بسم الله الرحمن الرحيم

1. بسم الله الرحمن الرحيم

2. By Doaa Hegab Ass. Lecturer of dermatology & venereology Metabolic syndrome & infertility

3. Metabolic syndrome is a combination of medical disorders that increase the risk of developing cardiovascular disease and diabetes. • It affects one in five people, and prevalence increases with age. Some studies estimate the prevalence in the USA to be up to 25% of the population. • Metabolic syndrome is also known as metabolic syndrome X, syndrome X, insulin resistance syndrome andReaven's syndrome.

4. Etiology • The exact pathophysiology is extremely complex and has been only partially elucidated. Most patients are older, obese, sedentary, and have a degree of insulin resistance. Stress can also be a contributing factor. The most important factors are: • weight • genetics • aging • sedentary lifestyle, i.e., low physical activity and excess caloric intake. • Stress • A number of markers of systemic inflammation, including C-reactive protein, are often increased, as are fibrinogen, interleukin 6 (IL–6), Tumor necrosis factor-alpha (TNFα), and others.

5. Symptoms and features 1) Fasting hyperglycemia — diabetes mellitus type 2 or impaired fasting glucose, impaired glucose tolerance, or insulin resistance 2)High blood pressure 3)Central obesity (also known as visceral, male-pattern or apple-shaped adiposity), overweight with fat deposits mainly around the waist 4)Decreased HDL cholesterol 5)Elevated triglycerides Associated diseases and signs are: hyperuricemia, fatty liver (especially in concurrent obesity) progressing to non-alcoholic fatty liver disease, polycystic ovarian syndrome (in women), and acanthosis nigricans.

6. The various components of the NCEP ATP III and IDF definitions of the metabolic syndrome in men IDF, International Diabetes Federation (1999). NCEP ATP III, National Cholesterol Education Program—Adult Treatment Panel III (2001).

8. Hypogonadism • The standard definition of hypogonadism by the FDA and the Endocrine Society is a total T value <300 ng/dL (<10.4 nmol/L). • This test is typically ordered in the morning hours, when levels are highest. • Normal total testosterone levels range from 300 -1000ng/dl • Treatment is often prescribed for total testosterone levels below 350 ng/dl

9. Obesity and Infertility

10. Obesity is a cardinal feature of MetS. • Adverse effects of obesity on male fertility are postulated to occur through several mechanisms: • 1-Peripheral aromatization of testosterone to estrogen in excess peripheral adipose tissue may lead to secondary hypogonadism through hypothalamic-pituitary-gonadal axis inhibition. • 2- Oxidative stress at the level of the testicular microenvironment may result in decreased spermatogenesis and sperm damage. • 3- The accumulation of suprapubic and inner thigh fat may result in increased scrotal temperatures in severely obese men.

11. Leptin 1 Conversion of T to E 3 2

12. Disturbed hypothalamic-pituitary-gonadal axis in obese men with resultant significant depression in total testosterone and sex hormone–binding globulin. • Negative correlation between free testosterone & body mass index. • SHBG is especially relevant in obese males who are insulin resistant, as insulin is known to inhibit SHBG synthesis. • In summary, total testosterone, free testosterone, and SHBG are all commonly decreased in obese males

13. follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were normal or low in obese men. • LH pulse amplitude, but not pulse frequency, is decreased in obese men with hypogonadism. • It has been suggested that waist circumference is better at predicting T levels than is body mass index (BMI) • (Svartberg et al, 2004).

14. Obesity is associated with increased plasma levels of leptin, the obese gene product secreted from adipocytes. • Circulating leptin correlated inversly with total and free testosterone even after controlling for SHBG, LH and oestradiol and leptin is the best hormonal predictor of lower androgen levels in obese men. • Leptin receptors are present in testicular tissue and leptin may play a role in reduced androgen levels in obese men. • Elevated leptin levels in obese individuals interfere with luteinizing hormone/human chorionic gonadotropin stimulation of androgen production, thereby decreasing androgen levels.

15. Thus, the observed decrease in testosterone levels in obese males is likely due to several factors, including: • Decreased synthesis of testosterone • Inhibition of SHBG synthesis • Decreased gonadotropin secretion

16. A paradigm in which obesity is negatively correlated with NMS and positively correlated with sperm DNA damage. • Semen volume was negatively correlated with both waist circumference and W/H ratio. • Total sperm count was negatively correlated with weight, waist circumference, and hip circumference. • Total motile sperm was negatively correlated with weight, waist circumference, and hip circumference. • Total rapid progressive motile sperm count was negatively correlated with hip circumference and waist circumference.

17. Numerous authors have noted that MetS is associated with systemic proinflammatory states and increased oxidative stress with lipid peroxidation. (Dandona et al, 2005; Davi and Falco, 2005) • The elevated DNA Fragmentation Index (DFI) noted in obese men reflects an abnormally increased oxidative state in the testicular microenvironment and excurrent ductal system.

18. In addition to the molecular and hormonal changes in obesity, gross mechanical causes may also play an important role in impairing male reproductive health. • Suprapubic and thigh fat have been postulated by some investigators to cause elevated scrotal temperatures, thus decreasing fertility.

19. scrotal lipomatosis to characterize abnormally distributed scrotal fat present along the spermatic cord and testes. • Scrotal lipectomy???? • Varicocele with obesity????

20. Diabetes and Infertility

21. 1 2 3 semen Volume & concentration of the ejaculated sperm. ED failure of emission retrograde ejaculation

22. Hypogonadism is a risk factor for diabetes. • Hypogonadism is predictive of subsequent development of NIDDM, the underlying pathophysiology has not been fully established. Insulin resistance may indeed be a common etiology for both hypogonadism and onset of NIDDM. • Higher rates of hypogonadism in men with previously diagnosed NIDDM. • Increasing insulin resistance was associated with decreased testosterone secretion at the testicular level (Leydig cell) and was not due to changes in hypothalamic or pituitary function.

23. Possible therapeutic role for testosterone in men with NIDDM and hypogonadism, with improvement in numerous metabolic deficiencies in comorbid patients. • NIDDM with neuropathy reported a higher sperm concentration and lower sperm motility compared with diabetic men without neuropathy and controls due to decreased seminal secretion and an overall concentration of the ejaculated sperm.

24. Erectile dysfunction (ED), failure of seminal emission, and retrograde ejaculation are known complications of NIDDM that have an impact on male reproductive potential. ED in patients with NIDDM could be due to autonomic neuropathy or vascular disease, and ED severity is increased with worsening NIDDM. Failure of emission and retrograde ejaculation also result from autonomic neuropathy, with an estimated 32% of men with DM affected by some degree of ejaculatory dysfunction.

25. Dyslipidemia and Infertility

26. Dyslipidemia (isolated hypercholesterolemia, triglyceridemia, or both) is another sentinel feature of MetS that may have an impact on semen quality and fertility. Oxidative stress in the testes and/ or ductal system could be the major relationship between lipid abnormalities & decreased fertility. Decreased fertility with high-cholesterol diet & therapeutic gain in fertility with antioxidant and lipid-lowering agents. Total testosterone, free testosterone, and SHBG were also found to be directly correlated with HDL levels.

28. Hypertension and Infertility

29. Hypertension (HTN) represents a major risk factor for cardiovascular disease and for ED, but its direct effect on male fertility, if any, is not well understood. • End-organ damage is a well-documented aspect of hypertension, but to date, testicular end-organ injury caused by HTN has not been clearly defined. • Significant inverse relationship between blood pressure and total serum testosterone, free testosterone, and SHBG. • Androgen deficiency may be the root cause of HTN by inducing increased arterial stiffness

30. Androgen deprivation in men with prostate cancer could induce hypertension and arterial stiffness, even after only several months. Smith et al (2006)

31. Significant positive correlation between MetS and the inflammatory marker CRP.

32. MetS and Sexual Dysfunction

33. MS and erectile dysfunction are related, because the same risk factors are seen in both conditions. • 96.5% of the men with MS had erectile dysfunction. • Corona et al (2006) • Low T in men with MS was also related to other sexual symptoms, such as hypoactive sexual desire and decreased frequency of sexual intercourse, and depressive symptoms, although it was not certain whether these were primary or reactive to the sexual issues.

35. Makhside (2005) suggested the addition of hypogonadism to the constellation of aberrations seen in MetS.

36. Could Treatment of Hypogonadism Help to Correct Components of MS? • T therapy in men with androgen deficiency improves energy, body composition, and a number of other abnormalities. • Correcting the hypogonadism associated with insulin resistance and MS might correct some or all its components. • T replacement rapidly increased insulin sensitivity within a few days when used for hypogonadism in diabetic men, with improvement in a number of metabolic parameters related to MS, including fasting glucose, fasting insulin, HbA1C, and weight.

37. Saad et al (2008) compared the results of T treatment in elderly men with late onset hypogonadism with either a T gel or a long-acting injection. Both treatment parameters aided sexual symptoms and also improved waist circumference and several lipid parameters, with a trend toward lowering blood pressure. • Allen et al (2008) showed that T replacement therapy for a year selectively lessened visceral fat accumulation, the fraction that best correlates with cardiovascular risk.

39. Phosphodiestrases • The cyclic nucleotide phosphodiesterases (PDE) comprise a group of enzymes that degrade the phosphodiester bond in the second messenger molecules cAMP and cGMP. • They regulate the localization, duration, and amplitude of cyclic nucleotide signaling within subcellular domains. PDEs are therefore important regulators of signal transduction mediated by these second messenger molecules.

40. The PDE superfamily of enzymes is classified into 11 families, namely PDE1-PDE11.

42. For PDE1, the order of selectivity is: tadalafil> vardenafil> sildenafil. Nonselectivity of PDE5 inhibitors with respect to all PDE1 subtypes may induce vasodilatation, flushing, and tachycardia.

43. PDE5 inhibitors may also indirectly inhibit PDE3 by increasing cyclic cGMP levels, thereby elevating heart rate and vasodilation while inhibiting platelet aggregation.

44. For PDE6, the order of selectivity is: tadalafil> vardenafil ≈ sildenafil. PDE6 is only expressed in the retina and plays a decisive role in signal transduction of vision. Inhibition of this enzyme can induce visual disturbances, which have occurred at the highest clinically applied dose of sildenafil and to a lesser extent with vardenafil. No visual disturbances have been reported with tadalafil use.

45. For PDE11, the order of selectivity is: sildenafil> vardenafil> tadalafil. Musculoskeletal pain, in particular back pain, has been reported during therapy for erectile dysfunction (ED) with PDE5 inhibitors. The effects are more significant with tadalafil than with sildenafil or vardenafil.

46. Thanks