Prevalence and risk factors of diabetes in patients with Klinefelter syndrome: a longitudinal observational study

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1 Prevalence and risk factors of diabetes in patients with Klinefelter syndrome: a longitudinal observational study Mao Jiang-Feng, M.D., a Xu Hong-Li, M.D., a Wu Xue-Yan, M.D., a Nie Min, M.D., a Lu Shuang-Yu, M.D., a Xiang Hong-Ding, M.D., a and Liao Liang-Ming, M.D. b a Key Laboratory of Endocrinology, Department of Endocrinology, Peking Union Medical College Hospital, Ministry of Health, Beijing; and b Institute of Oncology, Fujian University of Traditional Chinese Medicine, Fujian, People's Republic of China Objective: To evaluate the prevalence and risk factors of diabetes in patients with Klinefelter syndrome. Design: Retrospective longitudinal study. Setting: Medical college hospital. Patient(s): Klinefelter group (n ¼ 39) and idiopathic hypogonadotropic hypogonadism (IHH) group (n ¼ 40). Intervention(s): Testosterone replacement therapy. Main Outcome Measure(s): The metabolic parameters, lipid profiles, and sex hormones were compared before and after T replacement therapy. The median duration of follow-up was 4 years in the Klinefelter group and 5.2 years in the IHH group. Result(s): The prevalence of diabetes was 20.5% (8 of 39) in the Klinefelter group and 5% in the IHH group. In the Klinefelter group, the incidence of diabetes was 12.5% in patients with 47,XXY karyotype and 57.1% in patients with other atypical karyotypes, such as 46XY/47XXY chimera. In the Klinefelter group, the average (SD) age at diagnosis of diabetes was years. Four subjects had diabetes before T therapy, and their blood glucose did not improve after T replacement. One patient had a history of acute pancreatitis. Two other subjects had very high triglyceride levels. During the follow-up, body weight increased more in Klinefelter patients than in IHH patients. Conclusion(s): The prevalence of diabetes is higher in Klinefelter patients than in IHH patients, possibly owing to abnormal karyotypes. Other risk factors, such as low T level, high body weight, acute pancreatitis, and high triglyceride levels, may also contribute to the development of diabetes. (Fertil Steril Ò 2012;98: Ó2012 by American Society for Reproductive Medicine.) Key Words: Klinefelter syndrome, diabetes, idiopathic hypogonadotropic hypogonadism, risk factors Discuss: You can discuss this article with its authors and with other ASRM members at fertstertforum.com/maoj-diabetes-klinefelter-syndrome/ Use your smartphone to scan this QR code and connect to the discussion forum for this article now.* * Download a free QR code scanner by searching for QR scanner in your smartphone s app store or app marketplace. Klinefelter syndrome (KS) is a congenital disease caused by additional copies of the X chromosome. It manifests as hypergonadotropic hypogonadism and azoospermia clinically and progressive seminiferous tubule hyaline degeneration pathologically. Klinefelter syndrome is the most common abnormal karyotype diseases, and the incidence in the population is Received December 5, 2011; revised July 19, 2012; accepted July 20, 2012; published online August 30, M.J.-F. has nothing to disclose. X.H.-L. has nothing to disclose. W.X.-Y. has nothing to disclose. N.M. has nothing to disclose. L.S.-Y. has nothing to disclose. X.H.-D. has nothing to disclose. L.L.-M. has nothing to disclose. M.J.-F. and X.H.-L. contributed equally to this work. This study was supported by a grant ( ) from the Natural Science Foundation of China. Reprint requests: Wu Xue-Yan, M.D., Peking Union Medical College Hospital, Department of Endocrinology, Beijing , People's Republic of China ( wsheyan@vip.sina.com). Fertility and Sterility Vol. 98, No. 5, November /$36.00 Copyright 2012 American Society for Reproductive Medicine, Published by Elsevier Inc. 1:500 1,000 (1). The classic karyotype is 47,XXY, whereas other karyotypes, such as 47XXY/46XY chimera, 48XXXY, and 48XXYY, could also be encountered occasionally. Diabetes is significantly more prevalent among KS patients. It has been reported that the incidence of diabetes in KS subjects is 15% 50% and is presumably caused by T deficiency (2 5).Other possible risk factors for diabetes in KS patients have not been fully elucidated. In the present study, a group of KS patients were followed up for a median period of 4 years (range, 1 30 years). VOL. 98 NO. 5 / NOVEMBER

2 ORIGINAL ARTICLE: REPRODUCTIVE ENDOCRINOLOGY Here, we report their sex hormone and metabolic profiles, especially diabetes-related features of these patients, and compare them with patients with idiopathic hypogonadotropic hypogonadism (IHH). MATERIALS AND METHODS Study Population This was a longitudinal, retrospective, and observational study. The retrospective analysis included data from January 1971 to December The observational study contained data generated from January 2003 to December 2011 during the follow-up. Diagnosis of KS included small testes and low T but elevated gonadotropin levels. The diagnosis was confirmed by karyotype analysis from cultured peripheral lymphocytes. Diagnosis of IHH included small testes and low gonadotropin and T levels. The study was approved by the Ethics Committee of Peking Union Medical College Hospital, and written consent was obtained from all patients. Data Collection Comprehensive clinical, physiologic, laboratory, and therapeutic data were retrieved from the database for patients in Beijing Union Hospital. Demographic information included age, sex, body weight, body mass index (BMI), and admission date. Anthroposomatologic parameters, such as lipid profile and fasting blood glucose levels, were compared before and after T replacement therapy (TRT) and between the two groups. The clinical features, comorbidities, and antidiabetic drugs in diabetic KS patients were fully described. The relationship between diabetes and karyotypes was also investigated. Study Definitions Metabolic syndrome was diagnosed according to the International Diabetes Federation 2004 criteria (6). According to the definition, for a man to be defined as having the metabolic syndrome they must have central obesity with waist circumference R90 cm, plus any two of four additional factors. These four factors include triglyceride R1.7 mmol/l, highdensity lipoprotein (HDL)-cholesterol <1.03 mmol/l (or treatment for dyslipidemia), systolic blood pressure R130 mm Hg or diastolic blood pressure R85 mm Hg (or treatment of previous hypertension), and fasting plasma glucose R5.6 mmol/ L (or previously diagnosed type 2 diabetes). Diabetes was diagnosed according to the World Health Organization criteria of Laboratory Measurements Blood samples were taken in a fasting state at 8:00 8:30 AM. Oral glucose tolerance tests (OGTTs) were conducted according to World Health Organization criteria. Briefly, after ingestion of 75 g glucose, serum glucose levels were measured at 0 and 120 minutes. In each patient, total T, total cholesterol, triglyceride, low-density lipoprotein (LDL)-cholesterol, and HDL-cholesterol were measured before and after TRT. Follicle-stimulating hormone, LH, and total T levels were measured using commercial kits by immunoradiometric assay before 2003 and chemiluminescent method (ACS 180 Automatic Chemiluminescence System; Bayer) after The intra- and interassay coefficients of variation of total T were 5.6% and 6.6%, respectively. Statistical Analysis Statistical software (SPSS 11.0) was used for data analysis. Data with normal distribution were expressed as mean SD; data with nonnormal distribution were expressed as medians. The independent t test was used to compare the difference between the Klinefelter group and the IHH group. The pairedsample t test was used to compare the difference before and after TRT. The c 2 test was used to compare the incidence of diabetes in both groups. In subgroup analysis, the c 2 test was also used to compare the incidence of diabetes in different karyotypes. Levels of statistical significance were set at P<.05. RESULTS KS Patients A total of 39 KS patients participated in the study. All patients received TRT and were followed up for a median period of 4 years, ranging from 1 to 30 years. They regularly visited our hospital at an interval of months. The anthroposomatologic parameters, such as gonadotropin levels, sex hormone levels, and lipid profiles before and after T replacement therapy, are listed in Table 1. The regimens of TRT were as follows. Before 1993, 100 mg compound T was injected IM at an interval of 10 days; after 1993, 250 mg T undecanoate was injected IM monthly. During the follow-up, serum T was measured repeatedly, and the interval time of injection was adjusted to keep the serum concentration of T R10 nmol/l. An OGTT was conducted 38 times in the Klinefelter group and 52 times in the IHH group. The OGTT was repeated in some patients during the follow-up if the diagnosis of diabetes could not be made at the first time. Metabolic syndrome. Before TRT, the prevalence of metabolic syndrome was 30.8%. After TRT for a median duration of 4 years the incidence of metabolic syndrome increased to 38.5%. Diabetes. Eight patients were diagnosed with diabetes. The total prevalence of diabetes was 20.5%, higher than in the IHH group (P¼.004). Subgroup analysis showed that the incidence of diabetes was 12.5% in patients with typical karyotype of 47,XXY and 57.1% in patients with other atypical karyotypes, such as 46XY/47XXY chimera (P¼.008). The average (SD) age at diagnosis of diabetes was years (range, years). Four patients presented diabetes before TRT, and the other four patients developed diabetes after TRT was administered. Four patients required insulin. Body weight. During the follow-up, the average body weight dramatically increased, by kg. Among nine patients whose body weight increased by kg (Fig. 1), two developed diabetes VOL. 98 NO. 5 / NOVEMBER 2012

3 Fertility and Sterility TABLE 1 Anthropometry parameters, T levels, and lipid profiles before and after TRT in KS and IHH patients. Item KS (n [ 39) IHH (n [ 40) Before TRT After TRT Before TRT After TRT Age (y) Height (cm) a Weight (kg) b a b,c BMI (kg/m 2 ) b b,c Testes size (ml) FSH (U/L) b a LH (U/L) b a T (nmol/l) b b CHOL (mmol/l) TG (mmol/l) a b LDL-c (mmol/l) b HDL-c (mmol/l) FBG (mmol/l) Incidence of metabolic syndrome (%) a 20 Incidence of diabetes (%) c Note: CHOL ¼ cholesterol; TG ¼ triglyceride; LDL-c ¼ LDL-cholesterol; HDL-c ¼ HDL-cholesterol; FBG ¼ fasting blood glucose. a Compared with KS group before TRT, P<.05. b Compared with the same group before TRT, P<.05. c Compared with KS group after TRT, P<.05. Comorbidities. Among the diabetic patients, one had acute pancreatitis, and two had very high levels of triglyceride (Table 2). IHH Patients A total of 40 IHH patients participated in the study. No patients underwent puberty at the age of 18 years. Testosterone was administered for a median of 5.2 years, ranging from 2 to 32 years. Metabolic syndrome. The prevalence of metabolic syndrome was 15% before TRT. After TRT for a median of 5.2 years, the incidence of metabolic syndrome increased to 20%. FIGURE 1 In the Klinefelter patient group, BMI dramatically increased in nine patients during follow-up. Diabetes. The prevalence of diabetes was 5% (2 of 40). The diagnosis was made at the age of 47 and 52 years, respectively. Both had TRT for approximately 20 years before the diagnosis. Blood glucose was well controlled by metformin and glimepiride. Weight. During the follow-up, average body weight increase was kg. Comorbidities. No comorbidities were documented. DISCUSSION The aim of this study was to investigate the metabolic abnormalities in KS patients. The results showed that in KS patients the prevalence of metabolic syndrome increased from 30.8% to 38.5% during a median follow-up period of 4 years, and the incidence of diabetes was 20.5%, significantly higher than in IHH patients and the normal population. The diabetic KS patients had the following clinical features: [1] diabetes occurring at a relatively young age (approximately 30 years); [2] other risk factors for diabetes, such as acute pancreatitis and high triglyceride levels; [3] blood glucose could not be well controlled, even though insulin was administered; [4] incidence of diabetes was still high regardless of TRT; and [5] some patients had low BMI when the diagnosis of diabetes was made (Table 2). To the best of our knowledge, to date, this study has the largest sample size and the longest follow-up time. The mechanisms of diabetes in KS have not been well elucidated (2). Testosterone deficiency has been assumed to be the underlying mechanism (7,8). It is reported that insulin resistance and the incidence of diabetes increased in patients with prostate cancer who received T deprivation therapy (9). Several other epidemic studies have also revealed that the incidence of metabolic syndrome and type 2 diabetes increased in male populations with low levels of VOL. 98 NO. 5 / NOVEMBER

4 ORIGINAL ARTICLE: REPRODUCTIVE ENDOCRINOLOGY TABLE 2 Basic line data and clinical features in patients with KS and diabetes (n [ 8). Therapeutic regimens for diabetes Starting T therapy (y) Height (cm) Weight (kg) Karyotype HbA1c (%) Comorbidities Age at diagnosis of diabetes (y) Patient no. P xxy 6.6 Severe pancreatitis, fatty liver Lantus þ NovoRapid P xxy/46xx 10.4 Fatty liver Novomix 30 þ metformin P xxy 11.2 Severe fatty liver Metformin P xxxy 6.9 Mental retardation Refuse to take medicine P xy/47xxy 9.9 TG 32 mmol/l, fatty liver Novomix 30 P xy/47xxy 7.7 Acute myeloid leukemia M3 Refuse to take medicine P xxy 9.1 Fatty liver Metformin þ regular insulin P xxy 6.4 TG 11 mmol/l Metformin T (10 12). Indeed, TRT has been shown to improve metabolic status and insulin sensitivity (13,14). Our study showed that the incidence of diabetes is much higher in KS patients than in IHH patients, even though they were all androgen-deficient populations and received similar TRT. This suggests that T deficiency or replacement did not play a necessary role in the development of diabetes. In addition, body weight and BMI significantly increased during long-term TRT (Fig. 1). The cause-and-effect relationship between T and diabetes is thus still very controversial. Abdominal obesity and metabolic syndrome are significant risk factors for diabetes. One study has found that the incidence of abdominal obesity and metabolic syndrome in KS patients was 44%, much higher than the 10% in the control group (7). Even with the same BMI, visceral adipose and waist circumference was significantly higher in KS patients than in a control group (15). Using a hyperinsulinemia euglycemia clamp, the most sensitive assay for insulin sensitivity, Yesilova et al. (16) discovered that KS patients have significantly lower insulin sensitivity than a control group. Consistent with these studies, our data showed that the incidence of metabolic syndrome in KS patients was 30.8% at the beginning and then increased to 38.5% during the follow-up. Another possible mechanism for diabetes may involve the extra copies of X chromosomes. The genes, locating in additional X chromosomes, lead to seminiferous tubule hyaline degeneration by means of a gene dosage effect (17). We speculated that the similar gene dosage effect might cause insulin secretion deficiency, increased insulin resistance, or both, and contribute to diabetes. Indeed, we found that there was a close relationship between karyotypes and diabetes (Table 3): the incidence of diabetes was 12.5% in patients with a karyotype of 47,XXY, whereas it increased to 57.1% in patients with other karyotypes (P¼.08). The result is consistent with other studies showing that the incidence of diabetes was 5 of 24 (20.8%) in patients with 47,XXY karyotype, but 7 of 7 patients (100%) with other karyotypes (4 patients with 46,XY/47,XXY chimera and 3 patients with 49,XXXXY) (2). The data revealed a tendency that the more copies of X chromosome, the higher the risk for diabetes. Autoimmune disease may also be involved in the development of diabetes. Islet cell antibodies and glutamic acid decarboxylase antibodies can be detected in some patients with KS and diabetes (18). In addition, our study found some other diabetic risk factors in KS patients, such as acute pancreatitis, high triglyceride TABLE 3 Relationship between incidence of diabetes and karyotype. Karyotype No. of patients (diabetes/total patients) Incidence of diabetes mellitus (%) Classic karyotype (47,XXY) 4/ Atypical karyotype (46XY/47XXY 4/ a chimera and others) Total 8/ a P¼.008 compared with patients with classic karyotype 47,XXY VOL. 98 NO. 5 / NOVEMBER 2012

5 Fertility and Sterility level, fat liver, and increased BMI after androgen therapy. As we know, pancreatitis and hypertriglyceridemia is beyond the side effects of T therapy (19). All these factors could aggravate insulin resistance and impair b cell function. There are limitations to our study. First, the sample size of our study was relatively small, especially the number of diabetic KS patients. This may potentially affect the relationship estimates between KS and diabetes. However, this issue may, at least in part, be obviated by the fact that our data appear largely consistent with previous studies on this topic. Second, we did not perform multivariable logistic regression analysis to exclude the contribution of physical activity, food intake, socioeconomic status, and education to the development of diabetes after long-term TRT. Third, the study is retrospective and observational and is potentially susceptible to several forms of bias. To conclude, our study shows that the prevalence of diabetes is significantly increasing in KS patients compared with IHH patients, independent of TRT. The gene dosage effects from the additional X chromosomes are speculated to be the important mechanism for diabetes. Other risk factors, such as abdominal obesity, increased body weight, hypertriglyceridemia, and pancreatitis are also contributing. Lifelong management of these risk factors, especially increasing BMI during TRT, is necessary. REFERENCES 1. Bojesen A, Gravholt CH. Klinefelter syndrome in clinical practice. Nat Clin Pract Urol 2007;4: Nielsen J, Johansen K, Yde H. Frequency of diabetes mellitus in patients with Klinefelter's syndrome of different chromosome constitutions and the XYY syndrome. Plasma insulin and growth hormone level after a glucose load. J Clin Endocrinol Metab 1969;29: Robinson S, Kessling A. Diabetes secondary to genetic disorders. Baillieres Clin Endocrinol Metab 1992;6: Becker KL, Hoffman DL, Underdahl LO, Mason HL. Klinefelter's syndrome: clinical and laboratory findings in50 patients. Arch Intern Med 1966;118: Bojesen A, Juul S, Birkebaek NH, Gravholt CH. Morbidity in Klinefelter syndrome: a Danish register study based on hospital discharge diagnoses. J Clin Endocrinol Metab 2006;91: Alberti KG, Zimmet P, Shaw J. Metabolic syndrome a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med 2006;23: Bojesen A, Kristensen K, Birkebaek NH, Fedder J, Mosekilde L, Bennett P, et al. The metabolic syndrome is frequent in Klinefelter's syndrome and is associated with abdominal obesity and hypogonadism. Diabetes Care 2006;29: Ota K, Suehiro T, Ikeda Y, Arii K, Kumon Y, Hashimoto K. Diabetes mellitus associated with Klinefelter's syndrome: a case report and review in Japan. Intern Med 2002;41: Saylor PJ, Smith MR. Metabolic complications of androgen deprivation therapy for prostate cancer. J Urol 2009;181: Kapoor D, Malkin CJ, Channer KS, Jones TH. Androgens, insulin resistance and vascular disease in men. Clin Endocrinol 2005;63: Laaksonen DE, Niskanen L, Punnonen K, Nyyssonen K, Tuomainen TP, Valkonen VP, et al. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care 2004;27: Svartberg J, Jenssen T, Sundsfjord J, Jorde R. The associations of endogenous testosterone and sex hormone-binding globulin with glycosylated hemoglobin levels, in community dwelling men: the Tromso Study. Diabetes Metab 2004;30: Corona G, Monami M, Rastrelli G, Aversa A, Tishova Y, Saad F, et al. Testosterone and metabolic syndrome: a meta-analysis study. J Sex Med 2011;8: Jones TH, Arver S, Behre HM, Buvat J, Meuleman E, Moncada I, et al. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care 2011; 34: Bojesen A, Høst C, Gravholt CH. Klinefelter's syndrome, type 2 diabetes and the metabolic syndrome: the impact of body composition. Mol Hum Reprod 2010;16: Yesilova Z, Oktenli C, Sanisoglu SY, Musabak U, Cakir E, Ozata M, et al. Evaluation of insulin sensitivity in patients with Klinefelter's syndrome: a hyperinsulinemic euglycemic clamp study. Endocrine 2005;27: Barbaro M, Oscarson M, Schoumans J, Staaf J, Ivarsson SA, Wedell A. Isolated 46, XY gonadal dysgenesis in two sisters caused by a Xp21.2 interstitial duplication containing the DAX1 gene. J Clin Endocrinol Metab 2007;92: Pamuk BO, Torun AN, Kulaksizoglu M, Algan C, Ertugrul DT, Yilmaz Z, et al. 49, XXXXY syndrome with autoimmune diabetes and ocular manifestations. Med Princ Pract 2009;18: Kaufman JM, Miller MG, Garwin JL, Fitzpatrick S, McWhirter C, Brennan JJ. Efficacy and safety study of 1.62% testosterone gel for the treatment of hypogonadal men. J Sex Med 2011;8: VOL. 98 NO. 5 / NOVEMBER