PCOS is a clinical heterogeneous entity of female androgen excess diagnosed by exclusion of other disorders responsible for androgen excess. The concept of secondary PCOS implies that there is a primary well-defined cause leading to the PCOS phenotype with underlying androgen overproduction, regardless of the origin. In these cases, we presume the term of ‘secondary PCOS’ could be used. In all these conditions, the potential complete recovery of the hyperandrogenemic state as well as the remission of the PCOS phenotype should follow the removal of the cause. If accepted, these concepts could help clinicians to perform in-depth investigations of the potential factors or disorders responsible for the development of these specific forms of secondary PCOS. Additionally, this could contribute to develop further research on factors and mechanisms involved in the development of the classic and the nonclassic PCOS phenotypes.
Renato Pasquali, Evanthia Diamanti-Kandarakis and Alessandra Gambineri
Evanthia Diamanti-Kandarakis, Olga Papalou, Eleni A Kandaraki and Georgia Kassi
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.
Sarantis Livadas, Anastasios Kollias, Dimitrios Panidis and Evanthia Diamanti-Kandarakis
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.
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.
A cross-sectional study was carried out to evaluate the diverse impacts of aging on IR.
An outpatient clinic was chosen for the study.
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.
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.
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.
Evanthia Diamanti-Kandarakis, Charikleia D Christakou, Eleni Kandaraki and Frangiskos N Economou
Polycystic ovary syndrome (PCOS) is now recognized to be the most common endocrinopathy in women of reproductive age with a prevalence of 6.6–6.8%. PCOS, a syndrome of unknown etiology, was initially regarded as a reproductive disorder. However, in the last 15 years the role of insulin resistance (IR) has been identified as a significant contributor to the pathogenesis of PCOS, and the metabolic and cardiovascular sequelae of the syndrome have been increasingly appreciated. The coexistence and interaction of reproductive and cardiometabolic abnormalities in the context of PCOS have created a need for a modified therapeutic management of affected women.
Insulin sensitizers, particularly metformin, have been introduced as a pharmaceutical option targeting not only IR, but several other aspects of the syndrome, including reproductive abnormalities. The landscape of the multifaceted actions of metformin evolves to broaden the therapeutic implications of this old drug in a new fashion for patients with PCOS. Most recently, the spectrum of metformin's targets has been expanded, and molecular studies have explored the tissue-specific mechanisms of metformin in the liver, the muscle, the endothelium, and the ovary. The use of metformin in pregnant women with PCOS comprises another scarcely explored, but promising area of research. This review attempts to cover the spectrum of metformin's cellular actions in different tissues and to summarize the current literature regarding the potential medical value of this medication in PCOS. Even if many of these actions are individually modest, they seem to be collectively sufficient to confer therapeutic benefits not only in cardiometabolic aspects but also in reproductive aspects of PCOS.
Evanthia Diamanti-Kandarakis, Sarantis Livadas, Stylianos A Kandarakis, Alexandra Margeli and Ioannis Papassotiriou
Neutrophil gelatinase-associated lipocalin (NGAL) and matrix metalloproteinase-9 (MMP-9) have been considered as important mediators of vascular remodeling and plaque instability. The formation of a complex with NGAL and MMP-9 is crucial for atherotic plaque erosion and thrombus formation. In women with polycystic ovary syndrome (PCOS), the incidence of cardiovascular clinical events is not increased, despite the fact that they display a wide spectrum of risk factors. Since the instability of atherosclerotic plaque is a key factor in the clinical manifestations of cardiovascular disease, molecules challenging the plaque stability should be investigated.
To determine serum levels of NGAL and MMP-9/NGAL complex in women with PCOS.
Subjects and methods
PCOS subjects (40) were compared with those (40) matched for age and body mass index (BMI) controls. In each subject, fasting levels of glucose, insulin, gonadotropins, estradiol, androgens, C-reactive protein, NGAL, and MMP-9/NGAL were determined.
NGAL and MMP-9/NGAL complex levels were significantly lower in the PCOS group compared with controls (30.4±24.3 vs 70.7±37.9 μg/l, P<0.0001) and (31.5±26.6 vs 115.1±66.9 μg/l, P<0.0001) respectively. When patients and controls were stratified according to BMI, it was shown that NGAL and MMP-9/NGAL levels were significantly lower in lean (P<0.0002 and P<0.0001 respectively) and overweight (P<0.0004 and P<0.002 respectively) PCOS subjects compared with controls.
These findings indicate that NGAL and MMP-9/NGAL complex, two molecules that activate atherotic plaque erosion, is in lower concentrations in PCOS subjects. The role of NGAL and MMP-9/NGAL complex needs to be further investigated, since suppression of these atheromatous molecules might have a protective role in women with PCOS.
Nicolas Galazis, Thalia Afxentiou, Mikalena Xenophontos, Evanthia Diamanti-Kandarakis and William Atiomo
Women with polycystic ovary syndrome (PCOS) are at increased risk of developing insulin resistance and type 2 diabetes mellitus (T2DM). In this study, we attempted to list the proteomic biomarkers of PCOS and T2DM that have been published in the literature so far. We identified eight common biomarkers that were differentially expressed in both women with PCOS and T2DM when compared with healthy controls. These include pyruvate kinase M1/M2, apolipoprotein A-I, albumin, peroxiredoxin 2, annexin A2, α-1-B-glycoprotein, flotillin-1 and haptoglobin. These biomarkers could help improve our understanding of the links between PCOS and T2DM and could be potentially used to identify subgroups of women with PCOS at increased risk of T2DM. More studies are required to further evaluate the role these biomarkers play in women with PCOS and T2DM.
Evanthia Diamanti-Kandarakis, Athanasia Piouka, Sarantis Livadas, Christine Piperi, Ilias Katsikis, Athanasios G Papavassiliou and Demetrios Panidis
Oocyte maturation process characterizes polycystic ovary syndrome (PCOS). The mechanisms of this abnormality leading to chronic anovulation are under investigation. Advanced glycosylated end products (AGEs), a marker of oxidative stress linked with oocyte maturation are localized in granulosa cells and are increased in sera, in women with PCOS. The aim of this study was to investigate the relationship, whether there is an association between the anti-mullerian hormone (AMH), a hormone produced by granulosa cells and AGEs in ovulatory and anovulatory PCOS (PCOS-Anov), as well as in non-PCOS anovulatory (Non-PCOS Anov) women.
Data from sixty women with PCOS (37 anovulatory and 23 regularly ovulating) were compared with eleven Non-PCOS Anov women and 25 normal women. In each subject biochemical, hormonal, and ultrasonographic parameters were studied.
AMH values were statistically significantly higher in PCOS-Anov (7.63±3.12) in comparison with ovulatory PCOS (PCOS-Ov; 4.92±2.50), Non-PCOS Anov (3.66±1.4), and controls (4.02±1.27 ng/ml). AGEs demonstrated a similar pattern: 8.70±1.65 in PCOS-Anov, 7.43±1.79, PCOS-Ov, 5.21±0.09, Non-PCOS Anov, and 5.85±0.89 U/ml in controls (P<0.005 for all comparison respectively). Follicle number was significantly higher in PCOS-Anov in comparison with other groups. A significant positive correlation between AMH and AGEs was observed (r: 0.326, P<0.01), and with the estimated AMH/AGEs ratio to follicle number (r: 0.42, P: 0.0001) and the presence of anovulation.
These data suggest that an oxidative marker, AGEs, and AMH, may interact in the anovulatory mechanisms in women with PCOS.
Gerard Conway, Didier Dewailly, Evanthia Diamanti-Kandarakis, Hector F Escobar-Morreale, Steven Franks, Alessandra Gambineri, Fahrettin Kelestimur, Djuro Macut, Dragan Micic, Renato Pasquali, Marija Pfeifer, Duarte Pignatelli, Michel Pugeat and Bulent O Yildiz
There is evidence for differences between endocrinologists and other specialists in their approach to diagnosis and management of the polycystic ovary syndrome (PCOS).
A mailed survey consisting of a simple questionnaire aiming to understand current practice for diagnosis and management of the PCOS by specialists across Europe.
The questionnaire consisted of 23 questions grouped to achieve information on i) the general characteristics of the respondents, ii) patients with PCOS seen by endocrinologists, iii) the main diagnostic criteria, iv) biochemical parameters used in the differential diagnosis of hyperandrogenism, v) long-term concerns, and, finally vi) treatment choices. A total of 357 questionnaires representing 13.3% of the members of European Society of Endocrinology (ESE) were available for final analysis; 93% of the respondents were endocrinologists
In relation to the diagnostic criteria, respondents were most likely to select menstrual irregularity as the most frequent criteria used for the diagnosis of PCOS although very high rates were achieved for the use of hirsutism and biochemical hyperandrogenism. It therefore appears that the NIH criteria were followed by the majority of respondents. The most frequent biochemical parameters in the differential diagnosis of hyperandrogenism were total testosterone or free androgen index. Obesity and type 2 diabetes were regarded as the principal long-term concerns for PCOS. The most common treatments for patients with PCOS were metformin (33%), lifestyle modification (25%), and oral contraceptives (22%). More direct treatments of infertility include clomiphene citrate alone or in combination with metformin, prescribed by 9 and 23%, respectively, whereas only 6% used other methods for induction of ovulation.
The survey produced by ESE is a good start for evaluating the perspective in the diagnosis and treatment of PCOS by endocrinologists in Europe.
Gerard Conway, Didier Dewailly, Evanthia Diamanti-Kandarakis, Héctor F Escobar-Morreale, Stephen Franks, Alessandra Gambineri, Fahrettin Kelestimur, Djuro Macut, Dragan Micic, Renato Pasquali, Marija Pfeifer, Duarte Pignatelli, Michel Pugeat and Bulent O Yildiz
Polycystic ovary syndrome (PCOS) is the most common ovarian disorder associated with androgen excess in women, which justifies the growing interest of endocrinologists. Great efforts have been made in the last 2 decades to define the syndrome. The presence of three different definitions for the diagnosis of PCOS reflects the phenotypic heterogeneity of the syndrome. Major criteria are required for the diagnosis, which in turn identifies different phenotypes according to the combination of different criteria. In addition, the relevant impact of metabolic issues, specifically insulin resistance and obesity, on the pathogenesis of PCOS, and the susceptibility to develop earlier than expected glucose intolerance states, including type 2 diabetes, has supported the notion that these aspects should be considered when defining the PCOS phenotype and planning potential therapeutic strategies in an affected subject. This paper offers a critical endocrine and European perspective on the debate on the definition of PCOS and summarises all major aspects related to aetiological factors, including early life events, potentially involved in the development of the disorder. Diagnostic tools of PCOS are also discussed, with emphasis on the laboratory evaluation of androgens and other potential biomarkers of ovarian and metabolic dysfunctions. We have also paid specific attention to the role of obesity, sleep disorders and neuropsychological aspects of PCOS and on the relevant pathogenetic aspects of cardiovascular risk factors. In addition, we have discussed how to target treatment choices based according to the phenotype and individual patient's needs. Finally, we have suggested potential areas of translational and clinical research for the future with specific emphasis on hormonal and metabolic aspects of PCOS.
Evanthia Diamanti-Kandarakis, Maurizio Dattilo, Djuro Macut, Leonidas Duntas, Efstathios S Gonos, Dimitrios G Goulis, Christina Kanaka Gantenbein, Marianna Kapetanou, Eftychia Koukkou, Irene Lambrinoudaki, Marina Michalaki, Shahla Eftekhari-Nader, Renato Pasquali, Melpomeni Peppa, Marinella Tzanela, Evangeline Vassilatou, Andromachi Vryonidou and COMBO ENDO TEAM: 2016
Aging and its underlying pathophysiological background has always attracted the attention of the scientific society. Defined as the gradual, time-dependent, heterogeneous decline of physiological functions, aging is orchestrated by a plethora of molecular mechanisms, which vividly interact to alter body homeostasis. The ability of an organism to adjust to these alterations, in conjunction with the dynamic effect of various environmental stimuli across lifespan, promotes longevity, frailty or disease. Endocrine function undergoes major changes during aging, as well. Specifically, alterations in hormonal networks and concomitant hormonal deficits/excess, augmented by poor sensitivity of tissues to their action, take place. As hypothalamic–pituitary unit is the central regulator of crucial body functions, these alterations can be translated in significant clinical sequelae that can impair the quality of life and promote frailty and disease. Delineating the hormonal signaling alterations that occur across lifespan and exploring possible remedial interventions could possibly help us improve the quality of life of the elderly and promote longevity.