Introduction

3. Hormonal Disturbance and Sexual Performance affection in Chronic Liver Diseases

4. Introduction • Liver has a major role in sex hormone metabolism. Liver insults may have an underappreciated effect on the health of population by compromising hormone status, particularly sex hormones. • Androgens reduce hepatic synthesis of SHBG while estrogens stimulate SHBG synthesis. Also hepatitis and aging increase circulating SHBG concentrations while obesity and diabetes decrease circulating SHBG. All of these factors affect the amount of circulating sex hormones.

5. Erectile dysfunction • Erectile dysfunction (ED) is a problem in patients with chronic liver diseases leading to worsening of health related quality of life (HRQoL) in those patients. The national institutes of health defined ED as the inability to achieve or maintain an erection sufficient for satisfactory sexual performance. • ED is a multifactorial disorder.

6. Mechanisms of action of testosterone on erectile function

7. NO plays an important role in liver biology as it has cytoprotective effects on hepatocytes by activating guanylyl cyclase which lead to cGMP synthesis. Also by induction of stress proteins as Hsp70 which protect against apoptosis.

8. Chronic Viral Hepatitis C(HCV) • HCV has a profound effect on HRQoL. Men with chronic HCV infection have markedly reduced sexual function compared to HCV-uninfected controls. • Plasma levels of total testosterone and free testosterone levels were lower in HCV-positive patients than in age matched controls, and the HCV patients with ED had significantly lower testosterone levels than those with normal sexual function. • HCV itself appears to play a causative role in causing erectile dysfunction

9. Sexual health indicators in men, as: low desire,erectile dysfunction, ejaculatory problems, and overall sexual dissatisfaction, are common during treating chronic hepatitis C with peginterferon and ribavirin “interferon associated libido loss”. • Decline in sexual health tend to be reversible when the therapy is stopped after maintained therapy for only 24 weeks, the reversal of that decline is not always complete and is less for those receiving the full 48 weeks course of therapy.

10. Chronic Viral hepatitis B (HBV) • HBV male patients’ compared to healthy (control) males of the same age had markedly lower IIEF-5 score and higher incidence of ED compared with controls. • HBV patients have ED in different degrees according to the severity of the disease. • Sex hormones could affect HBV transcription and replication as androgen receptors could bind directly to HBV genome, via enhancer I, to increase HBV transcription and replication. On the other hand, female estrogen receptor are able to down regulate HBV gene transcription, through remodeling the viral genome.

11. Nonalcoholic Fatty Hepatitis (NASH) • MS is composed of a clustering of metabolic risk factors in one individual as:abdominal obesity, high blood pressure, and high FBG, high HTG, and low HDL-C levels. NASH is the hepatic component of metabolic syndrome. • Testosterone plays a major role affecting the components of MS asandrogens tend to decrease lipoprotein lipase and up-regulate of β adrenergic receptors on adipocytes. The prevalence of low TT levels among men with ED and MS is four times as high as that among patients have MS without ED. • Higher serum levels of leptin were found in patients with NAFLD compared with controls. Leptin levels are inversely correlated with Testosterone so excess circulating leptin may be an important factor that leads to reduced androgens causing ED in males.

12. Relationship between hypogonadism, obesity and insulin resistance

13. There is an inverse relationship between blood pressure and serum testosterone. • Mechanism of testosterone affecting blood pressure: • Testosterone increases and strengthens the cardiac muscle mass and makes it more resistant to death during ischemia so improves cardiac output and thus improves blood pressure. • Genetic link between hypertension and serum testosterone levels found in men with family history of hypertension as they have lower testosterone levels. • HTGweaken vascular endothelial response, with significant decrease in NO production by reducing the neuronal NO-mediated cavernosal filling pressure. These changes were manifested as performance dysfunction in the sexual behavioral studies.

14. The link between elevated ROSlevels and ED has been established. NADPH oxidase causes excessive OS through overproducing ROS in the penis, and consequently induces ED. • SHBG is inversely related to IR, MS is a reflection of IR so, SHBG seem to be a good risk marker for the MS.

15. Alcoholic Liver Diseases • There are some controversies about the effect of alcohol on sexual function. In heavy alcohol consumption, the effect on erectile function might be irreversible because of the neurologic damage occurred. • Primary Gonadal dysfunction resulted from: • Direct toxic effect of ethanol and acetaldehyde on the gonads • Inhibition of LH binding to the Leydig cells. • Inhibition of the intratesticular activation of vitamin A • Hypothalamic-pituitary hypogonadism also results from direct toxic effect of ethanol as well as from the increasing concentrations of estrogens in the plasma.

16. Some researchers found no relation between alcohol consumption and ED. On the other hand others suggested that consumption of 8 or more drinks/week might significantly reduce the risk of ED. • Alcoholic men often show phenotypic changes due to inappropriate hormone balance, showing low serum testosterone and elevated estrogen levels. Decreased serum testosterone is due to alcohol itself and its metabolites toxicity to the testes which occurs early in alcohol intake, whereas increases in estrogen levels are evident after longer periods of alcohol intake, thus hypogonadism precedes liver feminization .

17. Hemochromatosis • Hypogonadism is caused by different mechanisms: • Direct iron deposition in the testes leading to testicular atrophy and hypogonadism. • Iron deposition in the anterior pituitary gland in 68% of HH cases. Also iron deposition in the gonadotrophic cells and in other secretory cells within the gland. • Decreased response of serum gonadotropins to GnRH stimulation caused secondary hypogonadism in 46% of HH patients. • Hypogonadism in HH was believed to be irreversible but due to consequent venesection therapy, levels of ferritin and transferrin could be normalized, and levels of LH and FSH could be increased to normal ranges.

18. Wilson’s disease • About 40% of the Wilson’s disease cases can be presented by hepatic manifestations while less than 10% of the patients can be presented by heart, kidney, bones and hormonal disorders. • Hepatic involvement can vary from asymptomatic to cirrhosis. Hypogonadism is mostly rare in men with Wilson’s disease

19. Cirrhosis • Sexual dysfunction in cirrhotic men comprises signs of -hypogonadism -feminization. • Hypogonadism: • Reduced production of albumin may affect the ratio of FT to albumin-bound testosterone, as well as TT amount. • Physical disturbance caused by protein malnutrition in cirrhotic patients. • Hypothalamic–pituitary– gonadal axis affected by reducing the pulsatile secretion of LH and the response to GnRH. • Estrogen/androgen ratio is usually increased. Testosterone and dihydroepiandrosterone levels are reduced, while the estradiol levels are normal or slightly elevated.

20. The mechanism of feminization: SHBG is significantly increased in patients with liver cirrhosis compared with healthy subjects. Serum FT and T/SHBG ratio decrease, while serum estrogen (E2), free E2, and the E2/T ratios increase, resulting in estrogen predominance and feminization of male patients. • 30% of cirrhotic men had erectile dysfunction before implantation of transjugular intrahepatic portosystemic stent shunt (TIPS) , whereas 70% demonstrated ED after TIPS as increased systemic estrogen levels suppress LH leading to decreased testosterone levels causing hypogonadism .

21. Hepatocellular Carcinoma( HCC) • Some studies showed that both estrogens and androgens affect the replication rate of hepatic cells which induce or at least promote the growth of HCC. • People diagnosed with HCC reported higher levels of sexual dysfunction secondary to multiple factors as: • Neuroendocrine changes due to related disease- or treatment; changes in body image ,gynecomastia, cachexia, and ascites. • Co-morbid medical conditions that may increase sexual morbidity (e.g., diabetes, HTN) • Medications that include sexual side effects (e.g., narcotics, antidepressants , hypertension medications, …..). • The psychological distress associated with poor prognosis.

22. The reason for the predominance of HCC in males remains unknown, but sex hormones may contribute to this phenomenon. Serum FT appeared to be associated with increased risk for HCC. The prevalence of most causes of HCC as HCV infection, hemochromatosis, alcohol consumption and cigarette smoking are more in males than females. • Diagnosis of cancer has been found to be associated with higher rates of sexual dysfunction compared with the general population. • Patients with HCC reported much higher rates of sexual problems compared with general population, including male erectile disorder (17% vs. 11%) .

23. Hormonal disturbance and sexual performance affection before and after liver transplantation • Liver transplantation is performed not only to ensure the patient's survival but also to improve all aspects of his life including the improvement of all sexual function domains. • Before liver transplantation, sexual dysfunction and sex hormone disturbances are mainly due to abnormality in the hypothalamic-pituitary-gonadal axis or origin of liver disease. • Many long-term condition in the majority of patients remained after LT causing ED as ED is multifactorial. • The extent of improvement of the erectile function after LT has been a controversial issue .

24. Diagnosis

26. Risk factors causing ED

28. Treatment First line therapy Medical: Oral Phosphodiesterase Type 5 (PDE5) Inhibitor Second line therapy • Intracavernosal injection: of Alprostadil alfadex. • Intraurethral injection: of Alprostadil alfadex. • Vacuum constriction devices. Third line therapy Penile prosthesis

30. The Use of Oral Phosphodiesterase Type 5 (PDE5) Inhibitors

31. PDE5-Is in chronic liver diseases • Sildenafil safety profile in impaired hepatic function men with ED found to be similar to those with no impairment of hepatic function. Sildenafil is well tolerated as it has a relatively short half-life (4–5 h) and is administered as needed in a maximum of one dose per day. • There are some controversies about the effect of sildenafil on patients with cirrhosis and portal hypertension.Some described acute variceal bleeding after administration of 25 mg sildenafil.While, others reported a decrease in portal and sinusoidal resistance after inhibition of PDE-5 patients in Child A liver cirrhosis . sildenafil, at low doses seem to have a great effect on the hemodynamic state of the liver. Also it slightly affects the systemic hemodynamic parameters. • These results show potential use of PDE-5 inhibitors in treatment of portal hypertension.

32. Managing failure of PDE5-I in treatment of ED

33. Herbal Viagra • There is a growing demand for herbal treatments for ED. Controversies about the efficacy of these herbal supplements have been reported as limited data support the efficacy and safety of the herbal ingredients such as yohimbine, ginseng and Gingko biloba for the treatment of ED. • Yohimbine, a herb derived from a tree found in Africa, has been used in the treatment of ED, but is contraindicated in patients with cardiovascular and neurological disease and causes many side effects including headaches, sweating and hypertension .

34. Red ginseng is one of the most widely used herbal remedies. It is used to enhance sexual function. Possible mechanisms of action ofred ginseng include hormonal effects similar to those of testosterone as it might induce relaxation of the smooth muscles of the corpus cavernosum via NO pathway . • In the United States, April 2003, the Food and Drug Administration (FDA) discovered that tablets marketed as “all-natural herbal products”(Vinarol) contained sildenafil. Also in Canada, the Chinese herbal preparation ‘HuaFo’ was also found to contain a compound have the same chemical composition of sildenafil .

35. Thank You