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PubMed1999

Correction of hyperandrogenemia by laparoscopic ovarian cautery in women with polycystic ovarian syndrome is not accompanied by improved insulin sensitivity or lipid-lipoprotein levels.

Polycystic ovarian syndrome (PCOS) is a common disorder associated with hyperandrogenemia and infertility. Abdominal obesity, insulin resistance, and dyslipoproteinemias are other common metabolic disorders typically found in women with PCOS. The cause-effect relationship between hyperandrogenemia and insulin resistance-dyslipoproteinemia remains unclear. In this study, we have investigated the changes in androgenemia, insulin sensitivity, and plasma lipid-lipoprotein levels after laparoscopic ovarian cautery (LOC) for ovulation induction in eight infertile women with clomiphene citrate-resistant PCOS. After LOC, significant decreases in androstenedione (43%), testosterone (48%), and free testosterone (48%) concentrations were observed (P < 0.05). Glucose utilization during an euglycemic-hyperinsulinemic clamp did not change after LOC. In addition, no significant changes after the surgical procedure were observed for cholesterol, triglycerides, and apolipoprotein concentrations measured in total plasma and in different lipoprotein fractions. In conclusion, within the short duration of observation of this study, our findings demonstrate that insulin resistance and lipoprotein abnormalities associated with PCOS are not secondary to hyperandrogenemia. The clinician, therefore, must be cognizant of the persistence of these metabolic risk factors for cardiovascular disease once successful ovulation and fertility is restored, and institute appropriate monitoring, counseling, and medical intervention as required.

Adult↗

PubMed1999

Spironolactone, but not flutamide, administration prevents bone loss in hyperandrogenic women treated with gonadotropin-releasing hormone agonist.

GnRH agonists (GnRHa) have recently been proposed for the treatment of hirsutism in women with the polycystic ovary syndrome (PCOS). As most of these subjects have increased androgen secretion from both ovaries and adrenal glands, the association of GnRHa with antiandrogen drugs might enhance the clinical response to treatment. On the other hand, this association might also potentiate the adverse effects of GnRHa on bone metabolism, generating a potentially harmful situation at the skeletal level. In this study we investigated in 41 PCOS patients the skeletal effects of a 6-month course of GnRHa (tryptorelin, 3.75 mg, i.m., monthly), either alone (n = 12) or associated with the antiandrogen drugs spironolactone (100 mg, orally, once daily; n = 14) or flutamide (250 mg, once daily; n = 15). In all subjects bone mineral density was measured before and after treatment by dual energy x-ray absorptiometry at the lumbar spine (L2-L4) and at the femoral neck and Ward's triangle. In addition, at baseline and after 6 months of therapy, bone metabolism markers (serum and urinary calcium, serum phosphorus and alkaline phosphatase, plasma osteocalcin, and urinary hydroxyproline) and endocrine parameters (serum gonadotropins, estradiol, and free testosterone) were assayed. Women given either GnRHa alone or associated with spironolactone or flutamide were similar for age and body mass index. At baseline, the 3 groups of PCOS women were also similar for endocrine and bone parameters. After 6 months, all treatments determined similar striking suppressions of serum gonadotropins and sex steroids. Concurrently, bone mineral density was significantly reduced at all examined sites in subjects receiving either GnRHa alone or GnRHa plus flutamide. Conversely, women given GnRHa plus spironolactone did not show any change in skeletal mass from baseline values (P < 0.05-0.01 among groups). Biochemical parameters of bone metabolism were consistent with densitometric assessments. In conclusion, after a 6-month course of therapy, bone mineral density is reduced in PCOS women given either GnRHa alone or GnRHa plus flutamide, but not in those receiving GnRHa plus spironolactone. The mechanisms of the bone-sparing effect of spironolactone remain to be determined. Nevertheless, this drug could represent a useful tool to prevent skeletal loss in women given GnRHa as well as in other hypoestrogenic conditions, in particular when estrogens are not recommended.

Adult↗

PubMed1999

The roles of insulin sensitivity, insulin-like growth factor I (IGF-I), and IGF-binding protein-1 and -3 in the hyperandrogenism of African-American and Caribbean Hispanic girls with premature adrenarche.

Recent reports indicate that girls with premature adrenarche are at risk of developing functional ovarian hyperandrogenism and polycystic ovarian syndrome (PCOS). As insulin and insulin-like growth factors (IGFs) have been implicated in the pathogenesis of PCOS, we hypothesize that they may also have a role in the hyperandrogenism of premature adrenarche. Thirty-five prepubertal girls (23 Caribbean Hispanics and 12 Black African-Americans) underwent a 60-min ACTH and LH-releasing hormone test. Insulin sensitivity (S(I)) was assessed using the frequently sampled i.v. glucose tolerance test with tolbutamide. Fasting levels of IGF-I, IGF-binding protein-1 (IGFBP-1), IGFBP-3, sex hormone-binding globulin, and free testosterone (T) were also obtained. The mean age of the patients was 6.8 yr, and bone age was 8.0 yr. Twenty-five patients had a family history of noninsulin-dependent diabetes mellitus and 19 patients had acanthosis nigricans. The mean S(I) for the entire group was 6.78 +/- 5.21 x 10(-4) min/microU x mL (normal prepubertal S(I), 6.5 +/- 0.54 x 10(-4) min(-1) x microU(-1) x mL(-1)). However, 15 of the 35 girls had an S(I) that was more than 2 SD below the mean reported for normal prepubertal children. Of these 15 patients, 13 were obese, and 14 had acanthosis nigricans. For the entire group of girls, the mean ACTH-stimulated levels of 17-hydroxypregnenolone (17OHPreg), dehydroepiandrosterone (DHEA), androstenedione (AS), 17-hydroxyprogesterone (17OHP), and T and the ACTH-stimulated ratios of 17OHPreg/17OHP, 17OHPreg/DHEA, 17OHP/AS, and DHEA/AS did not differ from the levels reported for Tanner stage II-III pubertal girls. The girls were divided into two groups based on their S(I) (group I, S(I) >2 SD below the mean for age; group II, normal S(I)). The group I girls with a reduced S(I) had significantly higher ACTH-stimulated levels of 17OHPreg (group I, 760 +/- 87.84 ng/dL; group II, 428.9 +/- 46.28 ng/dL; P = 0.002), 17OHPreg/17OHP ratio (group I, 3.95 +/- 0.36; group II, 2.96 +/- 0.35; P = 0.05), 17OHPreg/DHEA (group I, 2.06 +/- 0.21; group II, 1.4 +/- 0.13; P = 0.01), and free T (group I, 1 +/- 0.23 ng/dL; group II, 0.49 +/- 0.19 ng/dL; P = 0.014). Levels of sex hormone-binding globulin were lower in the group I girls. Furthermore, for the entire group of girls, the S(I) correlated inversely with ACTH-stimulated levels of 17OHPreg, DHEA, and AS and the ACTH-stimulated ratio of 17OHPreg/17OHP. IGF-I correlated inversely with S(I) (r = -0.94; P < 0.001) and correlated directly with the ACTH-stimulated levels of 17OHPreg (r = 0.8; P < 0.001) and AS (r = 0.63; P < 0.05). IGF-I also correlated with the ACTH-stimulated ratios of 17OHPreg/17OHP (r = 0.61; P < 0.05), 17OHPreg/DHEA (r = 0.9; P < 0.001), 17OHP/AS (r = 0.79; P < 0.001), and DHEA/AS (r = 0.96; P < 0.001). IGFBP-1 correlated inversely with the ACTH-stimulated levels of 17OHPreg (r = -0.38; P < 0.05) and DHEA (r = -0.36; P < 0.05). To summarize, the ACTH-stimulated delta5-steroid levels were higher in prepubertal girls with premature adrenarche and reduced S(I). There was a significant inverse correlation among ACTH-stimulated hormone levels, S(I), and IGFBP-1, whereas IGF-I correlated directly with ACTH-stimulated androgens. These findings support the hypothesis that insulin and IGFs may have a role in the hyperandrogenism of premature adrenarche just as they do in PCOS. Hence, in certain girls with premature adrenarche, hyperandrogenism may be the first presentation of PCOS and/or insulin resistance.

Adrenocorticotropic Hormone↗

PubMed1999

Divergent effects of weight reduction and oral anticonception treatment on adrenergic lipolysis regulation in obese women with the polycystic ovary syndrome.

The influence of weight reduction and female sex hormones on the regulation of lipolysis was investigated in isolated abdominal sc adipocytes from 20 obese hyperandrogenic women with polycystic ovary syndrome (PCOS). Nine PCOS women were reinvestigated after 8-12 weeks of weight reduction therapy (WR) with a very low calorie diet, inducing a mean loss of 8 +/- 3 kg, and 8 PCOS women were reinvestigated after 12 weeks of treatment with combined oral contraceptives (OC), containing ethinyl estradiol and norethisterone; the remaining 3 subjects were drop-outs. Both WR and OC normalized hyperandrogenicity. WR caused a 50% reduction of basal lipolysis rate and a 5- to 7-fold increased noradrenaline and terbutaline sensitivity (P < 0.02); the latter could be ascribed to a 2-fold increased beta2-adrenoceptor density (P < 0.02) as determined with radioligand binding. There was no change with regard to dobutamine (beta1-adrenoceptor sensitivity) or clonidine, (alpha2-adrenoceptor sensitivity) or to beta1-adrenoceptor density. OC treatment did not influence the basal lipolysis rate or beta2- or alpha2-adrenoceptor sensitivity, but lowered the beta1-adrenoceptor sensitivity 7-fold (P < 0.03) without a reduction in beta1-adrenoceptor density. The OC treatment effect was not observed when forskolin and dibutyryl cAMP, acting on adenylate cyclase or protein kinase A, respectively, were used, suggesting a partial uncoupling of beta1-adrenoceptors. WR therapy, but not OC therapy, caused, in addition to changes in lipolysis function, improved in vivo insulin sensitivity and lower plasma noradrenaline levels. These findings suggest that factors other than hyperandrogenicity modulate lipolysis regulation in obese subjects with PCOS. Disturbances in sympathetic pathways could be of pathogenic importance.

Adipocytes↗

PubMed2000

Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation.

In the last few years some studies assessed the effects of attenuation of hyperinsulinemia and insulin resistance, obtained by insulin sensitizing agents, in women with polycystic ovary syndrome (PCOS), suggesting potential scope for these drugs in treating the whole spectrum of reproductive, endocrine, and metabolic abnormalities found in such subjects. However, the results of these studies, mostly uncontrolled and short-term, are still inconclusive, and there is no long-term follow-up. In the present study, 23 PCOS subjects [mean (+/- SE) body mass index 30.0+/-1.1 kg/m2] were randomly assigned to double-blind treatment with metformin (500 mg tid) or placebo for 6 months, while maintaining their usual eating habits. Before and after treatment, menstrual history, endocrine and metabolic profiles, serum 17-hydroxyprogesterone response to GnRH-agonist testing, and insulin sensitivity measured by the glucose clamp technique were assessed. Eighteen of these women, as well as 14 additional PCOS patients, were subsequently given metformin in an open trial for 11.0+/-1.3 months (range 4-26), to assess long-term effects of treatment and baseline predictors of metformin efficacy on reproductive abnormalities. After metformin treatment, mean frequency of menstruation improved (P = 0.002), due to striking amelioration of menstrual abnormalities in about 50% of subjects. Women given metformin showed reduced plasma insulin (at fasting: P = 0.057; during the clamp studies: P<0.01) and increased insulin sensitivity (P<0.05). Concurrently, ovarian hyperandrogenism was attenuated, as indicated by significant reductions in serum free testosterone (P<0.05) and in the 17-hydroxyprogesterone response to GnRH-agonist testing (P<0.05). No changes were found in the placebo group. Only comparable minor changes in body mass index were found both in the metformin group and in the placebo group. In the open, long-term trial 17 women (54.8%) showed striking improvements of their menstrual abnormalities and were considered as responders. Logistic regression analysis of baseline characteristics in responders and nonresponders showed that plasma insulin, serum androstenedione, and menstrual history were independent predictors of the treatment's clinical efficacy. In 10 subjects whose menses proved regular after treatment, the great majority of cycles became ovulatory (32 out of 39 assessed, 79%). In conclusion, in women with PCOS metformin treatment reduced hyperinsulinemia and hyperandrogenemia, independently of changes in body weight. In a large number of subjects these changes were associated with striking, sustained improvements in menstrual abnormalities and resumption of ovulation. Higher plasma insulin, lower serum androstenedione, and less severe menstrual abnormalities are baseline predictors of clinical response to metformin.

17-alpha-Hydroxyprogesterone↗

PubMed2000

High prevalence of the polycystic ovary syndrome and hirsutism in women with type 1 diabetes mellitus.

The current recommendation for strict metabolic control of type 1 diabetes mellitus requires the administration of supraphysiological doses of insulin, which might result in insulin-mediated stimulation of androgen synthesis, as occurs in insulin-resistant states. At present, the prevalence of hyperandrogenic disorders in women with type 1 diabetes mellitus is unknown. Eighty-five women with type 1 diabetes mellitus were evaluated for symptoms and signs of hyperandrogenism. In 68 of the patients, several serum androgen and hormone concentrations were measured. The polycystic ovary syndrome (PCOS) was defined by the presence of menstrual dysfunction, together with clinical and/or biochemical evidence of hyperandrogenism, and exclusion of other etiologies. Eighteen healthy women, menstruating regularly, served as controls for the androgenic profiles. Thirty-three patients (38.8%) presented hyperandrogenic disorders (16 had PCOS, and 17 had hirsutism without menstrual dysfunction). Type 1 diabetic patients with PCOS presented increased serum total and free testosterone concentrations, and serum androstenedione levels, but had normal serum sex hormone-binding globulin and dehydroepiandrosterone-sulfate levels. Hirsute type 1 diabetic women without menstrual dysfunction presented normal serum androgen levels. There were no significant differences between hyperandrogenic and nonhyperandrogenic type 1 diabetes mellitus women in clinical variables such as the duration of diabetes, age at diagnosis of diabetes, conventional or intensive insulin therapy, mean daily insulin dosage, or metabolic control. In conclusion, women with type 1 diabetes mellitus have a high prevalence of hyperandrogenic disorders, including PCOS and hirsutism.

Adult↗

PubMed2000

A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain.

We prospectively estimated the prevalence of the polycystic ovary syndrome (PCOS), as defined by the NIH/NICHHD 1990 endocrine criteria, in a population of 154 Caucasian women of reproductive age reporting spontaneously for blood donation. Anthropometric data; the presence of hirsutism, acne, and androgenic alopecia; and the menstrual history were recorded by a single investigator. In 145 women, blood samples were also obtained for measurement of serum androgen levels. PCOS was defined by the presence of 1) oligomenorrhea, 2) clinical and/or biochemical hyperandrogenism, and 3) exclusion of hyperprolactinemia, thyroid disorders, and nonclassic 21-hydroxylase deficiency. Hirsutism was defined by a modified Ferriman-Gallwey score of 8 or more, acne was considered as a sign of hyperandrogenism when persistent after the second decade of life, and hyperandrogenemia was defined by an increase in circulating testosterone or dehydroepiandrosterone sulfate or an increase in the free androgen index above the 95th percentile of the control values derived from the nonhirsute, nonacneic women having regular menses who were not receiving hormonal therapy. PCOS was present in 10(6.5%), hirsutism was present in 11 (7.1%), and acne was present in 19 (12.3%) of the 154 women. Our results demonstrate a 6.5% prevalence of PCOS, as defined, in a minimally biased population of Caucasian women from Spain. The polycystic ovary syndrome, hirsutism, and acne are common endocrine disorders in women.

Adult↗

PubMed2000

Endocrine and metabolic effects of metformin versus ethinyl estradiol-cyproterone acetate in obese women with polycystic ovary syndrome: a randomized study.

Metformin, a biguanide antihyperglycemic drug, has been shown to improve ovarian function and glucose metabolism in women with polycystic ovary syndrome (PCOS), but results concerning its effects on insulin sensitivity are controversial. Oral contraceptive pills are commonly used in the treatment of PCOS; but, like metformin, their influence on insulin sensitivity is not well known. We randomized 32 obese (body mass index > 27 kg/m2) women with PCOS, either to metformin (500 mg x 2 daily for 3 months, then 1,000 mg x 2 daily for 3 months) or to ethinyl estradiol (35 microg)-cyproterone acetate (2 mg) oral contraceptive pills (Diane Nova) for 6 months. Metformin significantly decreased the waist-to-hip ratio, serum testosterone, fasting free fatty acid, and insulin concentrations and improved oxidative glucose utilization and menstrual cyclicity, with slight (but nonsignificant) improvements in insulin hepatic extraction and insulin sensitivity. Diane Nova significantly decreased serum testosterone and increased serum sex hormone-binding globulin concentrations and glucose area under the curve during oral glucose tolerance test. It is concluded that metformin, probably by way of its effect on adipose tissue, leads to reduction of hyperinsulinemia and concomitant improvement in the menstrual pattern; and therefore, it offers a useful alternative treatment for obese, anovulatory women with PCOS. Despite slight worsening of glucose tolerance, Diane Nova is an efficient treatment for women with hyperandrogenism and hirsutism.

Adult↗

PubMed2000

Androgen receptor gene CAG trinucleotide repeats in anovulatory infertility and polycystic ovaries.

Hyperandrogenism is currently thought to be central to the pathogenesis of polycystic ovarian syndrome (PCOS), a common endocrine disorder in premenopausal women characterized by irregular menstruation and anovulatory infertility. Although hyperandrogenism is characteristic, some women with PCOS have normal serum androgen levels. All androgens act through the X-linked androgen receptor (AR), the N-terminal domain of which contains a polyglutamine tract encoded by a highly polymorphic CAG trinucleotide repeat tract. Recently, variations in this CAG microsatellite tract, while remaining within the normal polymorphic range (11-38 CAGs), have been inversely correlated with receptor activity. Thus, short tracts are associated with high intrinsic AR activity and increased severity and earlier age of onset of the androgen-regulated tumor prostate cancer, whereas longer CAG tracts are associated with low AR activity and oligospermic infertility. To investigate the role of the CAG repeat tract in PCOS, we measured its length in 91 patients with ultrasound diagnosis of polycystic ovaries, irregular menstrual cycles, and anovulatory infertility and compared them to 112 control subjects of proven fertility with regular menses. Fluorescent-labeled DNA fragments containing the CAG repeat tract were amplified from leucocytic DNA, and their lengths were compared with internal size markers on an automated DNA Sequencer. There were no differences in the mean CAG length between patients and controls when both alleles were considered together or separately. Because there is a subset of PCOS patients whose serum androgens are normal, we compared differences in CAG length between patients whose serum testosterone (T) levels were below the normal laboratory mean, to those that were higher. There was a trend for a lower mean CAG biallelic length among anovulatory patients with T less than 1.73 nmol/L compared with those whose T was more than 1.73 nmol/L (22.47 +/- 0.36 vs. 23.25 +/- 0.29). This difference in CAG length between patients with low and high T levels (20.38 +/- 0.51 vs. 21.98 +/- 0.29) was highly significant (P = 0.004) when only the shorter allele of each individual was considered. Ethnic differences were also evident in our data; Indian subjects had a significantly shorter AR-CAG length compared with Chinese, being 22.08 +/- 0.50 and 23.16 +/- 0.17, respectively. Our data indicate an association between short CAG repeat length and the subset of anovulatory patients with low serum androgens, suggesting that the pathogenic mechanism of polycystic ovaries in these patients could be due to the increased intrinsic androgenic activity associated with short AR alleles.

Adult↗

PubMed2001

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.

Adolescent↗

PubMed2001

Metabolic and endocrine consequences of acute suppression of FFAs by acipimox in polycystic ovary syndrome.

To evaluate the effects of acute lowering of FFAs on glucose-induced insulin secretion and GH response to GHRH in polycystic ovary syndrome (PCOS), 27 PCOS subjects (11 lean and 16 obese) and 17 body mass index-matched controls (8 lean and 9 obese) were investigated. Patients underwent an oral glucose tolerance test and a GHRH test before and after administration of the antilipolytic drug acipimox (250 mg orally 3 h and 1 h before the starting of the tests). Blood samples were collected for 2 h after GHRH bolus and for 4 h after the oral glucose tolerance test. Serum concentrations of GH, insulin, glucose, and c-peptide were assayed in each sample, and the results were expressed as area under the curve (AUC). No significant differences were found as to glucose, insulin, and c-peptide AUC before and after acute FFA plasma reduction in any of the investigated groups. Basally, lower GH-AUC was found in lean PCOS compared with body mass index-matched controls and in obese vs. lean controls; no significant differences were found as to the same variable between the two obese groups. The acipimox induced FFA suppression elicited in the four groups a sustained increase in the GH response to its trophic hormone; indeed, the GH-AUC nearly doubled with respect to basal evaluation in all the studied groups. However, the antilipolytic drug was not able to abolish the differences found between lean groups in basal conditions. In conclusion, the presented data confirm that FFAs have a main role in regulating GH secretion at the pituitary level; however, it does not seem that they could explain the GH as well as insulin dysfunction of PCOS.

Adult↗

PubMed2001

Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial.

We hypothesized that the administration of troglitazone, an insulin-sensitizing agent of the thiazolidinedione class, would improve the ovulatory dysfunction, hirsutism, hyperandrogenemia, and hyperinsulinemia of polycystic ovary syndrome (PCOS) patients. Four hundred and ten premenopausal women with PCOS in a multicenter, double blind trial were randomly assigned to 44 weeks of treatment with placebo (PBO) or troglitazone [150 mg/day (TGZ-150), 300 mg/day (TGZ-300), or 600 mg/day (TGZ-600)]. We compared changes in ovulatory function (by monitoring the urinary level of pregnanediol-3-glucuronide daily), hirsutism (by a modified Ferriman-Gallwey scoring method), hormonal levels (total and free testosterone, androstenedione, sex hormone-binding globulin, LH, FSH, and the LH/FSH ratio), and measures of glycemic parameters (fasting levels of glucose, insulin, hemoglobin A(1c), and the glucose and insulin areas under the curve during an oral glucose challenge) among study groups. Of the 410 patients recruited, 305 (74.4%) met evaluability criteria and were included in the analyses. The patients' baseline characteristics were similar across all treatment arms. Ovulatory rates were significantly greater for patients receiving TGZ-300 and TGZ-600 than for those receiving PBO (0.42 and 0.58 vs. 0.32; P < 0.05 and 0.0001, respectively). Of PCOS patients treated with TGZ-600, 57% ovulated over 50% of the time compared with 12% of placebo-treated patients. There was a significant decrease in the Ferriman-Gallwey score with TGZ-600 compared with PBO (0.22 +/- 0.53 vs. -2.21 +/- 0.49; P < 0.05, respectively). Free testosterone decreased and sex hormone-binding globulin increased in a dose-related fashion with troglitazone treatment, and all three troglitazone treatment groups were significantly different from placebo. Nearly all glycemic parameters showed dose-related decreases with troglitazone treatment. The total number and severity of adverse events (including elevations in liver enzymes) and the proportion of patients withdrawn from the study due to the development of adverse effects were similar between treatment groups. Troglitazone improves the ovulatory dysfunction, hirsutism, hyperandrogenemia, and insulin resistance of PCOS in a dose-related fashion, with a minimum of adverse effects.

Adult↗

PubMed2001

The rise of estradiol and inhibin B after acute stimulation with follicle-stimulating hormone predict the follicle cohort size in women with polycystic ovary syndrome, regularly menstruating women with polycystic ovaries, and regularly menstruating women with normal ovaries.

Polycystic ovaries contain a larger number of antral follicles than control ovaries. The aim of this study was to test whether the increase in estradiol (E(2)) and inhibin B after stimulation with 300 IU recombinant FSH in the early follicular phase and the ovarian volume can predict the size of the follicle cohort in polycystic ovary syndrome (PCOS) patients (n = 10), patients with polycystic ovaries detected by ultrasound but with regular menstrual cycles (PCO; n = 10), and regularly menstruating patients with normal ovaries (n = 10). The follicle cohort size was measured as the FSH-sensitive follicles growing during a standardized in vitro fertilization stimulation. Linear regression analysis showed that the slopes of the regression lines of the E(2) increment and the inhibin B increment in relation to the number of follicles were not significantly different among the three groups, meaning that an increased sensitivity for FSH of the granulosa cells of polycystic ovaries was not found. For the total group (n = 30) we calculated that an E(2) increment of 100 pmol/L predicts 5.5 follicles (95% confidence interval, 2.8--8.2; r = 0.617; P < 0.001), and an inhibin B increment of 100 ng/L predicts 6.2 follicles (95% confidence interval, 3.5--9.0; r = 0.665; P < 0.001). The ovarian volume could not be used in a prediction model because the association with the number of follicles was different in the PCO group compared with the PCOS and the control group. Women with PCO and women with PCOS both had a follicle cohort twice as big as the cohort in control women (P < 0.01). The differences in menstrual cycle pattern between the PCO and PCOS groups cannot be explained by differences in cohort size.

Adult↗

PubMed2001

Adrenocortical secretion of dehydroepiandrosterone in healthy women: highly variable response to adrenocorticotropin.

Excess adrenal androgen (AA) levels are observed in 25--50% of women with the polycystic ovary syndrome (PCOS), and AA excess in PCOS may represent selection bias. Thus, it is possible that AA secretion among the general population is highly variable, and that those women who are predisposed to secreting greater amounts of AA have a greater probability of having PCOS. We now hypothesize that the levels of AAs are highly variable among normal nonhyperandrogenic women, and that this heterogeneity is the result of a variable response of AAs to ACTH stimulation. To test this hypothesis we prospectively studied the response of dehydroepiandrosterone (DHA) and cortisol (F) to a 60-min acute stimulation with ACTH-(1--24) in 56 healthy eumenorrheic nonhirsute healthy women with a mean age of 28.9 yr (range, 20--37 yr.) and a mean body mass index (BMI) of 29.2 kg/m(2) (18.2--46.2 kg/m(2)). Baseline samples and poststimulation samples were assayed for DHA and F. The basal and ACTH-stimulated levels of DHA, but not those of F, were negatively correlated with age, although neither the basal nor ACTH-stimulated responses of DHA and F varied with BMI. After controlling for age, the basal F level was negatively correlated to its net increment (i.e. Delta F; r = -0.54; P < 0.001), whereas there was no significant relationship between basal DHA and Delta DHA. We also compared the intersubject variability (coefficient of variation) for basal and stimulated levels of DHA and F. For basal (DHA(0)), 60 min (DHA(60)), and net increment in (Delta DHA) DHA levels, the coefficients of variation were 67.9%, 61.4%, and 76.0%, respectively; for F(0), F(60), and Delta F, they were 40.4%, 16.9%, and 31.3%, respectively. The variance in Delta DHA was significantly higher, and the variance in F(60) was significantly lower than that in all other variables; DHA(0), DHA(60), F(0), and Delta F had similar variances. In conclusion, in our population of healthy reproductive-aged women we observed that both basal and ACTH-stimulated levels of DHA after ACTH-(1--24) stimulation had significantly greater intersubject variance (approximately 60--70%) compared with the basal and poststimulation levels of F (approximately 15--40%). These data support the hypothesis that among normal women, AA (i.e. DHA) levels are highly variable compared to those of F. In addition, the intersubject variability in DHA levels is at least in part due to a variable response of AAs to ACTH stimulation. Whether the AA excess frequently observed in PCOS is due to the greater risk of those women with higher AA levels, basally and after ACTH stimulation, remains to be confirmed.

Adrenal Cortex↗

PubMed2002

Elevated free IGF-I levels in prepubertal Hispanic girls with premature adrenarche: relationship with hyperandrogenism and insulin sensitivity.

Girls with premature adrenarche (PA) (the onset of pubic hair before the age of 8 yr associated with elevated levels of adrenal androgens and no evidence of true puberty or adrenal dysfunction) may be at increased risk for development of polycystic ovarian syndrome (PCOS). Alterations in the IGF system, including elevated free IGF-I, have been demonstrated in PCOS and may be involved in its pathogenesis. Hyperinsulinemia, elevated total IGF-I, and decreased IGF-binding protein-1 (IGFBP-1) have also been reported in PA. Dysregulation of the IGF system may be involved in the pathogenesis of PA and its progression to PCOS. We compared the insulin/IGF system in 17 prepubertal girls with PA and nine prepubertal controls. Both groups were predominantly obese. Total and free IGF-I were elevated in the premature adrenarche group. No differences in basal insulin, insulin area under the curve in response to an oral glucose tolerance test, or IGFBP-1 were noted. These effects persisted when adjusted for adiposity using body mass index-Z score. Total and free IGF-I were positively correlated, and IGFBP-1 was negatively correlated with Delta4-androstenedione, but not with dehydroepiandrosterone sulfate. Free IGF-I trended toward higher levels in the insulin-resistant subgroup, compared with the insulin-sensitive subgroup. These results suggest altered regulation of the insulin/IGF system in prepubertal girls with PA and a possible role for free IGF-I in the pathogenesis of the hyperandrogenism of PA as well as its progression to PCOS.

Androgens↗

PubMed2002

Comment: CAPN10 alleles are associated with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is characterized by chronic anovulation infertility, hyperandrogenemia, and frequently insulin resistance. This study investigated whether polymorphisms in the CAPN10 gene are related with PCOS etiology. The allelic frequencies and genotypes of CAPN10 polymorphisms UCSNP-44, 43, 19, and 63 were determined in 55 well characterized women with polycystic ovaries and 93 unrelated healthy controls using spectrofluorimetric analyses and real-time PCR. Our data indicate that CAPN10 UCSNP-44 allele is associated with PCOS in the Spanish population (P = 0.01). These results support a role of Calpain 10 gene in PCOS susceptibility in humans.

Calpain↗

PubMed1995

The effects of potassium channel openers and blockers on the specific binding sites for [3H]glibenclamide in rat tissues.

The effects of K+ channel openers (PCOs), NIP-121, levcromakalim and nicorandil, and the blockers of the specific binding sites for [3H]glibenclamide, ATP-sensitive K+ channel blocker, were investigated in rat brain and cardiac ventricle membrane preparations. When the microsomes were incubated with [3H]glibenclamide, the specific glibenclamide binding was fully inhibited by unlabeled glibenclamide (1 microM) and apamin (100 microM). However, the specific glibenclamide binding was not influenced by excess NIP-121, levcromakalim and nicorandil, although glibenclamide antagonized the increase in the 86Rb+ efflux by PCOs. On the other hand, the binding of [3H]glibenclamide after a long pre-incubation (60 min) at 37 degrees C with NIP-121 and levcromakalim at pharmacological effective concentrations (10 nM to 1 microM) was significantly influenced. Both PCOs partially reduced both Kd and Bmax values of the specific [3H]glibenclamide binding in a concentration-dependent manner that was not regulated by GTP gamma S. The dose-effect relationships for the Bmax's of NIP-121 and levcromakalim seemed similar to those for vasorelaxation. These findings indicate that the pharmacological effect of PCO may be caused by the binding to its own specific sites but not to the specific sulfonylurea sites. The binding of PCOs may inhibit, in a negative allosteric manner the binding of sulfonylureas.

Animals↗

PubMed2006

Polycystic ovary syndrome and the postmenopausal woman.

Polycystic ovary syndrome (PCOS) is a common syndrome among young women. It is associated with fertility problems, clinical manifestations of hyperandrogenism and metabolic disturbance, particularly insulin resistance. The long-term consequences of PCOS have not been fully determined, but there is an increased risk of progression to diabetes and an increase in cardiovascular risk factors. The extent to which PCOS is present in postmenopausal women and the degree to which it increases various risk factors in addition to the known risk of the postmenopausal period are not yet known. This paper reviews the pathophysiology of PCOS and its long-term consequences and considers the evidence to date that is applicable to the postmenopausal woman.

Breast Neoplasms↗