Conversion of androgens to estrogens in cirrhosis of the liver.

Gordon GG, Olivo J, Rafil F, Southren AL. Abstract
The contribution, by peripheral conversion, of androstenedione and testosterone to the circulating estrogens was determined in men with cirrhosis of the liver. The conversion ratio of androstenedione to estrone, estradiol and testosterone and the conversion ratio of testosterone to estrone (but not estradiol) and androstenedione were significantly increased. The plasma concentrations of androstenedione and testosterone were increased and decreased respectively; the mean plasma concentration of androstenedione being similar to that found in normal women. The metabolic clearance rate of androstenedione was not altered in cirrhosis although the metabolic clearance rate of testosterone was decreased. The production rate of androstenedione was elevated while that of testosterone was reduced. The instantaneous contribution of plasma androstenedione to estrone and estradiol was increased in cirrhosis as was the contribution of testosterone to estrone (but not to estradiol). Thus the increased estradiol levels in cirrhosis result, in large part, from increased peripheral conversion from the androgens. The percent contribution of plasma testosterone to plasma androstenedione was decreased although the absolute amount derived by conversion was normal. The percent contribution of plasma androstenedione to plasma testosterone was increased sevenfold in cirrhosis. The fraction of the daily androstenedione production derived from the plasma testosterone pool was not significantly altered. However, a significant fraction of the daily production rate of testosterone was derived from androstenedione. Thus, 15% of the circulating testosterone is not secreted but is derived by peripheral conversion from androstenedione. Normal levels of gonadotropins were found in cirrhosis.

Can Cirrhosis Cause Low Testosterone?
Numerous studies published since the 1970s have highlighted the link between hypogonadism and cirrhosis of the liver. The general consensus is that when the liver does not function optimally, being one of the body’s major organs, the person cannot manufacture enough low testosterone to stay healthy. Additionally, alcohol itself has a negative effect on testosterone production, and can also play a role in lowering levels, as well as cause cirrhosis, but it is not always possible to differentiate between the damage caused by each of the factors. Low testosterone as a result of cirrhosis is likely to manifest in a number of uncomfortable side effects, and in order to protect your quality of life, you need to find a professionalTestosterone Replacement Las Vegas clinic to find the best way to make life more comfortable. In patients who have cirrhosis low testosterone impacts on the reproductive system in profound ways. Sufferers report a lower libido, reduced testicle size, erectile dysfunction and infertility. In men who suffer from cirrhosis and have had their testosterone levels monitored, higher levels of estrogen were also picked up. Numerous tests have also proven that the body does not respond to low levels by increasing its production of FSH (follicle stimulating hormone) and LH (luteinizing hormone), indicating the problem lies within the endocrine system. Levels of low testosterone and the severity of its effects on the body have also been found to correspond directly with the severity of the cirrhosis the person has. In another study, cirrhosis sufferers showed a decreased level of testosterone in response to hCG hormone, leading medical experts to believe that hypogonadism is a primary effect of cirrhosis.

only a small amount of blood is supplied to the liver by arteries. and you need to get professional help from a Las Vegas Testosterone Therapy clinic to improve your quality of life. viruses. The main vein that returns blood from the intestines is called the portal vein. and they must have an intimate relationship with the blood since the substances that are added or removed by the liver are transported to and from the liver by the blood.While the side effects of low testosterone as a result of cirrhosis seem to impact directly and markedly on the sexual function of the person in question. Once the blood has passed through the sinusoids. toxic metals (such as iron and copper that accumulate in the liver as a result of genetic diseases). there is a big chance that it will impact on your testosterone levels. a lower muscle mass and increased amount of body fat and mood disorders like depression. In fact. for example. The tiniest veins (called sinusoids because of their unique structure) are in close contact with the liver cells. clotting proteins that are necessary in order for blood to clot. which returns the blood to the heart. This results in clusters of newly-formed liver cells (regenerative nodules) within the scar tissue. The liver also has an important role in regulating the supply of glucose (sugar) and lipids (fat) that the body uses as fuel. two of which are producing substances required by the body. It performs many critical functions. Why does cirrhosis cause problems? The liver is an important organ in the body. the liver cells must be working normally. As the portal vein passes through the liver. after which the inflammation and repair that is associated with the dying liver cells causes scar tissue to form. it breaks up into increasingly smaller and smaller veins. the liver cells line up along the length of the sinusoids. and removing toxic substances that can be harmful to the body. which could be further exacerbated after a history of excessive alcohol intake. The relationship of the liver to the blood is unique. The diseases that lead to cirrhosis do so because they injure and kill liver cells. There are many causes of cirrhosis including chemicals (such as alcohol. and certain medications). . especially over the long term. drugs. The liver cells that do not die multiply in an attempt to replace the cells that have died. If cirrhosis affects your life. Unlike most organs in the body. In order to perform these critical functions. This close relationship between the liver cells and blood from the portal vein allows the liver cells to remove and add substances to the blood. Men with low testosterone are likely to suffer from general fatigue and lethargy. the hepatic vein. it is collected in increasingly larger and larger veins that ultimately form a single vein. fat. and autoimmune liver disease in which the body's immune system attacks the liver. and alcohol abuse is one of the causes of infertility in men. for example. Most of the liver's supply of blood comes from the intestinal veins as the blood returns to the heart. other symptoms of the hormone deficiency may also present. Alcohol lowers testosterone production and can affect the production of healthy sperm cells. What is cirrhosis? Cirrhosis is a complication of many liver diseases characterized by abnormal structure and function of the liver.

(Pitting edema refers to the fact that pressing a fingertip firmly against an ankle or leg with edema causes an indentation in the skin that persists for some time after release of the pressure. Bile is a fluid produced by liver cells that has two important functions: to aid in digestion and to remove and eliminate toxic substances from the body. the liver is unable to add or remove substances from blood that bypasses it.) The swelling often is worse at the end of a day after standing or sitting and may lessen overnight as a result of the loss of the effects of gravity when lying down. . At the same time. the scarring within the cirrhotic liver obstructs the flow of blood through the liver and to the liver cells. and they can accumulate in the body. veins with lower pressures that bypass the liver. all of the ducts combine into one duct that enters the small intestine. Unfortunately. loss of the normal contact between blood passing through the liver and the liver cells. The excess salt and water first accumulates in the tissue beneath the skin of the ankles and legs because of the effect of gravity when standing or sitting. To a minor extent. and the pressure in the portal vein increases. This accumulation of fluid (called ascites) causes swelling of the abdomen. In addition. Ultimately. intimate relationship with the blood. In cirrhosis. bile gets to the intestine where it can help with the digestion of food. Even though the liver cells that survive or are newly-formed may be able to produce and remove substances from the blood. the relationship between blood and liver cells is destroyed. This accumulation of fluid is called edema or pitting edema. It is a combination of reduced numbers of liver cells. called canaliculi. and increased weight. toxic substances contained in the bile enter the intestine and then are eliminated in the stool. blood "backs-up" in the portal vein. just like the relationship between the liver cells and blood in the sinusoids. and blood bypassing the liver that leads to many of the manifestations of cirrhosis. In this way. they do not have the normal. such as from the elastic band of a sock. a condition called portal hypertension. A second reason for the problems caused by cirrhosis is the disturbed relationship between the liver cells and the channels through which bile flows. blood in the portal vein seeks other veins in which to return to the heart. may be enough to cause pitting. As a result of the obstruction to the flow of blood through the liver. abdominal discomfort. fluid also may accumulate in the abdominal cavity between the abdominal wall and the abdominal organs. digestion in the intestine also is reduced. Because of the obstruction to flow and high pressures in the portal vein. The bile that is produced by liver cells is secreted into very tiny channels that run between the liver cells that line the sinusoids. any type of pressure. As a result. the liver is not able to eliminate toxic substances normally. and this interferes with the liver cells' ability to add or remove substances from the blood. The canaliculi empty into small ducts which then join together to form larger and larger ducts. the canaliculi are abnormal and the relationship between liver cells and canaliculi is destroyed. signals are sent to the kidneys to retain salt and water in the body. As cirrhosis worsens and more salt and water are retained. Actually. ______________________________________________________________________- What are the complications of cirrhosis? Edema and ascites As cirrhosis of the liver becomes severe.In cirrhosis.

For reasons yet unknown. the veins in the lower esophagus and upper stomach expand and then are referred to as esophageal and gastric varices. the latter due to the effect of acid on the blood). As a result of the increased flow of blood and the resulting increase in pressure. and bacteria that enter the abdomen (usually from the intestine) are killed or find their way into the portal vein and to the liver where they are killed. but this is rare. Normally. While using the protein for their own purposes. Therefore. more bacteria find their way from the intestine into the ascites. the bacteria make substances that they release into the intestine. Bleeding from varices usually is severe and. Some patients with SBP have no symptoms. . and worsening ascites. can have toxic effects on the brain.abdominal pain and tenderness. referred to as spontaneous bacterial peritonitis or SBP. In addition. Ordinarily. for example. Bleeding from esophageal varices In the cirrhotic liver. the larger the varices and the more likely a patient is to bleed from the varices into the esophagus or stomach. the scar tissue blocks the flow of blood returning to the heart from the intestines and raises the pressure in the portal vein (portal hypertension). Hepatic encephalopathy Some of the protein in food that escapes digestion and absorption is used by bacteria that are normally present in the intestine. infection within the abdomen and the ascites. can be fatal. These substances then can be absorbed into the body. while others have fever. patients hospitalized because of actively bleeding esophageal varices have a high risk of developing spontaneous bacterial peritonitis. Some of these substances. without immediate treatment. for example. the fluid that collects in the abdomen is unable to resist infection normally. The most common veins through which blood bypasses the liver are the veins lining the lower part of the esophagus and the upper part of the stomach. passing stool that is black and tarry due to changes in the blood as it passes through the intestine (melena). In cirrhosis. ammonia. chills. the abdominal cavity contains a very small amount of fluid that is able to resist infection well.Spontaneous bacterial peritonitis (SBP) Fluid in the abdominal cavity (ascites) is the perfect place for bacteria to grow. diarrhea. the colon. these toxic substances are carried from the intestine in the portal vein to the liver where they are removed from the blood and detoxified. it causes blood to flow around the liver through veins with lower pressure to reach the heart. the higher the portal pressure. Bleeding also may occur from varices that form elsewhere in the intestines. and orthostatic dizziness or fainting (caused by a drop in blood pressure especially when standing up from a lying position). When pressure in the portal vein becomes high enough. SBP is a life.threatening complication. Symptoms of bleeding from varices include vomiting blood (the vomitus can be red blood mixed with clots or "coffee grounds" in appearance. is likely to occur.

Blood flowing through the lungs is shunted around the alveoli and cannot pick up enough oxygen from the air in the alveoli. . The other occurs rapidly over a week or two. There are two types of hepatorenal syndrome. Instead. instead. such as retention of salt. are maintained. Sleeping during the day rather than at night (reversal of the normal sleep pattern) is among the earliest symptoms of hepatic encephalopathy. drugs that are eliminated by the kidneys. Other symptoms include irritability. some of the blood in the portal vein bypasses the liver through other veins.As previously discussed. These patients can experience difficulty breathing because certain hormones released in advanced cirrhosis cause the lungs to function abnormally. One type occurs gradually over months. This syndrome is a serious complication in which the function of the kidneys is reduced. drugs may be used that do not need to be detoxified or eliminated from the body by the liver. for example. This suggests that the reduced function of the kidneys is the result of the accumulation of toxic substances in the blood when the liver fails. liver cells cannot function normally either because they are damaged or because they have lost their normal relationship with the blood. particularly with exertion. and. the toxic substances accumulate in the blood. severe hepatic encephalopathy causes coma and death. the kidneys usually begin to work normally again. When the toxic substances accumulate sufficiently in the blood. Hepatopulmonary syndrome Rarely. In addition. If liver function improves or a healthy liver is transplanted into a patient with hepatorenal syndrome. Ultimately. particularly sedatives and drugs that are used to promote sleep. Doses of many drugs that normally are detoxified by the liver have to be reduced to avoid a toxic buildup in cirrhosis. confusion. inability to concentrate or perform calculations. The basic problem in the lung is that not enough blood flows through the small blood vessels in the lungs that are in contact with the alveoli (air sacs) of the lungs. when cirrhosis is present. some patients with advanced cirrhosis can develop hepatopulmonary syndrome. the function of the brain is impaired. It is a functional problem in the kidneys. a condition called hepatic encephalopathy. Hepatorenal syndrome Patients with worsening cirrhosis can develop hepatorenal syndrome. meaning there is no physical damage to the kidneys. loss of memory. The toxic substances also make the brains of patients with cirrhosis very sensitive to drugs that are normally filtered and detoxified by the liver. or depressed levels of consciousness. The hepatorenal syndrome is defined as progressive failure of the kidneys to clear substances from the blood and produce adequate amounts of urine while other important functions of the kidney. As a result the patient experiences shortness of breath. Alternatively. the reduced function is due to changes in the way the blood flows through the kidneys themselves. The result of these abnormalities is that toxic substances cannot be removed by the liver cells.

Hypersplenism is the term used to describe this condition. from simple and uncomplicated fatty liver(steatosis). The anemia can cause weakness. As the pressure in the portal vein rises in cirrhosis. it increasingly blocks the flow of blood from the spleen. to the more serious fatty liver with inflammation (steatohepatitis or alcoholic hepatitis). The term nonalcoholic is used because NAFLD occurs in individuals who do not consume excessive amounts of alcohol. A secondary liver cancer is one that originates elsewhere in the body and spreads (metastasizes) to the liver. NAFLD is associated with a condition called insulin resistance. the leucopenia can lead to infections. Nonalcoholic fatty liver disease (NAFLD) refers to a wide spectrum of liver diseases that. low blood sugar (hypoglycemia). and it is associated with a low red blood cell count (anemia)." accumulating in the spleen. Sometimes. and the spleen swells in size. What are the common causes of cirrhosis?   Alcohol is a very common cause of cirrhosis. which. it filters out more and more of the blood cells and platelets until their numbers in the blood are reduced. and the thrombocytopenia can impair the clotting of blood and result in prolonged bleeding. As the spleen enlarges. Liver cancer (hepatocellular carcinoma) Cirrhosis due to any cause increases the risk of primary liver cancer (hepatocellular carcinoma). ranges from simple steatosis. and/or a low platelet count (thrombocytopenia). to cirrhosis. including ones that cause an increased in red blood cell count (erythrocytosis). the microscopic picture of NAFLD is similar to what can be seen in liver disease that is due to excessive alcohol. yet. Alcohol causes a range of liver diseases. and high blood calcium (hypercalcemia ).). white blood cells. liver cancers can produce and release a number of substances. The most common symptoms and signs of primary liver cancer are abdominal pain and swelling. weight loss. like alcoholic liver disease. All stages of NAFLD have in common the accumulation of fat in liver cells. the spleen is so enlarged that it causes abdominal pain. an enlarged liver. high levels of alcohol consumption injure liver cells. is associated with metabolic . The blood "backs-up.Hypersplenism The spleen normally acts as a filter to remove older red blood cells. to nonalcoholic steatohepatitis (NASH). Thirty percent of individuals who drink daily at least eight to sixteen ounces of hard liquor or the equivalent for fifteen or more years will develop cirrhosis. particularly in the Western world. Primary refers to the fact that the tumororiginates in the liver. to cirrhosis. The blood that drains from the spleen joins the blood in the portal vein from the intestines. a condition referred to as splenomegaly. low white blood cell count (leucopenia). and platelets (small particles that are important for the clotting of blood. The development of cirrhosis depends upon the amount and regularity of alcohol intake. in turn. In addition. in many respects. Chronic. and fever.

In fact. arthritis. copper accumulates in the liver. Inherited (genetic) disorders that result in the accumulation of toxic substances in the liver. Doctors now believe that cryptogenic cirrhosis is due to NASH (nonalcoholic steatohepatitis) caused by long standing obesity.    syndrome and diabetes mellitus type 2. and.) However. Public health officials are worried that the current epidemic of obesity will dramatically increase the development of NAFLD and cirrhosis in the population. In Wilson disease. and testicular dysfunction causing loss of sexual drive. metabolic syndrome. Finally. eyes. Examples include the abnormal accumulation of iron (hemochromatosis) or copper (Wilson's disease). One important clue that NASH leads to cryptogenic cirrhosis is the finding of a high occurrence of NASH in the new livers of patients undergoing liver transplant for cryptogenic cirrhosis. The fat in the liver of patients with NASH is believed to disappear with the onset of cirrhosis. sometimes. the majority of patients infected with hepatitis A recover completely within weeks. Bile is a fluid produced by the liver that contains substances required for digestion and absorption of fat in the intestine. the number of livers that are transplanted for NAFLD-related cirrhosis is on the rise. In hemochromatosis. Treatment is with oral medication. Over time. Cirrhosis. which increases the amount of copper that is eliminated from the body in the urine. The bile ducts are passages within the liver through which bile travels to the intestine. NAFLD is the most common liver disease in the United States and is responsible for 24% of all liver disease. Treatment is aimed at preventing damage to organs by removing iron from the body through bloodletting (removing blood). Most patients with viral hepatitis will not develop chronic hepatitis and cirrhosis. For example. It is termed cryptogenic cirrhosis because for many years doctors have been unable to explain why a proportion of patients developed cirrhosis. Chronic viral hepatitis is a condition where hepatitis B or hepatitis C virus infects the liver for years. the progression to cirrhosis from NASH is thought to be slow and the diagnosis of cirrhosis typically is made in patients in their sixties. and insulin resistance. (Bilirubin is produced by the . which. liver cancers. Over time. without developing chronic infection. which leads to tissue damage and cirrhosis. iron accumulation in different organs throughout the body causes cirrhosis. (See discussion that follows. Cryptogenic cirrhosis (cirrhosis due to unidentified causes) is a common reason for liver transplantation. causes progressive liver damage and leads to cirrhosis. psychiatric disturbances and other neurological difficulties occur if the condition is not treated early. heart muscle damage leading to heart failure. and this has made it difficult for doctors to make the connection between NASH and cryptogenic cirrhosis for a long time. and type 2 diabetes. a study from France suggests that patients with NASH have a similar risk of developing cirrhosis as patients with long standing infection with hepatitis C virus. In contrast. Primary biliary cirrhosis (PBC) is a liver disease caused by an abnormality of the immune system that is found predominantly in women. tremor. in turn. such as the pigment bilirubin.Obesity is the most important cause of insulin resistance. as well as other compounds that are waste products. The abnormal immunity in PBC causes chronic inflammation and destruction of the small bile ducts within the liver. there is an inherited abnormality in one of the proteins that controls copper in the body. type 2 diabetes. some patients infected with hepatitis B virus and most patients infected with hepatitis C virus develop chronic hepatitis. and brain. patients inherit a tendency to absorb an excessive amount of iron from food.

These pieces of information suggest the possibility of liver disease and cirrhosis. Along with the gallbladder. or a history of hepatitis. the large bile ducts outside of the liver become inflamed. The possibility of cirrhosis may be suggested by the history. biopsy often is reserved for those patients in whom the diagnosis of the type of liver disease or the presence of cirrhosis is not clear. In PSC. other tests can be used to determine the severity of the cirrhosis and the presence of complications. . In some patients. the bile ducts make up the biliary tract. Infants can be born without bile ducts (biliary atresia) and ultimately develop cirrhosis. Other infants are born lacking vital enzymes for controlling sugars that leads to the accumulation of sugars and cirrhosis. How is cirrhosis diagnosed and evaluated? The single best test for diagnosing cirrhosis is biopsy of the liver. eventually causing cirrhosis.    breakdown of hemoglobin from old red blood cells. In certain parts of the world (particularly Northern Africa). The abnormal immune activity in autoimmune hepatitis causes progressive inflammation and destruction of liver cells (hepatocytes). The following are some examples of how doctors discover.). Autoimmune hepatitis is a liver diseasefound more commonly in women that is caused by an abnormality of the immune system. or routine testing. leading ultimately to cirrhosis. scarring. carry a small risk for serious complications. As the destruction of the hepatocytes proceeds. Primary sclerosing cholangitis (PSC) is an uncommon disease frequently found in patients with Crohn's disease and ulcerative colitis. Less common causes of cirrhosis include unusual reactions to some drugs and prolonged exposure to toxins. and the toxic effects of accumulating waste products culminates in cirrhosis. If cirrhosis is present. therefore. As the inflammation continues to destroy more of the bile ducts. and. Obstruction to the flow of bile leads to infections of the bile ducts and jaundice. In PBC. a history of intravenous drug abuse. The combined effects of progressive inflammation. scar tissue (fibrosis) forms and spreads throughout the areas of destruction. and obstructed. it also spreads to destroy nearby liver cells. as well as chronic heart failure (cardiac cirrhosis). Tests also may be used to diagnose the underlying disease that is causing the cirrhosis. physical examination. diagnose and evaluate cirrhosis:  In taking a patient's history. infection of the liver with a parasite (schistosomiasis) is the most common cause of liver disease and cirrhosis. On rare occasions. the physician may uncover a history of excessive and prolonged intake of alcohol. the absence of a specific enzyme can cause cirrhosis and scarring of the lung (alpha-1 antitrypsin deficiency). injury to the bile ducts (usually as a result of surgery) also can cause obstruction and cirrhosis of the liver. the destruction of the small bile ducts blocks the normal flow of bile into the intestine. narrowed. Liver biopsies. however.

 Patients who are known to have chronic viral hepatitis B or C have a higher probability of having cirrhosis.           . Abnormal elevation of liver enzymes in the blood (such as ALT and AST) that are obtained routinely as part of yearly health examinations suggests inflammation or injury to the liver from many causes as well as cirrhosis. Swelling of the abdomen (ascites) and/or the lower extremities (edema) due to retention of fluid is common among patients with cirrhosis. reduced levels of albumin in the blood or abnormal bleeding suggest cirrhosis. for example. radiating blood vessels. particularly alcoholic cirrhosis. that are made up of enlarged. Advanced cirrhosis leads to a reduced level of albumin in the blood and reduced blood clotting factors due to the loss of the liver's ability to produce these proteins. Computerized tomography (CT or CAT) or magnetic resonance imaging (MRI) scans and ultrasound examinations of the abdomen done for reasons other than evaluating the possibility of liver disease may unexpectedly detect enlarged livers. strongly suggests cirrhosis. although other diseases can cause them commonly. including the liver. these spider telangiectasias also can be seen in individuals without liver disease. Jaundice (yellowness of the skin and of the whites of the eyes due to elevated bilirubin in the blood) is common among patients with cirrhosis. which suggest cirrhosis. congestive heart failure. have small red spider-like markings (telangiectasias) on the skin. Some patients with cirrhosis. a genetic disease of the liver in which iron is handled abnormally and which leads to cirrhosis. and fluid in the abdomen. A cirrhotic liver also feels firmer and more irregular than a normal liver. Some patients with cirrhosis have enlarged livers and/or spleens. A doctor can often feel (palpate) the lower edge of an enlarged liver below the right rib cage and feel the tip of the enlarged spleen below the left rib cage. but jaundice can occur in patients with liver diseases without cirrhosis and other conditions such as hemolysis (excessive break down of red blood cells). abnormally nodular livers. However. a genetic disease in which there is abnormal handling and accumulation of copper throughout the body. Thus. Patients with elevated levels of iron in their blood may have hemochromatosis. enlarged spleens. which can lead to cirrhosis. particularly on the chest. Patients with abnormal copper deposits in their eyes or certain types of neurologic disease may have Wilson's disease. Esophageal varices may be found unexpectedly during upper endoscopy (EGD).

  . The fluid then can be examined and tested. Liver cancer (hepatocellular carcinoma) may be detected by CT and MRI scans or ultrasound of the abdomen. both of which can lead to cirrhosis. Auto-antibodies (antinuclear antibody. anti-smooth muscle antibody and anti-mitochondrial antibody) sometimes are detected in the blood and may be a clue to the presence of autoimmune hepatitis or primary biliary cirrhosis. If there is an accumulation of fluid in the abdomen. The results of testing may suggest the presence of cirrhosis as the cause of the fluid. Liver cancer most commonly develops in individuals with underlying cirrhosis. a sample of the fluid can be removed using a long needle.

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