The quantitative insulin sensitivity check index is not ...

Gynecological Endocrinology, July 2011; 27(7): 468–474

PCOS

The quantitative insulin sensitivity check index is not able to detect early metabolic alterations in young patients with polycystic ovarian syndrome

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STEFANO ANGIONI, STEFANIA SANNA, ROBERTA MAGNINI, GIAN BENEDETTO MELIS, & ANNA MARIA FULGHESU Department of Obstetrics and Gynaecology, University of Cagliari, Cagliari, Italy (Received 9 May 2010; accepted 10 May 2010)

Abstract Objective. To verify whether QUICKY is a suitable method for the identification of metabolic deterioration in normal weight patients affected by polycystic ovarian syndrome (PCOS). Design. Prospective clinical study. Patient(s). Seventy-nine PCOS normal weight adolescent subjects, 50 eumenorrheic, normal weight, non-hirsute controls matched for age and BMI. Method(s). Quantitative insulin sensitivity check index (QUICKY) and integrated secretory area under the curve of insulin values (I-AUC) during oral glucose tolerance test were calculated. Result(s). Seventy-nine PCOS and 50 controls were studied. Normal insulin sensitivity was defined as upper control 95th percentile by QUICKY values 50.31, I-AUC at 180 min 5 16,645. When applying the calculated I-AUC cut-off, 41 PCOS were classified as normoinsulinemic and 38 as hyperinsulinemic, whereas using the calculated QUICKY cut-off, only 19 PCOS could be classified as insulin resistant (IR). Fifteen out of the 60 non-IR PCOS presented hyperinsulinemia; fasting glucose and insulin levels and QUICKY were not sufficient to identify these subjects. Thus, QUICKY displayed a low sensitivity (44%) and specificity (91%) in the diagnosis of the metabolic disorder disclosed by I-AUC. Conclusions. In young normal weight patients with PCOS the prevalence of early alterations of insulin metabolism are not detectable by QUICKY studies.

Keywords: Hyperinsulinemia, insulin resistance, QUICKY, OGTT, PCOS

Introduction Polycystic ovary syndrome (PCOS) is a complex disorder characterised by hyperandrogenism and chronic anovulation [1]. Indeed, patients with PCOS present an increased risk for hypertension, coronary heart disease and diabetes mellitus type 2 (DMT2) [2]. These complications are generally attributed to hyperinsulinemia and insulin resistance (IR), frequently concomitant in patients with PCOS, although the relationship between these two aspects is still under debate. It is an acknowledged fact that IR leads to compensatory hyperinsulinemia, eliciting a magnified effect in other less traditionally responding tissues. However, the presence of a chronic hyperinsulinemia

per se is a well-known long-term risk factor for cardiovascular disease due to the specific responsiveness not only of the ovaries but also of arterial walls to increased levels of insulin [3]. The identification of hyperinsulinemia and IR in young patients with PCOS is not a minor issue. In fact although adolescents and young women suffering from PCOS are mainly affected by gynecological problems, at a later age, major health problems may be represented by vascular events very likely related to metabolic alterations associated with this disease. At the current time the diagnosis of these problems in adolescents is still a matter of debate [4]. The oral glucose tolerance test (OGTT), assessing plasma glucose and insulin levels to evaluate the area under the curves of both analytes, has been used in

Correspondence: Dott. Stefano Angioni, Department of Obstetrics and Gynaecology, University of Cagliari, via Ospedale, 09124, Cagliari, Italy. E-mail: [email protected] ISSN 0951-3590 print/ISSN 1473-0766 online ª 2011 Informa UK, Ltd. DOI: 10.3109/09513590.2010.492886


Quicky in PCOS determining insulin sensitivity in addition to insulin secretion [5–7]. However, the gold standard for the evaluation of insulin activity in vivo is represented by the euglycemic glucose clamp technique. Because of the cost, time, and technical demands involved with this technique, as well as the discomfort of glucose clamp, several simpler methods have been developed for the measurement of insulin sensitivity [8]. The quantitative insulin sensitivity check index (QUICKY) is a mathematical model that uses fasting glucose and insulin concentrations to estimate IR and/or b cell function and has shown results comparable with those obtained with clamp in obese children and adolescents [9–11]. Considering the complexity of performing a complete metabolic study, many authors have considered the evaluation of IR as a satisfactory surrogate for the metabolic assessment of PCOS independently from BMI and QUICKY has commonly been applied to identify patients with PCOS with metabolic disturbances [12–15]. Early identification of young patients with metabolic disturbances may prove to be of particular importance in an attempt to prevent the future development of cardiovascular complications. The aim of this study was to verify whether QUICKY is a suitable method for the early identification of metabolic disorders in normal weight young girls with PCOS.

Materials and methods Patients Seventy-nine normal weight adolescent subjects with PCOS took part in the study. Patients were referred to the Adolescent Center for gynecological diseases of the Department of Obstetrics and Gynecology, University of Cagliari, San Giovanni di Dio Hospital, due to the presence of oligomenorrhea or secondary amenorrhea, hirsutism and/or acne. The diagnosis of PCOS was made according to Rotterdam criteria in presence of at least two of the following: (1) oligomenorrhea and/or anovulation; (2) hyperandrogenism (clinical and/or biochemical); (3) polycystic ovaries, with the exclusion of other aetiologies [16]. Prior to the study all subjects were screened for other causes of hyperandrogenism, such as CAH by ACTH-test (0.250 mg IV Synacthen, Ciba-Geigy, Varese, Italy) [17] or hyperprolactinemia. None had used hormonal contraceptives over the 2 months immediately preceding the study. Fifty normal weight healthy adolescent girls with regular menstrual cycles matched for BMI and age and with no clinical or biochemical signs of hyperandrogenism who were referred to our center for ultrasound screening, participated in this study as a control

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group. At the time of the study no subjects were taking any medication. The study was carried out in accordance with the declaration of Helsinki of the World Medical Association and Institutional review board approval was obtained. Written informed consent for participation in the study was obtained from all patients. Clinical protocol Control subjects and PCOS were studied between 5 and 8 days following menstrual bleeding, which was progestin-induced in amenorrhoic patients. All patients were studied at least 15 days following administration of medroxyprogesterone acetate to achieve a standard endocrine condition in all subjects and avoid the occurrence of sporadic luteal phases. At the time of admittance to the study, the presence of a dominant follicle, recent ovulation, or luteal phase was excluded by ultrasound examination and serum P evaluation. After 12 h overnight fasting plasma was obtained for assessment of baseline gonadotropins, E2, SHBG, androstenedione, total T, free T, 17-hydroxyprogesterone, and dehydroepiandrosterone sulphate; subsequently, patients underwent a 75 g OGTT. Data analysis Insulin, C-peptide, and glucose serum concentrations were analysed prior to (time 0) and at 30, 60, 90, 120 and 180 min after oral glucose load. A normal glycemic response to OGTT was defined according to the criteria of the National Diabetes Data Group [18]. Insulin, C-peptide and glucose response to glucose load were expressed as area under the curve (I-AUC), which was calculated according to the trapezoidal rule. QUICKY was obtained by the product of the fasting values of glucose (mmol/l) and insulin (mU/ml) and divided by a constant (1/log(I0) 6 log(G0)). To identify the prevalence of hyperinsulinemia and IR in adolescent PCOS, insulin response to OGTT and QUICKY obtained in the control group were pooled to establish the upper control 95th percentile values using the mean + standard deviation as previously described [5,10,19]. Based on 95% confidence limits the insulinemic response to the OGTT test was considered normal when the insulin AUC was lower than 16645 mIU/ml after180 min and the QUICKY cut-off was calculated at 0.31. The body mass index (BMI) was calculated according to the following formula: body weight in kilograms/height in m2. Normal weight was considered for 18 BMI 25.

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Assays Plasma baseline levels of gonadotropins, sex hormone-binding globulin, A, Total T, Free T, 17OHP and DHEAS were determined. Insulin, glucose and C peptide serum concentration were analysed in all samples after oral glucose challenge and were measured by RIA methods (Diagnostic systems laboratories, inc.(DSL), Webster, TX). Plasma samples for hormone determination were maintained at 7208C until assayed. All hormones were measured by RIA methods using commercial kits (Radim, Pomezia, Italy). Immunoradiometric assay (IRMA) on solid phase (coated tube), based on monoclonal double-antibody technique was used for LH, FSH, and SHBG detection. Steroids were assayed using an RIA method. Glucose was measured within 24 h of blood collection using a glucose oxidase method (Beckman Glucose Analyzer; Beckman Instruments, Fullerton, CA). The samples in the tubes without heparin were immediately centrifuged in a refrigerated centrifuge, and the sera obtained stored at –208C until assay. The assay of insulin and C peptide was performed by RIA (Ares Serono, Milan, Italy). The intra- and inter-assay coefficients of variation were 5 9% for all hormones. All results are expressed as mean + SD. Data were stored and analysed using the Statistical Package for Social Sciences, version 5.0, on an IBM-compatible computer. Abnormally distributed

variables were logarithmically transformed. Statistical analysis was performed by one-way analysis of variance (ANOVA) with Bonferroni’s correction for post hoc multiple comparison and Student’s t test for unpaired data, when necessary. A p value 5 0.05 was considered statistically significant. Results No subjects included in either PCOS or control groups were affected by impaired glucose tolerance (IGT) or type 2 diabetes. Table I shows the clinical and hormonal features of PCOS and control groups. As expected, clinical signs of hyperandrogenism were observed in PCOS, together with significantly increased levels of circulating androgens and LH/ FSH. Table II reports the results of metabolic assessment. It is worthy of note that basal glycemia was found to be normal in all subjects, but fasting insulin, I-AUC after 180 and QUICKY were significantly higher in PCOS girls compared to controls. On the basis of results obtained using the normal QUICKY cut-off, 19 out of 79 PCOS subjects were classified as IR. All patients and control subjects underwent glucose loading and glycemic, insulinemic and C-pep levels were measured every 30 min for 3 h. Applying the calculated I-AUC cut-off, 41 PCOS were classified as normoinsulinemic and 38 as hyperinsulinemic on OGTT. Four IR PCOS

Table I. Clinical and hormonal characteristics in adolescents population: PCOS vs. control group.

No. of patients Age (years) (M + SD) BMI (kg\m2) (M + SD) Hirsutism (%) Oligomenhorrea (%) WHR (M + SD) LH/FSH (M + SD) E2 (pmol/l) (M + SD) A (nmol/l) (M + SD) Tot T (nmol/l) (M + SD) Free T (nmol/l) (M + SD) 17OHP (nmol/l) (M + SD) DHEAS (mmol/l) (M + SD) SHBG (nmol//l) (M + SD)

PCOS

Controls

p value

79 16.37 + 3.79 20.84 + 2.19 58 100 0.75 + 0.33 1.14 + 0.77 121.5 + 154.2 10.13 + 5.00 3.02 + 1.40 6.87 + 3.24 4.46 + 2.25 5.49 + 2.96 55.22 + 33.79

50 16.87 + 4.55 20.76 + 2.37 18 0 0.6 + 0.2 0.69 + 0.38 133.6 + 160.45 7.26 + 2.15 2.06 + 1.14 5.44 + 2.06 3.94 + 1.86 6.47 + 7.36 64.74 + 33.87

NS NS 0.0001 0.0001 NS 0.0001 NS 0.001 0.006 0.02 NS NS NS

Table II. Metabolic characteristics in adolescent population: PCOS vs. control groups.

No. of patients Fasting glucose(mmol/l)(M + SD) Fasting insulin (pmol/l)(M + SD) I-AUC 180 min (UI/ml)(M + SD) QUICKY (M + SD)

PCOS

Controls

p value

79 4.41 + 0.31 106.57 + 47.13 16538.7 + 8467.8 0.33 + 0.02

50 4.23 + 0.88 72.2 + 23.47 10,002.2 + 3654 0.35 + 0.02

NS 0.001 0.0001 0.02


Quicky in PCOS identified on the basis of the QUICKY test were not hyperinsulinemic. However, 15 PCOS presenting QUICKY values under cut-off values were also affected by hyperinsulinemia. Half of the hyperinsulinemic subjects examined in the present study presented normal fasting insulin levels, while the remaining half showed hyperinsulinemia only 90 min or more after glucose load (Figure 1). QUICKY failed to identify 15/38 cases displaying hyperinsulinemia on I-AUC at 180 min evaluation (sensitivity 44%, specificity 91%). Table III illustrates the anthropometric and hormonal characteristics of all groups studied compared to controls when the aforementioned cut-offs were applied. Total testosterone levels were significantly higher in hyper I-AUC patients than in controls

Figure 1. Glycemic (top), insulinemic (mid) and Cpep (bottom) levels under 3 h OGTT in PCOS screened on the basis of I-AUC and QUICKY values. [~] Normoinsulinemic PCOS patients; [.] non-IR (non-insulin resistance) hyperinsulinemic PCOS patients; [&] controls; ['] IR (insulin resistance) hyperinsulinemic PCOS patients. {p 5 0.05 IR Hyper I AUC vs. non-IR hyper I AUC; *p 5 0.05 IR Hyper I AUC vs. normo I-AUC; ¼ j p 5 0.05 IR Hyper I AUC vs. controls.

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independently from the IR. Moreover, patients presenting IR showed significantly higher free T levels than non-IR hyper I-AUC. Discussion The prevalence of PCOS has previously been studied in European populations using NIH criteria, although to date no studies have been performed using the revised Rotterdam criteria to assess the prevalence of PCOS in Europe [19,20]. Moreover, ethnic backgrounds may affect the syndrome phenotype and the prevalence of hyperinsulinemia and/or IR in PCOS may therefore differ between various populations [21]. Van Hoof reported a very low incidence of metabolic alterations in a large cohort of young PCOS girls screened exclusively by means of fasting studies, but the prevalence of hyperinsulinemia under glucose load has not yet been investigated in young patients with PCOS [13]. The causes of metabolic abnormalities in PCOS remain to be clarified, but include obesity-related IR, an intrinsic abnormality of post-receptor insulin signaling (e.g. excess serine phosphorylation) and abnormal insulin secretion [22,23]. On the other hand, resistance to insulin hallmarks the onset of normal pubertal development, returning to prepubertal values at the end of puberty in non-obese subjects [24]. Consequently, in adolescence a physiological resistance to insulin should be considered in comparison to adult subjects. Over the past 20 years the gold standard method used to quantify insulin sensitivity has been the hyperinsulinemic-euglycemic clamp technique. In the quest for a non-invasive measurement of insulin sensitivity, several fasting models have been proposed. These tests are based on fasting insulin and fasting glucose, and use straightforward mathematical calculations to assess insulin sensitivity and b cell function. Among others, QUICKY is a simple and accurate method for the assessment of insulin sensitivity which is widely used in the majority of clinical studies [9–11]. Another largely used parameter, the homeostatic model assessment calculation (HOMA), which uses fasting glucose and insulin concentrations to estimate IR and /or b cell function has recently shown poor sensitivity when compared to OGTT in evidencing young PCOS with early insulin alterations [25]. In view of the fact that a criterion of normality for IR and insulin secretion has not yet been defined in adolescence we decided to study the presence of IR and hyperinsulinemia in normal weight PCOS and in a control group matched for BMI and age of the same ethnic background. Normal weight subjects were chosen to avoid secondary IR due to obesity [4,26].

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Table III. Anthropometrics and hormonal characteristics of adolescent PCOS and control population screened on the basis of I-AUC (normo and hyper I-AUC) and on the basis of QUICKY (insulin-resistant – IR and non-insulin-resistant – non-IR).


No. of patients BMI (kg\m2) FSH (IU/l) LH (UI/l) E2 (pmol/l) A (nmol/l) Tot T (nmol/l) Free T (nmol/l) 17OHP (nmol/l) DHEAS (mmol/l) SHBG (nmol/l)

Normo I-AUC

Hyper I-AUC IR

Hyper I-AUC non IR

Controls

41 20.74 + 2.21 5.68 + 1.47 7.1 + 5.37* 143.39 + 192.43 10.71 + 5.42{,{ 2.11 + 1.34 6.3 + 2.87 4.4 + 2.26 5.08 + 2.59 51.31 + 27.73

15 21.01 + 2.18 5.33 + 1.55 5.8 + 3.3 92.1 + 59.6 10.6 + 5.86x 3.0 + 1.78x 7.7 + 4.53x 4.65 + 2.26 6.2 + 4.33 54.35 + 44.76

23 20.9 + 2.25 5.48 + 4.18 5.28 + 4.18 79.49 + 52.06 8.56 + 2.83 ˜ 3.27 + 1.31oˆN 6.12 + 3.03 4.43 + 2.4 5.9 + 2.63 64.65 + 37.85

50 20.76 + 2.37 6.7 + 2.9 4.4 + 2.42 133.6 + 160.45 7.26 + 2.15 2.06 + 1.14 5.44 + 2.06 3.94 + 1.86 6.47 + 7.36 64.74 + 33.87

Note: values are mean + SD. *p 5 0.05 normo I-AUC vs. controls. { p 5 0.01 normo I-AUC vs. controls. { p 5 0.05 normo I-AUC vs. NIR hyper I-AUC. x p 5 0.05 IR hyper I-AUC vs. controls. { p 5 0.05 NIR hyper I-AUC vs. controls.

Our study group failed to find a causal relationship between the presence of IR and hyperinsulinemia under glucose load. Half of the hyperinsulinemic subjects examined in the present study presented normal fasting insulin levels, while the remaining half showed hyperinsulinemia only 90 min or more after glucose load. In the latter group the presence of corresponding high values of C-pep demonstrates that hypersecretion indeed occurred, although IR had not been revealed by the fasting study. It is quite likely that compensatory glycogenolysis occurred to maintain normal glycemic levels; a reduction of glycemic levels 80 min after load was reported in the same group. Our findings are in agreement with the results reported by Ibanez, demonstrating higher serum insulin levels after OGTT with normal insulin sensitivity in a population of PCOS adolescent girls [27]. The cause underlying the increased response of b cells in these subjects is as yet unknown. In view of the young age of the subjects studied, only a partial resistance to insulin was to be expected. Euglycemic clamp was not performed in this study and it is possible that QUICKY may have failed as early marker of insulin sensitivity in our young normal weight subjects as was shown for HOMA in similar conditions [27]. However, in adult PCOS subjects we previously demonstrated the ability of euglycemic clamp to evidence alterations of insulin sensitivity in obese, but not in normal weight hyperinsulinemic subjects [5]. Our results raise the issue as to whether IR is effectively absent in non-obese young PCOS with normal QUICKY score. In fact, recent data have shown that QUICKY and HOMA, although easier than OGTT, could not replace the role of post-challenge plasma glucose level in the screening

of IGT in PCOS women [28]. Moreover, it is not clear whether high levels of insulin necessarily indicate the presence of a disorder but it may be hypothesised that adaptation to the chronic risk of hypoglycemia in hyperinsulinemic subjects could lead to IR after some time. In this study, we demonstrate that a normal QUICKY score is not sufficient to exclude early metabolic abnormalities such as hyperinsulinemia in young lean PCOS subjects. Moreover, hyperinsulinemia per se could contribute towards the onset of hyperandrogenism independently of peripheral IR. In fact, our results demonstrated significant differences in androgen levels between normo and hyper-insulinemic groups, although no endocrine differences were revealed between IR and non-IR populations. This finding may contribute towards interpreting the contrasting results existing in this field [29,31]. In addition, in view of the importance of high insulin levels as a possible risk factor for cardiovascular disease, the correct identification of candidates, also in young age, is of overwhelming importance [26,32,33]. In fact, recent data have shown not only an increased prevalence of cardiovascular disease but also higher cardiovascular morbidity and mortality in PCOS [34,35]. In conclusion, the results obtained in this study underline the importance of performing an OGTT to screen hyperinsulinemia in young patients with PCOS, independently of body weight and of fasting study results. Hyperinsulinemic subjects should undergo a correct prophylaxis (regular physical activity, dietary modification) and follow-up while awaiting the results of future studies that may clarify whether this condition underlies an increased cardiovascular risk in subjects with PCOS.

Quicky in PCOS Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.


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