Impaired glucose tolerance is associated with changes in clinical and biochemical parameters in women with polycystic ovary syndrome

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1 Acta Obstetricia et Gynecologica. 2006; 85: ORIGINAL ARTICLE Impaired glucose tolerance is associated with changes in clinical and biochemical parameters in women with polycystic ovary syndrome KATHARINA WALCH, CHRISTOPH GRIMM, FRIEDRICH NAGELE, JOHANNES HUBER, MONIKA WÖLFLER, ELISABETH VYTISKA-BINSTORFER, GERTRUD UNFRIED & LUKAS HEFLER Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria Abstract Background. To characterize the phenotype of women with polycystic ovary syndrome with and without impaired glucose tolerance by determining various polycystic ovary syndrome-associated clinical and laboratory parameters. Methods. In a prospective clinical study, we evaluated a series of 102 Caucasian women with polycystic ovary syndrome. Women completed a detailed questionnaire and underwent a standardized oral glucose tolerance test. Various polycystic ovary syndrome-associated laboratory values such as hormonal and metabolic parameters were determined in these women and correlated to clinical data and the presence/absence of impaired glucose tolerance. Furthermore, the insulin resistance was calculated using the homeostasis model assessment index and correlated with clinical and biochemical parameters. Results. Eighty-eight (86.3%) and 14 (13.7%) women were diagnosed as having non-impaired glucose tolerance and impaired glucose tolerance, respectively. Presence of impaired glucose tolerance was associated with an increased body mass index, increased body weight, elevated serum levels of bioavailable testosterone, insulin like growth factor-1, insulin, HbA1c, leucocytes, uric acid, alkaline phosphatase, hepatic C-reactive protein, and decreased serum levels of sex-hormone binding globulin. No association was ascertained with subfertility, hirsutism, and menstrual irregularities. We ascertained a positive correlation between the homeostasis model assessment index and body mass index, body weight, alkaline phosphatase, and hepatic C-reactive protein. Conclusions. Impaired glucose tolerance seems to be associated with a specific phenotype within polycystic ovary syndrome. This phenotype is more likely to present with biochemical parameters similar to an inflammatory reaction and a metabolic disorder. Key words: polycystic ovary syndrome, impaired glucose tolerance, clinical parameters, biochemical parameters Abbreviations: ALAT: alanine aminotransferase, ASAT: aspartate aminotransferase, BMI: body mass index, CRP: C- reactive protein, DHEAS: dehydroepiandrosterone sulfate, DHT: dihydrotestosterone, FSH: follicle-stimulating hormone, g- GT: gamma-glutamyltransferase, HOMA: homeostasis model assessment, IGF-1: insulin-like growth factor 1, IGT: impaired glucose tolerance, LH: luteinizing hormone, OGTT: oral glucose tolerance test, PCOS: polycystic ovary syndrome, SHBG: sex-hormone binding globulin, TNF a: tumor necrosis factor alpha, TSH: thyroid-stimulating hormone Introduction Polycystic ovary syndrome (PCOS) is a common and complex endocrine disorder affecting 5 10% of women of reproductive age (1,2). It is characterized by hyperandrogenism and chronic anovulation leading to menstrual irregularities and subfertility (3). Impaired glucose tolerance (IGT) and even frank diabetes are key features of PCOS. Recently, large prospective studies recognized a varying degree of IGT as a significant finding in up to 40% of affected women (4,5). The compensatory hyperinsulinemia seems to be crucially involved in the pathophysiology of this syndrome leading to its typical phenotype, hyperandrogenism, and chronic anovulation. It is known that insulin acts as a cogonadotropin in the ovary leading to an increased ovarian androgen Correspondence: Katharina Walch, Department of Obstetrics and Gynecology, Division of Gynecological Endocrinology and Reproductive Medicine, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. katharina.walch@meduniwien.ac.at (Received 4 March 2005; accepted 12 June 2005) ISSN print/issn online # 2006 Taylor & Francis DOI: /

2 870 K. Walch et al. production via thecal cell proliferation (6), upregulation of luteinizing hormone (LH), and insulin-like growth factor 1 (IGF-1) receptors (7,8), and the induction of androgen-synthesizing enzymes (9). With respect to anovulation, it has been proposed that the higher the degree of insulin resistance in PCOS women, the lower the probability of spontaneous ovulation and the more severe the menstrual irregularities (10). Furthermore, hyperinsulinemia is associated with impaired lipolysis and may lead to central obesity. Intra-abdominal fat deposits are assumed to further induce insulin resistance by expression and secretion of several peptide hormones and cytokines, including tumor necrosis factor alpha (TNF a) and free fatty acids (11,12). It has been suggested that women with PCOS and with IGT have different phenotypic characteristics compared to women without IGT (13). Women with IGT are more likely to be obese and have hirsutism, lower LH, LH/follicle-stimulating hormone (FSH) ratios, and testosterone levels. It can be reasonably speculated that presence of IGT might be indicative of two different syndrome entities within the PCOS. In order to better characterize the two subgroups of women with PCOS, i.e. women with IGT versus women without IGT, we determined various PCOSassociated laboratory parameters in a large series of affected Caucasian women and correlated the results with clinical data. Materials and methods In this study, we analyzed data of 102 women with PCOS visiting the Department of Obstetrics and Gynecology, Division of Gynecological Endocrinology and Reproductive Medicine, Medical University of Vienna, from April 2002 to April Institutional Review Board approval was obtained for this study and patients consent was obtained from all women prior to inclusion. Inclusion criteria for the present study are given in Table I. Hirsutism was evaluated by using the Ferriman Gallwey score (14). A score /8, independently ascertained by two investigators, classified a woman as hirsute. According to the literature (15), the following criteria were used to define PCO: presence of 12 or more follicles in each ovary measuring 29 mm in diameter and/or increased volume (/10 ml). Women with any acute disease, with adrenal hyperplasia (17-OH progesterone /8.3 nmol/l), hyperprolactinemia (prolactin /231.1 mu/l), or hypothyroidism (thyroid-stimulating hormone (TSH) /4.5 mu/l) as well as women having received any hormonal treatment or insulin-lowering agents during the last three months were excluded from the study. All participants were of Caucasian origin. Applying the above criteria, 102 women were included in this prospective study. Women were referred to our outpatient clinic for diagnosis and treatment of hormonal disorders or to the assisted reproduction unit by their general practitioners or gynecologists. The main reasons for consultation were subfertility, menstrual irregularities, hirsutism, acne, or obesity. Eighty-four (82.4%) women reported infertility for at least one year. Median duration of infertility in this subgroup was 1.8 (range, ) years. No patient included in our study was aware of having IGT or frank diabetes before we performed the oral glucose tolerance test (OGTT). After filling out a detailed questionnaire asking for personal and family history, menstrual irregularities, parity, desire for a child, smoking and drinking habits, and current medication, women with PCOS were sampled in the early follicular phase. If women were amenorrheic, withdrawal bleeding was induced with progestagens and blood samples were obtained thereafter. If no bleeding occurred, blood was taken during amenorrhea after excluding pregnancy by a commercially available pregnancy test. All investigated serum parameters (Table III) were determined by the same investigator group of our hospital-based laboratory using commercially available assays. Androstendione and C-peptide were determined by chemiluminiscence immunoassay (CLIA). Most hormonal parameters (TSH, LH, FSH, prolactin, progesterone, estradiol, testosterone, and dehydroepiandrosterone sulfate (DHEAS)) were determined by electrochemiluminiscence immunoassay (ECLIA). We determined androstandiol glucoronide, insulin, and dihydrotestosterone (DHT) (after extraction and chromatography) by radioimmunoassay (RIA). For determination of sex-hormone binding globulin (SHBG), we used Table I. Criteria used to include women with PCOS into the study. 1. Presence of menstrual irregularities, i.e. oligo-(menstrual cycles of at least 35 days) or amenorrhea (absence of menstrual bleeding for longer than 6 months) 2. Hirsutism or biochemical signs of hyperandrogenism (at least two of the following values beyond the cut-off levels: serum androstendione /10.7 nmol/l, serum testosterone /2.9 nmol/l, and SHBG B/30 nmol/l) 3. Polycystic ovaries in ultrasound 4. Caucasian origin

3 Impaired glucose tolerance in polycystic ovary syndrome 871 fluorescence immunoassay (DELFIA). Bioavailable estradiol and bioavailable testosterone were calculated from estradiol/testosterone and SHBG. After acidic extraction, IGF-1 was determined by enzymelinked immunosorbent assay (ELISA). Alkaline phosphatase, aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), and gamma-glutamyltransferase (g-gt) were determined by an enzyme-kinetic test. We determined uric acid by uricase-pap method, and C-reactive protein (CRP) by an immunologic turbidity method. The blood count was determined by Sysmex XE-2100 and HbA1c by HPLC separation of the Hb-fraction. After an overnight fast, a standard 75-g OGTT was performed to identify IGT and non-igt women. Following the recently published recommendations of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (16), we assessed the performed OGTTs with respect to IGT. An IGT was ascertained when at least one value was above the cut-off values of 110 mg/dl (6.12 mmol/l) and 140 mg/dl (7.78 mmol/l) for the 0 min /fasting level and the 120-min value, respectively. Frank diabetes was diagnosed at a fasting value of 126 mg/dl (7.01 mmol/l) or a 120-min value of 200 mg/dl (11.12 mmol/l). We calculated the homeostasis model assessment (HOMA) index with the formula: fasting insulin (mu/ml) /fasting glucose (mmol/l)/22.5. For statistical analysis, we used the SPSS statistical software system (SPSS 11.0, SPSS Inc., Chicago, IL). After testing for normality using the KolmogorovSmirnov test, values are given as means (standard deviation (SD)). Groups were compared using the t-test. x 2 -tests were performed where appropriate. Continuous parameters were compared using the Pearson s correlation test. p-values B/0.05 were considered statistically significant. Results After performing an OGTT, 88 (86.3%) of the 102 included women were classified as having non-igt and 14 (13.7%) as having IGT. Three of the 14 women in the IGT group presented with frank diabetes in the OGTT. Women s clinical characteristics broken down by presence or absence of IGT are shown in Table II. No significant differences were ascertained. The clinical and biochemical characteristics of women in the two subgroups with and without IGT are given in Table III. As expected, IGT was associated with higher body weight and subsequently increased body mass index (BMI). Serum levels of bioavailable testosterone, IGF-1, insulin, HbA1c, leucocytes, uric acid, alkaline phosphatase, and hepatic CRP were significantly elevated in the IGT subgroup, whereas serum levels of SHBG were found to be significantly decreased. Furthermore, we calculated the insulin resistance by using the HOMA index, correlated the HOMA index with some investigated parameters, and report the respective results in Table IV. We ascertained a positive correlation between the HOMA index and BMI, body weight, alkaline phosphatase, and CRP. The number of first-degree relatives with cardiovascular disease in the IGT group was significantly increased compared to the non-igt group (p/ 0.04). In 29% of the IGT group, at least one firstdegree relative presented with hypertension, deep vein thrombosis, or myocardial infarction, whereas in the non-igt group only 8% had relatives with cardiovascular disease. There was no significant difference between the number of first-degree relatives with diabetes in the IGT and the non-igt groups. Discussion IGT and subsequent insulin resistance are ascertained in a certain percentage of women with PCOS and postulated to be crucially involved in the pathogenesis of this syndrome (17). We aimed at characterizing the two different phenotypes with respect to clinical and laboratory parameters in a large series of Caucasian women with PCOS. Of note, in the current study the percentage of women with IGT (13.7%) is relatively low compared to the percentages given in the literature (13). Table II. Women s characteristics broken down by presence or absence of impaired glucose tolerance (IGT). Characteristics Non-IGT (n/88) IGT (n/14) p-value (OR and 95% CI) Age (years) 27.7 (4.9)* 28.7 (4.8)* 0.5 $ No. of women with subfertility (3.1 [ ]) % No. of women with hirsutism (1.3 [0.35.1]) % No. of women with oligomenorrhea (0.6 [0.21.9]) % No. of women with amenorrhea (1.6 [0.55.1]) % *Values are given as means (standard deviation); $ Value is calculated by performing a t-test; % Values are calculated by performing x 2 -test.

4 872 K. Walch et al. Table III. Clinical and biochemical characteristics of women with PCOS broken down by presence or absence of impaired glucose tolerance (IGT). Parameter Non-IGT IGT p -value Parameter Non-IGT IGT p -value Weight (kg) 73 (17.5) 88.5 (17.2) IGF-1 (nmol/l) 25.7 (9.9) 17.4 (7.2) 0.03 BMI (kg/m 2 ) 27.2 (6.7) 32.5 (6.6) Androstandiol 8.3 (5.5) 10 (4.9) 0.3 glucoronide (nmol/l) TSH (mu/l) 2 (1.2) 2.2 (1.04) 0.4 DHT (nmol/l) 1 (0.3) 1 (0.3) 0.3 LH (U/l) 13.3 (6.9) 10.6 (4.2) 0.2 Insulin (pmol/l) 97.2 (87.4) (290.8) 0.02 FSH (U/l) 6.6 (2.1) 6.2 (1.1) 0.5 C-peptide (nmol/l) 0.7 (0.4) 1.1 (0.8) 0.1 LH/FSH 2.1 (1.1) 1.8 (0.9) 0.3 HbA1c (rel.%) 5.2 (0.3) 5.6 (0.7) Prolactin (mu/l) (123) (29.7) 0.3 Hematocrit (%) 40.8 (2.7) (3) 0.8 Progesterone (nmol/l) 2.9 (3.8) 2.5 (0.9) 0.7 Leukocytes (G/l) 6.7 (1.8) 8.0 (2.6) 0.03 Estradiol (pmol/l) (109.4) (27.5) 0.6 Thrombocytes (G/l) (58) (87.5) 0.1 Bioavailable estradiol (pmol/l) (47.7) (28.6) 0.3 Uric acid (mmol/l) (65.5) (29.8) Testosterone (nmol/l) 2.8 (1) 3.1 (1) 0.3 Alkaline 81.7 (23.4) 97.7 (48.4) 0.04 phosphatase (U/l) Bioavailable testosterone (nmol/l) 1 (0.3) 1.4 (0.7) ASAT (U/l) 20.8 (13.8) 19.3 (13.2) 0.7 SHBG (nmol/l) 44.3 (27.8) 24.6 (14.6) 0.01 ALAT (U/l) 23.4 (18.5) 25.4 (21.8) 0.7 Androstendione (nmol/l) 11.4 (4.1) 11 (4.5) 0.7 g-gt (U/l) 19.3 (13.8) 22.6 (14.9) 0.4 DHEAS (mmol/l) 8.1 (3.5) 7.1 (3) 0.3 CRP (mg/l) 6 (2) 10 (5) Values are given as means (standard deviation). Possible explanations for this finding might be the inclusion of mostly young, otherwise healthy women and the diagnostic methods used to detect IGT. We used a standardized OGTT, while others classified patients as IGT or non-igt on the basis of fasting glucose and insulin levels (13) or by using the euglycemic clamp technique (18). Not surprisingly, we found increased body weight and higher BMI to be associated with IGT, which is in accordance with data from the literature (4). As expected, HbA1c, insulin, and C-peptide, although not reaching statistical significance, are increased in women with PCOS and IGT. Furthermore, a negative correlation between insulin and SHBG has been shown in our series as well as in previously published studies (19). We found IGF-1 to be significantly decreased in the IGT group, which is consistent with data reporting a downstream effect of hyperinsulinemia on the somatotropic axis in PCOS women (20). In addition to hormonal parameters, we ascertained differences in metabolic features between the two subgroups. Women in the IGT group are more likely to exhibit inflammatory reactions as evidenced by an increased leucocyte count as well as elevated CRP levels. It can be hypothesized that CRP is likewise involved in the pathogenesis of the PCOS with IGT and in the metabolic syndrome, including hypertension, obesity, and insulin resistance, in which CRP levels were also found to be significantly elevated (21,22). Uric acid and alkaline phosphatase were elevated in women with IGT, which is a further indication of the involvement of insulin resistance in metabolic disorders in women with PCOS. Moreover, we found a moderate activation of the coagulation cascade, as fibrinogen Table IV. Correlation between the HOMA index and various investigated clinical and biochemical parameters. Parameter p-value r -value Parameter p-value r -value Weight Androstendione 0.2 /0.2 BMI DHEAS 0.1 /0.2 TSH IGF /0.1 LH 0.1 /0.3 Androstandiol glucoronide FSH 0.6 /0.08 DHT 0.1 /0.3 Prolactin 0.2 /0.2 Uric acid Estradiol 0.9 /0.01 Alkaline phosphatase Bioavailable estradiol ASAT 0.3 /0.2 Testosterone 0.1 /0.2 ALAT Bioavailable testosterone g-gt SHBG 0.1 /0.2 CRP

5 Impaired glucose tolerance in polycystic ovary syndrome 873 levels and platelet counts were slightly elevated in the IGT group. In the present study, we characterized women with PCOS with and without IGT by various clinical and laboratory parameters. IGT was only ascertained in a fraction of Caucasian women with an established diagnosis of PCOS. Distinct differences between the two subgroups with respect to the evaluated laboratory parameters were noted. The IGT phenotype is more likely to present with biochemical characteristics similar to an inflammatory reaction and a metabolic disorder. We provide further data that PCOS is a heterogeneous group of disorders. References 1. Asuncion M, Calvo RM, San Millan JL, Sancho J, Avila S, Escobar-Morreale HF. A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. J Clin Endocrinol Metab. 2000;/85:/ Knochenhauer ES, Key TJ, Kashar-Miller M, Waggoner W, Boots LR, Azziz R. Prevalence of the polycystic ovary syndrome in unselected black and white women of the Southeastern United States: a prospective study. J Clin Endocrinol Metab. 1998;/83:/ Zacur HA. Polycystic ovary syndrome, hyperandrogenism, and insulin resistance. Obstet Gynecol Clin North Am. 2001;/ 28:/ Legro RS, Kunselman AR, Dodson WC, Dunaif BA. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab. 1999;/84:/ Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care. 1999;/22:/ Dubela AJ, Spaczynski RZ, Olive DL. Insulin and insulin-like growth factor I stimulate the proliferation of human ovarian theca-interstitial cells. Fertil Steril. 1998;/69:/ Adashi EY, Resnick CE, D Ercole AJ, Svoboda ME, Van Wyk JJ. Insulin-like growth factors as intraovarian regulators of granulose cell growth and function. Endocr Rev. 1985;/6: / Poretsky L, Cataldo NA, Rosenwaks Z, Giudice LC. The insulin-related ovarian regulatory system in health and disease. Endocr Rev. 1999;/20:/ Kristiansen SB, Endoh A, Casson PR, Buster JE, Hornsby PJ. Induction of steroidogenic enzyme genes by insulin and IGF-I in cultured adult human adrenocortical cells. Steroids. 1997;/ 62:/ Robinson S, Kiddy D, Gelding SV, Willis D, Niththyananthan R, Bush A, et al. The relationship of insulin insensitivity to menstrual pattern with hyperandrogenism and polycystic ovaries. Clin Endocrinol (Oxf). 1993;/39:/ Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW, et al. Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest. 1996;/97:/ Gonzalez F, Thusu K, Abdel-Rahman E, Prabhala A, Tomani M, Dandona P. Elevated serum levels of tumor necrosis factor a in normal-weight women with polycystic ovary syndrome. Metabolism. 1999;/48:/ Mor E, Zogrbyan A, Saadat P, Bayrak A, Tourgeman DE, Zhang C, et al. The insulin resistant subphenotype of polycystic ovary syndrome: clinical parameters and pathogenesis. Am J Obstet Gynecol. 2004;/190:/ Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab. 1961;/21:/ Pache TD, Hop WC, Wladimiroff JW, Schipper J, Fauser BC. How to discriminate between normal and polycystic ovaries. Radiology. 1992;/17:/ Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2003; 26: De Leo V, La Marca A, Petraglia F. Insulin-lowering agents in the management of polycystic ovary syndrome. Endocr Rev. 2003;/24(5):/ Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989;/38:/ Nestler JE, Powers LP, Matt DW, Steingold KA, Plymate SR, Rittmaster RS, et al. A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. Clin Endocrinol Metab. 1991;/72(1):/ Morales AJ, Laughlin GA, Butzow T, Maheshwari H, Baumann G, Yen SS. Insulin, somatotropic, and luteinizing hormone axes in lean and obese women with polycystic ovary syndrome: common and distinct features. J Clin Endocrinol Metab. 1996;/81(8):/ Pickup JC, Mattock MB, Chusney GD, Burt D. NIDDM as a disease of the innate immune system: association of acutephase reactants and interleukin-6 with metabolic syndrome X. Diabetologia. 1997;/40:/ Kelly C, Lyall H, Petrie J, Gould G, Connell J, Sattar N. Low grade chronic inflammation in women with polycystic ovarian syndrome. J Clin Endocrinol Metab. 2001;/86:/24535.

Determining the insulin resistance rate in Polycystic Ovary Syndrome patients (PCOs)

Abstract: Determining the insulin resistance rate in Polycystic Ovary Syndrome patients (PCOs) Ashraf Olabi, Ghena Alqotini College of medicine, Aleppo University Hospital Obstetrics and Gynacology, Syria.