THE PANCREAS

The pancreas is composed of a head and a tail. The purpose of the pancreatic head is used to secrete pancreatic enzymes. The purpose of the pancreatic tail is to produce insulin. I will first discuss the pancreatic head.

THE PANCREATIC HEAD

The pancreatic head synthesizes and produces the following enzymes, which are released by the acini cells:

1. Trypsinogen

2. Chymotrypsinogen

3. Pro carboxy polypeptidase

All are enzymatically inactive until they are activated by enterokinase when they enter the intestinal tract.

Once these enzymes are activated, they are called trypsin and chymotrypsin, which cleave proteins into peptides. Carboxypolypeptidase, which is now the activated form of pro carboxy polypeptidase, then splits these peptides into amino acids. Pancreatic lipases include cholesterol esterase, which hydrolyzes cholesterol esters and phospholipase, which splits fatty acids from phospholipids.

The pancreas also secretes pancreatic amylase, which breaks down carbohydrates.

Bicarbonate ions (sodium) also make up a portion of pancreatic secretions, which alkalize the gastric secretions of the stomach. If necessary, bicarbonate ions can be increased by five times the normal amount. There are four stimuli of pancreatic secretions:

1. The first is acetylcholine via the vagus nerve

2. The second is gastrin produced by the stomach

3. The third is cholecystokinin secreted by the duodenum, which is responsible for pancreatic enzyme release

4. The fourth is secretin, which increases sodium bicarbonate ions

The primary job of pancreatic enzymes is to oxidize fatty acids (complex sugars) through the use of chromium via amylase. Chromium is trivalent and is very acceptable to oxygen. Chromium, therefore, causes immediate oxidation (injects oxygen between the oil and sugar of the fatty acid causing pre-combustion, which readies the fatty acids for combustion and energy exchange. The head of the pancreas regulates the most alkaline substance, which is starch, and when there is an increased alkalinity of the blood, there is an increase in fatty acid oxidation via chromium.

It is worth mentioning that there are three steps necessary in the breakdown of fatty acids, which are as follows:

1. Fatty acids are first prepared via ptyalin in the saliva, (which contains large amounts of potassium), activated by having the mumps.

2. The second step is through aerobic enzymation in the small intestines, which is the chromium oxidation step I just spoke about. According to Dr. Brockman having the chickenpox activates this step.

3. The final step is an anaerobic step, which occurs, between the liver-gallbladder and the head of the pancreas (duct of worsung) where trypsin and chymotrypsin are secreted. According to Dr. Brockman, this is stimulated or activated by having the measles.

The measles encourages the expression, appropriate potency, and types of pancreatic enzymes. Patients who continually contract the measles are trying to kick in their pancreas to release the pancreatic enzymes.

The following blood tests are used to determine pancreatic head conditions:

1. CALCIUM-besides bonding to lipoproteins, calcium also bonds to the oily portion of fatty acids. This is necessary if the fatty acids want to pass through the intestinal wall. If there is poor oxidation of fatty acids, then there will be a certain amount of calcium, which will be needed to bond to the fatty acids, decreasing the calcium levels in the blood.

2. LACTIC ACID DEHYDROGENASE (LDH)-is a glycolytic enzyme that functions as a catalyst in carbohydrate metabolism, which aids the pyruvic and lactic acid interchange. LDH is a byproduct of muscle metabolism. When sugar and water (fatty acid metabolism) are exchanged across a muscle cell interface, the byproduct left is called lactic acid. Lactic acid is also a byproduct of fatty acid metabolism via the alkalizing and oxidizing affects of the pancreatic head. When lactic acid combines with the venous blood (carbon dioxide), there is a hydrogen displacement. The lactic acid then bonds to a double hydrogen forming lactic acid dehydrogenase.

LDH is then a byproduct of carbohydrate and fatty acid metabolism. The organs and glands that that are most responsible for sugar and water interchange across the muscle cell interface are the pancreas and the posterior pituitary (via antidiuretic hormone.) LDH is found chiefly in the heart, kidneys, liver, skeletal muscles, as well as all tissues. LDH is a normal component of cerebral spinal fluid.

THE GALLBLADDER

The purpose of the gallbladder is to store bile, which was produced via the liver (600-1200 mL are produced daily) and received the precursors from the spleen and the adrenals. Biliverdin and bilirubin are pigments that are used in red blood cell production. When red blood cells reach the 120-day mark, they are broken down via the spleen and tissue macrophages (reticuloendothelial cells). These pigments are released and utilized to form bile.

Hemoglobin is also split into globin and heme. The heme is transferred in the blood with transferrin to form with the pyrrole nuclei. Biliverdin is then reduced to form bilirubin. The salts that help produce bile for emulsification of fat are produced via the adrenal glands. The precursor of bile salts is cholesterol, which is also produced via the liver and then converted into cholic acid or chendodeoxycholic acid equally. 80% of all cholesterol is converted into these two acids. These acids combined with glycine and taurine to form glyco and tauro conjugated bile acids, with the salts of the acids being secreted in the bile. The release of bile via gallbladder contractions is caused by cholecystokinin.

The purpose of bile is three-fold:

• The first is to transform a fat into soap via saponification (oxidation of fat), which leads to emulsification. In order for the salts to be infused into the fat, lecithin must be present. This decreases the surface tension of the fat molecule allowing agitation to break up the fat into small sizes. Therefore, the components of bile are lecithin, which are choline and inositol, cholesterol and bile salts.

• The second thing bile salts do is to help absorb fatty acids, monoglycerides, cholesterol and other lipids by forming minute complexes called “micelles.” These are highly soluble, highly charged and are easily absorbed, increasing absorption of fat by 40 percent.

• The third purpose of bile is to excrete waste products, such as excessive cholesterol produced by the liver and bilirubin, which is the end product of hemoglobin degradation.

The following tests determine liver function:

1. SGPT (SERUM GLUTAMIC PYRUVIC TRANSAMINASE) (ALT) -SGPT has a maximum concentration in the liver sinusoid membranes. SGPT is also found in large amounts in the kidneys, heart and skeletal muscle. SGPT is the primary Krebs cycle expresser. It occurs as the result of the catabolic release of fat. Pyruvates are those substances that balance fats in an anti-oxidant media. The oxygen from the iron, and the antioxidant media from fat, which is the lubricator vitamin known as vitamin A, is balanced by pyruvates. Vitamin A is also used in the sinusoids of the lungs, spleen, kidney, sinuses and lymphatic tissue.

SGPT exists in the blood serum as a consequence of substances being released by the fatty membranes of the liver sinusoids and lymphatic ducts. The liver sinusoids store food while the lymphatic ducts house toxins. Picture a layer of vitamin A that holds food or toxins in the cell. Now, as that layer of fat (vitamin A) is being burned off, oxidized via iron, foods or toxins are released from the sinusoids or lymphatic in a controlled manner, allowing foods or toxins to be released and directed to the next destination.

SGPT shows the fat and the fatty acid storage ability that takes place in the liver. SGPT is the primary kreb cycle expresser, which occurs as the result of the release of catabolic fats from the liver.

2. TOTAL IRON-is the indicator of the process of oxidation vs. the antioxidation (fat). This occurs in the liver, as mentioned above.

3. GGTP-SERUM GAMMA GLUTAMYL TRANSFERASE (TRANSPEPTIDASE) is another liver enzyme test that is more concerned with liver/gallbladder/pancreatic problems and alcoholism. SGPT is more concerned with the release of foodstuffs from the liver.

4. TOTAL BILIRUBIN-as mentioned above, bilirubin is formed by the destruction of hemoglobin by the liver (kupfer cells), bone marrow and spleen. Impaired production or excretion of hemoglobin results in jaundice/liver disease. Total bilirubin is made up of direct and in-direct bilirubin. Direct bilirubin is what is called the post hepatic form, which has already been reacted on by the liver (conjugated). The elevation is usually caused by biliary obstruction. Indirect bilirubin is the pre-hepatic form, which has not been reacted on by the liver (unconjugated) and elevation occurs during liver failure. As you can see, SGPT and total iron are liver function tests, and GGTP and total bilirubin are related more to gallbladder dysfunction.

THE STOMACH

Phosphorus works in the stomach to stabilize sugars and activate starches by the twofold process of phosphorylation. Phosphorus in conjunction with HCl, pepsin, zinc, and vitamin C via the thymus helps in the:

1. Stabilization of sugar-simple sugars are easily oxidized (combusted) before they reach the liver, resulting in low sugar levels. Pepsin stabilizes these simple sugars, so they can be transferred to the liver for storage.

2. Activation of starches-HCl is necessary to breakdown oily carbohydrates (grains), which are difficult to oxidize (combust), thus making them readily available for oxidation.

The above two mechanisms establish an HCl-pepsin balance in the stomach for proper pH digestion.

The presence of both HCl and pepsin in the stomach are critical for preparing carbohydrates and proteins for further digestion in the small intestines. Phosphorus indicates the amount of acid balance in the body. It does this by regulating secretions of HCl and pepsin in the stomach by the foods you eat. For example, when you eat foods that are high in phosphoric acid, there will be a release of pepsin to neutralize the acid. On the other hand, foods low in phosphoric acid content will cause large amounts of HCl to be released. Phosphorus then carries carbohydrates across the intestinal wall for absorption by the liver. Phosphorus also affects the intrinsic factor function by releasing alkaline B vitamins into inorganic foods, converting them into organic foods for storage in the liver sinusoids.

Patients that have an acid pH in their stomach should avoid excessive amounts of acid forming foods such as meats, dairy, grains and junk foods.

Patients that have an alkaline pH should avoid excessive amounts of alkaline forming foods such as fruits and vegetables.

Diet has a dramatic affect on the acidity or alkalinity of the stomach and is usually the culprit in stomach conditions.

The 3 Phases Of Gastric Secretion

1. The Cephalic Phase- which is the result of hunger, sight, smell and thought about food neurologically controlled by the cerebral cortex that project to appetite centers in the amygdala or hypothalamus. This phase accounts for 1/5th of the digestive juices produced.

2. The Gastric Phase- when the food enters the stomach it excites long vasovagal and local enteric nerves that stimulate the release of gastric juices accounting for 2/3rds of the 1500 ml’s released daily.

3. The Intestinal Phase – once the food enters the duodenum, it triggers the release of gastrin from the intestinal mucosa thus inhibiting the release of gastric juices. The presence of food in the small intestines initiates an enterogastric reflex, which also inhibits gastric secretions. The presence of secretin and cholecystokinin are responsible for pancreatic enzyme release. Cholecystokinin releases bile via the gallbladder and also inhibits gastric function. Acids, protein by-products, gastric inhibitory peptide, vasoactive intestinal polypeptide, and somatostatin all inhibit gastric secretions. Since the stomach is poor at absorption, very little takes place. It is only when you reach the small intestines that you find folds known as valvulae conniventes, which increase the surface area of the small intestines 3 fold. Extending from these conniventes are small projections called villi, which increase the absorption another 10 fold. These villi are close together and their outer epithelial cells form a brush border protruding into the chyme. This increases the absorptive power another 600 fold. This makes the surface of the small intestines 250 sq. meters (About the size of a tennis court). The absorptive capacity of the small intestines is astounding. It can absorb several kilograms of carbohydrates, 500-1000 grams of fat (20-40 ounces), 500-700 grams (20-28 ounces) of protein, and 20 or more liters of water daily.

There are four types of glands that are found in the gastrointestinal tract:

1. Salivary cells are found in the mouth, pancreas, and the liver

2. Mucous glands- Mucous contains, water, electrolytes, glycoproteins, and HCO3

ions. The function of mucous is to adhere tightly to the food while it coats the

intestinal wall. Mucous prevents food from contacting the mucosa. Mucous also

causes fecal particles to adhere together to form a mass. Mucous is also very

resistant to digestive juices, and can buffer acids or alkaline enzymes. The

esophagus also secretes mucous. The mucous glands secrete mucous in response

to vagal stimulation, gastrointestinal enzymes, and irritating factors. Mucous glands

that are in the upper duodenal area between the pylorus and papilla of vata are

called “Brunner’s glands”. Crypts of Lieberkuhn are found in the small intestines.

3. Tubular cells- are found in the stomach and are of 2 types: the oxyntic or gastric and the pyloric. The first, oxyntic, are your parietal and chief cells. The parietal cells secrete HCl, intrinsic factor for B12 absorption, and histamine. The chief cells secrete pepsinogen, intrinsic factor and mucous. The second type of tubular gland is called the pyloric gland. The pyloric glands mainly secrete mucous

but also pepsinogen and gastrin. The oxyntic glands are located in the body and fundus of the stomach comprising 80% of the stomach; the pyloric glands are found in the antral portion of the stomach. These tubular cells are also found in the upper part of the small intestines. Pepsinogen, which is not reactive, is activated and transformed into pepsin by coming in contact with HCl. Pepsin is a proteolytic

enzyme that is highly reactive in an acid media between (1.8-3.5). Therefore, both HCl and pepsin are responsible for protein digestion. Other enzymes of the stomach include gastric lipase and amylase; both are extremely weak and play a minor role in the digestion of fats and starches. Gelatinase, another enzyme, is responsible for liquification of proteoglycans found in meat. The stomach also secretes intrinsic factor, which is responsible for B12 absorption in the ileum.

B12 is responsible for red blood cell maturation. Gastric secretions have a pH of 1.0-3.5.

4. The stomach also secretes gastric amylase and lipase.

The Neurotransmitters Affecting Gastric Secretions Are:

1. Acetylcholine-which is responsible for pepsinogen via peptic cells, gastrin via gastric cells, HCl via parietal cells and mucous secretions.

2. Gastrin (2 types G17 and G34) named for the number of amino acids that make them up, and histamine (an amino acid derivative) both stimulate HCl production.

When gastric or acetylcholine are present histamine has a much stronger effect on acid production. All of these neurotransmitters activate receptor sites on secretory cells, which stimulate the secretory process. Amino acids, caffeine and alcohol can also stimulate gastric secretory activity.

Neural Control Of The Gastrointestinal System

The GI tract is controlled by:

A. Reflex activity between the brain stem (vagus nerve dorsal motor nuclei), such as the stomach motor and secretory activity, pain and strong powerful colonic contractions.

B. The spinal cord via the autonomic nervous system. The sympathetic division extends from T5-L3 forming the celiac and mesenteric plexuses and the sympathetic chain ganglion, which inhibits peristalsis and digestive secretions by the inhibition of the myenteric and submucosal plexus with norepinephrine. Usually, they control long range communication between the stomach, small intestine, ileocecal valve and the colon, by controlled slowing or speeding up of movement of food and fecal material.

C. The parasympathetic outflow division originates from S1-S3 and stimulates the movement of fecal material and reabsorption of H2O and electrolytes. Remember that almost all sympathetic or parasympathetic activity is afferent in nature. This means that distention, mucosal irritation from foods, drugs, preservatives, pH etc. send afferent messages to the brain stem initiating the proper course of action to occur.

D. The GI tract has its own nervous system called the enteric nervous system and is found in the gut wall extending from the esophagus to the anus (100 million neurons are the number of neurons in the spinal cord). The enteric nervous system releases the following neurotransmitters: acetylcholine, norepinephrine, ATP, serotonin, dopamine, cholecystokinin, substance P, vasoactive intestinal polypeptide, somatostatin, and leu-enkephalin. Acetylcholine stimulates intestinal activity norepinephrine inhibits intestinal activity.

The enteric nervous system is composed of 2 plexuses

1. myenteric plexus (Auerbach’s) found between the circular and longitudinal fibers and controls peristaltic movement. The myenteric plexus is composed of linear chains of interconnecting neurons. When stimulated it increases:

• Tonic contractions

• Rhythmic contractions

• Velocity of conduction

• Rate of rhythm

· · ·

Please note that the myenteric plexus does play a role in inhibition of the pyloric sphincter and the ileocecal valve.

2. Submucosal plexus (Meissner’s plexus) is found in the submucosa and is responsible for digestive secretions and blood flow. The purpose of the enteric nervous system is to control peristalsis and digestive secretions short range over small distances. This is most beneficial since the body uses a finer control over the local digestive process.

Digestion And Absorption In The Gastrointestinal Tract

Carbohydrate Digestion- There are 3 major sources of carbohydrates in the diet

Sucrose, a disaccharide known as cane sugar

Lactose, a disaccharide known as milk sugar

Starches (grains), which are long polysaccharides

When monosaccharides form disaccharides, hydrogen is removed from one monosaccharide and a hydroxyl group is removed from the other monosaccharide, forming water in a process (condensation). When disaccharides split into monosaccharides the process is called hydrolysis (the addition of water to form the 2 monosaccharides). Humans cannot digest cellulose.

Carbohydrate digestion starts in the mouth via an alpha amylase known as ptyalin, secreted by the parotid glands. This enzyme hydrolyzes starches into maltose and other small polymers of glucose (3-9 glucose molecules long.). 3-5% of all starches are digested in the mouth. As the food enters the stomach ptyalin continues to digest the carbohydrates so that within 1 hour, upon entering the stomach, most of the carbohydrates are converted into maltose. When the pH falls below 4.0 ptyalin starts to become inactive. By the time the chyme reaches the duodenum and jejunum, pancreatic amylase, which is much more potent then ptyalin (more concentrated), converts the remaining polymers into maltose.

In the lining membranes of the intestinal lumen (microvilli brush border) there are four enzymes produced:

Lactase, which splits lactose into galactose and glucose

Sucrase, which splits sucrose into fructose and glucose

Maltase, which splits maltose into glucose.

Alpha Dextrinase, which splits all of the above as well as dextrins

2. Protein Digestion-Protein digestion starts in the stomach via pepsin. Pepsin is also important for digesting collagen, an albuminoid found in meats. Pepsin is most active at a pH of 2-3. The HCl produced by the body has a pH of .8. When proteins leave the stomach they are mostly in the form of proteases, peptones, and large polypeptides. When the chyme reaches the small intestines the pancreatic enzymes trypsin and chymotrypsin split proteins into small peptides and carboxypolypeptidase then split a small percentage of these into amino acids. The bulk of the peptides are broken down by the multiple peptidases located in the brush border of the intestinal membrane.

The most important peptidases are aminopolypeptidase and several dipeptidases. These split the proteins down to di and tri-peptides, which enter the microvilli membrane into the interior of the epithelial cell where other peptidases break up the remaining di and tripeptides into amino acids to be absorbed into the blood stream. Please note that di, tri, and polypeptides can still enter the blood stream and can cause allergic reactions. 99 % of all protein is absorbed as amino acids.

3. Fat Digestion The most abundant fat in the diet is in the form of triglycerides, which contains a glycerol nucleus and 3 fatty acids (stearic, and palmitic acid, which are saturated and oleic acid which is unsaturated). All 3 come from animal and not plant origin. The usual diet contains phospholipids, cholesterol and cholesterol esters.

Cholesterol is formed in the liver from degraded products of fatty acid molecules, which give cholesterol its fatty characteristics. Fat (butterfat) is digested in the stomach via gastric lipase (tributyrase) in very small amounts. 99% of fat digestion takes place in the intestines via bile. Bile contains bile salts and a phospholipid known as lecithin in the form of ionized sodium salts. Bile salts have the ability to form micelles, small globules of fat attached to the bile salt. This occurs because the sterol portion of the bile salt is highly soluble in fat and a polar portion of the bile salts and lecithin are highly soluble in water. This reducing and changing the polarity reduces the interfacial tension between the fat cells so digestive enzymes can continue to break down the fat. This increases the total surface area of the fat a 1000 fold. Pancreatic lipase is responsible for splitting 99% of the triglycerides into 3 fatty acids and 2 monossachrides.

Cholesterol, its ester (cholesterol +1 molecule of a fatty acid) and phosopholipids (via cholesterol ester hydrolase and phospholipidase respectively) are broken down via hydrolysis of the fatty acids from their molecular structures. The bile salts, when attached to lipids create micelles, which are highly charged and increase the absorption of these fatty acids, glycerol, free cholesterol and the remaining portion of the phospholipids. Please note that without bile salts much of the fat will be blocked from entering the blood stream.

THE STOMACH

Phosphorus works in the stomach to stabilize sugars and activate starches by the twofold process of phosphorylation. Phosphorus in conjunction with HCl, pepsin, zinc, and vitamin C via the thymus helps in the:

1. Stabilization of sugar-simple sugars are easily oxidized (combusted) before they reach the liver, resulting in low sugar levels. Pepsin stabilizes these simple sugars, so they can be transferred to the liver for storage.

2. Activation of starches-HCl is necessary to breakdown oily carbohydrates (grains), which are difficult to oxidize (combust), thus making them readily available for oxidation.

The above two mechanisms establish an HCl-pepsin balance in the stomach for proper pH digestion.

The presence of both HCl and pepsin in the stomach are critical for preparing carbohydrates and proteins for further digestion in the small intestines. Phosphorus indicates the amount of acid balance in the body. It does this by regulating secretions of HCl and pepsin in the stomach by the foods you eat. For example, when you eat foods that are high in phosphoric acid, there will be a release of pepsin to neutralize the acid. On the other hand, foods low in phosphoric acid content will cause large amounts of HCl to be released. Phosphorus then carries carbohydrates across the intestinal wall for absorption by the liver. Phosphorus also affects the intrinsic factor function by releasing alkaline B vitamins into inorganic foods, converting them into organic foods for storage in the liver sinusoids.

Patients that have an acid pH in their stomach should avoid excessive amounts of acid forming foods such as meats, dairy, grains and junk foods.

Patients that have an alkaline pH should avoid excessive amounts of alkaline forming foods such as fruits and vegetables.

Diet has a dramatic affect on the acidity or alkalinity of the stomach and is usually the culprit in stomach conditions.

The 3 Phases Of Gastric Secretion

1. The Cephalic Phase- which is the result of hunger, sight, smell and thought about food neurologically controlled by the cerebral cortex that project to appetite centers in the amygdala or hypothalamus. This phase accounts for 1/5th of the digestive juices produced.

2. The Gastric Phase- when the food enters the stomach it excites long vasovagal and local enteric nerves that stimulate the release of gastric juices accounting for 2/3rds of the 1500 ml’s released daily.

3. The Intestinal Phase – once the food enters the duodenum, it triggers the release of gastrin from the intestinal mucosa thus inhibiting the release of gastric juices. The presence of food in the small intestines initiates an enterogastric reflex, which also inhibits gastric secretions. The presence of secretin and cholecystokinin are responsible for pancreatic enzyme release. Cholecystokinin releases bile via the gallbladder and also inhibits gastric function. Acids, protein by-products, gastric inhibitory peptide, vasoactive intestinal polypeptide, and somatostatin all inhibit gastric secretions. Since the stomach is poor at absorption, very little takes place. It is only when you reach the small intestines that you find folds known as valvulae conniventes, which increase the surface area of the small intestines 3 fold. Extending from these conniventes are small projections called villi, which increase the absorption another 10 fold. These villi are close together and their outer epithelial cells form a brush border protruding into the chyme. This increases the absorptive power another 600 fold. This makes the surface of the small intestines 250 sq. meters (About the size of a tennis court). The absorptive capacity of the small intestines is astounding. It can absorb several kilograms of carbohydrates, 500-1000 grams of fat (20-40 ounces), 500-700 grams (20-28 ounces) of protein, and 20 or more liters of water daily.

There are four types of glands that are found in the gastrointestinal tract:

1. Salivary cells are found in the mouth, pancreas, and the liver

2. Mucous glands- Mucous contains, water, electrolytes, glycoproteins, and HCO3

ions. The function of mucous is to adhere tightly to the food while it coats the

intestinal wall. Mucous prevents food from contacting the mucosa. Mucous also

causes fecal particles to adhere together to form a mass. Mucous is also very

resistant to digestive juices, and can buffer acids or alkaline enzymes. The

esophagus also secretes mucous. The mucous glands secrete mucous in response

to vagal stimulation, gastrointestinal enzymes, and irritating factors. Mucous glands

that are in the upper duodenal area between the pylorus and papilla of vata are

called “Brunner’s glands”. Crypts of Lieberkuhn are found in the small intestines.

3. Tubular cells- are found in the stomach and are of 2 types: the oxyntic or gastric and the pyloric. The first, oxyntic, are your parietal and chief cells. The parietal cells secrete HCl, intrinsic factor for B12 absorption, and histamine. The chief cells secrete pepsinogen, intrinsic factor and mucous. The second type of tubular gland is called the pyloric gland. The pyloric glands mainly secrete mucous

but also pepsinogen and gastrin. The oxyntic glands are located in the body and fundus of the stomach comprising 80% of the stomach; the pyloric glands are found in the antral portion of the stomach. These tubular cells are also found in the upper part of the small intestines. Pepsinogen, which is not reactive, is activated and transformed into pepsin by coming in contact with HCl. Pepsin is a proteolytic

enzyme that is highly reactive in an acid media between (1.8-3.5). Therefore, both HCl and pepsin are responsible for protein digestion. Other enzymes of the stomach include gastric lipase and amylase; both are extremely weak and play a minor role in the digestion of fats and starches. Gelatinase, another enzyme, is responsible for liquification of proteoglycans found in meat. The stomach also secretes intrinsic factor, which is responsible for B12 absorption in the ileum.

B12 is responsible for red blood cell maturation. Gastric secretions have a pH of 1.0-3.5.

4. The stomach also secretes gastric amylase and lipase.

The Neurotransmitters Affecting Gastric Secretions Are:

1. Acetylcholine-which is responsible for pepsinogen via peptic cells, gastrin via gastric cells, HCl via parietal cells and mucous secretions.

2. Gastrin (2 types G17 and G34) named for the number of amino acids that make them up, and histamine (an amino acid derivative) both stimulate HCl production.

When gastric or acetylcholine are present histamine has a much stronger effect on acid production. All of these neurotransmitters activate receptor sites on secretory cells, which stimulate the secretory process. Amino acids, caffeine and alcohol can also stimulate gastric secretory activity.

Neural Control Of The Gastrointestinal System

The GI tract is controlled by:

A. Reflex activity between the brain stem (vagus nerve dorsal motor nuclei), such as the stomach motor and secretory activity, pain and strong powerful colonic contractions.

B. The spinal cord via the autonomic nervous system. The sympathetic division extends from T5-L3 forming the celiac and mesenteric plexuses and the sympathetic chain ganglion, which inhibits peristalsis and digestive secretions by the inhibition of the myenteric and submucosal plexus with norepinephrine. Usually, they control long range communication between the stomach, small intestine, ileocecal valve and the colon, by controlled slowing or speeding up of movement of food and fecal material.

C. The parasympathetic outflow division originates from S1-S3 and stimulates the movement of fecal material and reabsorption of H2O and electrolytes. Remember that almost all sympathetic or parasympathetic activity is afferent in nature. This means that distention, mucosal irritation from foods, drugs, preservatives, pH etc. send afferent messages to the brain stem initiating the proper course of action to occur.

D. The GI tract has its own nervous system called the enteric nervous system and is found in the gut wall extending from the esophagus to the anus (100 million neurons are the number of neurons in the spinal cord). The enteric nervous system releases the following neurotransmitters: acetylcholine, norepinephrine, ATP, serotonin, dopamine, cholecystokinin, substance P, vasoactive intestinal polypeptide, somatostatin, and leu-enkephalin. Acetylcholine stimulates intestinal activity norepinephrine inhibits intestinal activity.

The enteric nervous system is composed of 2 plexuses

1. myenteric plexus (Auerbach’s) found between the circular and longitudinal fibers and controls peristaltic movement. The myenteric plexus is composed of linear chains of interconnecting neurons. When stimulated it increases:

• Tonic contractions

• Rhythmic contractions

• Velocity of conduction

• Rate of rhythm

· · ·

Please note that the myenteric plexus does play a role in inhibition of the pyloric sphincter and the ileocecal valve.

2. Submucosal plexus (Meissner’s plexus) is found in the submucosa and is responsible for digestive secretions and blood flow. The purpose of the enteric nervous system is to control peristalsis and digestive secretions short range over small distances. This is most beneficial since the body uses a finer control over the local digestive process.

Digestion And Absorption In The Gastrointestinal Tract

Carbohydrate Digestion- There are 3 major sources of carbohydrates in the diet

Sucrose, a disaccharide known as cane sugar

Lactose, a disaccharide known as milk sugar

Starches (grains), which are long polysaccharides

When monosaccharides form disaccharides, hydrogen is removed from one monosaccharide and a hydroxyl group is removed from the other monosaccharide, forming water in a process (condensation). When disaccharides split into monosaccharides the process is called hydrolysis (the addition of water to form the 2 monosaccharides). Humans cannot digest cellulose.

Carbohydrate digestion starts in the mouth via an alpha amylase known as ptyalin, secreted by the parotid glands. This enzyme hydrolyzes starches into maltose and other small polymers of glucose (3-9 glucose molecules long.). 3-5% of all starches are digested in the mouth. As the food enters the stomach ptyalin continues to digest the carbohydrates so that within 1 hour, upon entering the stomach, most of the carbohydrates are converted into maltose. When the pH falls below 4.0 ptyalin starts to become inactive. By the time the chyme reaches the duodenum and jejunum, pancreatic amylase, which is much more potent then ptyalin (more concentrated), converts the remaining polymers into maltose.

In the lining membranes of the intestinal lumen (microvilli brush border) there are four enzymes produced:

Lactase, which splits lactose into galactose and glucose

Sucrase, which splits sucrose into fructose and glucose

Maltase, which splits maltose into glucose.

Alpha Dextrinase, which splits all of the above as well as dextrins

2. Protein Digestion-Protein digestion starts in the stomach via pepsin. Pepsin is also important for digesting collagen, an albuminoid found in meats. Pepsin is most active at a pH of 2-3. The HCl produced by the body has a pH of .8. When proteins leave the stomach they are mostly in the form of proteases, peptones, and large polypeptides. When the chyme reaches the small intestines the pancreatic enzymes trypsin and chymotrypsin split proteins into small peptides and carboxypolypeptidase then split a small percentage of these into amino acids. The bulk of the peptides are broken down by the multiple peptidases located in the brush border of the intestinal membrane.

The most important peptidases are aminopolypeptidase and several dipeptidases. These split the proteins down to di and tri-peptides, which enter the microvilli membrane into the interior of the epithelial cell where other peptidases break up the remaining di and tripeptides into amino acids to be absorbed into the blood stream. Please note that di, tri, and polypeptides can still enter the blood stream and can cause allergic reactions. 99 % of all protein is absorbed as amino acids.

3. Fat Digestion The most abundant fat in the diet is in the form of triglycerides, which contains a glycerol nucleus and 3 fatty acids (stearic, and palmitic acid, which are saturated and oleic acid which is unsaturated). All 3 come from animal and not plant origin. The usual diet contains phospholipids, cholesterol and cholesterol esters.

Cholesterol is formed in the liver from degraded products of fatty acid molecules, which give cholesterol its fatty characteristics. Fat (butterfat) is digested in the stomach via gastric lipase (tributyrase) in very small amounts. 99% of fat digestion takes place in the intestines via bile. Bile contains bile salts and a phospholipid known as lecithin in the form of ionized sodium salts. Bile salts have the ability to form micelles, small globules of fat attached to the bile salt. This occurs because the sterol portion of the bile salt is highly soluble in fat and a polar portion of the bile salts and lecithin are highly soluble in water. This reducing and changing of the polarity reduces the interfacial tension between the fat cells so digestive enzymes can continue to break down the fat. This increases the total surface area of the fat a 1000 fold. Pancreatic lipase is responsible for splitting 99% of the triglycerides into 3 fatty acids and 2 monossachrides.

Cholesterol, its ester (cholesterol +1 molecule of a fatty acid) and phosopholipids (via cholesterol ester hydrolase and phospholipidase respectively) are broken down via hydrolysis of the fatty acids from their molecular structures. The bile salts, when attached to lipids create micelles, which are highly charged and increase the absorption of these fatty acids, glycerol, free cholesterol and the remaining portion of the phospholipids. Please note that without bile salts much of the fat will be blocked from entering the blood stream.

LIVER

The liver has at least 500 separate functions. If we looked at the classification of these functions we could narrow them down to 2 classifications. The first classification would be one of food processing. The liver is responsible for changing inorganic food to organic food, via the process of denitrification, in which thyroxin is necessary. Lipid metabolism of cholesterol, triglycerides and phospholipids occurs mainly in the liver. Such is the case with carbohydrate, as well as lipoprotein metabolism.

1. CLASSIFICATION ONE-FOOD PROCESSING

For example, when it comes to carbohydrate metabolism the liver does the following:

• Causes gluconeogenesis from fats and proteins

• Acts as a storage center for glycogen and balances blood sugar by the method called “glucose buffer function.”

As far as fat metabolism is concerned, the liver does the following:

• Forms lipoproteins, phospholipids, and cholesterol, of which 80% is used to make bile salts. Both phospholipids and cholesterol are used to make cell membranes, hormones, and intracellular structures. The liver also converts carbohydrates and proteins into fats. The liver also oxidizes fatty acids quickly. Fat is quickly turned into glycerol and three fatty acids, and then through beta-oxidation, becomes acetyl coenzyme A, via the Kreb cycle. It is then sent to other cells in the form of acetoacetic acid, which cells convert back to acetyl coenzyme A.

As far as protein metabolism is concerned:

• The liver forms all major plasma proteins except for gamma globulins. The liver also forms fibrinogen, prothrombin and accelerator globulin.

As far as vitamins and minerals are concerned:

• The liver also stores vitamin A, D, and B12

• The liver also stores iron as ferritin, by using apoferritin to attach to the iron forming ferritin. When there is a decrease of iron in the blood, ferritin releases the iron from the liver.

According to Dr. Brockman, iodine is responsible for catabolism, which is a release of the foods from the liver sinusoids. Vanadium is responsible for anabolism, by storing foods in the liver sinusoids.

2. CLASSIFICATION TWO-IMMUNITY AND TOXIC REMOVAL-The endo-reticular portion, which is the most distal area, is responsible for blood filtration of all poisons, toxins, bacteria, virus, parasites, environmental pollutants, pesticides, industrial chemicals, food additives, metabolic wastes, excessive hormones, medications, and any and all filth that one can put into their body. At the present time, there are thought to be 200,000 foreign chemicals in the environment. The liver, through its various enzyme pathways, is responsible for neutralization of the various poisons.

The first system is the cytochrome P450 group of enzymes known to contain 500 different enzymes. This group of enzymes is also known as the “Phase 1” system. Phase 1 enzymes chemically oxidize substances into more toxic compounds. It is interesting to note that these intermediates can be very reactive and carcinogenic. The substrates that make up the cytochrome P450 group are thought to originate from steroids, sterols, and fatty acids.

The second system, known as the Phase 2 system, converts these substances into nontoxic and readily excreted substances. So, the cytochrome P450 group oxidizes a substance with oxygen, and the Phase 2 system often uses the oxygen site for further metabolism. The phase 2 conjugation pathway system is the addition of an endogenous substance, such as a carbohydrate derivative (glucuronic acid), or amino acids glycine and glutathione, or sulfate, to a foreign compound.

This conjugated compound is now less polar and less lipid soluble, thus facilitating excretion and reducing the likelihood of toxicity. There are three conjugation systems: glycine, sulfate, and glucuronides conjugation. The liver must identify food from toxins. It must program and reconstruct those substances that the thyroid has prepared.

Through the use of copper and iron (cytochromes), the liver tags the microbe or toxin. The iron is used to fight infection and for transportation for beneficial hosting. An example of this would be monocytes attacking a virus and engulfing it and transporting it away from the liver.

Copper is used to neutralize toxins. Once a substance leaves the liver, whether it is food, microbe, or chemical poison, the process of oxidation starts. Iron or copper, prior to its proper destination, must not oxidize the substance. Antioxidants, such as cholesterol and triglycerides, surround the substance so that you can have sufficient time for oxidation and proper combustion of the surrounded substance at the proper time.

Premature oxidation is what allows toxins, microbes, food and metabolic wastes to be released into the system before it reaches its destination.

THE PANCREAS

The pancreas is composed of a head and a tail. The purpose of the pancreatic head is used to secrete pancreatic enzymes. The purpose of the pancreatic tail is to produce insulin. For more information check the pancreatic head and tail sections.

THE TESTICLES

MALE REPRODUCTIVE PHYSIOLOGY

Genes on the short arm of the Y chromosome control testicular differentiation.

There are three principle cell types that make up the testis:

1. Germ cells-from primitive ectodermal cells

2. Supporting cells-derived from coelomic epithelium, which make up the Sertoli cells or granulosa cells of the ovary

3. Stromal (interstitial cells)-from the mesenchyme, which differentiate into the Leydig cells

Sexual dimorphism comes 6-8 weeks after gestation, when the testes are totally developed, within 3 months post gestation. Testicular descent occurs within 7 months and is controlled by dihydrotestosterone and androgens, which may enhance the release of calcitonin gene-related peptide from the genital femoral nerve promoting descent. The INSL3 gene is a member of the insulin-like superfamily that can affect the descent as well. The anti-mullarian (AMH) hormone may also affect this as well. The testes are a network of tubules from Sertoli or germ cells and are used for the production and transport of sperm thru these ducts. Sertoli cells produce AMH, inhibins, activins, prodynorphin, and factors that affect spermatogenesis, such as transferrin. At the same time, it produces androgens from the interstitial or Leydig cells, which consistently produce testosterone. The cytoplasm has a soapy appearance due to the cytoplasm being totally filled with esterified cholesterol. This will be hydrolyzed and the free cholesterol moved to the mitochondria where, under the control of StAR (steroidogenic acute regulatory protein), is converted into pregnenolone, which is then converted into testosterone in the endoplasmic reticulum. The preoptic area and the medial basal area of the hypothalamus and the arcuate nucleus are responsible for GnRH (gonadotrophin releasing hormone) (LHRH luteinizing hormone releasing hormone) in pulsations. The amplitude of pulsations is also affected by catecholamine, dopamine and endomorphic related mechanisms. LH and FSH also control testicular function.

LH receptors are found on the membrane of the Leydig cells and are members of the G-protein-coupled seven transmembrane domain receptor families. The binding of LH activates both adenylate cyclase-cyclic AMP and phospholipase. Cyclic AMP binds to protein kinase, which activates the synthesis of enzymes to produce testosterone. The primary site of action for FSH is on the plasma membrane of the Sertoli cells, where it binds to a receptor and uses the same channels as LH to convert testosterone into estradiol. Testosterone and estradiol influence FSH secretion.

PATHWAYS OF TESTOSTERONE PRODUCTION

CHOLESTEROL

StAR

CHOLESTEROL SIDE CHAIN CLEAVAGE ENZYME

PREGNENOLONE

ADRENALS

AND TESTES 3 BETA-HYDROYSTEROID DEHYDROGENASE

PROGESTERONE

17 ALPHA HYDROXYLASE

OH-PROGESTERONE

17,20-LYASE

ANDROSTENEDIONE

TESTES 17 BETA-HYDROXYSTEROID DEHYDROGENASE

TESTOSTERONE

5ALPHA REDUCTASE AROMATASE

PERIPHERAL

TISSUES

DIHYDROTESTOSTERONE ESTRADIOL

There is also much paracrine control in the testes such as:

1. Testicular peptides inhibins and activins

2. Growth factors such as transforming growth factor, IGF-1 and fibro growth factor

3. Immune-derived cytokines, TNF and interleukins

4. Vasopeptides, angiotensin 2 and natriuretic peptide

When testosterone reaches the plasma, it is either bound to albumin 54% of the time, sex hormone binding globulin 44% of the time, and 2% will be found as free testosterone.

UTERUS PROSTATE

The uterus and prostate play a vital role in oxygen/carbon dioxide/water balance in the body. It does this via a relationship between the mineral potassium and carbon dioxide. The actual function of the uterus and the prostate is to bind fat with water.

The catalyst, which creates this blending of fat and water, is selenium and potassium. The selenium has an affinity for fat and water creating sexual energy and sexual desire.

This energy is coined the “expression of life force.”

Selenium is usually found with high quantities of vitamin F. Vitamin F is also used in the production of the three fatty acids known as linolenic, linoleic and arachidonic acid. When these fatty acids are in combination, they are called the combusted fats. Fats are activated by selenium, and that activation causes a blending of these oils (fats) and water, which occurs at the cell membrane level. Potassium then draws these fatty acids into the cell forcing water into the fat causing a combustion activity with oxygen, creating energy, and a byproduct called carbon dioxide.

As you may have noted in practice, most female patients with uterine problems complain of water retention, lack of energy and excessive fatty deposition, especially in the hips, buttocks and thighs. The proverbial cellulite is a typical uterine condition.

Please note that the bladder, bowel, prostate, and uterus are organs that are also concerned with water balance.

THE ENDOMETRIUM

Implantation occurs in the uterus via the endometrium, which develops spiral arteries in the formation of uteroplacental vessels. Menstruation occurs when the endometrium hemorrhages due to blood flow directed changes via sterogenic hormones

The endometrium is composed of two layers:

1. A FUNCTUNALIS LAYER-which prepares for implantation of the blastocyst (proliferation, and degradation)

2. A LOWER BASALIS LAYER-which is to provide a regenerative functional layer to prepare for the next implantation

There are 5 cycles to the endometrial cycle:

1. MENSTRUAL-postmenstrual reepithelialization

2. ENDOMETRIAL PROLIFERATION-due to estradiol

3. ABUNDANT EPITHELIAL SECRETION-due to estradiol and progesterone

4. PREMENSTRUAL ISCHEMIA-due to volume involution, causes a stasis of blood in the spiral arteries via steroid hormones. Degradation of the stromal reticular network via stromal infiltration by polymorphonuclear, mononuclear leukocytes and secretory exhaustion, which helps shrink the endometrium

5. MENSTRUATION-via progesterone withdrawal causes a severe vasoconstriction of the spiral arteries followed by desquamation. Bleeding occurs once the arteries relax leading to hypoxia-reperfusion injury, creating hematomas and fissures leading to detachment, fragmentation, lysis, and apoptosis. The bleeding is fragments of endometrium, blood and liquefied cellular debris.

Estrogen and progesterone receptors are found in the cells of the endometrium and are reached via blood supply. Progesterone acts as an anti-estradiol hormone by limiting the synthesis of estradiol receptors, converting estradiol into estrone and increasing inactivation of estradiol via sulfonation.

The following tests indicate a uterus prostate problem:

1. Potassium-regulates this fat/water/carbon dioxide exchange

2. Carbon dioxide is released when potassium forces water into the fat

THE PARATHYROIDS

Located on the posterior portion of the thyroid are four-five parathyroid glands weighing 120 grams total, with an ellipsoidal shape having the dimensions of 6x5x2 millimeters. The blood supply for the parathyroids is the inferior thyroid artery. The chief cells, which are the major cells of the parathyroids, synthesize and secrete parathormone (PTH) (which is 84 amino acid’s long) that comes from a pre-proparathormone, which is 110 amino acids long.

Though calcium is the major factor controlling the secretion of PTH, secretion of newly synthesized PTH is from preformed pools of PTH, where cAMP only stimulates these pools. cAMP is the major regulator of PTH secretion. Beta-androgenic catecholamines, dopamine, secretin and prostaglandin E can activate adenylate cylclase and increase cAMP, thereby stimulating PTH regulation.

The basic function of PTH is to control calcium concentration in the extracellular fluid (ECF). Parathyroid hormone, calcitonin and calciferous are the principle calcitrope hormones. Sodium, calcium, and potassium play a central role in the transmission of information between cells.

Phosphates act as:

• Cytoplasmic buffers

• Participate in energy exchange

• Makeup membranes and nucleic acids

The bulk of calcium, phosphates, and magnesium in the body are found in the skeleton. RDA’s of calcium is between 8-1200 mgs, for magnesium 4-600 mgs and 8-1200 mgs for phosphate. Less than 2% of calcium, magnesium and phosphates are found in the plasma and extracellular fluid and are controlled in narrow limits. Steady states of calcium, magnesium and phosphorus approximate urine loss against intestinal absorption and skeletal mineral apposition against mineral absorption. Magnesium in the cells is complexed to phosphate, citrates and anions such as ATP, AMP, and ADP (such as MgATP2).

Phosphates are covalently incorporated into proteins, lipids, and nucleic acids. Many enzymes go thru dramatic shifts in activity via phosphorylation and dephosphorylation.

Ionized cellular calcium regulates secondary cell messengers. Calcium can increase in a cell due to electrical impulses, hormones, and intracellular signals. Calcium also interacts with proteins such as protein kinase C, and ion channels found in plasma membranes and the sarcoplasmic reticulum.

Parathormone levels elevate cell calcium levels in the renal tubules and the osteoblasts. Calcium is transported from the cytoplasm by exchange with sodium. Contracted striated muscle relaxes with rapid removal of calcium from the cytoplasm into the sarcoplasmic reticulum. Plasma membranes undergo many complex interactions with cellular calcium via membrane permeability and pump activity.

In erythrocytes, cellular calcium increases potassium permeability. Mitochondria contain most of the intracellular calcium. There are many cytoplasmic enzyme changes via calcium such as adenylate cylclase, guanylate cylclase, cAMP, ATPase and protein C kinase. Since calcium can regulate contractile proteins, it can affect striated muscle, secretory granule contraction, exocytosis, mitotic spindle function and ciliary beating.

Calcium concentrations can be reduced quickly via repetitive nerve stimulation. Albumin accounts for 70% of the protein binding of calcium. Magnesium bonds to the same site on the albumin molecule as calcium, but with a lower affinity, thereby having more magnesium in a diffusible form. Magnesium is also affected just the way calcium is to parathormone, and to a lesser degree calcitonin.

70 % of phosphates are bound to phospholipids and phosphoproteins and are also affected in and out of plasma compartments by parathormone, calcitonin, and calciferols.

PTH enhances phosphate secretion and inhibits sodium reabsorption in the proximal tubules. PTH stimulates both bone formation and reabsorption (catabolism and anabolism) via influencing osteoclasts, osteoblasts, and osteocytes. PTH enhances synthesis of hyaluronate and inhibits citrate decarboxylation and collagen synthesis while it increases alkaline phosphatase levels.

Other affects of PTH include changes in blood flow, mitosis of lymphocytes, enhanced lipolysis and increased gluconeogenesis from the liver and kidney. PTH reacts with specific receptors on the bone and kidney (renal cortex) activating adenylate cylclase and intracellular messenger cAMP

According to Guyton’s Physiology on the physiology of calcium and phosphate “phosphates act as buffers, participate in energy exchange, and are an essential component of membranes and nucleic acids. 70 % of phosphates are bound to phospholipids and phosphoproteins.”

Phosphates do not affect PTH or calcitonin (CT) levels, but PTH and CT affect phosphate levels. The function of vitamin D and the formation of bone and teeth are all tied together in a common system, along with the two regulatory hormones parathyroid hormone (parathormone), calcitonin and the calciferols. In mammals, the bulk of calcium, phosphates and magnesium are found in the skeleton as hydroxyapatite. Less than 2% are found in the extracellular fluid.

Plasma calcium is used for clotting and kinin formation, regulates plasma membrane potential and exocytosis. As stated above, albumin accounts for 70% of the bound calcium. Magnesium also binds to albumin, and since it has a lower specificity for the receptors, it creates more free magnesium in the plasma. Calcium, magnesium, and phosphates continuously enter the plasma via the kidneys (intestinal brush borders) and the ruffled border of bones.

Calcium, phosphates, and magnesium are depressed in vitamin D deficiencies. Phosphates are reabsorbed by the proximal convoluted tubules due to PTH, and PTH also absorbs magnesium and calcium from the distal tubules. Calcium is poorly absorbed in the intestinal tract, as are most other bivalent cations. Calcium absorption can be dramatically affected by vitamin D, which has a potent effect on increased calcium absorption in the intestinal tract. In fact calcium, magnesium and phosphates are depressed in vitamin D deficiencies and increased with vitamin D excess. Calcium absorption is also increased by dietary sugars.

The D vitamins (calciferols) are steroid molecules of 4 rings. Calciferols are absorbed in the chylomicrons of the small intestines (60-90%) and are bound to alpha globulins. Vitamin D is also stored in the adipose tissue. It is not actually vitamin D, but a vitamin D compound that is formed between the liver and the kidneys, known as 1,2,5-dihydroxycholecalciferol. This 1,2,5-dihydroxycholecalciferol is also stimulated by parathyroid hormone. Another vitamin D compound that is important is D3 (cholecalciferol), found in the skin.

BONE FORMATION

Skeletal tissue consists of an extracellular matrix 55% organic and 45% inorganic and cells. The purpose on the skeletal system is to regulate the distribution of inorganic compounds, such as calcium, for the remodeling and the formation and reabsorption of the matrix.

There are 3 types of cells

1. Osteoblasts-derived from pre-osteoblasts from the mesenchyme. They are cuboid in shape, have a lot of Golgi apparatus for collagen processing, and lots of alkaline phosphatase. Osteoblasts are located in the bone-forming surface and are responsible for elaborating organic compounds from the extracellular matrix and the mineralized bone. The unmineralized matrix forms the osteoid zone and is separated from the mineralized bone via the calcification front. Osteoblasts form bone by the release of alkaline phosphatase, which increases the concentration of phosphate into the bone matrix.

2. Osteocytes-once osteoblasts, they are surrounded by an organic matrix and are now called osteocytes.

3. Osteoclasts-are also found on the bone surface. They are multinucleated, highly mobile moving along the bone surface reabsorbing bone. Osteoclasts break bone down. The cytoplasm contains abundant mitochondria, vacuoles, and lysosomes containing acid hydrolases such as carbonic anhydrate. Other cells found in bone are endothelial cells, fibroblasts, preosteoclasts, and preosteoblasts. Other inorganic components that make up the inorganic matrix are calcium, phosphate in a crystalline structure known as hydroxyapatite, with fluorine, sodium, potassium, magnesium and carbonate.

80% of the skeletal mass is made of cortical (compact) bone (long bones). Cortical bone is composed of packed osteons (haversian systems) surrounding a central canal, and volkmann canals, which radiate from the central canal connecting neighboring osteons to form an anatomizing network for blood and lymph. 20% is trabeculae bone (spongy) (vertebra, the ends of long bones and flat bones.) In trabeculae bone, lamellas are arranged in longitudinal bundles and anastomose with the marrow cavity. Please note that the surface area of trabeculae bone is 5 times that of compact bone.

Bone formation is controlled by osteoblast differentiation, proliferation, matrix formation and mineralization (by alkaline phosphatase cleaving phosphate groups.)

Bone contains many growth factors such as:

• Transforming growth factor B produced by the osteoblasts, which stimulate mitogenesis and collagen synthesis

• IGF 1 and IGF 2

Bone proteins consist of 13 forms of collagen, osteonectin (a carbohydrate containing protein), osteocalcin, osteopontin (produced by osteoblasts) and proteoglycans (glycosaminoglycans), which are controlled by autocrine, paracrine and systemic hormone regulation. Osteocalcin is a protein making up 1-2% of the total bone protein and depends on vitamins D, K, and C.

PROMOTERS OF BONE FORMATION

• INSULIN

• IGF 1 and 2

• ESTROGENS/ANDROGENS

• GROWTH HORMONE

• THYROID HORMONE

• PTH

PROMOTERS OF BONE REABSORPTION

• PTH

• Interleukin 1

• Prostaglandins

• Thyroid hormone

• Epidermal growth factor

• Vitamin A

• Tumor necrosing factor

INHIBITS BONE REABSORPTION

• Calcitonin

• Phosphate

• Glucocorticoids

FORMATION OF THE CALCIFEROLS

7-DEHYDRO CHOLESTEROL OR ERGOSTEROL

PLUS LIGHT

LUMSTEROL PREVITAMIN D TACHYSTEROL

VITAMIN D2 D3

(CHOLECALCIFEROL) (ERGOCALCIFEROL)

DIHYDROTACHYSTEROL

D3 is formed through irradiation of 7 dehydrocholesterol. Dihydroxycholecalciferol lines the intestinal epithelium, absorbing large quantities of calcium when needed in the blood or bone. On the other hand, phosphorus is easily absorbed, unless there are large quantities of calcium that combine with phosphate creating an insoluble calcium phosphate compound that is excreted from the bowel. Ninety percent of all calcium loss is from the bowel. Ten percent is excreted in the urine. The ten percent that is excreted in the urine is controlled by parathyroid hormone, which also causes the excretion of phosphorus.

Plasma calcium is found in three different forms:

• 40% is combined with plasma proteins

• 10% is bound to phosphates and is not usable

• 50% is in the ionized and diffusible state necessary for heart function, bone formation, and nervous system control.

Phosphates exist in two states HPO4, HPO4. When the pH of the extracellular fluid becomes acid, there is an increase in HPO4 and a decrease in HPO4, with the reverse also being true. Phosphorus levels can dramatically change without affecting function. On the other hand, increased amounts of calcium in the blood can cause central nervous system depression. Decreased calcium in the blood can lead to tetney.

Parathormone controls calcium ion concentration in the extracellular fluid by controlling calcium absorption in the intestines, excretion via the kidneys (increases distal tubular reabsorption of calcium and magnesium) and release of calcium from the bones.

Magnesium can exert control over PTH retention.

Calcitonin (CT) is secreted by the parafollicular cells of the thyroid gland as mentioned above, has the opposite effect of parathormone. Although the effect is much weaker than parathormone, there is still that balance necessary to be maintained.

Calcium also stimulates the secretion of CT, as does beta androgenic catecholamines, gastrin, and cholecystokinin. CT decreases alkaline phosphatase, pyrophosphatase activity, and hydroxyproline production. CT inhibits calcium reabsorption from bone.

Therefore parathormone, which is a polypeptide (110 amino acids long), together with calcitonin (32 amino acid’s long), regulates the calcium-phosphorus ratio. If you lack calcium/phosphorus in the blood, then parathormone will shift them out of the bone and decrease excretion from the distal kidney tubules.

Bone is composed of:

• 90-95% collagen (protein)

• 5% ground substance, which is composed of fluid, proteoglycans, chondroitin sulfate and hyaluronic acid.

• 5% bone salts composed of calcium and phosphorus. The major crystalline salt is hydroxyapatite (CA10 (PO4) 6 (OH) 2), along with other bone salts such as magnesium, sodium, carbonate, uranium, plutonium, strontium and K.

PHOSPHORUS AND CALCIUM INVOLVEMENT IN DIGESTION

Phosphorus is also the regulator of the stomach. Phosphorus regulates the amount of HCl and pepsin in the stomach, which controls carbohydrate metabolism via the process of phosphorylation. Phosphorylation is the process that hydrogenates the carbohydrate, which alters the pH for glycogen storage in the liver. Oxygen, on the other hand, oxidizes carbohydrates for immediate use.

The thymus, which will be covered later, assists the parathyroids in the process of phosphorylation. If the phosphorus in the stomach is too low, then the carbohydrate cannot be hydrogenated and the HCl content of the stomach increases, causing an acid stomach. When the phosphorus content is too high, there is a depletion of HCl content in the stomach. This creates an alkaline stomach.

Calcium is the regulator of the small intestines. Calcium, along with B12 and folic acid, attach to lipoproteins so that they can be polarized through the intestinal wall, via magnesium. At the proper time, the calcium will be severed from the lipoprotein when needed for hormone, enzyme, and antibody formation. At that point, the calcium will be released back into the body. The following tests can be used to assess parathyroid function:

1. CALCIUM

2. PHOSPHORUS

THE PANCREAS

The pancreas is composed of a head and a tail. The purpose of the pancreatic head is used to secrete pancreatic enzymes. The purpose of the pancreatic tail is to produce insulin. I will first discuss the pancreatic head.

THE PANCREATIC TAIL

The pancreatic tail (islets of Langerhan) produces the following hormones:

1. Insulin-which has a molecular weight of 5,808, is produced by the beta cells and has the following functions:

a. Inhibits liver phosphorylate for prevention of glycogen breakdown

b. Increases activities of enzymes that promote glycogen synthesis

a. Increases the flow of glucose to the liver

b. Increases sugar flow into fat cells, causing the production of glycerol for fat production with fatty acids

c. Increases membrane permeability for glucose, amino acids, potassium, magnesium, and phosphates

f. Increases translation of messenger RNA and the formation of proteins

g. Decreases the rate of gluconeogenesis in the liver

h. Decreases catabolism of proteins

It is interesting to note that gastrin, secretin, cholecystokinin, somatotrophin, cortisol, glucagon, progesterone and estrogen all affect the release of insulin.

It is also interesting that resting muscles use fatty acids for energy and, when working hard, use glucose for energy.

2. Glucagon-which has a molecular weight of 3,485 and is 29 amino acids long, is produced by the alpha cells and has the following functions:

a. Promotes the breakdown of glycogen in the liver (glucogenesis) by the following process. Glycogen is activated by adenyl cylclase, which is found in the hepatic cell membranes. This forms cAMP (adenosine mono-phosphate), which activates the protein kinase. The protein kinase then activates phosphorylate B kinase, which is converted into phosphorylate A kinase, which causes the degradation of glycogen into glucose 1 phosphate, which is then dephosphorylated into glucose and released into the bloodstream.

b. Promotes gluconeogenesis in the liver

3. Somatostatin-which is 14 amino acids long, produced by delta cells and does the following:

a. Decreases insulin and glucagon secretion

b. Decreased motility, secretions of the stomach and the GI tract

It is interesting that somatostatin is the same chemical substance as somatotrophin inhibiting hormone, which is released by the hypothalamus and suppresses the anterior pituitary from releasing growth hormone.

4. Pancreatic polypeptide secreted by the PP cells and has uncertain functions.

The overall purpose of the pancreatic tail is to regulate muscle tone by balancing sugar and water across the muscle cell interface (membrane.) The pancreas via insulin utilizes zinc as a carrier mechanism to create this effect. As you may recall, actin is the active fiber that is burning and myosin, the stable protein block that contracts and is dramatically affected by this process.

If sugar and water are not balanced accurately, then we have a loss or increased amount of insulin penetration into the cell. This will cause the body great difficulty with sugar metabolism. This may lead to a crystalline blockage, especially at the level of the motor end plate, creating neurological problems. The true pancreatic patient does not have stamina and ages quickly. One of the first complaints of a diabetic is that they sweat a lot and have increased urination, which causes the diabetic to drink a lot of water.

The hypoglycemic, on the other hand, has poor circulation and muscle coordination. The tone of the blood vessels is poor and causes the blood vessel walls to prolapse, allowing blood to pool in the central cavity of the body. The hypoglycemic patient breaks out into cold sweats with spastic trembling to get sugar across the muscle wall. Hypoglycemics also hold fluid, as the kidneys go alkaline which prevents urination.

In order for sugar to be handled properly it must go through the following four processes:

Reaction 1-Copper via the parotids must first tag the carbohydrate. The parathyroids, through the process of “phosphorylation,” add phosphorus to the carbohydrate. So, the first thing that takes place with the preparation of sugar is the phosphorus injecting ability of choline and inositol into the sugar, creating the proper acid-alkaline balance within that sugar for further breakdown. Therefore, the first step in preparing the sugar zinc compound (insulin) occurs in the stomach via pepsin. Chlorine is then added to the compound via HCl acid/pepsin release in the stomach, which is controlled by the adrenal medulla. Once the carbohydrate is properly prepared, it now enters the bloodstream and travels to the liver.

Reaction 2-Once in the liver, the thyroid converts sugar into glycogen by removing nitrogen via iodine. Then glycogen is released by epinephrine and is then activated on by adenyl cylclase that is found in the hepatic cell membranes. This forms cAMP (adenosine mono-phosphate), which activates protein kinase. The protein kinase then activates phosphorylate B kinase, which is converted into phosphorylate A kinase, which causes the degradation of glycogen into glucose 1 phosphate, which is then dephosphorylated into glucose and released into the bloodstream. This only occurs if there are sufficient amounts of zinc and selenium (insulin) outside the liver, which will draw the sugar out of the liver and into the blood.

Zinc is also used to make peptidases for protein digestion and is a component part of LDH via inter-conversion of pyruvic acid into lactic acid. Zinc is also an integral part of carbonic anhydrase, which is found in red blood cells. The purpose of carbonic anhydrase is to adhere to carbon dioxide and water so that it can be expired by the lungs.

Carbonic anhydrase is also found in the gastrointestinal tract and kidneys.

Reaction 3-In order for the insulin/sugar compound to leave the blood and enter the extracellular fluid, glucagon is now necessary for this to occur. When zinc is in higher quantities in the extracellular fluid, in combination with selenium, they draw sugar out of the blood and into the extracellular fluid. The uterus and prostate control selenium. This will be discussed later.

Reaction 4-When the sugar/insulin compound reaches the cell membrane, the selenium draws the sugar into the membrane. At this point, there is a selenium and potassium regulator known as oxytocin, which is released by the posterior pituitary (and closely resembles antidiuretic hormone), which holds the sugar for storage in the cell membrane. This membrane oxytocin is the regulator at every cell membrane for sugar and water entry into the cell to be metabolized. The oxytocin now causes the internal potassium to oxidize the chloride, shifting chloride out of the way, allowing the sugar and water to pass into the cell, which is then combusted to form lactic acid and converted back into lactic acid dehydrogenase in the veins.

The following blood tests determine pancreatic tail function:

1. PHOSPHORUS-indicates the amount of acid balance in the body. It does this via regulating secretions of HCl/pepsin ratios in the stomach. For example, if the food you eat contains large amounts of phosphoric acid, pepsin will be released to neutralize the acid. If the food contains very little phosphoric acid, large amounts of HCl will be released. Phosphoric acid, as explained before, creates the proper balance of choline and inositol into the sugar, affecting sugar metabolism from this point forward. Increases in blood acidity may be due to an increase of zinc and sugar. Alkaline blood is due to a decrease of zinc and sugar. The pancreatic tail regulates this acidity/alkalinity via insulin/glucagon.

2. LACTIC ACID DEHYDROGENASE-is a byproduct of sugar metabolism, as mentioned above. Lactic acid dehydrogenase (LDH) is a glycolytic enzyme that functions as a catalyst in carbohydrate metabolism, which aids the pyruvic and lactic acid interchange. LDH is a byproduct of muscle metabolism. When sugar and water (fatty acid metabolism) are exchanged across a muscle cell interface, a byproduct known as lactic acid is produced. Lactic acid is a byproduct of fatty acid metabolism via the alkalizing and oxidizing effect of the pancreatic head. When lactic acid combines with the venous blood (carbon dioxide), there is a hydrogen displacement. Lactic acid then bonds to a double hydrogen, forming lactic acid dehydrogenase. The organs and glands most responsible for the sugar and water interchange across a muscle cell interface are the pancreas and posterior pituitary (via antidiuretic hormone.)

LDH is chiefly found in the heart, kidneys, liver, skeletal muscle, as well as all tissues. LDH is a normal component of the cerebral spinal fluid.

THE PITUITARY GLAND

The pituitary, the existence of which has been known for 2000 years, sits in the sella turcica of the sphenoid bone. The sella turcica forms the roof of the sphenoid sinus. The lateral walls are comprised of durra or bone, which abut the cavernous sinuses and can affect the 3rd, 4th, and 6th cranial nerves and the internal carotid arteries since they transverse thru this area.

The cavernous sinuses can exert a great deal of CSF pressure but, due to the diaphragm sellae, the gland will not become compressed nor will the optic chiasm and tracts, which lie immediately above the diaphragm sellae. Also lying in close proximity to the cavernous sinuses are the internal carotid arteries, cranial nerves 3, 4, 5 and 6, the third ventricle and the optic chiasm, which lies above the diaphragm sellae.

The pituitary is divided into three parts:

1. ADENOHYPOPHYSIS-is the anterior portion, which is derived from Rathke’s pouch. This is divided into three lobes: the pars distalis (anterior lobe,) the pars inter-media (intermediate lobe) and the pars tuberalis.

2. NEUROHYPOPHYSIS-is the posterior portion and is composed of the pars nervosa, the infundibular stalk, and the median eminence. The major supply of axons to the neural lobe is the magnicellular secretory neurons from the paraventricular and supraoptic nuclei of the hypothalamus. These axon terminals also secrete AVP (regulating blood osmolarity, pressure, and fluid balance) and oxytocin into the surrounding capillary beds leading into the hypophyseal veins. The infundibular stalk is surrounded by the pars tuberalis, and together they make up the hypophyseal stalk.

3. VESTIGIAL INTERMEDIATE LOBE

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The pituitary gland is regulated by the hypothalamus via feedback mechanisms of hormones and from paracrine and autocrine secretions from the pituitary itself. It attaches to the hypothalamus via the stalk thru the diaphragm sellae and into the median eminence.

The pituitary is derived from the:

• ECTODERM-which forms the pars distalis/tuberalis and the intermediate lobe

• NEURAL PORTION-which forms the infundibulum, posterior pituitary, and neural stalk

The pituitary weighs between 4-900 mgs (during pregnancy up to 1 gram), is bean shaped and brownish in color with dimensions of 9 mm A/P, 6mm S/I, 13 mm laterally. The hypothalamus receives its blood supply from the superior (provides 10-20 % of the blood supply) and inferior hypophyseal arteries (supply blood to the posterior pituitary), which are derived from the internal carotid arteries. These arteries form a capillary network in the median eminence (external to the blood-brain barrier).

This capillary network picks up hypothalamic secretions from the hypothalamic nerve endings delivering them into the long and short hypophyseal portal veins, which are now transported to the anterior pituitary. Please note that retrograde blood flow causes bi-directional movement of blood between the hypothalamus and pituitary. Once the hypothalamic releasing hormones reach the pituitary, they activate G protein receptors on the cell membrane, creating a cascading chain reaction for the production of their pituitary hormone counterparts. Blood drainage of the pituitary leaves through the cavernous sinuses and the petrosal veins and out the jugular foramina via the jugular vein. Note that the blood supply to the pituitary via the hypothalamus is not unidirectional and can flow both ways creating ultra-short biofeedback loops.

The hypothalamus releases its secretions via hypothalamic neurons, which end in the infundibulum and permeate into the fenestrations at the perigomitolar capillaries. This enters the portal vein, which enters the capillary circulation of the anterior pituitary (which provides 80-90 % of the blood supply to the pituitary). The pituitary, as stated above, is attached to the hypothalamus via the pituitary infundibulum.

The diaphragm sellae has a 5mm opening for the hypophyseal stalk and allows transmission of pulsations of CSF. The purpose of the pituitary infundibulum is to act as a direct pathway for hormonal secretion between the hypothalamus and the pituitary. Pituitary hormones are released as pulsations, which does affect hormonal levels minute, by minute, which may give false positives when measuring hormonal levels.

Each releasing factor (hormone) that is released from the hypothalamus causes a release of a hormone from the anterior pituitary. The hypothalamus also produces two hormones called anti-diuretic hormone and oxytocin. The anti-diuretic hormone is formed primarily by the supraoptic nuclei, whereas oxytocin is formed primarily in the paraventricular nuclei. The major nerve tracts of the neurohypophysis arise from these two nuclei, from large cells termed magnocellular cells forming the supra optico hypophyseal tract and the paraventricular hypophyseal tract. AVP and oxytocin tracts are also distributed widely and project into the brain stem affecting the vagal nuclei, glossopharyngeal nuclei, and the spinal cord, sending information to the ANS to evaluate blood pressure. Vasopressinergic and oxytocin fiber pathways (which have different effects than those that end in the posterior pituitary) also terminate in the choroid plexus, which influences salt and water exchange between the brain (especially regions associated with emotion and memory) and the CSF.

Neurological impulses from the two nuclei above, cause a secretory granular release of these two hormones into the posterior pituitary, which are then released into the adjacent capillaries. It is interesting to note that the differences between oxytocin and anti-diuretic hormone are two amino acids. Otherwise, the chains are identical. The functions are entirely different, as you will see.

The anterior pituitary is controlled by the hypothalamus in a slightly different manner than the posterior pituitary. Oxytocin and anti-diuretic hormone (AVP) are produced in the hypothalamus and are released into the posterior pituitary, via the neurological tracts of those nuclei mentioned above in the hypothalamus. Other neurological tracts secrete other neuropeptides called TRH (thyrotrophin releasing factor), CRH (corticotrophin releasing hormone), VIP and neurotensin. Paraventricular hypophyseal tracts located on either side of the ventricles are both unmylenated and descend thru the infundibulum. The releasing factors from the hypothalamus are transmitted to nerve endings, which then release these factors into a primary plexus of veins known as the hypophyseal portal system. These veins are located in the pituitary infundibulum and travel into the anterior pituitary, releasing the hypothalmic hormones into and stimulating the anterior pituitary.

THE ANTERIOR PITUITARY

(PARS DISTALIS, PARS GLANDULARIS)

The anterior lobe is composed of 3 divisions:

1. PARS DISTALIS – largest and produces most of the hormones

2. THE INTERMEDIA-the least developed

3. TUBERALIS-attached to the pituitary stalk and produces many of the glycoproteins. At this poin, there are cells that produce specific hormones, from specific releasing factors released from specific areas in the hypothalamus. There are 5 specific secreting cells that arise from totipotential pituitary stem cells of the anterior pituitary. They are:

• CORTICOTROPHIC CELLS-which express POMC (pro-opiomelanocortin) peptides including ACTH

• SOMATOTROPH CELLS-which express growth hormone

• THYROTROPHS-which express TSH

• GONADOTROPHS-which express FSH and LH

• LACTOTROPH CELLS-which produce prolactin

These hormones are produced in the anterior pituitary and are now released into the hypophyseal portal veins. They continue down through the circulatory system to target sites in the body. Any hormones that are now released from the target sites reenter the bloodstream and are transported back to the hypothalamus via the hypothalamic artery and to the pituitary via the hypophyseal artery. This is why it should be looked at as a “neuroendocrine axis” due to this dual control mechanism. It makes much more sense and is more reliable to have each system checking and balancing each other.

The following hormones are released from the anterior pituitary:

1. FOLLICLE STIMULATING HORMONE (GONADOTROPHINS) -are released by lutenizing hormone-releasing hormone (LHRH) via the hypothalamus. Gonadotrophin cells make up 10-15 % of the anterior pituitary. FSH and LH regulate gonadal steroid hormone biosynthesis and germ cell production. FSH, LH, TSH, and HCG are all glycoproteins. The purpose of follicle stimulating hormone is to stimulate the growth of the follicle on the ovary. FSH, LH, TSH AND HCG all have identical alpha subunit chains. These are polypeptides containing 92 amino acids, whereas the beta subunit chains contain 117, 121, and 145 amino acids. LHRH synthesizes these alpha and beta gonadotrophin subunits forming and secreting FSH, LH, CRH (corticotrophin releasing hormone) and progesterone.

The follicle-stimulating hormone increases estrogen levels. As estrogen levels rise in the bloodstream, they enter the hypothalamic artery and decrease the output of LHRH from the hypothalamus. There are also a group of peptide hormones produced by the gonads called inhibins, which are produced by the follicular-luteal and sertoli cells of the gonads that inhibit FSH secretion, without affecting LH secretion. Activins also produced by the above cells stimulate GnRF, which induces FSH production. Activins and inhibins regulate granulose cell growth, differentiation, steroid hormone production, oocyte maturation and follicular development.

You will notice that most hormones either increase or decrease the output of other hormones through this kind of a feedback mechanism. If a hormone increases the output of another hormone, then it is said to be a positive feedback mechanism. On the other hand, if a hormone decreases the output of another hormone, then it is said to be a negative feedback mechanism.

2. CORTOCOTROPHIN STIMULATING HORMONE (ADRENO-CORTICOTROPHIC STIMULATING HORMONE) (ACTH)-ACTH production is inhibited by angiotensin 2, activins, inhibins, cytokines and cell-to-cell communication.

Corticotrophs constitute 20% of the anterior pituitary. ACTH is a 39 amino acid peptide made from a 241 amino acid structure called pro-opiomelanocortin (POMC). This is cleaved in tissue-specific fashion to yield small peptide hormones. POMC is also transcribed in other tissues such as the brain, liver, kidney, gonads and the placenta. POMC expression within the hypothalamus is cleaved into MSH and is thought to regulate hair color and appetite control. POMC is controlled by CRH, arginine, vasopressin, stress, circadian rhythms and the negative feedback of cortisol. Pro-inflammatory cytokines (interleukins 1 and 6, TNF (tumor necrosing factor) and physical stress increases ACTH release.

ACTH circadian rhythms begin at 4 am and peak at 7 am, and are generated by the supra chiasmic nucleus, which signals CRH release. ACTH is secreted in bursts and increases in frequency 3-5 hours after sleep and is highest upon awakening. Adrenal steroid hormones reach their peak between 11 pm and 3 am. ACTH circadian rhythms are entrained by visual cues and the light/dark reactions. The rhythms are affected by sleep/wake, light/dark reactions, spontaneous bursts and stress via CRH. Glucocorticoids inhibit while CRH stimulates the synthesis of ACTH by binding to high-affinity receptors stimulating cyclic-AMP activating protein kinase A of the POMC mRNA (pro-opiomelanocortin). POMC undergoes post-translation processing including glycosylation, enzymatic cleavage, phosphorylation, NH2 terminal acetylation, and COOH amidation via amidase, which catalyzes the formation of a monocarboxylic acid and ammonia by cleavage of the C-N bond of a monocarboxylic acid amide.

ACTH is also cleaved into beta-MSH and beta-endorphin. The actions of ACTH on the adrenals is to maintain adrenal size, function and adrenal steroid genesis thru specific cell membrane receptors, which requires a G protein-coupled melanocyte 2 receptor (3500 on each adrenal cell) and calcium ion channels for ACTH to bind. This activates adenyl cylclase, which increases cAMP and protein kinase A activity and phosphorylation of many proteins. ACTH secretion activates the conversion of cholesterol into pregneolone (hormone production) and protein synthesis via p450 enzyme transcription for cortisol, aldosterone and 17-hydro progesterone, which is necessary to produce steroid hormones. Exercise, which is exhausting and for short durations increases ACTH immensely. Pain, infection, trauma and hypoglycemia also affect ACTH.

ACTH is controlled by a 3-tier system:

1. Hypothalamic secretions such as CRH and vasopressin

2. Intra pituitary cytokines and growth factors

3. Glucocorticoid negative feedback on the hypothalamus

Glucocorticoid target neurons lie outside the hypothalamus in the hippocampus, septum, and amygdale nucleus, and are part of the visceral brain involved in emotional states. At the hippocampus glucocorticoid receptors determine the set point for cortisol. Glucocorticoids affect cerebral vascular permeability, choroid transport of H20 and electrolytes, regulating CSF synthesis and brain volume. Although most steroids that affect the brain come from the circulation, these steroids produced in the brain are called neurosteroids (estradiol, pregnenolone, dehydroepiandosterone located in the oligodendroglial cells). Glucocorticoids inhibit the release of CRH and AVP. Morphine stimulates the release of ACTH.

3. THYROID STIMULATING HORMONE (TSH) -Thyrotrophs make up 5% of the anterior pituitary. TSH is a glycoprotein where the cells are located in the anteromedial portion of the anterior pituitary.

TSH is composed of two subunits an:

• Alpha subunit-which is similar to lh, fsh, and hcg

• Beta subunit-which is 112 amino acids long

TRH increases transcription of both alpha and beta units, whereas dopamine inhibits them. TRH stimulates glycosylation of TSH within the rough endoplasmic reticulum, which is then sent to the Golgi apparatus, folded and put into secretory granules. Estrogens, glucocorticoids, and GH modify TSH secretion. Stress also inhibits the release of TSH and GH. TRH binds to the thyrotrophin membranes, and through calcium ion channels and cGMP (cyclic guanosine monophosphate), which act as secondary messengers, produce between 100-400mU/day of TSH. TSH secretion is pulsating in nature, pulsing every 2-3 hours. Circadian peaks with the onset of sleep are between 9 pm-5am, are at a minimum between 4-7pm, and do not appear to be sleep entrained. This is also accompanied by an ultradian rhythm of 90-180 minutes. TSH stimulates the thyroid to produce thyroxin, which determines metabolic rate with pulsating variations of thyroxin at 1-2 hour intervals.

TSH is decreased by warm temperature, starvation, and infection via tumor necrosing factor. TSH does the following:

a. Stimulates phospholipid metabolism

b. Stimulates purine and pyrimidine precursors and their incorporation into nucleic acids

TSH is regulated by an open loop feedback via thyroxin, whereby thyroxin passes into the CSF of the lateral ventricles and is taken up by the epithelial cells of the choroids plexus. When thyroxin levels are low, these stimulate TRH-secreting neurons in the hypothalamus. TSH may be modified by estrogens, glucocorticoids, and GH and are inhibited by the pituitary and hypothalamic cytokines. Thyrotrophin is also inhibited by somatostatin and dopamine.

4. LUTEINIZING HORMONE-plays an important role in ovulation and the release of estrogen in the female and testosterone in the male.

5. LUTEOTROPHIC STIMULATING HORMONE (PROLACTIN) -lactotroph cells comprise 15-25 % of the anterior pituitary, and most come from GH-producing cells. Prolactin is 199 amino acids long, closely resembles GH, and is produced in the pituitary by small polyhedral cells. Approximately 100 ugs of prolactin are produced daily as compared to 50 times this for GH. Dopamine secretions via the tuber infundibular pathways inhibit prolactin, by inhibiting adenyl cylclase activity and the release and synthesis of prolactin. Prolactin is also inhibited by calcitonin and transforming growth factor. Prolactin-releasing factors include GnRH, TRH, VIP, oxytocin and estrogen (which increases gene transcription and secretion.) Prolactin is released in moderate amounts during mid-day and increase around bedtime. Prolactin stimulates the development of breast tissue (along with growth hormone and IGF 1) and the secretion of milk.

During pregnancy, the pituitary doubles due to PRL producing cells. Prolactin levels can increase from 200 micrograms to 500 micrograms and ammonic PRL may increase to 100 times that of the blood. Suckling causes the mechanoreceptors in the breasts to stimulate nerves in the nipple, which travel to the spinal cord, stimulating the release of prolactin. Then they travel to the spinal cord up through the spin thalamic tract to the lateral cervical nucleus, and to the medulla. Neurological impulses ascend to the oxytocin neurons of the magnicellular cells, to the supraoptic nuclei and the paraventricular nucleus, finally affecting the pituitary. Oxytocin is affected by mating, emotional and physical stress, and cycles related to sleep. The principle inhibitor of prolactin is dopamine.

Prolactin is neurologically controlled by many tuber hypophyseal neurons, where the set point is controlled by dopamine secretion (inhibits PRL where serotoninergic stimulates the release). The posterior pituitary also affects PRL release via oxytocin, AVP, and TRH. Prolactin acts through receptors in the liver, breast, adrenal cortex, kidneys, epidermis, lungs, myocardium, pancreatic islets, brain, lymphocytes, ovaries/uterus and testicle/prostate. These are the same receptors used for GH reception. Prolactin and oxytocin together regulate milk production, whereas oxytocin is used for milk let down. Both hormones are under the control of the gonadal steroidal hormones. Milk is synthesized in the glandular cells of the alveoli. Oxytocin receptors are found on these glandular cells, which cause these cells to contract expelling milk into the ducts, where oxytocin causes a widening and contracting of these same ducts.

REGULATION OF THE MENSTRUAL CYCLE

On the first day of menstrual bleeding, the follicles are small, accompanied by low levels of estradiol. Pulsations of LH are fast, about 1 every 60 seconds. FSH levels are high, which increase follicular size and estradiol production. As estradiol production increases, it acts as a negative feedback loop on the hypothalamus, decreasing LH to 1 pulsation every 90 seconds. At the 15th, day estradiol, which is at a peak, triggers the hypothalamus to release GnRH and high amounts of FSH and LH, which then stimulates the dissolution of the follicular wall, releasing the ovum into the fallopian tube. The Follicular cells now undergo differentiation and become the corpus luteum (yellow body) that secretes large amounts of progesterone. This will maintain pregnancy due to its negative feedback on GnRH, FSH and LH production.

The time frame is fixed for the corpus luteum. This also produces small amounts of estradiol. If the egg is not fertilized and implanted in the endometrial lining, then the corpus luteum digresses due to prostaglandin F production, which causes luteolysis, decreasing progesterone and estradiol production. This causes a sloughing off of the endometrium within 28-30 days, or at the end of pregnancy prior to parturition. Just prior to parturition, there is an increase in FSH and LH production and oxytocin is released in an explosive pulsating fashion. Stresses on reproduction include:

• Mental

• Diet chemical

• Physical exercise

• Pain and injury

• Infection

All create reductions in GnRH, FSH, LH, and gonadotrophins. Fuels essential for reproductive function are glucose and fatty acids.

6. MELANOCYTE-STIMULATING HORMONE-This stimulates the melanocytes to produce melatonin for skin pigmentation and sexual drive.

7. SOMATOTROPHIN (GROWTH HORMONE) (GH)-Makes up 50% of the cells of the anterior pituitary and produces between .25-52 mgs every 24 hours with a storage capacity of 5-10 mgs at any time. Somatotrophin is a 191 amino acid chain with a molecular weight of 22,005 and a half-life between 9-27 minutes. The purpose of growth hormone is to create growth in the body. It does this by:

• Promoting protein synthesis, amino acid transport, increased urinary nitrogen retention, increases lean muscle tissue and energy expenditure

• Increases fatty-acid breakdown for energy

• Decreasing glucose utilization, by enhancing glycogen deposition and insulin secretion

• Increasing bone growth through osteoclastic activity, epiphysis growth, osteoclastic differentiation, and activity and increases bone mass by endochondral bone formation.

• Having acute insulin-like effect followed by lipolysis, decreased glucose transport, decreased lipogenesis (by inhibiting lipoprotein lipase) and increased lipolysis.

GH has been described as being, anabolic, lipolytic and diabetogenic. GH does the following:

a. Stimulates the Liver-RNA synthesis, plasma protein synthesis, somatomedin release and replication

b. Stimulates Muscles-amino acid transport and incorporation

c. Stimulates vascular outgrowth of blood vessels

d. Stimulates hemopoeitic centers via increasing mitosis

e. Stimulates adipose tissue lipolysis

GHRH, GH secretagogues, and SRIF receptor subtypes 2 and 5, mediate GH secretion and controls GH. GHRH induces GH gene transcription and hormone release whereas SRIF inhibits GHRH but not GH biosynthesis. Ghrelin, which is 28 amino acids long, induces GHRH and GH production. Ghrelin is synthesized in peripheral tissues, especially the gastric mucosa neuroendocrine cells. GH release is from rhythms, with a maximum of 2 mgs per day in late puberty, to 20 micrograms in older or obese people. Most GH is released during nocturnal times, irrespective of sleep, with the highest release during slow wave sleep and lowest during REM sleep. Feedback mechanisms also increase GH release such as:

• Exercise

• Physical and emotional stress

• Slow wave sleep

• Fasting

• High-protein meals

• Specific amino acids such as arginine and leucine

• High carbohydrate meals when blood sugar is falling.

• The sex hormones estrogen, progesterone, testosterone, and TSH also modify GH

High levels of glucocorticoids suppress GH. 3 inhibitory peptides, GH itself, somatostatin, and IGF 1 also regulate GH. Other factors that stimulate GH release are insulin in hypoglycemia (which can also suppress GH), arginine, leucine, lysine, norepinephrine, AVP, alpha-MSH, glucagon, epinephrine, 5-hydroxytryptophane, melatonin, and potassium. Other factors that inhibit GH are acetylcholine, progesterone, morphine, melatonin and increased intake of free fatty acids. GH secretion is low in obese people due to high somatostatin levels. Depression also leads to decreased levels of GH. GH has an inverse relationship to insulin and GHRH containing nerve fibers that arise from the arcuate and ventromedial nucleus.

GHRH via GHRH cell membrane receptors increase adenyl cyclase, cAMP, protein kinase C and intra calcium ion concentration whereby somatostatin has the opposite dominant effect on these same receptors. IGF 1 (somatostatin C) also influences the hypothalamus to reduce GHRH via the hippocampus (and are excitatory), from the amygdale, which can be excitory (basso lateral amygdale) and inhibitory (corticomedial amygdale).

The ventromedial nucleus regulates fat and carbohydrate metabolism. This nucleus contains gluco receptors stimulating insulin secretion and GH release. From a biochemical blood chemistry perspective, the pituitary hormones deal with the growth of the body.

This is accomplished by hormones of the anterior pituitary controlling lipoprotein digestion and placement for growth and repair, via the control of all organs and glands that control digestion, assimilation, and metabolism. Without digestion and proper placement of the prepared foods by the body, you have no growth. The primary purpose of the pituitary is one of anabolism, rather than catabolism. This means that any catabolic disease that overcomes the human body may have their roots in the anterior pituitary.

The following blood tests are used to determine anterior pituitary function:

1. CHOLESTEROL-This is a byproduct of protein metabolism, which is the bonding of oily fats to nitrogen and is produced by every cell in the body. This is called your endogenous cholesterol. Exogenous cholesterol comes from dietary intake. It is the combination of the above two that shows cholesterol levels.

Did you know that the majority of cholesterol produced and taken in through diet forms an enzyme called cholic acid? Cholic acid is an enzyme, which is released by the gallbladder to emulsify fats, which you take in through your diet.

If you do not take in any fat, then your body does not need any cholic acid. Since 50-60% of your cholesterol is used to produce cholic acid, your cholesterol levels will rise. Such is the case with all the people on low-fat diets trying to reduce their cholesterol levels. 25-35% of the cholesterol is used as a precursor to make your sex hormones, estrogen, progesterone, and testosterone. Cholesterol is also used to make antibodies and acts as a mucous lubricant for mucus, synovial, and cellular membranes.

Since the anterior pituitary controls protein digestion and placement, you can see why cholesterol, which is a byproduct of protein metabolism, can be of use in determining a problem with the anterior pituitary.

2. BLOOD UREA NITROGEN-This is an end product of protein metabolism. When lipoproteins enter the liver via the calcium magnesium gradient, the liver changes the foodstuff from an inorganic to an organic state, and can now process the food.

Cleaving a nitrogen atom (breaking a bond) from the amino acid molecule does this. Thyroxin, which is produced by the thyroid, is what “cleaves off” this nitrogen atom from the protein. So, thyroxin oxidizes the protein molecule via iodine, by splitting off one nitrogen atom. When the nitrogen is released, it is converted into ammonia, then to urea, via the ornithine cycle. From the liver, it is sent to the kidneys, via the blood stream, to be released in the urine.

3. MAGNESIUM AND CALCIUM-Calcium is the substance that pushes proteins, fatty acids, and triglycerides through the intestinal wall and through the cell membrane of each cell. When the calcium to magnesium ratio is greater than two-parts calcium to one-part magnesium, there is a movement of the above through the intestinal wall. This calcium to magnesium phenomenon creates an electrical osmotic gradient that draws the calcium and lipoprotein across the membrane of the cell. Magnesium is also very abundant within the cell, approximately one-sixth the amount of potassium.

The calcium magnesium ratio within the cells is five to one.

In plasma, 75 percent of the magnesium is in the ionic state, with the remainder bound to protein. Magnesium, within the cell, acts as a catalyst for enzymes associated with carbohydrate metabolism. Increased extracellular magnesium decreases neurological and muscular-skeletal activity.

The anterior pituitary and its hormones are used to control the mineral magnesium in this endeavor. Calcium, due to its “ratio effect,” can also be looked at when determining anterior pituitary function.

THE PITUITARY GLAND

The pituitary, the existence of which has been known for 2000 years, sits in the sella turcica of the sphenoid bone. The sella turcica forms the roof of the sphenoid sinus. The lateral walls are comprised of durra or bone, which abut the cavernous sinuses and can affect the 3rd, 4th, and 6th cranial nerves and the internal carotid arteries since they transverse thru this area.

The cavernous sinuses can exert a great deal of CSF pressure but, due to the diaphragm sellae, the gland will not become compressed nor will the optic chiasm and tracts, which lie immediately above the diaphragm sellae. Also lying in close proximity to the cavernous sinuses are the internal carotid arteries, cranial nerves 3, 4, 5 and 6, the third ventricle and the optic chiasm, which lies above the diaphragm sellae.

The pituitary is divided into three parts:

1. ADENOHYPOPHYSIS-is the anterior portion, which is derived from Rathke’s pouch. This is divided into three lobes: the pars distalis (anterior lobe,) the pars intermedia (intermediate lobe) and the pars tuberalis.

2. NEUROHYPOPHYSIS-is the posterior portion and is composed of the pars nervosa, the infundibular stalk, and the median eminence. The major supply of axons to the neural lobe is the magnocellular secretory neurons from the paraventricular and supraoptic nuclei of the hypothalamus. These axon terminals also secrete AVP (regulating blood osmolarity, pressure, and fluid balance) and oxytocin into the surrounding capillary beds leading into the hypophyseal veins. The infundibular stalk is surrounded by the pars tuberalis, and together they make up the hypophyseal stalk.

3. VESTIGIAL INTERMEDIATE LOBE

.

The pituitary gland is regulated by the hypothalamus via feedback mechanisms of hormones and from paracrine and autocrine secretions from the pituitary itself. It attaches to the hypothalamus via the stalk thru the diaphragm sellae and into the median eminence.

The pituitary is derived from the:

• ECTODERM-which forms the pars distalis/tuberalis and the intermediate lobe

• NEURAL PORTION-which forms the infundibulum, posterior pituitary, and neural stalk

The pituitary weighs between 4-900 mgs (during pregnancy up to 1 gram), is bean shaped and brownish in color with dimensions of 9 mm A/P, 6mm S/I, 13 mm laterally. The hypothalamus receives its blood supply from the superior (provides 10-20 % of the blood supply) and inferior hypophyseal arteries (supply blood to the posterior pituitary), which are derived from the internal carotid arteries. These arteries form a capillary network in the median eminence (external to the blood-brain barrier).

This capillary network picks up hypothalamic secretions from the hypothalamic nerve endings delivering them into the long and short hypophyseal portal veins, which are now transported to the anterior pituitary. Please note that retrograde blood flow causes bi-directional movement of blood between the hypothalamus and pituitary. Once the hypothalamic releasing hormones reach the pituitary, they activate G protein receptors on the cell membrane, creating a cascading chain reaction for the production of their pituitary hormone counterparts. Blood drainage of the pituitary leaves through the cavernous sinuses and the petrosal veins and out the jugular foramina via the jugular vein. Note that the blood supply to the pituitary via the hypothalamus is not unidirectional and can flow both ways creating ultra-short biofeedback loops.

The hypothalamus releases its secretions via hypothalamic neurons, which end in the infundibulum and permeate into the fenestrations at the perigomitolar capillaries. This enters the portal vein, which enters the capillary circulation of the anterior pituitary (which provides 80-90 % of the blood supply to the pituitary). The pituitary, as stated above, is attached to the hypothalamus via the pituitary infundibulum.

The diaphragm sellae has a 5mm opening for the hypophyseal stalk and allows transmission of pulsations of CSF. The purpose of the pituitary infundibulum is to act as a direct pathway for hormonal secretion between the hypothalamus and the pituitary. Pituitary hormones are released as pulsations, which does affect hormonal levels minute, by minute, which may give false positives when measuring hormonal levels.

Each releasing factor (hormone) that is released from the hypothalamus causes a release of a hormone from the anterior pituitary. The hypothalamus also produces two hormones called antidiuretic hormone and oxytocin. Anti-diuretic hormone is formed primarily by the supraoptic nuclei, whereas oxytocin is formed primarily in the paraventricular nuclei. The major nerve tracts of the neurohypophysis arise from these two nuclei, from large cells termed magnocellular cells forming the supra optico hypophyseal tract and the paraventricular hypophyseal tract. AVP and oxytocin tracts are also distributed widely and project into the brain stem affecting the vagal nuclei, glossopharyngeal nuclei, and the spinal cord, sending information to the ANS to evaluate blood pressure. Vasopressinergic and oxytocin fiber pathways (which have different effects than those that end in the posterior pituitary) also terminate in the choroid plexus, which influences salt and water exchange between the brain (especially regions associated with emotion and memory) and the CSF.

Neurological impulses from the two nuclei above, cause secretory granular release of these two hormones into the posterior pituitary, which are then released into the adjacent capillaries. It is interesting to note that the differences between oxytocin and anti-diuretic hormone are two amino acids. Otherwise, the chains are identical. The functions are entirely different, as you will see.

The anterior pituitary is controlled by the hypothalamus in a slightly different manner than the posterior pituitary. Oxytocin and anti-diuretic hormone (AVP) are produced in the hypothalamus and are released into the posterior pituitary, via the neurological tracts of those nuclei mentioned above in the hypothalamus. Other neurological tracts secrete other neuropeptides called TRH (thyrotrophin releasing factor), CRH (corticotrophin releasing hormone), VIP and neurotensin. Paraventricular hypophyseal tracts located on either side of the ventricles are both unmylenated and descend thru the infundibulum. The releasing factors from the hypothalamus are transmitted to nerve endings, which then release these factors into a primary plexus of veins known as the hypophyseal portal system. These veins are located in the pituitary infundibulum and travel into the anterior pituitary, releasing the hypothalmic hormones into and stimulating the anterior pituitary.

THE POSTERIOR PITUITARY

(NEUROHYPOPHYSIS, INFUNDIBULAR PROCESS)

The posterior pituitary includes the pars nervosa, infundibular stalk, and the median eminence, and is directly innervated by the supraoptic hypophyseal and the tuber hypophyseal neurological tracts. The median eminence, which lies in the tuber cinereum, has an internal zone from which the supraoptic and paraventricular magna cellular neurons control the posterior pituitary and an external zone, which receives information from the hypophyseal trophic neurons (sensory trophic neurons.) The magnocellular neurons embrionically arise out of neuroepithelial cells lining the third ventricle, which form the supraoptic nuclei above the optic chiasm, and the paraventricular nucleus located in the third ventricle.

A third structure, which is also considered part of the median eminence, is the pars tuberalis, which surrounds the infundibulum and pituitary stalk. The median eminence is composed of nerve endings and blood vessels and is truly the functional link between the hypothalamus and the pituitary. The median eminence receives blood supply from the posterior communicating and superior hypophyseal artery (from the internal carotid) and drains thru the cavernous sinuses.

The blood then flows thru capillary loops, which anastomose and drain into the sinusoids, which become the pituitary portal veins. The pituitary portal veins drain into the pituitary, the neural stalk and specialized neuro tissues that lie at the base of the hypothalmic pituitary juncture. This forms the base of the third ventricle, creating a funnel (infundibulum), and literally draining into the CSF as well as releasing neurosecretions into the anterior pituitary.

The 2 major hypothalamic/posterior pituitary nerve tracts, which arise from magnicellular cells, are the bilateral supraoptic nucleus and the paraventricular nucleus and they produce (via ribosome protein synthesis) a pre-prohormone. Then, via glycosylation in the Golgi apparatus, the pre-prohormone is made into the prohormone and transported via neurosecretory granules (inactive state), where the secretory granular membrane adheres to the plasma membrane, releasing the granular material into the cell. It is then stored in the posterior pituitary as a neurophysin.

Then, through the process of exocytosis, anti-diuretic hormone (AVP) and neurophysin 2 are released via neuron bombardment into the blood stream. There are two receptor sites: V1 found in smooth muscle, and V2 found in renal epithelial. V2 activates antidiuretic activity by activation of adenylate cylclase.

Once the neurophysin is cleaved, the hormones are released. Capillaries and glue like non-secretory cells (pituicytes) help bind together the posterior pituitary. The capillaries are different in that they allow diffusion of the neurosecretory cells into the blood stream, unlike other capillaries in the brain that are subject to the blood brain barrier, preventing diffusion into circulation. The purpose of the posterior pituitary is to regulate body cell osmolarity by regulating sodium concentration, and by effective extracellular fluid regulation via osmoreceptors.

Osmoreceptors for thirst and AVP release respond to slight changes in extracellular fluid osmolarity. The primary osmoreceptors that are triggered are triggered by urea and glucose for sensing changes in osmolarity and are found in the brain and outside the blood brain barrier. For example, an increase in ECF (extracellular fluid) osmolarity causes shrinkage of the cells, stimulating the osmoreceptors inside the cells to stimulate the release of AVP and angiotensin 2, conserving H20. Bar receptors are of two types:

• Low pressure found in the right side and left atrium of the heart

• High pressure found in the carotid sinus and aortic arch. This stimulates the vagus nerve and the glossly pharyngeal to the nucleus tractus solitarius then via noradrengic projections into the PVN and SON, which then inhibits the release of AVP

To a lesser degree, a drop in blood volume stimulates angiotensin 2 and AVP release, stimulating thirst and increasing blood volume. Once blood volume is up, the oropharyngeal reflex and the release of atrial natriuretic peptide suppresses thirst. In actuality, the purpose then becomes regulating cell volume against extracellular fluid. The goal is to create a balance in Intra and extracellular osmolarity, whereby permeability would be perfect for passive and active transport (keeping the highways open between the cells and the extracellular fluids they bathe in.) This allows cell metabolites, CO2, hormones, enzymes and antibodies to diffuse with ease out of the cell while letting food, enzymes, hormones and oxygen to enter the cell.

From an active standpoint, sodium constantly leaks into the cell, and potassium leaks out of the cell. This is due to their respective concentration gradients. Via active transport, the sodium-potassium ATPase extrudes the sodium to outside the membrane, and at the same time potassium is pulled back in. As potassium is leaking out via passive diffusion, it is being pulled back in via active transport.

The following hormones, which are octal peptides with similar structural formulas, are released from the posterior pituitary:

1. ANTI-DIURETIC HORMONE (AKA VASOPRESSIN, ARGININE VASOPRESSIN, AVP) and its related neurophysin one (propressophysin, prohormone) cause the kidneys to retain water, excrete sodium while retaining potassium, and raising blood pressure through vasoconstriction. The most important factor regulating vasopressin is blood osmolarity and circulating blood volume. Increases in osmolarity and decreases in volume both increase vasopressin release. Blood osmolarity is kept within a fine range +- 1.8% of 282 mmo/kg. Other factors that affect blood osmolarity include emotional stress, nausea and blood pressure.

1) Aldosterone has the opposite effect, as well as constricting blood vessels and elevating blood pressure.

The glucocorticoids and mineral corticoids, released by the adrenal cortex, counteract the function of antidiuretic hormone.

Since glucocorticoids control sugar levels in the body, you can see how diabetes insipidus can occur. AVP release is also enhanced by prostaglandin E 2, morphine, nicotine, acetylcholine, histamine, barbiturates and hypoxia. Other factors that suppress AVP are alcohol and atrial natriuretic peptide.

DIABETES INSIPIDUS

This is a condition where there is a large volume of urine that is dilute (hypotonic) and tasteless (insipidus.) In diabetes mellitus, the urine is hypertonic and sweet tasting like honey (mellitus.)

1. OXYTOCIN AND ITS RELATED NEUROPHYSIN 2 (PROOXYPHYSIN) causes contraction of the uterus during the birth process and causes the contraction of the myo-epithelial cells in the breasts when the baby suckles. Oxytocin is also involved in maintaining the uterus in a quiet state during pregnancy. Oxytocin is also responsible for maternal behavior. Oxytocin is found in the ovary, placenta, testis, renal medulla, thymus and anterior pituitary. Oxytocin may also affect feeding behavior, gonadotrophin secretion, response to stress (decreasing stress), stimulation of the tubules in the spermatic ducts, regulating blood pressure, temperature, and heart rate. Just like AVP, oxytocin release is stimulated by plasma hypertonicity and suppressed by plasma hypotonicity via binding to high-affinity receptors. It stimulates cAMP, which increases natriferic and hydro-osmotic responses of the tissue.

4. 4. The posterior pituitary and the adrenal glands regulate mineral, water and sugar levels in the body. Factors that stimulate oxytocin secretion are nausea, saity, cholecystokinin and angiotensin 2. Factors that inhibit oxytocin are opiods, relaxing and ANP.

Both oxytocin and AVP and their related neurophysin are synthesized in both the supra-optical (most oxytocinergic) (dorsal portion) and vasopressin (ventral portion), which project into the posterior pituitary and via the paraventricular nucleus, which is divided into 3 distinct magno cellular divisions consisting of:

• Oxytocinergic neurons

• Vasopressin neurons

• Par cellular division that synthesizes peptides, corticotrophin releasing hormone, thyrotrophin releasing hormone, somatostatin, and opiods. Projections from pare cellular neurons project into the median eminence, brain stem and the spinal cord for autonomic function. The supra chiasmic nucleus in the third ventricle secretes only vasopressin and controls circadian and seasonal rhythms. Ventricular neurons triggered by nerve action potentials, via cholinergic and noradrenergic neurotransmitters, and several other neuropeptides including angiotension 2, atrial peptide (AP), and atrial natriuretic factor (ANF) cause an influx of calcium. This induces movement of the neuro secretory granules to the membrane surface, causing a release of the hormones from the granules into per vascular space. From there, it enters into the capillary system of the posterior pituitary, or via microtubule tracts. Acetylcholine stimulates AVP via nicotinic acid receptor stimulation and oxytocin release where adrenergic influences inhibit oxytocin and AVP secretion thru beta androgenic receptors. They are then transported via vesicles into the axons to the neural lobe. Both hormones and their neurophysins are released in fixed ratios.

Other substances released from the posterior pituitary include:

• Somatostatin

• SRIF (somatotrophin release inhibiting factor)

• TRH

• Substance P

• LHRH

• GNRH (gonadotrophin- releasing hormone)

• Dopamine

• Serotonin

• Histamine

• Beta-melanocyte-stimulating hormone (b-MSH)

• An opium peptide named dynorphin a 1-8, which is present in AVP-containing neurons

From a biochemical perspective, the posterior pituitary controls biochemistry by maintaining potassium levels in all cells. As you may already be aware, potassium levels are highest within the cell. The purpose of potassium within cells is to maintain water levels. Potassium has been coined the “oxidative life principle” of the body. If this balance is affected, cells can either burst or shrink.

In so doing, potassium literally pulls foodstuffs (that are stored in the cell membrane) through the membrane of the cell and into the mitochondria for energy. Now, via the demand of the cell, the potassium, which is controlled by the posterior pituitary, donates oxygen to this hydrogenated foodstuff on the membrane and draws it into the cell. When the pressure gradient of potassium becomes too high on the inside of the cell, potassium, along with metabolic waste products, is transported out of the cell. Therefore, by balancing water levels in body, the posterior pituitary can balance the body’s pH.

The posterior pituitary also balances the pH of the body by affecting sugar levels (which are acids) and minerals (which are alkaline). So, in essence, the posterior pituitary, the pancreas, and adrenals dramatically affect the above.

The following blood tests assess the functions of the posterior pituitary:

1. POTASSIUM as mentioned above is the primary indicator for posterior pituitary function.

2. TRIGLYCERIDES are composed of a molecule of glycerol and three molecules of fatty acids. The energy necessary for active transport across a cell membrane, via the influence of potassium, is supplied by fatty acids.

3. GLUCOSE although affected by many other organs and glands, glucose is also affected by the posterior pituitary.

4. BUN/CREATININE RATIO blood urea nitrogen and creatinine are residue byproducts found at the end of protein and muscle metabolism. They are kept in continual balance via the water content in our body. The kidneys flush out the blood urea nitrogen and creatinine when the concentrations get too high, via antidiuretic hormone release from the posterior pituitary.

THE PINEAL

Calcification of the pineal is from an appetite form of calcium phosphate that is laid down in a matrix of ground substance secreted by pinealocytes (primordial photoreceptor cells) and has no effect on the pineal. Lining the ventricles (especially the third and fourth) and the central canal of the spinal cord are ependymal cells that are ciliated, which are then modified forming secretory tissues. The most well known is the pineal. The pineal is derived from the roof of the third ventricle and is composed of two types of cells pinealocytes and glial-like cells. The pineal integrates information encoded by light into organized secretions of rhythmic character. It receives its light encoded information from norandrogenic sympathetic nerve terminals regulating melatonin production. The pathway for melatonin production starts at the retina and then proceeds to the supra chiasmic nucleus (SCN) of the hypothalamus via the retina hypophyseal tract. The supra chiasmic nucleus neurons are inhibited by melatonin. Melatonin regulates circadian rhythms thru its effect on the supraoptic nucleus, which has been called the master circadian pacemaker. This is why melatonin can be used for jet lag and seasonal disorders. The SCN also provides input to the paraventricular nucleus providing direct innervations to the cervical sympathetic pre-ganglionic, extending into the upper thoracic to the postganglionic noradrengic, extending into the pineal. Lack of light causes a release of norepinephrine from the postganglionic that act on beta androgenic receptors in the pinealocytes.

Other structures formed by the third ventricle are the:

• Sub commissural organ-its cells secrete an insoluble fluid into the lumen of the aqua duct. This secretion forms a cord-like structure extending down to the caudal spinal canal.

• Sub formic organ which contains neurosecretory neurons and receives cholinergic fibers from the midbrain. This contains neuropeptide, angiotensin 2 (converted from angiotension one), which is produced from its precursor angiotensinogen and atriopeptin. The sub formic organ plays an important role in water regulation by regulating and controlling thirst and AVP release.

• Organium vasculosum of the lamina terminalis-this entire structure has its own circulation independent from the other organs. Its nerve ending contains LHRH, somatostatin, and neurophisms, from the median eminence.

The roof of the fourth ventricle forms the area post rema. All of these tissues have large interstitial spaces so large molecules can leave the blood and enter these spaces lacking the blood brain barrier condition.

The pineal weighs between .1-.18 grams. The pineal gland is a true secretory structure, which contains many biologically active substances and is occasionally the site of significant human disease. It is now known from comparative anatomy that the pineal gland is a vestigial remnant of what was the third eye (a light sensitive organ) in lower animals. The superior cervical ganglion via postganglionic sympathetic nerves also influences the pineal. Preganglionic fibers from the superior sympathetic chain found in the lateral column of the spinal cord receive impulses from descending branches of the supra chiasmic nucleus located in the hypothalamus. This nucleus receives nerve input from the retina, called the retina hypothalamic tract, which stimulates pineal secretions. Light dark shifts are the most important rhythm makers of the pineal. The pineal gland, as noted above, is controlled by the amount/types of light that pass through our eyes.

Also crucial to the pineal regulation is noradrenergic fibers that end in the interstitial spaces or on the plasma membrane of the pinealocytes (secretory cells.) All pineal parenchymal cells are regulated by beta-adrenergic receptors. The pineal plays an important role in regulating sexual and reproductive function.

The pineal gland also secretes:

• Biogenic amines such as norepinephrine, serotonin, histamine, melatonin and dopamine

• Peptides-LHRH, TRH, somatostatin, vasotocin (oxytocin) and the inhibitory neurotransmitter GABA

• Pinealin-insulin-like substance that lowers blood sugar.

• Melatonin-produces sleepiness via increasing the number of alpha waves, a feeling of well-being, elation and increased REM sleep. Lack of melatonin causes sleeplessness and depression. Melatonin is also used to regulate the reproductive axis and the onset of puberty. Melatonin mediates its effects thru G-protein receptors affecting circadian rhythms via inhibition of the SCN of the hypothalamus, which is the circadian pacemaker. Melatonin is also used to treat immune conditions and jet lag as mentioned above.

Melatonin is made from tryptophan and serotonin via the melatonin, producing enzyme hydroxyindole-O-methyltransferase, which is also found in the retina and in red blood cells. L-tryptophan is converted into 5-hydroxytryptophan by tryptophan hydroxylase. 5-hydroxytryptophan is converted into serotonin by 5-hydroxytryptophan decarboxylase.

Serotonin is then converted into n-acetyl serotonin by n-acetyl transferase + acetyl-CoA and n-acetyl serotonin is converted into melatonin. The pineal also produces monoamine oxidase and histamine N-methyl transferase. Melatonin is stimulated thru increased sympathetic activity, hypoglycemia, L-dopa and can be affected by sleep, diet activity, and posture. Melatonin receptors are dense in the SC nucleus, and in the ovaries inhibit gonadotropin secretions as well as GH secretions from the pituitary.

During the evening, melatonin is high and serotonin in the pineal is low.

Serotonin is also released into sympathetic nerve endings, as is dopamine and norepinephrine. The melatonin and similar substances pass either by way of the blood or through the fluid of the third ventricle to the anterior pituitary gland, which controls gonad trophic hormone secretion.

As mentioned above, the pineal works as the body’s antenna. It becomes the media between the body’s internal environment and the external surrounding environment. The pineal is used greatly by deaf or blind people, psychics, and top grade athletes. The pineal works with vision, smell, taste, touch, and hearing. The pineal forms a reticular formation with the posterior pituitary to deal with humidity in the external environment and water balance within the body. It also sets up a reticular formation with the various cranial nerves and influences sex organs and their development, brain maturity, puberty and the onset of menopause. It also retards sexual development by inhibition of the hypothalamic releasing factors.

According to Dr. Brockman, the mineral of the pineal is silica, a mineral that reflects vibration in a hormonal circuit. Silica picks up light and sound waves (vibrations), which then reflect into the eyes/ears triggering a cascade of events mentioned above. It should be noted that pulsating or artificial light influence the pineal and confuses it, resulting in multiple disease states.

The pineal is known as the biological clock of the body and can be affected by traumatic emotional or physical shocks. It can also adjust the pH of your body to external environmental changes. It does this by balancing sodium (which is acid and controlled by the adrenal cortex) and chloride (which is alkaline and is controlled by the adrenal medulla.) It is interesting to note that silica, which is found in sand and sodium, and chloride, found in salt water, have a calming and relaxing effect on the body. Ask anyone who is relaxing at the beach. Sodium and chloride are very responsive to the movement of light and sound in the body.

The following blood chemistries assess the function of the pineal:

1. SODIUM

2. CHLORIDE

THE HYPOTHALAMUS

The hypothalamus is located right above the pituitary gland that sits in the sella turcica of the sphenoid bone. The hypothalamus is attached to the pituitary gland by the pituitary infundibulum. The hypothalamus is the “major player” in the function of the endocrine system, where neurological energy is transposed into chemical energy (HORMONE RELEASING HORMONES.)

The hypophyseal vein transports these releasing hormones to the anterior pituitary. In other words, all neurological transmission and communication that is directed toward the hypothalamus help determine what hormones are to be released.

In fact, the pons varoli, medulla oblongata and the hypothalamus, form a network of visceral trophic sensors that receive information from many hormones (estrogen, testosterone, thyroid, etc.) and all sensory tropic nerves, including but not limited to all the cranial nerve nuclei, located in the medulla oblongata. Therefore, all cranial nerve activity, such as sight, smell, taste, hearing, and balance, influences hypothalamic secretions.

The hypothalamus also receives all sensory trophic information through the thalamus via the spinal cord and brain stem. Neurological control over the hypothalamus comes from many other sources such as:

1. The limbic system and brain stem which connect to the periventricular and arcuate nuclei which stimulate GHRH

2. Emotional stress triggers thru the red nucleus, stria terminalis, and amygdale complex

3. Circadian rhythms are regulated via the supra chiasmatic nucleus

4. GH and sleep are regulated by the cortex and sub cortical nuclei

5. Dopa minergic and histaminergic in the arcuate and mammilla nuclei, respectively

6. Catechol minergic ascend and arise from the ventral lateral medulla and the tractus solitarius

7. Serotoninergic fibers from the raphae nucleus

There are also peripheral hormones, metabolic signals, and cytokines that affect hypothalamic secretions, via the medial basal hypothalamus and the pituitary gland (acetyl choline stimulates GH secretion.) The hypothalamus also produces anti-diuretic hormone and oxytocin, which are made up of small peptides that are attached to large proteins found along the neural tracts from the hypothalamus to the posterior pituitary.

Let us not forget the vagus nerve that affects all parasympathetic outflow to all organs from the heart to the descending colon. The hypothalamus also receives communications from the external environment, such as light, pain, temperature, and odorants. As you can see, there is a multitude of information directed toward the hypothalamus. The hypothalamus then serves as the link between the endocrine and nervous systems. In fact, the hypothalamus is composed of both nervous and endocrine tissue. The hormones that the hypothalamus produces are peptides, except for dopamine, which is a biogenic amine. The neurological tissue stimulates the endocrine tissue to produce the following hormones:

1. GONADOTROPHIN RELEASING HORMONE GnRH (FOLLICLE STIMULATING HORMONE RELEASING HORMONE)

GnRH is a ten amino acid protein that stimulates the pituitary to produce follicle-stimulating hormone. There are 2 genes encoding GnRH, and they are:

• GnRH 1-stimulates the release of the pituitary hormone

• GnRH 2- serves as a neurotransmitter in the forebrain

GnRH binds to a membrane receptor on the pituitrophes (G-protein-coupled receptor), which stimulates LH and FSH synthesis and secretion. GnRH receptors on the hypothalamus are affected and suppressed by steroids, estrogens, progesterones, and gonadotrophins.

GnRH receptors are stimulated by calcium and protein C kinase. Calcium is important in GnRH stimulation and the release of gonadotrophins. GnRH receptors can increase or decrease uptake regulation or self-priming based on seasonal periods, malnutrition, and lactation or by GnRH downgrade due to high levels of GnRH.

GnRH from the hypothalamus sends neurons to the portal circulation in the median eminence in coordinated, repetitive and spasmodic pulses into the portal blood. Neurological control is via neurotransmitter systems in the brain stem and limbic system, which includes norepinephrine and glutamate, which drive the reproductive axis, dopamine, GABA and opioids, which then inhibit GnRH neurons and serotonin.

2. ADRENOCORTICO-TROPHIC HORMONE RELEASING HORMONE

(CORTICOTROPHIN RELEASING HORMONE) (CRH)

CRH stimulates the pituitary to produce the adrenocorticotrophic hormone. CRH neurons are located in the parvi-cellular division of the hypothalamus. They send projections into the median eminence. Glucocorticoids inhibit the release of CRH and AVP. CRH neurons, which contain AVP, arise from the periventricular nucleus, SC nucleus, amygdala, and raphae nucleus in the brain stem. Inhibition of CRH is from the hippocampus and locus ceruleus of the midbrain. Neurotransmitters that are cholinergic and serotoninergic excite CRH release and noradrenergic inhibit CRH release.

The HPA axis ‘s primary job is to maintain homeostasis in the body, as internal and external stressors affect it. The system is comprised of neurological control causing the release of catacholamines from the adrenal medulla, as well as hypothalamic-pituitary control over ACTH. This axis also controls behavioral response to stress via CRH-like peptides called urocortin 1, 2 and 3. CRH binds to a specific receptor and stimulates hormonal release only in the presence of Ca++ increasing

cAMP and enhances the transcription rate of ACTH and its pro hormone POMC (pro-opiomelanocortin). CRH is also found in the limbic system and is used in the processing of sensory information and in the regulation of ANS function. CRH is also located in the amygdale, substantia nigra, solitary tract nucleus, cerebral cortex, pineal, spinal cord, lungs, and liver. GI tract and is also found in the human placenta.

CRH increases sympathetic activity, blood pressure, heart -rate, cardiac output and suppresses GH and hunger. CRH and AVP play important roles in regulating inflammatory responses in the body via cytokines due to their extinguishing effects on inflammation.

CRH also acts as a vasodilator on the uterine lining, regulating decidulization or implantation of the fertilized egg. The human placenta has the largest concentration of CRH outside the hypothalamus. The CRH system is also regulated by a CRH-binding hormone, which inhibits CRH action.

Glucocorticoids are lipid soluble, inhibit CRH and can enter thru the blood brain barrier and bind to two receptors which are the:

1. Mineral corticoid receptors for aldosterone and glucocorticoids

2. Gluco corticoid receptors which have low affinity for mineral corticoids

It has been said that the type mineral corticoid receptors regulate basal activity, and the glucocorticoid receptors are responsible for stress reactions. CRH runs on a circadian rhythm, which peaks in the early morning and falls during the day until midnight, then starts to increase at 1:00 pm. Glucocorticoids inhibit the release of CRH and AVP.

3. THYROID STIMULATING HORMONE RELEASING HORMONE (THYROTROPHIN RELEASING HORMONE (TRH)

TRH is a tripeptide that stimulates the pituitary to produce thyroid-stimulating hormone (thyrotropin) via glycosylation of thyrotrophin. This happens with a maximum circadian rhythm between 9pm-5am, and a minimum circadian rhythm between 4 pm and 7 pm, accompanied by an ultradian rhythm of 90-180 minutes. TRH is also a potent releaser of prolactin and may in some cases cause the release of growth hormone and corticotropin. The binding sites are on the plasma membrane of the pituitary cells where TRH hydrolyzing phosphatidylinositol and phosphorylation via protein kinases, stimulate mRNA coding for thyrotrophin.

TRH is also found in all parts of the brain, cerebral cortex, circum ventricular structures, posterior pituitary, pineal, spinal cord, islets of Langerhan, myocardium, prostate/testes and various parts of the GI tract. The TSH of these tissues far exceeds that in the hypothalamus. TRH receives nerve supply from catecholamines, neuropeptide Y and somatostatin-containing axons, and is released thru peptidergic neurons into the portal hypothalamic pituitary circulation.

TSH has many affects on the CNS such as:

• Increasing and improving motor function and activity, good for ALS patients (amyotrophic lateral sclerosis).

• Altering sleep

• Increasing blood pressure

• Producing anoxia

• Releasing norepinephrine and dopamine

• Ameliorating human behavior disorders

• Protecting against spinal shock

4. MELANOTROPHIC STIMULATING HORMONE RELEASING HORMONE

Which stimulates the pituitary to produce the melanocyte-stimulating hormone.

5. LUTENIZING HORMONE RELEASING HORMONE (LHRH)

LHRH is a deca peptide, which is derived from a precursor molecule called pre-pro LHRH (92 aa’s long), which stimulates the pituitary. LHRH neurons from the hypothalamus more specifically the arcuate nucleus, medial basilar hypothalamus and the pre-optic nuclei from the anterior hypothalamus, project into the median eminence (about 1-3000 neurons) and terminate in capillaries of the portal vein descending into the pituitary stalk to produce the lutenizing hormone in the anterior pituitary.

LHRH is also found in the limbic system (hippocampus, cingulated cortex and olfactory bulb) and has been implicated in sexual drive, mating behavior, and emotional expression. Pituitary receptors are found on the plasma membrane, which then increases calcium concentration, hydrolysis of inositol phosphates and phosphorylation of protein C kinase. LHRH binds to the receptor, which initiates transcription of subunit genes, translated to subunit mRNA. This is followed by post-transitional modification of the precursor subunits and subunit folding and combination, followed by mature hormone packaging and secretion. LHRH also stimulates gonadotrophin synthesis.

Dopamine, norepinephrine, serotonin, opioids, estrogen and progesterone produced by the brain regulate LHRH secretion. LHRH secretion by the hypothalamus causes the pituitary to produce FSH and LH. It appears that pulse frequency of LHRH influences LH and FSH secretion, whereby fast pulses favors LH secretion and slow pulses favor FSH secretion.

Pulse frequencies affect the receptor concentration on the cell membranes of the pituitary gland, which increases receptor concentration with pulsations of 30 minutes and decreases the number of receptors when pulsations (every two hours) decrease.

The half-life of LHRH is 2-4 minutes, which depends on a number of carbohydrate residues making up the glycoprotein and sialic acid content of the gonadotrophin. Ovarian steroids and peptides modify the secretions of FSH and LH.

LH stimulates androstenedione production of the theca cells where FSH regulates estradiol production in the granulose cells, as well as follicular growth. The release of the egg from the follicle is due to sudden bursts of LH during mid-cycle.

After ovulation, the follicle becomes a corpus luteum that secretes both estradiol and progesterone, which is also under the control of FSH and LH. The endometrium of the uterus has many receptors for estrogen, which increases endometrial growth Progesterone limits the estrogenic effect on the endometrium, but increases cell differentiation. Both a withdrawal of either estrogen or progesterone causes a sloughing off of the functional portion of the endometrium called the functionalist layer and the deeper remaining layer, the basal layer is regenerated due to estrogen.

The entire reproductive function (no more oocytes), and most of the endocrine function is lost after menopause. Menses occurs approximately every 24-35 days.

6. LUTEOTROPHIC HORMONE RELEASING HORMONE

Unlike other hypothalamic hormones that stimulate the pituitary to release hormones, this hormone inhibits prolactin (PRL) secretion by the pituitary. Prolactin inhibiting factor (PIF) with dopamine is the most important. PIF is a secretory product of the tuber infundibular dopaminergic pathways. Y-amino butyric acid (GABA) and prolactin releasing factors such as TRH, AVP, VIP, oxytocin, PHI-27 (peptide-histodine-isoleucine-27), EGF (epidermal growth factor), angiotensin 2, substance P and interleukin 6 stimulate the pituitary to produce the leutotrophic hormone.

Prolactin secretion is also affected by autocrine/paracrine factors in the anterior and neuro intermediate lobe, whereby these factors gain access thru the sinusoids via short portal vessels. PRL is reduced by acetylcholine and calcitonin. PRL is also affected by estrogens, pregnancy, lactation, menstrual cycle, light, olfactory cues, and stress. Neurological control comes from serotoninergic neurons from the dorsal raphae nucleus, which activate PRL neurons in the paraventricular nucleus.

7. SOMATOTROPHIC HORMONE RELEASING HORMONE (GHRH)

GHRH stimulates the pituitary via a circadian rhythm that is reactive to stress, and the pituitary stalk can block its action. Negative feedback control of GHRH is mediated by GH and IGF-1, which is synthesized by the liver under the control of GH. IGF-1 is a critical growth factor that is responsible for the growth promoting activities of GH. IGF-1 now via negative feedback stops production of GH by directly influencing the pituitary receptors.

The GHRH receptor is a G-protein coupled receptor. GHRH stimulates GH secretion via calcium channels, which activate adenyl cyclase and the phosphatidylinositol cycle, thereby stimulating transcription of GH mRNA.

Somatostatin (growth hormone-release inhibiting factor) blocks the effect of GHRH and inhibits TSH secretion, as well. On the other hand, glucocorticoids enhance GHRH secretion.

Somatostatin also acts as a neurotransmitter and neuromodulator in the CNS and PNS. In the gut, somatostatin is found in the myenteric plexus where it acts as a neurotransmitter on the epithelial cells, which influence adjacent cells (paracrine function such as the islet pancreas cells). Somatostatin also acts in an autocrine fashion, where it can stimulate surrounding cells to produce it.

A gut exocrine secretion, which is modulated by the intraluminal action called a lumone.. Somatostatin-14 is found in the brain (cortex, lateral septum, amygdale, brain stem nuclei, thalamus, and hippocampus) and inhibits GH and somatostatin. There is a wealth of data linking decreased levels of somatostatin in the CSF of the forebrain with Alzheimer’s, major depression and neuro psychiatric disorders.

Somatostatin 28 is found in the GI tract (especially in the duodenum and jejunum) and inhibits the secretion of the salivary glands, parathyroid glands, calcitonin via the thyroid, PRL and ACTH. It also inhibits all pancreatic and gall bladder endocrine and exocrine gland function such as gastrin, secretin, motilin, insulin, glucagon, VIP, rennin, and glucentin (enteroglucagon). Somatostatin 28 also inhibits gastric acid and jejuna fluid secretion and emptying, pancreatic bicarbonate and enzyme secretion, intestinal absorption, bile flow and GI blood flow. Somatostatin can inhibit immune cell function and also inhibits the growth of tumor cells.

Please note that these releasing hormones are peptides, with the exception of dopamine, which is the principle PRL (release inhibiting factor.) These do not, by themselves, act as sole controllers of each pituitary secretion, but are performed by a combination of releasing hormones that either inhibit or stimulate hormone release from the anterior pituitary. For example, TRH can release PRL, TSH, ACTH, GH, and LHRH. PRL inhibits TSH and GH.

FAT STORAGE, THE BRAIN GUT ADIPOSE AXIS LEPTINS

Long term energy and fat storage is controlled by the hypothalamic axis. Energy homeostasis is regulated via the triune of behavior, autonomic and hormonal inputs.

Lepton, which is 167 AA’s long, is secreted by adipocytes with minor levels secreted by the skeletal muscle, placenta, and stomach. A decrease in fat deposits due to starvation and anorexia nervosa decreases lepton levels. Lepton also triggers puberty and fertility. Lepton is actively taken up by the capillary endothelial and microvascular system of the choroids plexus of the brain. Once it passes the blood-brain barrier, there are specific receptors (which are cytokine) found in the arcuate, ventromedial, and dorsal medial nuclei of the hypothalamus. Lepton also appears to inhibit feeding and increases metabolism.

As far as the neurological circuitry is concerned, below is a brief description from Guyton’s physiology as to the hypothalamus’s far-reaching effects. Not only does it affect the body chemically, and physically, but mentally and emotionally, as well. As you will note, the hypothalamus is considered to be part of a system known as the limbic system.

THE LIMBIC SYSTEM

The limbic system refers to all the neuronal circuitry necessary to control emotional behavior and motivational drives. A major part of the limbic system is the hypothalamus but it also consists of the:

1. SEPTUM

2. PARAOLFACTORY AREA

3. EPITHALAMUS

4. ANTERIOR NUCLEUS OF THE THALAMUS

5. PORTIONS OF THE BASAL GANGLIA

6. HIPPOCAMPUS

7. AMYGDALA

The purpose of this system is to affect behavioral control, body temperature, body weight, appetite and osmolality of body fluids. The portion of the cerebral cortex that lies directly above the limbic system is known as the limbic cortex.

The purpose of this cortex is to form a two-way communication system between the limbic system and the cerebral cortex. Also, note that the reticular nuclei, and their associated nuclei in the brainstem (cranial nerve nuclei), mediate control over the limbic system, which elicit many behavioral functions and patterns such as rage, anger, grief, pain, etc. They also exert influence over the autonomic nervous system, via the hypothalamus.

*PITUITARY

*PINEAL

*I have included the pituitary and pineal, which are involved in the endocrine axis that is affected/or affects the hypothalamus.

The hypothalamus, through hormonal release, causes the pituitary to release/store hormones that can affect our emotions, as well as maintaining biochemical balance throughout the body. The pineal, through sensory feedback from the eye (light), acts as an environmental sensor or third eye and produces a hormone called melatonin, which inhibits the release of sex hormones affecting sexual drive and behavior.

The hypothalamus is made up of an anterior, posterior and lateral portion with each portion consisting of the following:

THE ANTERIOR HYPOTHALAMUS

The anterior hypothalamus is divided into the:

1. PARAVENTRICULAR NUCLEUS (PVN)-which is composed of neurons from the:

a. Magnicellular nucleus, which contain oxytocin and vasopressin neurons that extend into the posterior pituitary and regulate fluid balance, blood pressure, lactation, and parturition. The magnocellular division also releases the following hormones peptides and neurotransmitters:

• Angiotension 2

• Cholecystokinin

• Glucagon

• Oxytocin

• Peptide 782

• Pro encephalin B (dynorphin, rimorphin, alpha-neo-endorphin)

• Vasopressin

b. Neurons projecting into the brain stem and spinal cord regulating a variety of ANS responses

c. Parvicellular nucleus (PVN), which is composed of CRH neurons that project into the median eminence regulating ACTH synthesis and release. Visceral sensory output to the PVN occurs thru the nucleus of the solitary tract via the thoracic abdominal viscera, which send dense catecholaminergic projections to the PVH thru the ventro lateral medulla.

The parvicellular division releases the following hormones/peptides and neurotransmitters

• Y-amino butyric acid

• Angiotension 2 stimulates drinking thirst reflex.

• Atrial natriuretic factor

• Cholecystokinin

• CRH

• Dopamine

• FSHRH

• Glucagon

• Neuropeptide Y

• Neurotensin

• Peptide 782

• Pro encephalin A (met and leu-enkephalins, BAM 22P, metorphamide)

• Somatostatin

• TRH

• Vasopressin

• Vasoactive intestinal peptide/peptide-histidine-isoleucine (PHI)

2. MEDIAL PREOPTIC AREA-decreases heart rate, blood pressure and bladder contraction.

3. SUPRAOPTIC NUCLEI-for release of vasopressin

4. OPTIC CHIASMA

5. INFUNDIBULUM

6. POSTERIOR PREOPTIC AND ANTERIOR HYPOTHALAMIC AREA-for the regulation of body temperature through panting, sweating and thyrotropin inhibition.

THE POSTERIOR HYPOTHALAMUS

The posterior hypothalamus controls shivering, increases blood pressure and pupil dilation. The posterior hypothalamus is composed of the:

1. DORSOMEDIAL NUCLEI-for gastrointestinal stimulation

2. PERIFORNICAL NUCLEUS-for hunger, rage and increased blood pressure

3. VENTROMEDIAL NUCLEUS-for neuro-endocrine control and satiety

4. MAMILLARY BODY-for the feeding reflex.

5. ARCUATE NUCLEI AND PERIVENTRICULAR ZONE-Dopamine fibers from this nucleus project into the median eminence and releases the following hormones/ peptides and neurotransmitters:

• Acetylcholine

• Y-amino butyric acid

• Dopamine

• GHRH

• Neuropeptide Y

• Neurotensin

• Pancreatic polypeptide

• Pro encephalin A

• Prolactin

• Pro-opiomelanocortin (ACTH, beta-lipotropin, Y-melanocyte stimulating hormone, beta-endorphins)

• Somatostatin

• Substance P

•

THE LATERAL HYPOTHALAMUS

The lateral hypothalamic area is for thirst and hunger.

THE BLOOD BRAIN BARRIER

THE ROLE OF THE CIRCUMVENTRICULAR ORGANS

The role of the circum ventricular organs (CVOs) is to act as doormen, so to speak, about what vital information crosses into the brain and what does not. More specifically, vital sensory chemical information (hormones, metabolites, toxins, bacteria, etc) to maintain homeostasis needs to be allowed to pass thru into these CVOs, which have a rich blood supply and can give vital information to the glial cells and neurons that reside in these blood vessels This is done thru key junctures (CVOs) that lie in the midline of the brain in the third and fourth ventricles, and include the:

• Median eminence that gives sensory input to adjacent nuclei such as the arcuate, ventro medial, dorsal medial and para ventricular nuclei. The para ventricular nucleus then sends magnicellular neuron projections to the posterior pituitary to release arginine, vasopressin or oxytocin

• Area post rema lies in the fourth ventricle and sends efferent projections into the nucleus of the solitary and ventral lateral medulla. It receives sensory input from the vagus and gloss pharyngeal nerves and the carotid sinus nerve. The area post rema can induce vomiting in response to foreign substances and control of blood pressure.

• Posterior pituitary (see posterior pituitary)

• Sub commissural organ located at the junction of the 3rd ventricle and cerebral aqueduct below the pineal that is composed of ependymal cells that secrete glycosylated protein. These extrude thru the aqueduct of the 4th ventricle, down the spinal cord lumen, and terminate in the caudal equine.

• Subfornical organ located in the third ventricle having receptors for angiotensin 2 and atrial natriuretic peptide that project into sites of the hypothalamus, producing oxytocin and AVP. The SFO is also a blood pressure fluid regulator. The SFO innervates the parvicellular neurons of the para ventricular nucleus, which project into the median eminence releasing CRH and regulating neuroendocrine and autonomic control.

• Organium vasculosum of the lamina terminalis is located in the third ventricle and is innervated by neurons that secrete many neurotransmitters and peptides such as LHRH, somatostatin, dopamine, serotonin, acetylcholine, oxytocin, vasopressin and TRH. The organium vasculosum has a dramatic effect on fluid regulation (osmolality), electrolyte balance, reproduction, and thermoregulation.

So the CVOs act as a critical link between the chemical cues from the body, transposing them into neurological cues (communications) to regulate hormonal, autonomic and behavioral responses. This is where the vascular endothelial cells of the brain prevent passage of polarized macromolecules (hormones, peptides.) Perimicroglial cells, neurons and glial cells that arise in the CVOs contribute neurological intelligence to the integrity of this complex by transposing this chemical information into neurological information, stimulating key neuronal cell groups of the median eminence, posterior pituitary, and the hypothalamus, maintaining homeostasis.

Blood chemistry tests that determine the function of the hypothalamus:

1. CALCIUM is the largest and most abundant mineral in the body.

The purpose of calcium is to attach to all lipoproteins, fatty acids, and triglycerides within the digestive tract. All minerals that are involved in biochemical reactions within the body are in an ionic state. They will have a positive or negative charge.

The purpose of these electrically charged ions is to act as magnets, repelling and attracting biochemical substances through the body. The purpose of hormones and releasing factors is to direct these mineral magnets and their biochemical substances throughout the body to specific sites, at specific times, creating growth/repair, energy and all the chemicals necessary for your survival.

The mineral calcium (which is a cation) is the substance that pushes proteins, fatty acids, and triglycerides through the intestinal wall. When the calcium to magnesium ratio is greater than two-part calcium to one-part magnesium, there is movement of food substances through the intestinal wall. This calcium to magnesium phenomenon creates an electrical osmotic gradient that draws the calcium/lipoprotein across the cell membrane.

The hypothalamus, through its releasing factors, creates growth, reproduction, digestion, assimilation, metabolism and protein deposition in cells. You can see why calcium would be dramatically affected by hypothalamic malfunctions. The releasing factors are all geared for protein deposition in cells, as well as controlling triglycerides, cholesterol, and fatty acid distribution throughout the body. These releasing factors also influence the production of energy and the creation of hormones, enzymes, and antibodies. It’s rather obvious that other blood tests such as protein, cholesterol and triglycerides can all be used and are affected by hypothalamic malfunctions.

2. POTASSIUM AND SODIUM

The purpose of potassium is to create an action potential with sodium across a neurological membrane. When a neurological impulse passes through a cell membrane, there is a large influx of potassium out of the cell, and a large inflow of sodium into the cell, allowing the propagation of the neurological impulse, which then must be repolarized (sodium pumped out of the cell and potassium pumped in.) Since the hypothalamus is neurologically controlled via a vast network of sensory trophic nerves, sodium and potassium, levels must be observed as indicators of hypothalamic function, since they literally control neurological activity on a chemical level. This then would have a dramatic effect on communication between the body and hypothalamus, creating improper hormonal release to the pituitary.

THE PITUITARY STALK (INFUNDIBULUM)

HYPOPHYSEAL STALK

MEDIAN EMINENCE, TUBEROINFUNDIBULAR AND TUBEROHYPOPHYSEAL NEURONS

The median eminence lies in the center of the tuber cinereum and is the site of an array of blood vessels, from the superior hypophyseal artery (which is a branch of the internal carotid) from which the pituitary portal vessels arise. This drains into the pituitary sinus and is the site where hypothalamic neurons from the ventral hypothalamus (tuber hypophyseal neurons) regulate the release of hormones from the anterior pituitary into the hypophyseal-portal system.

The pars tuberalis, which is a thin glandular tissue sheath around the infundibulum that can secrete LH and TSH, makes up part of the median eminence and is a subdivision of the adenohypophysis. This surrounds the infundibular stalk and together they make up the hypophyseal stalk. The median eminence is considered to be the functional link between the hypothalamus and the pituitary.

There are three zones that make up the median eminence and they are:

1. EPENDYMAL LAYER-which is made from ependymal cells that form the floor of the third ventricle. This ependymal layer contains tanycytes, which act as the blood brain barrier between itself and the third ventricle (CSF and blood.)

2. INTERNAL ZONE-which is composed of axons from the supraoptic and

paraventricular magnocellular neurons heading to the posterior pituitary.

3. EXTERNAL ZONE-is the exchange point of the hypothalamic releasing factors.

There are two types of tuber hypophyseal neurons that project into this zone.

a. Peptides neurons which release thyrotrophin releasing hormone, corticotrophin releasing hormone, luteinizing hormone releasing hormone and somatostatin

b. Monoamines and bio-amines such as dopamine, serotonin, and norepinephrine, which come in contact with the pituitary portal veins.

These tuber hypophyseal neurons synthesize the neurotransmitters in the following way:

1. There is an uptake of amino acids into aminergic neurons such as tyrosine that are the precursor for dopamine, epinephrine, and norepinephrine.

2. Enzymatic synthesis, whereby tyrosine is hydroxylated by tyrosine hydroxylase to form L-dopa, which is decarboxylated to form dopamine, which is hydroxylated to form norepinephrine which is methylated to form epinephrine.

3. Storage phase

4. Released of preformed granules in response to neural depolarization, whereby granules are extruded thru the nerve endings.

5. Interaction with the catecholamines with receptors located on the postsynaptic neuron.

6. Reuptake process after the release of the preformed hormones and neurotransmitters, any unused hormones/neurotransmitters that are still left in the synaptic cleft, are taken up into the presynaptic neuron.

7. Degradation of neurotransmitters, dopamine, and norepinephrine, which are bound to postsynaptic membranes are freed into presynaptic membranes, which are then destroyed by monoamine oxidase.

8. Monoamine oxidase inhibitors (parglycine, isocarboxazid) then make up more neurotransmitters and hormones.

There are distinct pathways within the median eminence and they include:

DOPAMINERGIC PATHWAYS-most of the cells that synthesize dopamine arise from the midbrain, project to the forebrain and the basal ganglia (causing Parkinson’s), and to the cerebral cortex, causing schizophrenia. They also project to the arcuate nucleus of the hypothalamus and to the median eminence.

NORADRENERGIC PATHWAYS-originate from the midbrain, locus ceruleus, and project to the forebrain (cerebral cortex), the limbic system, hypothalamus, brain stem, and spinal cord. They play a role in visceral homeostasis, regulating sleep, appetite, emotional happiness and physical activity. This is the site of action for amphetamines and antidepressant drugs.

CENTRAL ADRENERGIC PATHWAYS-are the least plentiful and are the cell bodies that originate in the midbrain. They are extensive in the hypothalamus and the median eminence.

CENTRAL SEROTONINERGIC PATHWAYS-all originate from the raphae nucleus in, which fibers ascend to innervate the forebrain and the diencephalons. These fibers also terminate in the hypothalamus (paraventricular nucleus, median eminence and the lumen of the 3rd ventricle). Fibers also project downward into the brain stem and the spinal cord.

CENTRAL CHOLINERGIC PATHWAYS-(muscarine and nicotinic receptors) are found in the brain and hypothalamus, with some fibers originating from the nucleus basalis of the forebrain to the hippocampus. Loss of these neurons causes Alzheimer’s. These pathways control AVP, ACTH, and GH secretion.

AMINO ACID TRANSMITTERS-glutamine, aspartate, glycine and inhibitory GABA is found in hypothalamic neurons and can modify tuber hypophyseal function.

The medial eminence then can be said to consist of three components:

• Neural

• Vascular blood supply from the hypophyseal artery, which is a branch of the internal carotid and drains via the portal veins, which drain into the pituitary sinus.

• Epithelial-The nerve endings, basement membranes, interstitial space and the capillary wall of the median eminence release all the neuropeptides and can be stimulated by increasing potassium in the presence of calcium. This also increases anterior pituitary secretions. The extra and per vascular spaces of the median eminence are where billions of neurons are bathed in interstitial fluid in a multitude of hormones and neurotransmitters. The supraoptic and paraventricular hypophyseal tracts pass thru the eminence and some tracts end here as well.

The purpose of the pituitary infundibulum is to make sure all chemical and neurological information from the hypothalamus, and through many neurological pathways with the brain, can communicate and control the pituitary gland properly. The nervous and endocrine systems communicate thru pulsations (circulatory disturbances of blood and CSF) and vibrations (neurological transmissions.) If the pituitary infundibulum has adhesions (via the diaphragm sellae) can lead to improper communication with the pituitary.

The pituitary infundibulum is derived from the posterior wall of Rathke pouch.

The intermediate lobe produces melanocyte-stimulating hormone (MSH), which increases skin pigmentation by stimulating melanin granules in melanocytes. MSH is synthesized by pro-opiomelanocortin (POMC) a precursor of ACTH. Beta-lipotropin and beta-endorphin also produce melatonin and serotonin that create a phenomenon similar to photosynthesis in plants, called biosynthesis in humans. During biosynthesis, you also have a light and dark reaction, which is controlled by melatonin and serotonin.

Melatonin controls response of tissue to light and darkness, and the more melatonin in the skin, the more the skin coloration changes when exposed to light. High-density fats such as cholesterol always cause browning of the skin. Low-density fats such as triglycerides always cause lightening of the skin.

Serotonin, on the other hand, controls the waking and sleeping reactions within our bodies. Sleeping relates to darkness or nighttime, and waking relates to daylight or daytime. During the light reaction, we have our waking hours and fatty acid combustion (which is the breakdown of triglycerides to yield energy for body metabolism.) This relates to the catabolic phase of metabolism. The dark reaction, which is during the sleep hours, is the anabolic phase, utilizing cholesterol for growth and repair.

The following blood chemistries assess the function of the pituitary infundibulum:

1. CHOLESTEROL:

2. TRIGLYCERIDES:

Any imbalance in either cholesterol or triglycerides can be affected by the pituitary infundibulum, as mentioned above.