The treatment of insulin resistance does not improve adrenal cytochrome P450c17alpha enzyme dysregulation in polycystic ovary syndrome

OBJECTIVE: To determine whether metformin. when given to non-diabetic women with polycystic ovary syndrome (PCOS), results in a reduction of insulin resistance and hyperinsulinemia while body weight is maintained. Also we aimed to see whether the reduction in insulin levels attenuates the activity of adrenal P450c17alpha enzyme in patients with PCOS. DESIGN: We investigated the 17-hydroxyprogesterone (17-OHP) and androstenedione responses to ACTH, insulin responses to an oral glucose tolerance test (OGTT) and glucose disposal rate in an insulin tolerance test before and after metformin therapy (500 mg, orally, twice daily, for 12 weeks). METHODS: The presence of hyperinsulinemia in 15 women with PCOS was demonstrated by an OGTT and results were compared with those of 10 healthy women. Insulin sensitivity was measured by the rate of endogenous glucose disposal after i.v. bolus injection of insulin. 17-OHP and androstenedione responses to ACTH were measured in all the women with PCOS and the normal women. RESULTS: Women with PCOS were hyperinsulinemic (102.0+/-13.0 (S.E.M.) VS 46.2+/-4.4 pmol/l) and hyperandrogenemic (free testosterone 15.3+/-1.7 vs 7.9+/-0.6 nmol/l; androstenedione 11.8+/-0.8 vs 8.2+/-0.6 nmol/l) and more hirsute (modified Ferriman-Gallwey score, 17.7+/-1.6 vs 3.0+/-0.3) than healthy women. In addition, women with PCOS had higher 17-OHP and androstenedione responses to ACTH when compared with healthy women. Metformin therapy resulted in some improvement in insulin sensitivity and reduced the basal and post-glucose load insulin levels. But 17-OHP and androstenedione responses to ACTH were unaltered in response to metformin. CONCLUSIONS: PCOS is characterized by hyperactivity of the adrenal P450c17alpha enzyme and insulin resistance. It seems that there is no direct relationship between insulin resistance and adrenal P450c17alpha enzyme dysregulation.     

Metformin versus ethinyl estradiol-cyproterone acetate in the treatment of nonobese women with polycystic ovary syndrome: a randomized study

Metformin, an insulin-sensitizing drug, has been shown to improve ovarian function and glucose metabolism in obese women with polycystic ovary syndrome (PCOS), but its effects and possible benefits in nonobese PCOS subjects are not well known. Seventeen nonobese (body mass index < 25 kg/m(2)) women with PCOS were randomized to receive either metformin (500 mg twice daily for 3 months, then 1000 mg twice daily for 3 months; n = 8) or ethinyl estradiol (EE, 35 microg)-cyproterone acetate (CA, 2 mg) oral contraceptive pills (EE-CA; n = 9). Waist to hip ratio; serum concentrations of sex steroids, glucose, and insulin during a 75-g oral glucose tolerance test; early phase insulin and C-peptide secretion; and insulin sensitivity using a euglycemic hyperinsulinemic clamp were assessed at baseline and at 3 and 6 months of treatment. Metformin did not have any effect on glucose tolerance or insulin sensitivity, but fasting insulin concentrations decreased from 44.4 +/- 5.1 (SE) to 29.8 +/- 4.3 pmol/liter (P = 0.03), the waist to hip ratio decreased from 0.78 +/- 0.01 to 0.75 +/- 0.01 (P = 0.01), and hepatic insulin clearance increased during the treatment. Furthermore, metformin decreased serum testosterone levels from 2.7 +/- 0.3 to 2.0 +/- 0.2 nmol/liter (P = 0.01) and improved menstrual cyclicity. EE-CA did not have any significant effect on glucose tolerance, serum insulin levels, or insulin sensitivity, but it increased slightly the body mass index (P = 0.09) and significantly serum leptin concentrations (P < 0.001) and decreased serum testosterone levels from 2.1 +/- 0.2 to 1.4 +/- 0.2 nmol/liter (P = 0.03). In conclusion, EE-CA seems to be an efficient mode of therapy for hyperandrogenic symptoms associated with PCOS, but its possible negative effects on insulin and glucose metabolism also have to be taken into consideration in nonobese subjects. Metformin improved hyperandrogenism, hyperinsulinemia, and menstrual cyclicity, most likely through its positive effect on insulin clearance and abdominal adiposity. Thus, similarly to obese PCOS women, nonobese PCOS subjects with anovulation may also benefit from metformin treatment.     

Metformin therapy increases insulin-stimulated release of D-chiro-inositol-containing inositolphosphoglycan mediator in women with polycystic ovary syndrome

Some actions of insulin are mediated by putative inositolphosphoglycan mediators, and a deficiency in D-chiro-inositol-containing inositolphosphoglycan (DCI-IPG) may contribute to insulin resistance in women with polycystic ovary syndrome (PCOS). Furthermore, similar effects of DCI and metformin, an insulin-sensitizing drug, have been demonstrated in PCOS women. To determine whether metformin improves insulin actions by increasing biologically active DCI-IPG in women with PCOS, we analyzed DCI-IPG during an oral glucose tolerance test in 19 obese women with PCOS before and after 4-8 wk of metformin or placebo. After treatment, the mean (+/-SE) area under the curve (AUC) during the oral glucose tolerance test of insulin (AUC(insulin)) decreased significantly more in the metformin group, compared with the placebo group [-3574 +/- 962 vs. +1367 +/- 1021 micro IU/min.ml (-26 +/- 7 vs. +10 +/- 7 nmol/min.liter), P = 0.003], but the AUC of DCI-IPG (AUC(DCI-IPG)) decreased similarly in both groups (-1452 +/- 968 vs. -2207 +/- 1021%/min, P = 0.60). However, the ratio of AUC(DCI-IPG)/AUC(insulin) increased by 160% after metformin and decreased by 29% after placebo (P = 0.002 between groups). Moreover, metformin seemed to improve the positive correlation between AUC(DCI-IPG) and AUC(insulin) but not placebo (r = 0.32, P = 0.68 at baseline; r = 0.52, P = 0.12 after metformin; and r = -0.39, P = 0.30 after placebo). We conclude that in obese women with PCOS, metformin may improve the action of insulin in part by improving insulin-mediated release of DCI-IPG mediators, as evidenced by increased bioactive DCI-IPG released per unit of insulin.     

The effects of metformin on insulin resistance and ovarian steroidogenesis in women with polycystic ovary syndrome

OBJECTIVE: Polycystic ovary syndrome (PCOS) is a form of functional ovarian hyperandrogenism and affects approximately 5-10% of women of reproductive age. Insulin resistance and hyperinsulinaemia appear to be almost universal feature of the polycystic ovary syndrome. Abnormal regulation of cytochrome P450c17alpha causes the exaggerated secretion of ovarian androgens in PCOS. The aim of the present study was to determine whether reduction of insulin levels by metformin would attenuate FSH, LH, 17-Hydroxyprogesterone (17-OHP) and androstenedione hyperresponsiveness to buserelin testing in PCOS women. DESIGN: The presence of hyperinsulinaemia in 16 women with PCOS was demonstrated by an oral glucose tolerance test (OGTT) and results were compared with 13 healthy women. PCOS women were also evaluated with insulin tolerance test (ITT) for the assessment of insulin sensitivity. FSH, LH, 17-OHP and androstenedione responses to buserelin testing were measured in all the women with PCOS. PCOS patients were given metformin (500 mg, orally, two times daily) for 12 weeks and re-evaluated at the end of the treatment period. RESULTS: Women with PCOS were hyperinsulinaemic (basal insulin 92.1+/-14.3 vs. 44.0+/-4.0 pmol/l; AUCinsulin 68087.4+/-8862.3 vs. 13075.5+/-1327.6 pmol/lx120 min) compared with healthy women. Metformin therapy improved menstrual disturbances in 25% of the women with PCOS and also resulted in some improvement in insulin sensitivity and reduced basal and post glucose load insulin levels. However, FSH, LH, 17-OHP and androstenedione responses to buserelin testing were unaltered in response to metformin. CONCLUSION: It is clear that PCOS is often associated with profound insulin resistance and hyperinsulinaemia. These abnormalities explain the increased prevalence of glucose intolerance in women with PCOS and metformin has beneficial effects on insulin sensitivity in women with PCOS. Amelioration of hyperinsulinaemia has no significant effect on ovarian cytochrome P450c17alpha enzyme activity. However, it can be used in obese women with PCOS as an adjuvant therapy and long term studies should be performed to evaluate the endocrine effects of metformin in women with PCOS.     

Effects of rosiglitazone in obese women with polycystic ovary syndrome and severe insulin resistance

Our objective was to evaluate the effectiveness of the insulin-sensitizing agent rosiglitazone in obese women with polycystic ovary syndrome (PCOS) and severe insulin resistance. Twelve obese women with PCOS were recruited. All were hirsute and anovulatory with acanthosis nigricans indicating severe insulin resistance. All women were treated with 4 mg of rosiglitazone daily for 6 months. A standard 75-g oral glucose tolerance test with insulin levels was performed before and after the women were treated with rosiglitazone. Glucose and insulin areas under the curve (AUC) were calculated. Serum levels of total and free testosterone, dehydroepiandrosterone sulfate, LH, and 17-hydroxyprogesterone were also measured before and after treatment. The body mass index was determined before and after treatment. There was a highly significant (r = 0.881, P < 0.0001) positive correlation between insulin response during oral glucose tolerance test and basal total testosterone levels. After treatment with rosiglitazone, there were significant decreases in fasting insulin levels (46.0 +/- 6.5 vs. 16.9 +/- 2.0 microU/ml; P < 0.001), insulin AUC (749.3 +/- 136.3 vs. 225.0 +/- 15.7 microU/ml; P = 0.003), fasting glucose levels (90.8 +/- 3.0 vs. 81.8 +/- 1.9 mg/dl; P = 0.003), and glucose AUC (437.9 +/- 25.0 vs. 322.5 +/- 14.7 mg/dl; P < 0.001). Both total testosterone (96.3 +/- 17.3 vs. 56.1 +/- 5.8 ng/dl; P = 0.01) and free testosterone (5.8 +/- 0.6 vs. 3.4 +/- 0.5 pg/ml; P < 0.001) decreased significantly after treatment, although there was no significant change in LH levels. Levels of SHBG increased significantly (18.3 +/- 3.4 vs. 25.8 +/- 6.6 nmol/liter; P = 0.009) after treatment, and dehydroepiandrosterone sulfate levels decreased significantly (P = 0.04). There was no significant change in body mass index (40.4 +/- 2.4 vs. 41.1 +/- 2.7 kg/m(2)). Eleven of the women reverted to regular ovulatory cycles during the treatment period. We conclude that 1) rosiglitazone therapy improves insulin resistance and glucose tolerance in obese women with PCOS; 2) rosiglitazone decreases ovarian androgen production, which appears to be independent of any changes in LH levels; 3) hyperinsulinemia appears to play a key role in the overproduction of ovarian androgens in these women because attenuation of insulin levels is associated with decreased testosterone levels; and 4) short-term rosiglitazone therapy helps restore spontaneous ovulation.     

Orlistat is as beneficial as metformin in the treatment of polycystic ovarian syndrome

The objective of this study was to evaluate and compare the effect of treatment with orlistat vs. metformin on the hormonal and biochemical features of patients with polycystic ovarian syndrome (PCOS). Twenty-one Caucasian women with PCOS [mean (+/-SEM) age 27 +/- 0.9 yr and body mass index 36.7 +/- 3.3 kg/m(2)] participated in this prospective, randomized, open-labeled study. All subjects had an 8-wk run-in period of dietary modification and then randomized to receive either metformin (500 mg three times daily) or orlistat (120 mg three times daily) for 3 months. Weight, blood pressure, and fasting blood samples were taken at screening, randomization, and on completion. Insulin resistance (IR) was calculated using the homeostasis model of assessment (HOMA)-IR method [HOMA-IR = (insulin x glucose)/22.5]. The results are expressed as mean +/- SEM. When compared with baseline, treatment with both orlistat [93.5 +/- 11.5 ng/dl (3.24 +/- 0.4 nmol/liter) vs. 114.5 +/- 11.5 ng/dl (3.97 +/- 0.4 nmol/liter), P = 0.039] and metformin [97.2 +/- 11.5 ng/dl (3.37 +/- 0.4 nmol/liter) vs. 120.0 +/- 8.7 ng/dl (4.16 +/- 0.3 nmol/liter), P = 0.048] produced a significant reduction in total testosterone. Treatment with orlistat produced a 4.69% reduction in weight (99.0 +/- 6.0 vs. 94.6 +/- 6.1 kg, P = 0.002), and this reduction was more significant than the reduction produced by metformin (4.69 vs. 1.02%, P = 0.006). There was no significant reduction seen after either treatment group for fasting insulin, HOMA-IR, SHBG, or any of the lipid parameters studied. In this study, orlistat produced a significant reduction in weight and total testosterone. The reduction in total testosterone was similar to that seen after treatment with metformin. Therefore, orlistat may prove to be a useful adjunct in the treatment of PCOS.     

Lifelong sequential changes in glucose tolerance and insulin secretion in genetically obese Zucker rats (fa/fa) fed a diabetogenic diet

Life-long sequential changes in glucose tolerance and insulin secretion were investigated in genetically obese Zucker rats (fa/fa) fed a diabetogenic diet rich in lard and sucrose. Comparisons were made with lean littermates (Fa/-) receiving normal chow diet. At 3-month intervals, seven to nine lean and obese rats had two permanent venous catheters implanted, allowing stress- and pain-free sampling of blood before, during, and after substrate administration. Intravenous glucose, iv arginine, and oral glucose tolerance were tested. The obese rats progressively developed hyperglycemia and severe hyperinsulinemia; their basal glycemia reached 8.8 +/- 1.1 vs. 5.8 +/- 0.2 mmol/liter in the lean rats at 46 weeks of age; respective insulinemia was 287.7 +/- 61.9 and 18.1 +/- 2.8 mU/liter (mean +/- SD). In the obese rats a distinct loss in glucose tolerance was seen with progression of age in spite of rising stimulated insulin secretion, which suggests progressive development of insulin resistance without exhaustion of B-cell secretory capacity. Absence of insulin deficiency was also suggested by immunohistochemical staining of pancreatic tissue specimens from obese rats, which showed large populations of insulin-containing cells. Like the obese animals, lean rats exhibited a decrease in insulin sensitivity with age. Relating basal individual glycemia and insulinemia, a rise by 1 mmol/liter in glycemia was associated with a 8.8-fold rise in basal insulinemia in lean rats, but only with a 1.8-fold increase in obese rats. Similar correlations for stimulated glycemia and insulinemia suggest impaired glucose sensitivity of pancreatic B-cells in obese vs. lean rats. In conclusion, hyperglycemia and hyperinsulinemia in insulin-resistant obese Zucker rats on a diabetogenic diet are not characterized by quantitatively deficient B-cell secretory capacity, but, rather, by impaired B-cell sensitivity to glucose with qualitatively intact regulation of glycemia and insulinemia at elevated plasma concentrations.     

The effects of short-term medroxyprogesterone acetate and micronized progesterone on glucose metabolism and lipid profiles in patients with polycystic ovary syndrome: a prospective randomized study

In this prospective, randomized study we determined 10-d effects of medroxyprogesterone acetate (MPA) and micronized progesterone (MP) either orally or per vaginally on hormonal parameters, glucose metabolism and lipid profiles in patients with polycystic ovary syndrome (PCOS). Twenty-eight consecutive women with PCOS were randomized to receive 10-d MPA, oral MP, or vaginal MP. Hormonal parameters, insulin levels, oral glucose tolerance test, lipid profiles, and homeostasis model assessment and quantitative insulin sensitivity check indexes were assessed in all groups before and after treatment. Oral MPA and oral MP decreased LH (15.64 +/- 13.17 to 7.27 +/- 4.35 IU/liter, P = 0.028, and 18.85 +/- 11.86 to 10.49 +/- 6.48 IU/liter, P = 0.009, respectively) and total testosterone (5.85 +/- 2.80 to 3.40 +/- 1.72 nmol/liter, P = 0.013, and 5.29 +/- 2.98 to 3.43 +/- 2.10 nmol/liter, P = 0.037, respectively) levels. Hormonal parameters did not change with vaginal MP. Basal insulin (123.42 +/- 97.50 to 87.38 +/- 48.68 pmol/liter; P = 0.021) and homeostasis model assessment levels decreased, and quantitative insulin sensitivity check index increased significantly in the oral MPA group. Low density lipoprotein cholesterol and lipoprotein (a) levels decreased only in the MPA group. In conclusion, short-term oral MP and especially oral MPA might ameliorate insulin sensitivity in patients with PCOS. Vaginal MP has no effect on glucose metabolism and lipid profiles. LH, total testosterone, and insulin levels may be affected from the short-term progesterone treatment.     

Glucose intolerance in obese adolescents with polycystic ovary syndrome: roles of insulin resistance and beta-cell dysfunction and risk of cardiovascular disease

The roles of insulin resistance and insulin secretion in the pathogenesis of glucose intolerance in polycystic ovary syndrome (PCOS) were evaluated in 11 adolescents with impaired glucose tolerance (IGT) and 10 with normal glucose tolerance (NGT). Hepatic glucose production and insulin-stimulated glucose disposal were measured using [6,6-(2)H(2)]glucose and a 3-h hyperinsulinemic (80 mu/m(2).min)-euglycemic clamp. First and second phase insulin secretions were evaluated during a hyperglycemic clamp. Automated blood pressure measurements were made to assess the nocturnal change in blood pressure. Hepatic glucose production was significantly higher in IGT vs. NGT. Insulin-stimulated glucose disposal was not different between the two groups. The first phase insulin level was lower in IGT (207.9 +/- 21.0 vs. 357.0 +/- 62.9 muu/mL; P = 0.025; 1247 +/- 126 vs. 2142 +/- 377 pmol/L) without a difference in second phase insulin. The glucose disposition index (product of insulin sensitivity x first phase insulin) was lower in IGT vs. NGT (278 +/- 40 vs. 567 +/- 119 mg/kg.min; P = 0.023; 1546 +/- 223 vs. 3249 +/- 663 micromol/kg.min). The glucose disposition index correlated inversely with OGTT glucose concentrations at 30, 60, and 120 min. Adolescents with PCOS-IGT lacked the normal nocturnal decline in blood pressure. We conclude that in obese adolescents with PCOS, glucose intolerance is associated with 1) decreased first phase insulin secretion, 2) decreased glucose disposition index, and 3) increased hepatic glucose production. These metabolic abnormalities are precursors of type 2 diabetes and are present early in the course of PCOS. Furthermore, the absence of nocturnal dipping in blood pressure may herald the early expression of cardiovascular disease risk in these adolescents.     

Metformin reduces serum C-reactive protein levels in women with polycystic ovary syndrome

Low-grade chronic inflammation, reflected in elevated levels of serum C-reactive protein (CRP), has recently been linked to obesity, insulin resistance syndromes such as polycystic ovary syndrome (PCOS), and an increased risk of cardiovascular disease. Because the insulin sensitizer metformin has been shown to improve metabolic disturbances in PCOS, it was of particular interest to examine serum CRP levels during metformin therapy. Twenty nonobese women [body mass index (BMI) /==" BORDER="0"> 27 kg/m(2)) with PCOS were randomized to receive either metformin (500 mg twice daily for 3 months, then 1000 mg twice daily for 3 months) or ethinyl estradiol (35 micro g)-cyproterone acetate (2 mg) oral contraceptive pills. The serum concentrations of CRP were significantly higher in obese than in nonobese subjects at baseline [4.08 +/- 0.53 (SE) vs. 1.31 +/- 0.28 mg/liter; P < 0.001] and correlated to BMI and to a lesser extent waist-hip ratio, suggesting that the elevated CRP levels may be related to obesity and not only to PCOS itself. During metformin treatment, serum CRP levels decreased significantly from 3.08 +/- 0.7 mg/liter to 1.52 +/- 0.26 mg/liter at 6 months in the whole study population (P = 0.006) and especially in obese subjects. In contrast, the treatment with ethinyl estradiol-cyproterone acetate increased serum CRP levels from 2.91 +/- 0.68 mg/liter to 4.58 +/- 0.84 mg/liter (P < 0.001). Whether this effect is related to estrogen action in the liver or whether it reflects increased inflammation process and possible risks for cardiovascular disease remains unclear. The decrease of serum CRP levels during metformin therapy is in accordance with the known beneficial metabolic effects of this drug and suggests that CRP or other inflammation parameters could be used as markers of treatment efficiency in women with PCOS.     

Insulin resistance is attenuated in women with polycystic ovary syndrome with the Pro(12)Ala polymorphism in the PPARgamma gene

Polycystic ovary syndrome (PCOS) is common in women of reproductive age and is associated with a high risk for development of type 2 diabetes. Insulin resistance, a key component in the pathogenesis of PCOS and glucose intolerance, is ameliorated by the thiazolidinediones, synthetic ligands for the PPARgamma. In the present study we have examined the relationship of the Pro(12)Ala polymorphism in the PPARgamma gene (PPARG) to clinical and hormonal features of PCOS. Two hundred and eighteen women with PCOS had a 75-g oral glucose tolerance test, and blood was obtained for measurement of serum androgen levels. Sixty percent of the subjects were Caucasian, 26% were African-American, 6% were Hispanic, 6% were South Asian, and 2% were Middle-Eastern. Compared with Caucasians, the African-American group had a higher prevalence of diabetes (19% vs. 5%, respectively), were more obese (body mass index, 40.9 +/- 1.8 vs. 36.3 +/- 0.8 kg/m(2); P < 0.05), and were more insulin resistant. Twenty-eight of 218 subjects had the Ala allele, all in the heterozygous state. The frequency of the Ala allele varied among the groups: 0.01 in African-Americans, 0.08 in Caucasians, and 0.15 in Hispanics. Nondiabetic Caucasians with an Ala allele (Pro/Ala group) were more insulin sensitive than those in the Pro/Pro group, as evidenced by a lower homeostasis model assessment index (5.18 +/- 1.33 vs. 6.54 +/- 0.54; P < 0.05) and lower levels of insulin at both the fasting (132 +/- 27 vs. 165 +/- 12 pmol/liter; P = 0.03) and 2 h (688 +/- 103 vs. 10190 +/- 99 pmol/liter; P = 0.04) time points during the oral glucose tolerance test. We conclude that Pro(12)Ala in PPARG is a modifier of insulin resistance in Caucasian women with PCOS.     

Responses of serum androgen and insulin resistance to metformin and pioglitazone in obese, insulin-resistant women with polycystic ovary syndrome

Severe insulin resistance is a key abnormality in obese women with polycystic ovary syndrome (PCOS). The purpose of this study was to evaluate whether pioglitazone decreases insulin resistance (IR) and hyperandrogenism to the same extent as metformin in obese women with PCOS who have not received any previous treatment. Fifty-two women with PCOS were randomly allocated to receive either pioglitazone (30 mg/d, n = 25) or metformin (850 mg three times daily, n = 27) and were assessed before and after 6 months. Body weight, body mass index, and waist to hip ratio increased significantly (P 相似文献   

Increased endothelin-1 levels in women with polycystic ovary syndrome and the beneficial effect of metformin therapy

Women with polycystic ovary syndrome who present with hyperandrogenemia, hyperinsulinemia, and insulin resistance appear to be at high risk of cardiovascular disease. Elevated levels of endothelin-1, a marker of vasculopathy, have been reported in insulin-resistant subjects with endothelial dysfunction. Male gender also seems to be an aggravating factor for cardiovascular disease. In this study we investigated endothelin-1 levels in women with polycystic ovary syndrome, and we evaluated the effect of an insulin sensitizer, metformin, on endothelin-1 levels. Plasma endothelin-1 levels were measured in 23 obese (mean age, 24.3 +/- 4.6 yr; body mass index, 35 +/- 5.6 kg/m(2)) and 20 nonobese women with polycystic ovary syndrome (24.1 +/- 3.6 yr; body mass index, 21.8 +/- 2.5 kg/m(2)) as well as in 7 obese and 10 nonobese healthy, normal cycling, age-matched women. Additionally, endothelin-1 levels were evaluated in a subgroup of women with polycystic ovary syndrome (10 obese and 10 nonobese) 6 months postmetformin administration (1700 mg daily). Our results showed that obese and nonobese women with polycystic ovary syndrome had higher levels of endothelin-1 compared with the controls [obese, 2.52 +/- 1.87 vs. 0.44 +/- 0.23 pmol/liter (by analysis of covariance, P < 0.02); nonobese, 1.95 +/- 1.6 vs. 0.43 +/- 0.65 pmol/liter (P < 0.009)]. All of the participating women with polycystic ovary syndrome (n = 43) when compared with the total group of controls (n = 17) demonstrated hyperinsulinemia (polycystic ovary syndrome, 24.5 +/- 19.6; controls, 11.2 +/- 3.4 U/liter; P < 0.03), lower glucose utilization (M40) during the hyperinsulinemic euglycemic clamps (3.4 +/- 2.4 vs. 5.6 +/- 1.75 mg/kg.min; P < 0.045, by one-tailed test), and higher levels of endothelin-1 (polycystic ovary syndrome, 2.52 +/- 1.87; controls, 0.44 +/- 0.23 pmol/liter; P < 0.02, analysis of covariance covariate for body mass index). A positive correlation of endothelin-1 with free T levels was also shown (r = 0.4, P = 0.002) as well as a negative correlation of endothelin-1 with glucose utilization (r = -0.3; P = 0.033) in the total studied population. Finally, after metformin therapy, endothelin-1 levels were significantly reduced in obese (endothelin-1 before, 3.25 +/- 2.2; endothelin-1 after, 1.1 +/- 0.9 pmol/liter; P < 0.003) and nonobese (endothelin-1 before, 2.7 +/- 2; endothelin-1 after, 0.7 +/- 0.4 pmol/liter; P < 0.01) women with polycystic ovary syndrome, with no change in body mass index. Moreover, after metformin therapy, hyperandrogenemia and hyperinsulinemia were normalized, and glucose utilization improved [obese before: total T, 0.9 +/- 0.15 ng/ml; fasting insulin, 22.2 +/- 12.1 U/liter; glucose utilization, 2.15 +/- 0.5 mg/kg.min; obese after: total T, 0.5 +/- 0.2 ng/ml; fasting insulin, 11.6 +/- 6 U/liter; glucose utilization, 4.7 +/- 1.4 mg/kg.min 9P < 0.003, P < 0.006, and P < 0.002, respectively); nonobese before: total T, 1 +/- 0.5 ng/ml; fasting insulin, 15.5 +/- 7.6 U/liter; glucose utilization, 3.4 +/- 0.7 mg/kg.min; nonobese after: total T, 0.8 +/- 0.5 ng/ml; fasting insulin, 9 +/- 3.8 U/liter; glucose utilization, 6 +/- 1.7 mg/kg.min (P < 0.04, P < 0.02, and P < 0.0008, respectively)]. In conclusion, our data clearly demonstrate that women with polycystic ovary syndrome, obese and nonobese, have elevated endothelin-1 levels compared with the age-matched control group. In addition, 6 months of metformin therapy reduces endothelin-1 levels and improves their hormonal and metabolic profile.     

The biological variation of testosterone and sex hormone-binding globulin (SHBG) in polycystic ovarian syndrome: implications for SHBG as a surrogate marker of insulin resistance

This study was designed to assess the biological variability of total testosterone and SHBG in polycystic ovarian syndrome (PCOS) and to determine the use of SHBG as a surrogate marker of insulin resistance in PCOS. Fasting blood samples were collected at 4-d intervals on 10 consecutive occasions from 12 PCOS patients and 11 age- and weight-matched controls. Duplicate samples were analyzed for SHBG, testosterone, and insulin in a single batch, and insulin resistance was calculated by the homeostasis model assessment method (HOMA-IR). The PCOS group had higher testosterone (mean +/- SD, 3.9 +/- 0.8 vs. 3.2 +/- 1.3 nmol/liter; P = 0.001), lower SHBG (28.6 +/- 17.1 vs. 57.6 +/- 30.2 nmol/liter; P = 0.001), and greater HOMA-IR (5.85 +/- 5.3 vs. 1.67 +/- 0.63 U; P = 0.001) than the controls. In contrast to HOMA-IR (1.09 vs. 0.48 U; P = 0.001), the intraindividual variation in SHBG was lower in the PCOS group (mean, 3.4 vs. 6.3 nmol/liter; P = 0.041). The index of individuality for SHBG and testosterone in PCOS was 0.49 and 0.69, respectively. This study shows that for patients with PCOS, SHBG is an integrated marker of insulin resistance that may be of use to identify insulin-resistant individuals for targeted treatment with insulin-sensitizing agents. However, SHBG and testosterone concentrations measured in isolation are inherently unsuitable for use as tests to detect hyperandrogenemia.     

The investigation of insulin resistance in patients with idiopathic hirsutism

Hirsutism, which is characterized by excessive growth of terminal hair in a male pattern, is a common clinical condition in women. It may result from various causes including polycystic ovary syndrome, nonclassic adrenal hyperplasia, adrenal or ovarian tumors, or it may be idiopathic. Idiopathic hirsutism (IH) is considered to be one of the most common forms of hirsutism. Although not universal, insulin resistance and hyperinsulinemia have been demonstrated in women with polycystic ovary syndrome. Because there are not enough data showing whether patients with IH also have insulin resistance, we intended to investigate the presence/absence of insulin resistance in women with IH. Thirty-two women with IH [mean age, 24.8 +/- 1.2 yr; body mass index (BMI), 24.6 +/- 0.8 kg/m2] and 17 healthy women (mean age, 25.8 +/- 0.6 yr; BMI, 22.5 +/- 0.6 kg/m2) were included in the study. Eight of 32 patients with IH had BMI higher than 30 kg/m2. The presence of insulin resistance was investigated by using basal insulin levels, the oral glucose tolerance test, the i.v. insulin tolerance test, and the homeostasis model assessment (HOMA) score in both groups. Six (18.7%) patients had impaired glucose tolerance (IGT). Overall, patients with IH had significantly (P < 0.05) higher basal insulin levels (10.5 +/- 1.1 mU/liter vs. 5.7 +/- 0.9 mU/liter) and HOMA scores (2.0 +/- 0.2 vs. 1.1 +/- 0.2) and lower plasma glucose disappearance rate values (5.2 +/- 0.2 vs. 6.0 +/- 0.3) than control subjects. However, patients with IGT were notably more obese than the patients with a normal glucose tolerance test. Analyses after omitting the patients with IGT showed that there was still a significant (P < 0.05) difference in terms of basal insulin levels and HOMA scores. Six of eight (75%) obese patients with IH showed IGT. These data suggest that IH is associated with insulin resistance and an increased prevalence of IGT in obese patients.     

Defining constant versus variable phenotypic features of women with polycystic ovary syndrome using different ethnic groups and populations

CONTEXT: The phenotype of women with polycystic ovary syndrome (PCOS) is variable, depending on the ethnic background. OBJECTIVE: The phenotypes of women with PCOS in Iceland and Boston were compared. DESIGN: The study was observational with a parallel design. SETTING: Subjects were studied in an outpatient setting. PATIENTS: Women, aged 18-45 yr, with PCOS defined by hyperandrogenism and fewer than nine menses per year, were examined in Iceland (n = 105) and Boston (n = 262). INTERVENTION: PCOS subjects underwent a physical exam, fasting blood samples for androgens, gonadotropins, metabolic parameters, and a transvaginal ultrasound. MAIN OUTCOME MEASURES: The phenotype of women with PCOS was compared between Caucasian women in Iceland and Boston and among Caucasian, African-American, Hispanic, and Asian women in Boston. RESULTS: Androstenedione (4.0 +/- 1.3 vs. 3.5 +/- 1.2 ng/ml; P < 0.01) was higher and testosterone (54.0 +/- 25.7 vs. 66.2 +/- 35.6 ng/dl; P < 0.01), LH (23.1 +/- 15.8 vs. 27.6 +/- 16.2 IU/liter; P < 0.05), and Ferriman Gallwey score were lower (7.1 +/- 6.0 vs. 15.4 +/- 8.5; P < 0.001) in Caucasian Icelandic compared with Boston women with PCOS. There were no differences in fasting blood glucose, insulin, or homeostasis model assessment in body mass index-matched Caucasian subjects from Iceland or Boston or in different ethnic groups in Boston. Polycystic ovary morphology was demonstrated in 93-100% of women with PCOS in all ethnic groups. CONCLUSIONS: The data demonstrate differences in the reproductive features of PCOS without differences in glucose and insulin in body mass index-matched populations. These studies also suggest that measuring androstenedione is important for the documentation of hyperandrogenism in Icelandic women. Finally, polycystic ovary morphology by ultrasound is an almost universal finding in women with PCOS as defined by hyperandrogenism and irregular menses.     

Functional significance of polycystic-size ovaries in healthy adolescents

CONTEXT: The relevance of adult polycystic ovary criteria to adolescence is unclear. OBJECTIVE: The objective was to determine the functional significance of polycystic-size ovaries (PSO) in healthy adolescents. DESIGN/SETTING/PARTICIPANTS/INTERVENTIONS: Healthy 11- to 18-yr-old postmenarcheal volunteers (n = 22) were recruited and divided into groups with normal size ovaries (VNSO; n = 10) or a polycystic-size ovary (VPSO; n = 12). They were secondarily compared with adolescents with polycystic ovary syndrome (PCOS; n = 8) matched for gynecological age and a PSO. All underwent GnRH agonist (GnRHag), oral glucose tolerance, and ACTH1-24 testing in our General Clinical Research Center. RESULTS: VPSO had a higher peak 17-hydroxyprogesterone (17PROG) response to GnRHag than VNSO (146 +/- 14 ng/dl, mean +/- sem, vs. 85 +/- 11; P = 0.008), as well as larger ovaries (13.3 +/- 0.7 cc vs. 8.5 +/- 0.8 cc). VPSO peak 17PROG was elevated (>137 ng/dl) in 42% (5 of 12). However, VPSO and VNSO androgen levels were similar, with the exception of one VPSO subject who had hyperandrogenemia and thus met criteria for PCOS. VPSO were similar to VNSO in LH, FSH, estradiol, and adrenal androgenic function. Although the VPSO group resembled the PCOS group in their 17PROG response to the GnRHag test, they differed in having significantly smaller ovaries and lower body mass index and in lacking evidence of peripheral androgen excess and of insulin resistance. CONCLUSION: A PSO in asymptomatic adolescents seems typically to be a normal variant. However, about half have a subclinical PCOS type of ovarian dysfunction; it is unknown whether this indicates a genetic carrier state or a risk for anovulation.     

Mechanisms of androgen deficiency in human immunodeficiency virus-infected women with the wasting syndrome

Although prior studies suggest reduced androgen levels in women with acquired immune deficiency syndrome wasting, little is known regarding the regulation of adrenal and ovarian androgen secretion in such patients. We investigated ovarian and adrenal function in 13 human immunodeficiency virus-infected women with acquired immune deficiency syndrome wasting and 21 age- and body mass index-matched healthy control subjects studied in the early follicular phase. Subjects received hCG (5000 U, im) on d 1 and Cosyntropin (0.25 mg, i.v.) on d 3 after dexamethasone (1 mg, orally, at 2400 h) pretreatment on d 2. At baseline, human immunodeficiency virus-infected subjects demonstrated significantly reduced T [18 +/- 2 vs. 25 +/- 2 ng/dl (0.6 +/- 0.1 vs. 0.9 +/- 0.1 nmol/liter); P = 0.02], free T [1.5 +/- 0.1 vs. 2.4 +/- 0.2 pg/ml (5.3 +/- 0.5 vs. 8.3 +/- 0.6 pmol/liter); P = 0.001], androstenedione [119 +/- 6 vs. 162 +/- 14 ng/dl (4.16 +/- 0.20 vs. 5.66 +/- 0.48 nmol/liter); P = 0.02], and dehydroepiandrosterone sulfate [0.96 +/- 0.17 vs. 1.55 +/- 0.19 microg/ml (2.6 +/- 0.5 vs. 4.2 +/- 0.5 micromol/liter); P = 0.047] levels compared with the control subjects. T [8 +/- 2 vs. 6 +/- 2 ng/dl (0.3 +/- 0.1 vs. 0.2 +/- 0.1 nmol/liter); P = 0.48], free T [0.5 +/- 0.2 vs. 0.4 +/- 0.1 pg/ml (1.7 +/- 0.7 vs. 1.5 +/- 0.5 pmol/liter); P = 0.85], 17 hydroxyprogesterone [0.5 +/- 0.2 vs. 0.7 +/- 0.2 microg/liter (1.6 +/- 0.6 vs. 2.0 +/- 0.6 nmol/liter); P = 0.63], and androstenedione [-1 +/- 12 vs. 8 +/- 11 ng/dl (-0.03 +/- 0.42 vs. 0.28 +/- 0.39 nmol/liter), P = 0.61] responses to hCG were not different between the groups. Cortisol responses were increased and dehydroepiandrosterone sulfate responses were decreased in the human immunodeficiency virus-infected vs. control subjects after ACTH stimulation. The ratio of DHEA to cortisol was significantly decreased at 60 (71 +/- 11 vs. 107 +/- 10; P = 0.02) and 90 (63 +/- 8 vs. 102 +/- 9; P = 0.004) min post-ACTH in the human immunodeficiency virus-infected patients compared with control subjects. Baseline urinary free cortisol levels were not different between the groups [36 +/- 9 vs. 36 +/- 5 microg/24 h (99 +/- 26 vs. 100 +/- 13 nmol/d)]. The DHEA to cortisol ratio correlated with the CD4 count (r = 0.67; P = 0.01). These data demonstrate significant shunting of adrenal steroid metabolism away from androgenic pathways and toward cortisol production in human immunodeficiency virus-infected women with the wasting syndrome. In contrast, our data suggest intact ovarian androgen responsivity to hCG stimulation. Further studies of the mechanism of adrenal steroid shunting and the efficacy of androgen replacement in human immunodeficiency virus-infected women are necessary.     

Endocrine consequences of premature pubarche in post-pubertal Caucasian girls

BACKGROUND: It has been postulated that intrauterine undernutrition may predispose to serious endocrine consequences, including precocious pubarche (PP), functional ovarian hyperandrogenism and insulin resistance syndrome. OBJECTIVE: The aim of this study was to determine whether a history of PP was associated with the development of hyperandrogenism and/or metabolic consequences and to evaluate the effect of birth weight on this association. PATIENTS: The study population comprised 27 Caucasian girls with a history of PP and 25 healthy girls of similar age (17.4 +/- 1.3 vs. 17.7 +/- 0.9 years). RESULTS: Gynecological age, irregular menses and oral contraceptive use were similar in the two groups. PP girls showed an increased Ferriman-Gallway Score [median (range) 8 (4-17) vs. 6 (2-10), P = 0.02] and tended to have more previous history of acne. No statistical differences were found between the groups for mean testosterone (1.7 +/- 0.7 vs. 1.4 +/- 0.7 nmol/l, P = 0.49) and dehydroepiandrosterone sulphate concentrations (7.2 +/- 3.7 vs. 5.8 +/- 2.0 micromol/l, P = 0.15), but mean Delta4-androstenedione concentrations (7.3 +/- 2.4 vs. 4.9 +/- 2.1 nmol/l, P = 0.007) and free androgen index (8.5 +/- 9.7 vs. 3.6 +/- 3.9 IU, P = 0.003) were significantly increased in the PP group. All girls showed normal glucose tolerance with an oral glucose tolerance test. Derived insulin resistance parameters were not statistically different between the two groups and fasting lipids were comparable in both groups. There was no significant effect of birth weight on androgen levels in the PP girls. Moreover, none of the PP girls demonstrated the above-described association. CONCLUSIONS: Precocious pubarche could be the first sign of future functional ovarian hyperandrogenism but a link between this condition and intrauterine undernutrition or insulin resistance could not be demonstrated in this study.     

Adrenal incidentaloma: a new cause of the metabolic syndrome?

A number of patients with adrenal incidentaloma are exposed to a slight degree of cortisol excess resulting from functional autonomy of the adrenal mass (usually a cortical adenoma). At present, there are only scant data on the unwanted effects of this endocrine condition referred to as subclinical Cushing's syndrome. The aim of the present study was to look for some features of the metabolic syndrome in patients with incidental adrenal adenoma. Forty-one patients (9 men and 32 women) bearing adrenal incidentaloma with typical computed tomography features of cortical adenoma were studied. For both patients and controls, exclusion criteria were age equal to 70 yr or greater, previous history of fasting hyperglycemia, or impaired glucose tolerance (IGT), severe hypertension, current use of medication or concomitant relevant illnesses, and body mass index (BMI) equal to 30 kg/m(2) or greater. Forty-one patients with euthyroid multinodular goiter accurately matched for sex, age, and BMI served for a 1:1 case-control analysis. The study design included an oral glucose tolerance test (75 g) and an endocrine workup aimed at the study of the hypothalamic-pituitary-adrenal axis. Age and BMI were fully comparable between patients (54.0 +/- 10.7 yr, 23.8 +/- 2.4 kg/m(2)) and controls (52.2 +/- 11.6 yr, 23.5 +/- 2.8 kg/m(2)). Fasting glucose and fasting insulin levels were not different between the two groups (4.96 +/- 0.61 mmol/liter vs. 4.88 +/- 0.58 mmol/liter; 67 +/- 34 pmol/liter vs. 59 +/- 32 pmol/liter), but the 2-h postchallenge glucose was significantly higher in patients than in controls (7.43 +/- 2.49 mmol/liter vs. 6.10 plus minus 1.44 mmol/liter, P = 0.01). Fifteen patients (36%) reached the World Health Organization criteria for IGT and two other patients (5%) reached those for diabetes, and 14% of the controls qualified for IGT (P = 0.01). No difference in the lipid pattern was seen between the two groups, but either systolic or diastolic blood pressure were higher in patients (135.4 +/- 15.5 mm Hg vs. 125.0 +/- 15.6 mm Hg, P = 0.003; 82.9 +/- 9.1 mm Hg vs. 75.3 +/- 6.6 mm Hg, P < 0.0001). We calculated the whole-body insulin sensitivity index derived from the oral glucose tolerance test that was significantly reduced in the patients (4.3 +/- 1.7 vs. 5.7 +/- 2.5, P = 0.01). In a multiple regression analysis, 2-h glucose was associated with BMI and midnight cortisol values (r(2) = 0.36, P = 0.002). The comparison of the patients with nonfunctioning adenoma (n = 29) with those with subclinical Cushing's syndrome (n = 12) yielded significant differences as to 2-h glucose and triglyceride levels, which were significantly higher in the second group (7.02 +/- 1.76 mmol/liter vs. 8.72 +/- 3.17 mmol/liter, P = 0.03; 1.06 +/- 0.4 mmol/liter vs. 1.73 +/- 0.96 mmol/liter, P = 0.002), but the insulin sensitivity index was conversely reduced (5.2 +/- 1.4 vs. 2.9 +/- 1.2, P < 0.0001). In conclusion, many patients with incidental adrenal adenoma display altered glucose tolerance, that may be explained by reduced insulin sensitivity, and increased blood pressure levels in comparison with carefully age- and BMI-matched controls. The slight hypercortisolism observed in some such patients may significantly contribute to this state of insulin resistance. Midnight serum cortisol appears as a sensitive marker of the metabolic effects of subclinical Cushing's syndrome.