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Background/Objectives: Resting metabolic rate (RMR) is an important contributor of energy balance and displays a well-documented relationship with sex, age, race and fat-free mass (FFM) in the existing scientific literature. However, the impact of other body composition components such as fat and liver fat on RMR remains unclear. This study aims to investigate the correlation of RMR with body composition parameters in a sample of patients with overweight and obesity. Methods: Retrospective data of patients with overweight or obesity referred for magnetic resonance imaging of liver fat during the period 2018-2023 were utilized for this study. Demographic and anthropometric data were collected, including body composition parameters (body fat, muscle mass) and RMR measured by bioelectrical impedance and indirect calorimetry, respectively. Results: The final sample included 53 patients (66% male), with a mean age of 48 years (±11.2) and a mean body mass index (ΒΜΙ) of 38.5 kg/m 2 (32.7, 44.7). Simple correlation models revealed that RMR was separately correlated with gender, age, BMI, muscle mass, and liver fat (all p < 0.05) but not with fat mass. When multiple regression models were employed, only muscle mass retained its statistically significant influence on RMR, while total and hepatic fat did not significantly affect RMR after controlling for other parameters (gender, age, muscle mass). Conclusions: These findings confirm the known correlation between muscle mass and RMR while highlighting the lack of association between total and hepatic fat and RMR in individuals with overweight and obesity.

Background: Although polycystic ovary syndrome (PCOS) is a very common endocrinopathy, there are several issues related to this disorder which perplex clinicians in their everyday practice., Objective: To determine the current state of knowledge among European endocrinologists concerning the full spectrum of PCOS., Methods: An online survey comprising 41 items covering various aspects of PCOS diagnosis and management was distributed to members of the European Society of Endocrinology., Results: A total of 505 European endocrinologists (64% females), with a mean age of 47 ± 11.6 years, participated in the survey. The Rotterdam criteria were the primary diagnostic tool for 85% of respondents. Most referrals (87.1%) occurred between ages 20 and 40 years. Twenty-five percent of physicians have access to mass spectrometry for the evaluation of androgen levels. While an extended metabolic profile was commonly employed as part of the workup, there was uncertainty regarding chronic anovulation diagnosis. Diabetes, including gestational or type 2, was recognized as a significant risk factor with universal screening irrespective of BMI status. Lifestyle modification and metformin were considered as standard interventions by all participants alongside oral contraceptives, though there was significant discrepancy in treatment duration., Conclusions: The Rotterdam diagnostic criteria are widely adopted for PCOS diagnosis among European endocrinologists. The current updated survey shows an emphasis on steroid profiling as an important part of diagnostic workup and a strong position held for recognition of PCOS as a metabolic condition with potentially serious implications. Current therapy thus shifted to the demand for prioritizing lifestyle interventions and metabolic therapies, either as monotherapy or in combination with standard hormone compounds., Competing Interests: Conflict of interest: Coauthor A.G. is on the editorial board of EJE. A.G. was not involved in the review or editorial process for this paper, on which A.G. is listed as an author. The other authors have nothing to disclose., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Infertility among women, particularly those living with obesity, presents a multifaceted challenge with implications for reproductive health worldwide. Lifestyle interventions, mainly focusing on weight loss, have emerged as promising strategies to improve fertility outcomes in this population. This review aims to explore the effectiveness of various lifestyle interventions, encompassing dietary modifications and exercise regimens, in enhancing fertility outcomes among women with obesity and associated conditions such as polycystic ovary syndrome, congenital adrenal hyperplasia, type 2 diabetes mellitus, premenopause, hypothyroidism and eating disorders. Methodology of study search encompass a broad spectrum, ranging from interventions targeting weight management through slow or rapid weight loss to dietary approaches emphasizing whole food groups, specific nutrients, and dietary patterns like low-carbohydrate or ketogenic diets, as well as the Mediterranean diet. By synthesizing existing findings and recommendations, this review contributes to the understanding of lifestyle interventions in addressing infertility, with an emphasis on the population of women of reproductive age with excess weight and known or unknown infertility issues, while promoting their integration into clinical practice to optimize reproductive health and overall well-being., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gitsi, Livadas and Argyrakopoulou.)

Aims: While hormonal assays are commonly used for thyroid function assessment, Doppler sonography provides valuable information on vascularization and blood flow. This study aimed to examine the potential associations between Doppler parameters and clinical characteristics of hypothyroid patients, such as the autoimmune nature of the disease and adequacy of LT4 replacement., Methods: A total of 338 patients with hypothyroidism, primarily caused by autoimmune thyroiditis (AT), were enrolled in this study. Exclusion criteria comprised specific medical conditions, medication history, and nodular abnormalities of the thyroid gland. Patient demographics (age, sex, BMI), treatment parameters (LT4 daily dose), and thyroid hormone levels (TSH, fT4) were recorded., Results: Among the enrolled patients, 85.2% had autoimmune thyroiditis. Suboptimal levothyroxine (LT4) replacement was observed in 20.1% of patients at the time of enrollment. Patients with autoimmune thyroiditis had increased elastography ratios compared to those without autoimmune disease and present a positive association of elastography ratios with vascularity. In patients without autoimmune thyroiditis, those with suboptimal LT4 replacement had lower total thyroid volume. Patients with suboptimal LT4 replacement had higher peak systolic velocity (PSV) and end-diastolic velocity (EDV) in the inferior thyroid artery and lower resistive index (RI). The severity of hypothyroidism, as indicated by LT4 dose/body mass index (BMI), was negatively correlated with thyroid volume and EDV values of superior and inferior thyroid arteries. PSV of the inferior thyroid artery can predict suboptimal LT4 replacement (sensitivity 81.8%, specificity 42%)., Conclusions: In situations where obtaining blood tests may be challenging, utilizing color Doppler ultrasound can serve as an alternative method to assess treatment responses and identify patients who require further hormonal examinations., (© 2024. Società Italiana di Ultrasonologia in Medicina e Biologia (SIUMB).)

(1) Background: After thyroid malignancy is ruled out, treatment options for multinodular goiter patients include surgery, levothyroxine suppressive therapy, and 131-I therapy. Surgery effectively reduces goiter size but carries risks of surgical and anesthetic complications. 131-I therapy is the only nonsurgical alternative, but its effectiveness diminishes with goiter size and depends on iodine sufficiency. This study aimed to assess the efficacy and safety of 0.1 mg rhTSH as an adjuvant to a fixed dose of 131-I therapy in patients with a recurrence of large multinodular goiter, several years after the initial thyroidectomy. (2) Methods: 14 patients (13 females and 1 male), aged 59.14 ± 15.44 (range, 35-78 years) received 11mciu of 131-I, 24 h after the administration of 0.1 mg rhTSH. The primary endpoint was the change in thyroid volume (by ultrasound measurements) as well as in the diameter of the predominant nodule during a follow-up period of 10 years. Secondary endpoints were the alterations in thyroid function and potential adverse effects. (3) Results: A significant decrease in the volume of initial thyroid remnants (32.16 ± 16.66 mL) was observed from the first reevaluation (at 4 months, 23.12 ± 11.59 mL) as well as at the end of the follow-up period (10 years, 12.62 ± 8.76 mL), p < 0.01. A significant reduction in the dominant nodule was also observed (from 31.71 ± 10.46 mm in the beginning to 26.67 ± 11.05 mm). (4) Conclusions: Further investigation is needed since this approach could be attractive in terms of minimizing the potential risks of reoperation in these patients.

Background: The first phase of the GAIL study ("Girls treated with an Aromatase Inhibitor and Leuprorelin," ISRCTN11469487) has shown that the combination of anastrozole and leuprorelin for 24 months is safe and effective in improving the predicted adult height (PAH) in girls with early puberty and compromised growth prediction by +1.21 standard deviation score (SDS; +7.51 cm) compared to inhibition of puberty alone, +0.31 SDS (+1.92 cm)., Objectives and Hypotheses: In the second phase of the GAIL study, we assessed the adult height (AH)/near-adult height (NAH) at the end of the first phase and, in addition, the efficacy of anastrozole monotherapy thereafter in further improving NAH., Methods: We measured the AH (age 16.5 years)/NAH [bone age (BA), 15 years] of the 40 girls included, divided into two matched groups: group A (20 girls on anastrozole + leuprorelin) and group B (20 girls on leuprorelin alone). Group A was further randomized into two subgroups: A1 and A2. Group A1 ( n = 10), after completion of the combined therapy, received anastrozole 1 mg/day as monotherapy until BA 14 years, with a 6-month follow-up. Group A2 ( n = 10) and group B ( n = 20), who received only the combined treatment and leuprorelin alone, respectively, were recalled for evaluation of AH/NAH., Results: AH or NAH exceeded the PAH at the completion of the 2-year initial phase of the GAIL study in all groups, but the results were statistically significant only in group A1: NAH-PAH group A1, +3.85 cm (+0.62 SDS, p = 0.01); group A2, +1.6 cm (+0.26 SDS, p = 0.26); and group B, +1.7 cm (+0.3 SDS, p = 0.08). The gain in group A1 was significantly greater than that in group A2 ( p = 0.04) and in group B ( p = 0.03). Anastrozole was determined to be safe even as monotherapy in Group A1., Conclusions: In early-maturing girls with compromised growth potential, the combined treatment with leuprorelin and anastrozole for 2 years or until the age of 11 years resulted in a total gain in height of +9.7 cm when continuing anastrozole monotherapy until the attainment of NAH, as opposed to +7.4 cm if they do not continue with the anastrozole monotherapy and +3.6 cm when treated with leuprorelin alone. Thus, the combined intervention ends at the shortest distance from the target height if continued with anastrozole monotherapy until BA 14 years., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Papadimitriou, Dermitzaki, Christopoulos, Livadas, Grivea and Mastorakos.)

Purpose: Polycystic ovary syndrome (PCOS) is an endocrine, metabolic, and reproductive disorder which, according to the Rotterdam criteria, affects up to 24% of women of childbearing age. Although the prevalence of infertility in this subpopulation of women is high, the optimal treatment has not been fully established yet. Insulin resistance is considered to be an important mechanism involved in the development of PCOS; hence, the aim of this narrative review is to present an overview of the current pharmacological insulin-sensitizing treatment modalities for infertile women with PCOS., Methods: A MEDLINE and PubMed search for the years 1990-2023 was performed using a combination of keywords. Clinical trials with insulin sensitizers used for infertility treatment as well as analyses of systematic reviews and meta-analyses were evaluated. When deemed necessary, additional articles referenced in the retrieved papers were included in this narrative review., Results: Several insulin-sensitizing compounds and various therapeutical protocols are available for infertility treatment of women with PCOS. Metformin is the most common adjuvant medication to induce ovulation in infertile women with PCOS and is more frequently administered in combination with clomiphene citrate than on its own. Recently, inositol and glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as possible options for infertility treatment in PCOS., Conclusion: The future of medical treatment of PCOS women with infertility lies in a personalized pharmacological approach, which involves various compounds with different mechanisms of action that could modify ovarian function and endometrial receptivity, ultimately leading to better overall reproductive outcomes in these women., (© 2023. The Author(s), under exclusive licence to Hellenic Endocrine Society.)

Background: Vitamin D testing (VDT) and supplement use (VDS) are on the rise, but most patients remain deficient (<30 ng/mL-VDD). We designed the present real-world study to assess this paradox., Methods: We reviewed data from all patients visiting our clinics between 2014 and 2022. We estimated the rate of patients with vitamin D adequacy (≥30 ng/mL) (VDA) by year and month of testing, the dose of VDS (low (≤1200 IU/day), medium (1201-3000 I/day) and high dose (>3000 IU/day)), intake duration (short-term (<12 months) and long-term use (≥12 months)), and timing of use (current use, former use, no use)., Results: We enrolled n = 6912 subjects with vitamin D measurements: n = 5195 females (75.2%), age 44.0 ± 16.8 years, BMI 27.9 ± 6.5 kg/m 2 ; never users: n = 5553 (80.3%), former users: n = 533 (7.7%), current users: n = 826 (12.0%). Current use of VDS was higher in females. VDT rose from 42.1% in 2014 to 92.7% in 2022, and VDA rose from 14.8% to 25.5% for the same time. VDA was found overall in n = 1511 (21.9%); Never users: n = 864 (15.6%), Former users: n = 123 (23.2%); and Current users: n = 370 (44.8%). The maximal VDA (67.9%) was found in subjects using high-dose VDS in the long term., Conclusions: Despite the significant rise in VDT and VDS use, VDA was found in a minority of patients. Prolonged use of high-dose supplements produces modest improvements in VDA.

Context: For some, chronic lymphocytic thyroiditis (Hashimoto thyroiditis) is an important risk factor for differentiated thyroid cancer (DTC). Surgical cohort studies even suggested a potential role for thyroid peroxidase antibodies (TPO-Abs) on that risk., Objective: Our clinical observations argued against that possibility. We designed the present study to evaluate the relationship of TPO-Abs and DTC in a large patient population., Methods: We recruited individuals who underwent thyroidectomies at 4 different clinical sites (USA: 1 clinic, 2000-2013, and Greece: 3 clinics, 2007-2021). We gathered data on TPO-Abs titers measured with commercially available chemiluminescence immunoassays, and reviewed patients' data including surgical pathology. TPO-Abs of 34 IU/mL or greater was deemed positive (TPO+) and TPO-Abs less than 34 IU/mL was deemed negative (TPO-). Odds ratios (OR) for DTC were calculated with the Fisher exact test and P less than .05 was deemed significant., Results: We reviewed data from 8461 consecutive thyroid surgery cases. TPO-Abs titers were available for 1635 individuals: DTC n = 716 (43.8%), benign pathology n = 919 (56.2%), TPO+ n = 540 (33.0%), and TPO- n = 1095 (67.0%). DTC was found at a lower frequency in TPO+ (198/540, 36.7%) compared to TPO- (518/1095, 47.3%) patients, OR 0.64 (0.52-0.80; P < .0001). Rising TPO-Abs titers conferred protection against DTC in a linear fashion: TPO-Abs less than 10 IU/mL: 59.3%, TPO-Abs less than 34 IU/mL: 47.4%, TPO-Abs 34 to 100 IU/mL: 42.6%, TPO-Abs 100 to 500 IU/mL: 32.0%, TPO-Abs greater than 1000 IU/mL: 19.4%; P less than .0001., Conclusion: Higher TPO-Ab titers appear protective against DTC in our large multicenter cohort of patients who underwent thyroidectomies. Rising preoperative TPO-Abs titers conferred linearly increasing protection against DTC., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Achieving optimal glucose control in individuals with type 1 diabetes (T1DM) continues to pose a significant challenge. While continuous insulin infusion systems have shown promise as an alternative to conventional insulin therapy, there remains a crucial need for greater awareness regarding the necessary adaptations for various special circumstances. Nutritional choices play an essential role in the efficacy of diabetes management and overall health status for patients with T1DM. Factors such as effective carbohydrate counting, assessment of the macronutrient composition of meals, and comprehending the concept of the glycemic index of foods are paramount in making informed pre-meal adjustments when utilizing insulin pumps. Furthermore, the ability to handle such situations as physical exercise, illness, pregnancy, and lactation by making appropriate adjustments in nutrition and pump settings should be cultivated within the patient-practitioner relationship. This review aims to provide healthcare practitioners with practical guidance on optimizing care for individuals living with T1DM. It includes recommendations on carbohydrate counting, managing mixed meals and the glycemic index, addressing exercise-related challenges, coping with illness, and managing nutritional needs during pregnancy and lactation. Additionally, considerations relating to closed-loop systems with regard to nutrition are addressed. By implementing these strategies, healthcare providers can better equip themselves to support individuals with T1DM in achieving improved diabetes management and enhanced quality of life.

Purpose: This study aimed to evaluate various therapeutic approaches, identify potential predictive factors for the recurrence and development of hypothyroidism, and examine specific clinical and laboratory characteristics of patients with subacute thyroiditis (SAT) due to SARS-CoV-2 infection., Methods: We retrospectively analyzed the medical records of 226 patients with confirmed SAT diagnosed from January 2020 to November 2022., Results: The mean age was 48.01 ± 0.75 years, and the F/M ratio was 2.3/1. At the end of the follow-up period, 69 patients (32.1%) had developed hypothyroidism. Treatment duration was significantly shorter with nonsteroidal anti-inflammatory drugs (NSAIDs) (17.40 ± 2.56 days), while time-to-symptom relief was shorter with glucocorticoids (CGs). Recurrence was observed only in those treated with corticosteroid preparations (14.1%). C-reactive protein levels at treatment discontinuation were higher in patients who experienced SAT recurrence, while the coexistence of Hashimoto's thyroiditis was a significant predictive factor for the development of hypothyroidism. The TSH value at the time of treatment withdrawal >4.12 μIU/mL showed optimal sensitivity and specificity for the prediction of permanent hypothyroidism. Regarding COVID-19, 34 patients (15%) experienced related SAT, with similar clinical manifestations of the disease but a higher BMI and shorter time-to-symptom relief., Conclusion: In conclusion, GCs administration alleviated acute symptoms earlier during the onset of SAT, whereas NSAIDs had a shorter treatment duration, and both regimens could not prevent the development of delayed hypothyroidism. The clinical characteristics of SAT due to COVID-19 infections were similar to those of typical SAT disease.

Background: In the last decade, the combination of the widespread use of streptavidin-biotin technology and biotin-containing supplements (BCS) in the daily clinical practice, have led to numerous reports of erroneous hormone immunoassay results. However, there are no studies assessing the clinical and biochemical significance of that phenomenon, when treating patients with hypothyroidism. Therefore, a prospective study was designed to investigate the potential alterations in the measurement of thyroid hormone concentrations and clinical consequences in patients with hypothyroidism using low -dose BCS containing less than 300 μg/day., Methods: Fifty-seven patients on thyroxine supplementation, as a result of hypothyroidism and concurrent use of BCS at a dose <300μg/day for 10 to 60 days were prospectively evaluated. Namely, TSH and free T4 (FT4) concentration measurements were performed, during BC supplementation and 10 days post BCS discontinuation and compared to 31 age-matched patients with supplemented hypothyroidism and without BCS., Results: A statistically significant increase in TSH and decline in FT4 concentrations was observed after BCS discontinuation. However, on clinical grounds, these modifications were minor and led to medication dose adjustment in only 2/57 patients (3.51%) in whom TSH was notably decreased after supplement discontinuation., Conclusion: Our study suggests that changes in thyroid hormones profiling, due to supplements containing low dose biotin, are of minimal clinical relevance and in most cases don't occult the need to adjust the thyroxine replacement dose in patients with hypothyroidism. Larger, well-designed trials are required to further evaluate this phenomenon., (© 2023. The Author(s).)

Women with polycystic ovary syndrome (PCOS) are at increased risk for dysglycemia and type 2 diabetes compared to healthy BMI-matched women of reproductive age: robust evidence exists supporting this notion. The presence of altered glycemic status in young women with the syndrome presents a distinct challenge for the clinician for several reasons. Firstly, the reported incidence of this disorder varies among the limited available studies. Furthermore, there is a lack of consensus on the best screening method, which women to screen, at what frequency, and which strategies need to be implemented to reduce the above risk. We provide data regarding the prevalence of dysglycemia in young women suffering from PCOS and the pathophysiological mechanisms underlying the disorder. In addition, we present evidence suggesting universal screening with the oral glucose tolerance test in young women with the syndrome, irrespective of age or BMI status, to identify and manage glycemic abnormalities in a timely manner. Regarding follow-up, oral glucose testing should be carried out at regular intervals if there are initial abnormal findings or predisposing factors. Finally, the efficacy of a well-balanced diet in conjunction with regular exercise and the use of non-pharmacologic agents in this specific population is discussed.

Certain nutraceuticals, mainly containing red yeast rice, might be considered as an alternative therapy to statins in patients with dyslipidemia, although there is still insufficient evidence available with respect to long-term safety and effectiveness on cardiovascular disease prevention and treatment. The aim of this study was to assess the lipid-lowering activity and safety of a dietary supplement containing a low dose of monacolin K combined with coenzyme Q10, grape seed and olive tree leaf extracts in patients with mild hypercholesterolemia. In total, 105 subjects with mild hypercholesterolemia (low-density lipoprotein cholesterol LDL-C levels 140-180 mg/dL) and low CV risk were randomly assigned into three treatment groups: lifestyle modification (LM), LM plus a low dosage of monacolin K (3 mg), and LM plus a high dosage of monacolin K (10 mg) and treated for 8 weeks. The primary endpoint was the reduction of LDL-C and total cholesterol (TC). LDL-C decreased by 26.46% on average ( p < 0.001) during treatment with 10 mg of monacolin and by 16.77% on average during treatment with 3 mg of monacolin ( p < 0.001). We observed a slight but significant reduction of the triglyceride levels only in the high-dose-treated group (mean -4.25%; 95% CI of mean -11.11 to 2.61). No severe adverse events occurred during the study. Our results confirm the LDL-C-lowering properties of monacolin are clinically meaningful even in lower doses of 3 mg/day.

Introduction: There is increasing evidence that vitamin D has widespread tissue effects. In addition to osteoporosis, vitamin D deficiency has been associated with cardiovascular disease, diabetes, cancer, infections and neurodegenerative disease. However, the effect of vitamin D supplementation on non-skeletal outcomes requires clarification, especially in postmenopausal women., Aim: This position statement provides an evidence-based overview of the role of vitamin D in the health of postmenopausal women based on observational and interventional studies., Materials and Methods: Literature review and consensus of expert opinion., Results and Conclusions: Vitamin D status is determined by measuring serum 25-hydroxyvitamin D levels. Concentrations <20 ng/ml (<50 nmol/l) and <10 ng/ml (<25 nmol/l) are considered to constitute vitamin D deficiency and severe deficiency, respectively. Observational data suggest an association between vitamin D deficiency and adverse health outcomes in postmenopausal women, although they cannot establish causality. The evidence from randomized controlled trials concerning vitamin D supplementation is not robust, since many studies did not consider whether people were deficient at baseline. Moreover, high heterogeneity exists in terms of the population studied, vitamin D dosage, calcium co-administration and duration of intervention. Concerning skeletal health, vitamin D deficiency is associated with low bone mass and an increased risk of fractures. Vitamin D supplementation at maintenance doses of 800-2000 IU/day (20-50 μg/day), after repletion of vitamin D status with higher weekly or daily doses, may be of benefit only when co-administered with calcium (1000-1200 mg/day), especially in the elderly populations and those with severe vitamin D deficiency. Concerning cardiovascular disease, vitamin D deficiency is associated with an increased prevalence of cardiovascular risk factors, mainly metabolic syndrome, type 2 diabetes mellitus and dyslipidemia. Vitamin D deficiency, especially its severe form, is associated with an increased risk of cardiovascular events (coronary heart disease, stroke, mortality), independently of traditional risk factors. Vitamin D supplementation may have a modestly beneficial effect on lipid profile and glucose homeostasis, especially in obese individuals or those ≥60 years old and at doses of ≥2000 IU/day (≥50 μg/day). However, it has no effect on the incidence of cardiovascular events. Concerning cancer, vitamin D deficiency is associated with increased incidence of and mortality from several types of cancer, such as colorectal, lung and breast cancer. However, the data on other types of gynecological cancer are inconsistent. Vitamin D supplementation has no effect on cancer incidence, although a modest reduction in cancer-related mortality has been observed. Concerning infections, vitamin D deficiency has been associated with acute respiratory tract infections, including coronavirus disease 2019 (COVID-19). Vitamin D supplementation may decrease the risk of acute respiratory tract infections and the severity of COVID-19 (not the risk of infection). Concerning menopausal symptomatology, vitamin D deficiency may have a negative impact on some aspects, such as sleep disturbances, depression, sexual function and joint pains. However, vitamin D supplementation has no effect on these, except for vulvovaginal atrophy, at relatively high doses, i.e., 40,000-60,000 IU/week (1000-1500 IU/week) orally or 1000 IU/day (25 μg/day) as a vaginal suppository., Competing Interests: Declaration of competing interest, (Copyright © 2022 Elsevier B.V. All rights reserved.)

Inconsistency exists across studies conducted in postmenopausal women regarding the effect of vitamin D deficiency (VDD) and supplementation on several aspects of menopausal health, such as fractures, vasomotor symptomatology, cardiovascular disease (CVD), cancer and infections, including coronavirus disease 2019 (COVID-19). The aim of this review is to critically summarize the evidence provided by observational studies and randomized controlled trials (RCTs) of vitamin D supplementation in postmenopausal women with VDD. Observational studies have found that VDD is associated with an increased risk of falls and fractures after the menopause. VDD also has a negative effect on menopausal symptomatology. VDD, especially its severe form, is associated with an increased risk of CVD risk factors and CVD events. VDD is associated with increased risk and mortality from several cancer types and risk of infections. The evidence from RCTs regarding the effect of vitamin D supplementation on falls, fractures, menopausal symptoms, cardiovascular disease, cancer and infections is not robust. Thus, skeletal health may benefit only when vitamin D is co-administered with calcium, especially in those ≥70 years old and with severe VDD. There is no evidence of a favorable effect on menopausal symptoms or risk of CVD or cancer, except for a modest reduction in cancer-related mortality. Inconsistency still exists regarding its effect on infection risk, disease severity and mortality due to COVID-19.

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 (<1 cm) and 161 (30.2%) macrocarcinomas (≥1 cm). The histology was consistent with papillary cancer (n = 503), follicular cancer (n = 12), Hürthle cell cancer (n = 9), medullary cancer (n = 5), and mixed histology cancers n = 4. Only 47 (1.9%) of our subjects had any form of thyroid cancer in the nodule that originally led to surgery. The cancers were multifocal in 165 subjects; had extrathyroidal extension in 61, capsular invasion in 80, lymph node involvement in 35, and bone metastasis in 2 subjects., 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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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.

Beyond being aging-related diseases, atherosclerosis and osteoporosis share common pathogenetic pathways implicated in bone and vascular mineralization. However, the contributory role of dyslipidemia in this interplay is less documented. The purpose of this narrative review is to provide epidemiological evidence regarding the prevalence of bone disease (osteoporosis, fracture risk) in patients with dyslipidemias and to discuss potential common pathophysiological mechanisms linking osteoporosis and atherosclerosis. The effect of hypolipidemic therapy on bone metabolism is also discussed. Despite the high data heterogeneity and the variable quality of studies, dyslipidemia, mainly elevated total and low-density lipoprotein cholesterol concentrations, is associated with low bone mass and increased fracture risk. This effect may be mediated directly by the increased oxidative stress and systemic inflammation associated with dyslipidemia, leading to increased osteoclastic activity and reduced bone formation. Moreover, factors such as estrogen, vitamin D and K deficiency, and increased concentrations of parathyroid hormone, homocysteine and lipid oxidation products, can also contribute. Regarding the effect of hypolipidemic medications on bone metabolism, statins may slightly increase BMD and reduce fracture risk, although the evidence is not robust, as it is for omega-3 fatty acids. No evidence exists for the effects of ezetimibe, fibrates, and niacin. In any case, more prospective studies are needed further to elucidate the association between lipids and bone strength.

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., Competing Interests: Conflict-of-interest statement: The authors have no conflict of interest to disclose., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Adequate vitamin D levels are particularly important in pregnant women for both 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. VDD 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 (<10 ng/mL). As a result, most newborns had VDD, which affected refugee newborns to a greater extent. Our results suggest a need to screen newcomer children and pregnant women for VDD in all host countries around the world. Such a screen will appropriately guide early and effective interventions with the goal to prevent adverse neonatal and maternal outcomes.

Purpose: 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., Methods: 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 I 2 index was employed for heterogeneity., Results: 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 < 0.001; I 2 81.6%). This risk remained significant both in studies matched or unmatched for participants' age. With regard to body mass index (BMI), the RR for developing T2DM in obese and non-obese PCOS women compared with their non-PCOS counterparts was 3.24 (95% CI 2.25-4.65; p < 0.001; I 2 30.9%) and 1.62 (95% CI 0.14-18.50; p = 0.70; I 2 89.9%), respectively. The RR for developing T2DM was 3.85 (95% CI 1.99-7.43; p < 0.001; I 2 46.2%) in obese compared with non-obese women with PCOS. This was also the case for overweight compared with lean women with PCOS., Conclusions: Women with PCOS present an increased risk of T2DM compared with non-PCOS women only if they are obese/overweight., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The hypoestrogenic period after menopause and associated metabolic imbalance might facilitate the onset of non-alcoholic fatty liver disease (NAFLD) and its progression. The prevalence of NAFLD increases in patients experiencing premature ovarian insufficiency, as well as surgical or natural menopause. The postmenopausal period is characterized by dyslipidemia and insulin resistance associated with an increased influx of free fatty acids to the liver with consequent steatosis and further progression of NAFLD. More than half of postmenopausal women with diabetes mellitus type 2 suffer from NAFLD. It is suggested that estrogens slow the progression of chronic liver diseases by suppression of inflammation, improvement of mitochondrial function, alleviation of oxidative stress, insulin resistance, and fibrogenesis. The hyperandrogenic state of polycystic ovary syndrome (PCOS) is associated with the development of NAFLD in women of reproductive age, but it is difficult to extend these findings to menopause due to inappropriate diagnosis of PCOS after menopause. Lifestyle intervention, including physical activity and dietary regimens, remains the first-line preventive and therapeutic option for NAFLD. There are contradictory reports on the use of menopausal hormonal therapy (MHT) and NAFLD. It is necessary to investigate the potential effects of estradiol dose, progesterone type, selective estrogen receptor modulators and tissue-selective estrogen complex compounds on NAFLD development and progression in postmenopausal women. The present review aims to explore the pathophysiological and clinical aspects of liver metabolic disturbances in women after menopause, focusing on the possible preventive and therapeutic strategies in NAFLD, including the potential role of MHT., (Copyright © 2021 Elsevier B.V. All rights reserved.)

'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.

Polycystic ovary syndrome (PCOS) is a frequent endocrine disease in women during the reproductive period. It is considered a complex metabolic disorder with long-term metabolic, as well as reproductive consequences. Main pathophysiological pathways are related to the increased androgen levels and insulin resistance. Nowadays, genetic origins of PCOS are acknowledged, with numerous genes involved in the pathogenesis of hyperandrogenemia, insulin resistance, inflammation, and disturbed folliculogenesis. Rotterdam diagnostic criteria are most widely accepted and four PCOS phenotypes have been recognized. Metabolic abnormalities are more common in phenotypes 1 and 2. Women with classic PCOS are more obese and typically have the central type of obesity, more prevalently displaying dyslipidemia, insulin resistance, and metabolic syndrome that could be associated with an increased risk of cardiovascular complications during life. Heterogeneity of phenotypes demands an individualized approach in the treatment of women with PCOS. Metabolic therapies involve a lifestyle intervention followed by the introduction of insulin sensitizers including metformin and inositols, glucagon-like peptide 1 receptor agonists (GLP-1 RA), as recently sodium-glucose cotransporter-2 (SGLT2) inhibitors. The addition of an insulin sensitizer to the standard infertility therapy such as clomiphene citrate improves ovulation and pregnancy rates. Our current review analyzes the contemporary knowledge of PCOS etiology and etiopathogenesis, its cardiometabolic risks and their outcomes, as well as therapeutic advances for women with PCOS., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Incidental finding of differentiated thyroid microcarcinomas (DTMc) in patients undergoing thyroid surgery for benign indications has 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. Materials and Methods: We reviewed data from two prospectively collected databases of consecutive patients undergoing thyroid surgery in two high-volume tertiary care referral centers, one in the United States (A) and the other one in Greece (B) over 18 years. We collected data on the preoperative surgical indication, fine-needle aspiration (FNA) cytology, and surgical pathology. We excluded subjects operated for thyroid cancer or with high risk for malignancy (FNA suspicious for thyroid cancer, follicular neoplasm, suspicious for follicular neoplasm, follicular lesion of undetermined significance/atypia of undetermined significance, or preoperative features of malignancy) and those with postsurgical pathology consistent with papillary thyroid cancer (PTC) ≥1 cm in largest diameter. We divided our subjects based on pathology data into those with chronic lymphocytic thyroiditis (CLT), Graves' disease (GD), or multinodular goiter (MNG). Results: We reviewed 6096 cases of thyroid surgery (A: 2711, B: 3385). We included 3909 subjects in the analysis. Overall, 569 (14.6%) PTC subjects were identified (A: 221/2003 [11%], B: 348/1906 [18.3%], odds ratios [OR] = 0.56, p  < 0.0001). CLT was present in 617 subjects; PTC sonographic was present in 143 subjects (23.2%) (A: 79/404 [19.6%], B: 64/213 [30%], OR = 0.56, p  = 0.003). GD was present in 359 subjects; PTC was present in 37 subjects (10.3%) (A: 12/197 [6.1%], B: 25/162 [15.4%], OR = 0.36, p  = 0.004). MNG was present in 2933 subjects; PTC was present in 389 subjects (13.3%) (A: 130/1402 [9.3%], B: 259/1531 [16.9%], OR = 0.50, p  < 0.0001). The incidence of PTC was significantly higher in CLT compared with MNG (OR = 1.75, p  < 0.0001) or GD (OR = 2.25, p  < 0.0001) but not in MNG compared with GD (OR = 1.29, p  > 0.05). Conclusions: Incidentally discovered PTC are more commonly identified in surgical specimens from subjects with CLT compared with patients with MNG, while patients with GD present with a lower incidence compared with both groups. These data support previously published findings that euthyroid Hashimoto thyroiditis favors carcinogenesis, while GD may have a protective role.

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/m 2 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 <0.05). Circulating androstenedione levels did not differ between PA-PP and PCOS women (0.11±0.05 vs. 0.12±0.03), but was higher than that of controls (0.02±0.0 nmol/l, p <0,05). Ovarian volume was increased in PA-PP and PCOS (11.14±3.3 vs. 10.99±4.61) compared to controls (6.74±1.83 cm 3 ). PA-PP women had a higher score of state/trait anxiety and depressive and eating disorder symptoms than controls, with a pattern that matched that of PCOS women. Only 14% of the PA-PP group fulfilled the Rotterdam PCOS criteria. Some women with a history of PA-PP displayed hormonal and psychologic profile similar to PCOS, and accordingly a regular monitoring of these girls during adulthood is advised., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Polycystic ovary syndrome (PCOS) is a common endocrine disease in women during reproductive age. It was shown that PCOS women are with high risk for dyslipidemia, glucose intolerance, type 2 diabetes and metabolic syndrome. These factors are considered to represent traditional risk factors for the occurrence of cardiovascular disease. Observed increased risk for hypertension in PCOS women seems to be associated with insulin resistance and hyperinsulinemia. Both conditions interfere with the endothelium-dependent vasodilatation mechanisms causing vascular muscle wall hypertrophy. Obesity and insulin resistance are considered key factors for the alteration of blood pressure in PCOS women. Higher cardiovascular risk is implicated in PCOS with aging and its consequent association with both systolic and diastolic blood pressure. The elements of renin-angiotensin-aldosterone system (RAAS) have an impact on endothelial dysfunction as a marker of cardiovascular damage that could be modified is women with PCOS. Androgens and components of RAAS are involved in the process of atherogenesis in PCOS women. Therefore, it is hypothesized that spironolactone treatment could ameliorate endothelial dysfunction in PCOS women. Recently it was shown that telmisartan, angiotensin II receptor antagonist poses insulinsensitizing capacity to activate PPAR gamma and mediate favorable metabolic and reproductive effects in hypertensive PCOS women., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Early activation of the adrenal zona reticularis, leading to adrenal androgen secretion, mainly dehydroepiandrosterone sulfate (DHEAS), is called premature adrenarche (PA). The fact that adrenal hyperandrogenism in females has been linked to a cluster of cardiovascular (CV) risk factors, even in prepubertal children, warrants investigation. Controversial results have been obtained in this field, probably due to genetic, constitutional, and environmental factors or differences in the characteristics of participants. In an attempt to understand, in depth, the impact of PA as a potential activator of CV risk, we critically present available data stratified according to pubertal status. It seems that prepubertally, CV risk is increased in these girls, but is somewhat attenuated during their second decade of life. Furthermore, different entities associated with PA, such as polycystic ovary syndrome, non-classical congenital adrenal hyperplasia, heterozygosity of CYP21A2 mutations, and the impact of DHEAS on CV risk, are reviewed. At present, firm and definitive conclusions cannot be drawn. However, it may be speculated that girls with a history of PA display a hyperandrogenic hormonal milieu that may lead to increased CV risk. Accordingly, appropriate long-term follow-up and early intervention employing a patient-oriented approach are recommended., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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., (Copyright © 2019 Livadas and Chrousos.)

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: 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 many patients, for whom the indication for its administration is not adequately established and the diagnosis is not well documented, are overusing it. This study aimed to evaluate the necessity for and determine potential prognostic factors of long-term LT4 supplementation., Methods: A prospective clinical cohort follow-up study was carried out. In 291 subjects (84% females) aged 48 ± 16 years on LT4 replacement therapy without a solid diagnosis of hypothyroidism being provided, the treatment was paused. At the beginning and after six to eight weeks of treatment discontinuation, thyrotropin (TSH) and free thyroxine levels were assessed, and thyroid ultrasound was performed. A TSH value of ≥4.5 IU/mL was considered as underlying hypothyroidism., Results: Among the 291 individuals, 114 became hypothyroid (group A), while 177 subjects remained euthyroid off LT4 (group B; 39.2% vs. 60.8%, p < 0.001). The groups were comparable regarding sex, family history, age, body mass index, duration of treatment, basal TSH and free thyroxine values, thyroid volume, and presence of thyroid autoantibodies. However, diffuse inhomogeneous echogenicity on ultrasound examination was significantly higher (p < 0.001) in group A., Conclusions: These findings suggest considerable overuse of thyroxine therapy. The results underline the initial need to establish the diagnosis firmly before treatment initiation and to undertake periodic evaluation of all patients on chronic LT4 treatment as to the necessity for treatment continuation. In all patients on long-term LT4 therapy in whom the diagnosis has not been definitively established, it appears rational to introduce a six- to eight-week period of LT4 replacement therapy discontinuation, preceded and followed by TSH tests, as the first-line approach-a procedure that could be implemented as part of a common strategy among the scientific community to decrease current LT4 overuse.

Background: The role of nonselective beta-blockers in cirrhotic patients with ascites has been recently questioned; however, definitive evidence in this regard is still lacking., Aims: To analyze published data on the influence of nonselective beta-blockers as compared to control group on survival of cirrhotic patients with ascites., Methods: Computerized bibliographic search on the main databases was performed. Hazard ratios from Kaplan-Meier curves were extracted in order to perform an unbiased comparison of survival estimates. Secondary outcomes were mortality in patients with refractory ascites, pooled rate of nonselective beta-blockers interruption, spontaneous bacterial peritonitis and hepato-renal syndrome incidence., Results: Three randomized controlled trials and 13 observational studies with 8279 patients were included. Overall survival was comparable between the two groups (hazard ratio = 0.86, 0.71-1.03, p = 0.11). Study design resulted as the main source of heterogeneity in sensitivity analysis and meta-regression. Mortality in refractory ascites patients was similar in the two groups (odds ratio = 0.90, 0.45-1.79; p = 0.76). No difference in spontaneous bacterial peritonitis (odds ratio = 0.78, 0.47-1.29, p = 0.33) and hepato-renal syndrome incidence (odds ratio = 1.22, 0.48-3.09; p = 0.67) was observed. Pooled rate of nonselective beta-blockers interruption was 18.6% (5.2-32.1%)., Conclusions: Based on our findings, nonselective beta-blockers should not be routinely withheld in patients with cirrhosis and ascites, even if refractory.

Polycystic ovary syndrome (PCOS) is the most common endocrine disease in women during the reproductive period. True PCOS phenotype is prone to develop metabolic consequences during life. Obese PCOS women with insulin resistance are carrying a risk for developing type 2 diabetes, and influencing liver function by generating liver steatosis and nonalcoholic fatty liver disease (NAFLD). Moreover, serum testosterone of over 3 nmol/L is associated with at least two-fold higher risk for the development of NAFLD in PCOS women. Numerous genes involved in the pathogenesis of hyperandrogenism, insulin resistance and inflammation are associated with the development of NAFLD in PCOS women. Liver biopsy is not considered as the first line procedure for the diagnosis of liver damage in a prevalent condition as PCOS. Therefore, simple and reliable surrogate markers as serum aminotransferases levels or surrogate indexes (i.e. fatty liver index and NAFLD-fatty liver score) could be used for the assessment of fatty liver in PCOS women. First line therapeutic approach for NAFLD in PCOS includes a change in lifestyle that implies dietary regiment and physical activity but without well-defined protocols. Second line therapy considers addition of drugs on the established lifestyle change. Metformin remains the drug of choice for reduction of insulin resistance and liver enzymes level. Liraglutide, glucagon-like peptide-1 receptor agonists, showed favorable effects on the reduction of liver fat content and visceral adipose tissue in overweight women with PCOS. Current review analyzes the impact of metabolic risk factors, diagnostic approach and management options on NAFLD in women with PCOS., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose of Review: The mechanism of puberty initiation remains an enigma, despite extensive research in the field. Pulsatile pituitary gonadotropin secretion under the guidance of hypothalamic gonadotropin-releasing hormone (GnRH) constitutes a sine qua non for pubertal onset. In turn, the secretion of GnRH in the human hypothalamus is regulated by kisspeptin and its receptor as well as by permissive or opposing signals mediated by neurokinin B and dynorphin acting on their respective receptors. These three supra-GnRH regulators compose the Kisspeptin, Neurokinin B and Dynorhin neurons (KNDy) system, a key player in pubertal onset and progression., Recent Findings: The recent discovery that makorin ring finger protein 3 is also involved in puberty initiation provided further insights into the regulation of the KNDy pathway. In fact, the inhibitory (γ-amino butyric acid, neuropeptide Y, and RFamide-related peptide-3) and stimulatory signals (glutamate) acting upstream of KNDy called into question the role of makorin ring finger protein 3 as the gatekeeper of puberty. Meanwhile, the findings that 'neuroestradiol' produced locally and endocrine disruptors from the environment may influence GnRH secretion is intriguing. Finally, epigenetic mechanisms have been implicated in pubertal onset through recently discovered mechanisms., Summary: The exact molecular machinery underlying puberty initiation in humans is under intensive investigation. In this review, we summarize research evidence in the field, while emphasizing the areas of uncertainty and underlining the impact of current information on the evolving theory regarding this fascinating phenomenon.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder with a significant psychological burden throughout the life course of affected women. Thus, use of mindful awareness may be beneficial as an adjunct to conventional medical management of women with PCOS. A randomized, controlled trial was conducted at the Evgenideion Hospital of the Athens University Medical School to explore the impact of an 8-week mindfulness stress management program on measures of depression, anxiety and stress as well as on the quality of life in reproductive age women with PCOS. The study was approved by the Research Ethics Committee. Twenty-three and 15 women with PCOS were randomly allocated to the intervention or control group, respectively. All participants were administered DASS21, PSS-14, PCOSQ, Daily Life and General Life Satisfaction Questionnaires and provided three-timed daily samples of salivary cortisol, before and after the intervention. Intervention group participants were provided with the Credibility/Expectancy Questionnaire at the day of enrolment, to check for possible placebo effect on the outcome. Post-intervention, between-group results revealed statistically significant reductions in stress, depressive and anxiety symptoms, as well as in salivary cortisol concentrations, along with an increase in Life Satisfaction and Quality of Life scores in the intervention group only. There was no significant "placebo" effect on the outcome measures. Mindfulness techniques seem promising in ameliorating stress, anxiety, depression and the quality of life in women with PCOS and could be used as an adjunct method to the conventional management of these women.

Objective: 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., Design: Anthropometrical, metabolic and hormonal data were analyzed from 203 women with PCOS (NIH criteria) and 76 age-matched controls., Results: 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, p<0.001), total testosterone (r= 0.210, p<0.001), insulin (r=0.271, p<0.001), triglycerides (r=0.285, p<0.001), HOMA score (r=0.206, p=0.001), FAI (r=0.329, p<0.001) and negatively correlated with SHBG (r=-0.300, p<0.001) and HDL (r=-0.222, p<0.001). 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-IR>2: 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-IR >2)., Conclusions: 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.

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.

Background: Polycystic 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., Objective: To 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., Design: A cross-sectional study was carried out to evaluate the diverse impacts of aging on IR., Setting: An outpatient clinic was chosen for the study., Participants: A total of 1345 women with PCOS (Rotterdam criteria) and 302 controls of Caucasian origin and Greek ethnicity comprised the study group., Main Outcome and Measures: The impact of age on IR, as calculated using homeostasis model assessment of IR (HOMA-IR) index, and several PCOS characteristics were evaluated., Results: In PCOS, age (-0.045±0.008) was negatively, and BMI positively (0.18±0.007) associated with HOMA-IR (R(2)=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, P<0.001), which was neutralized in obese patients (r: -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 (P<0.001) and overweight (P: 0.004), but not obese, women (P: 0.202) across age quartiles., Conclusions: Aging 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., (© 2014 European Society of Endocrinology.)

Background: Visceral adiposity index (VAI) is a novel gender-specific index based on waist circumference (WC), BMI, and lipid parameters. Although VAI does not actually estimate visceral adiposity, it accurately reflects visceral fat function and insulin resistance. This index has not been studied in children thus far. This study aims to fill this gap., Methods: In a cohort of Saudi children and adolescents, anthropometric measurements and metabolic/hormonal profile were obtained., Results: A total of 543 subjects, 292 of whom were boys, were included (mean age: 11.9 ± 3.3 y; BMI: 19.8 ± 5.6 kg/m(2)). In all subjects, VAI was inferior to BMI and WC regarding its correlations with adiponectin, leptin, insulin resistance (homeostasis model of assessment-insulin resistance (HOMA-IR)), C-reactive protein (CRP) level, and systolic blood pressure, but it exhibited a stronger association with glucose in boys (r = 0.23; P < 0.01). In stepwise multivariate analyses, only BMI was consistent as an independent predictor of adiponectin, leptin, HOMA-IR, and CRP. VAI was the only index independently associated with glucose., Conclusion: Although VAI is related to glucose in children, it seems to be inferior to BMI in terms of association with insulin resistance, adipokines, and subclinical inflammation. Until specific studies can be performed in children, VAI should be extrapolated with caution in this age range.

Objective: To investigate the impact of dietary intervention on Advanced Glycation End products (AGEs) intake on the hormonal and metabolic profile in women with polycystic ovary syndrome (PCOS)., Methods: After baseline evaluation, 23 women with PCOS [mean ± SD, age: 23.4 ± 5.7 years; body mass index (BMI): 26 ± 5.7 kg/m2] underwent the following consecutive 2-month dietary regimens: a hypocaloric diet with ad-libitum AGEs content (Hypo), an isocaloric diet with high AGEs (HA) and an isocaloric diet with low AGEs (LA). Metabolic, hormonal and oxidative stress status was assessed and AGEs levels were determined in all subjects after the completion of each dietary intervention., Results: Serum levels of AGEs, testosterone, oxidative stress, insulin and HOMA-IR index were significantly increased on the HA compared to the Hypo diet and subsequently decreased on the LA diet (compared to HA) (p<0.05 for all parameters). BMI remained unaltered throughout the HA and LA periods compared to the Hypo period. Serum AGEs were strongly correlated with insulin, as well as with HOMA, during the LA dietary period (r=0.53, p=0.02 and r=0.51, p=0.03, respectively). For the same period, dietary AGEs were correlated with insulin levels (rho=0.49, p=0.04)., Conclusions: Modifications of dietary AGEs intake are associated with parallel changes in serum AGEs, metabolic, hormonal and oxidative stress biomarkers in women with PCOS. These novel findings support recommendations for a low AGEs dietary content along with lifestyle changes in women with PCOS.

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 conditions in vivo and 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: To study oxidative stress (OS) markers on neonates. The specific aim was to evaluate advanced glycation end products (AGEs) and advanced oxidation protein products (AOPPs) serum levels along with the hormonal/metabolic profile and their possible relationship in a cohort of polycystic ovary syndrome PCOS(N) and gestational diabetes GDM(N) neonates and their mothers PCOS(M) and GDM(M)., Design: Prospective controlled study., Setting: Academic medical center., Patient(s): The study population comprised 151 mother/neonate pairs., Intervention(s): Diet and/or insulin administration in GDM(M)., Main Outcome Measure(s): Anthropometric, metabolic, hormonal parameters, and OS markers., Result(s): The AGEs and AOPPs were higher in PCOS(M) and GDM(M) compared with controls (M). The same significant difference was observed in the corresponding groups of neonates. A strong relationship between mothers and neonates regarding AGEs (r = 0.605) and AOPPs levels (r = 0.735) was disclosed. Analogous findings were observed regarding androgens and insulin resistance in mothers and neonates, respectively., Conclusion(s): The present study demonstrated that in PCOS(N), the OS status was similar to that of GDM(N) and strongly associated with their mothers' oxidative status. These findings may have clinical implications, as exposure of PCOS(N) to high OS levels during pregnancy could affect several health issues of neonates., (Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Visceral Adiposity Index (VAI) is a gender-specific mathematical index estimated with the use of simple anthropometric (body mass index and waist circumference) and biochemical (triglycerides and high density lipoprotein cholesterol) parameters. Recent studies have shown that VAI reflects accurately the degree of visceral adiposity and insulin resistance. However, up to now, VAI has not been evaluated if it correlates with carbohydrate metabolism disorders, as well as with adipokine secretion from the fat mass., Methods: In a cohort of 308 out of 414 adult Saudi subjects screened for the study, detailed personal medical history, anthropometrics and metabolic/hormonal profiles were obtained. Additionally, the circulating concentrations of several circulating adipokines, namely adiponectin, leptin, tumour necrosis factor-α (TNF-α) and resistin, were measured., Results: Stepwise multivariate analysis showed that VAI was the sole determinant of adiponectin levels (R(2)  = 0·07, beta ± SE: -0·25 ± 0·05), while BMI and female gender predicted leptin levels (R(2)  = 0·26, 0·10 ± 0·01 and 0·61 ± 0·15, respectively). Furthermore, the presence of impaired fasting glucose (IFG)/diabetes was predicted only by age and VAI., Conclusions: We report for the first time the direct relations of VAI with adipose tissue secretion, as well as with functional glycaemic disorders. Because VAI is estimated easily with data obtained in everyday practice, it could be used as an indirect index of adiponectin levels and the risk of impaired glucose metabolism., (© 2012 The Authors. European Journal of Clinical Investigation © 2012 Stichting European Society for Clinical Investigation Journal Foundation.)

Endocrine complications due to haemosiderosis are present in a significant number of patients with beta-thalassemia major (BTM) worldwide and often become barriers in their desire for parenthood. Thus, although spontaneous fertility can occur, the majority of females with BTM is infertile due to hypogonadotropic hypogonadism (HH) and need assisted reproductive techniques. Infertility in these women seems to be attributed to iron deposition and iron-induced oxidative stress (OS) in various endocrine organs, such as hypothalamus, pituitary, and female reproductive system, but also through the iron effect on other organs, such as liver and pancreas, contributing to the impaired metabolism of hormones and serum antioxidants. Nevertheless, the gonadal function of these patients is usually intact and fertility is usually retrievable. Meanwhile, a significant prooxidants/antioxidants imbalance with subsequent increased (OS) exists in patients with BTM, which is mainly caused by tissue injury due to overproduction of free radicals by secondary iron overload, but also due to alteration in serum trace elements and antioxidant enzymes. Not only using the appropriate antioxidants, essential trace elements, and minerals, but also regulating the advanced glycation end products, could probably reduce the extent of oxidative damage and related complications and retrieve BTM women's infertility.

Polycystic ovary syndrome (PCOS) constitutes a continuum spectrum of symptoms starting from the early prepubertal years and continuing after menopause. The phenotypic expression varies through time, depending on several internal (e.g. ovarian/adrenal steroidogenesis, insulin resistance) and external factors (e.g. quality and quantity of food, exercise). Moreover, the emergence of new definitions with the use of ovarian morphology, besides chronic anovulation and hyperandrogenism, as diagnostic criteria, increased the phenotypic variety of PCOS presentation. In this review, the clinician is provided with useful information regarding grey zones in assessing anovulation, hyperandrogenism, ovarian morphology and the difficulties in differential diagnosis of PCOS. Furthermore, the lack of substantial data characterizing metabolic/hormonal profile and the potential cardiovascular risk in newer PCOS phenotypes, as well as the absence of longitudinal data questioning a possible shift from one phenotype to another are underlined. These notions indicate that despite the initial presentation of a patient with PCOS, close follow-up and therapeutic interventions aiming to reduce long-term cardiovascular risk are warranted., (Copyright © 2013 S. Karger AG, Basel.)