant trend of TyG-index was observed only among females for incident CVD (P = 0.035). A significant interaction was found between age groups (i.e. ≥ 60 vs < 60 years) and TyG-index for CVD outcomes in the multivariate model (P-value for interaction = 0.046). Accordingly, a significant association between the TyG-index and outcomes was found only among the younger age group. Among the population aged < 60 the addition of TyG-index to the Framingham risk score (FRS) did not show improvement in the predictive ability of the FRS, using integrated discrimination improvement. CONCLUSION: The TyG-index is significantly associated with increased risk of CVD/CHD incidence; this issue was more prominent among the younger population. However, adding TyG-index to FRS does not provide better risk prediction for CVD.

A comparison of the effects of oral contraceptives on the clinical and biochemical manifestations of polycystic ovary syndrome: a crossover randomized controlled trial.

STUDY QUESTION: Do oral contraceptives (OCs) containing progestins with low androgenic or antiandrogenic activities have different effects to those containing levonorgestrel (LNG) on clinical, androgenic and metabolic manifestations of polycystic ovarian syndrome (PCOS)? SUMMARY ANSWER: The three OCs tested had similar effects on clinical findings of hyperandrogenism (HA), whereas products containing LNG were less effective on androgenic profiles and had detrimental effects on lipid profiles. WHAT IS KNOWN ALREADY: Despite data available on the effects of OCs, the superiority of products with low androgenic or antiandrogenic progesterone components in comparison with older products used in women with PCOS has not been clarified. STUDY DESIGN, SIZE, DURATION: This study is a crossover randomized controlled six-arm trial, with all six arms including two 6-month treatment periods, one period with OCs containing LNG, and the other with one of three OCs containing desogestrel (DSG), cyproterone acetate (CPA) or drospirenone (DRSP). The trial was conducted between February 2016 and January 2018 and enrolled 200 patients with PCOS. PARTICIPANTS/MATERIALS, SETTING, METHODS: Two hundred women with PCOS (ages 18-45 years) were recruited at the endocrine outpatient clinic of the Research Institute for Endocrine Sciences (RIES) of the Shahid Beheshti University of Medical Sciences, Tehran, Iran. A blocking or stratification random allocation (block size = 6) using a computer-based random number generator was prepared to assign participants to treatment groups. Both the clinical examiner and data analyst were blinded to participants during the trial. Outcomes of interest, including anthropometric and clinical manifestations and hormonal, and biochemical parameters were assessed at baseline, after 3 and 6 months of each treatment and after the washout period. MAIN RESULTS AND THE ROLE OF CHANCE: This study detected a higher decrease in free-androgen index (FAI) levels after 3 months of treatment with OCs containing DSG (95% CI: -2.3, -1.0), CPA (95% CI: -2.4, -1.1) and DRSP (95% CI: -2.6, -1.4), compared with products containing LNG (P < 0.001). Use of OCs containing DSG (95% CI: -3.6, -1.5), CPA (95% CI: -3.1, -0.8) and DRSP (95% CI: -3.4, -1.1) for 6 months was associated with more decrease in FAI, compared with products containing LNG (P < 0.001). The study showed that use of OCs containing DSG, CPA and DRSP for 3-6 months was associated with a higher increase of sex hormone-binding globulin (SHBG), compared with products containing LNG (P < 0.001). We also observed more decrease in dehydroepiandrosterone sulfate levels after use of OCs containing DSG (P = 0.003), CPA (P = 0.012) and DRSP (P < 0.001) for 6 months, compared with products containing LNG. Our results showed that the use of OCs containing DRSP for 6 months was associated with more improvement in acne, compared with products containing LNG (P = 0.007). Women treated with OCs containing CPA, and DRSP for 3 months had higher TG and HDL levels and lower LDL levels, compared with those treated with products containing LNG (P < 0.05). After 6 months of treatment, patients treated with OCs containing DRSP had a sharper decline in LDL levels and more increase in HDL levels, compared to those treated with products containing LNG (P = 0.001). LIMITATIONS, REASONS FOR CAUTION: Considering this trial was conducted in women diagnosed with Androgen Excess Society criteria, the results may not be generalizable for mild phenotypes diagnosed using Rotterdam criteria. Other limitations of the study include the high dropout rate, the lack of a gold standard androgen assay and the multiple end points. WIDER IMPLICATIONS OF THE FINDINGS: Our results support the views of clinicians, who suggest an OC with a low androgenic or antiandrogenic progestin, if available, to treat PCOS. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the RIES, Shahid Beheshti University of Medical Sciences, Tehran, Iran. There are no conflicts of interest. TRIAL REGISTRATION NUMBER: IRCT201702071281N2. TRIAL REGISTRATION DATE: 21 February 2017. DATE OF FIRST PATIENT'S ENROLMENT: 21 March 2017.

Endogenous testosterone does not improve prediction of incident cardiovascular disease in a community-based cohort of adult men: results from the Tehran Lipid and Glucose Study.

Introduction: To explore the predictive value of testosterone added to the Framingham Risk Score (FRS) for cardiovascular disease (CVD).Methods: Among 816 men, 30-70 years/old, without prevalent CVD, from a community-based cohort (Tehran Lipid and Glucose Study), we assessed the predictive value of testosterone with incident CVD, using three multivariate Cox proportional-hazards models. Model I: FRS variables; model II: Model I plus total testosterone; model III: Model II plus Systolic blood pressure (SBP) * total testosterone (the best fit interaction-term between testosterone and FRS variables). Discriminations and goodness-of-fit were assessed by the C-statistic and the approach of Grønnesby, respectively. p Value <.05 was significant.Results: During 12 years of follow-up, 121 CVD events occurred. In all models, age, treated SBP, smoking, and diabetes were associated with increased CVD (p values <.05). Neither testosterone (models II and III), nor SBP * testosterone (model III) were associated with CVD (p values >.05). The C-statistics for models I, II, and III were 0.819, 0.820, and 0.821, respectively, indicating no significant improvement in the discrimination power. The models' goodness-of-fit did not improve compared with the FRS.Conclusion: Testosterone could not add to the predictive value of FRS for CVD in men, either directly, or through interactions with FRS variables.

Effects of oral contraceptives on the quality of life of women with polycystic ovary syndrome: a crossover randomized controlled trial.

BACKGROUND AND OBJECTIVE: A limited number of studies have evaluated the effects of oral contraceptives (OCs) on the quality of life (QOL) of polycystic ovary syndrome (PCOS) patients. This study aimed to compare the effects of using OCs containing levonorgestrel (LNG) and those containing desogestrel (DSG), cyproterone acetate (CPA) or drospirenone (DRSP) for 6 months on the QOL with PCOS. METHODS: In this crossover randomized controlled 6-arm trial, 200 eligible patients with PCOS scheduled for OC therapy were randomly assigned to one of the 6 study arms. All 6 arms include two 6-month treatment periods, one period with OCs containing LNG, and the other with each of the 3 OCs containing DSG, CPA, or DRSP. Outcomes of interest were the total score of QOL and its domains, which were assessed using a specific and valid health-related quality of life questionnaire for PCOS, which is consisted of six domains, including psychosocial-emotional, self-image, fertility, sexual function, hirsutism, and obesity- menstrual disorders. RESULTS: Finally, a total of 88 patients were analyzed for this study. The results showed that use of OCs containing DSG, CPA, and DRSP for 3 months was not associated with significant differences in the total scores of QOL compared to those OCs containing LNG, whereas, after 6 months of treatment, patients treated with OCs containing CPA had more improvements in their total scores of QOL, in comparison to OCs containing LNG (P < 0.042). We found no significant differences in QoL domains, including psychosocial-emotional, self-image, fertility, sexual function, hirsutism, and obesity-menstrual disorders after 3-6 months of treatment with DSG, CPA, or DRSP, compared to LNG. The sequence and period effects were not significant in any of the analyses at 3 and 6 months of treatment. The carry-over effect was not significant for most outcomes assessed. CONCLUSIONS: This crossover study demonstrated non-inferiority of OCs with newer generation progestins on different domains of QOL, in comparison with older compounds, although usage of products containing CPA was significantly associated with more improvement in total QOL of PCOS patients, compared to those containing LNG after 6-month of treatment. TRIAL REGISTRATION: IRCT201702071281N2 .

Nasopharyngeal B-cell lymphoma with pan-hypopituitarism and oculomotor nerve palsy: a case report and review of the literature.

BACKGROUND: Primary nasopharyngeal lymphoma (NPL) is a very rare tumor of Waldeyer ring (WR) lymphoid tissue. It is challenging to differentiate lymphoma infiltration of pituitary from a pituitary adenoma, meningioma infiltration, and other sellar lesions to plan a suitable treatment strategy. We presented for the first time a unique case of NPL with an unusual presentation of oculomotor nerve palsy associated with pan-pituitary involvement in a diabetic patient. CASE PRESENTATION: A 64-year old diabetic woman with no previous history of malignancy presented with intermittent diplopia for about the last nine months. Severe headache, left eye ptosis and hypoglycemic episodes were added to her symptoms after a while. Further complaints include generalized weakness, loss of appetite, generalized musculoskeletal pain, and 6-7 kg weight loss within six months. Her family history was unremarkable. Physical examinations of eyes indicated left eye 3rd, 4th, and 6th nerve palsy. But, she was not anisocoric, and the pupillary reflexes were normal on both eyes. No lymphadenopathy, organomegaly and other abnormalities were found. Magnetic resonance imaging (MRI) showed a heterogeneous enhancement in the seller and suprasellar regions, enlargement of the stalk, parasellar dural enhancement and thickening of the sphenoid sinus without bone erosion. Also, both cavernous sinuses were infiltrated and both internal carotid arteries were encased by the neoplastic lesion. It suggested an infiltrative neoplastic lesion which compressed the cranial nerves. Pituitary hormone levels assessment indicated a pan-hypopituitarism. Following nasopharyngeal mucosal biopsy, the immunohistochemistry (IHC) findings revealed a low-grade non-Hodgkin's B-cell lymphoma. Systemic workup, including cerebrospinal fluid (CSF) studies, bone marrow aspiration, chest and abdominopelvic high-resolution computed tomography (HRCT) indicated no other involvement by the lymphoma. After chemotherapy courses, central adrenal insufficiency, partial central diabetes incipidious (CDI) and central hypothyroidism have been resolved. To our best knowledge, we found 17 cases of NPL with cranial nerve palsy, 1 case of NPL with pan-hypopituitarism and no NPL case with both cranial nerve palsy and pituitary dysfunction. CONCLUSIONS: The incidence of cranial neuropathy in patients with diabetes should not merely be attributed to diabetic neuropathy without further evaluation.

Assessment of the simultaneous effect of hypothyroidism and thyroid autoimmunity with gestational diabetes on the incidence of type 2 diabetes.

INTRODUCTION: Despite the evidence available on the adverse impact of gestational diabetes (GDM) and thyroid disorders on developing type 2 diabetes (T2DM), the concurrent influence of these disorders on the incidence of T2DM has not been reported yet. METHODS: In this prospective study, 1894 non-diabetic women aged 20 to 60 years, with a history of at least one term delivery, without diagnosed hyperthyroidism were selected at the initiation of the Tehran Thyroid Study (TTS). Pooled logistic regression analyses were used to investigate the association of GDM, thyroid disorders i.e., hypothyroidism and/or thyroid peroxidase antibody (TPOAb) positivity and interaction between GDM and thyroid disorders with the risk of incident T2DM. RESULTS: Of the 1894 participants of the present study, 346 (18.3%) had a history of GDM, and 832 (43.9%) had thyroid disorders. The total cumulative incidence rate of T2DM at the median follow-up time of ~ 12 years was overall 12/1000 person-years (95% confidence interval (CI): 10/1000-13/1000), with an incidence rate of 16/1000 (95%CI: 13/1000-20/1000) in women with GDM; and 11/100,000 (95%CI: 9/100,000-12/1000) among those without GDM. After adjustment for age, the risk of incident T2DM increased among individuals with the previous GDM compared to women without a history of GDM (odds ratio (OR): 1.54, 95%CI: 1.06, 2.25). No significant associations were found between either thyroid disorders or the interaction between GDM and thyroid disorders with the development of T2DM; (OR: 1.14, 95%CI: 0.82, 1.58) and (OR: 1.27, 95%CI: 0.66, 2.43), respectively. CONCLUSION: GDM and thyroid disorders have no concurrent impacts on the incidence of T2DM.

Abdominal Obesity Phenotypes and Incidence of Thyroid Autoimmunity: A 9-Year Follow-up.

PURPOSE: The association between obesity and autoimmune diseases has been suggested by several previous studies. The objective of our study was to assess the association of abdominal obesity phenotypes with thyroid autoimmunity. MATERIALS AND METHODS: This study was conducted within the framework of a population-based cohort study, Tehran Thyroid Study (TTS) on 4708 subjects without thyroid autoimmunity at baseline. Participants were categorized into four abdominal obesity phenotypes according to waist circumference (WC) and other metabolic syndrome components. Serum concentrations of thyroid peroxidase antibody (TPOAb), free T4 (FT4), thyrotropin (TSH), glucose, and lipid profiles were measured after 3, 6 and 9 years of follow-up. Cox proportional hazard models were used to evaluate associations of different phenotypes with the incidence of thyroid autoimmunity, adjusted for age, sex, FT4, and TSH. RESULTS: Highest and lowest incidence rates of TPOAb positivity were observed among metabolically unhealthy, non-abdominally obese (MUNAO) [8.78 (7.31-10.55) per 1000 person-years of follow-up] and metabolically unhealthy abdominally obese (MUAO) [4.98 (3.88-6.41) per 1000 person-years of follow-up] phenotypes. Considering the metabolically healthy non-abdominal obese (MHNAO) individuals as reference, none of metabolically healthy abdominally obese (MHAO), MUNAO, and MUAO phenotypes were associated with increased risk of developing TPOAb positivity. Compared to individuals with high WC, the incidence rate (95%CI) of TPOAb positivity was higher among those with normal WC: 8.44 (7.13-10.0) vs 5.11 (4.01-6.51) per 1000 person-years, respectively. Higher WC was not associated with incident TPOAb positivity. CONCLUSION: There was no significant association between baseline abdominal obesity phenotype status and development of TPOAb positivity over 9 years of follow-up.