Download Hormonal Disturbance and Sexual Performance affection in Chronic


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
performance.

ED is a multifactorial disorder.
sexual
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 upregulate 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:
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
1)
2)
3)

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 .

1)
2)
3)

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.

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.
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.
2)
3)
4)

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 .


1)
2)
3)
4)
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.

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%) .
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 .
Risk factors causing ED
Disease
Depression: low desire in 50–60%
untreated patients
Pathophysiology of ED
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 Fear of using (PDE5i) in case of nitrate requirement.
*present in 44–65% of ageing men Concomitant depression in more than 50% of patients.
with CVD. In cardiac failure, ED Low motivation to trigger desire or act upon it because of fear of further MI
may affect up to 80% of men,
* After MI, many men (10–54%)
decrease sexual activity or do not
resume it
lower urinary tract symptoms
Renal failure:
*Due to increased smooth-muscle tone, reduced NO in nerves and fibrosis
of penile tissue , seen in 20 % of cases with these symptoms
low desire in 45-100% of uremic *Low testosterone in men: Leydig cell high LH and FSH levels and GnRH
patients and in those undergoing reduced
*Co-morbid depression
haemodialysis
*Low zinc levels
*Anemia of renal failure
Diabetes:
49% of men with type 2 diabetes
over the age of 66 have ED
Metabolic syndrome.
Hypogonadism
Adrenal disease.
Neurological and
Cerebrovascular disease.
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.
Endothelial dysfunction and down-regulation of NOS
Lack of testosterone affects brain processing of sexual stimuli.
Lack of precursor sex hormones
Direct damage to regions involved in processing sexual stimuli, vascular
disorders, depression, physical disability or adverse effects of drug
Drugs
Antipsychotics in patients with
schizophrenia cause low desire in 50–
73%
Pathophysiology of ED
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-selective
β blockade
Immunomodulants
Interferon ∞
Antidepressants: SSRIs can
cause low desire in 30–50% of men Stimulation 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.
Treatment
First line therapy
Medical: Oral Phosphodiesterase Type 5 (PDE5) Inhibitor
Second line therapy
1.
Intracavernosal injection:
2.
Intraurethral injection: of Alprostadil alfadex.
Vacuum constriction devices.
3.
of Alprostadil alfadex.
Third line therapy
Penile prosthesis
Review of Literature
The Use of Oral Phosphodiesterase Type 5 (PDE5)
Inhibitors
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
Yes
No
Do not use
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.
Effective
Ineffective
Increase to higher dose
Effective
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)
Ineffective
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
Continue next algorithm

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.

Review of Literature
Managing failure of PDE5-I in treatment of ED
Failure of PDE5 inhibitor
Refer to specialist
Assessment of cause of failure
Reversible cause
Incorrect use of drug or
non-compliance
Patient education
and retrial of oral
drug with follow-up
Irreversible or non-identifiable cause
Incorrect
dosage
Retrial of oral therapy
with dose optimization
with follow-up
Penile prosthesis
Identification of
Comorbidities
Appropriate investigations, patient
education, and modification or
treatment of co-morbidity with
continued PDE5 inhibitors
Failure of medical
Possible psychological
components
Start counselling, with
possible referral to sex
therapist and follow-up
Hypogonadism
Combination of
PDE5 inhibitor
and testosterone
Penile injection
Vacuum constriction device
Daily PDE5 inhibitor
Combination of:
- PDE5 inhibitor + intracavernosal injection
- PDE5 inhibitor + intraurethral alprostadil
- PDE5 inhibitor + vacuum constriction device

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 .