Androgen response to endogenous insulin secretion during the frequently sampled intravenous glucose tolerance test in normal and hyperandrogenic women

Women with ovarian hyperandrogenism frequently have insulin resistance, whose underlying mechanism remains to be determined. In the present study we have investigated the relationship between insulin sensitivity and the acute effect of endogenous insulin secretion on circulating androgen levels. Insulin sensitivity, glucose-mediated insulin release, and glucose/insulin-stimulated androgen responses were determined during a frequently sampled iv glucose tolerance test in a group of 19 women with clinical evidence of polycystic ovary syndrome (PCOS) and 9 age- and weight-matched controls. Insulin (I), glucose, androstenedione, testosterone (T), free T, and dehydroepiandrosterone (DHEA) levels were measured before and during the 3 h following iv administration of glucose (300 mg/kg). Intravenous tolbutamide (300-500 mg) was injected 20 min after the glucose injection. Insulin sensitivity (SI) was calculated by application of the minimal model of glucose kinetics. Fasting androstenedione, T, free T, and I concentrations were significantly higher in the women with PCOS than in controls (P less than 0.02). In PCOS subjects, fasting I was correlated with both T (r = 0.51; P less than 0.05) and DHEA (r = 0.706; P less than 0.01). SI was significantly lower in PCOS subjects [SI, 68.35 +/- 8.34 min-1/(nmol/mL] than in control subjects (SI, 133.36 +/- 21.7 min-1/(nmol/mL)]. A significant decline in DHEA levels was observed in control subjects 3 h after glucose administration (from 28.4 +/- 3.0; final, 16.2 +/- 2.4; P less than 0.02). PCOS women with normal insulin sensitivity [SI, greater than 75.0 min-1/(nmol/mL)] showed a similar fall in DHEA (from 20.3 +/- 2.5 to 12.8 +/- 1.8 nmol/L; P less than 0.02). No significant change occurred in insulin-resistant PCOS subjects [SI, less than 75.0 min-1/(nmol/mL)]. Other androgen levels showed a modest nonsignificant decline during the study in PCOS and control groups. These findings confirm the weight-independent insulin resistance of some hyperandrogenic women. The failure of glucose-stimulated endogenous insulin secretion to significantly depress DHEA levels in insulin-resistant women with PCOS may account in part for their androgen excess.     

Normal and elevated 3 alpha-androstanediol glucuronide concentrations in women with various causes of hirsutism and its correlation with degree of hirsutism and androgen levels.

We investigated peripheral androgen metabolic activity in 54 hirsute females (HF) by evaluating the serum 3 alpha-androstanediol glucuronide (3AG) concentration, hirsutism score (HS), and etiology of hirsutism. Based on basal and ACTH-stimulated steroid profiles (1 h post-Cortrosyn, 0.25 mg, i.v. bolus), the causes of hirsutism were determined to be increased adrenal androgen production (greater than 2 SD above normal mean), increased ovarian testosterone (T) production (greater than 2 SD above normal mean basal T of ovarian source only), or idiopathic cause (normal steroid profile). Serum 3AG levels in each group of HF were significantly higher (P less than 0.01-0.001) than those in normal females [normal: 2.9 +/- 0.94 nmol/L (n = 28); HF: increased adrenal androgen production of undefined cause, 7.7 +/- 7.5 nmol/L (n = 14); 21-hydroxylase deficiency, 7.6 +/- 7.4 nmol/L (n = 5); increased ovarian T production 5.5 +/- 3.5 nmol/L (n = 18); idiopathic cause, 5.8 +/- 4.8 nmol/L (n = 17)]. However, normal 3AG levels (less than 5.2 nmol/L) were present in 50-67% of HF in each group. Collectively, 3AG levels in HF correlated significantly (P less than 0.01) with dehydroepiandrosterone (DHEA; r = 0.41) and DHEA sulfate (DS; r = 0.44), while the correlation with androstenedione (r = 0.15) or T (r = 0.19) was not significant. Serum 3AG and adrenal androgen levels decreased in all subjects after dexamethasone treatment (0.5-1 mg at hour of sleep; 2 mg/day for 3-5 days). The correlation between 3AG and HS was significant (r = 0.6-0.74; P less than 0.01-0.001) only in HF with increased adrenal androgen secretion and idiopathic cause, and was not significant (r = 0.42) in HF with increased ovarian T secretion. There was no significant correlation between androgen levels and HS. We conclude that the serum 3AG level was not consistently elevated in HF and did not differ significantly between the various causes. Significant correlations between 3AG and DHEA/DS levels, and the simultaneous decrease in 3AG and adrenal androgens after dexamethasone administration in HF suggest that adrenal androgens contribute significantly to 3AG production. The significant correlation between 3AG and HS in HF with increased adrenal androgen secretion and idiopathic cause indirectly suggests an adrenal androgen contribution to both 3AG production and hirsutism in these HF. The insignificant correlation between 3AG and HS in HF with increased ovarian T secretion may result from a confounding effect of ovarian T on hirsutism.     

Ovarian age-related responsiveness to human chorionic gonadotropin in women with polycystic ovary syndrome

Ovarian steroid secretion capacity starts to decline as early as around the age of 30 yr. Whether an age-related decrease in androgen secretion, as in normal women, also occurs in women with polycystic ovary syndrome (PCOS) and whether the enhanced androgen production in PCOS remains throughout the fertile period of life are not known. The aim of this study was to determine the age-related serum basal and gonadotropin-stimulated androgen levels in women with PCOS and to compare the results with those obtained from our previous study in healthy women with normal ovaries. Human chorionic gonadotropin (hCG) stimulation tests were carried out among 42 women with PCOS (age, 16-44 yr; body mass index, 31.02 +/- 1.1 kg/m(2)). An im injection of 5000 IU hCG was given 2-4 d after spontaneous or progestin-induced menstrual bleeding, and blood samples for LH, FSH, inhibin B, 17-hydroxyprogesterone, androstenedione (A), testosterone (T), and estradiol assays were collected at 0, 24, 48, and 96 h. In women with PCOS, basal serum T and A levels were about 50% higher than in healthy women. The responses of A and T to hCG [area under the curve (AUC), 96 h)] were significantly higher in women with PCOS than in normal women [A, 1183.6 +/- 60 (+/-se) vs. 814.4 +/- 39 (P 相似文献   

The age-associated decline of androgens in reproductive age and menopausal Black and White women

CONTEXT: The effect of race and obesity on the age-associated decline of androgens in reproductive-aged and menopausal women has not been well characterized. OBJECTIVE: Our objective was to determine the impact of racial differences and body mass index (BMI) on the change in androgen levels during a woman's reproductive and early menopausal years. DESIGN AND SETTING: We conducted a frequency-matched cross-sectional study at a tertiary academic medical center. PATIENTS OR OTHER PARTICIPANTS: Subjects included 260 healthy, nonhirsute and eumenorrheic, self-identified Black and White women, ages 15-60 yr. INTERVENTIONS: A medical and reproductive history, physical exam, and blood sampling were determined in the fasting state during the early follicular phase. MAIN OUTCOME MEASURES: Serum levels of androgens or androgen metabolites (dehydroepiandrosterone sulfate, androstenedione, and total and free testosterone) and SHBG were measured and the BMI, the waist-to-hip ratio (WHR), and the basal insulin resistance estimated by the homeostasis model assessment for insulin resistance determined. RESULTS: After controlling for differences in BMI, insulin resistance, and WHR, Black women had lower androgen levels than age-matched White women. All androgens, or androgen metabolites, declined similarly across the reproductive lifespan and menopausal transition in both Black and White women. Race was a significant predictor of dehydroepiandrosterone sulfate, androstenedione, and total and free testosterone but not SHBG. CONCLUSIONS: Eumenorrheic, nonhirsute Black women have a lower range of normal androgen levels than White women of the same age, BMI, WHR, and homeostasis model assessment index for insulin resistance. Race and age-adjusted data should be considered when evaluating androgen levels in women between the ages of 15 and 60 yr.     

Increased levels of serum advanced glycation end-products in women with polycystic ovary syndrome

OBJECTIVE: Women with polycystic ovary syndrome (PCOS) carry a number of cardiovascular risk factors and are considered to be at increased risk for atherosclerosis. Elevated concentrations of advanced glycation end-products (AGE), which exert their effects through interaction with specific receptors (RAGE), have been implicated in the cellular and tissue damage during atherosclerotic processes. DESIGN/PATIENTS: We investigated serum AGE levels in 29 young women with PCOS as well as the expression of their receptor, RAGE, in circulating monocytes and compared them levels with 22 healthy control women. MEASUREMENTS/RESULTS: Women with PCOS had higher levels of serum AGE proteins compared to healthy individuals (9.81 +/- 0.16 vs. 5.11 +/- 0.16, P < 0.0001), and increased RAGE expression was observed in monocytes of PCOS women compared to controls (30.91 +/- 10.11 vs. 7.97 +/- 2.61, P < 0.02). A positive correlation was observed between AGE proteins and testosterone (T) levels (r = 0.73, P < 0.0001). The correlation between AGE proteins and T levels remained high (partial correlation coefficient = 0.61, P = 0.0001) after controlling for body mass index (BMI), insulin levels and the area under the curve for glucose (AUCGLU) during an oral glucose tolerance test (OGTT). A positive correlation was also observed between AGE proteins and the free androgen index (FAI) (r = 0.58, P < 0.0001), waist-to-hip ratio (WHR) (r = 0.31, P < 0.02), insulin (r = 0.46, P < 0.001), homeostasis model assessment (HOMA) (r = 0.47, P < 0.0001), AUCGLU (r = 0.52, P < 0.002) and RAGE (r = 0.59, P < 0.01). A negative correlation was observed between AGE proteins and glucose/insulin ratio (GLU/INS) (r = -0.35, P < 0.01), and the quantitative insulin sensitivity check index (QUICKI) (r =-0.50, P < 0.01). In multiple regression analysis T was the only independent predictor of AGE levels (P < 0.0001, b = 0.044) between BMI, insulin, SHBG and AUCGLU (adjusted R2 = 0.59, F = 44.41, P < 0.0001). CONCLUSION: These data clearly demonstrate, for the first time, that PCOS women without overt hyperglycaemia have increased AGE levels and elevated RAGE expression when compared with controls.     

Lower insulin sensitivity differentiates hirsute from non-hirsute Sicilian women with polycystic ovary syndrome

OBJECTIVE: It is well known that hyperandrogenism and insulin-resistance with or without compensatory hyperinsulinism are closely associated, but the Rotterdam Consensus has concluded that principally obese women with polycystic ovary syndrome (PCOS) should be evaluated for the metabolic syndrome. Our aim was to study insulin sensitivity in PCOS women with hirsutism regardless of obesity. METHODS: Clinical characteristics, sex hormones and fasting- and after OGTT-glycemia and insulinemia, homeostatic model of insulin resistance (HOMA IR), and Matsuda index of insulin sensitivity were analyzed in 130 women with PCOS. Hirsutism has been evaluated through the Ferriman-Gallwey (FG) map scoring system. RESULTS: PCOS women with hirsutism (57.7% of participants) showed significant higher values of total testosterone levels (P = 0.016), free testosterone (P = 0.027), DHEA sulfate (P = 0.017), and Delta4androstenedione (P = 0.018). They had similar body mass index (BMI) (P = 0.073) and were significantly less insulin sensitive (P = 0.002) than those without hirsutism (42.3% of participants). In women with PCOS and hirsutism, there was a significant correlation between FG score and insulin-sensitivity indexes (HOMA IR, rho = 0.33, P = 0.005; Matsuda index, rho = -0.34, P = 0.003) but not with the androgen levels. Moreover, women with hirsutism showed a significantly greater insulin (P = 0.019), C-peptide (P = 0.002), and glucose (P = 0.024) areas under the curve (auc2h). CONCLUSIONS: Our study suggests that the increased responsiveness of the pilo-sebaceous unit to androgens seems to be influenced by insulin sensitivity and that insulin resistance should be assessed in all hirsute women with PCOS regardless of their BMI, as insulin resistance was found in hirsute women irrespective of whether they were overweight or obese.     

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.     

Effect of rosiglitazone on insulin resistance, C-reactive protein and endothelial function in non-obese young women with polycystic ovary syndrome

OBJECTIVE: Women with polycystic ovary syndrome (PCOS) exhibit elevated levels of serum C-reactive protein (CRP) and impaired endothelium dysfunction which are directly correlated with insulin resistance. Because rosiglitazone improves insulin sensitivity, we tested whether rosiglitazone treatment ameliorates high-sensitivity (hs)CRP levels and endothelial dysfunction in these patients. DESIGN: Thirty-one women with PCOS were recruited (mean age, 24.7+/-3.9 (s.e.) years; mean body mass index (BMI), 25.6+/-3.2 kg/m2). All women were treated with 4 mg rosiglitazone daily for 12 months. METHODS: Serum levels of testosterone, LH, FSH, sex hormone-binding globulin (SHBG), insulin and hsCRP were measured. The BMI, hirsutism scores and insulin sensitivity indices were calculated before and after treatment. Arterial endothelium and smooth muscle function was measured by examining brachial artery responses to endothelium-dependent and endothelium-independent stimuli before and after treatment. RESULTS: After treatment with rosigitazone there were significant decreases in serum testosterone (91.2+/-37.5 vs 56.1+/-21.8 ng/dl; P < 0.01) and fasting insulin concentrations (12.5+/-7.6 vs 8.75+/-4.03 microU/ml; P = 0.015). Insulin resistance indices were significantly improved after rosiglitazone treatment (P < 0.05). There were no significant changes in BMI, waist circumference, serum total cholesterol, low-density lipoprotein (LDL)-cholesterol, FSH and LH levels. Hirsutism score was decreased significantly after treatment (10.8+/-1.8 vs 7.6+/-1.7; P < 0.05). Twenty-four of the women reverted to regular menstrual cycles. Levels of SHBG increased significantly after treatment (28.7+/-8.7 vs 48.4+/-11.2 nmol/l; P < 0.01). Serum hsCRP levels were decreased significantly after rosiglitazone treatment (0.25+/-0.1 vs 0.09+/-0.02 mg/dl; P = 0.006). There was also significant improvement in endothelium-dependent vascular responses after rosiglitazone treatment (9.9+/-3.9 vs 16.4+/-5.1%; P < 0.01). CONCLUSIONS: We conclude that rosiglitazone treatment improves insulin sensitivity in women with PCOS. It also decreases androgen production without significant weight gain. More importantly, it has beneficial effects on endothelial dysfunction and low-grade chronic inflammation in normal weight young women with PCOS.     

Serum adiponectin in women with polycystic ovarian syndrome and its relation to clinical, metabolic and endocrine parameters

Several studies have demonstrated that low levels of serum adiponectin are present in obesity, insulin resistance, hypertension and hyperlipidemias. The aim of our study was to determine whether serum adiponectin level is different between patients with polycystic ovarian syndrome (PCOS) and control subjects. We also investigated relationships between various cardiovascular risk factors, levels of serum adiponectin and other hormones, such as androstendione, testosterone, estradiol, DHEAS, sex hormone binding globulin (SHBG), and leptin. We also analysed the correlation between serum adiponectin and free androgen index. Ninety-one women with clinical diagnosed PCOS and 53 healthy control subjects, carefully matched by body mass index (BMI) and age, were enrolled in the study. The fasting blood samples were obtained and all participants underwent an oral 75 g glucose tolerance test. The prevalences of impaired glucose tolerance (IGT), hypertension and hypertriglyceridemia were higher in the PCOS group. PCOS women had increased androgen concentrations and higher free androgen index and decreased level of serum SHBG. Lower serum adiponectin concentrations were observed among cases than in controls (median 13.7 microg/ml vs 17.8 microg/ml, p<0.001) despite being matched by BMI. In the PCOS group adiponectin levels correlated significantly with: BMI (r=-0.32, p=0.002), waist circumference (r=-0.32, p=0.003), waist-to-hip ratio (WHR, r=-0.38, p=0.001), triglycerides (r=-0.31, p=0.007), SHBG (r=0.30, p=0.003) and free androgen index (r=-0.29, p=0.02). In contrast, the adiponectin level does not appear to be related to total testosterone, DHEAS and leptin levels. The adiponectin and SHBG levels were found to be decreased in PCOS women with IGT compared to PCOS women with normal glucose tolerance, but after adjustment by BMI or WHR, the differences were no longer statistically significant. To exclude a possible confounding effect due to a higher prevalence of IGT in the PCOS group, this comparison was repeated for the subgroup of 58 PCOS women and 48 control women after excluding those with IGT. Neither adiponectin nor SHBG were significantly different between those subgroups. Multiple regression analysis revealed that serum adiponectin concentrations were best predicted by WHR, free androgen index and presence of IGT when all patients were considered. In PCOS subjects, the only independent predictor of adiponectin concentrations was glucose tolerance status. CONCLUSIONS: Lower adiponectin levels were observed in PCOS group than in control women, and these differences were probably due to higher prevalence of IGT in these cases.     

多囊卵巢综合征患者性激素结合球蛋白和总睾酮与胰岛素抵抗的相关性

目的 了解性激素结合球蛋白(SHBG)和总睾酮在预测多囊卵巢综合征(PCOS)患者胰岛素抵抗和生殖内分泌以及糖脂代谢紊乱中的作用.方法 选择2004年6月至2006年5月在复旦大学附属妇产科医院就诊的344例PCOS患者为病例组,年龄12～35岁,平均年龄(23±5)岁.选择同期月经规律、基础体温双相的100名妇女作为对照组,比较PCOS患者SHBG和总睾酮与对照组的差异,并用Spearman相关分析法分别分析SHBG和总睾酮与其他指标的相关性,Logistic回归分析胰岛素抵抗的风险因子并做SHBG对胰岛素抵抗的受试者操作特征(ROC)曲线,获得预测胰岛素抵抗的风险值,比较不同水平SHBG患者的糖脂代谢紊乱的程度.结果 PCOS患者SHBG为(114±88)mmol/L,与对照组[(201±106)mmol/L]比较差异有统计学意义(t=-5.60,P<0.01),总睾酮为(2.8±1.0)nmol/L,与对照组[(1.7±0.6)nmol/L]比较差异有统计学意义(t=7.73,P<0.01);SHBG与空腹胰岛素、胰岛素释放试验曲线下面积、口服葡萄糖耐量试验(OGTT)的葡萄糖曲线下面积、胰岛素抵抗指数、甘油三酯和腰围/臀围比呈负相关(r值分别为:-0.30、-0.26、-0.29、-0.19、-0.20、-0.29、-0.22,均P<0.01);总睾酮与空腹胰岛素(r=0.14,P<0.01)、胰岛素释放试验(1、2、3 h的r值分别为0.15、0.12、0.11,均P<0.05)以及相应的曲线下面积(r=0.15,P<0.05)、胰岛素抵抗指数(r=0.11,P<0.05)呈正相关.Logistic回归分析发现SHBG是PCOS患者胰岛素抵抗的独立危险因素(OR=3.741).由ROC曲线得到SHBG预测胰岛素抵抗的大致风险值为88 mmol/L(95%CI为0.668～0.774).在低SHBG(<88 mmol/L)患者中,空腹胰岛素、胰岛素释放试验相应的曲线下面积、胰岛素抵抗指数、空腹血糖、OGTT的葡萄糖曲线下面积与高SHBG(≥88 mmoL/L)患者比较差异有统计学意义(t值分别为-6.45、-5.08、-6.19、-3.16、-3.66,均P<0.01),甘油三酯也高于高SHBG患者(t=-2.06,P<0.05).结论 PCOS患者总睾酮水平高于对照组,SHBG低?     

Lack of linear relationship between hyperinsulinaemia and hyperandrogenism

OBJECTIVE: Because of continued debate about the role of insulin in the development of hirsutism and in the induction of the polycystic ovary syndrome, we have evaluated the hormonal pattern in a group of hirsute patients. PATIENTS: Fifty-four hirsute patients (age range 18-39 years) of whom 26 patients were obese (O) (BMI 28-53 kg/m2 and W/H greater than 0.85), 12 with ultrasonographic evidence of polycystic ovaries (O PCO) and 14 with normal ovaries. Twenty-eight patients were within normal weight range, and, of these, 14 presented ultrasonographic evidence of polycystic ovaries and 14 had normal ovaries. Two groups of age-matched subjects (obese and normal weight), normally menstruating, without hirsutism or history of endocrinopathies or ultrasonographic evidence of polycystic ovaries, served as controls. MEASUREMENTS: Androstenedione and testosterone were evaluated in all patients by RIA, following ether extraction, DHEAS, LH, FSH and insulin were evaluated directly by RIA. SHBG was evaluated by the concanavalin method. Free testosterone (FT%) was calculated according to the formula FT = 4.038-1.607 log SHBG. Integrated areas under the response curve were calculated for LH and insulin respectively following i.v. administration of GnRH (100 micrograms) or oral administration of glucose (75 g). RESULTS: Results (mean +/- standard deviation) showed comparable values of androstenedione in all groups of obese patients and in obese controls (7.3 +/- 2.6 in patients with polycystic ovaries, 7.1 +/- 2.9 in non-polycystic ovary patients and 7.4 +/- 2.6 nmol/l in obese controls, respectively), regardless of baseline and area insulin, the presence or absence of polycystic ovaries, or hirsutism. SHBG levels showed a similar pattern (24 +/- 10, 23.8 +/- 7.9 and 36 +/- 19 nmol/l) as did the percentage of free testosterone, regardless of the presence or absence of hirsutism. Regression analysis of the insulin and LH values (baseline and area) against the androgens and SHBG plasma levels showed that only LH area correlated positively with testosterone (r = 0.36, P less than 0.03), androstenedione (r = 0.44, P less than 0.02), % free testosterone (r = 0.53, P less than 0.001), testosterone/SHBG ratio (r = 0.39, P less than 0.03) and inversely with SHBG (r = -0.57, P less than 0.001). CONCLUSIONS: These results showed (1) no linear relationship between high levels of insulin, ovarian androgen production or free hormone availability, and (2) make it very doubtful that insulin plays a primary role in polycystic ovarian syndrome or hirsutism.     

DECREASED SEX HORMONE BINDING GLOBULIN (SHBG) AND INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN (IGFBP-1) IN EXTREME OBESITY

Obesity may be characterized by abnormal sex steroid secretion and reduced sex hormone binding globulin (SHBG) which in turn is related to fat distribution and insulin secretion. Recent in-vitro and in-vivo evidence suggests that insulin is the common mechanism regulating the secretion of SHBG and insulin-like growth factor small binding protein (IGFBP-1). IGFBP-1 appears not only to be a carrier for insulin growth factors (IGFs) but also to play an active role in growth processes, independent of growth hormone secretion. We have examined the possible relationship between fasting insulin, SHBG, testosterone, IGF-1, IGFBP-1 and fat distribution in 25 extremely obese, menstruating women (mean weight 107 +/- 3 kg) with normal glucose tolerance. Fat distribution was assessed from measurements of the waist to hip ratio (W/H). The obese women showed an elevated fasting insulin (mean +/- SEM; 21 +/- 2 mumol/l), a normal IGF-1, but reduced IGFBP-1 (14.6 +/- 2 micrograms/l); in 15 women IGFBP-1 levels were undetectable by the present assay. In addition, SHBG levels were reduced in the obese women (24 +/- 2 nmol/l) but total testosterone values (1.9 +/- 0.1 nmol/l) were normal. The elevated fasting insulin levels were positively correlated with increasing upper segment obesity as expressed by a rising W/H ratio (P less than 0.01, r2 = 0.306) and inversely correlated with SHBG (P less than 0.01, r2 = 0.483). Similarly, reduced SHBG values showed an inverse correlation with increasing W/H ratio (P less than 0.001, r2 = 0.383). No correlation was found between IGFBP-1 and W/H ratio but a strong positive correlation was seen between IGFBP-1 and SHBG (P less than 0.001, r2 = 0.466). Furthermore, an equally significant inverse correlation was found between IGFBP-1 and insulin levels (P less than 0.001, r2 = 0.474).(ABSTRACT TRUNCATED AT 250 WORDS)     

Hormonal profile in women with polycystic ovarian syndrome with or without type 1 diabetes mellitus

CONTEXT: Anti-Müllerian hormone (AMH) levels are increased in polycystic ovarian syndrome (PCOS), but it is not known whether other forms of hyperandrogenism, such as PCOS observed in women with type 1 diabetes mellitus (DM1), are also associated with elevated AMH levels. OBJECTIVE: Our objective was to compare AMH and steroid levels in women with PCOS with and without DM1. DESIGN: We compared the clinical, hormonal, and ultrasonographic characteristics of 17 women with PCOS and DM1 (DM1+PCOS), 20 women with PCOS without DM1 (PCOS), and 35 normal women (control) in a cross-sectional study. RESULTS: The Ferriman-Gallwey score, serum testosterone, free androgen index, 17OH-progesterone, and ovarian volume were elevated in both groups of PCOS women compared with controls. Serum androstenedione, LH/FSH ratio, and follicle number, however, were higher and SHBG was lower in PCOS compared with DM1+PCOS and controls. AMH levels were higher in PCOS (76.0 +/- 36.3 pmol/liter) than in DM1+PCOS (18.8 +/- 7.4 pmol/liter) and controls (13.9 +/- 8.3 pmol/liter). AMH levels correlated with follicle number in the three groups. Serum AMH/follicle number ratio was higher in PCOS than in DM1+PCOS and controls. CONCLUSIONS: Women with DM1+PCOS have normal levels of AMH, inhibin B, estradiol, SHBG, and LH/FSH, suggesting that the pathophysiology of hyperandrogenism in PCOS patients with DM1 appears to be different from that in PCOS without DM1. However, hirsutism score and androgen levels were similar in both groups of women with PCOS. We postulate that insulin treatment acts as a co-gonadotropin increasing follicle recruitment, hence not increasing AMH levels.     

Polycystic ovarian morphology with regular ovulatory cycles: insights into the pathophysiology of polycystic ovarian syndrome

To determine the relevance of polycystic ovarian morphology (PCOM) to the pathophysiology of polycystic ovarian syndrome (PCOS), biochemical features associated with PCOS were examined in 68 women with an established history of regular ovulatory cycles and no clinical evidence of hyperandrogenism. Ovarian morphology was objectively assessed by pelvic ultrasound. LH, FSH, estradiol (E(2)), testosterone (T), androstenedione (Delta(4)A), SHBG, and dehydroepiandrosterone sulfate (DHEAS) were measured at baseline in the early follicular phase (EFP) in all subjects. LH, FSH, E(2), and progesterone (P(4)) were then measured daily for a complete menstrual cycle in 16 women with normal ovarian morphology and in 26 women with PCOM. T, Delta(4)A, SHBG, and DHEAS levels were measured in pools of three daily samples in each of the EFP, midcycle, and midluteal phases. An additional 26 normal women (13 with normal ovarian morphology and 13 with PCOM) were studied in the EFP to assess pulsatile LH secretion, insulin and glucose levels, and the ovarian response to human chorionic gonadotropin. At baseline, there were no differences in body mass index or hirsutism scores between women with PCOM and normal ovaries. In daily samples across the menstrual cycle LH, FSH, E(2), and P(4) did not differ between women with PCOM and those with normal ovaries, and there was no difference in LH pulse amplitude or frequency in the EFP frequent sampling studies. In women with PCOM, T (P < 0.01), free T (P < 0.005), and DHEAS (P < 0.01) levels were higher at baseline in the EFP, and SHBG was lower (P < 0.05). Differences in Delta(4)A did not reach significance (P = 0.14). T, free T, Delta(4)A, and DHEAS were also increased in PCOM across the menstrual cycle (P < 0.05). In addition, 17-hydroxyprogesterone (P < 0.02), Delta(4)A (P < 0.01), and T (P < 0.01) responses to human chorionic gonadotropin were greater in women with PCOM. Fasting glucose was not different between the two groups, but fasting insulin was higher (P < 0.02) in PCOM women as was insulin resistance calculated from homeostatic model assessment (P < 0.01). These studies demonstrate that PCOM in nonhirsute women with documented ovulatory cycles is associated with normal E(2), P(4), and gonadotropin dynamics, but higher androgen and insulin levels and lower SHBG levels. Taken together, these findings suggest that PCOM with ovulatory cycles exists as a discrete entity, represents the mildest form of ovarian hyperandrogenism, and is associated with greater insulin resistance than in women with normal ovarian morphology. The absence of any neuroendocrine abnormality in women with PCOM and ovulatory cycles suggests that gonadotropin dysfunction is not required for increased androgen secretion, but may be critical for development of the anovulatory disorder associated with PCOS.     

Age-related differences in features associated with polycystic ovary syndrome in normogonadotrophic oligo-amenorrhoeic infertile women of reproductive years.

OBJECTIVE: To assess the effect of age on clinical, endocrine and sonographic features associated with polycystic ovary syndrome (PCOS) in normogonadotrophic anovulatory infertile women of reproductive years. DESIGN: Cross-sectional study. METHODS: Four hundred and seventy-two oligo-amenorrhoeic infertile patients, presenting with normal FSH and oestradiol concentrations, aged 17-42 years underwent a standardised initial evaluation including: cycle history, body mass index, waist-to-hip ratio and transvaginal ultrasound scanning of ovaries. Fasting blood samples were obtained for extensive endocrine evaluation. Cycle duration, serum levels of gonadotrophins, androgens, oestradiol, insulin, glucose, inhibin B as well as mean number of follicles, ovarian volume and ovarian stroma echogenicity were assessed. RESULTS: Older women had significantly lower LH and androgen and inhibin B serum levels. Similarly, older women presented with a reduced number of ovarian follicles. Age was inversely correlated with cycle duration (r=-0.112, P=0.02), LH (r=-0.154, P=0.001), testosterone (r=-0.194, P=0.001), androstenedione (r=-0.170, P=0.001), dehydroepiandrosterone (r=-0.157, P=0.001), insulin (r=-0.126, P=0.02), inhibin B (r=-0.118, P=0.03) serum levels and mean follicle number (r=-0.100, P=0.03). A positive correlation was observed between age and glucose to insulin ratio (r=0.138, P=0.009). CONCLUSIONS: Advanced age in normogonadotrophic anovulatory infertile women is associated with lower LH and androgen levels and with a decreased number of ovarian follicles. Although during reproductive years observed differences are relatively small, these age-related changes may affect the observed incidence of PCOS.     

Relationships between dehydroepiandrosterone-sulphate and anthropometric, metabolic and hormonal variables in a large cohort of obese women

OBJECTIVE: The aim of the present study was to measure dehydroepiandrosterone-sulphate (DHEA-S) levels in obesity and assess the relationships between DHEA-S and anthropometric, metabolic and hormonal variables. SUBJECTS AND METHODS: We evaluated the serum DHEA-S levels in 217 obese but otherwise normal female subjects (age (mean +/- SEM): 39.4 +/- 0.9, range 18-67 years, body mass index (BMI) = 36.1 +/- 0.4, range 27.1-57.1 kg/m2). RESULTS: DHEA-S levels showed an age-dependent fall similar to that observed in normal women (n = 156, age 46.2 +/- 1.2, range 22-69 years, BMI < 25 kg/m2). Adjusting for age, obese women had mean DHEA-S levels higher than the control group (P < 0.02). In obese patients, DHEA-S levels were directly associated with serum testosterone, androstendione, IGF-I, fT3 levels and 24 h-urinary cortisol. On the other hand, DHEA-S levels were negatively associated with age, total cholesterol, triglycerides levels and systolic blood pressure. No correlation was found with BMI, waist:hip ratio, basal and post-OGTT insulin and glucose, free fatty acids, GH, PRL, fT4, TSH, SHBG levels or diastolic blood pressure. Multiple regression analysis indicated that in obese women, DHEA-S levels were associated negatively to age and positively to testosterone, androstendione and IGF-I levels and daily urinary cortisol. In a subgroup of 20 obese women, DHEA-S levels significantly (P < 0.001) fell after OGTT without any correlation with the insulin response. CONCLUSIONS: The present results show that dehydroepiandrosterone-sulphate levels are not reduced in obesity, being slightly increased, particularly in young adulthood. Dehydroepiandrosterone-sulphate levels are positively and independently associated with androgen, 24-h urinary cortisol and IGF-I levels but do not seem associated with insulin levels or cardiovascular risk indices.     

Mild androgen phenotypes

Mild androgen phenotypes are found in 30-40% of patients referred to an endocrine clinic because of suspected hyperandrogenic syndrome. These disorders are characterized by clinical or biological signs of hyperandrogenism in women with normal ovulatory menstrual cycles. Three main mild androgen disorders may be distinguished: ovulatory polycystic ovarian syndrome (PCOS), idiopathic hyperandrogenism, and idiopathic hirsutism. Ovulatory PCOS includes ovulatory hyperandrogenic patients presenting with polycystic ovaries. Using ESHRE/ASRM criteria for diagnosis of PCOS, this disorder is now part of PCOS spectrum. While in vivo and in vitro studies have confirmed the similarities between the two forms of PCOS, ovulatory PCOS presents clinicians with some unique problems. In fact, fertility is not a problem, but insulin resistance is present, and although milder than in classic PCOS it may be associated with an increased cardiovascular and metabolic risk. Because of this, an ovarian sonography should be performed in all ovulatory hyperandrogenic patients, and when polycystic ovaries are found cardiovascular and metabolic risk should be carefully evaluated. Ovulatory PCOS patients with altered glucose tolerance and/or with dyslipidaemia may need treatment with insulin-sensitizing agents. Idiopathic hyperandrogenism regroups ovulatory patients with increased androgen levels and normal ovaries, while idiopathic hirsutism includes ovulatory patients presenting with hirsutism but normal circulating androgens and normal ovaries. The differentiation between these two disorders may be difficult because commercial assays of androgen levels are generally unreliable. While idiopathic hyperandrogenism may be associated with insulin resistance, neither disorder is associated with an increased cardiovascular risk. The main clinical problem is hirsutism, and this may be approached by aesthetic or pharmacological therapies.     

Smaller LDL particle size in women with polycystic ovary syndrome compared to controls

OBJECTIVE: Women with polycystic ovary syndrome (PCOS) have an increased risk of cardiovascular disease. The contribution of lipid abnormalities to this higher risk, in particular atherogenic modifications of low density lipoprotein (LDL) such as a shift towards smaller LDL, has not been properly explored. We aimed to examine LDL size variation in relation to androgens and other risk factors in women with PCOS. DESIGN: Comparison of clinical and biochemical measurements in women with PCOS and women with normal ovarian function, of similar age and body mass index (BMI). PATIENTS: Thirty-one women with PCOS and 27 controls were studied. Patients were recruited from the outpatient endocrine clinic. MEASUREMENTS: Fasting total cholesterol, triglycerides (TG), high density lipoprotein (HDL), LDL, glucose, insulin, gonadotrophins, androgens, oestradiol, 17 OH progesterone and SHBG were measured. LDL particle diameter was calculated based on distance travelled in polyacrylamide native gels. Recumbent blood pressure was measured automatically. RESULTS: LDL particle size appeared to be significantly smaller in hyperandrogenic PCOS as compared to regularly cycling women (P = 0006), independent of variations in lipid levels. SHBG was the only independent predictor of LDL size in this population, with a strong correlation, which persisted after adjustment for all confounding variables. CONCLUSIONS: Our results suggest that androgen excess and mild insulin-resistance (both responsible for lower SHBG) may have an early modifying effect on low density lipoprotein size in polycystic ovary syndrome women. The denser pattern observed in polycystic ovary syndrome women could by itself constitute a higher cardiovascular risk, even in the absence of overt dyslipidaemia, and contribute to the excess risk of cardiovascular disease reported in this syndrome.