Transcriptional regulation of endothelin-1 expression by advanced glycation end-products in human aortic endothelium is mediated via NF-kappaΒ and AP-1

Advanced Glycation End-products (AGEs) are produced by the non-enzymatic glycation of proteins, lipids and nucleic acids, resulting in an overload of highly reactive molecules of endogenous or exogenous (dietary) origin. Increased AGE levels in circulation and concomitant elevated tissue deposition have been associated with diabetic complications, atheromatosis, ageing and more recently with polycystic ovary syndrome pathogenesis. Interaction of AGEs with their receptor RAGE (Receptor for AGEs) activates intracellular signaling pathways which induce targeted gene expression in endothelium including upregulation of cell adhesion molecules and endothelin-1 (ET-1), implicated in vascular injury and endothelial dysfunction. The purpose of this study is to explore the molecular mechanism of AGE-induced regulation of ET-1 gene/protein expression in human endothelial cells and investigate its functional relevance in normal rat vascular endothelium

Insulin resistance in PCOS

Polycystic ovary syndrome (PCOS) is the commonest endocrinopathy affecting women of reproductive age, manifested with a variety of clinical signs, none of which is pathognomonic. The association of insulin resistance and reproductive abnormalities with clinical hyper-androgenism in a woman was first demonstrated by Achard and Thiers in the “diabetes of bearded woman.” The link of PCOS with insulin resistance was subsequently established by clinical studies characterizing the profound insulin resistance in obese and lean PCOS patients. Insulin resistance, hyperinsulinemia, and beta-cell dysfunction are very common in PCOS, but are not required for the diagnosis. The numerous in vivo and in vitro data supporting the central role of insulin resistance in the pathogenesis of PCOS found a broad clinical application in the management of the syndrome, where the regulation of cycle abnormalities and the facilitation of pregnancy in obese PCOS patients was assisted by co-administration of agents such as the well-known insulin sensitizers. The documentation of the presence of insulin resistance contributed substantially to unravel several metabolic components present in the syndrome. Today our knowledge about PCOS appears to have broader health implications and to have profoundly altered our view of the gravity of this condition

Insulin sensitizers targeting metabolic and reproductive consequences in polycystic ovary syndrome

The central importance of insulin resistance in the pathophysiology of polycystic ovary syndrome (PCOS) has been established by pioneering and elegant studies. In addition to the known hormonal and reproductive abnormalities that characterize this syndrome, metabolic disorders, as well as morbidities such as the enhanced risk for type 2 diabetes and increased risk for cardiovascular disease, have also been demonstrated. Current therapeutic approaches justifiably include insulin-sensitizing agents promising to comfort women with PCOS. Management with insulin sensitizers appears to embrace beneficially in a global fashion several aspects of the syndrome and target most of the associated metabolic and reproductive consequences

PCOS in adolescents

Polycystic ovary syndrome (PCOS), a heterogeneous syndrome of unknown aetiology, is the leading cause of anovulation, hirsutism and infertility in women. This multifactorial syndrome emerges at puberty and has cardiovascular and metabolic sequelae through menopause. The common features of normal puberty, namely menstrual irregularities and insulin resistance, obscure the diagnosis of adolescent PCOS, while there are no established diagnostic criteria for PCOS in this age group. The clinical implications of PCOS diagnosis in adolescents remain unclear. Experts in the field still ponder whether PCOS should be managed at such a young age with a view to hindering the long-term sequelae of the syndrome. (C) 2009 Elsevier Ltd. All rights reserved

Targets to treatmetabolic syndrome in polycystic ovary syndrome

Introduction: Metabolic syndrome is comprised of a combination of the following states: increased insulin resistance, dyslipidemia, cardiovascular disease, and increased abdominal obesity. Women with polycystic ovary syndrome (PCOS) have an increased risk of developing metabolic syndrome over the course of their lives. Metabolic syndrome increases risk of major cardiovascular events, morbidity, quality of life, and overall health care costs. Though metabolic syndrome in women with PCOS is an area of great concern, there is no effective individual medical therapeutic to adequately treat this issue. Areas Covered: This article will review key aspects of metabolic syndrome in PCOS. We will discuss classic and novel therapeutics to address metabolic syndrome in women with PCOS. We will conclude with the importance of developing strategic interventions to increase the compliance to lifestyle and dietary modification, in addition to appreciation of the emerging pharmaceutical therapeutics available. Expert Opinion: Innovation in lifestyle modification, including diet, exercise, with and without dedicated stress reduction techniques is the future in treatment of metabolic syndrome in PCOS. Application of novel interventions, such as group medical care, may improve future adherence to lifestyle modification recommendations, in addition to or in combination with pharmaceutical therapeutics

The role of genes and environment in the etiology of PCOS

Both genes and the environment contribute to PCOS. Obesity, exacerbated by poor dietary choices and physical inactivity, worsens PCOS in susceptible individuals. The role of other environmental modifiers such as infectious agents or toxins are speculative. Phenotype confusion has characterized genetic studies of PCOS. Although several loci have been proposed as PCOS genes including CYP11A, the insulin gene, the follistatin gene, and a region near the insulin receptor, the evidence supporting linkage is not overwhelming. The strongest case can be made for the region near the insulin receptor gene (but not involving this gene), as it has been identified in two separate studies, and perhaps most importantly has not yet been refuted by larger studies. However, the responsible gene at chromosome 19p13.3 remains to be identified. To date, no gene has been identified that causes or contributes substantially to the development of a PCOS phenotype

Aging ovary and the role for advanced glycation end products

Objective: The hypothalamic gonadotropin-releasing hormone pulse generator, the pituitary gonadotropes, the ovaries, and the uterus play a crucial role in female fertility. A decline in reproductive performance represents a complex interplay of actions at all levels of the hypothalamic-pituitary-ovarian axis. Recently, in the field of female reproductive aging attention is drawn to the carbonyl stress theory. Advanced glycation end products (AGEs) contribute directly to protein damage, induce a chain of oxidative stress (OS) reactions, and increase inflammatory reactions. Here, we highlight some of the mechanisms underlying glycation damage in the ovary. Methods: Searches of electronic databases were performed. Articles relevant to possible role of OS, AGEs, and receptor for AGE (RAGE) in aging ovary were summarized in this interpretive literature review. Results: Follicular microenvironment undergoes an increase in OS with aging. Data support the role of OS in ovulatory dysfunction because AGEs are well-recognized mediators of increased OS. RAGE and AGE-modified proteins with activated nuclear factor-kappa B are expressed in human ovarian tissue. It was suggested that accumulation of AGEs products at the level of the ovarian follicle might trigger early ovarian aging or could be responsible for reduced glucose uptake by granulosa cells, potentially altering follicular growth. Moreover, impaired methylglyoxal detoxification causing relevant damage to the ovarian proteome might be one of the mechanisms underlying reproductive aging. Conclusions: Further investigation of the role for the AGE-RAGE axis in the ovarian follicular environment is needed, and results could relate to assisted reproduction technology outcomes and new measures of ovarian reserve