Excess Metabolic and Cardiovascular Risk is not Manifested in all Phenotypes of Polycystic Ovary Syndrome: Implications for Diagnosis and Treatment.

AIM: To assess the potential differences in the metabolic and cardiovascular disease (CVD) risk between the distinct phenotypes of the Polycystic Ovary Syndrome (PCOS) according to the Rotterdam definition regardless of body mass index (BMI). PATIENTS-METHODS: The study included 300 women; 240 women with PCOS, according to the Rotterdam criteria and 60 controls without PCOS. All women were further subdivided, according to their BMI, into normal-weight and overweight/obese and PCOS women were furthermore subdivided to the 4 phenotypes of the syndrome. A complete hormonal and metabolic profile as well as the levels of high sensitivity C reactive protein (hsCRP) and lipoprotein-associated phospholipase A2 (Lp-PLA2) were measured. OUTCOMES: Levels of surrogate markers of subclinical atherosclerosis (hsCRP and Lp-PLA2), levels of evaluated CVD risk score using risk engines, and several correlations of CVD risk factors. RESULTS: hsCRP levels were higher but not significantly so in PCOS women compared with controls. In lean PCOS patients, Lp-PLA2 levels were significantly higher, compared with lean controls, mainly in the 2 classic phenotypes. Overweight/obese patients in all 4 phenotypes had significantly higher Lp-PLA2 levels compared with overweight/obese controls. Evaluated CVD risk according to 4 risk engines was not different among phenotypes and between PCOS patients and controls. There were several correlations of risk factors with metabolic syndrome and non-alcoholic fatty liver disease requiring appropriate treatment. CONCLUSION: Only 2 of 4 Rotterdam phenotypes, identical with those of the classic PCOS definition, have excess cardiometabolic risk. These need to be treated to prevent CVD events.

Increased frequency of the DI genotype of the angiotensin-I converting enzyme and association of the II genotype with insulin resistance in polycystic ovary syndrome.

OBJECTIVE: The polycystic ovary syndrome (PCOS) is a common and complex disease with unclear pattern of inheritance, characterized by an androgen excess, while hyperinsulinemia and insulin resistance (IR) are common features of the syndrome. The angiotensin I converting enzyme (ACE) insertion (I)/deletion (D) gene polymorphism was proved to be involved in many pathophysiological conditions, including hypertension and IR. DESIGN: The purpose of this study was to evaluate the involvement of the ACE gene polymorphism in the pathogenesis of PCOS. METHODS: In a case-control association study involving 801 PCOS women and 266 healthy controls, hormonal determinations and ACE polymorphism genotyping were performed. The PCOS women were classified into three groups: Group A presented biochemical hyperandrogenism, combined with anovulation and polycystic ovarian morphology; Group B, clinical hyperandrogenism combined with anovulation and polycystic ovarian morphology; and Group C, chronic anovulation and polycystic ovarian morphology. RESULTS: A significant increase in the frequency of the DI genotype of the ACE polymorphism was detected in PCOS women as a whole (P=0.035), in PCOS Group A (P=0.039) and Group B (P=0.010), while there was no difference in Group C (P=0.939). Significant difference was also observed in hyperandrogenic PCOS women as a whole (Group A+B) (P=0.017). The II genotype was positively correlated with HOMA-IR and QUICKI and with fasting insulin and glucose/insulin ratio in these groups. CONCLUSIONS: The association study of the ACE I/D polymorphism in PCOS women demonstrates an increase in the DI genotype incidence and an association of the II genotype with IR.

Serum anti-Müllerian hormone (AMH) levels are differentially modulated by both serum gonadotropins and not only by serum follicle stimulating hormone (FSH) levels.

It is generally accepted that serum AMH levels are thought to reflect the size of the ovarian follicle pool. Therefore, an inverse correlation between serum AMH and Follicle Stimulating Hormone (FSH) levels has been noted in older women with abnormal or exhausted follicular development, such as menopause, leading to the use of serum AMH as a marker of ovarian reserve. In clinical practice the use of serum AMH for the assessment of ovarian reserve has been expanding to women irrespective of age, such as women in early menopause or women undergoing ovarian stimulation for in vitro fertilization (IVF). To our knowledge, this opinion article aims to show that serum AMH levels are differentially modulated by both serum gonadotropins, depending on the degree of ovarian reserve. For instance, in conditions of increased LH and normal to low FSH such as young PCOS women with hyperandrogenemia, serum AMH levels are increased and tend to be associated to serum LH, while in conditions of increased FSH such as premature ovarian failure, serum AMH levels are decreased and tend to be associated to serum FSH. The evidence that supports the theory of a link between AMH and LH in PCOS comes from both in vitro and in vivo experiments. Serum AMH levels have been directly linked to serum LH levels in the most severe forms of PCOS. LH has also been shown in vitro to directly increase serum AMH levels in PCOS derived granulosa cells. Finally, hyperandrogenism, obesity, insulin resistance and OCs administration, indirectly affect serum AMH levels, by modulating serum LH. Concerning PCOS, the correlation between AMH and LH can be used in the future for the assessment of the severity of PCOS, of the amelioration of PCOS under OCs treatment, as well as of the efficacy of infertility treatment in clomiphene resistant PCOS women. Apart from PCOS, the clinical implications of this theoretical approach might become important in a variety of medical conditions. For instance, serum AMH levels might be used in the future as a marker of cysts formation in the ovaries as well as of ovarian endometriosis, or as a marker of ovarian response to treatment of ovarian cysts or ovarian endometriosis by oral contraceptives, etc. Additionally, in infertile women with hypothalamic amenorrhea, serum AMH levels might be used for the assessment of ovarian recovery under treatment.

The impact of oral contraceptives and metformin on anti-Müllerian hormone serum levels in women with polycystic ovary syndrome and biochemical hyperandrogenemia.

OBJECTIVE: To assess the impact of metformin and of two different oral contraceptives (OCs) containing cyproterone acetate and drospirenone, on serum anti-Müllerian hormone (AMH) levels, in a cohort of women with polycystic ovary syndrome (PCOS) with hyperandrogenism. DESIGN: Prospective randomised study. SETTING: Division of Endocrinology and Human Reproduction, Aristotle University of Thessaloniki. PATIENTS: Forty-five (45) women with PCOS diagnosed according to the criteria proposed in 1990 by the NIH. INTERVENTIONS: Women with PCOS were randomised into three groups, all treated for 6 months: Group A received an OC containing 35 µg ethinylestradiol plus 2 mg cyproterone acetate, Group B received an OC containing 30 µg ethinylestradiol plus 3 mg drospirenone and Group C received metformin 850 mg × 2. Main outcome measure(s). Anti-Müllerian hormone levels were measured by a specific ELISA. RESULTS: AMH was significantly decreased under treatment with 35 µg ethinylestradiol plus 2 mg cyproterone acetate (p = 0.002 at 3 months and p < 0.001 at 6 months). Treatment with 30 µg ethinylestradiol plus 3 mg drospirenone, and treatment with metformin 850 mg × 2 did not significantly affect serum AMH levels. AMH was significantly decreased under OCs treatment compared to metformin 850 mg × 2 (p = 0.005). CONCLUSION(S): AMH serum levels were significantly decreased under treatment with 35 µg ethinylestradiol plus 2 mg cyproterone acetate, due to decrease in androgens and suppression of gonadotropins.

Adiponectin levels reflect the different phenotypes of polycystic ovary syndrome: study in normal weight, normoinsulinemic patients.

Diagnosis of polycystic ovary syndrome (PCOS), at present very common in women of reproductive age, is implicated with potential long-term metabolic consequences that are difficult to be investigated due to the heterogeneity in the manifestation of the syndrome. The present study constitutes an effort to explore the graduated metabolic impact of the different PCOS phenotypic groups through the levels of adiponectin, an adipose-derived hormone, in 100 normal weight, normoinsulinemic patients with PCOS.

Anti-mullerian hormone is associated with advanced glycosylated end products in lean women with polycystic ovary syndrome.

OBJECTIVE: 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. Design Cross-sectional study. METHODS: 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. RESULTS: 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. CONCLUSIONS: These data suggest that an oxidative marker, AGEs, and AMH, may interact in the anovulatory mechanisms in women with PCOS.

Anti-Mullerian hormone levels reflect severity of PCOS but are negatively influenced by obesity: relationship with increased luteinizing hormone levels.

The objective of the study was the comparison of anti-Müllerian hormone (AMH) levels among obese or overweight and normal-weight women with the four different polycystic ovary syndrome (PCOS) phenotypes and healthy control subjects. AMH levels were evaluated in four age- and body mass index (BMI)-matched groups of 25 normal-weight and 25 obese or overweight women each, belonging to the four main subsets of the syndrome resulting from combinations of the three diagnostic criteria [group 1: oligo- and/or anovulation (ANOV), hyperandrogenemia (HA), and polycystic ovaries (PCO) on ultrasonographic evaluation; group 2: ANOV and HA; group 3: HA and PCO, group 4: ANOV and PCO], and in 50 (25 obese or overweight and 25 normal weight) age- and BMI-matched healthy control subjects. Age, BMI, waist circumference, FSH, LH, prolactin, testosterone, Delta(4)-androstenedione, dehydroepiandrosterone-sulfate, 17alpha-OH-progesterone, fasting insulin, glucose, AMH, free androgen index, and homeostasis model assessment for insulin resistance index were analyzed. AMH levels were significantly higher in PCOS groups 1 and 2 compared with groups 3 and 4 and the control group and higher in PCOS groups 3 and 4 compared with the control group. AMH levels were significantly increased in normal-weight compared with obese and overweight women. AMH concentrations were independently predicted, in order of significance, by LH and testosterone levels, BMI (negatively), and the total number of follicles 2-9 mm in diameter. The differences in circulating AMH levels between the main phenotypic groups of PCOS women appear to reflect the severity of the syndrome, but are negatively affected by obesity. Increased LH levels might be the most significant independent link between PCOS-associated disorders of ovulation and the observed increase in circulating AMH concentration.

Plasma visfatin levels in normal weight women with polycystic ovary syndrome.

BACKGROUND: The present study was designed to measure plasma visfatin levels in normal weight women with polycystic ovary syndrome (PCOS) and to assess possible correlations between visfatin and the hormonal or metabolic parameters of the syndrome. METHODS: Twenty-five normal weight [body mass index (BMI)<25 kg/m(2)] women with PCOS, 24 obese and overweight (BMI>25 kg/m(2)) controls (ovulating women without clinical or biochemical hyperandrogenism), and 24 normal weight controls were studied. Blood samples were collected between the 3rd and the 7th days of a menstrual cycle in the control groups and during a spontaneous bleeding episode in the PCOS groups at 9:00 A.M., after an overnight fast. Circulating levels of LH, FSH, prolactin (PRL), testosterone (T), Delta(4)-androstenedione (Delta(4)-Alpha), dehydroepiandrosterone sulfate (DHEA-S), 17alpha-OH-progesterone (17OH-P), sex hormone-binding globulin (SHBG), insulin, glucose, and visfatin were measured. RESULTS: Plasma visfatin levels and the visfatin-to-insulin ratio were significantly lower in normal weight controls than in both normal weight women with PCOS and overweight or obese controls. The visfatin-to-insulin ratio was significantly higher in normal weight women with PCOS than in overweight or obese controls. Plasma visfatin levels were found to be positively correlated with LH and Delta(4)A levels, as well as with free androgen index (FAI) values, and negatively correlated with SHBG. LH and SHBG levels were found to be the only independent significant determinants of circulating visfatin. In the control groups, plasma visfatin levels were significantly correlated with BMI, waist (W) measurement, and waist-to-hip ratio (WHR). CONCLUSIONS: Visfatin levels are positively associated with obesity in healthy women of reproductive age. Moreover, the present study indicates, for the first time, a possible involvement of increased visfatin levels in PCOS-associated metabolic and hormonal disturbances.

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

BACKGROUND: 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. Insulin resistant (IR) polycystic ovary syndrome (PCOS) women, have elevated serum AGEs, increased receptor (RAGE) expression, and increased deposition with differential localization in the polycystic ovarian tissue (theca and granulosa) compared to normal. OBJECTIVE: To determine whether the raised AGE levels in noninsulin resistant women with PCOS is a distinct finding compared with those presenting the isolated components of the syndrome and among PCOS subphenotypes. Noninsulin resistant women were selected in order to show that serum AGEs are elevated in PCOS independently of the presence of IR. DESIGN: Clinical trial. PATIENTS: One hundred and ninety-three age- and BMI-matched young lean noninsulin resistant women were studied. Among them, 100 women were diagnosed with PCOS according to Rotterdam criteria, and divided to subphenotypes (hyperandrogenaemia with or without PCO morphology and with or without anovulation). Sixty-eight women with the isolated components of the PCOS phenotype were also studied along with 25 healthy women. MEASUREMENTS: Serum AGE levels, metabolic, hormonal profiles and intravaginal ultrasound were determined in all subjects. RESULTS: The studied population did not differ in BMI, fasting insulin concentration, waist : hip and glucose : insulin ratios. PCOS women exhibited statistically higher AGEs levels (7.96 +/- 1.87 U/ml, P < 0.001) compared with those with isolated hyperandrogenaemia (5.61 +/- 0.61 U/ml), anovulation (5.53 +/- 1.06 U/ml), US-PCO morphology (5.26 +/- 0.25 U/ml) and controls (5.86 +/- 0.89 U/ml). CONCLUSIONS: In PCOS, serum AGEs are distinctly elevated compared with women having the isolated characteristics of the syndrome. No difference was observed between PCOS subphenotypes. As chronic inflammation and increased oxidant stress have been incriminated in the pathophysiology of PCOS, the role of AGEs as inflammatory and oxidant mediators, may be linked with the metabolic and reproductive abnormalities of the syndrome.