Alessandra Gambineri

Obesity and the polycystic ovary syndrome

The polycystic ovary syndrome (PCOS) is a condition characterized by hyperandrogenism and chronic oligo-anovulation. However, many features of the metabolic syndrome are inconsistently present in the majority of women with PCOS. Approximately 50% of PCOS women are overweight or obese and most of them have the abdominal phenotype. Obesity may play a pathogenetic role in the development of the syndrome in susceptible individuals. In fact, insulin possesses true gonadotrophic function and an increased insulin availability at the level of ovarian tissue may favour excess androgen synthesis. Obesity, particularly the abdominal phenotype, may be partly responsible for insulin resistance and associated hyperinsulinemia in women with PCOS. Therefore, obesity-related hyperinsulinemia may play a key role in favouring hyperandrogenism in these women. Other factors such as increased estrogen production rate, increased activity of the opioid system and of the hypothalamic-pituitary-adrenal axis, decreased sex hormone binding globulin synthesis and, possibly, high dietary lipid intake, may be additional mechanisms by which obesity favours the development of hyperandrogenism in PCOS. Irrespective of the pathogenetic mechanism involved, obese PCOS women have more severe hyperandrogenism and related clinical features (such as hirsutism, menstrual abnormalities and anovulation) than normal-weight PCOS women. This picture tends to be more pronounced in obese PCOS women with the abdominal phenotype.Body weight loss is associated with beneficial effects on hormones, metabolism and clinical features. A further clinical and endocrinological improvement can also be achieved by adding insulin-sensitizing agents and/or antiandrogens to weight reduction programmes. These obviously emphasize the role of obesity in the pathophysiology of PCOS.

Obesity and infertility

Purpose of reviewTo summarize major factors affecting fertility in obesity. Recent findings Fertility can be negatively affected by obesity. In women, early onset of obesity favours the development of menses irregularities, chronic oligo-anovulation and infertility in the adult age. Obesity in women can also increase risk of miscarriages and impair the outcomes of assisted reproductive technologies and pregnancy, when the body mass index exceeds 30 kg/m2. The main factors implicated in the association may be insulin excess and insulin resistance. These adverse effects of obesity are specifically evident in polycystic ovary syndrome. In men, obesity is associated with low testosterone levels. In massively obese individuals, reduced spermatogenesis associated with severe hypotestosteronemia may favour infertility. Moreover, the frequency of erectile dysfunction increases with increasing body mass index. SummaryMuch more attention should be paid to the impact of obesity on fertility in both women and men. This appears to be particularly important for women before assisted reproductive technologies are used. Treatment of obesity may improve androgen imbalance and erectile dysfunction, the major causes of infertility in obese men.

Epidemiology, diagnosis and management of hirsutism: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome Society

BACKGROUND Hirsutism, defined by the presence of excessive terminal hair in androgen-sensitive areas of the female body, is one of the most common disorders in women during reproductive age. METHODS We conducted a systematic review and critical assessment of the available evidence pertaining to the epidemiology, pathophysiology, diagnosis and management of hirsutism. RESULTS The prevalence of hirsutism is ~10% in most populations, with the important exception of Far-East Asian women who present hirsutism less frequently. Although usually caused by relatively benign functional conditions, with the polycystic ovary syndrome leading the list of the most frequent etiologies, hirsutism may be the presenting symptom of a life-threatening tumor requiring immediate intervention. CONCLUSIONS Following evidence-based diagnostic and treatment strategies that address not only the amelioration of hirsutism but also the treatment of the underlying etiology is essential for the proper management of affected women, especially considering that hirsutism is, in most cases, a chronic disorder needing long-term follow-up. Accordingly, we provide evidence-based guidelines for the etiological diagnosis and for the management of this frequent medical complaint.

The polycystic ovary syndrome: a position statement from the European Society of Endocrinology.

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 patients 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.

The natural history of the metabolic syndrome in young women with the polycystic ovary syndrome and the effect of long‐term oestrogen–progestagen treatment

Little is known about the natural history of polycystic ovary syndrome (PCOS), although preliminary data indicate that affected women are more susceptible than the general population to diabetes and cardiovascular diseases at post‐menopausal ages. The aim of this study was to follow‐up all main features of the metabolic syndrome in a group of young women with PCOS and to investigate the long‐term effects on metabolism and body composition of oestrogen–progestagen (OP) compounds, which are frequently used in these women to treat hyperandrogenism and related clinical features.

The role of low-grade inflammation in the polycystic ovary syndrome

PCOS is not only the most frequent cause of oligomenorrhea in young women, but also a metabolic disorder characterized by insulin resistance, glucose intolerance, dyslipidemia, and obesity, especially the visceral phenotype. PCOS represents a broad spectrum of endocrine and metabolic alterations which change with age and with increasing adiposity. In fact, during adolescence and youth the predominant clinical manifestations of PCOS are menstrual abnormalities, hirsutism and acne, whereas in peri-menopausal and post-menopausal periods metabolic disorders and an increased risk for cardiovascular diseases prevail. The pathogenetic links between PCOS and metabolic or cardiovascular complications are still debated. However, recent evidence has been focused on a condition of low-grade chronic inflammation as a potential cause of the long-term consequence of the syndrome. In this review we describe the state of low-grade inflammation observed in PCOS. In addition, we hypothesize the potential mechanisms responsible for the generation of this inflammatory state and the role played by low-grade inflammation in linking hyperandrogenism and insulin resistance with the metabolic and cardiovascular long-term complications of the syndrome.

Serum steroid profiling by isotopic dilution-liquid chromatography–mass spectrometry: Comparison with current immunoassays and reference intervals in healthy adults

BACKGROUND The simultaneous, rapid and reliable measurement of a wide steroid panel is a powerful tool to unravel physiological and pathological hormone status. Clinical laboratories are currently dominated by high-throughput immunoassays, but these methods lack specificity due to cross-reactivity and matrix interferences. We developed and validated an isotopic dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS) method for the simultaneous measurement of cortisol, corticosterone, 11deoxycortisol, androstenedione, deoxycorticosterone (DOC), testosterone, 17OHprogesterone, dehydroepiandrosterone (DHEA) and progesterone in serum, and compared it to routine immunoassays employed in our laboratory. We also established adult reference intervals in 416 healthy subjects. METHODS 0.9 ml of serum were spiked with labelled internal standards (IS) and extracted on C18 cartridges. Eluate was injected into a two-dimensional LC-system, purified in a perfusion column and separated on a C8 column during a 21 min gradient run. Analytes were revealed by atmospheric pressure chemical ionization (APCI) followed by multiple reaction monitoring (MRM) analysis. RESULTS Of the four immunoassays compared with the ID-LC-MS/MS method, only the results of ElecsysE170 for cortisol, testosterone in males and progesterone>1 ng/ml were in agreement with ID-LC-MS/MS. ElecsysE170 for testosterone in females and progesterone<1 ng/ml, Immulite2000 for androstenedione, DSL-9000 for DHEA and 17OHP Bridge for 17OHprogesterone, respectively, showed poor agreement. Reference intervals and steroid age and fertility related fluctuations were established. CONCLUSION Our ID-LC-MS/MS method proved to be reliable and sensitive in revealing steroid circulating concentrations in adults and in highlighting the limits of routine immunoassays at low concentrations.

Metabolic effects of obesity on reproduction

Obese women are characterized by similar comorbidities to men, particularly type 2 diabetes mellitus and cardiovascular diseases. Moreover, they also develop some specific problems, including fertility-related disorders and some hormone-dependent forms of cancer. The relationship between excess body fat and reproductive disturbances appears to be stronger for early-onset obesity. Early onset of obesity, particularly during adolescence, favours the development of menses irregularities, chronic oligo-anovulation and infertility in adulthood. Moreover, obesity in women can increase the risk of miscarriage and impair the outcome of assisted reproductive technologies. The main factor implicated in the association between obesity and fertility-related disorders is insulin excess, which accompanies insulin resistance. Hyperinsulinaemia may be directly responsible for the development of androgen excess, through its effects in reducing sex hormone-binding globulin synthesis and circulating concentrations, and in stimulating ovarian androgen production rates. Androgen excess, in turn, represents one of the major factors leading to altered ovarian physiology and associated ovulatory disturbances. Obesity-associated hyperleptinaemia may represent an additional factor involved in anovulation, not only through the induction of insulin resistance, but also through a direct impairment of ovarian function.

Polycystic Ovary Syndrome

Abstract:  Polycystic ovary syndrome (PCOS), one of the most common causes of ovulatory infertility, affects 4–7% of women. Although it was considered that PCOS may have some genetic component and that clinical features of this disorder may change throughout a life span, starting from adolescence to postmenopausal age, no effort has been made to define differences in the phenotype and clinical presentation according to age. Indeed, it has been widely recognized in the last decade that several features of metabolic syndrome (MS), particularly insulin resistance and hyperinsulinemia, are inconsistently present in the majority of women with PCOS. This represents an important factor in the evaluation of PCOS throughout life, which implies that PCOS by itself may not be a hyperandrogenic disorder exclusively related to young and fertile‐aged women, but may also have some health implications later in life. In young women with PCOS, hyperandrogenism, menses irregularities, and insulin resistance may occur together, emphasizing the pathophysiological role of excess androgen and insulin on PCOS. Hyperandrogenism and infertility represent the major complaints of PCOS in adult fertile age. In addition, obesity and MS may affect more than half these women. Later in life, it becomes clear that the association of obesity (particularly the abdominal phenotype) and PCOS renders affected women more susceptible to develop type 2 diabetes mellitus (T2DM), with some difference in the prevalence rates among countries, suggesting that environmental factors are important in determining individual susceptibility. Little is known about ovarian morphology and androgen production in women with PCOS after menopause. Some studies found that morphological ultrasonographic features consistent with polycystic ovaries are very common in postmenopausal women, and that these features are associated with higher than normal testosterone levels and metabolic alterations. There is an obvious need for further research in this area. Identification of major complaints and features of PCOS during the different ages of an affected woman may help, in fact, to plan individual therapeutic strategies, and, possibly, prevent long‐term chronic metabolic diseases.

Polycystic Ovary Syndrome Is a Risk Factor for Type 2 Diabetes: Results From a Long-Term Prospective Study

Polycystic ovary syndrome (PCOS) recently has been identified as a risk factor associated with type 2 diabetes. However, the evidence derives from cross-sectional observational studies, retrospective studies, or short-term prospective studies. This long-term prospective study of a large cohort of women with PCOS, followed from youth to middle age, aimed at estimating, for the first time, the incidence and potential predictors of type 2 diabetes in this population. A total of 255 women with PCOS were followed for at least 10 years (mean follow-up 16.9 years). Six women were patients with diabetes at baseline, and another 42 women developed type 2 diabetes during the follow-up. The incidence rate of type 2 diabetes in the study population was 1.05 per 100 person-years. The age-standardized prevalence of diabetes at the end of follow-up was 39.3%, which is significantly higher with respect to that of the general Italian female population of a similar age (5.8%). The likelihood of developing type 2 diabetes significantly increased as BMI, fasting glucose, and glucose area under the curve at baseline increased and significantly decreased as sex hormone–binding globulin (SHBG) levels at follow-up increased. This study demonstrates that the risk of type 2 diabetes is markedly elevated in middle-aged women with PCOS and suggests including BMI, glucose, and SHBG-circulating levels in the risk stratification.