The Interconnection between Hepatic Insulin Resistance and Metabolic Dysfunction-Associated Steatotic Liver Disease-The Transition from an Adipocentric to Liver-Centric Approach.

The central mechanism involved in the pathogenesis of MAFLD is insulin resistance with hyperinsulinemia, which stimulates triglyceride synthesis and accumulation in the liver. On the other side, triglyceride and free fatty acid accumulation in hepatocytes promotes insulin resistance via oxidative stress, endoplasmic reticulum stress, lipotoxicity, and the increased secretion of hepatokines. Cytokines and adipokines cause insulin resistance, thus promoting lipolysis in adipose tissue and ectopic fat deposition in the muscles and liver. Free fatty acids along with cytokines and adipokines contribute to insulin resistance in the liver via the activation of numerous signaling pathways. The secretion of hepatokines, hormone-like proteins, primarily by hepatocytes is disturbed and impairs signaling pathways, causing metabolic dysregulation in the liver. ER stress and unfolded protein response play significant roles in insulin resistance aggravation through the activation of apoptosis, inflammatory response, and insulin signaling impairment mediated via IRE1/PERK/ATF6 signaling pathways and the upregulation of SREBP 1c. Circadian rhythm derangement and biological clock desynchronization are related to metabolic disorders, insulin resistance, and NAFLD, suggesting clock genes as a potential target for new therapeutic strategies. This review aims to summarize the mechanisms of hepatic insulin resistance involved in NAFLD development and progression.

Effects of early life overnutrition and hyperandrogenism on spatial learning and memory in a rat model of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a complex disorder characterized by endocrine and metabolic abnormalities such as obesity and insulin resistance. PCOS is also associated with psychiatric disorders and cognitive impairment. The animal model of PCOS was induced by treating rats with 5α-dihydrotestosterone (5α-DHT) and additionally modified to induce adiposity by litter size reduction (LSR). Spatial learning and memory were assessed using the Barnes Maze test, and striatal markers of synaptic plasticity were analyzed. Striatal insulin signaling was estimated by the levels of insulin receptor substrate 1 (IRS1), its inhibitory phosphorylation at Ser307, and glycogen synthase kinase-3α/ß (GSK3α/ß) activity. Both LSR and DHT treatment significantly decreased striatal protein levels of IRS1, followed by increased GSK3α/ß activity in small litters. Results of the behavioral study showed that LSR had a negative effect on learning rate and memory retention, whereas DHT treatment did not induce impairment in memory formation. While protein levels of synaptophysin, GAP43, and postsynaptic density protein 95 (PSD-95) were not altered by the treatments, DHT treatment induced an increase in phosphorylation of PSD-95 at Ser295 in both normal and small litters. This study revealed that LSR and DHT treatment suppressed insulin signaling by downregulating IRS1 in the striatum. However, DHT treatment did not have an adverse effect on learning and memory, probably due to compensatory elevation in pPSD-95-Ser295, which had a positive effect on synaptic strength. This implies that hyperandrogenemia in this setting does not represent a threat to spatial learning and memory, opposite to the effect of overnutrition-related adiposity.

The role of transforming growth factor beta in thyroid autoimmunity: current knowledge and future perspectives.

The complex mechanisms, which are related to the pathophysiology and the development of autoimmune thyroid diseases, involve transforming growth factor beta (TGF-ß) and its interplay with the immune system. The aim of this review is to examine the role of TGF-ß regarding thyroid autoimmunity and explore the potent role of this molecule either as a diagnostic or prognostic marker or a therapeutic target regarding autoimmune thyroid diseases. TGF-ß is clearly a master regulator of the immune response, exerting either inhibitory or facilitatory effects on cells of the immune system. Thus, this molecule is involved in the pathogenesis and development of autoimmune thyroid diseases. Recent research has revealed the involvement of TGF-ß in the pathophysiology of autoimmune thyroid diseases. The role of TGF-ß in the development of autoimmune thyroid diseases varies, depending on its concentrations, the type of the activated TGF-ß signalling pathway, the genetic predisposition of the patient and the pathophysiologic stage of the disease. TGF-ß could emerge as a useful diagnostic or prognostic marker for the evolution of thyroid autoimmunity. Promising perspectives for the effective therapeutic use of TGF-ß regarding thyroid autoimmunity exist. The main treatment approaches incorporate either enhancement of the immunosuppressive role of TGF-ß or inhibition of its facilitatory role in the autoimmune thyroid diseases. Further research towards deeper understanding of TGF-ß physiology and clinical application of its possible therapeutic role regarding thyroid autoimmunity is needed.

Overweight and obesity in polycystic ovary syndrome: association with inflammation, oxidative stress and dyslipidaemia.

Polycystic ovary syndrome (PCOS) is associated with altered lipid profile and increased small, dense LDL particles (sdLDL). Considering that paraoxonase 1 (PON1) is an antioxidative enzyme located on HDL particles, the aim of this study was to investigate the connection between oxidative stress (OS) and PON1 activity with lipoprotein subclasses in PCOS depending on obesity. In 115 PCOS patients, lipoprotein subclasses distributions were determined by gradient gel electrophoresis. OS status was assessed by total oxidative status (TOS), advanced oxidation protein products, malondialdehyde (MDA), prooxidant-antioxidant balance (PAB), total antioxidative status (TAS) and superoxide dismutase (SOD) and PON1 activity. Overweight/obese PCOS patients (n 55) had increased OS compared with normal weight patients (n 60). In addition, overweight/obese group had lower HDL size and higher proportion of HDL 3a subclasses (P < 0·05). PAB was in negative correlation with HDL 2a (P < 0·001), whereas MDA and SOD correlated positively with HDL 3 subclasses (P < 0·05). Serum PON1 activity was positively associated with proportions of PON1 activity on HDL 2b (P < 0·05) and 2a (P < 0·01), but negatively with the proportion on HDL 3 particles (P < 0·01). LDL B phenotype patients had increased TAS, SOD and PON1 activity on HDL 2b, but decreased PON1 activity on HDL 3 subclasses. OS is associated with altered lipoprotein subclasses distribution in PCOS patients. Obesity in PCOS affects the profile of HDL subclasses, reflected through the reduced proportion of PON1 activity on HDL 3 subclasses in the presence of sdLDL particles.

AMPK Activation Is Important for the Preservation of Insulin Sensitivity in Visceral, but Not in Subcutaneous Adipose Tissue of Postnatally Overfed Rat Model of Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a well-known reproductive syndrome usually associated with obesity, insulin resistance, and hyperinsulinemia. Although the first signs of PCOS begin early in adolescence, it is underexplored whether peripubertal obesity predisposes women to PCOS metabolic disturbances. To highlight that, we examined the impact of postnatal overfeeding-induced obesity, achieved by litter size reduction during the suckling period, on metabolic disturbances associated with visceral and subcutaneous adipose tissue (VAT and SAT) function in the 5α-dihydrotestosterone (5α-DHT)-induced animal model of PCOS. We analyzed markers of insulin signaling, lipid metabolism, and energy sensing in the VAT and SAT. Our results showed that postnatally overfed DHT-treated Wistar rats had increased VAT mass with hypertrophic adipocytes, together with hyperinsulinemia and increased HOMA index. In the VAT of these animals, insulin signaling remained unchanged while lipogenic markers decreased, which was accompanied by increased AMPK activation. In the SAT of the same animals, markers of lipogenesis and lipolysis increased, while the activity of AMPK decreased. Taken together, obtained results showed that postnatal overfeeding predisposes development of PCOS systemic insulin resistance, most likely as a result of worsened metabolic function of SAT, while VAT preserved its tissue insulin sensitivity through increased activity of AMPK.

Unfavorable Hormonal and Psychologic Profile in Adult Women with a History of Premature Adrenarche and Pubarche, Compared to Women with Polycystic Ovary Syndrome.

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 <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 cm3). 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.

Health-related quality of life questionnaire for polycystic ovary syndrome (PCOSQ-50): a psychometric study with the Serbian version.

This study aimed to analyze the measurement properties of the Health-related quality of life questionnaire for polycystic ovary syndrome (PCOSQ-50) in a sample of Serbian women with polycystic ovary syndrome (PCOS). Seventy-six women with PCOS from an endocrinology clinic and 28 healthy women participated between October 2016 and March 2017. The measure was rigorously translated and culturally adapted into Serbian. Psychometric evaluation included descriptive analysis, internal consistency (Cronbach's alpha coefficient), test-retest reliability (intraclass-correlation coefficient - ICC) and construct validity testing. Cronbach's alpha coefficient ranged from 0.67 to 0.96 for domain scales of PCOSQ-50 scores, while the ICCs for test-retest reliability for these domains ranged from 0.66 to 0.89. Women with PCOS had significantly lower scores than healthy women for hirsutism, obesity and menstrual disorders and the total PCOSQ-50 scale score (p ≤ 0.03), but not for the psychosocial and emotional, fertility, sexual function, and coping scales. These results show that the Serbian PCOSQ-50 measure is acceptable and could produce reliable and valid assessments of PCOS-related quality of life for at least four out of seven domains. Considering that validity testing is an iterative process, additional work is needed before the whole measure is used in routine clinical practice.

Hyperhomocysteinemia induced by methionine dietary nutritional overload modulates acetylcholinesterase activity in the rat brain.

Methionine is the only endogenous precursor of homocysteine, sulfur-containing amino acid and well known as risk factor for various brain disorders. Acetylcholinesterase is a serine protease that rapidly hydrolyzes neurotransmitter acetylcholine. It is widely distributed in different brain regions. The aim of this study was to elucidate the effects of methionine nutritional overload on acetylcholinesterase activity in the rat brain. Males of Wistar rats were randomly divided into control and experimental group, fed from 30th to 60th postnatal day with standard or methionine-enriched diet (double content comparing to standard, 7.7 g/kg), respectively. On the 61st postnatal day, total homocysteine concentration was determined and showed that animals fed with methionine-enriched diet had significantly higher serum total homocysteine concentrations comparing to control rats (p < 0.01). Acetylcholinesterase activity has been determined spectrophotometrically in homogenates of the cerebral cortex, hippocampus, thalamus, and nc. caudatus. Acetylcholinesterase activity showed tendency to decrease in all examined brain structures in experimental comparing to control rats, while statistical significance of this reduction was achieved in the cerebral cortex (p < 0.05). Brain slices were stained with haematoxylin and eosin (H&E) and observed under light microscopy. Histological analysis of H&E-stained brain slices showed that there were no changes in the brain tissue of rats which were on methionine-enriched diet compared to control rats. Results of this study showed selective vulnerability of different brain regions on reduction of acetylcholinesterase activity induced by methionine-enriched diet and consecutive hyperhomocysteinemia.

Recurrent spontaneous abortions, Hashimoto thyroiditis and alopecia totalis: response to anticoagulation and intravenous immunoglobulin therapy.

INTRODUCTION: Although numerous studies indicated a link between antithyroid antibodies and recurrent spontaneous abortions (RSA), consensus on the treatment of this condition is still lacking. CASE REPORT: We present a case of a 35-year-old pregnant woman (gestation week 4) with primary hypothyroidism, total alopecia, high level of positive antithyroid antibodies, and history of two recurrent spontaneous abortions in early pregnancy. Along with L-thyroxin substitution, intravenous human immunoglobulin (IVIg) combined with anticoagulation and antiaggregation therapy was introduced. During pregnancy her scalp hair completely re-grew, and following gestation week 39 she delivered healthy female child. CONCLUSION: Thyroid antibodies could contribute to previous recurrent abortions in our patient. It is suggested that in older primiparas with Hashimoto thyroiditis and history of RSA, a combined treatment with IVIg, anticoagulation and antiaggregation therapy should be considered.

Environmental factors affecting female fertility.

INTRODUCTION: Over the recent years, scientific community has increased its interest on solving problems of female fertility pathology. Many factors acting separately or in combination affect significantly the reproductive life of a woman. This review summarizes current evidence regarding the direct and/or indirect action of environmental factors and endocrine disrupting chemicals (EDCs; i.e. heavy metals, plasticizers, parabens, industrial chemicals, pesticides, or medications, by-products, anti-bacterial agents, perfluorochemicals) upon assisted and non-assisted female fertility, extracted from in vivo and in vitro animal and human published data. Transgenerational effects which could have been caused epigenetically by the action of EDCs have been raised. METHODS: This narrative review englobes and describes data from in vitro and in vivo animal and human studies with regard to the action of environmental factors, which include EDCs, on female fertility following the questions for narrative reviews of the SANRA (a scale for the quality assessment of narrative review articles). The identification of the studies was done: through the PubMed Central and the PubMed of the MEDLINE, the Google Scholar database and the Cochrane Library database until December 2023 combining appropriate keywords ("specific environmental factors" including "EDCs" AND "specific negative fertility outcomes"); by manual scanning of references from selected articles and reviews focusing on these subjects. It includes references to EDCs-induced transgenerational effects. RESULTS: From the reported evidence emerge negative or positive associations between specific environmental factors or EDCs and infertility outcomes such as infertility indices, disrupted maturation of the oocytes, anovulation, deranged transportation of the embryo and failure of implantation. CONCLUSION: The revealed adverse outcomes related to female fertility could be attributed to exposure to specific environmental factors such as temperature, climate, radiation, air pollutants, nutrition, toxic substances and EDCs. The recognition of fertility hazards related to the environment will permit the limitation of exposure to them, will improve female fertility and protect the health potential of future generations.

Adipose-derived extracellular vesicles - a novel cross-talk mechanism in insulin resistance, non-alcoholic fatty liver disease, and polycystic ovary syndrome.

Obesity is the best described risk factor for the development of non-alcoholic fatty liver disease (NAFLD)/metabolic dysfunction associated steatotic liver disease (MASLD) and polycystic ovary syndrome (PCOS) while the major pathogenic mechanism linking these entities is insulin resistance (IR). IR is primarily caused by increased secretion of proinflammatory cytokines, adipokines, and lipids from visceral adipose tissue. Increased fatty acid mobilization results in ectopic fat deposition in the liver which causes endoplasmic reticulum stress, mitochondrial dysfunction, and oxidative stress resulting in increased cytokine production and subsequent inflammation. Similarly, IR with hyperinsulinemia cause hyperandrogenism, the hallmark of PCOS, and inflammation in the ovaries. Proinflammatory cytokines from both liver and ovaries aggravate IR thus providing a complex interaction between adipose tissue, liver, and ovaries in inducing metabolic abnormalities in obese subjects. Although many pathogenic mechanisms of IR, NAFLD/MASLD, and PCOS are known, there is still no effective therapy for these entities suggesting the need for further evaluation of their pathogenesis. Extracellular vesicles (EVs) represent a novel cross-talk mechanism between organs and include membrane-bound vesicles containing proteins, lipids, and nucleic acids that may change the phenotype and function of target cells. Adipose tissue releases EVs that promote IR, the development of all stages of NAFLD/MASLD and PCOS, while mesenchymal stem cell-derived AVs may alleviate metabolic abnormalities and may represent a novel therapeutic device in NAFLD/MASLD, and PCOS. The purpose of this review is to summarize the current knowledge on the role of adipose tissue-derived EVs in the pathogenesis of IR, NAFLD/MASLD, and PCOS.

Insulin-sensitizing agents for infertility treatment in woman with polycystic ovary syndrome: a narrative review of current clinical practice.

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.

EndoBridge 2023: highlights and pearls.

EndoBridge 2023 took place on October 20-22, 2023, in Antalya, Turkey. Accredited by the European Council, the 3-day scientific program of the 11th Annual Meeting of EndoBridge included state-of-the-art lectures and interactive small group discussion sessions incorporating interesting and challenging clinical cases led by globally recognized leaders in the field and was well attended by a highly diverse audience. Following its established format over the years, the program provided a comprehensive update across all aspects of endocrinology and metabolism, including topics in pituitary, thyroid, bone, and adrenal disorders, neuroendocrine tumors, diabetes mellitus, obesity, nutrition, and lipid disorders. As usual, the meeting was held in English with simultaneous translation into Russian, Arabic, and Turkish. The abstracts of clinical cases presented by the delegates during oral and poster sessions have been published in JCEM Case Reports. Herein, we provide a paper on highlights and pearls of the meeting sessions covering a wide range of subjects, from thyroid nodule stratification to secondary osteoporosis and from glycemic challenges in post-bariatric surgery to male hypogonadism. This report emphasizes the latest developments in the field, along with clinical approaches to common endocrine issues. The 12th annual meeting of EndoBridge will be held on October 17-20, 2024 in Antalya, Turkey.

Prevalence of metabolic syndrome in women with polycystic ovary syndrome.

OBJECTIVE: The polycystic ovary syndrome (PCOS) and the metabolic syndrome (MetS) are common disorders that share many characteristics, particularly abdominal obesity and insulin resistance. Our objective was to compare the prevalence of MetS between a large cohort of patients with PCOS and body mass index -matched controls. DESIGN: Cross-sectional study. PATIENTS: We studied 1223 patients with PCOS and 277 healthy women. Diagnosis of PCOS was based on the revised Rotterdam criteria. Women with PCOS were divided into those who fulfilled both the Rotterdam criteria and the diagnostic criteria of the 1990 National Institutes of Health definition of PCOS (group 1, n = 905) and into those with the additional phenotypes introduced by the Rotterdam criteria (group 2, n = 318). Diagnosis of MetS was based on four different definitions. MEASUREMENTS: Anthropometric, metabolic, hormonal and ultrasonographic features of PCOS. RESULTS: The prevalence of metabolic syndrome (MetS) was higher in women with PCOS than in controls when the National Cholesterol Education Program Adult Treatment Panel III definition of MetS was applied (15·8% and 10·1%, respectively; P = 0·021) but not with the three more recent MetS definitions. The prevalence of MetS was higher in group 1 than in controls regardless of the applied MetS definition. In contrast, the prevalence of MetS was similar in group 2 and in controls regardless of the applied MetS definition. In logistic regression analysis, PCOS did not predict the presence of MetS. CONCLUSIONS: Polycystic ovary syndrome per se does not appear to increase the risk of MetS independent of abdominal obesity.

Comparison of markers of insulin resistance and circulating androgens between women with polycystic ovary syndrome and women with metabolic syndrome.

STUDY QUESTION: Do women with the polycystic ovary syndrome (PCOS) differ from those with the metabolic syndrome (MetS) in markers of insulin resistance (IR) and circulating androgens? SUMMARY ANSWER: Women with MetS have more pronounced IR than those with PCOS whereas only the latter have elevated circulating androgens. WHAT IS KNOWN ALREADY: PCOS and MetS share many similarities, including abdominal obesity and IR, and PCOS is regarded as the ovarian manifestation of MetS. However, there are limited data on the differences between markers of IR and circulating androgens between women with these two syndromes. STUDY DESIGN, SIZE, DURATION: A prospective study in 1223 Caucasian women with PCOS and 277 women without PCOS, matched for BMI, was performed between May 2004 and December 2011. The presence/absence of MetS in PCOS+ and PCOS- women was recorded and comparisons among the resulting four groups were performed. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study was performed in a university department of obstetrics and gynecology. The following markers of IR were determined: serum glucose and insulin levels, glucose/insulin ratio, area under the oral glucose tolerance test, homeostasis model assessment of IR index and quantitative insulin sensitivity check index. MAIN RESULTS AND THE ROLE OF CHANCE: PCOS+MetS+ women (n = 361) were more insulin-resistant than PCOS+MetS- women (n = 862) (P < 0.001 for the comparisons in all markers of IR). Similarly, PCOS-MetS+ women (n = 66) were more insulin-resistant than PCOS-MetS- women (n = 211) (P < 0.001 for the comparisons in all markers of IR). In contrast, PCOS+MetS+ showed only borderline significant differences in some markers of IR compared with PCOS-MetS+ women (P < 0.05). Similarly, PCOS+MetS- women showed only borderline significant differences in some markers of IR compared with PCOS-MetS- women (P = 0.037). Moreover, PCOS-MetS+ women were more insulin-resistant than PCOS + MetS- women (P < 0.001 for the comparisons in all markers of IR). Regarding circulating androgens, PCOS+MetS+ women had higher levels of circulating androgens than PCOS-MetS+ women (P < 0.001 for the comparisons in all circulating androgens). Similarly, PCOS+MetS- women had higher levels of circulating androgens than PCOS-MetS- women (P < 0.001 for the comparisons in all circulating androgens). In contrast, circulating androgens did not differ between PCOS+MetS+ women and PCOS+MetS- women. Similarly, circulating androgens did not differ between PCOS-MetS+ women and PCOS-MetS- women. LIMITATIONS, REASONS FOR CAUTION: Only Caucasian women were included in the study. IR was not assessed with the euglycemic hyperinsulinemic clamp. WIDER IMPLICATIONS OF THE FINDINGS: Even though MetS and PCOS have many similarities, they are distinct disorders. PCOS does not appear to simply represent the ovarian manifestation of MetS. Further studies are required to assess the contribution of hyperandrogenism to the pathogenesis of IR in PCOS. STUDY FUNDING/COMPETING INTEREST(S): No external funding was either sought or obtained for this study.

Age- and body mass index-related differences in the prevalence of metabolic syndrome in women with polycystic ovary syndrome.

AIM: To compare the prevalence of metabolic syndrome (MetS) between women with polycystic ovary syndrome (PCOS) and controls across different age (≤20, 21-30 and 31-39 years old) and body mass index (BMI) (normal weight, overweight and obese) groups. METHODS: We studied 1223 women with PCOS and 277 BMI-matched controls. The prevalence of MetS in women with PCOS and controls was estimated according to four different MetS definitions. RESULTS: In subjects ≤20 and 21-30 years old, the prevalence of MetS did not differ between women with PCOS and controls regardless of the MetS definition, even though women with PCOS were more obese than controls in the ≤20 years old group. In subjects 31-39 years old, the prevalence of MetS was higher in women with PCOS than in controls but the former were more obese than controls. The prevalence of MetS did not differ significantly between women with PCOS and controls in any of the BMI groups (normal weight, overweight or obese) regardless of the MetS definition. CONCLUSION: The prevalence of Mets appears to be primarily determined by obesity and age whereas PCOS per se appears to be a less important contributing factor.

Environmental factors affecting pregnancy outcomes.

INTRODUCTION: Pregnancy represents a fragile period in the life of a woman, vulnerable to hazardous environmental substances which might affect maternal and fetal metabolism. The possible influence of environmental factors, including endocrine disrupting chemicals (EDCs), upon the mother and the fetus before and/or during pregnancy might be associated directly and/or indirectly to deleterious pregnancy outcomes. Because the existence of such associations would be, to our view, of major importance to the scientific community, their investigation is the scope of this critical review. METHODS: This critical review includes in vivo animal and human studies regarding the role of environmental factors, including EDCs, on pregnancy outcomes complying with the SANRA (a scale for the quality assessment of narrative review articles) questions for narrative reviews. Studies were identified by searching the MEDLINE (PubMed and PubMed Central), the Cochrane library and the Google Scholar databases till October 2022 with the combinations of the appropriate key words (detailed environmental factors including EDCs AND detailed negative pregnancy outcomes) as well as by scanning references from already included articles and relevant reviews manually. Because environmental factors and EDCs have been associated to epigenetic alterations, special care has been given to EDC-induced transgenerational effects on pregnancy outcomes. RESULTS: The existing evidence suggests positive associations between specific environmental factors and negative pregnancy outcomes such as ectopic pregnancies, pregnancy losses, gestational diabetes, hypertensive disorders of pregnancy, preterm births, birth defects, intrauterine growth restriction, and small or large for gestational age babies. CONCLUSION: Environmental factors and EDCs may have a catalytic effect on the course and the outcomes of pregnancy.

AMPK Activation as a Protective Mechanism to Restrain Oxidative Stress in the Insulin-Resistant State in Skeletal Muscle of Rat Model of PCOS Subjected to Postnatal Overfeeding.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy in women of reproductive age, often associated with obesity and insulin resistance. Childhood obesity is an important predisposing factor for the development of PCOS later in life. Being particularly interested in the interplay between prepubertal obesity and hyperandrogenemia, we investigated the effects of early postnatal overfeeding, accomplished by reducing litter size during the period of suckling, on energy sensing and insulin signaling pathways in the gastrocnemius muscle of a rat model of PCOS-induced by 5α-dihydrotestosterone (DHT). The combination of overfeeding and DHT treatment caused hyperinsulinemia and decreased systemic insulin sensitivity. Early postnatal overfeeding induced defects at critical nodes of the insulin signaling pathway in skeletal muscle, which was associated with reduced glucose uptake in the presence of hyperandrogenemia. In this setting, under a combination of overfeeding and DHT treatment, skeletal muscle switched to mitochondrial ß-oxidation of fatty acids, resulting in oxidative stress and inflammation that stimulated AMP-activated protein kinase (AMPK) activity and its downstream targets involved in mitochondrial biogenesis and antioxidant protection. Overall, a combination of overfeeding and hyperandrogenemia resulted in a prooxidative and insulin-resistant state in skeletal muscle. This was accompanied by the activation of AMPK, which could represent a potential therapeutic target in insulin-resistant PCOS patients.

Diagnostic and prognostic value of 99mTc-Tektrotyd scintigraphy and 18F-FDG PET/CT in a single-center cohort of neuroendocrine tumors.

Introduction: The aim was to assess the diagnostic value of 99mTc-Tektrotyd scintigraphy (TCT) and positron emission tomography/computed tomography using F-18 fluorodeoxyglucose (18F-FDG PET/CT) in the detection and follow-up of neuroendocrine tumors (NETs), and their predictive value for disease progression. Material and methods: In this retrospective cohort, TCT and 18F-FDG PET/CT were performed in 90 patients (37 men, 53 women, mean age 52.7 ±15.1), with NET. Correlation of Ki67 and tumor grade versus Krenning score and SUVmax was assessed, Kaplan-Meier analysis was used for progression-free survival (PFS), and Cox regression analysis was performed to identify the association between progression-related factors and PFS. Results: Out of 90, true positive TCT was detected in 56 (62.2%) patients, true negative in 19 (21.1%), false positive in 4 (4.4%), false negative in 11 (12.2%), while 18F-FDG PET/CT was true positive in 69 (76.7%) patients, true negative in 10 (11.1%), false positive in 5 (5.5%), false negative in 6 (6.7%). Mean 18F-FDG PET/CT SUVmax was 6.8 ±6.2. Diagnostic sensitivity of TCT was 83.6%, specificity 82.6%, accuracy 83.3% vs. 18F-FDG PET/CT sensitivity was 92.0%, specificity 66.7%, accuracy 87.8%. A significant correlation between Ki67 and SUVmax was found in positive 18F-FDG PET/CT findings, unlike the correlation between Ki67 and Krenning score. Median PFS was 25 months (95% CI: 18.2-31.8), in 18F-FDG PET/CT positive patients 23 months (95% CI: 16.3-29.7) and 18F-FDG PET/CT negative 26 months (p = 0.279). Progression-free survival predictors were SUVmax and Krenning score. Conclusions: In our study, TCT and 18F-FDG PET/CT have high diagnostic accuracy in detection of NET. Higher Krenning score on TCT and SUVmax in positive 18F-FDG PET/CT findings are predictors of disease progression. 99mTc-Tektrotyd scintigraphy and 18F-FDG PET/CT can be useful complementary tools in management of patients with NETs and in predicting patients' outcome.