Eleni Kandaraki

Increased serum advanced glycation end-products is a distinct finding in lean women with polycystic ovary syndrome (PCOS).

Backgroundu2002 Nonenzymatic advanced glycation and oxidation end‐products, advanced glycation end‐products (AGEs), impart a potent impact on vessels and other tissues in diabetic state and in euglycaemic conditions with increased oxidative stress.

Accumulation of dietary glycotoxins in the reproductive system of normal female rats

The aim of the present study was to investigate whether dietary advanced glycation end-products (AGEs) can be detected in the ovarian tissue of normal female rats and whether they can affect their metabolic or hormonal profile. Sixty normal rats (20 animals in each group) were randomly assigned to regular diet, either high (H-AGE) or low (L-AGE) in AGE content for 6xa0months. H-AGE rats demonstrated higher levels of fasting glucose (Pu2009<u20090.001), insulin (Pu2009<u20090.069), and serum AGEs (Pu2009<u20090.001) than control and L-AGE rats. Additionally, the H-AGE group showed increased AGE localization in the theca interna cells of the ovarian tissue compared to control/L-AGE rats (Pu2009=u20090.003). Furthermore, increased receptor for AGE (RAGE) staining was also observed in granulosa cells compared to control/L-AGE samples (Pu2009=u20090.038). In the H-AGE group, plasma testosterone was higher than in control rats (Pu2009<u20090.001) and in the L-AGE group (Pu2009<u20090.001). However, H-AGE rats did not exhibit higher body weight compared with normal (Pu2009=u20090.118) and L-AGE-fed rats (Pu2009=u20090.35). These results demonstrate for the first time that administration of high AGE diet in female rats for a prolonged period is associated with increased deposition of AGEs in the theca cells and of RAGE in the granulosa and theca interna cells of the ovarian tissue compared with the corresponding ovarian compartments of the control and L-AGE-fed animals. The metabolic alterations in conjuction with the increased deposition in ovarian tissues of dietary glycotoxins and elevated levels of testosterone in H-AGE-fed animals compared to the controls suggest an impact of environmental factors on ovarian tissue and these findings need further exploration.

Defects in insulin signaling pathways in ovarian steroidogenesis and other tissues in polycystic ovary syndrome (PCOS)

The polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age today. Women with PCOS often demonstrate defective ovarian steroid biosynthesis and present with hyperandrogenemia. Moreover, 50-70% of PCOS women are insulin resistant and hyperinsulinemic. Insulin acts on the ovary via its own receptor and interacts with gonadotrophins, modulating steroidogenesis. The precise role of insulin and the molecular mechanisms that take place are not yet completely explicated. This review will be focused on insulins action on the ovary and other target tissues, describing the intracellular signaling pathways implicated in steroidogenesis and their defects in women with PCOS.

Phenotypic expression, body mass index and insulin resistance in relation to LH levels in women with polycystic ovary syndrome

OBJECTIVEnTo evaluate LH levels in women with the classic (1990 criteria) and the newer (2003 criteria) PCOS phenotypes, and to examine the impact of BMI and insulin resistance indices on hormone levels.nnnSTUDY DESIGNnIn this controlled clinical study 936 women with PCOS, classified as classic (n=729) and newer (n=207), and 204 controls were included. All women were divided into normal-weight (BMI<25 kg/m(2)) and overweight plus obese (BMI≥25 kg/m(2)). Serum LH, FSH, anthropometrics, androgens, fasting insulin and glucose, HoMA-IR, number of follicles, and ovarian volume were assessed.nnnRESULTSnWomen with classic PCOS presented significantly higher LH and LH/FSH ratios, and lower glucose/insulin levels than those with the newer phenotype and controls. Overweight plus obese women of all groups had lower LH levels than normal-weight women. Independent positive correlations between LH and androgens and negative correlation between LH and BMI were found.nnnCONCLUSIONSnThe higher LH concentrations of the classic phenotypes of PCOS could be attributed to the higher androgen levels, which desensitize the hypothalamus to the negative feedback regulation by progesterone. Moreover, the lower LH levels of overweight plus obese women of all groups could be attributed to the increased peripheral aromatization of androgens to estrogens in adipose tissue leading to suppression of LH secretion.nnnCONDENSATIONnBoth normal-weight and overweight women with classic PCOS phenotypes present higher LH levels and LH-to-FSH ratios than women with similar BMI but the newer phenotypes.

Dietary glycotoxins affect scavenger receptor expression and the hormonal profile of female rats

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 Alzheimers 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.

Peripheral targets in obesity treatment: a comprehensive update

Obesity is a major epidemic of our time and is associated with diseases such as metabolic syndrome, type 2 diabetes mellitus and atherosclerotic cardiovascular disease. Although weight loss drugs, when accompanied by diet and exercise, could be a very helpful medical tool in treating obese or overweight patients, their usefulness has been questioned due to the complexity of this type of medication, which regards a plethora of issues such as efficacy and safety of the drug and also risks and benefits among different patients. In general, obesity drugs that target peripheral pathophysiological mechanisms can be divided into two main categories. The first category includes anti‐obesity agents able to reduce or limit energy absorption, such as pancreatic lipase and microsomal triglyceride transfer protein inhibitors. The second category consists of a heterogeneous group of compounds aiming to decrease fat mass by increasing energy expenditure or by redistributing adipose tissue. Angiogenesis inhibitors, beta‐3 receptor agonists, sirtuin‐I activators, diazoxide and other molecules belong to this group. The glucagon‐like peptide‐1 receptor agonists consist the third category of peripheral anti‐obesity agents discussed therein.

The effect of pharmaceutical intervention on lipid profile in polycystic ovary syndrome.

The polycystic ovary syndrome (PCOS), a prevalent endocrinopathy of women, has been associated with a clustering of adverse metabolic features, which co‐exist with reproductive dysfunction. Lipid abnormalities are very common in lean as well as obese women with PCOS and should be cautiously considered in the therapeutic management of the syndrome. Clinicians should also critically assess the lipidemic effect of pharmaceutical intervention, primarily aimed at hyperandrogenism, anovulation or insulin resistance. Because dyslipidemia may contribute to long‐term cardiometabolic and reproductive sequelae in PCOS, it should be considered as an additional therapeutic target when these patients are assigned to appropriate pharmaceutical treatment.

Visceral adiposity index (VAI) is related to the severity of anovulation and other clinical features in women with polycystic ovary syndrome

The clinical phenotype of polycystic ovary syndrome (PCOS) includes reproductive and hormonal aberrations. Visceral adiposity index (VAI) is an indicator which could connect hyperandrogenism and anovulation. The objective was to evaluate the relationship between VAI, menstrual disorders and hormonal, biochemical and ultrasound parameters in women with PCOS.

MECHANISMS IN ENDOCRINOLOGY: Nutrition as a mediator of oxidative stress in metabolic and reproductive disorders in women.

Nutrition can generate oxidative stress and trigger a cascade of molecular events that can disrupt oxidative and hormonal balance. Nutrient ingestion promotes a major inflammatory and oxidative response at the cellular level in the postprandial state, altering the metabolic state of tissues. A domino of unfavorable metabolic changes is orchestrated in the main metabolic organs, including adipose tissue, skeletal muscle, liver and pancreas, where subclinical inflammation, endothelial dysfunction, mitochondrial deregulation and impaired insulin response and secretion take place. Simultaneously, in reproductive tissues, nutrition-induced oxidative stress can potentially violate delicate oxidative balance that is mandatory to secure normal reproductive function. Taken all the above into account, nutrition and its accompanying postprandial oxidative stress, in the unique context of female hormonal background, can potentially compromise normal metabolic and reproductive functions in women and may act as an active mediator of various metabolic and reproductive disorders.

Additive effects of dietary glycotoxins and androgen excess on the kidney of a female rat model

Abstract Background Dietary glycotoxins and androgen excess have been independently associated with a negative influence on the kidney. There are no data concerning the additive effects of these two factors on the kidney function and structure, in females. The present study aims to investigate the effect of dietary glycotoxins and androgen excess on the kidneys of an androgenized female rat model. Methods The study involved 80 female Wistar rats divided into 3 groups. The animals from group A were androgenized at 4 weeks of age (n = 30), rats of group B were androgenized at 12–20 weeks of age (n = 20) and group C consisted of non-androgenized animals (n = 30). All groups were further randomly assigned, either to a high-Advanced Glycation End product diet (HA diet) or low-AGE diet (LA diet), for 3 months. Results The rats fed with HA diet had significantly higher serum creatinine levels (p ⩽ 0.0002), when compared with those fed with LA diet. The androgenized group fed with HA diet exhibited higher levels of serum AGE (p = 0.0005), creatinine levels (p < 0.0001) and C-reactive protein (CRP) levels (p ⩽ 0.002), when compared with the non-androgenized group fed with HA diet. AGE immunoreactivity was higher on the renal tubules of the androgenized animals fed with HA diet, when compared with the animals fed with LA diet, but did not significantly differ among the two groups. Conclusions The above mentioned data suggest that dietary glycotoxins, in combination with increased androgen exposure, exert a more profound negative impact on the kidney of an androgenized female rat model that mimics the metabolic characteristics of polycystic ovary syndrome.