ORIGINAL ARTICLES: REPRODUCTIVE ENDOCRINOLOGY
Insulin resistance and its relationship with high molecular weight adiponectin in adolescents with polycystic ovary syndrome and a maternal history of polycystic ovary syndrome Sevil Cankaya, M.D.,a Berfu Demir, M.D.,b Sezin Erturk Aksakal, M.D.,b Berna Dilbaz, M.D.,b Canan Demirtas, Ph.D.,c and Umit Goktolga, M.D.d a Kovancılar State Hospital, Elazıg; b Department of Obstetrics and Gynecology, Etlik Zubeyde Hanim Women's Health Teaching and Research Hospital and c Department of Medical Biochemistry, Gazi University School of Medicine, Ankara, Turkey; and d Kosovo Pay Hospital and IVF Clinic, Kosovo
Objective: To assess the rate of insulin resistance (IR) and the relationship between IR and high molecular weight (HMW) adiponectin in normal weight adolescents with polycystic ovary syndrome (PCOS) and a maternal history of PCOS. Design: Case-controlled study. Setting: Adolescent clinic of a teaching and research hospital. Patient(s): Forty normal weight adolescents with PCOS and a maternal history of PCOS and 40 normo-ovulatory age- and body mass index (BMI)-matched controls. Intervention(s): A 75-g oral glucose tolerance test (OGTT) was performed for each participant. Main Outcome Measure(s): Homeostasis model assessment of IR and HMW adiponectin. Result(s): There were no statistically significant differences between the PCOS and control groups in terms of fasting glucose, fasting insulin, and lipid parameters. Although total and free T were significantly higher, HMW adiponectin levels were significantly lower in the PCOS group compared with the control group. When the PCOS group was compared according to the IR, the HMW adiponectin level was significantly lower in the adolescents with PCOS and IR. The adolescents with PCOS and biochemical hyperandrogenemia had significantly lower HMW adiponectin levels and significantly higher homeostasis model assessment of IR score compared with the adolescents with PCOS and normoandrogenemia. Conclusion(s): The adolescents with PCOS had a significantly increased rate of IR without clinical Use your smartphone findings of metabolic disorders or obesity. The HMW adiponectin levels were negatively correlated to scan this QR code with IR. (Fertil SterilÒ 2014;102:826–30. Ó2014 by American Society for Reproductive Medicine.) and connect to the Key Words: High molecular weight adiponectin, polycystic ovary syndrome, insulin resistance Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/cankayas-insulin-hmw-adiponectin-pcos-adolescents/
Received March 17, 2014; revised May 10, 2014; accepted May 19, 2014; published online June 25, 2014. S.C. has nothing to disclose. B.D. has nothing to disclose. S.E.A. has nothing to disclose. B.D. has nothing to disclose. C.D. has nothing to disclose. U.G. has nothing to disclose. During the follow-up period of the study, Drs. Sevil Cankaya and Umit Goktolga were affiliated with Etlik Zubeyde Hanim Women's Health Teaching and Research Hospital, Ankara, Turkey. Supported by the Educational Committee of Etlik Zubeyde Hanim Women's Health Teaching and Research Hospital, Ankara, Turkey. Reprint requests: Berfu Demir, M.D., Department of Obstetrics and Gynecology, Etlik Z€ ubeyde Hanım Women's Health Teaching and Research Hospital, Yeni Etlik Street No:55, 06010 Ankara, Turkey (E-mail: [email protected]). Fertility and Sterility® Vol. 102, No. 3, September 2014 0015-0282/$36.00 Copyright ©2014 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2014.05.032 826
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T
he polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, and is characterized by menstrual disorders beginning in the peripubertal period (oligomenorrhea, dysfunctional uterine bleeding) and clinical findings of hyperandrogenism (hirsutism, acne, oily skin, androgenic alopecia) and infertility (1). Polycystic ovary syndrome affects VOL. 102 NO. 3 / SEPTEMBER 2014
Fertility and Sterility® 4%–6% of women of reproductive age, and is responsible for 50%–70% of cases with anovulatory infertility (1). Two main criteria are used in the diagnosis of PCOS. The most frequently used 2004 Rotterdam diagnostics criteria include at least two of the following three criteria: [1] oligo-ovulation and/or anovulation (OA); [2] clinical and/or biochemical signs of hyperandrogenism; and [3] polycystic ovaries (PCO) (by ultrasound) and exclusion of other androgen excess disorders (2). Patients with PCOS have the risk of insulin resistance (IR), obesity, and cardiovascular diseases. Hyperinsulinemia and IR have been reported in 25%–60% of women with PCOS (3). Adiponectin, a recently discovered adipocytokine, is an adipocyte-derivative biologically active molecule generated from adipose tissue. Adiponectin is effective in the circulation as an insulin sensitizer, anti-inflammatory, and antiatherosclerotic agent. Adiponectin is classified into three groups as low, medium, and high molecular weight (HMW) adiponectin (4, 5). Few studies demonstrate the relationship between IR and adiponectin levels in women with PCOS, and most studies investigated total adiponectin levels (6–8). Recent clinical studies suggest that the HMW form of adiponectin has a closer association with IR and metabolic syndrome than the total form of adiponectin (9–11). We present a prospective study designed to investigate the rate of IR and the relationship between IR and HMW adiponectin in normal weight adolescents with PCOS and a maternal history of PCOS.
II, hyperandrogenism þ OA; type III, hyperandrogenism þ PCO; and type IV, OA þ PCO (15). Blood samples were obtained in the morning after an overnight fast on day 3 of the initiated or spontaneous menstrual cycle. Free triiodothyronine, free thyroxin (FT4), TSH, DHEAS, PRL, FSH, LH, E2, 17a-hydroxyprogesterone (17-OHP), free T, total T, total cholesterol, triglyceride, lowdensity lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and HMW adiponectin (in micrograms per milliliter) levels were measured. The intra-assay coefficient of variation (CV) for insulin ranged between 1.6% and 2.2%, and the interassay CV between 6.1% and 6.5%. The sensitivity of the assay was 1 mIU/mL. Blood samples were collected from the adolescents with amenorrhea on any day of the cycle. A 75-g oral glucose tolerance test (OGTT) was performed with measurement of serum glucose (at fasting, 60, and 120 minutes), and insulin (at fasting). A second-hour glucose concentration during the 75-g OGTT R140 mg/dL was considered as impaired glucose tolerance (16). Homeostasis model assessment for IR (HOMA-IR) score was calculated according to the equation: [Fasting insulin (mU/mL) Fasting glucose (mmol/mL)]/ 22.5 (17). The IR was defined by the HOMA-IR score R2.7 (18). Ultrasonographic examination was performed using 5.0 MHz transabdominal probe (General Electric LOGIQ 5 PRO). Follicle number R12 with 2–9 mm in diameter and increased ovary volume (>10 mL) were identified as PCO.
Hormonal Immunoassays
MATERIALS AND METHODS The present study was conducted with adolescents seen in the adolescent clinic of Etlik Zubeyde Hanim Women's Health Teaching and Research Hospital, Ankara, Turkey, between April 2011 and November 2011. The inclusion criteria were as follows: [1] PCOS diagnosed according to the 2004 Rotterdam criteria; [2] age, 15–20 years; [3] body mass index (BMI), 18–25 kg/m2; and [4] maternal history of PCOS. The control group comprised age- and BMI-matched adolescents with no family history or diagnosis of PCOS, who were seen in the clinic for other reasons (e.g., cystitis, vaginitis). The study was approved by the Institutional Review Board (27.01.2011/ no. 133). Written informed consent was obtained from all subjects before their enrollment in the study. Oligomenorrhea was defined as a menstrual bleeding frequency longer than 35 days. Amenorrhea was defined as an interim between menstrual bleedings longer than 6 months. Clinical hyperandrogenism was accepted as hirsutism, acne, oily skin, and androgenic alopecia. Anthropometric measurements were performed with subjects wearing light clothing without shoes. The height and weight of all subjects were measured, and BMI was calculated as weight (in kilograms)/height (in meters squared). The scoring of hirsutism was performed using the modified Ferriman-Gallwey system (12), and a score higher than 8 was diagnosed as hirsutism. Alopecia was evaluated with Ludwig scoring (13), and acne was evaluated using the criteria identified by Hayashi et al. (14). Polycystic ovary syndrome is classified into four phenotypes as follows: type I, hyperandrogenism þ OA þ PCO; type VOL. 102 NO. 3 / SEPTEMBER 2014
Glucose and lipid profile measurements were determined using a Vitros Chemistry System 5.1/FS device (Johnson & Johnson Company). Serum FSH, LH, E2, PRL, P, total T, and free T levels were measured using the chemiluminescence method with the DXI-800 device (Beckman-Coulter). The DHEAS and 17-OHP levels were determined with the radioimmunoassay method using the GAMA Kauntur device (Medisis Company). The HMW adiponectin was measured with the B€ uhlmann Multimeric Adiponectin ELISA kit, and insulin was measured with the DiaMetra ELISA kit with micro-ELISA method in the hormone laboratory of Gazi University, School of Medicine.
Statistical Analysis Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) Windows version 17.0. Distribution of the continuous variables was checked using the Kolmogorov-Smirnov test. Student's t test was used for variables with normal distribution. After testing the skewed distribution, comparisons between the groups were tested using the Mann-Whitney U test. The c2 test was used to analyze nominal variables. Continuous variables were expressed as mean SD. Correlation analysis was applied in the evaluation of the linear relationship between variants determined with measurement. A value of P< .05 was accepted as statistically significant.
RESULTS The demographic characteristics of the groups are presented in Table 1. One adolescent in the PCOS group was excluded 827
ORIGINAL ARTICLE: REPRODUCTIVE ENDOCRINOLOGY
TABLE 1
TABLE 3
Demographic characteristics of PCOS and control group. PCOS group (n [ 39) Age (y) 17.79 1.59 21.51 1.92 BMI (kg/m2) Clinical signs of hyperandrogenism Ferriman-Gallwey 8.95 3.98 score Acne 1.46 0.46 (38.4%) Alopecia 1.43 0.7 (33.3%)
Control group (n [ 40)
P value
17.43 1.69 21.25 1.75
.321 .527
0.65 2.23
.001a
0 0
.001a .001a
Note: Data are presented as mean SD. BMI ¼ body mass index; PCOS ¼ polycystic ovary syndrome. a P< .05. Cankaya. IR, HMWA, PCOS adolescent. Fertil Steril 2014.
from the study because she was lost to follow-up. Groups were comparable regarding age and BMI. The clinical signs of hyperandrogenism, including hirsutism, acne, and alopecia, were significantly higher in the PCOS group than in the control group (P< .05) (Table 1). Of a total of 39 adolescents with PCOS, 23 (58.9%) had hyperandrogenism þ OA þ PCO; 9 (23%) had hyperandrogenism þ OA; 2 (5%) had hyperandrogenism þ PCO, and 5 (12.8%) had OA þ PCO (Table 2). There were no statistically significant differences between the PCOS and control groups in terms of fasting glucose, fasting insulin and lipid parameters (Table 3). The second-hour glucose concentrations in OGTT were significantly higher in the PCOS group than in the control group. Although total and free T were higher, HMW adiponectin levels were lower in the PCOS group compared with the control group (Table 3). In the PCOS group, one adolescent was diagnosed with impaired fasting glucose (R100 mg/dL) and three adolescents were diagnosed with impaired glucose tolerance (second-hour glucose, 140–199 mg/dL). The IR was determined in 69% and 2.5% of adolescents in the PCOS and control groups, respectively. None of the adolescents was diagnosed with diabetes mellitus. When the PCOS group was compared according to IR status, the level of HMW adiponectin was significantly lower in insulin-resistant PCOS adolescents (3.83 2.1 vs. 1.69 0.9; R ¼ 0.51, P¼ .006). The adolescents with PCOS and biochemical hyperandrogenism had significantly lower HMW adiponectin levels and significantly higher HOMA-IR
TABLE 2 The prevalence of phenotypes in PCOS group. Phenotype Type 1 (hyperandrogenism þ OA þ PCO) Type 2 (hyperandrogenism þ OA) Type 3 (hyperandrogenism þ PCO) Type 4 (OA þ PCO)
n (%) 23 (58.9) 9 (23) 2 (5) 5 (12.8)
Note: OA ¼ oligo/anovulation; PCO ¼ polycystic ovary; PCOS ¼ polycystic ovary syndrome. Cankaya. IR, HMWA, PCOS adolescent. Fertil Steril 2014.
828
Comparison of hormonal and metabolic parameters of the PCOS and control groups.
Total T (ng/mL) Free T (ng/mL) DHEA-S (mg/dL) 17-OHP (ng/mL) FSH/LH ratio E2 (pg/mL) TSH (mIU/mL) ft3 (pmol/L) Free thyroxine (pmol/L) Total cholesterol (mg/dL) HDL (mg/dL) LDL (mg/dL) Triglyceride (mg/dL) Fasting glucose (mg/dL) 2nd hour glucose (mg/dL) Fasting insulin (mU/mL) HOMA-IR HMW adiponectin (mg/mL)
PCOS group (n [ 39)
Control group (n [ 40)
P value
0.50 0.23 3.37 1.58 308.21 232.34 2.82 10.08 2.57 1.22 77.43 44.70 2.35 1.06 5.07 0.82 14.68 2.89
0.38 0.17 1.91 1.08 236.0 102.15 0.81 0.42 1.44 0.96 66.04 49.43 2.53 1.02 5.35 0.63 14.05 2.57
.017a .001a .079 .211 .001a .287 .466 .098 .314
154.97 21.61
152.88 26.02
.698
56.72 11.26 78.10 18.83 104.59 73.34 81.54 6.22
56.93 9.19 83.23 21.06 85.25 39.11 81.75 7.89
.929 .259 .461 .895
92.00 21.93
82.33 15.74
.027a
17.38 8.49
7.13 10.45
.001a
3.21 1.44 1.71 0.72
1.31 1.96 4.71 2.00
.001a .001a
Note: Data are presented as mean SD. 17-OHP ¼ 17-hydroxyprogesterone; ft3 ¼ free triiodothyronine; HDL ¼ high-density lipoprotein; HMW ¼ high molecule weight; HOMAIR ¼ homeostasis model assessment for insulin resistance; LDL ¼ low-density lipoprotein. a P< .05. Cankaya. IR, HMWA, PCOS adolescent. Fertil Steril 2014.
score compared with normoandrogenemia.
adolescents
with
PCOS
and
DISCUSSION The present study demonstrated that normal weight, healthy adolescents with PCOS and a maternal history of PCOS have higher IR and lower HMW adiponectin than age- and BMI- matched controls. The main finding of our study is that IR can be found in normal weight adolescents with PCOS without clinical findings of metabolic disorders or obesity. In addition, HMW adiponectin levels were negatively correlated with IR. We also noted that biochemical hyperandrogenism is associated with IR and low HMW adiponectin in adolescents with PCOS. The incidence of PCOS was reported as 6%–10% in the general population and as 20%–40% in families of women with PCOS (19, 20). First degree relatives of women with PCOS have a high risk of developing PCOS symptoms and endocrine disorders, such as obesity, IR, and hyperlipidemia (19, 21–24). In a cross-sectional study involving nine peripubertal girls with first degree relatives diagnosed with PCOS and 10 age-matched controls (insulin sensitivity by frequently sampled IV glucose tolerance test [GTT]) was significantly reduced by almost threefold in first degree relatives diagnosed with PCOS compared with controls, and remained significantly reduced even after correction for waist-to-height ratio and BMI Z-score (25). Similarly, in a cross-sectional study involving 19 adolescents whose mothers or sisters had been VOL. 102 NO. 3 / SEPTEMBER 2014
Fertility and Sterility® diagnosed with PCOS and 21 healthy age-matched controls, oral and IV IR tests (quantitative insulin sensitivity check index, HOMA-IR, and glucose disposal index) demonstrated lower insulin sensitivity among first degree relatives diagnosed with PCOS versus controls (26). The women with PCOS have an 11-fold increase in the prevalence of metabolic syndrome, and the risk is enhanced even at a young age (27). According to a meta-analysis, women with PCOS have an increased prevalence of impaired glucose tolerance (odds ratio [OR], 2.54, 95% confidence interval [CI] 1.44–4.47), type 2 diabetes (OR, 4.00, 95% CI 1.97–8.10), and metabolic syndrome (OR, 2.20, 95% CI 0.68–6.30) compared with age- and BMI-matched controls (28). In addition, women with PCOS have a higher risk for early-onset cardiovascular disease (29). There are controversial reports regarding the higher risk of metabolic syndrome in adolescents with PCOS. Although some studies showed an association with increased incidence of IR (30–33), others have been unable to find any positive effect of IR in adolescents with PCOS (34, 35). Villa et al. (36) demonstrated that in adolescents with PCOS, the basal insulin value and HOMA-IR were significantly higher than in the non-PCOS group. In a prospective study, glucose, insulin levels, and the frequency of abnormal OGTT were not different between lean and obese adolescents with PCOS, but the IR was higher in the obese group (37). Mean HOMAIR score was twofold higher in obese than in nonobese adolescents with PCOS. In addition, they demonstrated that impaired glucose tolerance is an indicator for increased IR in nonobese adolescents with PCOS. Therefore, screening of IR should be considered for adolescents with PCOS independent of BMI (38). O'Connor et al. (39) investigated the relationship between IR, adiponectin, and its oligomers HMW, medium, and low molecular weight adiponectin. They found that total, medium, and low molecular weight adiponectin concentrations did not differ between the PCOS group and controls, but HMW adiponectin concentrations were significantly lower in the PCOS group. In a prospective study that included 19 women with PCOS, the relationship between adiponectin, resistin, and the indices of IR such as OGTT, HOMA-IR, and QUICKI were evaluated. The investigators found that adiponectin and resistin were inversely correlated, but important, adiponectin did not correlate with the indices of IR in women with PCOS (40). In a cross-sectional study including 98 PCOS women and 103 controls, HMW adiponectin was significantly lower in women with PCOS compared with both BMI- and IRmatched controls (P¼ .009 and P¼ .027, respectively). However, an interaction between waist-to-hip ratio and plasma T contributed to its variance (P¼ .026), and suggested that IR was not a major indicator of decreased adiponectin levels (39). In the present study, adolescents with PCOS and IR had low HMW adiponectin levels independent of BMI. It can be speculated that low HMW adiponectin levels may be an early determinant of IR and metabolic disorders in patients with PCOS without obesity. To our knowledge this is the first study to evaluate the relationship between IR and HMW adiponectin in normal weight adolescents with PCOS and a maternal history of PCOS. VOL. 102 NO. 3 / SEPTEMBER 2014
Evaluation of the IR technique is the limitation of our study. Although the euglycemic-hyperinsulinemic clamp technique is considered the gold standard for assessing IR, it is not feasible to apply it to a large sample size. Nevertheless, in the literature, the HOMA-IR score was found well correlated with the clamp technique (25, 26, 41). In conclusion, adolescents with PCOS had a significantly increased rate of IR independent of BMI. The HMW adiponectin levels were lower in normal weight adolescents with PCOS and inversely correlated with IR. The IR with low HMW adiponectin levels may indicate the future development of metabolic disorders in adolescents with PCOS, even in the absence of obesity.
REFERENCES 1. 2. 3.
4.
5.
6.
7.
8.
9.
10.
11.
12. 13. 14. 15. 16. 17.
Franks S, The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group. Polycystic ovary syndrome. N Engl J Med 1995;333:853–61. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004;19:41–7. Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 1989;38:1165–74. Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, Ouchi N, et al. Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood 2000;96:1723–32. Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R. Hormonal regulation of adiponectin gene expression in 3T3-L1 adipocytes. Biochem Biophys Res Commun 2002;290:1084–9. Mirza SS, Shafique K, Shaikh AR, Khan NA, Anwar Qureshi M. Association between circulating adiponectin levels and polycystic ovarian syndrome. J Ovarian Res 2014;7:18. Lee H, Oh JY, Sung YA. Adipokines, insulin-like growth factor binding protein-3 levels, and insulin sensitivity in women with polycystic ovary syndrome. Korean J Intern Med 2013;28:456–63. Orlik B, Madej P, Owczarek A, Ska1ba P, Chudek J, OlszaneckaGlinianowicz M. Plasma omentin and adiponectin levels as markers of adipose tissue dysfunction in normal weight and obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 2013 Dec 9. http://dx.doi.org/ 10.1111/cen.12381. [Epub ahead of print]. Hara K, Horikoshi M, Yamauchi T, Yago H, Miyazaki O, Ebinuma H, et al. Measurement of the high-molecular weight form of adiponectin in plasma is useful for the prediction of insulin resistance and metabolic syndrome. Diabetes Care 2006;29:1357–62. Lara-Castro C, Luo N, Wallace P, Klein RL, Garvey WT. Adiponectin multimeric complexes and the metabolic syndrome trait cluster. Diabetes 2006; 55:249–59. Nakashima R, Kamei N, Yamane K, Nakanishi S, Nakashima A, Kohno N. Decreased total and high molecular weight adiponectin are independent risk factors for the development of type 2 diabetes in Japanese-Americans. J Clin Endocrinol Metab 2006;91:3873–7. Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 1961;21:1440–7. Ludwig E. Classification of the types of androgenetic alopecia (common baldness) occurring in the female sex. Br J Dermatol 1977;97:247–54. Hayashi N, Akamatsu H, Kawashima M. Establishment of grading criteria for acne severity. J Dermatol 2008;35:255–60. Guastella E, Longo RA, Carmina E. Clinical and endocrine characteristics of the main polycystic ovary syndrome phenotypes. Fertil Steril 2010;94:2197–201. Diagnosis and classification of diabetes mellitus. American Diabetes Association. Diabetes Care 2005;28(Suppl 1):S37–42. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412–9. 829
ORIGINAL ARTICLE: REPRODUCTIVE ENDOCRINOLOGY 18.
19.
20.
21.
22. 23.
24.
25.
26.
27.
28.
29. 30.
830
Yin J, Li M, Xu L, Wang Y, Cheng H, Zhao X, et al. Insulin resistance determined by Homeostasis Model Assessment (HOMA) and associations with metabolic syndrome among Chinese children and teenagers. Diabetol Metab Syndr 2013;5:71. Kahsar-Miller MD, Nixon C, Boots LR, Go RC, Azziz R. Prevalence of polycystic ovary syndrome (PCOS) in first-degree relatives of patients with PCOS. Fertil Steril 2001;75:53–8. Legro RS, Driscoll D, Strauss JF 3rd, Fox J, Dunaif A. Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc Natl Acad Sci U S A 1998;95:14956–60. Coviello AD, Sam S, Legro RS, Dunaif A. High prevalence of metabolic syndrome in first-degree male relatives of women with polycystic ovary syndrome is related to high rates of obesity. J Clin Endocrinol Metab 2009;94:4361–6. Moini A, Eslami B. Familial associations between polycystic ovarian syndrome and common diseases. J Assist Reprod Genet 2009;26:123–7. Sam S, Legro RS, Bentley-Lewis R, Dunaif A. Dyslipidemia and metabolic syndrome in the sisters of women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005;90:4797–802. Sam S, Sung YA, Legro RS, Dunaif A. Evidence for pancreatic beta-cell dysfunction in brothers of women with polycystic ovary syndrome. Metabolism 2008;57:84–9. Trottier A, Battista MC, Geller DH, Moreau B, Carpentier AC, Simoneau-Roy J, et al. Adipose tissue insulin resistance in peripubertal girls with first-degree family history of polycystic ovary syndrome. Fertil Steril 2012;98:1627–34. Raissouni N, Kolesnikov A, Purushothaman R, Sinha S, Bhandari S, Bhangoo A, et al. Altered glucose disposition and insulin sensitivity in peri-pubertal first-degree relatives of women with polycystic ovary syndrome. Int J Pediatr Endocrinol 2012;2012:14. Dokras A, Bochner M, Hollinrake E, Markham S, Vanvoorhis B, Jagasia DH. Screening women with polycystic ovary syndrome for metabolic syndrome. Obstet Gynecol 2005;106:131–7. Moran LJ, Misso ML, Wild RA, Norman RJ. Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update 2010;16:347–63. Orio F, Palomba S, Colao A. Cardiovascular risk in women with polycystic ovary syndrome. Fertil Steril 2006;86(Suppl 1):S20–1. Coviello AD, Legro RS, Dunaif A. Adolescent girls with polycystic ovary syndrome have an increased risk of the metabolic syndrome associated with
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
increasing androgen levels independent of obesity and insulin resistance. J Clin Endocrinol Metab 2006;91:492–7. Leibel NI, Baumann EE, Kocherginsky M, Rosenfield RL. Relationship of adolescent polycystic ovary syndrome to parental metabolic syndrome. J Clin Endocrinol Metab 2006;91:1275–83. Huang J, Ni R, Chen X, Huang L, Mo Y, Yang D. Metabolic abnormalities in adolescents with polycystic ovary syndrome in south China. Reprod Biol Endocrinol 2010;8:142. Roe AH, Prochaska E, Smith M, Sammel M, Dokras A. Using the androgen excess-PCOS society criteria to diagnose polycystic ovary syndrome and the risk of metabolic syndrome in adolescents. J Pediatr 2013;162:937–41. Rossi B, Sukalich S, Droz J, Griffin A, Cook S, Blumkin A, et al. Prevalence of metabolic syndrome and related characteristics in obese adolescents with and without polycystic ovary syndrome. J Clin Endocrinol Metab 2008;93: 4780–6. Fulghesu A, Magnini R, Portoghese E, Angioni S, Minerba L, Melis GB. Obesity-related lipid profile and altered insulin incretion in adolescents with polycystic ovary syndrome. J Adolesc Health 2010;46:474–81. Villa P, Rossodivita A, Sagnella F, Moruzzi MC, Mariano N, Lassandro AP, et al. Ovarian volume and gluco-insulinaemic markers in the diagnosis of PCOS during adolescence. Clin Endocrinol (Oxf) 2013;78:285–90. Poomthavorn P, Chaya W, Mahachoklertwattana P, Sukprasert M, Weerakiet S. Glucose metabolism in obese and lean adolescents with polycystic ovary syndrome. J Pediatr Endocrinol Metab 2013;26:319–24. Flannery CA, Rackow B, Cong X, Duran E, Selen DJ, Burgert TS. Polycystic ovary syndrome in adolescence: impaired glucose tolerance occurs across the spectrum of BMI. Pediatr Diabetes 2013;14:42–9. O'Connor A, Phelan N, Tun TK, Boran G, Gibney J, Roche HM. High-molecular-weight adiponectin is selectively reduced in women with polycystic ovary syndrome independent of body mass index and severity of insulin resistance. J Clin Endocrinol Metab 2010;95:1378–85. Lewandowski KC, Szosland K, O'Callaghan C, Tan BK, Randeva HS, Lewinski A. Adiponectin and resistin serum levels in women with polycystic ovary syndrome during oral glucose tolerance test: a significant reciprocal correlation between adiponectin and resistin independent of insulin resistance indices. Mol Genet Metab 2005;85:61–9. Mather KJ, Hunt AE, Steinberg HO, Paradisi G, Hook G, Katz A, et al. Repeatability characteristics of simple indices of insulin resistance: implications for research applications. J Clin Endocrinol Metab 2001;86:5457–64.
VOL. 102 NO. 3 / SEPTEMBER 2014
Insulin resistance and its relationship with high molecular weight adiponectin in adolescents with polycystic ovary syndrome and a maternal history of polycystic ovary syndrome Sevil Cankaya, M.D.,a Berfu Demir, M.D.,b Sezin Erturk Aksakal, M.D.,b Berna Dilbaz, M.D.,b Canan Demirtas, Ph.D.,c and Umit Goktolga, M.D.d a Kovancılar State Hospital, Elazıg; b Department of Obstetrics and Gynecology, Etlik Zubeyde Hanim Women's Health Teaching and Research Hospital and c Department of Medical Biochemistry, Gazi University School of Medicine, Ankara, Turkey; and d Kosovo Pay Hospital and IVF Clinic, Kosovo
Objective: To assess the rate of insulin resistance (IR) and the relationship between IR and high molecular weight (HMW) adiponectin in normal weight adolescents with polycystic ovary syndrome (PCOS) and a maternal history of PCOS. Design: Case-controlled study. Setting: Adolescent clinic of a teaching and research hospital. Patient(s): Forty normal weight adolescents with PCOS and a maternal history of PCOS and 40 normo-ovulatory age- and body mass index (BMI)-matched controls. Intervention(s): A 75-g oral glucose tolerance test (OGTT) was performed for each participant. Main Outcome Measure(s): Homeostasis model assessment of IR and HMW adiponectin. Result(s): There were no statistically significant differences between the PCOS and control groups in terms of fasting glucose, fasting insulin, and lipid parameters. Although total and free T were significantly higher, HMW adiponectin levels were significantly lower in the PCOS group compared with the control group. When the PCOS group was compared according to the IR, the HMW adiponectin level was significantly lower in the adolescents with PCOS and IR. The adolescents with PCOS and biochemical hyperandrogenemia had significantly lower HMW adiponectin levels and significantly higher homeostasis model assessment of IR score compared with the adolescents with PCOS and normoandrogenemia. Conclusion(s): The adolescents with PCOS had a significantly increased rate of IR without clinical Use your smartphone findings of metabolic disorders or obesity. The HMW adiponectin levels were negatively correlated to scan this QR code with IR. (Fertil SterilÒ 2014;102:826–30. Ó2014 by American Society for Reproductive Medicine.) and connect to the Key Words: High molecular weight adiponectin, polycystic ovary syndrome, insulin resistance Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/cankayas-insulin-hmw-adiponectin-pcos-adolescents/
Received March 17, 2014; revised May 10, 2014; accepted May 19, 2014; published online June 25, 2014. S.C. has nothing to disclose. B.D. has nothing to disclose. S.E.A. has nothing to disclose. B.D. has nothing to disclose. C.D. has nothing to disclose. U.G. has nothing to disclose. During the follow-up period of the study, Drs. Sevil Cankaya and Umit Goktolga were affiliated with Etlik Zubeyde Hanim Women's Health Teaching and Research Hospital, Ankara, Turkey. Supported by the Educational Committee of Etlik Zubeyde Hanim Women's Health Teaching and Research Hospital, Ankara, Turkey. Reprint requests: Berfu Demir, M.D., Department of Obstetrics and Gynecology, Etlik Z€ ubeyde Hanım Women's Health Teaching and Research Hospital, Yeni Etlik Street No:55, 06010 Ankara, Turkey (E-mail: [email protected]). Fertility and Sterility® Vol. 102, No. 3, September 2014 0015-0282/$36.00 Copyright ©2014 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2014.05.032 826
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T
he polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, and is characterized by menstrual disorders beginning in the peripubertal period (oligomenorrhea, dysfunctional uterine bleeding) and clinical findings of hyperandrogenism (hirsutism, acne, oily skin, androgenic alopecia) and infertility (1). Polycystic ovary syndrome affects VOL. 102 NO. 3 / SEPTEMBER 2014
Fertility and Sterility® 4%–6% of women of reproductive age, and is responsible for 50%–70% of cases with anovulatory infertility (1). Two main criteria are used in the diagnosis of PCOS. The most frequently used 2004 Rotterdam diagnostics criteria include at least two of the following three criteria: [1] oligo-ovulation and/or anovulation (OA); [2] clinical and/or biochemical signs of hyperandrogenism; and [3] polycystic ovaries (PCO) (by ultrasound) and exclusion of other androgen excess disorders (2). Patients with PCOS have the risk of insulin resistance (IR), obesity, and cardiovascular diseases. Hyperinsulinemia and IR have been reported in 25%–60% of women with PCOS (3). Adiponectin, a recently discovered adipocytokine, is an adipocyte-derivative biologically active molecule generated from adipose tissue. Adiponectin is effective in the circulation as an insulin sensitizer, anti-inflammatory, and antiatherosclerotic agent. Adiponectin is classified into three groups as low, medium, and high molecular weight (HMW) adiponectin (4, 5). Few studies demonstrate the relationship between IR and adiponectin levels in women with PCOS, and most studies investigated total adiponectin levels (6–8). Recent clinical studies suggest that the HMW form of adiponectin has a closer association with IR and metabolic syndrome than the total form of adiponectin (9–11). We present a prospective study designed to investigate the rate of IR and the relationship between IR and HMW adiponectin in normal weight adolescents with PCOS and a maternal history of PCOS.
II, hyperandrogenism þ OA; type III, hyperandrogenism þ PCO; and type IV, OA þ PCO (15). Blood samples were obtained in the morning after an overnight fast on day 3 of the initiated or spontaneous menstrual cycle. Free triiodothyronine, free thyroxin (FT4), TSH, DHEAS, PRL, FSH, LH, E2, 17a-hydroxyprogesterone (17-OHP), free T, total T, total cholesterol, triglyceride, lowdensity lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and HMW adiponectin (in micrograms per milliliter) levels were measured. The intra-assay coefficient of variation (CV) for insulin ranged between 1.6% and 2.2%, and the interassay CV between 6.1% and 6.5%. The sensitivity of the assay was 1 mIU/mL. Blood samples were collected from the adolescents with amenorrhea on any day of the cycle. A 75-g oral glucose tolerance test (OGTT) was performed with measurement of serum glucose (at fasting, 60, and 120 minutes), and insulin (at fasting). A second-hour glucose concentration during the 75-g OGTT R140 mg/dL was considered as impaired glucose tolerance (16). Homeostasis model assessment for IR (HOMA-IR) score was calculated according to the equation: [Fasting insulin (mU/mL) Fasting glucose (mmol/mL)]/ 22.5 (17). The IR was defined by the HOMA-IR score R2.7 (18). Ultrasonographic examination was performed using 5.0 MHz transabdominal probe (General Electric LOGIQ 5 PRO). Follicle number R12 with 2–9 mm in diameter and increased ovary volume (>10 mL) were identified as PCO.
Hormonal Immunoassays
MATERIALS AND METHODS The present study was conducted with adolescents seen in the adolescent clinic of Etlik Zubeyde Hanim Women's Health Teaching and Research Hospital, Ankara, Turkey, between April 2011 and November 2011. The inclusion criteria were as follows: [1] PCOS diagnosed according to the 2004 Rotterdam criteria; [2] age, 15–20 years; [3] body mass index (BMI), 18–25 kg/m2; and [4] maternal history of PCOS. The control group comprised age- and BMI-matched adolescents with no family history or diagnosis of PCOS, who were seen in the clinic for other reasons (e.g., cystitis, vaginitis). The study was approved by the Institutional Review Board (27.01.2011/ no. 133). Written informed consent was obtained from all subjects before their enrollment in the study. Oligomenorrhea was defined as a menstrual bleeding frequency longer than 35 days. Amenorrhea was defined as an interim between menstrual bleedings longer than 6 months. Clinical hyperandrogenism was accepted as hirsutism, acne, oily skin, and androgenic alopecia. Anthropometric measurements were performed with subjects wearing light clothing without shoes. The height and weight of all subjects were measured, and BMI was calculated as weight (in kilograms)/height (in meters squared). The scoring of hirsutism was performed using the modified Ferriman-Gallwey system (12), and a score higher than 8 was diagnosed as hirsutism. Alopecia was evaluated with Ludwig scoring (13), and acne was evaluated using the criteria identified by Hayashi et al. (14). Polycystic ovary syndrome is classified into four phenotypes as follows: type I, hyperandrogenism þ OA þ PCO; type VOL. 102 NO. 3 / SEPTEMBER 2014
Glucose and lipid profile measurements were determined using a Vitros Chemistry System 5.1/FS device (Johnson & Johnson Company). Serum FSH, LH, E2, PRL, P, total T, and free T levels were measured using the chemiluminescence method with the DXI-800 device (Beckman-Coulter). The DHEAS and 17-OHP levels were determined with the radioimmunoassay method using the GAMA Kauntur device (Medisis Company). The HMW adiponectin was measured with the B€ uhlmann Multimeric Adiponectin ELISA kit, and insulin was measured with the DiaMetra ELISA kit with micro-ELISA method in the hormone laboratory of Gazi University, School of Medicine.
Statistical Analysis Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) Windows version 17.0. Distribution of the continuous variables was checked using the Kolmogorov-Smirnov test. Student's t test was used for variables with normal distribution. After testing the skewed distribution, comparisons between the groups were tested using the Mann-Whitney U test. The c2 test was used to analyze nominal variables. Continuous variables were expressed as mean SD. Correlation analysis was applied in the evaluation of the linear relationship between variants determined with measurement. A value of P< .05 was accepted as statistically significant.
RESULTS The demographic characteristics of the groups are presented in Table 1. One adolescent in the PCOS group was excluded 827
ORIGINAL ARTICLE: REPRODUCTIVE ENDOCRINOLOGY
TABLE 1
TABLE 3
Demographic characteristics of PCOS and control group. PCOS group (n [ 39) Age (y) 17.79 1.59 21.51 1.92 BMI (kg/m2) Clinical signs of hyperandrogenism Ferriman-Gallwey 8.95 3.98 score Acne 1.46 0.46 (38.4%) Alopecia 1.43 0.7 (33.3%)
Control group (n [ 40)
P value
17.43 1.69 21.25 1.75
.321 .527
0.65 2.23
.001a
0 0
.001a .001a
Note: Data are presented as mean SD. BMI ¼ body mass index; PCOS ¼ polycystic ovary syndrome. a P< .05. Cankaya. IR, HMWA, PCOS adolescent. Fertil Steril 2014.
from the study because she was lost to follow-up. Groups were comparable regarding age and BMI. The clinical signs of hyperandrogenism, including hirsutism, acne, and alopecia, were significantly higher in the PCOS group than in the control group (P< .05) (Table 1). Of a total of 39 adolescents with PCOS, 23 (58.9%) had hyperandrogenism þ OA þ PCO; 9 (23%) had hyperandrogenism þ OA; 2 (5%) had hyperandrogenism þ PCO, and 5 (12.8%) had OA þ PCO (Table 2). There were no statistically significant differences between the PCOS and control groups in terms of fasting glucose, fasting insulin and lipid parameters (Table 3). The second-hour glucose concentrations in OGTT were significantly higher in the PCOS group than in the control group. Although total and free T were higher, HMW adiponectin levels were lower in the PCOS group compared with the control group (Table 3). In the PCOS group, one adolescent was diagnosed with impaired fasting glucose (R100 mg/dL) and three adolescents were diagnosed with impaired glucose tolerance (second-hour glucose, 140–199 mg/dL). The IR was determined in 69% and 2.5% of adolescents in the PCOS and control groups, respectively. None of the adolescents was diagnosed with diabetes mellitus. When the PCOS group was compared according to IR status, the level of HMW adiponectin was significantly lower in insulin-resistant PCOS adolescents (3.83 2.1 vs. 1.69 0.9; R ¼ 0.51, P¼ .006). The adolescents with PCOS and biochemical hyperandrogenism had significantly lower HMW adiponectin levels and significantly higher HOMA-IR
TABLE 2 The prevalence of phenotypes in PCOS group. Phenotype Type 1 (hyperandrogenism þ OA þ PCO) Type 2 (hyperandrogenism þ OA) Type 3 (hyperandrogenism þ PCO) Type 4 (OA þ PCO)
n (%) 23 (58.9) 9 (23) 2 (5) 5 (12.8)
Note: OA ¼ oligo/anovulation; PCO ¼ polycystic ovary; PCOS ¼ polycystic ovary syndrome. Cankaya. IR, HMWA, PCOS adolescent. Fertil Steril 2014.
828
Comparison of hormonal and metabolic parameters of the PCOS and control groups.
Total T (ng/mL) Free T (ng/mL) DHEA-S (mg/dL) 17-OHP (ng/mL) FSH/LH ratio E2 (pg/mL) TSH (mIU/mL) ft3 (pmol/L) Free thyroxine (pmol/L) Total cholesterol (mg/dL) HDL (mg/dL) LDL (mg/dL) Triglyceride (mg/dL) Fasting glucose (mg/dL) 2nd hour glucose (mg/dL) Fasting insulin (mU/mL) HOMA-IR HMW adiponectin (mg/mL)
PCOS group (n [ 39)
Control group (n [ 40)
P value
0.50 0.23 3.37 1.58 308.21 232.34 2.82 10.08 2.57 1.22 77.43 44.70 2.35 1.06 5.07 0.82 14.68 2.89
0.38 0.17 1.91 1.08 236.0 102.15 0.81 0.42 1.44 0.96 66.04 49.43 2.53 1.02 5.35 0.63 14.05 2.57
.017a .001a .079 .211 .001a .287 .466 .098 .314
154.97 21.61
152.88 26.02
.698
56.72 11.26 78.10 18.83 104.59 73.34 81.54 6.22
56.93 9.19 83.23 21.06 85.25 39.11 81.75 7.89
.929 .259 .461 .895
92.00 21.93
82.33 15.74
.027a
17.38 8.49
7.13 10.45
.001a
3.21 1.44 1.71 0.72
1.31 1.96 4.71 2.00
.001a .001a
Note: Data are presented as mean SD. 17-OHP ¼ 17-hydroxyprogesterone; ft3 ¼ free triiodothyronine; HDL ¼ high-density lipoprotein; HMW ¼ high molecule weight; HOMAIR ¼ homeostasis model assessment for insulin resistance; LDL ¼ low-density lipoprotein. a P< .05. Cankaya. IR, HMWA, PCOS adolescent. Fertil Steril 2014.
score compared with normoandrogenemia.
adolescents
with
PCOS
and
DISCUSSION The present study demonstrated that normal weight, healthy adolescents with PCOS and a maternal history of PCOS have higher IR and lower HMW adiponectin than age- and BMI- matched controls. The main finding of our study is that IR can be found in normal weight adolescents with PCOS without clinical findings of metabolic disorders or obesity. In addition, HMW adiponectin levels were negatively correlated with IR. We also noted that biochemical hyperandrogenism is associated with IR and low HMW adiponectin in adolescents with PCOS. The incidence of PCOS was reported as 6%–10% in the general population and as 20%–40% in families of women with PCOS (19, 20). First degree relatives of women with PCOS have a high risk of developing PCOS symptoms and endocrine disorders, such as obesity, IR, and hyperlipidemia (19, 21–24). In a cross-sectional study involving nine peripubertal girls with first degree relatives diagnosed with PCOS and 10 age-matched controls (insulin sensitivity by frequently sampled IV glucose tolerance test [GTT]) was significantly reduced by almost threefold in first degree relatives diagnosed with PCOS compared with controls, and remained significantly reduced even after correction for waist-to-height ratio and BMI Z-score (25). Similarly, in a cross-sectional study involving 19 adolescents whose mothers or sisters had been VOL. 102 NO. 3 / SEPTEMBER 2014
Fertility and Sterility® diagnosed with PCOS and 21 healthy age-matched controls, oral and IV IR tests (quantitative insulin sensitivity check index, HOMA-IR, and glucose disposal index) demonstrated lower insulin sensitivity among first degree relatives diagnosed with PCOS versus controls (26). The women with PCOS have an 11-fold increase in the prevalence of metabolic syndrome, and the risk is enhanced even at a young age (27). According to a meta-analysis, women with PCOS have an increased prevalence of impaired glucose tolerance (odds ratio [OR], 2.54, 95% confidence interval [CI] 1.44–4.47), type 2 diabetes (OR, 4.00, 95% CI 1.97–8.10), and metabolic syndrome (OR, 2.20, 95% CI 0.68–6.30) compared with age- and BMI-matched controls (28). In addition, women with PCOS have a higher risk for early-onset cardiovascular disease (29). There are controversial reports regarding the higher risk of metabolic syndrome in adolescents with PCOS. Although some studies showed an association with increased incidence of IR (30–33), others have been unable to find any positive effect of IR in adolescents with PCOS (34, 35). Villa et al. (36) demonstrated that in adolescents with PCOS, the basal insulin value and HOMA-IR were significantly higher than in the non-PCOS group. In a prospective study, glucose, insulin levels, and the frequency of abnormal OGTT were not different between lean and obese adolescents with PCOS, but the IR was higher in the obese group (37). Mean HOMAIR score was twofold higher in obese than in nonobese adolescents with PCOS. In addition, they demonstrated that impaired glucose tolerance is an indicator for increased IR in nonobese adolescents with PCOS. Therefore, screening of IR should be considered for adolescents with PCOS independent of BMI (38). O'Connor et al. (39) investigated the relationship between IR, adiponectin, and its oligomers HMW, medium, and low molecular weight adiponectin. They found that total, medium, and low molecular weight adiponectin concentrations did not differ between the PCOS group and controls, but HMW adiponectin concentrations were significantly lower in the PCOS group. In a prospective study that included 19 women with PCOS, the relationship between adiponectin, resistin, and the indices of IR such as OGTT, HOMA-IR, and QUICKI were evaluated. The investigators found that adiponectin and resistin were inversely correlated, but important, adiponectin did not correlate with the indices of IR in women with PCOS (40). In a cross-sectional study including 98 PCOS women and 103 controls, HMW adiponectin was significantly lower in women with PCOS compared with both BMI- and IRmatched controls (P¼ .009 and P¼ .027, respectively). However, an interaction between waist-to-hip ratio and plasma T contributed to its variance (P¼ .026), and suggested that IR was not a major indicator of decreased adiponectin levels (39). In the present study, adolescents with PCOS and IR had low HMW adiponectin levels independent of BMI. It can be speculated that low HMW adiponectin levels may be an early determinant of IR and metabolic disorders in patients with PCOS without obesity. To our knowledge this is the first study to evaluate the relationship between IR and HMW adiponectin in normal weight adolescents with PCOS and a maternal history of PCOS. VOL. 102 NO. 3 / SEPTEMBER 2014
Evaluation of the IR technique is the limitation of our study. Although the euglycemic-hyperinsulinemic clamp technique is considered the gold standard for assessing IR, it is not feasible to apply it to a large sample size. Nevertheless, in the literature, the HOMA-IR score was found well correlated with the clamp technique (25, 26, 41). In conclusion, adolescents with PCOS had a significantly increased rate of IR independent of BMI. The HMW adiponectin levels were lower in normal weight adolescents with PCOS and inversely correlated with IR. The IR with low HMW adiponectin levels may indicate the future development of metabolic disorders in adolescents with PCOS, even in the absence of obesity.
REFERENCES 1. 2. 3.
4.
5.
6.
7.
8.
9.
10.
11.
12. 13. 14. 15. 16. 17.
Franks S, The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group. Polycystic ovary syndrome. N Engl J Med 1995;333:853–61. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004;19:41–7. Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 1989;38:1165–74. Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, Ouchi N, et al. Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood 2000;96:1723–32. Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R. Hormonal regulation of adiponectin gene expression in 3T3-L1 adipocytes. Biochem Biophys Res Commun 2002;290:1084–9. Mirza SS, Shafique K, Shaikh AR, Khan NA, Anwar Qureshi M. Association between circulating adiponectin levels and polycystic ovarian syndrome. J Ovarian Res 2014;7:18. Lee H, Oh JY, Sung YA. Adipokines, insulin-like growth factor binding protein-3 levels, and insulin sensitivity in women with polycystic ovary syndrome. Korean J Intern Med 2013;28:456–63. Orlik B, Madej P, Owczarek A, Ska1ba P, Chudek J, OlszaneckaGlinianowicz M. Plasma omentin and adiponectin levels as markers of adipose tissue dysfunction in normal weight and obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 2013 Dec 9. http://dx.doi.org/ 10.1111/cen.12381. [Epub ahead of print]. Hara K, Horikoshi M, Yamauchi T, Yago H, Miyazaki O, Ebinuma H, et al. Measurement of the high-molecular weight form of adiponectin in plasma is useful for the prediction of insulin resistance and metabolic syndrome. Diabetes Care 2006;29:1357–62. Lara-Castro C, Luo N, Wallace P, Klein RL, Garvey WT. Adiponectin multimeric complexes and the metabolic syndrome trait cluster. Diabetes 2006; 55:249–59. Nakashima R, Kamei N, Yamane K, Nakanishi S, Nakashima A, Kohno N. Decreased total and high molecular weight adiponectin are independent risk factors for the development of type 2 diabetes in Japanese-Americans. J Clin Endocrinol Metab 2006;91:3873–7. Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 1961;21:1440–7. Ludwig E. Classification of the types of androgenetic alopecia (common baldness) occurring in the female sex. Br J Dermatol 1977;97:247–54. Hayashi N, Akamatsu H, Kawashima M. Establishment of grading criteria for acne severity. J Dermatol 2008;35:255–60. Guastella E, Longo RA, Carmina E. Clinical and endocrine characteristics of the main polycystic ovary syndrome phenotypes. Fertil Steril 2010;94:2197–201. Diagnosis and classification of diabetes mellitus. American Diabetes Association. Diabetes Care 2005;28(Suppl 1):S37–42. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412–9. 829
ORIGINAL ARTICLE: REPRODUCTIVE ENDOCRINOLOGY 18.
19.
20.
21.
22. 23.
24.
25.
26.
27.
28.
29. 30.
830
Yin J, Li M, Xu L, Wang Y, Cheng H, Zhao X, et al. Insulin resistance determined by Homeostasis Model Assessment (HOMA) and associations with metabolic syndrome among Chinese children and teenagers. Diabetol Metab Syndr 2013;5:71. Kahsar-Miller MD, Nixon C, Boots LR, Go RC, Azziz R. Prevalence of polycystic ovary syndrome (PCOS) in first-degree relatives of patients with PCOS. Fertil Steril 2001;75:53–8. Legro RS, Driscoll D, Strauss JF 3rd, Fox J, Dunaif A. Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc Natl Acad Sci U S A 1998;95:14956–60. Coviello AD, Sam S, Legro RS, Dunaif A. High prevalence of metabolic syndrome in first-degree male relatives of women with polycystic ovary syndrome is related to high rates of obesity. J Clin Endocrinol Metab 2009;94:4361–6. Moini A, Eslami B. Familial associations between polycystic ovarian syndrome and common diseases. J Assist Reprod Genet 2009;26:123–7. Sam S, Legro RS, Bentley-Lewis R, Dunaif A. Dyslipidemia and metabolic syndrome in the sisters of women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005;90:4797–802. Sam S, Sung YA, Legro RS, Dunaif A. Evidence for pancreatic beta-cell dysfunction in brothers of women with polycystic ovary syndrome. Metabolism 2008;57:84–9. Trottier A, Battista MC, Geller DH, Moreau B, Carpentier AC, Simoneau-Roy J, et al. Adipose tissue insulin resistance in peripubertal girls with first-degree family history of polycystic ovary syndrome. Fertil Steril 2012;98:1627–34. Raissouni N, Kolesnikov A, Purushothaman R, Sinha S, Bhandari S, Bhangoo A, et al. Altered glucose disposition and insulin sensitivity in peri-pubertal first-degree relatives of women with polycystic ovary syndrome. Int J Pediatr Endocrinol 2012;2012:14. Dokras A, Bochner M, Hollinrake E, Markham S, Vanvoorhis B, Jagasia DH. Screening women with polycystic ovary syndrome for metabolic syndrome. Obstet Gynecol 2005;106:131–7. Moran LJ, Misso ML, Wild RA, Norman RJ. Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update 2010;16:347–63. Orio F, Palomba S, Colao A. Cardiovascular risk in women with polycystic ovary syndrome. Fertil Steril 2006;86(Suppl 1):S20–1. Coviello AD, Legro RS, Dunaif A. Adolescent girls with polycystic ovary syndrome have an increased risk of the metabolic syndrome associated with
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
increasing androgen levels independent of obesity and insulin resistance. J Clin Endocrinol Metab 2006;91:492–7. Leibel NI, Baumann EE, Kocherginsky M, Rosenfield RL. Relationship of adolescent polycystic ovary syndrome to parental metabolic syndrome. J Clin Endocrinol Metab 2006;91:1275–83. Huang J, Ni R, Chen X, Huang L, Mo Y, Yang D. Metabolic abnormalities in adolescents with polycystic ovary syndrome in south China. Reprod Biol Endocrinol 2010;8:142. Roe AH, Prochaska E, Smith M, Sammel M, Dokras A. Using the androgen excess-PCOS society criteria to diagnose polycystic ovary syndrome and the risk of metabolic syndrome in adolescents. J Pediatr 2013;162:937–41. Rossi B, Sukalich S, Droz J, Griffin A, Cook S, Blumkin A, et al. Prevalence of metabolic syndrome and related characteristics in obese adolescents with and without polycystic ovary syndrome. J Clin Endocrinol Metab 2008;93: 4780–6. Fulghesu A, Magnini R, Portoghese E, Angioni S, Minerba L, Melis GB. Obesity-related lipid profile and altered insulin incretion in adolescents with polycystic ovary syndrome. J Adolesc Health 2010;46:474–81. Villa P, Rossodivita A, Sagnella F, Moruzzi MC, Mariano N, Lassandro AP, et al. Ovarian volume and gluco-insulinaemic markers in the diagnosis of PCOS during adolescence. Clin Endocrinol (Oxf) 2013;78:285–90. Poomthavorn P, Chaya W, Mahachoklertwattana P, Sukprasert M, Weerakiet S. Glucose metabolism in obese and lean adolescents with polycystic ovary syndrome. J Pediatr Endocrinol Metab 2013;26:319–24. Flannery CA, Rackow B, Cong X, Duran E, Selen DJ, Burgert TS. Polycystic ovary syndrome in adolescence: impaired glucose tolerance occurs across the spectrum of BMI. Pediatr Diabetes 2013;14:42–9. O'Connor A, Phelan N, Tun TK, Boran G, Gibney J, Roche HM. High-molecular-weight adiponectin is selectively reduced in women with polycystic ovary syndrome independent of body mass index and severity of insulin resistance. J Clin Endocrinol Metab 2010;95:1378–85. Lewandowski KC, Szosland K, O'Callaghan C, Tan BK, Randeva HS, Lewinski A. Adiponectin and resistin serum levels in women with polycystic ovary syndrome during oral glucose tolerance test: a significant reciprocal correlation between adiponectin and resistin independent of insulin resistance indices. Mol Genet Metab 2005;85:61–9. Mather KJ, Hunt AE, Steinberg HO, Paradisi G, Hook G, Katz A, et al. Repeatability characteristics of simple indices of insulin resistance: implications for research applications. J Clin Endocrinol Metab 2001;86:5457–64.
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