Men Sexual Dysfunction Associated with Obesity and Metabolic Syndrome

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2 Men Sexual Dysfunction Associated with Obesity and Metabolic Syndrome By Aly A. Abbassy, MD, FACE Professor of Medicine (Endocrinology) Alexandria University

3 My Talk will include: 1-Types of Men sexual dysfunction 2-Introduction 3-Pathophysiuology of Sexual dysfunction 4-Low testosterone.cvd and T2D 5-Clinical studies of testosterone replacement in men with obesity,ms,t2d and low testosterone concentration 6-Conclusions 7-Take Home Message

4 Types of Sexual Dysfunction 1. Loss of Libido (low sex desire) 2. Erectile Dysfunction (ED) -Poor morning erection -Weak erection -Impotence -Premature ejaculation -Retrograde ejaculation

5 INTRODUCTION

6 In the European Male Aging Study database (2007) of 3,369 men between the ages of 40 and 79 years, three sexual symptoms (poormorning erections, low sexual desire, and ED) had a syndromic relationship with decreased testosterone levels. Wu FC, et al. N Engl J Med 2010

7 Moreover, in the European Male Aging Study (2007), low serum testosterone was more frequent in men with comorbidities such as obesity, metabolic syndrome, and type 2 diabetes.

8 Hypogonadism in men with type 2 diabetes was associated with decreased sexual desire, more symptoms of depression, and lower luteinizing hormone levels. Kapoor D, et al. Int J Androl 2007.

9 Men with obesity, the metabolic syndrome, and type 2 diabetes have low total and free testosterone and low sex hormone binding globulin (SHBG). Christina Wang, et al. Diabetes Care, 2011.

10 Conversely, the presence of low testosterone and/or SHBG predicts the development of metabolic syndrome and type 2 diabetes. Christina Wang, et al. Diabetes Care, 2011.

11 Visceral adiposity present in men with low testosterone, the metabolic syndrome, and/or type 2 diabetes acts through proinflammatory factors. Christina Wang, et al. Diabetes Care, 2011.

12 These inflammatory markers contribute to vascular endothelial dysfunction with adverse sequelae such as increased cardiovascular disease (CVD) risk and erectile dysfunction. Christina Wang, et al. Diabetes Care, 2011.

13 Low serum total testosterone predicts the development of central obesity and accumulation of intra-abdominal fat. Allan CA & McLachlan RI. Curr Opin Endocrinol Diabetes Obes 2010 MacDonald AA et al. Hum Reprod Update 2010 Brand JS et al. Int J Epidemiol 2011

14 Also, low total and free testosterone and SHBG levels are associated with an increased risk of developing the metabolic syndrome, independent of age and obesity. Allan CA & McLachlan RI. Curr Opin Endocrinol Diabetes Obes 2010 MacDonald AA et al. Hum Reprod Update 2010 Brand JS et al. Int J Epidemiol 2011

15 Conversely, high BMI, central adiposity, and the metabolic syndrome are associated with and predict low serum total and to a lesser extent free testosterone and SHBG levels. Allan CA & McLachlan RI. Curr Opin Endocrinol Diabetes Obes 2010 MacDonald AA et al. Hum Reprod Update 2010 Brand JS et al. Int J Epidemiol 2011 Laaksonen DE, et al. J Clin Endocrinol Metab 2005

16 BMI Central obesity MS Total, F. testosterone & SHBG Allan CA & McLachlan RI. Curr Opin Endocrinol Diabetes Obes 2010 MacDonald AA et al. Hum Reprod Update 2010 Brand JS et al. Int J Epidemiol 2011

17 Obesity SHBG Total T Low total T Or SHBG Associated with T2D Corona G et al. Int J Androl Colangelo LA et al. Diabetes Care 2009.

18 Total T FT SHBG Stronger predictor of T2D FT is higher in diabetic men in comparison to non diabetic men. Corona G et al. Int J Androl

19 Bilateral orchidectomy or GRH agonist In old men with cancer prostate risk of T2D and CVD Keating NL, et al. J Natl Cancer Inst 2010.

20 Several studies confirmed association of Obesity T2D MS with sexual dysfunction including erectile dysfunction Diaz-Arjonilla M, et al. Int J Impot Res 2009

21 Pathophysiology of Men sexual Dysfunction

22 Angiotensinogen Adiponectin PAI-1 Metabolic syndrom e vascular damage Clinical relevance: Insulin resistance/ Endothelial Dysfunction Diabetes mellitus type2 Cardiovascular disease Stroke Erectile dysfunction Classical Hypogonadism Visceral obesity T- deficiency Hypothalamuspituitary GnRH LH - - IL-6 TNF Insulin Leptin - Lyedig Cell funtion Estradiol levels Aromatase activity in adiposity Complex multidirectional interactions between testosterone and obesity, metabolic syndrome, and type 2 diabetes mediated by cytokines and adipokines leading to comorbidities such as ED and increased CVD risk. FFA, free fatty acids; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; PAI-1, plasminogen activator inhibitor-1.

23 The clinical observation that ED occurs at an earlier age and with greater frequency in men with diabetes compared with non diabetic men is supported by multiple population-based epidemiological studies. Lindau ST, et al. Diabetes Care 2010

24 In the Look Ahead Study, 49.8% of men with diabetes reported mild or moderate ED. Rosen RC et al. J Sex Med 2009

25 There are few studies evaluating the prevalence of reduced libido in men with diabetes. Decreased sexual desire is primarily affected by the presence of ED and by depression.

26 These investigators found significantly lower serum bioavailable testosterone (P<0.006) and free testosterone (P<0.027) in men with ED. Kapoor D, et al. Int J Androl 2007.

27 ED in the past was ascribed to autonomic neuropathy or obliterative vascular disease; more recent studies identify endothelial dysfunction as an early abnormality that is potentially more amenable to therapy. Traish AM, et al. FEBS J 2009.

28 Men with T2D can have other causes of ED. In a study of 8,373 men with type 2 diabetes, ED was associated with: 1. Poor metabolic control 2. Smoking 3. Alcohol 4. Antidepressants 5. Anti-hypertensives 6. CVD medications 7. Histamine 2 receptor antagonists. Fedele D, et al. Int J Epidemiol 2000.

29 There are multiple causes for low libido in the general population and in men with type 2 diabetes in addition to testosterone deficiency, including medications: - SRI - Anti-androgen and Alcoholism Fedele D, et al. Int J Epidemiol 2000

30 Low testosterone, CVD risks, and type 2 diabetes

31 Low serum testosterone is associated with an increase in all-cause mortality that is independent of the metabolic syndrome and diabetes. Shores MM, et al. Arch Intern Med Khaw KT, et al. Circulation Haring R, et al. Eur Heart J Laughlin GA, et al. J Clin Endocrinol Metab 2008.

32 Low testosterone is associated with increased mortality in older men

33 Testosterone deficiency and CVD are both associated with visceral fat accumulation, metabolic syndrome, type 2 diabetes, increased inflammatory cytokines, hyperlipidemia, and abnormalities of coagulation. Maggio M, et al. Int J Impot Res 2009.

34 Low testosterone predicted the increased risk of CVD independent of age, obesity, hyperlipidemia, and lifestyle in men with or without type 2 diabetes. Khaw KT, et al. Circulation Haring R, et al. Eur Heart J Laughlin GA, et al. J Clin Endocrinol Metab 2008.

35 Insulin resistance commonly occurs in chronic heart failure, and it has been shown to improve with testosterone replacement therapy. Malkin CJ, et al. Eur J Heart Fail 2007.

36 A randomized double-blind crossover trial demonstrated a significant reduction in insulin resistance in hypogonadal men with type 2 diabetes. Kapoor D, et al. Eur J Endocrinol 2006.

37 The mechanisms by which testosterone improves insulin sensitivity is multifactorial and likely to be due to a combination of testosterone effects on liver, muscle, and adipose tissues and by reducing the production of inflammatory cytokines (e.g., TNF-a, IL-1b, and IL-6), which cause insulin resistance. Jones TH & Saad F. Atherosclerosis 2009.

38 This finding was confirmed in three further studies in men with metabolic syndrome and/or type 2 diabetes. Jones TH, et al. Diabetes Care Heufelder AE, et al. J Androl Kalinchenko SY, et al. Clin Endocrinol (Oxf) 2010.

39 Some beneficial effects of testosterone on important CVD risk factors, which include insulin resistance, glycemic control, lipid profile, central adiposity, body composition, and inflammatory state in hypogonadalmen with type 2 diabetes, as well as sexual health. Jones TH, et al. Diabetes Care 2011.

40 Clinical studies of testosterone replacement in men with obesity, metabolic syndrome, type 2 diabetes, and low testosterone concentrations

41 It is well known that testosterone replacement reduces body fat mass and waist circumference in hypogonadal men with and without obesity. Mårin P, et al. Obes Res Jones TH & Saad F. Atherosclerosis 2009.

42 The Look Ahead study reported that weight loss and increased physical activity were mildly beneficial in maintaining erections or improving ED in men with type 2 diabetes. Wing RR, et al. J Sex Med 2010.

43 Evidence from several studies demonstrated that testosterone promotes insulin sensitivity in hypogonadal men with and without type 2 diabetes. Mårin P, et al. Obes Res 1993.

44 The Testosterone Replacement in Older Men with either Metabolic Syndrome or Type 2 Diabetes (TIMES 2) trial recruited hypogonadal men with total testosterone <318 ng/dl (11 nmol/l) or free testosterone <6.5 ng/dl (225 pmol/l) and either metabolic syndrome or type 2 diabetes. Testosterone treatment improved libido Jones TH, et al. Diabetes Care 2011.

45 Leptin levels correlate with body fat content and have been shown to decrease with testosterone replacement in type 2 diabetes and the metabolic syndrome. Kalinchenko SY, et al. Clin Endocrinol (Oxf) Kapoor D, et al. Eur J Endocrinol 2007.

46 Testosterone treatment moderately improved the number of nocturnal erections, sexual thoughts and motivation, number of successful intercourse sessions, scores of erectile function, and overall sexual satisfaction in men with baseline serum testosterone <346 ng/dl (<12 nmol/l). Rochira V, et al. J Androl 2006.

47 Testosterone replacement can restore nocturnal erections in hypogonadal men, but the effects are greater when testosterone and a phospho-diesterase (PDE)-5 inhibitor are administered together.

48 ED in many men with diabetes is improved by one of the PDE-5 inhibitors when used on demand. Hatzichristou D, et al. Diabet Med 2008.

49 Testosterone replacement therapy has been reported to improve erections in men who did not respond satisfactorily to a PDE-5 inhibitor alone. Rochira V, et al. J Androl 2006.

50 Testosterone therapy results in a small but significant fall in total cholesterol and in some LDL cholesterol. HDL cholesterol may fall, rise, or remain unchanged. There is some evidence that after an initial decrease, HDL cholesterol levels then return to baseline. Jones TH, et al. Diabetes Care Kapoor D, et al. Eur J Endocrinol Jones TH & Saad F. Atherosclerosis 2009.

51 Conclusions Obesity is accompanied by increased adipokines, cytokines, and other proinflammatory factor production from adipocytes and macrophages mainly in visceral fat. These factorsmay alter insulin responsiveness in fat, liver, muscle, and endothelial function resulting in metabolic syndrome, type 2 diabetes, ED, and CVD.

52 Conclusions Many men with type 2 diabetes, especially those who are obese, have low serum total testosterone and SHBG levels. Small-scale studies of testosterone treatment in men with metabolic syndrome or type 2 diabetes and borderline low or normal testosterone levels showed small improvement in glycemic control

53 Conclusions It is important for the clinician to recognize that low testosterone and sexual dysfunction are commonly found in patients with obesity, metabolic syndrome, and type 2 diabetes.

54 Take Home Message : It should be known to all medical specialists that obesity,ms and type 2 diabetes is associated with sexual dysfunction due to decreased total and free testosterone Testosterone replacement, in addition to diet, exercise, glycemic control, and PDE-5 inhibitors, should be considered in symptomatic hypogonadal men with type 2 diabetes and serum testosterone below the reference range.

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