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.

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.

Mechanisms of action of testosterone on erectile function

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.

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

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.

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.

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 as androgens 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.

There is an inverse relationship between blood pressure and serum testosterone.

Mechanism of testosterone affecting blood pressure:

1) 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.

2) Genetic link between hypertension and serum testosterone levels found in men with family history of hypertension as they have lower testosterone levels.

HTG weaken 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.

The link between elevated ROS levels 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.

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:1) Direct toxic effect of ethanol and acetaldehyde on

the gonads 2) Inhibition of LH binding to the Leydig cells. 3) 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.

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 .

Hypogonadism is caused by different mechanisms:

1) Direct iron deposition in the testes leading to testicular atrophy and hypogonadism.

2) 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.

3) 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.

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

Sexual dysfunction in cirrhotic men comprises signs of -hypogonadism -feminization.

Hypogonadism:1) Reduced production of albumin may affect the ratio

of FT to albumin-bound testosterone, as well as TT amount.

2) Physical disturbance caused by protein malnutrition in cirrhotic patients.

3) Hypothalamic–pituitary– gonadal axis affected by reducing the pulsatile secretion of LH and the response to GnRH.

4) Estrogen/androgen ratio is usually increased. Testosterone and dihydroepiandrosterone levels are reduced, while the estradiol levels are normal or slightly elevated.

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 .

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:

1) Neuroendocrine changes due to related disease- or treatment; changes in body image ,gynecomastia, cachexia, and ascites.

2) Co-morbid medical conditions that may increase sexual morbidity (e.g., diabetes, HTN)

3) Medications that include sexual side effects (e.g., narcotics, antidepressants , hypertension medications, …..).

4) The psychological distress associated with poor prognosis.

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%) .

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 .

Hormonal disturbance and sexual performance affection before and after liver transplantation

DiseasePathophysiology of ED

Depression: low desire in 50–60% untreated patients

Neurotransmitters of frontal limbic circuitry thought to be affected in depression. Indirect mechanism via sleep disturbance, low self image, despair, alcohol withdrawal

Coronary artery disease, myocardial infarction, or both *present in 44–65% of ageing men with CVD. In cardiac failure, ED may affect up to 80% of men,* After MI, many men (10–54%) decrease sexual activity or do not resume it

Fear of using (PDE5i) in case of nitrate requirement.Concomitant depression in more than 50% of patients.Low motivation to trigger desire or act upon it because of fear of further MI

lower urinary tract symptomsRenal failure:low desire in 45-100% of uremic patients and in those undergoing haemodialysis

*Due to increased smooth-muscle tone, reduced NO in nerves and fibrosis of penile tissue , seen in 20 % of cases with these symptoms*Low testosterone in men: Leydig cell high LH and FSH levels and GnRH reduced *Co-morbid depression *Low zinc levels *Anemia of renal failure

Diabetes: 49% of men with type 2 diabetes over the age of 66 have ED

Neuropathy, endothelial dysfunction and smooth-muscle changes. Low NO is common in ageing diabetic men which is important for relaxation of penile smooth-muscle and necessary for engorgement of the penis during erection.

Metabolic syndrome. Endothelial dysfunction and down-regulation of NOSHypogonadismLack of testosterone affects brain processing of sexual stimuli.Adrenal disease. Lack of precursor sex hormones

Neurological andCerebrovascular disease.

Direct damage to regions involved in processing sexual stimuli, vascular disorders, depression, physical disability or adverse effects of drug treatment

Risk factors causing ED

DrugsPathophysiology of ED

Antipsychotics in patients withschizophrenia cause low desire in 50–73%

Traditional antipsychotics and risperidone via reduced dopamine and increased prolactin, α-blockade, and muscarinic blockade.

Antihypertensive: when compared with ACE inhibitors and angiotensin II antagonists, β blockers reduce desire in men.

Probably applies to agents with selective and non-selectiveβ blockade

Immunomodulants

Interferon ∞

Antidepressants: SSRIs can cause low desire in 30–50% of menStimulation of serotonin receptors including 5HT3 receptors

Anti-androgens: GnRH agonists, flutamide, cyproterone acetate, spironolactone in high doses.

Suppression of GnRH, or LH, or antagonism of androgen receptor, or combination of these factors.

TreatmentFirst line therapy

Medical: Oral Phosphodiesterase Type 5 (PDE5) Inhibitor

Second line therapy1. Intracavernosal injection: of Alprostadil

alfadex.

2. Intraurethral injection: of Alprostadil alfadex.

3. Vacuum constriction devices.

Third line therapyPenile prosthesis

Review of Literature

Yes No

Patient with erectile dysfunction requests therapy with a PDE5 inhibitor

Any contraindications?

High or intermediate risk of coronary artery disease Nitrate use Retinitis pigmentosa Nonarteritic anterior ischemic optic neuropathy

Initial dose Start patient with middle dose of chosen medication (50 mg of

sildenafil, 10 mg of tadalafil, or 10 mg of vardenafil). Instruct patient to take medication approximately 1–2 hr before

anticipated sexual activity. Best results are obtained by the stimulation of endogenous nitric

oxide with psychic (fantasy) and physical (penile) stimulation. Medications should not be used more than once per 24 hr.

Do not use

Effective

Ineffective

Increase to higher dose

Patient may require a lower dose if there are side effects.

Common side effects are headache, flushing, dyspepsia, gastrointestinal symptoms, and nasal congestion, plus visual abnormalities and rash (especially for sildenafil) and back pain or myalgia (especially for tadalafil)

If patient does not have a response, consider:

A trial of medication on at least 6 different days at the maximal dose

Use of medication at least 2 hr after a meal especially for sildenafil and vardenafil)

Unrecognized hypogonadism

Effective Ineffective

Continue next algorithm

The Use of Oral Phosphodiesterase Type 5 (PDE5) Inhibitors

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.

Managing failure of PDE5-I in treatment of ED

Review of Literature

Failure of PDE5 inhibitor Refer to specialist

Reversible cause

Incorrect use of drug or non-compliance

Irreversible or non-identifiable cause

Possible psychological components

Incorrect dosage

Identification of Comorbidities

Combination of PDE5 inhibitor and testosterone

Hypogonadism

Assessment of cause of failure

Patient education and retrial of oral

drug with follow-up

Retrial of oral therapy with dose optimization

with follow-up

Start counselling, with possible referral to sex therapist and follow-up

Appropriate investigations, patient education, and modification or treatment of co-morbidity with

continued PDE5 inhibitors

Penile injection Vacuum constriction device Daily PDE5 inhibitor Combination of: - PDE5 inhibitor + intracavernosal injection - PDE5 inhibitor + intraurethral alprostadil - PDE5 inhibitor + vacuum constriction device

Failure of medical

Penile prosthesis

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 .

Red ginseng is one of the most widely used herbal remedies. It is used to enhance sexual function. Possible mechanisms of action of red 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 ‘Hua Fo’ was also found to contain a compound have the same chemical composition of sildenafil .