Comparison of ovarian stromal blood flow between fertile women with normal ovaries and infertile women with polycystic ovary syndrome

BACKGROUND: Conflicting information exists in the literature with respect to ovarian stromal blood flow in women with polycystic ovary syndrome (PCOS). We compared the ovarian stromal blood flow and serum vascular endothelial growth factor (VEGF) concentration between fertile women with normal ovaries and infertile women with PCOS. METHODS: In the second to fourth day of the menstrual period, they underwent transvaginal scanning with three-dimensional (3D) power Doppler to determine total antral follicle count (AFC), total ovarian volume, total ovarian vascularization index (VI), flow index (VFI) and vascularization flow index (VFI). Serum FSH, LH and VEGF concentrations were also checked. RESULTS: 107 fertile controls and 32 PCOS women were recruited. Fertile controls and PCOS women had similar total ovarian VI/FI/VFI after controlling for age of the woman, although PCOS women had significantly higher total AFC, total ovarian volume and serum LH concentration than fertile controls. Total ovarian VI/FI/VFI were significantly higher in normal weight (BMI < 25 kg/m2) PCOS women than their overweight (> or = 25 kg/m2) counterparts. CONCLUSIONS: Fertile controls and PCOS women had similar total ovarian 3D power Doppler flow indices. Normal weight PCOS women had significantly higher total ovarian 3D power Doppler flow indices than their overweight counterparts.     

Contraception: Ovarian stromal blood flow in women with polycystic ovaries--a possible new marker for diagnosis?

Blood flow changes in the ovarian stroma of women embarkingon in-vitro fertilization treatment were assessed on day 2 or3 of the menstrual cycle using colour and pulsed Doppler ultrasound.Women were divided into three groups: group 1, 63 women withregular, ovulatory menstrual cycles and normal ovaries on ultrasoundscan; group 2, 13 women similar to group 1 but with polycysticovaries (PCO) on ultrasound scan; and group 3, 12 women withbiochemical evidence of previous anovulatory cycles and/or oligo-menorrhoeaand/or elevated serum luteinizing hormone concentrations (>10IU/1) in the early follicular phase together with PCO on ultrasoundscan. A subjective assessment of the intensity and quantityof coloured areas in the ovarian stroma appeared to be greaterin both groups 2 and 3 compared with group 1. Mean (SEM) ovarianstromal peak systolic blood flow velocity (V_max) was 16.88 (1.79)and 16.89 (2.36) cm/s in groups 2 and 3 respectively. Thesevelocities were significantly greater than the mean (SEM) ovarianstromal V_max of group 1; 8.74 (0.68) cm/s (P < 0.001). Mean(SEM) ovarian stromal time averaged maximum velocity (TAMX)was 10.55 (0.91) and 10.89 (1.80) cm/s in groups 2 and 3 respectively,both significantly greater than mean ovarian stromal TAMX ofgroup 1, (P < 0.001). There was no significant differencein pulsatility index (PI) between the three groups. There thusappears to be significantly greater ovarian stromal blood flowvelocity in women with polycystic ovaries as detected by colourand pulsed Doppler ultrasound. Increased ovarian stromal bloodvelocity may be a new parameter to assist in the ultrasounddiagnosis of PCO. The increase in stromal blood flow velocitymay help to explain the excessive response often seen duringgonadotrophin administration in women with PCO and is consistentwith the theory that the PCO may be a primary disorder of theovary.     

Ovarian stromal blood flow changes after laparoscopic ovarian cauterization in women with polycystic ovary syndrome

BACKGROUND: Women with PCOS have significant differences in intra-ovarian and uterine artery haemodynamics. The aims of this study were to compare the ovarian stromal blood flow before and after laparoscopic ovarian diathermy, and to evaluate the value of these parameters in predicting the outcome of treatment in women with polycystic ovaries. METHODS: Colour Doppler blood flow within the ovarian stroma was recorded and serum concentrations of FSH, LH and testosterone were measured in 52 women with polycystic ovaries before and after laparoscopic ovarian diathermy. Ovulation was evaluated by folliculometry and progesterone assay in the first menstrual cycle after operation. RESULTS: Six to 10 weeks after the diathermy, serum concentrations of LH and testosterone decreased significantly (P = 0.001). The mean +/- SD peak systolic velocity decreased from 14.04 +/- 6.28 to 12.49 +/- 6.32 cm/s (P = 0.001), pulsatility index increased from 0.98 +/- 0.36 to 1.78 +/- 0.72 (P = 0.001), and resistance index increased from 0.55 +/- 0.16 to 0.71 +/- 19 (P = 0.001). A total of 73% of the women ovulated. There were significant negative correlations between pulsatility index and LH (r = -0.43, P = 0.001), pulsatility index and testosterone (r = -0.40, P = 0.003) and pulsatility index and LH/FSH ratio (r = -0.53, P = 0.001). CONCLUSIONS: Laparoscopic ovarian diathermy in women with polycystic ovary syndrome may result in a decrease in ovarian stromal blood flow velocity. There was a significant correlation between hormonal and ovarian stromal blood-flow changes. Changes in the Doppler parameters were significantly higher in women who ovulated. The measurement of ovarian stromal blood flow by colour Doppler may be of value in predicting the outcome of treatment.     

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.     

Immunolocalization of Fas and Fas ligand in the ovaries of women with polycystic ovary syndrome: relationship to apoptosis

Both Fas (APO-1, CD95), an apoptosis-inducing receptor, and its ligand, Fas ligand (FasL, CD95L), have been localized to the ovary. Granulosa cell apoptosis occurs in antral follicular atresia. In polycystic ovary syndrome (PCOS), antral follicles accumulate with some atretic features. The ovarian expression of Fas and FasL was examined in PCOS by immunohistochemistry and correlated with immunodetection of apoptotic cells. Fas immunostaining was present in pre-antral follicle oocytes, some primary and secondary pre-antral follicle granulosa cells, and both granulosa and theca of antral follicles. Thecal staining persisted with advancing atresia, while granulosa staining declined. In antral follicles, abundant Fas-positive cells co-localized with scattered nuclei immunopositive for apoptosis. Ovarian vascular myocytes were strongly Fas-immunopositive. FasL immunostaining was present in pre-antral follicles in oocytes and variably in granulosa. In antral follicles, granulosa and thecal FasL staining increased with advancing atresia. Normal control ovaries showed follicular Fas and FasL staining patterns similar to those in PCOS, but vascular staining was less prominent. In one healthy follicle, Fas immunostaining was seen in the oocyte and weakly in mural granulosa and theca interna. The results suggest that in PCOS, an alteration in Fas-mediated apoptosis, does not cause abnormal folliculogenesis, but may promote ovarian vascular remodelling.     

Comparative study of plasma ghrelin levels in women with polycystic ovary syndrome, in hyperandrogenic women and in normal controls

BACKGROUND: Ghrelin is a novel peptide associated with energy balance, obesity, and perhaps gonadal function. The present study was designed in order: (i) to compare plasma ghrelin levels between women with PCOS, women who presented only with hyperandrogenaemia and healthy controls; and (ii) to investigate the relationship between circulating ghrelin and the heterogeneity of clinical and biochemical manifestations of PCOS. METHODS: Two hundred and fifty-nine women with PCOS, 25 women who had only hyperandrogenaemia and 46 controls, were studied. Women with PCOS were further divided, based on the presence of chronic anovulation, biochemical hyperandrogenaemia, clinical hyperandrogenism, and polycystic ovary morphology on ultrasound evaluation. In all women, the basal levels of gonadotrophins, androgens, 17-OH-progesterone, sex hormone-binding globulin, glucose, insulin and ghrelin were measured. RESULTS: Women with PCOS had lower ghrelin levels, compared to both women with hyperandrogenaemia and controls; women with hyperandrogenaemia had lower ghrelin levels, compared to controls, but not significantly so. While PCOS-associated hyperandrogenaemia was inversely related to ghrelin levels, anovulation and polycystic ovary morphology were associated with higher concentrations. Ghrelin levels were negatively correlated with 17-OH-progesterone levels. CONCLUSIONS: In PCOS, circulating ghrelin and androgens are inversely related and it is possible that this peptide is involved in steroidal synthesis and/or action. It is also likely that different clinical and biochemical manifestations of the syndrome are also associated with different ghrelin concentrations.     

The effects of the somatostatin analogue octreotide on ovulatory performance in women with polycystic ovaries

The elevated luteinizing hormone (LH) and androgen concentrationscharacteristic of women with polycystic ovaries (PCO) are consideredcrucial factors in their infertility. The somatostatin analogueoctreotide lowers LH and androgen concentrations in women withPCO. The effects of octreotide given concurrently with humanmenopausal gonadotrophin (HMG) were therefore compared withthat of HMG alone in 28 infertile women with PCO resistant toclomiphene. In 56 cycles of combined HMG and octreotide therapythere was more orderly follicular growth compared with the multiplefollicular development observed in 29 cycles in which HMG wasgiven alone (mean number of follicles > 15 mm diameter onthe day of human chorionic gonadotrophin (HCG) administration:2.5 ± 0.2 and 3.6 ± 0.4 respectively; P = 0.026).There was a significantly reduced number of cycles abandoned(>4 follicles > 15 mm diameter on day of HCG) in patientstreated with octreotide + HMG, so that HCG had to be withheldin only 5.4% of cycles compared to 24.1% with HMG alone (P <0.05). The incidence of hyperstimulation was also lower on combinedtreatment. Octreotide therapy resulted in a more ‘appropriate’hormonal milieu at the time of HCG injection, with lower LH,oestradiol, androstenedione and insulin concentrations. Althoughgrowth hormone concentration was similar on both regimens, significantlyhigher insulin growth factor-I concentrations were observedon the day of HCG in women on combined therapy than on HMG alone.     

Ovary: Follistatin concentrations in follicular fluid of normal and polycystic ovaries

Follistatin (FS) is an activin/inhibin binding protein whichis believed to act in an autocrine/paracrine manner to regulategrowth and differentiation. Although FS has been identifiedin human follicular fluid, it remains unclear how its concentrationchanges during selection and atresia, and what the concentrationsof FS are in follicles of women with polycystic ovary syndrome(PCOS). Towards this goal, we have measured by radioimmunoassaythe concentrations of FS in follicular fluid obtained from dominantand atretic cohort follicles of normal cycling women, preovulatoryfollicles of in-vitro fertilization (IVF) patients, and smallGraafian follicles of patients with PCOS. In all cases, thefollicular fluid concentration of FS was much higher (100-fold)than that reported in serum. The FS concentrations (ng/ml) were203 ± 42 (normal dominant), 185 ± 17 (atreticcohort), 185 ± 5 (IVF), and 250 ± 14 (PCOS). Therewas no statistical difference between these mean values of FS.Further, there were no significant correlations between thefollicular fluid concentrations of FS and the concentrationsof oestradiol, progesterone, or androstenedione. These resultsindicate that human Graafian follicles, regardless of whetherthey are healthy or atretic, normal or PCOS, contain high steady-stateconcentrations of FS in the micro-environment. Collectively,these data fit with the hypothesis that major increases anddecreases in the concentration of FS in the micro-environmentmay not play a key role in the mechanisms of selection, atresia,and PCOS in women. The possibility of regulation of intrinsicactivin and inhibin activity through FS binding is discussed.     

Ovarian steroidogenic response to human chorionic gonadotrophin in obese women with polycystic ovary syndrome: effect of metformin.

BACKGROUND: The aim of the present study was to investigate the steroidogenic response pattern to HCG in obese women with polycystic ovary syndrome (PCOS) and the possible effects of metformin treatment on it. METHODS: A single injection of human chorionic gonadotrophin (HCG, 5000 IU) was given to 12 obese [body mass index (BMI) > or = 27 kg/m2] women with PCOS and to 27 control women. Blood samples for assays of 17alpha-hydroxyprogesterone (17-OHP), androstenedione, testosterone and oestradiol were collected at baseline and 1, 2 and 4 days after the injection. Responses to HCG were also assessed in the PCOS women after 2-month treatment with metformin (500 mg x 3 daily). RESULTS: Serum 17-OHP and oestradiol concentrations peaked at 24 h in the PCOS women and preceded the maximum testosterone concentration, which was seen at 48 h. In the control women the maximum concentrations of all these steroids were reached 96 h after HCG. After metformin treatment, the basal serum testosterone concentration and the areas under the androstenedione (AUC(A)) and testosterone (AUC(T)) response curves after HCG decreased significantly. CONCLUSIONS: The results demonstrate that obese PCOS women have a male-type steroidogenic response pattern to a single injection of HCG and a higher androgen secretory capacity than control women, which may be explained by the increased thecal cell activity in the polycystic ovary. The slight alleviation of hyperandrogenism brought about by metformin therapy appears to be due to its effect on ovarian steroidogenesis possibly mediated by decreased insulin action.     

Obstetric outcome in women with polycystic ovarian syndrome

Women with polycystic ovarian syndrome (PCOS) often have insulin resistance and hyperinsulinaemia and may therefore be at an increased risk for gestational diabetes mellitus (GDM). Hyperinsulinaemia may also be associated with pre-eclampsia. Information concerning outcome of pregnancies in PCOS women is scanty and somewhat controversial. Therefore, 99 pregnancies were retrospectively evaluated in women with PCOS and the findings were compared with an unselected control population. The average body mass index (BMI) in PCOS patients was greater than that in controls (25.6 versus 23.0) (P < 0.0001), and PCOS patients were more often nulliparous than controls (76 versus 42%) (P < 0.001). The multiple pregnancy rate was 9.1% in PCOS patients and 1.1% in controls [odds ratio (OR) 9.0; 95% confidence interval (CI) 3.5-23.3]. GDM developed in 20% of the PCOS patients and in 8.9% of the controls (P < 0.001). After logistic regression analysis, BMI >25 seemed to be the greatest predictor for GDM (adjusted OR 5.1; CI 3.2-8.3), while PCOS remained as another independent predictor (adjusted OR 1.9; CI 1.0-3.5). In contrast, PCOS was not a significant predictor for pre-eclampsia, which was merely associated with nulliparity. Premature delivery (16.1% in PCOS and 6.5% in controls) was explained to a large extent by multiple pregnancies and marginally by nulliparity and PCOS. In singleton pregnancies, there was no difference in birth weights, Apgar scores or perinatal morbidity of infants. In conclusion, PCOS slightly increases the risk for GDM, but does not have an important effect on the rate of premature delivery and pre-eclampsia.     

Microvascular dysfunction in women with polycystic ovary syndrome

BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with multiple cardiovascular risk factors and an increased prevalence of arterial dysfunction. However, microvascular dysfunction in PCOS has not been assessed. METHODS: Subjects comprised 12 women with PCOS and 12 age-matched controls with normal ovaries. Microvascular function was assessed by observing forearm skin microvascular erythrocyte flux responses, to cumulative iontophoretic doses of 1% (w/v) acetylcholine (ACh) and 1% (w/v) sodium nitroprusside (SNP), using laser Doppler imaging. RESULTS: Basal microvascular perfusion was comparable in PCOS and controls. The increase in skin microvascular perfusion in response to ACh was however generally blunted in PCOS women (P = 0.018). Peak ACh-induced erythrocyte flux was also less (p < 0.04) in PCOS women (125.1 +/- 21.7, i.e. 5.3-fold basal flux) than in controls (200.8 +/- 28.5, i.e. 8.3-fold basal flux). Analysis of covariance indicated this effect was unrelated to differences in body mass index or serum testosterone but serum insulin may be a weak confounder. No differences were noted between the PCOS and control groups in their response to SNP. CONCLUSION: Despite its limited sample size studied, this is the first demonstration that women with PCOS exhibit microvascular endothelial dysfunction, indicated by an inhibited vasodilatory response to ACh.     

Endocrinology: Subjects with polycystic ovaries without hyperandrogenaemia exhibit similar disturbances in insulin and lipid profiles as those with polycystic ovary syndrome

Polycystic ovaries (PCO) are detected using ultrasonographyin a proportion of women who do not have clinical symptoms ofthe polycystic ovary syndrome (PCOS). The aim of this studywas to compare the metabolic and endocrine differences betweenwomen with such ultrasound-detected PCO and women with PCOS,and to relate these changes to clinical presentation with particularreference to cycle irregularity. A group of 118 women showingPCO on vaginal ultrasound scan was divided into those who hadno hyperandrogenaemia (n = 21) and those who had increased androgensand a clinical presentation normally associated with PCOS (n= 97). These were compared with a reference group of 26 normalsubjects. Glucose tolerance, lipid concentrations and endocrineprofiles were compared between groups. Apart from higher concentrationsof androgens in the PCOS group, there were no significant differencesbetween the PCO and PCOS groups in either fasting and stimulatedinsulin and glucose or in concentrations of sex hormone-bindingglobulin, gonadotrophins and blood lipids or in ovarian volume.Both PCO and PCOS subjects with cycle irregularity had significantlyhigher concentrations of serum fasting and stimulated insulinindependent of androgens and body mass index than those withnormal cycles. It was concluded that: (i) PCO and PCOS patientshave equivalent disturbances in relation to insulin and glucosemetabolism as well as lipid and lipoprotein disturbances comparedto reference subjects; (ii) higher serum insulin values areassociated with menstrual irregularity in both groups; (iii)ultrasound evidence for PCO predicts similar metabolic sequelaeto PCOS and can therefore be used for studies of the geneticsand long term risks for this condition.     

Abnormal glucose tolerance in Chinese women with polycystic ovary syndrome

BACKGROUND: The aims of this study were to analyse the prevalence of impaired glucose tolerance (IGT) and diabetes mellitus (NIDDM) in Chinese polycystic ovary syndrome (PCOS) patients and to assess the ability of screening tests to predict these abnormalities within this population. METHODS: A total of 102 PCOS patients were evaluated. All patients underwent oral glucose tolerance tests (OGTTs) with blood samples taken at 0, 1 and 2 h. The 2-h plasma glucose level was used to categorize subjects as having IGT or NIDDM. RESULTS: The prevalence of IGT was 20.5% and that of NIDDM was 1.9%. There was no significant relationship between BMI and 2-h plasma glucose levels. The areas under the receiver operating characteristic (ROC) curve for glucose to insulin ratio (G:I), homeostasis model assessment (HOMA) and quantitative insulin sensitivity check index (QUICKI) were 0.702, 0.734 and 0.733 respectively. ROC analysis suggested a threshold value of 10.7 in G:I ratio (73.9% sensitivity and 59.5% specificity), a value of 2.14 in HOMA (73.9% sensitivity and 73.4% specificity) and a value of 0.34 in QUICKI (73.9% sensitivity and 73.4% specificity) for the prediction of abnormal glucose tolerance (IGT and NIDDM). CONCLUSIONS: Chinese women with PCOS are at increased risk of IGT and NIDDM. Even though G:I, HOMA and QUICKI are easier than OGTT, they could not replace the role of 2-h post-challenge plasma glucose level in the screening of IGT and NIDDM in PCOS women.     

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.     

Ovulation induction using laparoscopic ovarian drilling in women with polycystic ovarian syndrome: predictors of success

BACKGROUND: Although laparoscopic ovarian drilling (LOD) hasbeen widely used to induce ovulation in women with polycysticovarian syndrome (PCOS), predicting the clinical response tothis treatment remains to be elucidated further. This studywas carried out to identify factors that may help to predictthe outcome of LOD. METHODS: This retrospective study included200 patients with anovulatory infertility due to PCOS who underwentLOD between 1990 and 2002. The influence of the various patients'pre-operative characteristics on the ovulation and pregnancyrates after LOD was evaluated. In addition, women were dividedinto two or three categories according to the severity of eachof the various clinical and biochemical parameters of PCOS.The success rates were compared between the categories of eachfactor using contingency table analyses. Multiple logistic regressionanalysis was used to identify independent predictors of successof LOD. RESULTS: Women with body mass index (BMI) 35 kg/m²,serum testosterone concentration 4.5 nmol/l, free androgen index(FAI) 15 and/or with duration of infertility >3 years seem tobe poor responders to LOD. In LOD responders, serum LH levels>10 IU/l appeared to be associated with higher pregnancy rates.CONCLUSION: Marked obesity, marked hyperandrogenism and/or longduration of infertility in women with PCOS seem to predict resistanceto LOD. High LH levels in LOD responders appear to predict higherprobability of pregnancy.     

Differences in connective tissue gene expression between normally functioning, polycystic and post-menopausal ovaries

Arrested follicular maturation is a characteristic feature of polycystic ovary syndrome (PCOS). Follicles mature in ovarian stroma composed of extracellular matrix (ECM). However, little is known of the expression of ECM genes in polycystic ovaries. The present study compares the expression levels of genes coding for collagens, matrix metalloproteinases (MMP), their inhibitors (TIMP) and cathepsins in polycystic ovaries using fertile and post-menopausal ovaries as controls. In northern analyses, the gene expression profiles of type I and III collagen of PCOS samples resembled those observed in normal follicular phase ovaries, while mRNA levels of proalpha1(IV) collagen and TIMP-3 mRNA were significantly lower in polycystic than control ovaries. During the normal menstrual cycle, an increase was observed in MMP-9 gene expression during the luteal phase. In post-menopausal ovaries, mRNA levels for type I, III and IV collagens and osteonectin were reduced, while the MMP, TIMP (excluding TIMP-3) and cathepsins did not reflect this metabolic down-regulation. Immunohistochemical staining for MMP-9 and TIMP-4 suggested differences between polycystic and normally functioning ovaries. These data demonstrate that normal ovarian functions are associated with changes in production and degradation of ECM. The alterations observed in the production and/or distribution of type IV collagen, TIMP-3 and TIMP-4 suggest involvement of basement membranes in the pathogenesis of PCOS.     

High ovulatory rates with use of troglitazone in clomiphene-resistant women with polycystic ovary syndrome.

This preliminary report reviews our experience with 18 infertile patients with clomiphene-resistant polycystic ovary syndrome (PCOS). In the first treatment cycle, troglitazone was administered alone. During cycles 2-5, clomiphene was added with increments of 50 mg (up to 200 mg/day) if the previous cycle was anovulatory. Basal body temperature charts and serum progesterone were obtained to confirm ovulation. In a total of 66 treatment cycles, ovulation occurred in 44 (67%) and pregnancy in seven (11%). There were no significant changes in body weight, waist:hip ratio or liver enzymes during treatment. Troglitazone, alone or with clomiphene, induced ovulation in 15 of 18 patients (83%) and seven (39%) of them achieved pregnancy. This is the first report on ovulatory rates in clomiphene-resistant women with PCOS when troglitazone was used alone or with clomiphene. Recently, metformin and clomiphene were successfully used in women with PCOS. However, our patients represent a more resistant population of women with PCOS, with each patient serving as her own historical control by previous resistance to clomiphene. Although the pregnancy rate (39%) was promising for clomiphene-resistant women with polycystic ovary syndrome, it does not seem to have a definite advantage over gonadotrophins.     

Mechanism and management of ovulatory failure in women with polycystic ovary syndrome

Polycystic ovary syndrome is the most important cause of chronicanovulation. In women who fail to respond to clomiphene, low-doseFSH given in a step-wise fashion can induce normal folliculargrowth and ovulation. The failure of the action of endogenousFSH in these women may be related to reduced biological activityof circulating FSH, but may also involve inhibition of its actionat follicular level by polypeptide growth factors such as EGF.     

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.     

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.