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Polycystic ovary syndrome (PCOS) often coexists with a wide spectrum of dysglycemic conditions, ranging from impaired glucose tolerance to type 2 diabetes mellitus (T2D), which occur to a greater extent compared to healthy body mass index-matched women. This concurrence of disorders is mainly attributed to common pathogenetic pathways linking the two entities, such as insulin resistance. However, due to methodological flaws in the available studies and the multifaceted nature of the syndrome, there has been substantial controversy as to the exact association between T2D and PCOS which has not yet been elucidated. The aim of this review is to present the best available evidence regarding the epidemiology of dysglycemia in PCOS, the unique pathophysiological mechanisms underlying the progression of dysglycemia, the most appropriate methods for assessing glycemic status and the risk factors for T2D development in this population, as well as T2D risk after transition to menopause. Proposals for application of a holistic approach to enable optimal management of T2D risk in PCOS are also provided. Specifically, adoption of a healthy lifestyle with adherence to improved dietary patterns, such the Mediterranean diet, avoidance of consumption of endocrine-disrupting foods and beverages, regular exercise, and the effect of certain medications, such as metformin and glucagon-like peptide 1 receptor agonists, are discussed. Furthermore, the maintenance of a healthy weight is highlighted as a key factor in achievement of a significant reduction of T2D risk in women with PCOS.

Adequate vitamin D levels are particularly important in pregnant women for both the maternal and neonatal health. Prior studies have shown a significantly high prevalence of vitamin D deficiency (VDD) among refugees. However, no study has addressed the prevalence of VDD in pregnant refugees and its effects on neonatal health. In this study, we examined the prevalence of VDD in refugee pregnant women living in Greece and compared our results with Greek pregnant inhabitants. Vitamin D deficiency was frequent in both groups but was significantly more common in refugees (92.2% vs 67.3% of Greek women, p=0.003) with 70.6% of refugees having severe hypovitaminosis D (

‘Snow White and the Seven Dwarfs’, a fairytale that is widely known across the Western world, was originally written by the Brothers Grimm, and published in 1812 as ‘Snow White’. Though each dwarf was first given an individual name in the 1912 Broadway play, in Walt Disney’s 1937 film ‘Snow White and the Seven Dwarfs’, they were renamed, and the dwarfs have become household names. It is well known that myths, fables, and fairytales, though appearing to be merely children’s tales about fictional magical beings and places, have, more often than not, originated from real facts. Therefore, the presence of the seven brothers with short stature in the story is, from an endocrinological point of view, highly intriguing, in fact, thrilling. The diversity of the phenotypes among the seven dwarfs is also stimulating, although puzzling. We undertook a differential diagnosis of their common underlying disorder based on the original Disney production’s drawings and the unique characteristics of these little gentlemen, while we additionally evaluated several causes of short stature and, focusing on endocrine disorders that could lead to these clinical features among siblings, we have, we believe, been able to reveal the underlying disease depicted in this archetypal tale.

Introduction Chronic lymphocytic thyroiditis is an important risk factor for differentiated thyroid cancer (DTC) in surgical series, but the role of thyroid peroxidase antibodies (TPO) seems less clear in that regard. We designed the present study to evaluate that effect in our large patient population. Methods We recruited subjects operated with total thyroidectomy in 4 sites (USA: 1, Greece: 3) during a period of 14 consecutive years. We gathered data on TPO antibodies titers measured with commercially available radioimmunoassays, and reviewed data on surgical pathology. TPO≥34IU/ml was deemed high (TPO+). Odds ratios (OR) for DTC were calculated with Fischer's exact test. p Results We reviewed data on 8,425 thyroid surgeries, and TPO titers were available for 1,620 subjects: DTC n=702 (43.3%), benign pathology (BEN) n=918 (56.7%), TPO+ n=524 (32.3%) and TPO- (1000IU/ml n=28/144 (19.4%), p Conclusions High TPO Antibodies appear protective against DTC in our large multicentre cohort of patients operated with a total thyroidectomy. Rising preoperative TPO titers confer linearly increasing protection against DTC in the surgical specimen. More research is needed to fully understand the role of thyroid autoimmunity in the genesis of DTC. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Introduction Hashimoto's thyroiditis raises the risk for differentiated thyroid cancer (DTC) in surgical series, but the role of thyroid peroxidase antibodies (TPO) remains controversial in that regard. We designed the present study to evaluate the effect of preoperative TPO titers in the risk of DTC. Methods A comprehensive search was conducted in PubMed, CENTRAL and Scopus databases in November 2021 for the terms "thyroid cancer" and "TPO" or "peroxidase antibodies". We characterized the differential risk found in patients with high titers of TPO (TPO+), as compared to those with low or undetectable titers (TPO-) with regard to DTC. Data are expressed as odds ratio (OR) with 95% confidence interval (CI). Results We retrieved and reviewed 408 records; 21 retrospective cohort studies (2006-2022) from 7 countries and n=30,5536 subjects, fulfilled the eligibility criteria: 15 studies in East Asia with n=25,125 subjects (82.2%) and 6 studies in the Western world with n=5,428 subjects (17.8%)]. These comprised n=17,684 subjects with benign disease (57.9%) and n=12,869 with DTC (42.1%). The reference used for TPO+ was 23.6±18.8 (Range 5.1-60.0 IU/ml); n=6,307 patients were TPO+ (20.6%) and n=24,246 were TPO- (79.4%). DTC was present in n=2,960 TPO+ patients (46.9%) and n=9,909 TPO- patients (40.9), OR 1.28, (95%CI 1.21-1.35), p A high titer of TPO was associated with increased risk for DTC in both Asian cohorts, [OR 1.36 (1.28-1.45, p Conclusions Thyroid peroxidase antibodies are an integral part of Hashimoto's thyroiditis, which is a well characterized risk factor for thyroid cancer and seem to increase that risk as well. That effect seems significantly higher in East Asia as compared to the Western World region. Further studies are needed to characterize the effects of the immune response, with regard to thyroid cancer risk. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Saturday, June 11, 2022 1:24 p.m. - 1:29 p.m.

Context Thyroid nodules’ size should not be the sole criterion for thyroidectomy; however, many patients undergo surgery for large or slowly growing nodules. Objective We evaluated risk for clinically significant thyroid cancer in patients with large or slowly growing nodules. Methods We reviewed data from 2 prospectively collected databases of patients undergoing thyroidectomies in tertiary referral centers in the USA and Greece over 14 consecutive years. We collected data on the preoperative surgical indication, FNA cytology, and surgical pathology. We included subjects operated solely for large or growing thyroid nodules, without any known or presumed thyroid cancer or high risk for malignancy, family history of thyroid cancer, or prior radiation exposure. Results We reviewed 5523 consecutive cases (USA: 2711; Greece: 2812). After excluding 3059 subjects, we included 2464 subjects in the present analysis. Overall, 533 thyroid cancers were identified (21.3%): 372 (69.8%) microcarcinomas ( Conclusion The risk of synchronous, clinically important thyroid cancers is small, but not null in patients with large or slow growing thyroid nodules. Therefore, more precise preoperative evaluation is needed to separate the patients who would clearly benefit from thyroid surgery from the vast majority of those who do not need to be operated.

Background Polycystic ovary syndrome (PCOS) is considered a risk factor for the development of type 2 diabetes mellitus (T2DM). However, which is the most appropriate way to evaluate dysglycemia in women with PCOS and who are at increased risk are as yet unclear. Aim of the study To determine the prevalence of T2DM, impaired glucose tolerance (IGT), and impaired fasting glucose (IFG) in PCOS women and potential factors to identify those at risk. Subjects and methods The oral glucose tolerance test (OGTT), biochemical/hormonal profile, and ovarian ultrasound data from 1614 Caucasian women with PCOS and 362 controls were analyzed in this cross-sectional multicenter study. The data were categorized according to age and BMI. Results Dysglycemia (T2DM, IGT, and IFG according to World Health Organization criteria) was more frequent in the PCOS group compared to controls: 2.2% vs 0.8%, P = 0.04; 9.5% vs 7.4%, P = 0.038; 14.2% vs 9.1%, P = 0.002, respectively. OGTT was essential for T2DM diagnosis, since in 88% of them basal glucose values were inconclusive for diagnosis. The presence of either T2DM or IFG was irrespective of age (P = 0.54) and BMI (P = 0.32), although the latter was associated with IGT (P = 0.021). There was no impact of age and BMI status on the prevalence of T2DM or IFG. Regression analysis revealed a role for age, BMI, fat deposition, androgens, and insulin resistance for dysglycemia. However, none of the factors prevailed as a useful marker employed in clinical practice. Conclusions One-third of our cohort of PCOS women with either T2DM or IGT displayed normal fasting glucose values but without confirming any specific predictor for dysglycemic condition. Hence, the evaluation of glycemic status using OGTT in all women with PCOS is strongly supported.

The exact risk of type 2 diabetes mellitus (T2DM) in women with polycystic ovary syndrome (PCOS) is unknown. It is also unclear if obesity independently increases T2DM risk in this population. The aim of this study was to systematically review and synthesize the best available evidence regarding the association between PCOS and T2DM, stratified according to obesity status. A comprehensive search was conducted in PubMed, CENTRAL and Scopus databases up to October 31, 2020. Data are expressed as relative risk (RR) with 95% confidence interval (CI). The I2 index was employed for heterogeneity. The eligibility criteria were fulfilled by 23 studies (319,780 participants; 60,336 PCOS and 8847 type 2 diabetes cases). Women with PCOS demonstrated a higher risk of T2DM than those without PCOS (RR 3.45, 95% CI, 2.95–4.05, p

Background Levothyroxine (LT4-Rx) is one of the most commonly prescribed drugs worldwide and the vast majority of patients receive long-term treatment. However, in a recent study of LT4-Rx withdrawal in 291 subjects, it was found that 60% of those remained biochemically euthyroid two months after LT4-Rx discontinuation1. Aim of the study A prospective clinical cohort follow-up study was carried out to address this issue. We registered all patients presented in our clinical practice who were not on LT4-Rx for a solid diagnosis of hypothyroidism and abruptly discontinued treatment. All subjects underwent weight, height, TSH, TPO, Tg-Abs and free T4 measurement and thyroid ultrasound on enrolment, 2-4 months later, and at the end of follow up. A TSH value of ≥4.5IU/mL was considered as underlying hypothyroidism. Results We enrolled 802 consecutive subjects (83% females) aged 48±16 (range 18-84 years) with 8.8±7.3 years on LT4-Rx. The treatment indications and corresponding percentage for LT4-Rx were classified as a nodule(s) (35%), indefinite (25%), post-partum (7%) and Hashimoto's (33%); 48% of subjects were part of Group A and long-term follow-up up to 5 years was achieved in the remaining. Among the entire cohort, n=182 subjects became hypothyroid, while the remaining n=620 remained euthyroid off LT4-Rx (23 vs. 77%, p3IU/mL vs. 5.2% with baseline TSH Conclusions These findings suggest considerable overuse of thyroxine therapy. In cases of uncertainty, the existence of nodules, a low-normal TSH value, a relatively small T4 dose, and the absence of ATA are strong predictors of euthyroidism, and accordingly a treatment discontinuation trial is recommended. Furthermore, if hypothyroidism does not ensue 2-4 months post-treatment discontinuation, the likelihood to develop hypothyroidism in the long term is minimal.1. Livadas S, et al. Thyroid 2018. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Introduction Thyroglossal duct (TGD) carcinoma is an uncommon entity, located in the TGD remnant, and is diagnosed in patients undergoing evaluation of the neck for midline swelling, or incidentally after removal of a TGD cyst. Despite the presence of multiple publications on the topic, no systematic characterization of these tumors has been performed to date. The present study aims to characterize the tumors found patients diagnosed with TGD remnant malignancies. Methods We performed a systematic search for the term "Thyroglossal duct" in Pubmed, Embase and Cochrane databases on December 1, 2021 and retrieved 1229 records. We included all manuscripts containing cohorts, case reports or case series, when the manuscript or its abstract was available in English, Italian, French or Spanish language. We reviewed the demographics, the histological report of the thyroglossal duct and the thyroidectomy specimen (when this was performed) and the features of tumor aggressiveness, when these were available. Results We incorporated data from 366 manuscripts, comprising 1202 patients operated for TGD disease. Out of these, n=550 cancers were identified, consisting of n=475 (86.4%) Papillary thyroid carcinomas (PTC), n=8 Follicular thyroid carcinomas (FTC) (1.5%), n=5 Hürthle cell carcinomas (HCC) (0.9%), n=27 Squamous cell carcinomas (SCC) (4.9%), n=2 poorly differentiated/anaplastic thyroid carcinomas (ATC) (0.4%), n=1 Adeno-SCC (0.18%), n=1 Adenocarcinoma (0.18%), n=12 synchronous PTC/FTC (2.2%), n=1 synchronous PTC/SCC (0.18%) and n=18 of unclear histological diagnosis (4.75%). N=173/446 (38.8%) patients were males and n=273/446 (61.2%) were females; gender was not available in n=104 cases. Mean cancer size was 1.4±1.4cm (range 0.01-7.0cm); n=88/173 (50.9%) were microcarcinomas ( Conclusions TGD remnant cancers include various tumors, with histology and features of aggressive behavior similar to what we see in thyroid cancer cases. More research is needed to enhance our understanding of the mechanisms involved in the pathogenesis and malignant behavior of these infrequently identified tumors. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Background: Levothyroxine (LT4) is one of the most prescribed drugs worldwide. Once started, approximately 90% of patients continue treatment long term. However, accumulating evidence suggests that...

PURPOSE To compare the effects of insulin sensitizers metformin (MET) and myo-inositol (MI) on adiponectin levels and metabolic characteristics in women with polycystic ovary syndrome (PCOS) with respect to their body mass index (BMI). METHODS In this open label, parallel randomized clinical trial, 66 women with PCOS (33 normal-weight and 33 overweight/obese) were randomized to either MI (4 g/day) or MET (1500 mg/day) for a period of 6 months. Serum concentration of adiponectin, hormonal and metabolic laboratory outcomes and clinical assessment of BMI, body composition and Ferriman-Gallwey score (FG score) were evaluated before and after treatment. RESULTS After the 6-month intervention, comparison between MET and MI in time to treatment analysis showed no significant differences between the two treatments for all analyzed parameters. Only borderline significantly lower AUC glucose was found in the MET group in comparison to the MI group (p = 0.071). The main effect of treatment was shown for glucose concentration at 120 min OGTT (p = 0.032) and testosterone (p = 0.002). The main effect of time was shown for body mass (p = 0.004), waist circumference (p

Introduction: Despite the current state of evidence suggesting that thyroid nodules’ size should not be the sole criterion for the decision to undergo thyroidectomy, many patients are still operated for large, or growing nodules. In order to ascertain whether this is a justifiable approach, we performed the present study. Methods/ Subjects: We reviewed the data from two prospectively collected databases of patients undergoing thyroid surgery in two tertiary referral centers, one in the USA (A) and the other one in Greece (B) over 14 consecutive years. We collected data on the preoperative surgical indication, FNA cytology and surgical pathology. We included subjects with multinodular goiters, operated solely for large or growing thyroid nodules, who did not have any known or presumed thyroid cancer, or indications of high risk for malignancy (FNA suspicious for thyroid cancer, follicular neoplasm, suspicious for follicular neoplasm, FLUS/AUS, cellular specimen), family history of thyroid cancer or prior neck radiation exposure. Results: We reviewed 5523 consecutive cases of thyroid surgery (A:2711, B:2812). After excluding n=3059 subjects, we included n=2464 subjects in the present analysis. Overall 535 thyroid cancers were identified (21.7%): 349 (65.2%) were microcarcinomas ( Conclusions: Although the likelihood of identifying a clinically relevant thyroid cancer in a large or growing nodule, in the absence of risk enhancing features, is low; the risk of synchronous, clinically important, thyroid cancers is high in patients with large multinodular goiters. Therefore, more precise screening strategies are urgently needed to identify the patients, who would clearly benefit from thyroid surgery and protect those who do not need to be operated on.

If circulating adrenal androgens levels rise before the age of 8 years in girls, this phenomenon is termed premature adrenarche (PA), while the concomitant appearance of pubic hair is called premature pubarche (PP). Girls with PA-PP display an unfavorable hormonal profile compared to their normal peers and have an increased risk of developing polycystic ovary syndrome (PCOS) features peripubertally. However, the sequelae of premature adrenarche remains unclear. We assessed metabolic, hormonal, psychologic profiles, and ovarian morphology in 21 women of mean age (±SD) 21.3±3.3 years, BMI: 23.6±4.4 kg/m2 with PA-PP, 45 women with PCOS and 26 controls, matched for age and BMI. PA-PP women displayed a favorable lipid profile compared to PCOS and controls. Insulin resistance index (HOMA-IR), however, were similar in PA-PP and PCOS women (2.09±1.42, 2.08±0.83) and higher than controls (1.13±0.49, p

Polycystic ovary syndrome (PCOS), considered a lifelong condition, manifests mainly as a cluster of hyperandrogenic symptoms during the early reproductive years, with the affected woman gradually developing an adverse cardiometabolic profile over the years. However, some data point to the possibility of differences in the evolution of PCOS according to a woman’s weight. The aim of the present study was to evaluate the metabolic and hormonal profiles of women with PCOS over time. A total of 763 lean women with PCOS (BMI 20–25 kg/m2) and 376 controls were included. The study group was further divided into three age groups representing women post-adolescence, of reproductive age, and of late reproductive age. All subjects were assessed clinically, biochemically, and hormonally. Waist circumference, lipids, androgens, and insulin resistance index (homeostasis model assessment of IR index (HOMA-IR)) were significantly higher in the PCOS group compared with controls. Age subgroup analysis showed a progressive decrease of HOMA-IR and waist circumference, and lipid levels were comparable between PCOS and controls in all age groups. Androgens remained significantly higher in PCOS, but they gradually decreased through time. A significant negative association of age with waist circumference, androgens, insulin, and HOMA-IR was revealed. Univariate and multivariate regression analysis disclosed a strong correlation of HOMA-IR with age (p = 0.014, β − 0.19, SE coefficient 0.008) as a single parameter or in combination with total cholesterol (TC) (p

Background: Incidental finding of differentiated thyroid microcarcinomas (DTMc) in patients undergoing thyroid surgery for benign indications has become increasingly common. Even though carcinogene...

The mechanisms underlying the initiation of puberty, one of the cornerstones of human evolution, have not been fully elucidated as yet. However, recently, an accumulating body of evidence has helped unravel several critical aspects of the process. It is clear that a change in the pattern of pituitary gonadotropin secretion serves as a hormonal trigger for puberty induction. This change is directly guided by the hypothalamic GnRH pulse generation, a phenomenon regulated by the Kisspeptin-Neurokinin-Dynorphin (KNDy) system also in the hypothalamus. This represents the kisspeptin molecule, which is crucial in augmenting GnRH secretion at puberty, whose secretion is fine-tuned by the opposing signals neurokinin B and dynorphin. Recently, the novel kisspeptin inhibitory signal MKRN3 was described, whose role in puberty initiation provided further insight into the mechanistic aspects of pubertal onset. Furthermore, the description of higher inhibitory and stimulatory signals acting upstream of the KNDy neurons suggested that the trigger point of puberty is located upstream of the KNDy system and the GnRH pulse generator. However, the mechanism of pubertal onset should not be considered as an isolated closed loop system. On the contrary, it is influenced by such factors as adipose tissue, gastrointestinal function, adrenal androgen production, energy sensing, and physical and psychosocial stress. Also, fetal and early life stressful events, as well as exposure to endocrine disruptors, may play important roles in pubertal initiation, the latter primarily through epigenetic modifications. Here we present the available data in the field and attempt to provide an integrated view of this unique and crucial phenomenon.

Background/Aims: Polycystic ovary syndrome (PCOS) is associated with disordered carbohydrate metabolism and an increased risk for T2D. However, there are limited data on the magnitude of this risk. Furthermore, 50-80% of women with PCOS are obese and obesity is known to have a synergistic deleterious effect on glucose tolerance in affected women. We systematically reviewed the literature regarding the association between PCOS, obesity and T2D risk. Methods: A comprehensive search was conducted in PubMed, CENTRAL and Scopus databases. Data are expressed as relative risk (RR) with 95% confidence intervals (CI). The I2 index was employed for heterogeneity. The available data, did not allow us to analyze the impact of weight status as normal, overweight and obese and as a consequence the studied subjects were stratified as obese (BMI>30 kg/m2) and non-obese (BMI3-fold increased risk of T2D compared to women without PCOS, but this risk is substantially increased by the presence of obesity. Accordingly, weight reduction should be pursued in these women. References: 1. Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989;38(9):1165-1174.2. Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab. 1999;84(1):165-169.3. Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care. 1999;22(1):141-146.4. Rubin KH, Glintborg D, Nybo M, Abrahamsen B, Andersen M. Development and risk factors of type 2 diabetes in a nationwide population of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2017;102(10):3848-3857.

Non-classical congenital adrenal hyperplasia (NCCAH) is considered to be a common monogenic inherited disease, with an incidence range from 1:500 to 1:100 births worldwide. However, despite the high incidence, there is a low genotype-phenotype correlation, which explains why NCCAH diagnosis is usually delayed or even never carried out, since many patients remain asymptomatic or are misdiagnosed as suffering from other hyperandrogenic disorders. For affected adolescent and adult women, it is crucial to investigate any suspicion of NCCAH and determine a firm and accurate diagnosis. The Synacthen test is a prerequisite in the event of clinical suspicion, and molecular testing will establish the diagnosis. In most cases occurring under 8 years of age, the first symptom is premature pubarche. In some cases, due to advanced bone age and/or severe signs of hyperandrogenism, initiation of hydrocortisone treatment prepubertally may be considered. Our unifying theory of the hyperandrogenic signs system and its regulation by internal (hormones, enzymes, tissue sensitivity) and external (stress, insulin resistance, epigenetic, endocrine disruptors) factors is presented in an attempt to elucidate both the prominent genotype-phenotype heterogeneity of this disease and the resultant wide variation of clinical findings. Treatment should be initiated not only to address the main cause of the patient's visit but additionally to decrease abnormally elevated hormone concentrations. Goals of treatment include restoration of regular menstrual cyclicity, slowing the progression of hirsutism and acne, and improvement of fertility. Hydrocortisone supplementation, though not dexamethasone administration, could, as a general rule, be helpful, however, at minimum doses, and also for a short period of time and, most likely, not lifelong. On the other hand, in cases where severe hirsutism and/or acne are present, prescription of oral contraceptives and/or antiandrogens may be advisable. Furthermore, women with NCCAH commonly experience subfertility, therefore, there will be analysis of the appropriate approach for these patients, including during pregnancy, based mainly on genotype. Besides, we should keep in mind that since the same patient will have changing requirements through the years, the attending physician should undertake a tailor-made approach in order to cover her specific needs at different stages of life.

Background: Polycystic ovary syndrome (PCOS) constitutes one of the most common endocrine diseases that should be considered as a continuum. This life span disease is originating in foetal life and through long reproductive period falling into long-term consequences extending beyond menopause. Hence, it is considered to increase diabetes risk as well cardiovascular risk and outcomes. However, the natural course of the disorder is not completely understood, and recent data suggest differences in the evolution of the disease between normal-weight and obese patients, indicating that the cardiometabolic effects may be an epiphenomenon of the obesity and not of PCOS per se. We aimed to define the evolution of normal-weight Caucasian women with PCOS through the years. Materials and Methods: In this multicenter cross-sectional case control study 763 normal-weight women with PCOS according to Rotterdam criteria and 376 age and BMI-matched controls were included. The study group was further divided into three age groups, representing women post-adolescence, of reproductive age, and of late reproductive age to menopause. All the subjects were assessed clinically, biochemically, hormonally, and with the means of pelvic ultrasound. Results: Waist circumference, WHR, FG score, glucose, lipids, gonadotropin, androgen levels as well as HOMA-IR and ovarian volume were significantly higher in the PCOS group in comparison to controls. No statistical difference was noted among PCOS women diagnosed with the Rotterdam criteria vs. those who met the NIH criteria. Age subgroup analysis showed that androgens remained significantly higher among PCOS and controls, whereas insulin and lipid levels, as well as HOMA-IR, were comparable between PCOS and controls in all age groups. Pearson correlations of studied parameters with age revealed a significant negative association of age with waist circumference, FG score, androgens (testosterone, FAI, DHEAS, D4), insulin, FSH, and HOMA-IR. Finally, multiple regression analysis of factors affecting HOMA-IR disclosed a negative association with age (r:-0.123, p: 0.001) and a positive association with BMI (r: 0.105, p: 0.004) and DHEAS (r: 0.175, p: 0.001). Conclusions: Lipids, androgens, insulin resistance, and menstrual cyclicity are gradually improved in an age-dependent manner in PCOS lean patients and age and BMI matched controls. Normal-weight PCOS women exhibit a higher degree of IR and dyslipidaemia compared to their healthy peers, but these aberrations improve gradually. If PCOS women retain their normal weight over the years, they may develop a metabolic and hormonal profile comparable to that of their peers without PCOS later in life.

Introduction: Incidental finding of differentiated thyroid microcarcinomas (DTMc) in patients with thyroid nodules, undergoing thyroid surgery for benign indications, have become increasingly common. Even though carcinogenesis might relate to the background disease of the gland, the incidence of DTMc in the setting of various thyroid disorders remains unclear. We designed the present study to address this question. Methods/ Subjects: We reviewed the data from two prospectively collected databases of patients undergoing thyroid surgery in two high-volume tertiary care referral centers, one in the USA (A) and the other one in Greece (B) over 14 consecutive years. We collected data on the preoperative surgical indication, FNA cytology and surgical pathology. We excluded subjects operated for thyroid cancer or indications at high risk for malignancy (FNA suspicious for thyroid cancer, follicular neoplasm, suspicious for follicular neoplasm, FLUS/AUS, cellular specimen or sonographic features of malignancy), and those with post-surgical pathology consistent with PTC >9mm in largest diameter. We split our subjects based on pathology data in those with chronic lymphocytic thyroiditis (CLT), Graves disease (GR) or multinodular goiter (MNG). Incidence of DTMc or features of tumor aggressiveness were compared among groups, using Fischer’ s exact test and odds ratios (OR) were calculated. Categorical values were compared with Kruskal Wallis test. P values

In the currently overwhelming era of polypharmacy, the balance of the dynamic and delicate endocrine system can easily be disturbed by interfering pharmaceutical agents like medications. Drugs can cause endocrine abnormalities via different mechanisms, including direct alteration of hormone production, changes in the regulation of the feedback axis, on hormonal transport, binding and signaling, as well as similar changes to counter-regulatory hormone systems. Furthermore, drugs can interfere with the hormonal assays, leading to erroneous laboratory results that disorientate clinicians from the right diagnosis. The purpose of this review is to cover a contemporary topic, the drug-induced endocrinopathies, which was presented in the monothematic annual Combo Endo Course 2018. This challenging part of endocrinology is constantly expanding particularly during the last decade, with the new oncological therapeutic agents, targeting novel molecular pathways in the process of malignancies. In this new context of drug-induced endocrine disease, clinicians should be aware that drugs can cause endocrine abnormalities via different mechanisms and mimic a variety of clinical scenarios. Therefore, it is extremely important for clinicians not only to promptly recognize drug-induced hormonal and metabolic abnormalities, but also to address the therapeutic issues for timely intervention.

BackgroundPolycystic ovary syndrome (PCOS) represents a moving spectrum of hormonal to metabolic abnormalities, as women with the syndrome are aging. Hormonal abnormalities, anovulation, and hyperandrogenic signs were predominant during the early years of PCOS and fade away with the years. Metabolic abnormalities and insulin resistance (IR) remain throughout the PCOS life cycle; however, it is unclear as to how they change, as women with the syndrome are aging.ObjectiveTo evaluate the changes in IR and its associations with clinical, biochemical, hormonal, and ultrasound findings in a large cohort of women with PCOS and controls, as they are aging.DesignA cross-sectional study was carried out to evaluate the diverse impacts of aging on IR.SettingAn outpatient clinic was chosen for the study.ParticipantsA total of 1345 women with PCOS (Rotterdam criteria) and 302 controls of Caucasian origin and Greek ethnicity comprised the study group.Main outcome and measuresThe impact of age on IR, as calculated using homeostasis model assessment of IR (HOMA-IR) index, and several PCOS characteristics were evaluated.ResultsIn PCOS, age (−0.045±0.008) was negatively, and BMI positively (0.18±0.007) associated with HOMA-IR (R2=0.36). When data were stratified with regard to the BMI status, a negative association of age with HOMA-IR was found in lean, normal, and overweight patients (r: −0.266, −0.233, −0.192, Pr: −0.009, P: NS). Free androgen index and BMI were positively associated with HOMA-IR in all age quartiles. When mean HOMA-IR values were plotted according to BMI subgroups at different age quartiles, a significant gradual decrease in HOMA-IR was observed in normal (PP: 0.004), but not obese, women (P: 0.202) across age quartiles.ConclusionsAging increases IR in obese but not in lean and overweight women with PCOS. As BMI and androgens are positively associated with HOMA-IR and androgens decline through time, it appears that if women with PCOS do not become obese they may exhibit a better metabolic profile during their reproductive years.

SummaryBackground Nonclassical congenital adrenal hyperplasia (NC-CAH) is caused by mutations of the CYP21A2 gene. The clinical manifestations and hormonal derangements of NC-CAH are quite variable. Objectives (i) To define the phenotype and its relation to genotype according to gender and age and (ii) to evaluate the validity of currently applied hormonal criteria for establishing the diagnosis of NC-CAH. Patients and Methods The clinical, hormonal and molecular data of 280 subjects (235 female) with NC-CAH and a median age of 17·6 years were analysed. CYP21A2 genotyping was performed in all subjects. Results The majority of females aged less than 8 years presented with premature pubarche (88·3%), while those older than 8 presented with a polycystic ovary-like phenotype (63·2%). A total of 7·7% of the females and 51·1% of the males were asymptomatic at the time of diagnosis. In the total group, 50·4% of the subjects were compound heterozygotes for one classical (C) and one nonclassical (NC) mutation, while 46% of the alleles studied carried the p.V281L mutation. Basal 17OHP values were below 6 nm (2 ng/ml) in 2·1% of the subjects with NC-CAH, but none had peak 17OHP values post-ACTH lower than 30 nm (10 ng/ml). Conclusions NC-CAH has a variable phenotype depending on the age, gender and the presence of a classical mutation. A peak cut-off value of 17OHP post-ACTH lower than 30 nm excludes the diagnosis of NC-CAH, whereas basal 17OHP

Hyperandrogenemia modifies phenotypic characteristics of women with polycystic ovary syndrome (PCOS). The aim of the present study is to evaluate (a) the prevalence of hyperandrogenemia in PCOS women (Rotterdam criteria) and (b) the impact of either the degree or the type of hyperandrogenemia on phenotype. Anthropometric, clinical, hormonal, metabolic and ultrasound characteristics of 1,218 women with PCOS were analyzed in this cross-sectional study. The prevalence of hyperandrogenemia was 58.8 %. Women with hyperandrogenemia had higher luteinizing hormone (LH), follicle-stimulating hormone (FSH), free androgen index, lower sex-hormone-binding globulin (SHBG) and fasting glucose levels compared to women with normal androgens (p < 0.001 for all comparisons; p = 0.001 for fasting glucose). Regarding the presence of isolated hyperandrogenemia, the group with only elevated testosterone levels was termed GT and an analogous categorization was made for dehydroepiandrosterone sulfate (GD) and androstenedione (Δ4) (GΔ4), respectively. GT, GD and GΔ4 comprised the 17.2, 7.6 and 4.1 % of total cohort, respectively. These groups differed significantly between them in LH, LH/FSH ratio, and SHBG (p < 0.001). Hyperandrogenemia is found in almost 60 % of women with PCOS (Rotterdam criteria), and it affects hormonal characteristics of these women such as LH and SHBG values. Regarding the impact of isolated hyperandrogenemia on PCOS characteristics, it appears that Δ4 and testosterone elevations are associated with increased LH levels.

The levels of advanced glycation end products (AGEs) are increased under conditions of impaired glucose metabolism and/or oxidative stress, promoting insulin resistance and other endocrine abnormalities. AGEs play a major role in the pathogenesis of several diseases such as diabetes, atherosclerosis, polycystic ovary syndrome and Alzheimer's disease, contributing to progressive ageing. Receptor-based clearance of AGEs by the receptor for AGE (RAGE) and/or the macrophage scavenger receptor A (SR-A) is considered as a main factor for the regulation of the concentration of AGEs under these conditions. This study aimed to investigate the expression of RAGE (AGER) and SR-A (MSR1) under high/low-dietary AGE conditionsin vivoand their potential contribution to the metabolic and sex hormonal profile of female rats. Female Wistar rats were fed a low-AGE or high-AGE diet for 3 months. Serum samples were collected at baseline and at the completion of the 3-month period for the measurements of metabolic and hormonal parameters. Peripheral blood mononuclear cells (PBMCs) were isolated for the determination of the expression of RAGE and SR-A. The high-AGE diet-fed rats exhibited increased glucose, insulin and testosterone levels as well as decreased oestradiol and progesterone levels compared with the low-AGE diet-fed ones, thus indicating a metabolic and hormonal dysregulation attributed to high-AGE dietary exposure. The expression of RAGE was significantly down-regulated in the PBMCs of the high-AGE diet-fed rats (P=0.041), and it was correlated negatively with insulin and testosterone levels and positively with progesterone levels. The expression of SR-A was also decreased in the high-AGE diet-fed rats to marginal significance. Decreased monocytic expression of scavenger receptors such as RAGE and SR-A may result in a higher deposition of AGEs in peripheral endocrine tissues, thus promoting endocrine-related abnormalities and diseases.

OBJECTIVE: Advanced glycation end products (AGEs) activate the intracellular Nuclear Factor-ϰB pathway in endothelial cells, leading to production of endothelin-1 (ET-1), a peptide which causes endothelial dysfunction. The aim of the present study was to assess EΤ-1 and AGEs levels in women with polycystic ovary syndrome (PCOS) and controls and to investigate any potential relationship between them. DESIGN: Metabolic and hormonal data from 75 women with PCOS and 25 controls, matched for age and ΒΜΙ were analyzed and correlated to AGEs and ET-1 levels. RESULTS: Serum levels of EΤ-1 (1.55±0.13 vs. 0.37±0.10 pmol/l, p:0.003) and AGEs (8.34±1,81 vs. 5.77±0.78U/ml, p:0.002) were significantly higher in the PCOS group. EΤ-1 was correlated with AGES (r:0.54, p

Summary Background Increased prevalence of psychological morbidities, including anxiety, depression and eating disorders, has been reported in women with polycystic ovary syndrome (PCOS) in comparison with normal ovulating, nonhyperandrogenemic women. Aim of the study To investigate the relationship between the degree of anxiety, depression and eating disorders via self-reported symptoms and the severity of hormonal and metabolic aberrations in women with PCOS. For this purpose, the PCOS cohort was subdivided into three subgroups according to the degree of anxiety. Methods One hundred and thirty women with PCOS of similar age and BMI were studied. In each subject, hormonal and metabolic status as well as psychological profile was assessed with the use of specific questionnaires. Specifically, anxiety (trait and state) was assessed with the use of STAI-T and STAI-S, while depression and eating disorders were evaluated with the use of the Beck Depression Inventory and the Eating Attitudes test, respectively. Results The subgroups did not differ in age and BMI. Subjects with the highest STAI-S compared with those with the lowest STAI-S displayed significantly higher the homeostasis assessment model-insulin resistance (HOMA-IR) and free androgen index values (P

Background PCOS is presented by a broad spectrum of menstrual irregularities appearing often at puberty or later on during the reproductive years in women suffering from this multifaceted syndrome. To our knowledge, there is no evidence to suggest whether the time of onset of menstrual irregularities (peri or post pubertal) indicates a differential metabolic and/or hormonal profile as well as ovarian ultrasonographic findings, in adulthood in women with PCOS. Aim of the study To compare anthropometric, hormonal-metabolic profile and ultrasound findings in PCOS women with peripubertal onset of menstrual disorders with the corresponding data obtained from PCOS patients with post pubertal onset of menstrual irregularities, matched for BMI and age. Patients-methods 89 PCOS women were evaluated cross-sectionally at the age of 25 years. In 49 subjects menstrual irregularities were present from menarche, whereas in 40 women the irregularities appeared at least 3 years post menarche. Results Anthropometric parameters were comparable between the 2 groups. The 2 groups did not differ on metabolic and hormonal profile as well as ovarian ultrasound findings. Conclusions These data indicate that the timing of menstrual irregularities, do not appear to have an impact, on hormonal/metabolic profile and ovarian ultrasound morphology in patients diagnosed with PCOS, later in life.

Intriguing studies suggest that osteocalcin (OC) and its carboxylated (Gla)/uncarboxylated form are involved in the regulation of insulin secretion and action. Additionally, advanced glycated end products (AGEs) directly regulate the secretion of these osteoblast-derived molecules. In polycystic ovarian syndrome (PCOS), among the pathophysiological aberrations, deregulation of insulin secretion and action as well as elevated AGEs levels have been demonstrated. In this study, we evaluated the serum levels of osteocalcin and Gla osteocalcin and their possible associations with metabolic, hormonal, and ultrasonographic components of PSOS: 97 women were studied, 50 PCOS patients and 47 controls, matched for age and body mass index (BMI). In each subject, the levels of bone metabolism markers have been evaluated, and metabolic and hormonal profiles as well as ovarian ultrasound were carried out. Osteocalcin (4.30 ± 1.74 vs. 6.20 ± 1.78 ng/ml, P < 0.0005) values were significantly lower, whereas Gla osteocalcin (37.93 ± 6.87 vs. 9.64 ± 8.21 ng/ml, P < 0.0005) and receptor activator for nuclear factor-κB ligand (0.54 ± 0.26 vs. 0.16 ± 0.15 pmol/l, P < 0.0005) values were significantly higher in PCOS subjects compared to the control group, independently of obesity. A significant association was disclosed between osteocalcin and Gla osteocalcin with androgens, insulin resistance, AGEs, and ovarian morphology. Receiver operating curve analysis revealed that Gla osteocalcin [AUC, 0.975 (95% CI, 0.93–1.00)] as well as AGEs are significant prognostic factors of PCOS [AUC, 0.986 (95% CI, 0.97–1.00)]. Lower osteocalcin and elevated serum levels of its carboxylated form are displayed in PCOS subjects and are associated with several PCOS components. These findings suggest a potential interaction between bone-derived markers and the metabolic/hormonal abnormalities observed in PCOS. However, the pathophysiological mechanisms and moreover the possible clinical implications require further investigation.

Hyperthyroidism is a common endocrine disorder affecting 2% of females and 0.5% of males worldwide and antithyroid drugs constitute the first line of treatment in the majority of cases. These agents may cause severe adverse effects and among them liver failure, although rare, is a potential lethal one. This case illustrates the sudden and abrupt deterioration of hepatic function due to antithyroid drug administration. This case along with a concise literature review is presented aiming to increase the awareness of endocrinologists of possible fatal complications from the everyday use of common agents such as antithyroid drugs.

Females with a history of premature adrenarche are at high risk of developing polycystic ovary syndrome (PCOS) and features of the metabolic syndrome later in life. Coagulation disorders, subclinical inflammation, and oxidative stress have been reported in patients with PCOS and metabolic syndrome. These factors were studied in a group of adolescents with a history of premature adrenarche. This is a cross-sectional study that determined the biochemical-hormonal profile and indices of inflammation, coagulation, and oxidative stress in 45 adolescent girls with a history of premature adrenarche and 19 age- and body mass index-matched controls. Girls with premature adrenarche had hyperandrogenism and higher indices of insulin resistance than controls. They also had significantly higher C-reactive protein (0.76 +/- 0.65 vs 0.41 +/- 0.31 mg/L, P = .0001) and plasminogen activator inhibitor 1 (37.6 +/- 24.7 vs 24.47 +/- 4.6 ng/mL, P = .034), and lower tissue plasminogen activator values in comparison with controls (3.5 +/- 1.5 vs 5.2 +/- 2.12 ng/mL, P = .0019). Both C-reactive protein(r = 0.545, P = .0001) and plasminogen activator inhibitor 1 (r = 0.36, P = .04) were positively correlated with oxidative stress, whereas tissue plasminogen activator was positively correlated (r = 0.37, P = .02) with total antioxidant status. None of these factors was correlated with androgens or indices of insulin resistance. Adolescent girls with a history of premature adrenarche display metabolic deviations usually encountered in subjects with PCOS and metabolic syndrome, such as subclinical inflammation and fibrinolytic abnormalities.

Background: It has been shown in animals and in humans that retinol-binding protein 4 (RBP4) production from adipose tissue leads to generalized insulin resistance (IR). A more sensitive marker of circulating RBP4 is free plasma RBP4 expressed by RBP4 to transthyretin (TTR) ratio, since in circulation RBP4 is bound to TTR. Aim: To investigate RBP4 levels in insulin-resistant women with polycystic ovary syndrome (PCOS) and to estimate free plasma RBP4 expressed by RBP4/TTR ratio. Subjects and methods: Thirty-five PCOS subjects were compared with 45 controls matched for age and body mass index (BMI). In each subject, fasting values of glucose, insulin, gonadotropins, estradiol, androgens, C-reactive protein (CRP), RBP4, and TTR were determined. Results: PCOS subjects in comparison to controls were more insulin-resistant [homeostasis model assessment for IR (HOMA-IR): 2.6± 0.3 vs 1.9± 0.1, p=0.043], and presented lower RBP4 levels (28.3± 1.1 vs 32.4± 1.2 μg/ml, p=0.021) and RBP4/TTR ratio (0.26± 0.01 vs 0.31± 0.01, p=0.0014). When RBP4 and RBP4/TTR values where stratified according to BMI status (obese, overweight, and lean subjects), it was noticed that both RBP4 and RBP4/TTR values in lean PCOS were significantly lower than in controls (RBP4: 25.0± 5.5 vs 34.1± 9.0 μg/ml, p=0.0063, RBP4/TTR: 0.25± 0.3 vs 0.35± 0.1, p=0.016). No correlation was observed between RBP4 and RBP4/TTR with any hormonal or metabolic parameter including BMI. Conclusions: RBP4 and free plasma RBP4 expressed as RBP4/TTR ratio are statistically and significantly lower in insulin-resistant PCOS subjects in comparison to controls. Therefore, our findings do not confirm a link between IR, neither with RBP4 nor with free plasma RBP4 levels. The significance of these findings remains to be elucidated, since RBP4 might prove to have different actions, like other adipokines, from humans and rodents.

An earlier adiposity rebound, suggestive of adult obesity, has been reported in children with congenital hypothyroidism. We undertook this study to evaluate the effect of congenital hypothyroidism on: 1) the timing of adiposity rebound, 2) the long-term prognosis of BMI status, and 3) the factors potentially affecting adiposity in subjects with congenital hypothyroidism. We found that in children with congenital hypothyroidism the BMI values were higher during the first years of life compared to normal population, but subsequently normalized. After the initial rise of BMI, the decline (nadir) and subsequent rise (adiposity rebound), usually occurring in normal children at an age greater than 30 months, was less evident in our group of children with congenital hypothyroidism. The severity of hypothyroidism affected BMI values at 6 and 12, but not at 36 months of age. In conclusion, in children with congenital hypothyroidism, 1) the high BMI values in early childhood normalize in adolescence, and 2) the normally expected BMI fluctuations during the first years of life are attenuated. These findings constitute indirect evidence that thyroid function during fetal and neonatal life affects BMI status during the first years of life.

Thyroid dysfunction, especially hypothyroidism caused by Hashimoto's thyroiditis is more frequently observed in girls with Turner's syndrome (TS). The aim of the present study was to evaluate prevalence, etiology, karyotype distribution and age at onset of thyroid pathology in girls with TS. Data recorded in 84 girls with TS attending our clinic were analyzed. The mean age +/- standard deviation [SD] at their initial evaluation was 10.3 +/- 3.7 years (range, 0.5 to 19 years) and the mean period of observation was 8.4 +/- 4.4 years. The thyroid function had been evaluated at least once per year in all patients and thyroid autoantibodies (ATA) were available in 51 (60.7%). Hypothyroidism was detected in 24% of the studied subjects and hyperthyroidism in 2.5%. Elevated values of thyroid autoantibodies were detected in 42% of girls with TS, whose ATA had been determined, and 65% had hypothyroidism. Thyroid dysfunction was first noted after the age of 8 years with no difference in the distribution of new cases at the different ages or pubertal stages. There was no difference in the incidence of thyroid dysfunction related to the type of karyotype abnormality. Thyroid dysfunction is more frequently encountered in girls with TS (hypothyroidism: 24% in the total group and 65% in those with positive ATA, hyperthyroidism: 2.5%). Thyroid dysfunction was observed after the age of 8 years with no difference in the occurrence of new cases in the various age groups thereafter. Hence, thyroid function should be evaluated yearly in girls with TS past the age of 8 years and more frequently in those with positive thyroid autoantibodies.

Chronic pancreatitis (CP) is considered to be a rare cause of diabetes mellitus. However, in both the developed and developing world, there is an increasing number of patients suffering from pancreatitis probably due to lifestyle changes, which is partially associated with both social factors and the poor health status of immigrants. Owing to these circumstances, CP has evolved with one of the possible causes of diabetes in a selected group of patients and should be included in the differential diagnosis of diabetes. Several studies have shown that the long-term rate of diabetic complications in patients with CP and insulin-dependent diabetes is similar to that in patients with type 1 diabetes of equal duration. The hypothesis that early diagnosis of CP should result in better prognosis is not validated and may complicate the issue, since the risk of diabetes has been shown to increase significantly only once pancreatic calcification has developed. Accumulative evidence suggests that the risk of diabetes is not influenced by elective pancreatic surgical procedures other than distal pancreatectomy. The lack of contemporary data points to the urgent need for large prospective studies in order to accurately evaluate the special characteristics of disorders in glucose homeostasis in patients with CP.

Pituitary morphology in patients with Prop1 gene mutations varies. Most patients demonstrate a normal or small pituitary gland. Occasionally, pituitary enlargement of undetermined origin has also been detected. In the present study we use long-term magnetic resonance imaging findings to characterize the morphological abnormalities of the pituitary gland in 15 patients (aged 2.5-45 yr) with combined pituitary hormone deficiency caused by Prop1 gene mutations (GA296del/GA296del in seven, GA296del/A150del in two, A150del/A150del in five, and GA296del/R73H in one patient) and attempt to uncover the origin and nature of the pituitary enlargement. Small pituitary gland was detected in seven patients (25.2 +/- 14.4 yr of age), normal pituitary size in three patients (10.2 +/- 5.8 yr of age), and pituitary enlargement in five patients (6.5 +/- 2.7 yr of age). The pituitary enlargement consisted of a nonenhancing mass lesion interposed between the normally enhancing anterior lobe and the neurohypophysis. The pituitary stalk was displaced anteriorly, whereas the neurohypophysis was orthotopic, displaying a normal signal. Spontaneous regression of the mass lesion with normalization of the pituitary stalk position was observed in three patients. Our data indicate that although a small pituitary gland is usually observed in older subjects, a significant number of young patients with Prop1 gene mutations demonstrate pituitary enlargement with subsequent regression. The distinct magnetic resonance imaging characteristics of the pituitary enlargement in our patients in conjunction with pertinent data from Prop1-deficient mice suggest that the mass causing the pituitary enlargement most likely originates from the intermediate lobe.

Adrenarche was evaluated in five patients, aged 17.4 ± 3 years, with combined pituitary hormone deficiency (CPHD), caused by a PROP-1 gene defect. Adrenocorticotrophic hormone (ACTH), cortisol and dehydroepiandrosterone sulfate (DHEAS) were determined prior to and following the administration of corticotropinreleasing hormone (CRH) in four of the five patients, while only basal values of ACTH, cortisol and DHEAS were determined in the fifth. In the four patients in whom a CRH test was carried out, the mean basal values of cortisol, ACTH and DHEAS were 289 ±140 nmol/1, 4.5 ±1.7 μmol/1 and 0.26 ± 0.36 μmol/1, respectively. The corresponding post-CRH peak values were 584 ± 204 μmol/1, 12.7 ± 3.9 μmol/1 and 0.43 ± 0.41 μmol/1. In the fifth patient, basal ACTH, cortisol and DHEAS values? were 4 μmol/1, 411 μmol/1, and 2.33 μmol/1, respectively. Thus the basal and post CRH values of DHEAS (a marker of adrenarche) were low for age, while basal and post-CRH cortisol and ACTH values were within normal limits. For the interpretation of these findings two hypotheses can be proposed: 1) The PROP-1 gene is only expressed in the pituitary, and the role of PROP-1 is related to the maturation of the cells which synthesize the presumed adrenal androgen stimulating hormone (AASH). 2) The PROP-1 gene is also expressed in the adrenal cortex and, when defective, the zona reticularis does not function appropriately. Regardless of the interpretation involved, patients with CPHD caused by a PROP-1 gene defect also have insufficient adrenarche. This finding has possible important pathophysiological implications.

To study white blood cells count (WBC) in women suffering from PCOS and compare these results with age and BMI-matched healthy women. The specific aim of this study was to assess the possible correlations of WBC with the major components of PCOS, obesity, insulin resistance and hyperandrogenism.Anthropometrical, metabolic and hormonal data were analyzed from 203 women with PCOS (NIH criteria) and 76 age-matched controls.In the total population studied (N=279), WBC was significantly higher (P=0.003) in the PCOS group compared with age-matched healthy women and was positively correlated with BMI (r=0.461, p0.001), total testosterone (r= 0.210, p0.001), insulin (r=0.271, p0.001), triglycerides (r=0.285, p0.001), HOMA score (r=0.206, p=0.001), FAI (r=0.329, p0.001) and negatively correlated with SHBG (r=-0.300, p0.001) and HDL (r=-0.222, p0.001). Due to the fact that WHR was only available in the group of PCOS women, the role of central adiposity is assessed only in this group. Multiple regression analysis in the PCOS group, including WHR, revealed BMI, SHBG and TGL as the main predicting factors of WBC. Multinomial logistic regression analysis was also conducted and overweight/obesity was the sole independent risk factor for elevated WBC (higher tertile) (OR:0.907 CI:0.85-0.96, p=0.002). After dividing the sample based on BMI in the lean subgroups, WBC did not differ significantly between PCOS and controls, while multiple regression analysis indicated SHBG as the main predicting factor of WBC. Finally, we picked out the group of overweight/obese (BMI ≥25 kg/m2) women with PCOS and conducted another classification based on HOMA score (HOMA-IR≤2: insulin-sensitive women, HOMA-IR2: insulin-resistant women) in the group of overweight and obese women with PCOS separately. In overweight women with PCOS, WBC, although higher in the group of insulin-resistant, did not differ significantly between the two groups, while in the subcategory of overweight women WBC was significantly (p=0.02) higher in the group of insulin-resistant women (HOMA-IR2).Chronic low-grade inflammation and increased white cell count do occur in PCOS. Obesity and insulin resistance are the two leading parameters that act accumulatively in the development of leucocytosis, whereas hyperandrogenism does not seem to affect it.

Wolfram syndrome (WS), also known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness), is a neurodegenerative disease with autosomal recessive inheritance with incomplete penetrance. DIDMOAD is a very rare disease with an estimated prevalence of 1 in 770,000 and it is believed to occur in 1 of 150 patients with juvenile-onset insulin-dependent diabetes mellitus. Additionally, WS may also present with different endocrine and metabolic abnormalities such as anterior and posterior pituitary gland dysfunction. This mini-review summarizes the variable presentation of WS and the need of screening for other metabolic and hormonal abnormalities, coexisting in this rare syndrome.

Context: Bisphenol A (BPA) is a widespread industrial compound used in the synthesis of polycarbonate plastics. In experimental animals, neonatal exposure to BPA results in a polycystic ovary-like syndrome (PCOS) in adulthood. A bidirectional interaction between androgens and BPA levels has been disclosed. Objective: To determine BPA levels in PCOS women as well as the association between BPA and hormonal/metabolic parameters compared to a control group. Design, Setting, and Participants: Cross-sectional study of 71 PCOS (National Institutes of Health criteria) and 100 normal women, age- and body mass index–matched, in a University hospital setting. Main Outcome Measures: Anthropometric, hormonal, metabolic parameters and BPA blood levels were determined. Patients (PCOS) and controls (C) were further subdivided according to body mass index into lean and overweight subgroups, respectively. Results: BPA levels were significantly higher in the total PCOS group compared with the controls (1.05±0.56 vs. 0.72±0.37ng/ml, P < 0.001). PCOS women, lean (PCOS-L) and overweight (PCOS-OW), had higher BPA levels compared to the corresponding control group lean (C-L) and overweight (C-OW): (PCOS-L = 1.13±0.63 vs. C-L = 0.70±0.36, P < 0.001) (PCOS-OW = 0.96 ± 0.46 vs. C-OW = 0.72 ± 0.39, P < 0.05). A significant association of testosterone (r = 0.192, P < 0.05) and androstenedione (r = 0.257, P < 0.05) with BPA was observed. Multiple regression analysis for BPA showed significant correlation with the existence of PCOS (r = 0.497, P < 0.05). BPA was also positively correlated with insulin resistance (Matsuda index) in the PCOS group (r = 0.273, P < 0.05). Conclusions: Higher BPA levels in PCOS women compared to controls and a statistically significant positive association between androgens and BPA point to a potential role of this endocrine disruptor in PCOS pathophysiology.

ObjectiveOocyte maturation process characterizes polycystic ovary syndrome (PCOS). The mechanisms of this abnormality leading to chronic anovulation are under investigation. Advanced glycosylated end products (AGEs), a marker of oxidative stress linked with oocyte maturation are localized in granulosa cells and are increased in sera, in women with PCOS. The aim of this study was to investigate the relationship, whether there is an association between the anti-mullerian hormone (AMH), a hormone produced by granulosa cells and AGEs in ovulatory and anovulatory PCOS (PCOS-Anov), as well as in non-PCOS anovulatory (Non-PCOS Anov) women.DesignCross-sectional study.MethodsData from sixty women with PCOS (37 anovulatory and 23 regularly ovulating) were compared with eleven Non-PCOS Anov women and 25 normal women. In each subject biochemical, hormonal, and ultrasonographic parameters were studied.ResultsAMH values were statistically significantly higher in PCOS-Anov (7.63±3.12) in comparison with ovulatory PCOS (PCOS-Ov; 4.92±2.50), Non-PCOS Anov (3.66±1.4), and controls (4.02±1.27 ng/ml). AGEs demonstrated a similar pattern: 8.70±1.65 in PCOS-Anov, 7.43±1.79, PCOS-Ov, 5.21±0.09, Non-PCOS Anov, and 5.85±0.89 U/ml in controls (Pr: 0.326,Pr: 0.42,P: 0.0001) and the presence of anovulation.ConclusionsThese data suggest that an oxidative marker, AGEs, and AMH, may interact in the anovulatory mechanisms in women with PCOS.

Context: The very high carrier frequency of 21-hydroxylase deficiency worldwide has been postulated as indicating a survival advantage. The ‘mediators’ of such an effect remain speculative. Objective: To look for possible differences in the metabolic and atherogenic risk profile of carriers and noncarriers of CYP21A2 gene mutations at puberty in order to identify possible mediators of the presumed survival advantage for the carriers. It is anticipated that by studying atherogenic risk factors at such an early developmental stage, age-related alterations in these factors may be minimized. Methods: The study group included 45 adolescent girls diagnosed in our center with premature pubarche, 29 of whom were noncarriers and 16 carriers of CYP21A2 mutations. The two groups did not differ in chronological age, age at pubarche or menarche, pubertal stage, body mass index and waist-to-hip ratio. Biochemical and hormonal profile markers as well as markers of endothelial dysfunction were determined by appropriate methodology. Additionally, in each subject, an oral glucose tolerance test and a gonadotrophin-releasing hormone GnRH analogue stimulation test were carried out. Results: Endothelin-1 values were lower in the carriers compared to the noncarriers (p = 0.031). Higher tissue plasminogen activator and lower plasminogen activator inhibitor-1 values were found in carriers compared to noncarriers (p = 0.02 and Conclusions: Our findings that carriers of CYP21A2 gene mutations have a more favorable internal milieu with regard to the metabolic syndrome and atherogenesis support the theory that heterozygous CYP21A2 mutations provide a survival advantage. The mechanisms involved may be related to the insulin secretion-action pathway, hypothalamic-pituitary-adrenal axis responsiveness or other still unrecognized factors.

BackgroundNeutrophil gelatinase-associated lipocalin (NGAL) and matrix metalloproteinase-9 (MMP-9) have been considered as important mediators of vascular remodeling and plaque instability. The formation of a complex with NGAL and MMP-9 is crucial for atherotic plaque erosion and thrombus formation. In women with polycystic ovary syndrome (PCOS), the incidence of cardiovascular clinical events is not increased, despite the fact that they display a wide spectrum of risk factors. Since the instability of atherosclerotic plaque is a key factor in the clinical manifestations of cardiovascular disease, molecules challenging the plaque stability should be investigated.AimTo determine serum levels of NGAL and MMP-9/NGAL complex in women with PCOS.Subjects and methodsPCOS subjects (40) were compared with those (40) matched for age and body mass index (BMI) controls. In each subject, fasting levels of glucose, insulin, gonadotropins, estradiol, androgens, C-reactive protein, NGAL, and MMP-9/NGAL were determined.ResultsNGAL and MMP-9/NGAL complex levels were significantly lower in the PCOS group compared with controls (30.4±24.3 vs 70.7±37.9 μg/l, PPPPPPConclusionsThese findings indicate that NGAL and MMP-9/NGAL complex, two molecules that activate atherotic plaque erosion, is in lower concentrations in PCOS subjects. The role of NGAL and MMP-9/NGAL complex needs to be further investigated, since suppression of these atheromatous molecules might have a protective role in women with PCOS.

Thyroid volume (TV) varies between geographical regions. Thus, population-specific references for TV in regions with long-standing iodine sufficiency may be more accurate than a single international reference.The aim of the study was to determine TV and assess the prevalence of goiter and thyroid nodules in schoolchildren aged 5-18 years living in an iodine-replete area.Ultrasonography was used to assess TV and structure in 440 schoolchildren (200 boys and 240 girls) living in the Athens area. Urinary iodine excretion was also measured. Age, body surface area (BSA), body mass index (BMI), and Tanner stage were recorded.TV was significantly correlated with age in boys (r = 0.779, p0.0005) and girls (r = 0.669, p0.0005), and with BSA in boys (r = 0.730, p0.0005) and girls (r = 0.623, p0.0005). TV increased with the progress of puberty in boys (Tanner stage I: 3.42 mL; Tanner stage II-V: 7.35 mL; p0.0005) and girls (Tanner stage I: 3.74 mL; Tanner stage II-V: 5.99 mL; p0.0005). We used the 97th percentile value as the upper limit and calculated the prevalence of goiter to be 3.2%. There was a weak correlation between TV and BMI standard deviation score only in boys (r = 0.166, p = 0.023). Boys in Tanner stage II-V had larger TV than girls had in the same pubertal stage (7.35 mL vs. 5.99 mL, p = 0.001); such a difference was not observed in Tanner stage I. The median urinary iodine was 307.83 microg I/g creatinine, indicating iodine sufficiency. There was a significant inverse correlation between TV and urinary iodine. In 5.1% of the studied subjects one or more nodules were observed, whereas in 4.1% of cases the nodules were accompanied by hypoechogenicity.In healthy Greek children living in an iodine-replete area, the main determinants of TV in both boys and girls were age, BSA, and pubertal stage. The prevalence of goiter was 3.2% and that of altered echostructure was 9.2%.

Brown tumors are erosive bony lesions caused by rapid osteoclastic activity and peritrabecular fibrosis due to hyperparathyroidism, resulting in a local destructive phenomenon. Although brown tumors are the most pathognomonic sign of hyperparathyroidism, they are very rarely observed at present as a result of early detection of hypercalcemia and elevated parathyroid hormone levels. The rare appearance of this entity in everyday practice is troublesome for both patients and physicians, because whenever it emerges, diagnosis could be mistaken for a giant cell tumor of the bone. However, clinical, biochemical, and radiologic findings can easily guide the diagnosis if one considers the full continuum of findings and their association with subject’s medical history, instead of focusing only on bone lesion. In this report we present a case of brown tumor in the fibula with a short literature review, whose aggressive presentation and unawareness of the skeletal findings of hyperparathyroidism puzzled the caring doctors. This case illustrates the need for continuous vigilance of any physician, regardless of his specialty or his position in medical services structures.

Objective: The aim of our study was to determine the prevalence of impaired glucose tolerance (IGT) and type 2 diabetes (DM2) in obese children and adolescents of Greek origin and compare our data with pertinent literature findings in an attempt to uncover predictive, risk, and preventive factors. Research Methods and Procedures: A total of 117 obese children and adolescents 12.1 ± 2.7 years old underwent a 2-hour oral glucose tolerance test (OGTT). Insulin resistance (IR) and β-cell function were estimated using the homeostasis model assessment (HOMA)-IR and the insulinogenic index, respectively. Results: A total of 17 patients (14.5%) had IGT, and none had DM2. The overall prevalence rates of both IGT and DM2 in our subjects were lower than those reported in a recent multiethnic U.S. study. Nevertheless, the difference between our IGT data and those of the U.S. study was due mostly to the prepubertal subjects (9% vs. 25.4%), whereas no difference was observed in the pubertal population (18% vs. 21%). Fasting glucose, insulin, and HOMA-IR values were not predictive of IGT. The absolute value of insulin at 2 hours of the OGTT combined with the time-integrated glycemia (AUCG) can strongly predict IGT, whereas higher area under the curve for insulin (AUCI) values were found to be protective. Discussion: In ethnic groups less prone to diabetes development, IGT or DM2 in obese subjects is more likely to develop at puberty than at the prepubertal stage. It is advisable that physicians caring for obese adolescents perform an OGTT for early detection of IGT because HOMA-IR values, although higher in IGT subjects and indicative of IR, cannot predict IGT.