Basal metabolic rate in women with PCOS compared to eumenorrheic controls.

OBJECTIVE: PCOS is associated with obesity and insulin resistance. Efforts have focused on whether an abnormal energy homeostasis contributes to the development of obesity in these patients. There are conflicting results in the literature regarding whether women with PCOS have an altered basal metabolic rate (BMR), thereby leading to difficulties in weight loss. The objective of this study is to compare basal metabolic rate (BMR) in women with PCOS and controls. DESIGN: Cross-sectional study. PATIENTS: One hundred and twenty-eight PCOS patients diagnosed by original NIH consensus criteria and 72 eumenorrheic, non-hirsute controls were recruited from an academic medical centre. MEASUREMENTS: Assessment of BMR using the InBody portable bioelectrical impedance analysis (BIA) device and insulin resistance by HOMA-IR indices. RESULTS: PCOS women were younger than controls. As expected, PCOS subjects had higher body mass index (BMI), serum androgens and estimated insulin resistance. After adjusting for age and BMI, there was no significant difference in BMR between PCOS subjects (adjusted mean 5807 kJ/day, 95% CI 5715-5899) and controls (adjusted mean 5916 kJ/day, 95% CI 5786-6046) (P = 0·193). BMR was also comparable in a secondary analysis comparing PCOS women with and without insulin resistance. CONCLUSIONS: After adjusting for age and BMI, there was no difference in BMR between PCOS women and controls.

Association of fat to lean mass ratio with metabolic dysfunction in women with polycystic ovary syndrome.

STUDY QUESTION: Are differences in metabolic dysfunction between polycystic ovary syndrome (PCOS) and control women related to differences in their fat to lean mass (F/L) ratio? SUMMARY ANSWER: Compared with controls of similar body mass index (BMI), women with PCOS demonstrate adverse body composition characterized by increased whole body fat relative to lean mass (i.e. a higher F/L ratio), which is associated with differences in metabolic dysfunction between the two groups. WHAT IS KNOWN ALREADY: Previous studies examining body composition and insulin resistance (IR) in PCOS have yielded conflicting results. Excess total fat mass (i.e. fat mass index [fat BMI]) correlates with IR, whereas increased total lean mass (i.e. lean BMI) has been associated with higher insulin sensitivity. However, the role of the F/L ratio, which integrates the antagonistic effects of both fat and lean mass depots, on IR in PCOS, has not been investigated. STUDY DESIGN, SIZE, DURATION: We conducted a prospective cross-sectional study of 120 women between the ages of 22-44 years to study the relation of the F/L ratio with measures of insulin action and secretion in both steady and dynamic states. PARTICIPANTS/MATERIALS, SETTING, METHODS: Sixty PCOS (by NIH, 1990 criteria) and 60 control (age, race and BMI-matched) women were prospectively studied for body composition (by bioelectrical impedance analysis [BIA]) and basal IR and insulin secretion by the homeostasis model assessment (HOMA-IR and HOMA-%ß-cell function, respectively) in a tertiary care academic referral center. A subset of 12 PCOS and 12 matched control women also underwent a modified frequently sampled intravenous glucose tolerance test (FSIVGTT) to determine glucose uptake and insulin secretion in dynamic state. MAIN RESULTS AND THE ROLE OF CHANCE: Our results indicate that women with PCOS demonstrated greater degrees of hyperandrogenism, and higher waist-to-hip ratio (WHR), %body fat, fat BMI, F/L, fasting insulin levels, and HOMA-IR and HOMA-%ß-cell values, than controls. In models adjusted for WHR and free testosterone and diagnostic groups, fasting insulin levels, HOMA-IR, and HOMA-%beta cell function were positively related to the F/L ratio. A positive relationship was also found in both study groups between F/L and the FSIVGTT measures insulin sensitivity (Si) and acute insulin response to glucose (AIRg). The F/L tended to negatively correlate with glucose effectiveness or non-insulin-mediated glucose transport (Sg) only in PCOS women. LIMITATIONS, REASONS FOR CAUTION: Regional tissue sub-compartments, which have been shown to have potential independent associations with metabolic variables, cannot be determined by bioelectrical impedance analysis (BIA). WIDER IMPLICATIONS OF THE FINDINGS: The current results suggest that BIA could be used to assess F/L in place of dual energy X-ray absorptiometry (DXA) in research protocols, and that F/L could possibly be used as an alternative to WHR as a surrogate marker of metabolic dysfunction in clinical practice. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants R01-DK073632 and R01-HD29364 from the NIH and an endowment of the Helping Hand of Los Angeles, Inc. (to R.A.). The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: Not applicable.

Alterations in nonesterified free fatty acid trafficking rather than hyperandrogenism contribute to metabolic health in obese women with polycystic ovary syndrome.

OBJECTIVE: To determine whether alterations in nonesterified fatty acid (NEFA) dynamics or degree of hyperandrogenism (HA) contribute to the difference in insulin sensitivity between women with metabolically healthy obese polycystic ovary syndrome (PCOS) (MHO-PCOS) and women with metabolically unhealthy obese PCOS (MUO-PCOS). DESIGN: Prospective cross-sectional study. SETTING: Tertiary-care academic center. PATIENTS: One hundred twenty-five obese women with PCOS. INTERVENTION: Consecutive obese (body mass index [BMI] ≥ 30 kg/m2) oligo-ovulatory women (n = 125) with PCOS underwent an oral glucose tolerance test and a subgroup of 16 participants underwent a modified frequently sampled intravenous glucose tolerance test to determine insulin-glucose and -NEFA dynamics. MAIN OUTCOME MEASURES: Degree of insulin resistance (IR) in adipose tissue (AT) basally (Adipo-IR) and dynamically (the nadir in NEFA levels observed [NEFAnadir], the time it took for NEFA levels to reach nadir [TIMEnadir], and the percent suppression in plasma NEFA levels from baseline to nadir [%NEFAsupp]); peak lipolysis rate (SNEFA) and peak rate of NEFA disposal from plasma pool (KNEFA); whole-body insulin-glucose interaction (acute response of insulin to glucose [AIRg], insulin sensitivity index [Si], glucose effectiveness [Sg], and disposition index [Di]); and HA (hirsutism score, total and free testosterone levels, and dehydroepiandrosterone sulfate levels). RESULTS: A total of 85 (68%) women were MUO-PCOS and 40 (32%) were MHO-PCOS using the homeostasis model of assessment of IR. Subjects with MUO-PCOS and MHO-PCOS did not differ in mean age, BMI, waist-to-hip ratio, HA, and lipoprotein levels. By a modified frequently sampled intravenous glucose tolerance test, eight women with MUO-PCOS had lesser Si, KNEFA, and the percent suppression in plasma NEFA levels from baseline to nadir (%NEFAsupp) and greater TIMEnadir, NEFAnadir, and baseline adipose tissue IR index (Adipo-IR) than eight subjects with MHO-PCOS, but similar fasting NEFA levels and SNEFA. Women with MUO-PCOS had a higher homeostasis model of assessment-ß% and fasting insulin levels than women with MHO-PCOS. In bivalent analysis, Si correlated strongly and negatively with Adipo-IR and NEFAnadir, weakly and negatively with TIMEnadir, and positively with KNEFA and %NEFAsupp, in women with MUO-PCOS only. CONCLUSION: Independent of age and BMI, women with MUO-PCOS have reduced NEFA uptake and altered insulin-mediated NEFA suppression, but no difference in HA, compared with women with MHO-PCOS. Altered insulin-mediated NEFA suppression, rather than HA or lipolysis rate, contributes to variations in insulin sensitivity among obese women with PCOS.

Screening for Androgen Excess in Women: Accuracy of Self-Reported Excess Body Hair Growth and Menstrual Dysfunction.

CONTEXT: Epidemiologic studies of polycystic ovary syndrome (PCOS) are limited, especially in populations where diagnostic resources are less available. In these settings, an accurate, low-cost screening tool would be invaluable. OBJECTIVE: To test the use of a simple questionnaire to identify women at increased risk for PCOS and androgen excess (AE) disorders. STUDY DESIGN: Prospective cohort study from 2006-2010. SETTING: Community-based. PARTICIPANTS: Women aged 14 to 45 years. INTERVENTION: A screening telephone questionnaire consisting of 3 questions was tested, where participants were asked to self-assess the presence/absence of male-like hair and menstrual irregularity. Participants were then invited to undergo a direct examination, including completing a medical history and undergoing a modified Ferriman-Gallwey (mFG) hirsutism score, ovarian ultrasound, and measurement of circulating total and free testosterone, DHEAS, TSH, prolactin and 17-hydroxyprogesterone levels. MAIN OUTCOME MEASURE: Accuracy of questionnaire in predicting PCOS, AE, and irregular menses. RESULTS: Participants with self-assessed irregular menses and/or excess hair were labeled "Possible Androgen Excess (Poss-AE)" and those self-assessed with regular menses and no excess hair were labeled "Probable Non-Androgen Excess (Non-AE)." The study was completed in 206/298 (69%) of the Poss-AE and in 139/192 (73%) of the Non-AE. Of Poss-AE and Non-AE subjects, 82.5% and 15.8%, respextively, presented with PCOS. The calculated sensitivity, specificity, positive predictive value, and negative predictive value of the 3-question telephone survey to predict PCOS was 89%, 78%, 85%, and 83%, respectively. CONCLUSIONS: A simple telephone questionnaire, based on self-assessment of body hair and menstrual status, can be used with a high predictive value to identify women at risk for AE disorders, including PCOS, and to detect healthy controls. This approach could be an important tool for needed epidemiologic studies.

Nonreplication of the type 5 17beta-hydroxysteroid dehydrogenase gene association with polycystic ovary syndrome.

CONTEXT: Increased androgen production is a primary feature of polycystic ovary syndrome (PCOS) and appears to be an inherited trait. The gene for the steroidogenic enzyme type 5 17beta hydroxysteroid dehydrogenase (HSD17B5) was implicated as a candidate for the hyperandrogenemia of PCOS by a previous study that demonstrated an association of a single nucleotide polymorphism (SNP) in the promoter of this gene with PCOS. OBJECTIVE: The objective of the study was to replicate the previous report of association between the HSD17B5 gene and PCOS risk by genotyping the promoter SNP (as well as other SNPs in the region to provide improved coverage of the gene) in a large, well-characterized cohort suitable for replication study. DESIGN: Women with and without PCOS were genotyped for five SNPs in HSD17B5. SNPs and haplotypes were determined and tested for association with PCOS risk and phenotypic markers of PCOS. SETTING: Subjects were recruited from the reproductive endocrinology clinic at the University of Alabama at Birmingham; controls were recruited from the surrounding community. Genotyping took place at Cedars-Sinai Medical Center in Los Angeles. PARTICIPANTS: Participants included 287 white women with PCOS and 187 white controls. MAIN MEASUREMENTS: HSD17B5 genotype, PCOS risk, and testosterone levels were measured. RESULTS: No SNP or haplotype was significantly associated with PCOS risk, testosterone, or any of the traits tested. CONCLUSIONS: These data suggest that polymorphisms in the HSD17B5 gene are not associated with PCOS risk or elevated testosterone as previously reported.

Association of androgen receptor CAG repeat polymorphism and polycystic ovary syndrome.

CONTEXT: Genetically determined heightened androgen sensitivity may influence the phenotype of polycystic ovary syndrome (PCOS). To date, studies of the androgen receptor exon 1 polymorphic CAG repeat have produced conflicting results in PCOS. OBJECTIVE: We tested the hypothesis that a lower number of CAG repeats is associated with increased odds of PCOS. We also compared X-chromosome inactivation between cases and controls. DESIGN: Women with and without PCOS were genotyped for the CAG repeat and assessed for X-chromosome methylation. Association analyses were performed. SETTING: Subjects were recruited from the reproductive endocrinology clinic at the University of Alabama at Birmingham; controls were recruited from the surrounding community. Genotyping took place at Cedars-Sinai Medical Center in Los Angeles. PARTICIPANTS: Participants included 330 women with PCOS and 289 controls (77% white, 23% black). MAIN MEASUREMENTS: Androgen receptor genotype, X-chromosome methylation, and phenotyping for PCOS were measured. RESULTS: A smaller biallelic mean of CAG repeats was associated with increased odds of PCOS. X-chromosome inactivation was not different comparing cases with controls; however, in the subset with nonrandom inactivation, the chromosome bearing the shorter CAG allele was preferentially active in PCOS women. CONCLUSIONS: Association of shorter CAG repeats with PCOS is consistent with in vitro functional studies demonstrating higher activity of androgen receptors expressed from alleles with fewer CAG repeats, suggesting inherited alteration in androgen sensitivity may contribute to PCOS. In some women, such heightened sensitivity may also result from preferential expression of androgen receptors with shorter alleles. Thus, genetic and epigenetic changes may be involved in the pathogenesis of PCOS.

Variants in the 5alpha-reductase type 1 and type 2 genes are associated with polycystic ovary syndrome and the severity of hirsutism in affected women.

CONTEXT: Despite the importance of dihydrotestosterone in androgen action, polymorphisms in the genes for the two isoforms of 5alpha-reductase (SRD5A1 and SRD5A2) have not been evaluated as risk factors for polycystic ovary syndrome (PCOS). OBJECTIVE: The objective of the study was to test the hypothesis that haplotypes in the SRD5A1 and SRD5A2 genes are risk factors for PCOS and the severity of hirsutism in affected women. DESIGN: PCOS and control subjects were genotyped for seven single-nucleotide polymorphisms in SRD5A1 and eight single-nucleotide polymorphisms in SRD5A2. Haplotypes were determined and tested for association with PCOS diagnosis and component phenotypes. SETTING: Subjects were recruited from the reproductive endocrinology clinic at the University of Alabama at Birmingham; control subjects were recruited from the general surrounding community. Genotyping took place at Cedars-Sinai Medical Center in Los Angeles. PARTICIPANTS: A total of 287 White women with PCOS and 187 controls participated. MAIN MEASUREMENTS: SRD5A1 and SRD5A2 genotype, quantitative hirsutism score, and hormonal and metabolic phenotypes were assessed. RESULTS: Haplotypes within both genes were associated with PCOS risk. The Leu allele of the Val89Leu variant in SRD5A2 was associated with protection against PCOS; this allele is known to modestly reduce 5alpha-reductase activity. Haplotypes in SRD5A1 but not SRD5A2 were also associated with the degree of hirsutism in affected women. CONCLUSIONS: This study presents genetic evidence suggesting an important role of both isoforms of 5alpha-reductase in the pathogenesis of PCOS. That only SRD5A1 haplotypes were associated with hirsutism suggests that only this isoform is important in the hair follicle.

The severity of menstrual dysfunction as a predictor of insulin resistance in PCOS.

OBJECTIVE: The objective of the study was to evaluate the relationship between the severity of menstrual disturbances and the degree of insulin resistance in women with polycystic ovary syndrome (PCOS). DESIGN: This was a cross-sectional study. SETTING: The study was conducted at a tertiary care academic medical center. PATIENTS: Four hundred ninety-four women diagnosed with PCOS by the Rotterdam criteria and 138 eumenorrheic, nonhirsute, control women participated in the study. INTERVENTIONS: INTERVENTIONS in the study included history and physical examination and blood sampling. MAIN OUTCOME MEASURE(S): Physical assessment and total and free T, dehydroepiandrosterone sulfate, fasting glucose, and insulin levels and calculated homeostatic model assessment values for insulin resistance (HOMA-IR) were measured. RESULTS: Overall, 80% of PCOS subjects included had clinically evident oligomenorrhea. The remainder demonstrated vaginal bleeding intervals of fewer than 35 days (ie, with either polymenorrhea or clinically apparent eumenorrhea). Only 10% of PCOS subjects studied were ovulatory. After adjusting for body mass index, age, and race, all PCOS subjects with menstrual cycles longer than 35 days had significantly higher mean HOMA-IR levels than controls, and those with cycles longer than 3 months had the highest HOMA-IR levels. There was no difference in mean HOMA-IR levels between PCOS with regular vaginal bleeding (apparent eumenorrhea), regardless of whether they were anovulatory or not, or those with cycles fewer than 26 days, when compared with controls. CONCLUSIONS: Women with PCOS and overt oligomenorrhea comprise the vast majority of PCOS subjects seen clinically and have significantly more insulin resistance than controls. About 20% of PCOS women seen reported vaginal bleeding intervals of fewer than 35 days in length and did not generally have overt insulin resistance, regardless of whether they were ovulatory or not. Overall, the presence of clinically evident menstrual dysfunction can be used to predict the presence and possibly the degree of insulin resistance in women with PCOS.

Effects of endogenous androgens and abdominal fat distribution on the interrelationship between insulin and non-insulin-mediated glucose uptake in females.

BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism and insulin resistance. Glucose disposal occurs via noninsulin-mediated glucose uptake (NIMGU) and insulin-mediated glucose uptake (IMGU). It is unknown whether in PCOS NIMGU increases to compensate for declining IMGU and whether androgens and fat distribution influence this relationship. OBJECTIVES: The objective of the study was to compare in women with PCOS and controls the interrelationship between NIMGU [ie, glucose effectiveness (Sg)] and IMGU [ie, the insulin sensitivity index (Si)] and the role of androgens and fat distribution. PARTICIPANTS: Twenty-eight PCOS (by National Institutes of Health 1990 criteria) and 28 control (age, race, and body mass index matched) women were prospectively studied. A subset of 16 PCOS subjects and 16 matched controls also underwent abdominal computed tomography. MAIN OUTCOME MEASURES: Glucose disposal (by a frequently sampled iv glucose tolerance test), circulating androgens, and abdominal fat distribution [by waist to hip ratio and visceral (VAT) and sc (SAT) adipose tissue content] were measured. RESULTS: PCOS women had lower mean Si and similar Sg and abdominal fat distribution compared with controls. PCOS women with Si below the PCOS median (more insulin resistant) had a lower mean Sg than controls with Si above the control median (more insulin sensitive). In PCOS only, body mass index, free T, modified Ferriman-Gallwey score, and waist to hip ratio independently predicted Sg, whereas Si did not. In PCOS, VAT and SAT independently and negatively predicted Si and Sg, respectively. CONCLUSION: The decreased IMGU in PCOS is not accompanied by a compensatory increase in NIMGU or associated with excessive VAT accumulation. Increased general obesity, SAT, and hyperandrogenism are primary predictors of the deterioration of NIMGU in PCOS.

Abnormal expression of genes involved in inflammation, lipid metabolism, and Wnt signaling in the adipose tissue of polycystic ovary syndrome.

CONTEXT: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women. OBJECTIVE: Our objective was to compare gene expression pattern in sc abdominal adipose tissue in nonobese PCOS patients vs. body mass index-matched controls. RESEARCH DESIGN AND METHODS: Eleven PCOS subjects and 12 controls (body mass index 20-28 kg/m(2)) were recruited. Total RNA was isolated, and gene expression profiling was performed using Affymetrix Human Genome U133 arrays. Differentially expressed genes were classified by gene ontology. Microarray results for selected genes were confirmed by quantitative real-time PCR (RT-qPCR). Frequently sampled iv glucose tolerance tests were used to assess dynamic insulin sensitivity. RESULTS: Ninety-six genes were identified with altered expression of at least 2-fold in nonobese PCOS adipose tissues. Inflammatory response genes were significantly down-regulated. RT-qPCR confirmed decreases in expression of IL6 (12.3-fold), CXCL2 (18.3-fold), and SOCS3 (22.6-fold). Lipid metabolism genes associated with insulin resistance were significantly up-regulated, with confirmed increases in DHRS9 (2.5-fold), UCLH1 (2.6-fold), and FADS1 (2.8-fold) expression. Wnt signaling genes (DKK2, JUN, and FOSB) were differentially expressed. RT-qPCR confirmed significant expression changes in DKK2 (1.9-fold increase), JUN (4.1-fold decrease), and FOSB (60-fold decrease). CONCLUSIONS: Genes involved in inflammation, lipid metabolism, and Wnt signaling are differentially expressed in nonobese PCOS adipose tissue. Because these genes are known to affect adipogenesis and insulin resistance, we hypothesize that their dysregulation may contribute to the metabolic abnormalities observed in women with PCOS.

Steroidogenic regulatory factor FOS is underexpressed in polycystic ovary syndrome (PCOS) adipose tissue and genetically associated with PCOS susceptibility.

CONTEXT: Polycystic ovary syndrome (PCOS) is a heterogeneous common genetic disorder characterized by hyperandrogenemia and insulin resistance. Alterations in gene expression profiles of the ovary and adipose tissue identified the candidate gene FBJ murine osteosarcoma viral oncogene homolog (FOS) for further investigation of expression changes in metabolic tissues and genetic studies. OBJECTIVE: The objective of the study was to confirm the underexpression of the FOS gene in sc adipose and determine whether variants in this gene are risk factors for PCOS. DESIGN: RT-PCR was performed in sc fat from women with and without PCOS. Genotyping of single-nucleotide polymorphisms in the FOS locus was performed to test for association with PCOS. SETTING: The study was conducted at a tertiary care academic institution. PARTICIPANTS: Twenty-two PCOS and 13 control subjects were recruited for gene expression studies. We assembled a discovery genotyping cohort of 354 cases and 161 controls and a replication cohort of 476 cases and 315 controls, all of whom were Caucasian. MAIN MEASUREMENTS: Gene expression by quantitative real-time RT-PCR, FOS genotype, and PCOS status were measured. RESULTS: FOS expression was confirmed to be reduced in PCOS adipose tissue. Three single-nucleotide polymorphisms were significantly associated with PCOS in the discovery cohort (rs8006998, P = 0.0031; rs8013918, P = 0.0006; rs8013942, P = 0.0087). rs8006998 was also associated with PCOS in the replication cohort (P = 0.013). CONCLUSIONS: Differential gene expression in sc fat and genetic association at the FOS locus in PCOS subjects implicates a role for this transcription factor in PCOS. FOS dysfunction may be a common factor between hyperandrogenism and insulin resistance.

The phenotype of hirsute women: a comparison of polycystic ovary syndrome and 21-hydroxylase-deficient nonclassic adrenal hyperplasia.

OBJECTIVE: To test the hypothesis that women with polycystic ovary syndrome (PCOS) are distinguishable from those with 21-hydroxylase-deficient nonclassic adrenal hyperplasia on the basis of having polycystic ovaries and metabolic dysfunction. DESIGN: Prospective observational. SETTING: Tertiary care center. PATIENT(S): Fifty-two lean and 54 obese women with PCOS according to the 1990 National Institutes of Health criteria, 23 women with nonclassic adrenal hyperplasia, and 27 controls. INTERVENTION(S): History and physical examination, blood sampling, ovarian sonography, oral glucose tolerance, and acute adrenocorticotropin stimulation testing. MAIN OUTCOME MEASURE(S): The frequency of clinical, biochemical, and metabolic features. RESULT(S): Women with PCOS had a higher frequency of oligomenorrhea or amenorrhea than those with nonclassic adrenal hyperplasia. Mean androstenedione and DHEAS levels were highest in nonclassic adrenal hyperplasia. The degree of metabolic dysfunction was greatest in obese women with PCOS; women with nonclassic adrenal hyperplasia and lean women with PCOS did not differ in degree of metabolic dysfunction. Women with nonclassic adrenal hyperplasia had a lower prevalence of polycystic ovaries than those with PCOS. The proportion of patients with an LH/FSH ratio >2 was greater in women with PCOS, compared with those with nonclassic adrenal hyperplasia. Basal 17-hydroxyprogesterone levels >2 ng/mL were found in 87%, 25%, 20%, and 7% of women with nonclassic adrenal hyperplasia, lean women with PCOS, obese women with PCOS, and controls, respectively. CONCLUSION(S): Nonclassic adrenal hyperplasia should be excluded in all women presenting with hirsutism, with use of a basal follicular phase 17-hydroxyprogesterone level, regardless of the presence of polycystic ovaries or metabolic dysfunction; however, women with nonclassic adrenal hyperplasia have a higher prevalence of normal ovulation and lower likelihood of having an LH/FSH ratio >2 or polycystic ovaries.

Effect of sex steroids and insulin on dehydroepiandrosterone sulfate production by hepatoma G2 cells.

OBJECTIVE: To test the hypothesis that DHEAS production from DHEA occurs in hepatic cells and that this production is augmented by the presence of sex steroids or insulin. DESIGN: In vitro prospective experiment. SETTING: Academic medical center. INTERVENTION(S): Hepatoma G2 cells cultured in media supplemented with [1] DHEA (10(-5) mol/L) only, [2] DHEA (10(-5) mol/L) + T (10(-6) mol/L), [3] DHEA (10(-5) mol/L) + E(2) (10(-6) mol/L), [4] DHEA (10(-5) mol/L) + dihydrotestosterone (10(-6) mol/L), [5] DHEA (10(-5) mol/L) + insulin (10 ng/mL), or [6] DHEA (10(-5) mol/L) + insulin (100 ng/mL). MAIN OUTCOME MEASURE(S): Levels of DHEAS in the media were measured at 0, 2, 4, 6, 8, 12, 24, 48, and 72 hours after adding treatments at time-point 0. RESULT(S): Dehydroepiandrosterone sulfate was first detected in the hepatoma G2 cell culture media at 12 hours of incubation. The cumulative production rate of DHEAS increased linearly until 72 hours of incubation. When compared with the effect of treatment with DHEA only, treatment with DHEA plus T, dihydrotestosterone, or E(2) delayed the cumulative DHEAS production; alternatively, the addition of insulin did not alter DHEAS production. CONCLUSION(S): These data suggest that although hepatic cells have the ability of converting DHEA to DHEAS, neither sex steroids nor insulin results in the increased hepatic production of DHEAS.

Adipocytes from women with polycystic ovary syndrome demonstrate altered phosphorylation and activity of glycogen synthase kinase 3.

OBJECTIVE: To test the hypothesis that an abnormality in glycogen synthase kinase-3 (GSK3) is a pathogenic factor in polycystic ovary syndrome (PCOS). DESIGN: Prospective experimental study (adipocytes). SETTING: Tertiary-care academic medical center and teaching hospital. PATIENT(S): Twenty patients with PCOS and 21 healthy control women. INTERVENTION(S): Blood sampling, physical exam, biopsy of SC lower abdominal fat. MAIN OUTCOME MEASURE(S): Glucose transport and protein levels and phosphorylation state of glycogen synthase kinase (GSK)-3alpha and GSK3beta in adipocytes; assessment of GSK3beta activity. RESULT(S): Basal protein levels of glycogen synthase kinase (GSK3alpha and GSK3beta) did not differ between control women and women with PCOS, nor did basal or insulin-stimulated levels of serine phosphorylated GSK3alpha. However, in adipocytes of women with PCOS, insulin stimulation was not associated with increased serine phosphorylation of GSK3beta, in contrast to the case of control women. Tyrosine phosphorylation of GSK3beta also was higher in women with PCOS, compared with in control women. Consistent with the phosphorylation data, GSK3beta activity was elevated in PCOS adipocytes. CONCLUSION(S): These data suggest that GSK3beta is hyperactivated and resistant to down-regulation by insulin in PCOS. By using physiologic approaches, we demonstrated that abnormal GSK3beta regulation is a potential mechanism for the insulin resistance that is seen in some women with PCOS, which may contribute to their development of the syndrome.

Genetic variants in peroxisome proliferator-activated receptor gamma influence insulin resistance and testosterone levels in normal women, but not those with polycystic ovary syndrome.

OBJECTIVE: To investigate the relationship of the peroxisome proliferator-activated receptor gamma (PPARG) Pro12Ala and silent exon 6 (His447His) polymorphisms with the clinical features of polycystic ovary syndrome (PCOS). DESIGN: Patients with PCOS and control subjects were genotyped for Pro12Ala and His447His. Associations between genotype, diagnosis, and hormonal/metabolic parameters were assessed. SETTING: Subjects were recruited from the reproductive endocrinology clinic at the University of Alabama at Birmingham, Birmingham, Alabama. Control subjects were recruited from the surrounding community. Genotyping was performed at the Cedars-Sinai Medical Center in Los Angeles, California. PATIENT(S): Participants included 285 white women with PCOS and 187 controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The Pro12Ala and His447His genotypes, and hormonal and metabolic phenotypes. RESULT(S): The Pro12Ala and His447His genotypes did not influence risk of PCOS or its component phenotypes in patients with PCOS. In controls, Pro12Ala did not influence measures of insulin resistance or androgen production. However, carriers of the His447His T-allele had significantly decreased free and total T levels, and a significantly decreased homeostasis model assessment index of insulin resistance. Furthermore, haplotypes in controls bearing the His447His T-allele were also associated with decreased T. CONCLUSION(S): Peroxisome proliferator-activated receptor gamma does not appear to be an important modifier gene in PCOS. In controls, however, the His447His T-allele may be in linkage disequilibrium with a functional variant that influences insulin resistance and T production.

Preliminary evidence of glycogen synthase kinase 3 beta as a genetic determinant of polycystic ovary syndrome.

In this study of 352 women with polycystic ovary syndrome (PCOS) and 289 control women, haplotypes spanning the gene for glycogen synthase kinase 3beta (GSK3B) were constructed on the basis of nine single-nucleotide polymorphisms in white and black subjects separately. In each racial group, we observed that a specific, although different, GSK3B haplotype was associated with increased frequency of PCOS, suggesting that GSK3beta contributes to the pathophysiology and inherited basis of PCOS.

Family size in women with polycystic ovary syndrome.

Given that polycystic ovary syndrome (PCOS) is associated with oligo-ovulatory infertility and is an inherited trait, we hypothesized that the families of patients with PCOS are smaller than those of matched controls. However, our study of 106 white patients with PCOS, ages 18-45, and 53 healthy eumenorrheic nonhirsute white controls did not indicate a difference in family size between the groups; these results have important implications for the design of prospective studies of the heritability and genetics of PCOS.