Polycystic Ovary Syndrome Subgroups Research Articles

A molecular mechanism underlying ovarian dysfunction of polycystic ovary syndrome: hyperandrogenism induces epigenetic alterations in the granulosa cells

The objective of this study was to explore whether hyperandrogenism induces epigenetic alterations of peroxisome proliferator-activated receptor gamma 1 (PPARG1), nuclear corepressor 1 (NCOR1), and histone deacetylase 3 (HDAC3) genes in granulosa cells (GCs) of polycystic ovary syndrome (PCOS) women and whether these alterations are involved in the ovarian dysfunction induced by hyperandrogenism. Thirty-two infertile PCOS women and 147 infertile women with tubal blockage were recruited. PCOS women were divided into the hyperandrogenism (HA) PCOS group (n = 13) and nonhyperandrogenism (N-HA) PCOS group (n = 19). Sixty female Sprague-Dawley rats were used for PCOS model establishment. In GCs of HA PCOS women, PPARG1 mRNA expression was lower, whereas NCOR1 and HDAC3 mRNA expression were higher than N-HA PCOS women and controls (P < 0.05). When all women were divided into successful and failed pregnancy subgroups according to the following clinical pregnancy outcome, we found lower PPARG1 mRNA levels and higher NCOR1 and HDAC3 mRNA levels in the failed subgroup of HA PCOS (P < 0.05). Two hypermethylated CpG sites in the PPARG1 promoter and five hypomethylated CpG sites in the NCOR1 promoter were observed only in HA PCOS women (P < 0.01 to P < 0.0005). The acetylation levels of histone H3 at lysine 9 and p21 mRNA expression were decreased in human GCs treated with dihydrotestosterone in vitro (P < 0.05). PCOS rat models also showed alterations of PPARG1, NCOR1, and HDAC3 mRNA expression and methylation changes of PPARG1 and NCOR1, consistent with the results from humans. Hyperandrogenism induces the epigenetic alterations of PPARG1, NCOR1, and HDAC3 in GCs, which are involved in the ovarian dysfunction of HA PCOS.

The R453Q and D151A polymorphisms of Hexose-6-Phosphate Dehydrogenase Gene (H6PD) influence the polycystic ovary syndrome (PCOS) and obesity

Hexose-6-phosphate dehydrogenase (H6PDH) influences 11β-hydroxysteroid dehydrogenase activity, a key enzyme in the peripheral metabolism of cortisol that modulates insulin sensitivity in adipose tissue. To study the associations of R453Q and D151A polymorphisms in the H6PDH gene (H6PD) with polycystic ovary syndrome (PCOS) and their influence on clinical and metabolic variables, we genotyped 237 patients with PCOS and 135 control women for the R453Q (rs6688832) and D151A (rs34603401) variants in H6PD. The R453Q genotypes were distributed differently in patients and controls (χ2=9.55, P=0.002). Genotypes of D151A were distributed evenly in women with PCOS and controls, but showed a different distribution in non-obese and obese women (χ2=3.95, P=0.047), especially within the PCOS subgroup (χ2=4.65, P=0.031). A backward stepwise likelihood ratio logistic regression model (Nagelkerke's R2=0.490; χ2=164; P<0.0001) retained free testosterone (OR=1.13; 95% CI: 1.10–1.17) and H6PD Q453 alleles (OR=0.46; 95% CI: 0.27–0.79) as statistically significant predictors for PCOS, whereas homeostasis model assessment of insulin resistance and the H6PD D151A variant were excluded by the model. Both H6PD variants were associated with several phenotypic variables, including fasting insulin, homeostasis model assessment of insulin resistance and androstenedione levels. In summary, the R453Q and D151A variants of the H6PD gene are associated with PCOS and obesity, respectively, and may contribute to the PCOS phenotype by influencing obesity, insulin resistance and hyperandrogenism.

Effectiveness of GnRH antagonist multiple dose protocol applied during early and late follicular phase compared with GnRH agonist long protocol in non-obese and obese patients with polycystic ovary syndrome undergoing IVF/ICSI

ObjectiveTo evaluate the effectiveness of GnRH antagonist multiple dose protocol applied during early and late follicular phase (MDP-EL) in comparison with standard GnRH agonist luteal long protocol (LP) in each non-obese and obese polycystic ovary syndrome (PCOS) women undergoing IVF.MethodsTwo hundred eleven infertile women with PCOS were recruited and randomized to undergo either GnRH antagonist MDP-EL (antagonist group) or standard GnRH agonist luteal LP (agonist group). IVF cycle outcomes were compared between the two groups.ResultsTotal dose and days of recombinant human follicle stimulating hormone (rhFSH) administered were significantly fewer in the antagonist group than in the agonist group. Incidence of severe ovarian hyperstimulation syndrome was significantly lower in the antagonist group. However, IVF and pregnancy outcomes were similar in the two groups. When all subjects were divided into non-obese and obese subgroups, in non-obese PCOS subgroup, IVF and pregnancy outcomes were comparable in the antagonist and agonist groups but total dose and days of rhFSH were also significantly fewer in the antagonist group. Similar findings were also observed in obese PCOS subgroup.ConclusionGnRH antagonist MDP-EL is at least as effective as GnRH agonist LP and may be a more patient-friendly alternative in controlled ovarian stimulation for PCOS patients undergoing IVF, independent of body mass index.

Phenotype and metabolic profile of South Asian women with polycystic ovary syndrome (PCOS): results of a large database from a specialist Endocrine Clinic

Compared with other populations, South Asians have a greater propensity to insulin resistance and the metabolic syndrome (MetS). This is the first study to determine the distribution of phenotypes of polycystic ovary syndrome (PCOS) and their relationship to the MetS among indigenous South Asians. An evaluation of the phenotype and metabolic characteristics of PCOS was conducted by recruiting consecutive women diagnosed by Rotterdam consensus criteria from an Endocrine clinic in Colombo, Sri Lanka. Prevalence of MetS was determined, in relation to the phenotypic subgroup of PCOS and compared with ethnically matched, BMI- and age-adjusted controls (n =231). Acanthosis nigricans (AN) occurred in 64.6% of women with PCOS (n= 469). MetS occurred in 30.6% of the PCOS group compared with 6.34% of controls (P = 0.0001). Those with PCOS and MetS had significantly higher median BMI, blood pressure (BP), fasting plasma glucose, insulin and triglycerides and lower high-density lipoprotein and sex hormone-binding globulin (SHBG), but similar testosterone concentrations compared with those with PCOS alone. Prevalence of MetS was similar in the four PCOS phenotypes, although oligomenorrhoeic women were more obese compared with the normal cycling hyperandrogenic group. Multivariate logistic regression confirmed age ≥35 years, BMI ≥25 kg/m(2) and AN as significant predictors of MetS in PCOS. Case-control comparisons showed that the presence of PCOS results in higher odds of having the MetS, a high waist circumference, elevated diastolic BP, abnormal fasting lipids and high fasting insulin and plasma testosterone concentrations. Young indigenous South Asians with PCOS have greater odds of being centrally obese, with a third having the MetS that bears no relationship to the androgenic phenotype. Significant predictors for MetS within the PCOS cohort are advancing age, obesity determined by the Asian cut off (BMI >25 kg/m(2)) and AN, while family history of diabetes, hyperandrogenism and elevated SHBG have no predictive value.

The Effect of Exercise in PCOS Women Who Exercise Regularly.

To determine the prevalence of polycystic ovary syndrome (PCOS) in women who exercise regularly. All women under age 45 from an industrial company who had past history of exercising more than 6 months enrolled in this cross-sectional study. Prevalence of PCOS and comparison of BMI between PCOS and non-PCOS subgroups was done. The diagnosis of PCOS was based on the revised 2003 Rotterdam ESHRE/ASRM consensus criteria and exclusion of related disorders. The prevalence of PCOS in was 8.8%; 95% CI: 8.5%-9.1%. In obese subjects, mean BMI differed significantly between PCOS and non-PCOS women (29.3 ±3.3 kg/m(2) vs. 27.8 ± 2 kg/m(2), P=0.03). In lean subjects, there was no statistically significant difference in terms of BMI between PCOS and non-PCOS women (21.4 ± 1.9 kg/m(2) vs. 21.2 ± 2 kg/m(2), P>0.05). Obese PCOS patients show more difficulty in losing weight by exercise than lean PCOS patients. The role of hormonal alterations and PCOS per se in the responsiveness of weight loss to exercise remains to be determined.

Endothelial function in young women with polycystic ovary syndrome (PCOS): Implications of body mass index (BMI) and insulin resistance

Evidence regarding endothelial function in both obese and nonobese women with PCOS is contradictory. It is unknown whether obese women with PCOS carry an increased risk related to body mass index (BMI). To identify endothelial function and investigate its relationship to body mass index and insulin resistance in young women with PCOS. Twenty-two obese women with PCOS (BMI 35.2 ± 3.2) as well as fourteen lean women (BMI 22.8 ± 2.1)with PCOS were included in the study. Fasting serum insulin, blood glucose were estimated and HOMA and Quicki index were calculated. All patients were subjected to ultrasound recording of brachial artery diameter at rest and after reactive hyperemia (FMD) for assessment of endothelial function. Ten age matched healthy females with normal BMI were chosen as a control group. There were higher basal insulin levels with lower Quicki index and higher HOMA index in women with PCOS than normal group, but the differences were significant only between obese PCOS subgroup and control. On the other hand, FMD was significantly and equally decreased in both groups of women with PCOS, compared with control subjects (3.7 ± 3.2% in the nonobese subgroup and 3.5 ± 2.8% in the obese one vs. 10.6 ± 4.1% in control subjects, P, 0.001). FMD was not correlated with BMI nor insulin resistance indices. Endothelial dysfunction is already present in young women with PCOS. In this patient group, it cannot be attributed to insulin resistance or obesity.

Impaired Glucose Metabolism in Women with Polycystic Ovary Syndrome

Background: To compare the prevalence of impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) in lean and overweight/obese women with polycystic ovary syndrome (PCOS), with the data from a normal population sample. Methods: PCOS-affected women fulfilling ESHRE diagnostic criteria underwent an oral glucose tolerance test. Prevalence of IGT and T2DM in control sample of white healthy females was extracted from the published data from NHANES II. Results: In 225 women with PCOS, IGT was present in 6/104 (5.8%) lean and in 15/121 (12.4%) overweight/obese women. T2DM was present in 1/104 (1.0%) lean and in 3/121 (2.5%) overweight/obese PCOS women. In a sample of 643 women from NHANES II, the crude rate of IGT was 5.9%. IGT was significantly more common only in the overweight/obese PCOS subgroup as compared to the NHANES II cohort (χ² = 5.99, p < 0.01). Conclusions: IGT was found significantly more frequently only in overweight/obese PCOS subjects in comparison with healthy controls.

Association of the Pro12Ala polymorphism in peroxisome proliferator-activated receptor γ2 with decreased basic metabolic rate in women with polycystic ovary syndrome

The peroxisome proliferator-activated receptor (PPAR)gamma is a transcription factor involved in glucose homeostasis and energy metabolism. A missense mutation at codon 12 in the PPARgamma2 has been associated with increased body mass index (BMI) and attenuated insulin resistance (IR) in polycystic ovary syndrome (PCOS). We have recently shown a decreased basic metabolic rate (BMR) in PCOS. The aim of the present study is to determine the prevalence of the Pro12Ala polymorphism of the PPARgamma2 gene and its associations with indices of IR and BMR in lean and slightly overweight PCOS women. Case-control association study involving 156 PCOS women with biochemical hyperandrogenism, chronic anovulation and polycystic ovarian morphology in ultrasound and 56 unrelated healthy controls. Hormonal determinations were performed by electrochemiluminescence quantitation or RIA. BMR was measured by indirect calorimetry. All subjects were genotyped by a PCR-restriction fragment length polymorphism assay. Genotype frequencies of the Pro12Ala polymorphism in PPARgamma2 did not differ among PCOS women and control subjects. The presence of Pro12Ala polymorphism of PPARgamma2 was associated with lower BMR (P=0.04). This finding was valid in our subgroup of lean PCOS (BMI<25 kg/m(2)), in which the Ala variant was also associated with higher total testosterone values. The Pro12Ala polymorphism in the PPARgamma2 gene is associated with decreased BMR in women with PCOS and biochemical hyperandrogenemia. These young women are therefore at risk to increase their body weight and should restrict their energy intake by diet and enhance their energy expenditure by exercise.

Metabolic features of the reproductive phenotypes of polycystic ovary syndrome

BACKGROUND Polycystic ovary syndrome (PCOS) is a common condition in women of reproductive age with well established metabolic abnormalities. There are numerous diagnostic criteria generating several reproductive diagnostic phenotypes [National Institute of Health (NIH) hyperandrogenic anovulatory PCOS and non-NIH PCOS including hyperandrogenic ovulatory or non-hyperandrogenic anovulatory PCOS]. There is ongoing debate regarding the optimal diagnostic criteria for PCOS and on the metabolic implications of newer non-NIH PCOS phenotypes. METHODS We reviewed the literature on the presence of risk factors for type 2 diabetes (DM2) and cardiovascular disease (CVD) across the reproductive diagnostic phenotypes of PCOS with the aims of comparing the metabolic features of the NIH and non-NIH groups and identifying potential high metabolic risk phenotypes of PCOS. RESULTS NIH PCOS patients present with greater obesity, abdominal obesity, insulin resistance (IR) and risk factors for DM2 and CVD compared with non-NIH ovulatory and non-hyperandrogenic PCOS patients. Where differences in metabolic features exist between the phenotypes, they are generally related to the degree of total and abdominal obesity. There is emerging evidence suggesting ovulatory and non-hyperandrogenic PCOS have greater metabolic abnormalities than controls primarily linked to abdominal adiposity. There is currently no evidence that non-hyperandrogenic PCOS is associated with a less adverse metabolic profile than ovulatory PCOS. CONCLUSIONS Current metabolic evidence appears to justify the inclusion of both non-NIH PCOS groups (ovulatory and non-hyperandrogenic) as PCOS subgroups. NIH PCOS is associated with a more adverse metabolic profile including greater total and abdominal obesity, IR and risk factors for CVD and DM2 than non-NIH phenotypes.

Polycystic ovary syndrome is associated with severe platelet and endothelial dysfunction in both obese and lean subjects

Platelet hyporesponsiveness to the anti-aggregatory effects of nitric oxide (NO) occurs commonly in association with myocardial ischemia and coronary risk factors, often co-exists with endothelial dysfunction and represents an independent marker of long-term cardiovascular risk. We sought to determine whether polycystic ovary syndrome (PCOS), which has been postulated as a cardiovascular risk factor in women, is independently associated with this phenomenon. Twenty-four young women with PCOS (mean age 32.1 ± 1.3) were evaluated in lean ( n = 12) and obese ( n = 12) subgroups, and compared with age-matched lean normals ( n = 12). Platelet aggregation and its inhibition by the nitric oxide donor sodium nitroprusside (SNP) were assessed and compared with vascular endothelial function. Plasma concentrations of malondialdehyde (MDA), N G , N G -dimethyl- l-arginine (ADMA) and hs-CRP were measured as markers of oxidative stress, endothelial dysfunction and inflammation, respectively. Circulating endothelial progenitor cell (EPC) counts were also documented. In both PCOS subgroups, which demonstrated hyperaggregability to ADP, responses to SNP inhibition of aggregation (the principal end-point of the study) were significantly impaired ( P < 0.01 for both), as were their endothelium-dependent vascular responses to salbutamol ( P < 0.05 for both). However, vasomotor responses to nitroglycerin and circulating EPC counts did not vary between groups. PCOS subjects also had significantly elevated ADMA, MDA and hs-CRP levels relative to normals (all P < 0.05). Impairment of SNP response remained unaltered after mean 30 ± 2.4 months follow-up in PCOS subjects. We conclude that in PCOS subjects, independent of obesity and associated insulin resistance, profound and reproducible impairment of platelet responsiveness to NO is an additional component of cardiovascular homeostatic disturbance.

High serum concentration of total inhibin in polycystic ovary syndrome

To evaluate serum total inhibin (the sum of precursors, subunits, and mature molecules of inhibin) along with inhibin A and inhibin B in a large sample of women with polycystic ovary syndrome (PCOS) and to investigate whether these parameters differ between lean and overweight PCOS patients. Cross-sectional, controlled study. Academic health centers in Siena and Bologna, Italy. A group of women with PCOS (n = 145) was divided according to body mass index (BMI) into "lean PCOS" (BMI 19-25 kg/m(2), n = 52) and "overweight PCOS" (BMI 26-51 kg/m(2), n = 93). A group of healthy women (n = 90) with BMI 19-24 kg/m(2) and a history of regular menstrual cycles and normal results on physical examination served as controls. Blood samples were drawn between cycle days 3 and 5 in PCOS patients and controls. Serum concentrations of total inhibin, inhibin A, inhibin B, FSH, and LH were measured using commercially available immunoassays. Women with PCOS had serum total inhibin levels twice as high as in the control group (median = 115 vs. 47 pg/mL). Dimeric inhibin A concentration was lower in the PCOS group compared with controls (10 vs. 25 pg/mL), whereas inhibin B concentration did not differ significantly between PCOS and control groups. There was no difference of either total inhibin or inhibin A levels between lean and overweight women with PCOS, whereas the inhibin B level was higher in the lean PCOS subgroup compared with the overweight PCOS subgroup. Total inhibin did not show any linear correlation with inhibin B, inhibin A, or serum gonadotropins. Women with PCOS have high serum concentration of total inhibin but not of inhibin A or inhibin B, thus suggesting that PCOS women have an impaired processing of alpha-inhibin precursor proteins.

Polycystic Ovary Syndrome and Endometrial Cancer

An association between polycystic ovary syndrome (PCOS) and endometrial carcinoma was first suggested in 1949. Since then, several studies have been published that appear to support this association, and it is common practice among gynecologists and physicians to prescribe hormonal treatment to reduce this perceived risk, although there is no consensus as to the subgroup of PCOS in whom this is required. The mechanism(s) underlying any association are also unclear, but it is again widely assumed that chronic anovulation, which results in continuous estrogen stimulation of the endometrium unopposed by progesterone, is a major factor. However, obesity, hyperinsulinemia, and hyperandrogenism, which are also features of PCOS, are risk factors for endometrial carcinoma, but it does not necessarily follow that the incidence or mortality from endometrial cancer is increased in women with the syndrome. Potential strategies to prevent endometrial cancer in PCOS women are discussed.

Characterizing Discrete Subsets of Polycystic Ovary Syndrome as Defined by the Rotterdam Criteria: The Impact of Weight on Phenotype and Metabolic Features

A lack of standard criteria for diagnosing polycystic ovary syndrome (PCOS) has made it very difficult to compare phenotypes around the world. A workshop held recently in Rotterdam attempted to reconcile the differences by adding ultrasonography to expand the diagnostic criteria. PCOS is diagnosed if two of three findings are present: irregular menses (IM); clinical or biochemical hyperandrogenism (HA); and/or polycystic ovary morphology (PCOM) on pelvic ultrasound study, all in the absence of a disorder that can cause the same symptoms. The four possible diagnostic subgroups of PCOS are IM/HA/PCOM, IM/HA, HA/PCOM, and IM/PCOM. The phenotypic features of women in these subgroups were compared in a large population of women with PCOS residing in Boston and in Iceland. Of the 481 women evaluated, 71% met criteria for IM/HA/PCOM. Another 2% had IM/HA; 18% had HA/PCOM; and 9% had IM/PCOM. Virtually all women with IM/HA also had PCOM. Women with IM/HA and normal ovarian morphology differed from those with PCOM only by being older and having higher levels of follicle-stimulating hormone. Because follicle counts and the frequency of PCOM decline with advancing age in women with PCOS, the IM/HA/PCOM and IM/HA groups were combined and designated IM/HA. Ferriman-Gallwey scores and androgen levels were highest in the IM/HA and HA/PCOM groups. Ovarian volumes were higher in all subgroups compared to control women without PCOS. Women in the IM/HA subgroup had the highest body mass index (BMI) values and circulating insulin levels. Insulin resistance was most frequent in the IM/HA subgroup, but there were no group differences in fasting glucose or glycosylated hemoglobin levels, or in the frequency of type 2 diabetes. Women in the IM/HA and IM/PCOM subgroups had the largest ovarian volumes and the most follicles on ultrasound study. These parameters were greater in all groups of women with PCOS than in the control subjects. This study shows that women with PCOS defined by HA are most severely affected. They also have the highest BMIs, suggesting that weight gain or intrinsic insulin resistance may worsen symptoms of PCOS or lead to irregular cycles in women with HA at baseline. Further studies will be needed to learn whether phenotypic differences influence such long-term sequelae as infertility and cardiovascular disease.

South Asian women with polycystic ovary syndrome exhibit greater sensitivity to gonadotropin stimulation with reduced fertilization and ongoing pregnancy rates than their Caucasian counterparts

Polycystic ovary syndrome (PCOS) is a heterogeneous syndrome. In vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) is required for PCOS cases that are refractory to standard ovulation induction or have co-existing infertility factors in women with PCOS and Tubal factor subfertility. Objectives Assess ethnic variations in response to IVF/ICSI treatment. Study design Observational Comparative study in a University hospital fertility clinic in women with PCOS and Tubal factor subfertility. Women with PCOS (Asians: AP = 104; Caucasians: CP = 220) and those with tubal factor infertility seeking fertility treatment were assessed (Asians: AC = 84; Caucasians: CC = 200). Six hundred and eight fresh IVF or ICSI cycles using long protocol of GnRHa suppression and resulting in a fresh embryo transfer were compared. The primary endpoint was to assess the dose of gonadotropins used in the cycles. The secondary outcomes were: total number of oocytes retrieved, fertilization and ongoing clinical pregnancy rates. Results We found that the South Asian women presented at a younger age for the management of sub-fertility. An extended stimulation phase and Caucasian ethnicity showed an inverse correlation with the number of oocytes retrieved in the PCOS subgroup. Caucasian ethnicity was associated with a higher fertilization rate however increase in body mass index (BMI) and the laboratory technique of IVF appeared to have a negative impact on fertilization rates in the PCOS subgroup. Commencing down regulation on day 1 of the cycles was negatively associated with fertilization rates in the tubal group. In terms of clinical pregnancy rates, the Caucasian PCOS had a 2.5 times (95% CI: 1.25–5) higher chance of an ongoing clinical pregnancy as compared with their Asian counterpart. Also, a unit increase in the basal FSH concentration reduced the odds of pregnancy by 18.6% (95% CI: 1.8–32.6%) in the PCOS group. Conclusions The Asian PCOS have a greater sensitivity to gonadotropin stimulation with lower fertilization and ongoing clinical pregnancy rates as compared with their Caucasian counterparts.

Phenotypic Variation of Polycystic Ovary Syndrome

Background: Polycystic ovary syndrome (PCOS) is a common disorder in premenopausal women, but there has been little agreement on its diagnostic criteria due to its uncertain pathogenesis and the heterogeneity of symptoms. This study was performed in order to assess the differences in clinical, metabolic, and hormonal characteristics of women in the PCOS subgroups defined by ESHRE criteria. Methods: Subjects were divided into four PCOS subgroups based on ESHRE criteria. The grouping groupings included: 1) hyperandrogenism, oligomenorrhea, and polycystic ovary morphology (HA + OM + PCO); 2) hyperandrogenism and oligomenorrhea (HA + OM); 3) hyperandrogenism and polycystic ovary morphology (HA + PCO); and 4) oligomenorrhea and polycystic ovary morphology (OM + PCO). Reproductive hormones and metabolic profiles were measured. Results: Of the total number of subjects, 60 (40%) fulfilled the criteria for HA + OM + PCO, 50 (33%) for HA + OM, 11 (7%) for HA + PCO, and 30 (20%) for OM + PCO. There were no significant differences in clinical or metabolic features among the groups, except for LH, total cholesterol, and HDL cholesterol. Conclusion: In this population defined by ESHRE criteria, 73% of the patients met the former NIH definition for PCOS. Different phenotypes of PCOS cases were clinically or biochemically similar. Whether these women have an increased risk of infertility or metabolic complications remains to be determine.

Characterizing Discrete Subsets of Polycystic Ovary Syndrome as Defined by the Rotterdam Criteria: The Impact of Weight on Phenotype and Metabolic Features

The Rotterdam criteria for polycystic ovary syndrome (PCOS) defines discrete subgroups whose phenotypes are not yet clear. The phenotypic characteristics of women in the PCOS subgroups defined by the Rotterdam criteria were compared. The study was observational. Subjects were studied in an outpatient setting in Boston and Reykjavik. Four subgroups of subjects with PCOS defined by 1) irregular menses (IM), hyperandrogenism (HA), and polycystic ovary morphology (PCOM, n = 298); 2) IM/HA (n = 7); 3) HA/PCOM (n = 77); and 4) IM/PCOM (n = 36) and a group of controls (n = 64), aged 18-45 yr, were examined. Subjects underwent a physical exam; fasting blood samples for androgens, gonadotropins, and metabolic parameters; and a transvaginal ultrasound. The phenotype was compared between groups. Ninety-seven percent of women with IM/HA had PCOM. Therefore, the groups with and without PCOM were combined. The Ferriman-Gallwey score and androgen levels were highest in the hyperandrogenic groups (IM/HA and HA/PCOM), whereas ovarian volume was higher in all PCOS subgroups compared with controls, as expected based on the definitions of the PCOS subgroups. Body mass index and insulin levels were highest in the IM/HA subgroup. Subjects with PCOS defined by IM/HA are the most severely affected women on the basis of androgen levels, ovarian volumes, and insulin levels. Their higher body mass index partially accounts for the increased insulin levels, suggesting that weight gain exacerbates the symptoms of PCOS.

Hyperinsulinism and its interaction with hyperandrogenism in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. It has become increasingly evident that insulin resistance plays a significant role both as a cause and result of the syndrome. The purpose of this review is to summarize the possible mechanisms leading to insulin resistance and resultant hyperinsulinism (HI) and their interaction with hyperandrogenism (HA) in PCOS. We conducted a computerized search of MEDLINE for relevant studies in the English literature published between January 1966 and January 2000. We reviewed all studies that investigated the roles of insulin, insulin receptor, and insulin gene in insulin resistance and its interaction with hyperandrogenism in PCOS. Insulin resistance in PCOS seems to involve a postbinding defect in the insulin receptor and/or in the receptor signal transduction. Current research has focused on identifying a genetic predisposition for insulin resistance in this syndrome. The answer to the question whether HI or HA is the initiating event is still unclear inasmuch as there are clinical and molecular evidences to support both of these approaches. Our view is that whichever is the triggering insult, a vicious cycle is established where HI acts to aggravate HA and vice versa. In this model, obesity and genetic predisposition seem to be the independent factors that can give rise or contribute to HI, HA, or both simultaneously. It seems that "hyperinsulinemic hyperandrogenism" represents a significant subgroup of PCOS, which probably needs to be renamed and reclassified in the light of this new approach.

Growth hormone response to thyrotrophin releasing hormone in women with polycystic ovarian syndrome.

Recent clinical studies have suggested that women with polycystic ovarian syndrome (PCOS) may have disturbances of growth hormone (GH) kinetics and the GH/insulin-like growth factor (IGF)-I system. The knowledge that in various metabolic abnormalities there is a paradoxical sensitivity of pituitary somatotrophs to thyrotrophin releasing hormone (TRH) administration led to this investigation of the GH secretory response to TRH in women with PCOS. Twenty-four women with PCOS and 18 control women were studied. TRH was given as a single i.v. injection (time 0) and blood samples for GH measurements were obtained at -15, 0, 15, 30, 60 and 90 min. The GH responses were expressed as the area under the curve (AUC) or the differences from the basal value (Deltamax). The GH response to TRH (mean +/- SEM) was greater in women with PCOS (Deltamax 2.47 +/- 1. 73 versus 0.47 +/- 0.06 ng/ml, P < 0.05 and GH AUC 8.05 +/- 2.10 versus 2.58 +/- 0.18 ng/ml/90 min, P < 0.05). According to GH response to TRH, two PCOS subgroups were identified: (i) normal responders (n = 14) who showed Deltamax GH response (0.36 +/- 0.06 ng/ml)and GH AUC (1.93 +/- 0.64 ng/ml/90 min) similar to that in the controls and (ii) over-responders (n +/- 10) who showed a paradoxical increase in GH concentrations in response to TRH (Deltamax GH response 5.43 +/- 1.27 ng/ml and GH AUC 16.62 +/- 3.51 ng/ml per 90 min) that was significantly higher than in normally responding PCOS patients (P < 0.0001) or in controls (P < 0.0001). These data demonstrate an enhanced GH response to TRH administration in a subgroup of women with PCOS.

Circulating leptin concentrations in polycystic ovary syndrome: relation to anthropometric and metabolic parameters.

To determine the relation between metabolic and anthropometric parameters and circulating leptin concentrations in women with polycystic ovary syndrome (PCOS). Correlation of fasting serum leptin concentrations with anthropometric measures and multiple metabolic parameters including insulin and glucose responses to a 2-hour 75-g oral glucose tolerance test (OGTT) in 85 women with PCOS (17-36 years, body mass index (BMI) 29.9 +/- 0.9 kg/m2, mean +/- SD) and 18 control women (25-47 years, BMI 25 +/- 1.7 kg/m2). Diagnostic criteria for PCOS: characteristic ovarian morphology on ultrasound plus at least two of (1) elevated serum testosterone; (2) elevated serum androstenedione; and (3) reduced serum SHBG concentrations. Concentrations of androgens, lipids, PRL, gonadotrophins, and leptin were measured in the baseline fasting blood sample from an OGTT. Insulin and glucose were measured throughout OGTT. Serum leptin concentrations were measured by radioimmunoassay. Log leptin levels in the PCOS group correlated significantly with BMI (r = 0.85, P < 0.0001) and with 8 other parameters including waist/hip ratio (r = 0.51, P = 0.0005). By stepwise regression analysis, only BMI (P < 0.0001) and plasma high density lipoprotein concentration (P = 0.02) were independently correlated with log leptin levels, both positively. There was no effect of fat distribution, as measured by waist/ hip ratio, on leptin concentrations. Comparison of control subjects to a BMI-matched subgroup of 55 PCOS subjects revealed significantly higher circulating concentrations of LH, testosterone, DHEAS, progesterone and androstenedione, and higher glucose and insulin responses to OGTT in the PCOS group. Leptin levels were not different between the PCOS subgroup and control group (14.8 +/- 1.3 vs 12.1 +/- 2.3 micrograms/l, mean +/- SE, P = 0.26) and the relation of BMI to leptin levels determined by linear regression analysis also did not differ between the two groups. Our results indicate that circulating leptin concentrations in women with PCOS, a condition characterized by hyperandrogenaemia, increased LH concentrations and insulin resistance, are strongly related to BMI and not independently affected by circulating levels of insulin, gonadotrophins or sex hormones.

Dyslipidaemia in polycystic ovarian syndrome: different groups, different aetiologies?

The objective was to study the pathophysiology of the dyslipidaemia in polycystic ovarian syndrome (PCOS) patients, and to determine how it is related to hyperinsulinaemia, hyperandrogenism and dehydroepiandrosterone sulphate (DHEA-S) concentrations. The lipoprotein lipid profile, anthropometric measurements, endocrine profile and the presence of insulin resistance were evaluated in 31 PCOS patients and 20 age-matched healthy women, who served as controls. PCOS patients had higher fasting insulin concentrations, higher body mass indexes (BMI) and were hyperlipidaemic, with higher total cholesterol, low density lipoprotein (LDL) and triglyceride (TG) concentrations. There were no relationships between plasma lipids and anthropometric variables in the patient group as a whole. Insulin-resistant (IR) and non-IR (NIR) PCOS patients were then evaluated separately. Obesity with marked hyperandrogenism were the predominant features in patients with IR. NIR patients were not obese and had significantly less hyperandrogenism. The adrenal androgen DHEA-S was at the upper limit of its normal range in both groups. However, both PCOS subgroups exhibited similar significant abnormalities in terms of their lipid parameters. Insulin and DHEA-S concentrations were positively correlated with total cholesterol, LDL and TG, and negatively correlated with high density lipoprotein, in IR patients. In NIR subjects, insulin was not correlated with any of the lipids and DHEA-S was negatively related to cholesterol and LDL. Anthropometric variables were related to lipids in only the NIR patients. Thus PCOS subjects as a group exhibit dyslipidaemia, characterized by increased total cholesterol, LDL and TG concentrations. When divided into IR and NIR subjects, there were no differences in the degree of lipid abnormalities, despite significant variations in the BMI and androgen status. Thus, in PCOS subjects, dyslipidaemia may occur irrespective of insulin resistance. Insulin and DHEA-S concentrations were positively correlated with an atherogenic lipid profile in the IR group only. As distinct from syndrome X when IR was present, dyslipidaemia was not related to body weight or the waist:hip ratio. In the NIR group there was no relationship between lipids and insulin; DHEA-S, on the other hand, was negatively related to cholesterol and LDL concentrations. Thus, dyslipidaemia in PCOS patients may occur irrespective of insulin resistance, and may have different metabolic aetiologies depending on DHEA-S metabolism. It remains to be seen whether the two types of PCOS are associated with different risks for ischaemic heart disease.