Androgen Pattern and Erectile Function in Newly Diagnosed Type 2 Diabetes

Med. J. Cairo Univ., Vol. 84, No. 3, December: 341-347, 2016 www.medicaljournalofcairouniversity.net Androgen Pattern and Erectile Function in Newly Diagnosed Type 2 Diabetes AHMED I. EL-SAKKA, M.D.*; AL-SAYED M. AL-SALAMONY, M.D.** and ABEER M. AHMED, M.D.*** The Department of Urology, Faculty of Medicine, Suez Canal University, Ismailia*, the Department of Internal Medicine, Diabetes & Endocrinology Unit, Faculty of Medicine, Mansoura University** and the Department of Biochemistry, Faculty of Medicine, Menofia University*** Abstract Background: In this study, we assessed the alteration of androgen pattern and Erectile Dysfunction (ED) in male patients with recently diagnosed type 2 diabetes mellitus T2DM. Material and Methods: 176 newly diagnosed type 2 diabetic male patients underwent laboratory investigations, involving routine chemistry [glycemic indices; FBS and HbA1C] and [lipid profile; TC, TG, LDLc and HDLc]. Also, total testosterone (tt), sex hormone binding globulin, prolactin, insulin were assayed. In addition, calculated free (ft) and bioavailable (bt) testosterone were assessed. Erectile function was evaluated utilizing International Index of Erectile Function (IIEF). Results: 21.6% and 48.3% of our diabetic patients had low total testosterone (tt) and Erectile Dysfunction (ED) respectively. There were significant associations between low total testosterone (tt), severe Erectile Dysfunction (ED) and hyperglycemia (FBS) ( 200mg/dl), poorly controlled DM (HbA1c >7%) and dyslipidemia. After adjustment of covariates, a persistent significant association between decreased total testosterone (tt) as a dependent variable and increased HbA1c as a predictor was revealed by linear regression analysis. Conclusion: Newly diagnosed type 2 diabetic patients had a high prevalence of hypogonadism and Erectile Dysfunction (ED). Severe Erectile Dysfunction (ED) and hypogonadism were significantly associated with hyperglycemia and high HbA1c in recently diagnosed type 2 diabetes mellitus T2DM. Key Words: Erectile dysfunction Diabetes Androgen. Introduction HORMONAL alteration in diabetic patients is an interesting issue that was raised in the recent years [1]. Although, androgens alteration may have del- Correspondence to: Dr. Al-Sayed M. Al-Salamony, E-Mail: ssalamony2002@yahoo.com eterious effects on glycemic control and ultimately therapeutic strategy and prognosis of type 2 diabetes mellitus (DM), this effect is not studied in newly diagnosed type 2 DM. The endocrine society of clinical practice in their guideline recommended measurement of testosterone concentration in patients with type 2 DM due to the high prevalence of low testosterone level in those patients [2]. Hyperinsulinemia and increased glucose concentration are both negatively correlated with total (tt) and free (ft) testosterone levels in men [3]. Although several studies had reported that low level of testosterone played a role in the development of insulin resistance and type 2 DM [4], however the cause effect relationship between decreased testosterone and type 2 DM remains unsettled. Recently, investigators have demonstrated that, there were significant associations between low level of tt or Dehydroepiandrosterone Sulphate (DHEA-S) and poor control of DM [5]. Furthermore, the influence of DM control and subsequent androgen amelioration on the severity of Erectile Dysfunction (ED) was demonstrated [6]. Numerous studies have focused on the association between ED and long-standing type 2 DM [7] ; nevertheless, identifying patients who are at high risk for ED prior to or early at the time of type 2 DM diagnosis had not properly investigated. This study was designed to address the change of androgen pattern and erectile function in men at the time of type 2 DM diagnosis. Material and Methods Research design: This is a cross sectional officebased study. From January 2012 to December 2013, 341

342 Androgen Pattern & ED in Newly Diagnosed Type 2 DM included 176 newly diagnosed (less than 3 months duration) type 2 DM male patients who visited our Andrology Clinic at Diabetes and Endocrinology Center, at Al-Noor Specialized Hospital, Holly Makkah, KSA. (For routine assessment of erectile function at the time of DM diagnosis) and who agreed to participate were enrolled in this study. Aim of study: To assess pattern of androgen pattern and Erectile Dysfunction (ED) in patients with newly diagnosed type 2 Diabetes Mellitus (DM). ED assessment: All patients were assessed for ED using International Index for Erectile Function (IIEF). The erectile function domain consists of questions 1 to 5 and question 15 for assessing the global erectile function. Scoring of the IIEF domain of erectile function allowed classification of each patient as having no (26-30), mild (17-25), moderate (11-16), or severe (0-10) ED [8]. History and clinical examination: A thorough sexual, medical and psychosocial history was taken and a focused physical examination was performed on every patient excluding patients with other endocrinal abnormalities or chronic diseases other than diabetes. All patients were also interviewed for socio-demographics that included age, obesity, education, occupation, marital status and smoking habit. Medical history included hypertension, ischemic heart disease, dyslipidemia, obesity and current use of medication. Whenever useful, information provided by the patients was checked with the medical records. Laboratory assessment: Patients underwent routine laboratory investigations, in addition to total testosterone (tt), Sex Hormone Binding Globulin (SHBG), prolactin and insulin assessment. Calculated free (ft) and bioavailable (bt) testosterone were also assessed. We used the electrochemiluminescence immunoassay (ECLA) according to manufacturer's instructions (Elecsys Systems 20/10 Roche diagnostics corporation, Indianapolis, IN, USA) to assess the tt, prolactin, SHBG and insulin levels in the sera of the studied patients. The laboratory reference ranges were (2.6-24.9µU/ml), for fasting insulin, (9.2-27.8nmol/L) for total testosterone and 6-44nmol/L for SHBG, and 4.1-18.4ng/dL for PRL. cft was calculated from SHBG and T using the method of Vermeulen et al., and using a computer program and web site address supplied by Dr. T. Fiers, University Hospital Ghent, Ghent, Belgium (http://www.issam.ch/freetesto.htm). For cft, 0.225 nmol/l was taken as the lower limit of normal [9]. Because FT is the gold standard for diagnosing hypogonadism was defined as low ft [10]. Glycemic control was measured by glycosylated hemoglobin (HbA1c) using a high-performance liquid chromatography technique on a rinsed venous blood sample. Metabolic control was rated as follow: Good (4.7-6.2%), Fair (6.3-7%), Poor >7%. Metabolic control was evaluated according to the glycosylated hemoglobin values, dating not more than three months before the interview. Statistical analysis: The data were analyzed using the Statistical Package of Social Science (SPSS.11.0) software program. Unpaired t-test and one-way ANOVA were used to compare means of EF-Domain, tt, ft, bt, SHBG and insulin according to other variables. Testosterone level and ED severity were compared according to non-parametric classification of the measured variables using chi-square test. Multiple regression analysis was carried out to determine the association between tt as a dependent variable and HbA1c as a predictor, with adjustment for other covariates that have possible impacts on this association, such as age, FBS, BMI, lipid profile variables and insulin level. s below 0.05 were considered significant. Results Socio-demographics: A total of 176 newly diagnosed type 2 DM male patients who visited our andrology clinic were the subject of this study. Mean age ± SD was 48.2±8.9 years. The mean ages were 47.2±9.2 and 50.3±8. 1 years for eugonadal and hypogonadal patients respectively ( p> 0.05). Of the patients, 86.4% had completed or less than secondary school education, 75.6% were overweight or obese and 42% were former or current smokers. The mean BMI were 29 ±3.9 and 35.4±4.3 in eugonadal and hypogonadal patients respectively (p<) (Table 1). ED severity, hormonal pattern and DM: Of the patients 21.6% (n=38/176), and 48.3% (n=85/176) had low tt and ED respectively. In patients with ED (n=85), 22.4% had mild, 55.3% had moderate and 23.5% had severe degree (Table 2). The mean level of EF-domain was significantly lower in hypogonadal (16.4±3.9) versus eugonadal (22.8 ± 4.3) men (p<) (Table 1). In hypogonadal there were significant lower means of tt, ft, bt and higher mean of BMI in

Ahmed I. El-Sakka, et al. 343 comparison to eugonadal men, (Table 1). Decreasing tt and increasing severity of ED were each significantly associated with high level of FBS ( 200mg/dl), with poor control of diabetes (HbA1c >7%) and dyslipidemia (p< for each) (Table 3). There was significant association between hyperinsulinaemia and low tt level. No significant association was detected between hyperinsulinaemia and severity of ED ( p>0.05) (Table 2). There were significant associations between decrease of EF-domain and increasing of age, BMI, FBS, HbA1c (p< for each). Also the same significant differences were detected between decrease of EF-domain and hypertension as well as dyslipidemia (p< for each) (Table 3). In a multiple regression analysis models after adjusting for confounders; age, BMI, FBS, cholesterol, triglyceride, LDL, HDL, the relation between decreased tt as a dependent variable and increase HbA1c as a predictor was significant (p<0.05) (Table 4). Table (1): Clinical and biochemical parameters of patients with normal versus low testosterone levels. Parameters Abbreviations and symbols: EF BMI FBS HbA1 c tt ft bt SHBG Eugonadal : Erectile function. : Body Mass Index. : Fasting blood Sugar. : Glycosylated hemoglobin. : Total Testosterone. : Free Testosterone. : Bioavailable Testosterone. : Sex Hormone Binding Globulin. Hypogonadal p- value Age (yrs) 47.2±9.2 50.3±8.1 0.34 EF-Domain 22.8±4.3 16.4±3.9 BMI (kg/m 2 ) 29±3.9 35.4±4.3 0.00 1 FBS (mmol/l) 7.78± 1.73 10.23±2.03 0.03 HbA1c 7.9± 1.6 8.8± 1.9 0.07 tt (nmol/l) 16.4±4.8 8.8± 1.1 ft (nmol/l) 0.37±0.12 0.12±0.04 bt (nmol/l) 8.7±3 5.4± 1.9 SHBG (nmol/l) 30.1 ±6.4 24.4±5.5 Unpaired t-test was used to compare means of age, EF-Domain, BMI, FBS, HbA1c, tt, ft, bt and SHBG according to gonadal status. Significance level at p<0.05. Table (2): Pattern of total testosterone level and erectile dysfunction severity according to biochemical diagnostic variables of diabetes. Variables Pattern of testosterone Normal (N=138) Low (N=38) *pvalue No (N=91) Erectile dysfunction severity Mild (N=18) Moderate (N=47) Moderate (N=47) FBS: 6.08-<8.3mmol/L 98 (71%) 10 (26.3%) 0.00 1 57 (62.6%) 11 (61.1 %) 6 (12.7%) 2 (10%) 0.00 1 8.3-<1 1. 1mmol/L 31 (22.5%) 20 (52.6%) 25 (27.5 %) 5 (27.8%) 3 (6.4%) 2 (10%) 11.1mmol/L 9 (6.5%) 8 (21.1 %) 9 (9.9%) 2 (11.1%) 38 (80.9%) 16 (80%) HbA1c: 4.7-6.2% 31 (22.5%) 5 (13.2%) 59 (64.8%) 10 (55.6%) 5 (10.6%) 1 (5%) 0.00 1 6.3-7% 16 (11.6%) 4 (10.5%) 22 (24.2%) 6 (33.3 %) 3 (6.4%) 2 (10%) >7% 91 (65.9%) 29 (76.3%) 10 (11 %) 2 (11.1%) 39 (83%) 17 (85%) Insulin: (2.6-24.9µU/ml) 19.6± 14.4 29.9± 18.7 21.1 ± 13.6 21.7± 14.2 26.1 ± 17.3 22.8± 15.1 0.1 Dyslipidemia (): Cholesterol (mmol/l) 4.24±0.12 4.84±0.17 0.003 3.67±0.11 3.83±0.11 4.37±0.12 5.02±0.27 Triglyceride (mmol/l) 1.19+0.06 2.1±0.05 0.004 1.16±0.09 1.26±0.07 1.56±0.06 1.99±0.07 0.007 LDL (mmol/l) 3.21±0.08 3.1±0.059 0.32 3.13±0.11 3.26±0.09 3.15±0.11 3.34±0.11 0.4 HDL (mmol/l) 1.06±0.15 0.89±0.17 0.005 1.22±0.11 1.12±0.11 0.97±0.16 0.83±0.13 0.003 Abbreviations and symbols: BMI : Body Mass Index. FBS : Fasting Blood Sugar. LDL : Low-Density Lipoprotein. HDL : High-Density Lipoprotein. HbA1c : Glycosylated hemoglobin. *χ 2 : Chi-square test. : Was used to test the relationship between categorically coded FBS, and HbA1 c according to pattern of testosterone and severity of erectile dysfunction. Unpaired t-test and one-way ANOVA were used to compare means of insulin and lipid profile according to pattern of testosterone and severity of erectile dysfunction. χ 2 *pvalue

344 Androgen Pattern & ED in Newly Diagnosed Type 2 DM Table (3): Comparison of erectile function domain and sex hormones means according to clinical and biochemical variables. Variables <50 Age Yrs >_50 ВМI kg/m 2 <25 <30?30 Hypertension Yes No Dyslipidemia Yes No 6.1- <150 FBS mmolll 8.3 - <11.1 >_11.1 4.7-6.2% EF-Domain 23.1± 4.2 15.8± 4.4 22.6± 4.1 20.6± 5.2 16.7 ±4.8 17.4 3.9 22.9 ±4.4 16.8 ±4.9 23.2 ±4.2 21.8 ±4.1 19.6 ±4.4 17.1 ±3.4 24.2 ±5.1 Total Т 14.4± 5.4 0.82 13.6: 5.1 16.9% 5.5 0.003 16.9± 6.1 12.6 ±4.5 14.8 6.9 0.77 14.2 ±3.5 12.9 ±4.9 0.005 16.3 ±4.6 17.1 6.2 14.7 ±2.6 10.8 ±3.2 17.7 ±4.6 Free Т 0.39% 0.11 0.53 0.33: 0.14 0.4± 0.13 0.005 0.38± 0.16 0.28 +0.09 0.34 ::0.13 0.82 0.36 14 0.29 ±0.1 0.36 ±0.12 0.38 :0.15 0.003 0.33 +0.06 0.25 +0.1 0.41 ±0.12 Bioavailable Т 7.6± 2.8 0.26 7.3± 2.8 9.4± 3.1 8.7± 3.5 6.7 ±2.3 7.9 3.7 0.72 7.6 ±1.9 7.1 2.8 0.1 8.2 ±2.7 8.2 ±3.6 0.004 7.4 ±1.5 5.9 ±1.5 9.4 ±2.7 0.004 SHBG 28.2± 7.1 0.05 38.7± 6.2 27.7± 6.9 0.78 29.2± 5.1 27.9 ±6.9 28.1 6.8 0.84 27.7 ±5.4 26.1 ±6.5 0.004 31.7 ±5.4 30.4 ±4.6 0.08 26.6 ±5.2 28.1 ±3.8 32.1 ±4.4 0.14 Abbreviations and symbols: FBS : Fasting Blood Sugar. EF : Erectile Function. HbAlc : Glycosylated hemoglobin. ВМІ : Body Mass Index. SHBG : Sex Hormone Binding Globulin. Unpaired t-test and one-way ANOVA were used to compare means of erectile function domain and sex hormones according to age, BМІ, hypertension, dyslipidemia, FBS and HbA1c. Table (4): Multiple regression analysis using total testosterone as a dependent variable and HЪАІс as a predictor. ± Case label Age ВМI FBS Cholesterol Triglyceride LDL HDL Insulin SHBG (nmol /L) Abbreviations and symbols: ВМІ: Body Mass Index. Coefficient -0.320-0.319 -.0309-0.260-0.379-0.374-0.388-0.293 30.1±6.4 - - - SE 0.376 0.385 0.376 0.369 0.344 0.342 0.350 0.378 24.4+5.5 LDL HDL SHBG t -2.554-2.482-2.466-2.118 FBS : Fasting Blood Sugar. Multiple regression analysis was carried out to determine the association between tt as a dependent variable and HbA1c as a predictor, with adjustment for other covariates that have a possible impact on this association, age, FBS, ВМІ, lipid profile variables and insulin level. 3.309 3.301 3.326-2.325 28.4±6.6 : Low-Density Lipoprotein. : High-Density Lipoprotein. : Sex Hormone Binding Globulin. 3 6 7 0.039 0.024 ± ± HЪАІс % 6.3-7% 21.6 ±4.7 14.3 ±3.1 0.36 +0.15 7.2 ±1.7 27.2 ±6.5 >7% 15.9 ±3.8 12.3 ±2.9 0.27 +0.12 6.1 ±1.7 28.1 +7.1

Ahmed I. El-Sakka, et al. 345 Discussion In the current study, we investigated changes of erectile function and androgen pattern in men at the time of type 2 DM diagnosis. We found that 21.6% and 48.3% of patients had low tt and ED respectively at the time of type 2 DM diagnosis. It was reported that 25.2% had low tt and more than 87% had different degrees of ED severity in patients with long standing type 2 DM [5,11]. Although the prevalence of ED and low tt in patients with newly diagnosed type 2 DM is lower than in patients with well established type 2 DM, however this prevalence is considered remarkably high. In the present study, there was significant association between decrease of EF-domain and increase of age, BMI, FBS, HbA1c. In another study on the gulf region Al-Hunayan et al., reported on 323 men with newly diagnosed type 2 DM that, 31% had ED. Comparing potent men and men with ED, there were statistically significant differences for smoking, duration of smoking, hypertension, education level, BMI and serum HbA1c level. Among these, age was the most important risk factor identified [1,7]. In men with low plasma testosterone, the risk of type 2 DM is increased [12]. A systematic review and meta-analysis indicated that men with higher testosterone levels had a 42% lower risk of type 2 DM compared with men with a lower serum testosterone concentration [13]. In hypogonadal men with significant decrease in means of, tt, ft, bt, there was also decrease of EF-domain and increase in BMI in comparison to eugonadal men. There were significant associations between increased number of patients with low level of tt or severe ED and high level of FBS ( 200mg/dl), poor control of diabetes (HbA1c >7%) and dyslipidemia. Previous studies had reported that androgen deficiency in type 2 DM is commonly associated with hypogonadotropic hypogonadism [14]. It could be speculated that insulin resistance associated with type 2 DM determines a reduction of insulin action in the hypothalamus, leading to hypogonadotropic hypogonadism [15]. Elevated C-reactive protein concentrations in those patients could suggest that inflammation may play an important role in the pathogenesis of this syndrome [16]. On the other hand, administration of testosterone to hypogonadal men improves insulin sensitivity and glucose homeostasis [17]. In a double-blind placebo controlled crossover study, Kapoor et al., reported that testosterone replacement therapy in hypogonadal men with type 2 DM reduces insulin resistance, and improves both glycemic control and waist circum- ference [18]. Heufelder et al., reported that testosterone treatment improved insulin sensitivity, adiponectin, and high-sensitivity C-reactive protein and addition of testosterone to diet and exercise results in greater therapeutic improvements of glycemic control and reverses the Metabolic Syndrome (MetS) in hypogonadal patients with the MetS and newly diagnosed type 2 DM [19]. Furthermore, Corona et al., recently demonstrated that the DM associated central obesity and insulin resistance, rather than DM alone, plays the most important role in DM associated-hypogonadism [20]. In the current study; after adjusting for confounders, age, BMI, FBS, cholesterol, triglyceride, LDL, HDL, the relation between tt as a dependent variable and HbA1 c as a predictor was significant. In consistent with our results, Corrales et al., had shown that the fraction of diabetic men with subnormal levels of tt increased with age and obesity [21]. Supporting to our notion, previous reports indicated that the existence of chronic diseases subtracts 10% to 15% from the values of androgens found in men without chronic diseases [22]. Zou et al., reported that a significantly lower T/estradiol (E(2)) and SHBG level were present in MetS patients and concluded that relative hypogonadism was strongly associated with the prevalence of MetS in Japanese adult men who were newly diagnosed to have impaired glucose tolerance or type 2 DM [23]. In a more recent study Corona et al., reported that checking glucose and testosterone levels is mandatory in subjects with ED because testosterone substitution in impotent impaired fasting glucose subjects might ameliorate not only their sexual life but also their overall health [24]. In our study no significant association was detected between hyperinsulinaemia and severity of ED. This could be due to measurement error and regression dilution bias which is particularly relevant for biochemical and clinical variables in the physiologically disruptive non-equilibrium state of newly diagnosed clinical diabetes [25]. The increased risk of CV disease at the onset of type 2 DM was previously reported [13]. Due to the strong association between CV risk factors and ED, the existence of ED at the onset of DM could be highly expected. This prompted us to investigate pattern of androgen and erectile function in patients with newly diagnosed type 2 DM. Our study expands current knowledge in the sense that, as occurs in long standing type 2 diabetic men, the percentage of newly diagnosed type 2 diabetic patients with subnormal levels of tt is much higher than the non diabetic men.

346 Androgen Pattern & ED in Newly Diagnosed Type 2 DM This study has several limitations. First, it was a cross-sectional study so the causal pattern underlying the associations that we have claimed remained to be confirmed however, these initiatives to identify patients earlier in the natural history of type 2 DM have probably decreased the variability of many of the baseline variables measured in our study. Further, one of the problems we have in studies is the difference ranges quoted for testosterone level. In the current study we used our local lab reference of total testosterone <9.2nmol/L (9.2-27.8nmol/L) as a cut off level for diagnosis of hypogonadism. Second, there was no control group of patients with long standing type 2 DM or a control group of similar age, BMI and total cardiovascular risk to confirm the extent of changes in erectile function and androgen changes. However; the associations between newly diagnosed type 2 DM and increased severity of ED and hypogonadism were confirmed, even when biochemical and life-style variables were controlled for. Finally, due to its subtle prognosis, all newly diagnosed diabetic patients could have disease periods varying between 2-10 years. Therefore, exclusion of cases with micro or macro vascular complications while enrolling the newly diagnosed patients might have resonance. In this study we found that patients who had high level of FBS and HbA1c at the time of DM diagnosis had increased severity of ED and hypogonadism, even when biochemical and life-style variables were controlled. Conclusions: This study clearly demonstrated that ED and hypogonadism are prevalent among newly diagnosed type 2 DM patients. Severe ED and hypogonadism had significant associations with high level of FBS and HbA1c at the time of type 2 DM diagnosis. 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