Current Pharmaceutical Design - Volume 22, Issue 36, 2016

While the Rotterdam criteria look simple and easy to follow, in clinical practice diagnosis of PCOS may be problematic because of the use of inaccurate commercial androgen assays. Progresses in ovarian ultrasound and in AMH measurement have modified the way to make the diagnosis of PCOS and an update of Rotterdam criteria may be necessary. In classic severe form of PCOS, ovarian follicle count is a very reliable diagnostic criterion but AMH measurement may also present high diagnostic specificity and sensitivity. This finding is particularly important when no clinical signs of androgen excess are present and only commercial assays for androgen measurement are available. At the contrary, in mild PCOS phenotypes, sensitivity of AMH measurement is too low whileFNPO count maintains a high diagnostic sensitivity. However, at least in ovulatory hyperandrogenic PCOS phenotype, increased AMH values in association with enlarged ovarian size permit the diagnosis of ovulatory PCOS in 85% of these patients. Treatment of PCOS women has to be directed to get fertility or in patients not seeking fertility to solve or attenuate the psychological implications of androgen excess and of irregular menses and the risk of endometrial hyperplasia. The therapeutic protocols that are used in our department are presented.

Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine metabolic disorder and is presently considered a family pathology. It is associated with obesity, insulin resistance and metabolic syndrome. Racial, ethnic and environmental factors may be important in determining the clinical manifestations of this syndrome. Polycystic ovary syndrome is an exclusion diagnosis and, therefore, should be distinguished from the physiological changes typical for the age and from other hyperandrogenic disorders. Early diagnosis is important since this syndrome is associated with reproductive, oncologic and metabolic risks. Interestingly, the clinical features of this disorder may change throughout the lifespan of a PCOS woman, starting from adolescence to postmenopausal age. During the first decades of life the main features are in the reproductive area, while later in life metabolic abnormalities are more evident. While the assessment of insulin resistance is not part of the diagnosis of PCOS, it has been demonstrated that this metabolic component appears early in life and persists over time. Moreover during puberty and pregnancy, insulin resistance is exacerbated. Pregnancy represents an important stage, as the offspring of these patients may be reprogrammed and inherit some of the metabolic and reproductive features of their mothers. In the present review, we will focus on several metabolic aspects of the PCOS condition at different stages of life in a Chilean population.

Background: Insulin resistance and the associated compensatory hyperinsulinemia are common findings in women with PCOS, and may play a key role in this condition. Methods: In this article, we focused on the significance of insulin resistance in PCOS, reviewing the available literature on epidemiology, pathogenesis, pathophysiology and treatment of this condition. Results: It has been estimated that approximately 70% of these women are insulin resistant, but this figure is affected by frequent referral bias. In addition, there is metabolic heterogeneity between clinical phenotypes of PCOS. A fundamental issue is the role that hyperinsulinemia plays in androgen overproduction, which is enhanced by bidirectional links between insulin resistance and hyperandrogenism. Available data suggest that women with PCOS may have insulin action alterations of heterogeneous origins, which induce specific abnormalities in these subjects due to the presence of intrinsic defects. Obesity is a common finding in these patients and contributes to the association between PCOS and insulin resistance, combining with the effect of PCOS per se. Insulin sensitization shows several beneficial effects in the treatment of this condition. However, clinical response is heterogeneous. Conclusion: Insulin resistance is a common feature of women with PCOS, although it is not universal and differ between clinical phenotypes of PCOS. Insulin resistance and hyperandrogenism appear to be interrelated key factors in the pathogenesis of PCOS. We hypothesize that PCOS might represent a common end-stage clinical phenotype of different processes, in which there are impaired insulin action and hyperandrogenism, probably favoured by specific, intrinsic abnormalities of these women.

Background: Polycystic Ovary Syndrome (PCOS) is a complex heterogeneous disorder and the most common endocrinopathy amongst women of reproductive age. It is characterized by androgen excess, chronic anovulation and an altered cardiometabolic profile. PCOS is linked to impaired adipose tissue (AT) physiology and women with this disorder present with greater risk for insulin resistance (IR), hyperinsulinemia, central adiposity, nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) than matched for age and body mass index (BMI) women without PCOS. Hyperandrogenaemia appears to be driving adipocyte hypertrophy observed in PCOS under the influence of a hyperinsulinaemic state. Changes in the function of adipocytes have an impact on the secretion of adipokines, adipose tissue-derived proinflammatory factors promoting susceptibility to low grade inflammation. Methods: In this article, we review the existing knowledge on the interplay between hyperandrogenaemia, insulin resistance, impaired adipocyte biology, adipokines and chronic low-grade inflammation in PCOS. Results: In PCOS, more than one mechanisms have been suggested in the development of a chronic low-grade inflammation state with the most prevalent being that of a direct effect of the immune system on adipose tissue functions as previously reported in obese women without PCOS. Despite the lack of conclusive evidence regarding a direct mechanism linking hyperandrogenaemia to pro-inflammation in PCOS, there have been recent findings indicating that hyperandrogenaemia might be involved in chronic inflammation by exerting an effect on adipocytes morphology and attributes. Conclusion: Increasing evidence suggests that there is an important connection and interaction between proinflammatory pathways, hyperinsulinemia, androgen excess and adipose tissue hypertrophy and, dysfunction in PCOS. While lifestyle changes and individualized prescription of insulin-sensitizing drugs are common in managing PCOS, further studies are warranted to eventually identify an adipokine that could serve as an indirect marker of adipocyte dysfunction in PCOS, used as a reliable and pathognomic sign of metabolic alteration in this syndrome.

Background: The polycystic ovary syndrome (PCOS) is the commonest endocrine disorder in women of reproductive age and shows substantial phenotypic variability. According to the presence of the three diagnostic criteria of PCOS, i.e. oligo- and/or anovulation, hyperandrogenemia and/or clinical signs of high androgen levels, and polycystic ovaries, four different phenotypes of PCOS are identified. It appears that these phenotypes differ in the prevalence of several established and emerging cardiovascular risk factors. Methods: We searched the literature for studies that compared the cardiovascular risk profile of patients with the different phenotypes of PCOS. Results: Patients with both anovulation and hyperandrogenemia have more pronounced insulin resistance and higher levels of proinflammatory and prothrombotic mediators than patients with polycystic ovaries and either anovulation or hyperandrogenemia. Conclusion: Given that these differences appear to be mainly driven by the more pronounced obesity of the former patients, diet and exercise aiming at weight loss should constitute the cornerstone of management of PCOS and should be particularly emphasized in patients with the higher risk phenotypes of the syndrome.

Background: Polycystic ovary syndrome (PCOS) is a complex syndrome characterized by reproductive and metabolic implications. Lifestyle changes, such as diet and exercise, are considered first-line treatment for women affected by PCOS. Pharmacologic treatments target the hormonal and metabolic dysregulations associated to the disease such as insulin resistance, anovulation, hirsutism and menstrual irregularities. Objective: To focus on the role of inositol isoforms, as well as Mediterranean and ketogenic diets, as possible therapeutic strategies in PCOS women. Method: Narrative overview, synthesizing the findings of literature retrieved from searches of computerized databases. Results: Accumulating evidence suggests that two inositol isoforms, myo- and D-chiro-, may play a pivotal role in re-addressing both hormonal and metabolic parameters toward homeostasis, counteracting the symptoms and signs typical of this syndrome. In addition, studies focused on Mediterranean and ketogenic diet provided positive results in patients affected by obesity and type 2 diabetes, so these dietetic regimens could represent a fascinating dietetic treatment for the management of PCOS. Conclusion: Both the isoforms of inositol are effective in improving ovarian function and metabolism in patients with PCOS. In spite of accumulating evidence, it is currently not possible to draw firm conclusion(s) about the efficacy of these interventions considering the severe bias due to different samples size, dose, and duration of intervention among the published studies on this topic. Furthermore, future longitudinal cohort studies along with prospective interventional trials may contribute to better clarify the role of Mediterranean and ketogenic diets in the treatment of PCOS.

Advanced glycation end products (AGEs) are formed both during the endogenous and exogenous reactions and are implicated in the process of ageing, pathogenesis of diabetes, atherosclerosis, female fertility, and cancers. Food and smoking are the most important sources of exogenous AGEs in daily life. The biochemical composition of meal, cooking methods, time and temperature of food preparation may impact AGEs formation, therefore Western-type diet, rich in animal-derived products as well as in fast foods seems to be the main source of AGEs. Both, endogenous and exogenous AGEs can act intracellularly or during serum interaction with cell surface receptors called RAGE influencing variety of molecular pathways. Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age. The aetiology of this disorder remains unclear, however the environmental and genetic factors may play an important role in its pathogenesis. Nevertheless, PCOS women have increased factors for reproductive and cardiometabolic comorbidities. AGEs can contribute to the pathogenesis of PCOS as well as its consequences. It has been shown that chronic inflammation and increased oxidative stress may be a link between the mechanisms of AGEs action and the metabolic and reproductive consequences of PCOS. This review highlights that high dietary AGEs intake promotes deteriorating biological effects in women with PCOS, whereas AGEs restriction seems to have beneficial impact on women health. Better understanding AGEs formation and biochemistry as well as AGE-mediated pathophysiological mechanisms may open new therapeutic avenues converging to the achievement of the complete treatment of PCOS and its consequences.

Polycystic ovary syndrome (PCOS) is a common and complex endocrine disorder, often accompanied and complicated by insulin resistance, glucose intolerance and obesity. Gut, brain and metabolism are highly related with each other in obesity and diabetes as well as in PCOS. Central nervous system regulates food intake through complex interactions of homeostatic and hedonic systems while gastrointestinal system contributes to food intake and metabolism via orexigenic and anorexigenic gastrointestinal hormones. Ghrelin is the only circulating orexigenic hormone whereas anorexigenic peptides include glucagon like peptide-1 (GLP-1), gastric inhibitory peptide (GIP), peptide YY (PYY) and cholecystokinin (CCK). Compared to healthy women, patients with PCOS show decreased or unaltered fasting ghrelin levels, along with decreased or unaltered postprandial suppression of this hormone. GLP-1, PYY and CCK show unaltered or decreased levels both in fasting and postprandial states in PCOS whereas fasting levels of another gut hormone, GIP is either unaltered or increased. Dietary interventions associated with weight loss or short term oral contraceptive use in PCOS do not alter fasting or postprandial levels of these hormones. However use of metformin is associated with an increase in ghrelin, PYY, GLP-1 and GIP in women with PCOS. GLP-1 agonists and bariatric surgery, both having a significant impact on gut-brain axis, appear to be effective therapeutic options in obese women with PCOS. Finally, alterations in gut microbiota and possible interactions with gut-brain axis in PCOS is a topic of interest. Understanding the relationship between PCOS and homeostatic and hedonic systems, gastrointestinal hormones, and gut microbiota as well as potential effects of different therapeutic interventions on these systems will provide further understanding and novel treatment opportunities for this syndrome.

Background: The prevalence of adrenal hyperandrogenism (AH), as defined by increased circulating dehydroepiandrosterone-sulfate (DHEAS) levels, ranges from 15 to 45% in women with polycystic ovary syndrome (PCOS). Methods: The aim of this review is to update the pathogenesis and consequences of AH in PCOS, from molecular genetics to the clinical setting. Results: Mounting evidence derived from animal models suggests that genetically or enviromentally determined prenatal androgen excess, by influencing the hormonal and metabolic phenotype of susceptible female fetuses later in life, may be the capital event for the development of AH in PCOS. Because human placental aromatase activity is likely to prevent any deleterious effect of maternal hyperandrogenemia on the fetus, inheritance of the maternal steroidogenic defect is the more likely culprit, even though other factors such as changes in placental steroidogenesis itself or its nutritional efflux may also be involved in the building a deregulated enzymatic pathway from utero to adult life. Anyhow, the most important issue is whether or not AH influences the cardiometabolic risk of women with PCOS. On the one hand, AH has shown a controversial relationship with carbohydrate metabolism and adiposity, and is also associated with abnormalities in blood pressure regulation in these patients. On the other hand, DHEAS may exert a beneficial effect on the lipid profile of both lean and obese patients. Lastly, available studies in women with PCOS cast doubt upon a protective role of DHEAS levels on subclinical atherosclerosis, despite opposite data from the general population. Conclusion: AH is frequent in patients with PCOS yet unraveling its consequences for the management of this disorder requires future longitudinal studies.

Background: Hirsutism is defined as the presence of terminal hair with male distribution in women, and polycystic ovary syndrome (PCOS) is the most common etiology of hirsutism. Methods: The aim of this study is to review aspects of hair growth that are relevant for the understanding of hirsutism in PCOS, along with current treatment alternatives. Results: The prevalence of hirsutism in PCOS ranges from 70 to 80%, vs. 4% to 11% in women in the general population. Hirsutism in PCOS is associated with both ovarianderived androgen excess and individual sensitivity of the pilosebaceous unit to androgens. Interventions to decrease hirsutism in PCOS include the suppression of androgen excess by combined oral contraceptives (OCPs). If OCPs are contraindicated, mainly in the presence of insulin-resistance related comorbidities, a second-line option for reducing androgen secretion may be metformin associated with lifestyle changes. Other interventions should be guided by hirsutism severity, determined by the modified Ferriman-Gallwey score, and by the amount of distress hirsutism causes to the patient, and should be maintained for at least 6-12 months. Mild hirsutism is usually treated with a combination of non-pharmacological methods and OCPs, whereas moderate and severe hirsutism may require a combination of antiandrogens and OCPs, or, if OCPs cannot be used, antiandrogens plus a safe contraceptive method. In all cases, strong clinical support is crucial to ensure treatment adherence and success. Conclusion: The understanding of the pathophysiology of hirsutism in PCOS, as well as classifying its severity and the distress it causes to each patient is essential to choose the proper treatment. The presence of metabolic comorbidities and menstrual disturbances will also guide the individualized management of hirsutism in women with PCOS.

Background: Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine/ metabolic disorder characterized by hyperandrogenemia and in most cases, by hyperinsulinemia in addition to obesity. Besides ovarian dysfunction, endometrial physiology is also disrupted since this tissue is highly dependent on the action of steroids; in case of conception cycles, high percentage of abortion is observed. Because of the endocrine/metabolic alterations, PCOS-women present high probability to develop hyperplasia and endometrial cancer, where an imbalance of cell proliferation/apoptosis processes is detected. Additionally, insulin pathway and the endometrial energetic homeostasis are also compromised. Methods: The aim of this review was to report molecular alterations related to insulinresistance and/or obesity in PCOS-women endometria that could drive to infertility. For this, several methods were employed: immunohistocytochemistry, qPCR, western-blot, glucoseuptake, cell cultures, among others. Results: Diminished levels and activity of several insulin signaling pathway molecules, like IRS-1/AS160/PKCζ, were detected. Concomitantly, a defect in the synthesis and GLUT4 translocation to cell surface is induced. Oral administration of metformin (insulin sensitizer) to PCOS-patients increases GLUT4 endometrial levels, improving fertility of those patients. Another relevant feature is the high percentage of obesity in PCOS-women; adiponectin is an obesity marker and elicits an insulin-sensitizer action, being diminished in plasma of obese PCOSwomen similar to its endometrial level, adiponectin-receptors and APPL1, an adapter molecule of adiponectin pathway. Moreover, obesity and PCOS can induce a pro-inflammatory environment, exaggerating the alterations in insulin pathway. Conclusion: The evidences obtained in PCOS-endometria clearly indicate that these molecular defects could partially explain the reproductive failures of these patients.

Genetics-based studies of women with polycystic ovary syndrome (PCOS) implicate >20 PCOS risk genes that collectively account for <10% of PCOS. Clinicians now consider that either rare alleles or non-genetic, potentially epigenetic, developmental origins may contribute key pathogenic components to >90% of PCOS cases. Animal models convincingly demonstrate excess fetal testosterone exposure in females as a reliable, epigenetic, developmental origin for PCOS-like traits. In particular, nonhuman primates (NHPs) provide the most faithful emulation of PCOS-like pathophysiology, likely because of close similarities to humans in genomic, developmental, reproductive and metabolic characteristics, as well as aging. Recent appreciation of potential molecular mechanisms contributing to enhanced LH action in both PCOS women (GWAS-based) and PCOS-like monkeys (DNA methylation-based) suggest commonality in pathogenic origins. This review examines the translational relevance of NHP studies to PCOS, identifying characteristics of newborn females at risk for PCOS-like traits and potential prepubertal treatment interventions to ameliorate PCOS onset.

Ovarian cystic follicles are the sign of important causes of reproductive failure in numerous species. In this review, some morphological, endocrinological and clinical aspects of cystic follicles in women, cows, mares, sows and bitches are discussed. Follicular cysts are the consequence of the failure of a mature follicle to ovulate at the appointed time of ovulation in the estrous cycle. Although the etiology of follicular cysts remains unknown, this review examines the evidence about the role of endocrine signaling systems in the specific disease or syndrome in each of the species mentioned above. This review also describes, the changes in the pathways of endocrine mechanisms that would trigger disturbances in the intraovarian component underlying the aberrant persistence of follicular cysts. The knowledge of the morphological and endocrinological nature of cystic follicles in different species can provide relevant information to better understand specific diseases when it is integrally analyzed from the comparative medicine viewpoint.