Variants in the ACVR1 gene are associated with AMH levels in women with polycystic ovary syndrome

BACKGROUND: Polycystic ovaries display an increased number of pre-antraland antral follicles compared with normal ovaries, suggestingthat early and late follicle development are disturbed. Thepathophysiology of this process is poorly understood. Sincethe transforming growth factor β family members, anti-Müllerianhormone (AMH) and bone morphogenetic proteins (BMPs), inhibitFSH sensitivity, their signalling may contribute to the aberrantfollicle development in these women. Here, we investigated therole of ALK2, a type I receptor for AMH/BMP signalling, in PCOSusing a genetic approach. METHODS: Seven single nucleotide polymorphisms in the ACVR1 gene, encodingALK2, were genotyped in 359 PCOS patients and 30 normo-ovulatoryand 3543 population-based control women, and haplotypes weredetermined. Subsequently, the association of ACVR1 variantswith ovarian parameters and hormone levels was investigated. RESULTS: The polymorphisms rs1220134, rs10497189 and rs2033962 and theircorresponding haplotypes did not show different frequenciesfrom controls, but were associated with AMH levels in PCOS women(P = 0.001, P = 0.002 and P = 0.007, respectively). Adjustmentfor follicle number revealed that the association with AMH levelswas, in part, independent from follicle number, suggesting thatvariants in ACVR1 also influence AMH production per follicle. CONCLUSIONS: Genetic variation within ACVR1 is associated with AMH levelsand follicle number in PCOS women, suggesting that ALK2 signallingcontributes to the disturbed folliculogenesis in PCOS patients.     

Evidence of subpopulations with different levels of insulin resistance in women with polycystic ovary syndrome

BACKGROUND: Polycystic ovary syndrome (PCOS) is non-uniformly associated with insulin resistance (IR). We examined IR in women with PCOS. METHODS: Sixty-nine PCOS women were subjected to the insulin suppression test (IST) to determine their steady-state plasma glucose (SSPG) as a direct measure of insulin sensitivity. RESULTS: SSPG exhibited a multimodal distribution suggesting the existence of subpopulations. The heterogeneous distribution of plasma glucose at 180 min (P = 0.011), with three modes, suggested differences in the plasma glucose level trajectories during the IST. Hence, the population was separated into three groups: (i) (n = 33), subjects with SSPG < or = 152.5 mg/dl, corresponding to the first to fifth deciles; (ii) (n = 29), subjects in the interval 152.5 mg/dl < SSPG < or = 300 mg/dl; (iii) (n = 7), subjects with SSPG > 300 mg/dl, corresponding to the tenth decile. Plasma glucose distributions at 180 min showed differences in their mean values and ranges among groups (P < 0.0001). The trajectories of the groups differed significantly during the IST (P < 0.0001). CONCLUSIONS: insulin sensitivity in our patients exhibited a discontinuous distribution, implying that PCOS is a heterogeneous disorder possessing subpopulations regarding IR.     

Leptin, polycystic ovaries and polycystic ovary syndrome.

As soon as leptin was discovered four years ago, its potential as a player in the polycystic ovary syndrome (PCOS) was explored in a primitive way, though little light was shed on the enigma that is PCOS. As a second wave of leptin research is now available, we review how the expanded role of the cytokine in reproduction might yet impact upon our understanding of PCOS.     

Serum visfatin in relation to insulin resistance and markers of hyperandrogenism in lean and obese women with polycystic ovary syndrome

BACKGROUND: Visfatin, a protein secreted by adipose tissue, is suggested to play a role in pathogenesis of insulin resistance. In polycystic ovary syndrome (PCOS), insulin resistance might be involved in the development of endocrine and metabolic abnormalities. The aim of the study was to asses the relation between serum visfatin concentration and insulin sensitivity and markers of hyperandrogenism in lean and obese PCOS patients. METHODS: The study group consisted of 70 women with PCOS (23 lean and 47 obese) and 45 healthy women (25 lean and 20 obese). Euglycemic hyperinsulinemic clamp and the measurements of serum visfatin, sex hormones were performed. RESULTS: The PCOS group had lower insulin sensitivity (P=0.00049) and higher serum visfatin (P=0.047) in comparison to the control group. The decrease in insulin sensitivity was present in both the lean (P=0.019) and obese (P=0.0077) PCOS subjects, whereas increase in serum visfatin was observed only in lean PCOS subjects (P=0.012). In the whole group, serum visfatin was negatively correlated with insulin sensitivity (r=-0.27, P=0.004). This relationship was also observed in the subgroup of lean (r=-0.30, P=0.038), but not obese women. Additionally, in lean women, visfatin was associated with serum testosterone (r=0.47, P=0.002) and free androgen index (r=0.48, P=0.002), independently of other potential confounding factors. CONCLUSIONS: Visfatin is associated with insulin resistance and markers of hyperandrogenism in lean PCOS patients.     

Metabolic syndrome in young Czech women with polycystic ovary syndrome

METHODS: Sixty-nine young women with polycystic ovary syndrome (PCOS) [age 25.2+/- 4.7 years, with body mass index (BMI) 24.3 +/- 4.8 kg/m2; mean 6 SD] and 73 age-matched healthy females (BMI 22.3 +/- 3.3 kg/m2; mean +/- SD) were evaluated for the occurrence of features of metabolic syndrome according to the Adult Treatment Panel III. RESULTS: Overt metabolic syndrome (the presence of three and more risk factors) was not more common in PCOS women (1/64, 1.6%) than in healthy controls (0/73, 0%). On the other hand, in nearly 50% of PCOS women isolated features of metabolic syndrome, most often a decrease in high-density lipoprotein (HDL) cholesterol, were found. Women with at least one feature of metabolic syndrome were, in comparison with women without any of these features, significantly more obese (P = 0.0001), with lower insulin sensitivity (P = 0.05). When comparing PCOS women according to the degree of insulin sensitivity, as determined by euglycaemic clamp, isolated features of metabolic syndrome were found in 8/17 women above the upper quartile, compared with 11/16 women below the lower quartile of insulin sensitivity (P = 0.20). CONCLUSIONS: Overt metabolic syndrome is only rarely encountered in young Czech females affected by PCOS but its isolated features are relatively frequent, both in young PCOS patients and in age-matched control women.     

The impact of obesity and insulin resistance on the outcome of IVF or ICSI in women with polycystic ovarian syndrome

The impact of insulin resistance on the outcome of IVF or intracytoplasmic sperm injection (ICSI) in women with polycystic ovarian syndrome (PCOS) was examined. Insulin sensitivity was measured by the continuous infusion of glucose with model assessment (CIGMA) test. Insulin-resistant (n = 26) and non-insulin-resistant women (n = 30) with PCOS underwent a total of 100 cycles of long-term down-regulation with buserelin acetate, stimulation with human recombinant FSH, and IVF or ICSI. Blood samples were taken throughout ovarian stimulation for hormone assays. Insulin-resistant and non-insulin-resistant women had similar concentrations of FSH, LH, testosterone and androstenedione throughout stimulation, but insulin-resistant women had hyperinsulinaemia and lower sex hormone binding globulin concentrations. Insulin-resistant women also had lower oestradiol concentrations during stimulation and required higher FSH doses, but these differences disappeared after controlling for the higher body weight in the group of insulin-resistant women. Groups had similar number of oocytes collected, similar implantation and pregnancy rates, and the incidence of ovarian hyperstimulation syndrome was also similar. Obesity, independent of hyperinsulinaemia, was related to a lower oocyte count and increased FSH requirement. It is concluded that in PCOS women receiving long-term down-regulation and stimulation with recombinant FSH, insulin resistance is neither related to hormone levels nor to IVF outcome. Obesity, independent of insulin resistance, is associated with relative gonadotrophin resistance.     

多囊卵巢综合征胰岛素抵抗相关治疗进展

 胰岛素抵抗（IR）是多囊卵巢综合征（PCOS）重要发病机制之一。临床上应用二甲双胍或噻唑烷二酮类药物可改善PCOS患者IR,纠正其代谢紊乱和高雄激素血症,故有助于恢复正常月经,增加排卵率及妊娠率,且孕期应用二甲双胍可能减少流产、妊娠高血压病、妊娠糖尿病等并发症。     

Effects of two antiandrogen treatments on hirsutism and insulin sensitivity in women with polycystic ovary syndrome

Thirty-two women with polycystic ovary syndrome (PCOS) wereallocated to two antiandrogen treatment regimens; 28 women completedthe trial. Twenty women were treated with ethinyloestradioland cyproterone acetate (EO-CA) cyclically for 6 months andeight women were treated with the gonadotrophin releasing hormone(GnRH) analogue, goserelin for 6 months. Effects on hirsutism,insulin sensitivity (estimated by glucose clamp technique),blood lipids and hormones were measured. Women treated withEO-CA showed a reduction in hirsutism (P <0.05), and decreasedserum androgen concentrations (P <0.001) as well as reducedinsulin sensitivity (P <0.05). In women treated with goserelin,serum androgen concentrations also decreased (P <0.001),but there was no significant reduction of hirsutism. This group,however, showed an improved insulin sensitivity (P <0.05)despite an unchanged body mass index. Bone mineral density wasunaltered in both treatment groups. The reduction in androgenconcentrations caused by EO-CA was not paralleled by increasedinsulin sensitivity, most probably due to the effect of ethinyloestradiolper se. In contrast, the reduction in androgen concentrationsby goserelin was accompanied by an improved insulin sensitivity.     

The follicular excess in polycystic ovaries, due to intra-ovarian hyperandrogenism, may be the main culprit for the follicular arrest

This review exposes the follicular abnormalities responsible for anovulation in polycystic ovary syndrome (PCOS). The putative pathophysiological explanations involve the principal intra- and extra-ovarian regulators which intervene during normal folliculogenesis to control the initial recruitment and growth and then the cyclic recruitment. We propose the hypothesis that the follicular problem in PCOS is 2-fold, but with the two abnormalities being linked. First, the intra-ovarian hyperandrogenism may promote early follicular growth, leading to a 2-5 mm follicle excess. Second, the ensuing excessive number of selectable follicles would inhibit the selection process, presumably through follicle-follicle interaction involving granulosa cell (GC) products such as the anti-Müllerian hormone (AMH). These factors would induce a reversible refractoriness to the FSH-induced differentiation of GC. This explanation challenges but does not exclude other hypotheses about the follicular arrest, such as the premature LH action on the GC of selectable follicles. Hyperinsulinism or insulin resistance would act as a second hit, worsening the follicular arrest either through amplification of the intra-ovarian hyperandrogenism or through dysregulation of the GC. The loss of cyclic rhythm would prevent the inter-cycle elevation of FSH, thus perpetuating the impairment of the ovulation process.     

Insulin resistance in patients with polycystic ovary syndrome is associated with elevated plasma homocysteine

BACKGROUND: Elevated levels of plasma homocysteine have recently been implicated as a significant risk factor for cardiovascular disease, pre-eclampsia, and recurrent pregnancy loss, and have been found to be associated with insulin resistance in a number of clinical situations. We examined the relationship between plasma homocysteine and insulin resistance in patients with polycystic ovary syndrome (PCOS). METHODS: A total of 155 infertile patients with PCOS as defined by clinical, biochemical and ultrasound criteria were screened for insulin resistance utilizing single-sample fasting insulin and glucose measurement, calculated by glucose:insulin ratio or homeostasis model assessment (HOMA) index. Total plasma homocysteine was measured by fluorescence polarization immunoassay. One hundred normo-ovulatory women with normal ovaries being treated for other infertility diagnoses served as a control group. RESULTS: Insulin resistance was found in the majority of PCOS patients: -53.5% (83/155), 60.6% (94/155) and 65.8% (102/155), when defined by fasting insulin, glucose:insulin ratio, or logHOMA respectively. Mean plasma homocysteine in the PCOS group was significantly higher than in the normal ovary group (11.5 +/- 7.4 versus 7.4 +/- 2.1 micromol/l, P < 0.001). Insulin-resistant PCOS patients had significantly higher plasma homocysteine (12.4 +/- 8.4 micromol/l) than non-insulin-resistant PCOS patients (9.6 +/- 4.4 micromol/l) regardless of body mass index (P = 0.003 by groups, P = 0.005 by correlation of single samples). Thirty-four per cent (53/155) of the PCO patients had homocysteine values >95th percentile of the controls (11.0 micromol/l, P < 0.0001). Statistically significant correlations were found between all insulin resistance indices and homocysteine levels. Multiple logistic regression defined insulin resistance as the major factor examined that influenced homocysteine levels. CONCLUSIONS: Insulin resistance and hyperinsulinaemia in patients with PCOS is associated with elevated plasma homocysteine, regardless of body weight. This finding may have important implications in the short term regarding reproductive performance, and in the long term regarding cardiovascular complications associated with insulin-resistant PCOS.     

Pioglitazone and metformin in obese women with polycystic ovary syndrome not optimally responsive to metformin

BACKGROUND: In an observational study of 13 women with polycystic ovary syndrome (PCOS) not optimally responsive to metformin diet, we assessed the efficacy and safety of addition of pioglitazone. We also compared these 13 women to 26 women with PCOS, who were responsive to metformin diet, matched by age and by pre- treatment menstrual history and not different by obesity categories. METHODS: Prospectively, as outpatients, with diet constant [1500-2000 calorie (depending on entry body mass index), 26% protein, 44% carbohydrate, 30% fat], metformin (2.55 g/day) was given for 12 months to 39 women, 13 not optimally responsive, 26 responsive to metformin diet, followed by addition of pioglitazone (45 mg/day) for 10 months in the 13 non-responders. Outcome measures included changes in sex hormones, insulin, insulin resistance (IR), insulin secretion, high density lipoprotein cholesterol, weight, and menstrual status. RESULTS: In 13 non-responders, on metformin diet, median serum insulin fell (21 to 16 microIU/ml, P<0.05) and insulin secretion fell from 251 to 200 (P<0.01); weight, dehydroepiandrosterone sulphate (DHEAS), testosterone and IR were unchanged (P> or =0.07). Compared with 14% pre- treatment, on metformin diet, expected menses occurred 46% of the time at 3 months (P=0.05), 38% at 6 months (P=0.07), 27% at 9 months, and 24% at 12 months. In 26 responders, on metformin diet, median weight fell (93 to 87 kg), testosterone fell (50 to 32 ng/dl), insulin fell (26 to 16 microIU/ml), IR fell (5.32 to 3.45) and insulin secretion fell (351 to 271) (P< or =0.017 for all). The occurrence of expected menses in the 26 responders was 2.5-fold higher than in the 13 non-responders (P<0.0001). In 11 non-responders, on pioglitazone + metformin diet over 10 months versus antecedent metformin diet, DHEAS fell (211 to 171 microg/dl, P=0.02), insulin fell (16 to 10 microIU/ml, P= 0.001), IR fell (3.37 to 1.73, P=0.002), insulin secretion fell (217 to 124, P=0.004), sex hormone-binding globulin rose (31 to 43 nmol/l, P=0.006), and HDL cholesterol rose (38 to 42 mg/dl, P=0.003). On pioglitazone + metformin diet, the occurrence of expected menses was 2-fold higher than on metformin diet (P<0.0001). CONCLUSIONS: In women with PCOS who failed to respond optimally to metformin, when pioglitazone was added, insulin, glucose, IR, insulin secretion, and DHEAS fell, HDL cholesterol and sex hormone-binding globulin rose, and menstrual regularity improved, without adverse side-effects.     

Association between polycystic ovary syndrome and female-to-male transsexuality

BACKGROUND: The aim of this study is to understand the relationship between polycystic ovary syndrome (PCOS), altered hormonal characteristics and insulin resistance in female-to-male (FTM) transsexual patients. METHODS: We studied 69 Japanese FTM cases, aged 17-47 years, who were seen in the Gender Identity Disorder Clinic of Sapporo Medical University Hospital between December 2003 and May 2006. The subjects had never received hormonal treatment or sex re-assignment surgery. Prior to treatment, they received physical examinations entailing measurement of anthropometric, metabolic and endocrine parameters, after which we compared the values obtained according to the presence or absence of PCOS and/or obesity. Insulin resistance was determined using the homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: Of the 69 participating FTM cases, 40 (58.0%) were found to have PCOS. Of the 49 for whom HOMA-IR was calculated, 15 (30.6%) also showed insulin resistance, whereas of the 59 for whom adiponectin was measured, 18 (30.5%) showed hypoadiponectinaemia. Of 69 for whom androgens were measured, 29 (39.1%) showed hyperandrogenaemia. Insulin resistance was associated with obesity but not with PCOS. In contrast, hyperandrogenaemia was associated with both PCOS and obesity. CONCLUSION: FTM transsexual patients have a high prevalence of PCOS and hyperandrogenaemia.     

Follicular hyperandrogenism and insulin resistance in polycystic ovary syndrome patients with normal circulating testosterone levels

Polycystic ovary syndrome (PCOS) is a common reproductive disease with high heterogeneity. The role of excess androgen in PCOS etiology remains disputed, since around 20%–50% of PCOS women do not display hyperandrogenemia. The microenvironment of the ovary critically influences follicular development. In the present study, we assessed the role of androgen in PCOS by investigating whether excessive follicular fluid androgen was present in PCOS patients with normal serum androgen levels and influenced by follicular fluid insulin resistance (IR). Follicular fluid samples of 105 women with PCOS and 105 controls were collected. Levels of steroid hormones, glucose and insulin in the follicular fluid were examined and compared with data from serum biochemistry tests. We found that 64.9% (63/97) of PCOS patients with normal serum androgen levels displayed abnormally high follicular fluid androgen level. The follicular fluid androgen level was positively correlated with follicular fluid IR within a certain range and follicular fluid estrogen-to-testosterone (E2/T) ratio was significantly reduced in these patients. These results indicated that there existed a subgroup of PCOS patients who displayed excessive follicular fluid androgen and IR despite their normal circulating testosterone (T) levels. Our study highlights the importance of ovary hyperandrogenism and IR in the etiology of PCOS.     

Leptin concentrations in hirsute women with polycystic ovary syndrome or idiopathic hirsutism: influence on LH and relationship with hormonal, metabolic, and anthropometric measurements.

BACKGROUND: The known association between leptin, obesity and insulin action suggests that leptin may have a role in polycystic ovarian syndrome (PCOS) but this has only been addressed peripherally. METHODS: We assessed the influence of leptin on LH and investigated the relationship between leptin and body mass index (BMI), waist:hip ratio (WHR), androgen concentrations, fasting insulin and insulin:glucose ratio (IGR) in 27 women with PCOS and in 20 age- and weight-matched women with regular, ovulatory menstrual cycles and idiopathic hirsutism (IH). RESULTS: Leptin concentrations were significantly higher in obese PCOS women than in normal weight women with either PCOS or IH (P = 0.0028), but did not differ between obese women with PCOS and IH. WHR, insulin concentrations and IGR were significantly higher in obese PCOS patients in comparison with the three other groups. In IH patients, the association between leptin concentrations and WHR was lost after adjustment for BMI. In PCOS patients, a significant correlation was observed between leptin and fasting insulin concentrations, IGR, WHR and LH. After adjustment for BMI, only the correlation with LH remained significant. A stepwise regression model was set up with LH as the dependent variable to test the hypothesis that the concentrations of leptin might be modulating the concentrations of LH in PCOS patients. The relationship of LH concentrations with IGR was found to be BMI dependent. In contrast, leptin concentrations contributed negatively and significantly to LH concentrations, independently of either BMI or IGR. CONCLUSIONS: We speculate that the known attenuation in basal or stimulated response of LH in obese PCOS patients might be related to leptin resistance, which could influence LH hypersecretion. In IH ovulatory patients, normal LH concentrations suggest the presence of preserved regulatory mechanisms of GnRH pulsatility. Further studies are needed to specifically investigate the proposed correlation between leptin and GnRH modulation in PCOS.     

Difference in body weight between American and Italian women with polycystic ovary syndrome: influence of the diet

BACKGROUND: The study aim was to determine differences in body mass in two populations of women (USA and Italy) with polycystic ovary syndrome (PCOS), and to assess the effect of diet on body mass and cardiovascular risk factors. METHODS: Pools of women with PCOS from the USA (n = 343) and Italy (n = 301), seen between 1993 and 2001, were available for assessment. From these populations, 20 women who were seen consecutively in 2001 at each site had detailed analyses of diet and cardiovascular risk factors. RESULTS: In the entire group, American women had a significantly higher body mass compared with Italian women (P < 0.01). Also, the 20 women consecutively evaluated in the USA had a significantly higher mean (+/- SD) body mass index (40.3 +/- 1.0 kg/m(2)) than in Italy (29.7 +/- 1.0 kg/m(2)). US women had worse insulin resistance, lower levels of high-density lipoprotein-cholesterol (HDL-C) (P < 0.01) and higher levels of triglycerides (P < 0.01). Dietary analysis in the two groups indicated that the total daily calorific intake was similar (USA 2277 +/- 109; Italy 2325 +/- 68 Kcal), with no appreciable differences in dietary content of protein, carbohydrate and fat. However, the dietary saturated fat content was significantly higher in US women (31.9 +/- 3 versus 18.2 +/- 2 g/day, P < 0.01). Saturated fat intake correlated negatively with HDL-C (P < 0.01). CONCLUSIONS: Among women with PCOS, body mass was significantly higher in US women compared with Italian women. However, total calorie intake and dietary constituents were similar, except for a higher saturated fat in US women. It is hypothesized that diet alone does not explain differences in body mass; genetic and lifestyle factors likely contribute. An increased saturated fat intake may worsen the cardiovascular risk profile.     

The effects of chemotherapy and long-term gonadotrophin suppression on the ovarian reserve in premenopausal women with breast cancer

BACKGROUND: Reproductive function following cancer treatment is of increasing importance with improving survival rates. We therefore assessed the markers of the ovarian reserve in premenopausal women, to investigate and compare the effects of chemotherapy and long-term gonadotrophin withdrawal on ovarian function. METHODS: Fifty premenopausal (age range 28-52 years) women with early breast cancer were recruited. Serum hormone and ovarian ultrasound measurements were taken before treatment and at intervals up to 1 year during chemotherapy or gonadotrophin suppressive therapy. RESULTS: Pretreatment samples indicated a fall in anti-Müllerian hormone (AMH) concentration with age before changes in other hormone concentrations. AMH concentration showed a rapid and marked fall during chemotherapy, with undetectable concentrations in many women (P<0.0001). Inhibin B concentration showed a lesser fall (P<0.0001), whereas estradiol (E2) concentrations were maintained. Both antral follicle count (AFC) and ovarian volume fell (P<0.0001 and P<0.05 respectively). Regimens containing taxanes in addition to cyclophosphamide showed increased gonadotoxicity. Gonadotrophin suppression resulted in expected falls in E2 (P<0.05) and inhibin B (P<0.001) levels, but also resulted in a delayed fall in AMH level after 6 months (P<0.0001). CONCLUSIONS: These data confirm the value of AMH concentration as an early indicator of ovarian ageing including assessment of chemotherapy-induced ovarian follicle loss. FSH and AMH concentration measurements may be useful for the comparison of ovarian toxicity of different chemotherapy regimens.     

Elevated ambulatory day-time blood pressure in women with polycystic ovary syndrome: a sign of a pre-hypertensive state?

The aim of this study was to evaluate office and 24 h bloodpressures in women with polycystic ovary syndrome (PCOS) andnormal controls in relation to insulin sensitivity. Office bloodpressure, insulin sensitivity (euglycaemic hyperinsulinaemicclamp) and body fat distribution (skin-folds, waistrhip ratio)were investigated in 36 women with PCOS and 55 controls [bodymass index (BMI) for PCOS patients, mean (confidence interval)263 (24.6–282); controls, 25.1 (24.0–26.9)], andambulatory 24 h blood pressure was recorded in representativesubgroups of 17 and 16 women respectively. Compared with thecontrols, the women with PCOS had higher day-time systolic (meanSD,12611 versus 11912 mm Hg, P < 0.05) and mean arterial bloodpressures (927 versus 867 mm Hg, P < 0.05) in ambulatoryrecordings, and greater increases in pulse rate (70%; P <0.05) from night to day-time recordings, whereas the groupsdid not differ significantly in day-time diastolic blood pressure(746 versus 706 mm Hg, P = 0.05) or in night-time recordings.The women with PCOS had a more pronounced truncal-abdominalfat distribution (P < 0.05) and a lower insulin-mediatedglucose disposal (P < 0.01) during the clamp. The increasedday-time blood pressures in women with PCOS persisted afteradjusting for BMI, body fat distribution and insulin resistance.It is concluded that women with PCOS have an increased prevalenceof labile blood pressure, which may indicate a pre-hypertensivestate, adding a further risk factor for cardiovascular diseasein these women.     

The effects of a gonadotrophin-releasing hormone agonist on treatment with low dose follicle stimulating hormone in polycystic ovary syndrome

The objective of this study was to investigate whether the incidenceof monofollicular growth during stimulation with low dose folliclestimulating hormone (FSH) changes when adjuvant gonadotrophin-releasinghormone agonist (GnRHa) pre-treatment is administered in polycysticovary syndrome (PCOS). One group of patients (group 1) sufferingfrom clomiphene resistant PCOS was stimulated with low doseFSH. The results were compared with those from another groupof similar patients (group 2) subsequently stimulated with lowdose FSH combined with GnRHa. In group 1 15 patients had 39stimulation cycles performed; in group 2 13 patients had 33stimulation cycles performed. In group 1 44% of cycles weremonofollicular, whilst the corresponding figure in group 2 was14% (P = 0.04). Evidence was found for postponed atresia ingroup 2. In both groups 1 and 2 interindividual and intra-individualvariability of the FSH dose inducing follicular growth wereobserved. We concluded that during the use of GnRHa, stimulationwith low dose FSH less frequently resulted in monofolliculargrowth, possibly due to postponed atresia. Furthermore, theuse of GnRHa does not abolish the inter- and intra-individualvariability of the FSH dose inducing ongoing follicular growth.     

Influence of hypo- and hyperglycaemia on plasma leptin concentrations in healthy women and in women with polycystic ovary syndrome

BACKGROUND: Insulin resistance and obesity play an important role in the pathogenesis of polycystic ovary syndrome (PCOS). It is known that experimentally induced insulin resistance diminishes the stimulatory effect of insulin on leptin secretion. It is not yet known whether the long-term insulin resistance as found in PCOS patients alters the leptin response to hypo- and hyperglycaemia. METHODS: We induced hyper- and hypoglycaemia by glucose clamp technique in 7 patients with PCOS and 20 healthy controls. After a plasma glucose level of 8.8 mmol/l was reached, the plasma glucose level was reduced stepwise to 6.8, 4.8 and 2.8 mmol/l. RESULTS: The PCOS patients required lower glucose infusion rates to reach the glycaemic targets (P < 0.05). Serum insulin and C-peptide concentrations increased significantly during the clamp compared with the baseline in both groups (P < 0.001 for insulin, and P < 0.001, P < 0.005 for C-peptide control and PCOS, respectively) and increased significantly more in PCOS patients compared with the control group (both P < 0.05). Basal leptin levels were significantly higher in the PCOS group than in the control group (P = 0.005). In the controls, the leptin concentration increased significantly during the clamp (P < 0.001 for each glycaemic target), whereas in the PCOS group, leptin secretion increased only during hypoglycaemia (P = 0.04). CONCLUSIONS: Compared with the healthy controls, the response of leptin secretion to hyper- and hypoglycaemia was diminished in PCOS patients. Changes in leptin secretion seem not to be caused by hyper- and hypoglycaemia, but rather by hyperinsulinaemia. Reduced insulin sensitivity seems to be responsible for the diminished leptin response, which might contribute to the obesity found in PCOS patients.     

Polymorphisms in the insulin receptor substrate-1 (IRS-1) gene and the insulin receptor substrate-2 (IRS-2) gene influence glucose homeostasis and body mass index in women with polycystic ovary syndrome and non-hyperandrogenic controls

BACKGROUND: We aimed to evaluate the influence of the Gly972Arg variant of the insulin receptor substrate-1 gene (IRS-1) and the Gly1057Asp variant in IRS-2 on insulin resistance and glucose tolerance in women with polycystic ovary syndrome (PCOS) and healthy controls. METHODS: Genotypes, allelic frequencies, indexes of insulin resistance, glucose tolerance and hormone profiles were studied in a large sample of Spanish PCOS (n = 103) women compared with a control group (n = 48) of healthy women matched for body mass index. RESULTS: No differences in genotype or allelic frequencies were found between PCOS patients and healthy controls. When considering control subjects and PCOS patients as a whole, IRS-1 Arg972 carriers also presented with increased fasting insulin (133 +/- 60 versus 95 +/- 67 pmol/l, P = 0.008) and insulin resistance measured by homeostasis model assessment (4.3 +/- 2.1 versus 3.1 +/- 2.4, P = 0.009) compared with subjects homozygous for Gly972 alleles. These differences were even higher when restricting the analysis to PCOS patients. Subjects homozygous for the Gly1057 allele of IRS-2 presented with increased 60 and 90 min oral glucose tolerance test (OGTT) glucose levels compared with carriers of one or two Asp1057 alleles (7.9 +/- 2.1 versus 7.1 +/- 2.1 mmol/l, P = 0.042 and 7.0 +/- 2.1 versus 6.0 +/- 1.8 mmol/l, P = 0.014), and a similar tendency was observed for 120 min OGTT glucose levels. CONCLUSIONS: The Gly972Arg in IRS-1 and Gly1057Asp in IRS-2 polymorphisms influence glucose homeostasis in premenopausal women, but are not associated with PCOS.