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ABSTRACT Objective To report the evolution of patients with a suggestive clinical scenario and elevated serum insulin-like growth factor-1 (IGF-1), but growth hormone (GH) suppression in the oral glucose tolerance test (OGTT), in whom acromegaly was not initially excluded. Subjects and methods Forty six patients with a suggestive clinical scenario, who had elevated IGF-1 (outside puberty and pregnancy) in two measurements, but GH < 0.4 µg/L in the OGTT, were selected. Five years after initial evaluation, the patients were submitted to clinical and laboratory (serum IGF-1) reassessment. Patients with persistently elevated IGF-1 were submitted to a new GH suppression test and magnetic resonance imaging (MRI) of the pituitary. Results Four patients were lost to follow-up. During reassessment, 42 patients continued to show no “typical phenotype” or changes in physiognomy. Fifteen of the 42 patients had normal IGF-1. Among the 27 patients with persistently elevated IGF-1 and who were submitted to a new OGTT, GH suppression was confirmed in all. Two patients exhibited a lesion suggestive of microadenoma on pituitary MRI. In our interpretation of the results, acromegaly was ruled out in 40 patients and considered “possible” in only 2. Conclusion Our results show that even in patients with a suggestive clinical scenario and elevated IGF-1, confirmed in a second measurement and without apparent cause, acromegaly is very unlikely in the case of GH suppression in the OGTT.

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ABSTRACT Objectives Body mass index (BMI) is a widely used proxy of body composition (BC). Concerns exist regarding possible BMI misclassification among active populations. We compared the prevalence of obesity as categorized by BMI or by skinfold estimates of body fat percentage (BF%) in a physically active population. Subjects and methods 3,822 military firefighters underwent a physical fitness evaluation including cardiorespiratory fitness (CRF) by the 12 min-Cooper test, abdominal strength by sit-up test (SUT) and body composition (BC) by BF% (as the reference), as well as BMI. Obesity was defined by BF% > 25% and BMI ≥ 30 kg/m2. Agreement was evaluated by sensitivity and specificity of BMI, positive and negative predictive values (PPV/NPV), positive and negative likelihood (LR+/LR-), receiver operating characteristic (ROC) curves and also across age, CRF and SUT subgroups. Results The prevalence of obesity estimated by BMI (13.3%) was similar to BF% (15.9%). Overall agreement was high (85.8%) and varied in different subgroups (75.3-94.5%). BMI underestimated the prevalence of obesity in all categories with high specificity (≥ 81.2%) and low sensitivity (≤ 67.0). All indices were affected by CRF, age and SUT, with better sensitivity, NPV and LR- in the less fit and older groups; and higher specificity, PPV and LR+ among the fittest and youngest groups. ROC curves showed high area under the curve (≥ 0.77) except for subjects with CRF ≥ 14 METs (= 0.46). Conclusion Both measures yielded similar obesity prevalences, with high agreement. BMI did not overestimate obesity prevalence. BMI ≥ 30 was highly specific to exclude obesity. Because of systematic under estimation, a lower BMI cut-off point might be considered in this population.

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ABSTRACT Objectives To evaluate the ability of BMI, WC and WHtR to discriminate hyperglycemia in young people, and to determine whether there is an increase in the accuracy with the addition of WC and/or WHtR to BMI. Subjects and methods A cross-sectional study was conducted on 1,139 schoolchildren aged 6 to 17 years from Northeastern Brazil. Body weight, height, WC and fasting glucose levels were measured, and the BMI and WHtR were calculated. The presence of hyperglycemia was defined as a fasting glucose level ≥ 100 mg/dL. Results The prevalence of hyperglycemia was 6.6%. Strong correlations were observed between the anthropometric indicators studied (BMI vs. WC = 0.87; BMI vs. WHtR = 0.87; WC vs. WHtR = 0.90). Hyperglycemia was more likely to be present in young people with excess weight (PR = 1.70), high WC (PR = 1.85), and high WHtR (PR = 1.91). The accuracies to discriminate hyperglycemia were significant, but low, for the individual (BMI = 0.56; WC = 0.53; WHtR = 0.55) and combined indicators (BMI + WC = 0.55; BMI + WHtR = 0.55). Conclusion Our findings do not support the use of BMI, WC or WHtR as screening tools for hyperglycemia in children and adolescents.

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ABSTRACT Objectives To identify a clinical profile and laboratory findings of a cohort of hypoparathyroidism patients and determine the prevalence and predictors for renal abnormalities. Materials and methods Data from medical records of five different visits were obtained, focusing on therapeutic doses of calcium and vitamin D, on laboratory tests and renal ultrasonography (USG). Results Fifty-five patients were identified, 42 females and 13 males; mean age of 44.5 and average time of the disease of 11.2 years. The most frequent etiology was post-surgical. Levels of serum calcium and creatinine increased between the first and last visits (p < 0.001 and p < 0.05, respectively); and serum levels of phosphate decreased during the same period (p < 0.001). Out of the 55 patients, 40 had USG, and 10 (25%) presented with kidney calcifications. There was no significant difference in the amount of calcium and vitamin D doses among patients with kidney calcifications and others. No correlation between serum and urinary levels of calcium and the presence of calcification was found. Urinary calcium excretion in 24h was significantly higher in patients with kidney calcification (3.3 mg/kg/d) than in those without calcification (1.8 mg/kg/d) (p < 0.05). Conclusions The reduction of hypocalcemia and hyperphosphatemia suggest an effectiveness of the treatment, and the increase in serum creatinine demonstrates an impairment of renal function during follow-up. Kidney calcifications were prevalent in this cohort, and higher urinary calcium excretion, even if still within the normal range, was associated with development of calcification. These findings suggest that lower rates of urinary calcium excretion should be aimed for in the management of hypoparathyroidism.

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ABSTRACT Objective Parathyroid cancer (PC) represents < 1% of cases of PHPT. Tumors demonstrating atypical histopathologic features and don’t fulfill criteria for carcinoma are classified as atypical adenomas (APA). The purpose of this study was to determine a biochemical or ultrasonographic feature that can predict aggressive disease requiring more extensive surgery and closer follow-up. Subjects and methods Twenty eight patients operated for PHPT and diagnosed with atypical adenoma (23 patients) or carcinoma (5 patients) were enrolled in this study. The control group consisted of 102 patients operated between the same dates and diagnosed with classical PA. Classical adenomas, atypical adenomas, and carcinomas were compared according to their biochemical and ultrasonographic parameters. Results Serum Ca levels were significantly higher in the PC group compared with the APA and classical PA groups. Serum median PTH, Serum ALP and UCa was significantly higher in the APA and carcinoma groups compared to the classical PA group. ROC analysis was made to determine the best cut off values for predicting aggressive disease were 12.45 mg/dL, 265.05 pg/mL, 154.5 IU/l, 348.5 mg/day and 21.5 mm for Ca, PTH, ALP, UCa and the adenoma diameter, respectively. Multivariate analysis showed that serum Ca, ALP and isoechoic/cystic appearance were independent predictors for aggressive disease. Conclusion Preoperatively high PTH, ALP, and UCa levels and large lesions with isoechoic or cystic appearances may be predictive of atypical adenoma or carcinoma in patients being evaluated for PHPT. In such cases, surgeons may prefer en bloc parathyroidectomy to minimally invasive surgery.

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ABSTRACT Objective The purpose of this study was to evaluate whether female sexual dysfunction (FSD) is associated with metabolic syndrome (MS) and to identify factors that contribute to FSD in postmenopausal women. Subjects and methods This was a cross-sectional study in 111 sexually active women aged 45-65 years. We applied the Female Sexual Function Index (FSFI) to evaluate the participant’s sexual function and a structured questionnaire to collect demographic, socioeconomic, clinical, anthropometric, and laboratory data. Results The prevalences of MS and FSD were 68.5% and 70.3%, respectively. After logistic regression analysis, we identified the following variables associated with FSD: married status (prevalence ratio [PR] 1.69, 95% confidence interval [95% CI] 1.16-2.47, p < 0.01), 6-10 years elapsed since menopause (PR 1.60, 95% CI 1.22-2.09, p < 0.01), occurrence of climacteric symptoms (PR 1.01, 95% CI 1.00-1.02, p = 0.03), and history of sexual abuse (PR 1.40, 95% CI 1.12-1.73, p < 0.01). Conclusion We found a high prevalence of MS and FSD, but no association between both. Married status, time elapsed since menopause, climacteric symptoms, and history of sexual abuse emerged as factors associated with FSD on multivariate analysis.

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ABSTRACT Objectives The main purpose of this study was to estimate the incidence rate and prevalence of clinically relevant pituitary adenomas (PAs) within the Hospital Italiano Medical Care Program (HIMCP), a well-defined population of 150,000 members living in the urban and suburban area of the city of Buenos Aires. We defined clinically relevant PAs as those associated with endocrine dysfunction and/or mass effect. Subjects and methods A retrospective open cohort study was conducted, including all members of the HIMCP over 18 years old, with active memberships during the period of the study, from January 1st 2003, to January 1, 2014. The incidence rates (IRs) were standardized (SIR) to the World Health Organization (WHO) 2000 standard population and were expressed per 100,000 members/year. Prevalence was estimated at January 1, 2014, and was expressed per 100,000 persons. The clinical records have been electronically managed since 2001. All lab and imaging studies were done in-house. Results The overall SIR was 7.39/100,000/year (95% CI 4.47-10.31). Female patients had a specific IR significantly higher than male patients (5.85 vs.1.54) and represented 73% of the affected members. Regarding tumor size, 61.4% were microadenomas, and the mean age at diagnosis was 46.4 years. Prolactinomas had the highest SIR (5.41), followed by acromegaly (Acro) and non-functioning adenomas (NFAs) with overlapping 95% CIs (0.44-1.41 and 0.31-0.99, respectively). Microprolactinomas were more frequent in female (72.6%) (p < 0.01) and younger members (38 vs.60 years; p < 0.04). The overall prevalence rate was 97.76/100,000. Prolactinomas had the highest prevalence (56.29), followed by NFAs (21.48), Acro (14.07) and CD (5.93). Conclusion Our results demonstrate that clinically relevant PAs are more common than usually suspected, especially prolactinomas and growth-hormone secreting PAs. These data highlight the need to increase the awareness of PAs, thereby enabling early diagnosis and treatment.

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ABSTRACT Objective To compare the effects of a unique fixed combination levothyroxine/liothyronine (LT4/LT3) therapy in patients with primary hypothyroidism. Subjects and methods This is a randomized, double-blind, crossover study. Adults with primary hypothyroidism (n = 32, age 42.6 ± 13.3, 30 females) on stable doses of LT4 for ≥ 6 months (125 or 150 μg/day) were randomized to continue LT4 treatment (G1) or to start LT4/LT3 therapy (75/15 μg/day; G2). After 8 weeks, participants switched treatments for 8 more weeks. Thyroid function, lipid profile, plasma glucose, body weight, electrocardiogram, vital signs, and quality of life (QoL) were evaluated at weeks 0, 8 and 16. Results Free T4 levels were significantly lower while on LT4/LT3 (G1: 1.07 ± 0.29 vs. 1.65 ± 0.46; G2: 0.97 ± 0.26 vs. 1.63 ± 0.43 ng/dL; P < 0.001). TSH and T3 levels were not affected by type of therapy. More patients on LT4/LT3 had T3 levels above the upper limit (15% vs. 3%). The combination therapy led to an increase in heart rate, with no significant changes in electrocardiogram or arterial blood pressure. Lipid profile, body weight and QoL remained unchanged. Conclusions The combination therapy yielded significantly lower free T4 levels, with no changes in TSH or T3 levels. More patients on LT4/T3 had elevated T3 levels, with no significant alterations in the evaluated outcomes. No clear clinical benefit of the studied formulation could be observed. Future trials need to evaluate different formulations and the impact of the combined therapy in select populations with genetic polymorphisms.

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ABSTRACT Objective Our aim was to describe the distribution of selected biomarkers according to age and sex, adjusted for HOMA-IR and adiposity, in a subset of middle-aged individuals of Brazilian Longitudinal Study of Adult Health-ELSA without diabetes mellitus or CVD. Subjects and methods This cross-sectional study was conducted in 998 participants of the ELSA-Brasil without diabetes and/or cardiovascular disease. In addition to the traditional risk factors, several biomarkers concentrations were compared according to sex, age groups (35-44; 45-54 yrs) and HOMA-IR tertiles. Linear regression was used to examine independent associations of sex and age with selected novel biomarkers, adjusted for body adiposity and HOMA-IR. Results Fifty-five percent were women. Men had higher mean values of body mass index, waist circumference, blood pressure, plasma glucose, HOMA-IR, worse lipid profile and higher E-selectin and lower leptin concentrations than women; while women had higher levels of HDL-cholesterol and leptin than men. Mean values of waist circumference, systolic BP, plasma glucose and apolipoprotein B (Apo B) increased with age in both sexes. Leptin and E-selectin concentrations increased across HOMA-IR tertiles. Independent associations of Apo B with age were found only in male sex, while of leptin with body mass index and HOMA-IR, and of E-selectin with HOMA-IR in both sexes. Conclusions In conclusion, our data indicate age, sex, adiposity and, consequently, insulin resistance, influence circulating levels of Apo B, leptin and E-selectin, suggesting that those aspects should be taken into consideration when assessing these parameters for research or clinical purposes in individuals at relatively low cardiometabolic risk.

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ABSTRACT Objective The current study was aimed at analyzing sarcoplasmic reticulum Ca2+ ATPase (Serca2) and ryanodine receptor type 2 (Ryr2) gene expression in rats subjected to surgery that induced HF and were subsequently treated with T4 using physiological doses. Materials and methods HF was induced in 18 male Wistar rats by clipping the ascending thoracic aorta to generate aortic stenosis (HFS group), while the control group (9-sham) underwent thoracotomy. After 21 weeks, the HFS group was subdivided into two subgroups. One group (9 Wistar rats) with HF received 1.0 µg of T4/100 g of body weight for five consecutive days (HFS/T4); the other group (9 Wistar rats) received isotonic saline solution (HFS/S). The animals were sacrificed after this treatment and examined for signs of HF. Samples from the left ventricles of these animals were analyzed by RT-qPCR for the expression of Serca2 and Ryr2 genes. Results Rats with HF developed euthyroid sick syndrome (ESS) and treatment with T4 restored the T3 values to the Sham level and increased Serca2 and Ryr2 gene expression, thereby demonstrating a possible benefit of T4 treatment for heart function in ESS associated with HF. Conclusion The T4 treatment can potentially normalize the levels of T3 as well elevated Serca2 and Ryr2 gene expression in the myocardium in heart failure rats with euthyroid sick syndrome.

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ABSTRACT Prolactin is best known for its effects of stimulating mammary gland development and lactogenesis. However, prolactin is a pleiotropic hormone that is able to affect several physiological functions, including fertility. Prolactin receptors (PRLRs) are widely expressed in several tissues, including several brain regions and reproductive tract organs. Upon activation, PRLRs may exert prolactin’s functions through several signaling pathways, although the recruitment of the signal transducer and activator of transcription 5 causes most of the known effects of prolactin. Pathological hyperprolactinemia is mainly due to the presence of a prolactinoma or pharmacological effects induced by drugs that interact with the dopamine system. Notably, hyperprolactinemia is a frequent cause of reproductive dysfunction and may lead to infertility in males and females. Recently, several studies have indicated that prolactin may modulate the reproductive axis by acting on specific populations of hypothalamic neurons that express the Kiss1 gene. The Kiss1 gene encodes neuropeptides known as kisspeptins, which are powerful activators of gonadotropin-releasing hormone neurons. In the present review, we will summarize the current knowledge about prolactin’s actions on reproduction. Among other aspects, we will discuss whether the interaction between prolactin and the Kiss1-expressing neurons can affect reproduction and how kisspeptins may become a novel therapeutic approach to treat prolactin-induced infertility.

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SUMMARY Prader-Willi syndrome (PWS) is a genetic disorder frequently characterized by obesity, growth hormone deficiency, genital abnormalities, and hypogonadotropic hypogonadism. Incomplete or delayed pubertal development as well as premature adrenarche are usually found in PWS, whereas central precocious puberty (CPP) is very rare. This study aimed to report the clinical and biochemical follow-up of a PWS boy with CPP and to discuss the management of pubertal growth. By the age of 6, he had obesity, short stature, and many clinical criteria of PWS diagnosis, which was confirmed by DNA methylation test. Therapy with recombinant human growth hormone (rhGH) replacement (0.15 IU/kg/day) was started. Later, he presented psychomotor agitation, aggressive behavior, and increased testicular volume. Laboratory analyses were consistent with the diagnosis of CPP (gonadorelin-stimulated LH peak 15.8 IU/L, testosterone 54.7 ng/dL). The patient was then treated with gonadotropin-releasing hormone analog (GnRHa). Hypothalamic dysfunctions have been implicated in hormonal disturbances related to pubertal development, but no morphologic abnormalities were detected in the present case. Additional methylation analysis (MS-MLPA) of the chromosome 15q11 locus confirmed PWS diagnosis. We presented the fifth case of CPP in a genetically-confirmed PWS male. Combined therapy with GnRHa and rhGH may be beneficial in this rare condition of precocious pubertal development in PWS.

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SUMMARY Resistance to thyroid hormone (RTH) coexisting with ectopic thyroid is rare. Here we report a case of RTH with ectopic thyroid. A ten-year-old girl had been misdiagnosed as congenital hypothyroidism and treated with levothyroxine since she was born. Ten-year follow-up showed that the elevated thyrotropin was never suppressed by levothyroxine and no signs indicating hyperthyroidism or hypothyroidism despite elevated FT3 and FT4 levels. Therefore the girl developed no defects in physical and cognitive development. Pituitary adenoma was excluded by magnetic resonance imaging. Ultrasonography did not find the thyroid gland in the normal place, while the thyroid scan found a large lingual thyroid gland. The octreotide inhibition test showed a reduction in thyrotropin by 41.98%. No mutation was detected in the thyroid hormone receptor (THR) β, THRα, thyrotropin receptor (TSHR), and GNAS1 genes. To our knowledge, it is an interesting RTH case coexisting with lingual thyroid.