Endocrine System

The endocrine system is a complex, subtle, communications network that uses chemical messengers called hormones to effect the communication. The word, endocrine, means "secreting internally" and is intended to convey the notion that hormones are secreted directly into the bloodstream and not exported via ducts as is the case with some other glandular products.

Hormones are biochemicals that are synthesized by glandular cells in one location, moved to distant parts of the body by the bloodstream and have their effects by interacting with particular target cells, cells that have receptors for the particular hormone.

Association of a hormone with the receptors on a target cell profoundly changes that cell's activity.

The following table lists human hormones and what they do.

A diagram indicates how water soluble and non-water soluble hormones act on their target cells.

Notice that the more water soluble hormones do not actually enter their target cells. Instead they form weak bonds with receptor sites on the cell membrane. This lead to the idea of a "second-messenger" model of hormonal control where the hormone itself acts as the first-messenger going from the endocrine gland to the target cell and binding to a receptor on the target cell membrane.

This binding, in turn, stimulates, inside the target cell, a second chemical messenger which is often the chemical, cAMP (cyclic adenosine monophosphate). More specifically, the binding of the hormone on the receptor site of the cell membrane activates a second membrane protein (referred to as G-protein) which in turn influences the activity of an enzyme, adenylate cyclase, which catalyzes the production of cAMP. The cAMP then activates specific enzymes within the cell and thus initiates the hormone's specific action.

A lot of different hormones (including glucagon, adrenalin, parathyroid hormone, calcitonin and the tropic hormones of the anterior pituitary) appear to work via the adenylate cyclase system.

If these hormones simply act to regulate the adenylate cyclase activity of their target cells, then what is the basis for hormone specificity? The answer is: the presence or absence of specific hormone receptor sites on a cell's plasma membrane. Different cells have different hormone-specific receptor sites.

Non water soluble hormones (such as thyroid and steroid hormones) appear to work differently. These biochemicals, because they are hydrophobic ("water-hating"), can easily move through membranes and enter the cytoplasm of a cell. There, or in the nucleus itself, they are able to bind to a particular receptor molecule which then binds to specific regions of DNA and regulates the activity of specific genes.

In other words, by interacting with the genetic material of the target cell, this group of hormones helps to determine which instructions (mRNA) for protein synthesis gets produced and ultimately, which specialized enzymes get produced.

Let's look at a few examples.

The Pancreas

The pancreas is a compound organ composed of two kinds of glandular tissue. Most of it is exocrine (meaning that it secretes digestive enzyme products through a duct). But about 1 percent of the gland is composed of clusters of quite different cells that have an endocrine function. These cell clusters are referred to islet cells or Islets of Langerhans.

Each Islet has a good blood supply and within a cluster of these cells, there are two cell types: so-called alpha and beta cells. The alpha cells secrete glucagon; the beta cells secrete insulin. They are both involved in the regulation of metabolism but have opposing effects. Insulin promotes the storage of carbohydrate, protein and fat. Glucagon induces the breakdown of these materials. Both are small proteins and work by a second-messenger system.

Diabetes (diabetes mellitus) is a disease that causes a large amount of sugar to be excreted in the urine. While known for a long time, its cause was not understood until the last half of the 19th century. In 1889, two Germans, Johann von Mering and Oscar Minkowski, who were interested in the role of the pancreas, removed the pancreas of a dog and a short time later noticed that the dog's urine was attracting an unusually large number of ants. The dog also developed symptoms much like human diabetics. They carefully repeated their surgical experiments and had to conclude that the pancreas did much more than just participate in digestion.

For a number of years, evidence that the pancreas had an endocrine function eluded researchers. Finally, someone tied off pancreatic ducts (which stopped exocrine function) but did NOT produce diabetes. Examination of the atrophied pancreas months later revealed that it was the enzyme producing part that atrophied and NOT the islets regions. Therefore the hormone that prevented diabetes must come from the islet cells.

The hormone, insulin, was finally isolated in 1922 by Banting and Best in Toronto, Canada. They tied off the pancreatic ducts of a number of dogs, waited until the pancreas of the animals had atrophied, removed the degenerated pancreas and froze and macerated them in an a solution friendly to proteins. They then filtered the material and injected the filtrate into dogs that were suffering from diabetes. The dogs showed marked improvement.

The major symptom of diabetes is a lot of sugar in one's urine. How is insulin related to this?

The presence of sugar in urine means that there has to be a lot more sugar in the blood than what one would normally find. The kidneys attempt to remove it. The liver, in fact, is a major controller of blood sugar content. When sugar-laden blood enters the liver, the liver converts some of it to glycogen (a carbohydrate storage product). Conversely, when the blood sugar level is low, the liver converts some glycogen back to glucose.

Insulin's mode of participation in all this is not yet completely understood but it is known that insulin acts to decrease the supply of glucose and amino acids circulating in the blood and to increase the stores of glycogen, fat and protein. Notice that the promotion of fat and protein synthesis requires metabolic energy and that this is ultimately derived from the oxidation of glucose which further reduces its levels in the blood stream.

Too much insulin in one's system as a result of a hyperactive pancreas or too large a dose of insulin for a diabetic can result in a severe reaction called insulin shock. How does this work? Blood sugar levels fall so low that the brain, which has minimal stored food reserves, becomes hyperexcitable, convulsions often occur and unconsciousness follows. If not treated, death may ensue. What is the treatment for insulin shock? Anything with some sugar in it: maybe a glass of sweet orange juice. Recovery is often quite dramatic.

Much more common though is a deficiency in the amount of insulin (or a lack of tissue sensitivity to insulin). This is the condition known as diabetes. The liver and muscles do not convert enough sugar to glycogen and the overall utilization of carbohydrates is impaired.

The blood sugar levels of diabetics rises to abnormal levels. Part of the excess sugar appears in the urine. The diabetic loses more water because of the high glucose level in the urine leading to general body dehydration. Glycogen reserves become depleted as more and more glucose in dumped into the blood stream, but the affected person doesn't feel very energetic-- poor carbohydrate metabolism impairs any good use of the glucose. The affected person then begins to use up reserves of fats and protein and takes on an emaciated appearance. Further complications arise from the excessive but incomplete metabolism of fats which disturb blood pH. Unless treated, diabetes is a fatal disease.

Diabetics, even those being treated with insulin injections, often suffer very poor peripheral blood circulation. Much care must taken. Otherwise simple infections of extremities heal so poorly or not at all that sometimes amputation of the affected part is required.

The Adrenal Glands

Humans have two adrenal glands located near the kidneys. Each gland is really a double gland consisting of an outer cortex and an inner medulla. These regions produce very different hormones.

The adrenal medulla secretes adrenal (also known as epinephrine) and noradrenalin (also known as norepinephrine). They function in a similar but not identical manner.

Adrenalin causes a rise in blood pressure, acceleration of heartbeat, increased conversion of glycogen to glucose, rapid release of glucose into the blood, increased oxygen consumption and release of reserve red blood cells from the spleen into the circulating blood. The blood flow in skeletal and heart muscle is increased; the flow to smooth muscle in the digestive tract is decreased. Pupils of the eye dilate.

Taken together, these seem an odd assortment but consider what you want to have ready when you fight or when you need to run like hell because something is going to eat you.

One can live without the adrenal medullae, but one must have the cortices. The cortices are essential to life. Death is preceded by a severe disruption of ionic balance in the body fluids, low blood pressure, impairment of kidney function, impairment of carbohydrate metabolism loss of weight, muscular weakness and a peculiar browning of the skin.

Individuals suffering from Addison's disease (a condition where the adrenal cortices are insufficiently active) exhibit various degrees of the above symptoms.

The adrenal cortices are quite the chemical factories and produce many different hormones. All of the cortical hormones are similar and all are steroids, sometimes differing from one another by only one or two atoms of hydrogen or oxygen. These small chemical differences give rise to profoundly different hormonal properties.

The Thyroid Gland

Most vertebrates have two thyroid glands, located in the neck. The human thyroid has fused to form a single gland.

Years ago, one used to see a condition known as goiter where the whole thyroid gland became quite enlarged making the neck appear deformed and swollen. This was particularly common in such places as Switzerland and in the Great Lakes region of the US.

In 1883, a Swiss physician who believed that the thyroid had no important function, removed the gland from several of his patients. Most of the patients developed all of the symptoms usually reserved for people having goiter except for the swelling of the gland in the neck (he had removed the thyroid gland).

This was a curious thing since patients with no thyroid gland and patients with an excessively large thyroid gland all showed the same set of symptoms.

By the late 1890s, patients were being successfully treated with injections of thyroid extract or bits of sheep thyroid, but nothing specific was known about the "thyroid hormone."

In 1896, a German chemist, E. Baumann discovered that the thyroid gland contained iodine.

Finally, in 1905, David Marine noticed that a lot people in Cleveland, Ohio had goiter. He noticed that even the dogs in Cleveland had goiter. A lot of the trout in streams near Cleveland had goiter. Marine guessed that the problem might be a lack of iodine. Soil near the coasts have a bit of iodine in them but this was not true of the soils of the Great Lakes region.

Marine tried an experiment. He treated some animals that had goiter with a tiny bit of iodized water. Interestingly, the animal's goiters and associated symptoms disappeared. In 1916, Marine tried an experiment on about 2,500 children in Akron, Ohio. He fed the children small amounts of iodized table salt (table salt to which a small bit of potassium iodide had been added). He used another 2,500 children as controls. After a period of time, he found that only two children in the treated group had goiter and associated symptoms; in the control group there were 250 cases of goiter. It took years to convince a skeptical public that an iodine deficiency caused goiter.

The thyroid hormones increase oxygen consumption and metabolic rates in almost all cells of the body. These hormones influence carbohydrate and lipid metabolism and are necessary for normal growth and development.

The thyroid gland actively transports iodine from the blood stream into its glandular tissue where it uses the element to synthesize thyroid hormones. When dietary iodine is inadequate, thyroid hormone cannot be synthesized and results in a hypothyroid condition. The thyroid begins to enlarge to try to compensate and capture more iodine from the blood. When untreated hypothyroidism is found in newborns, it is termed cretinism; its victims suffer abnormal physical development and are mentally retarded.

A second, unrelated hormone, calcitonin, is also secreted by the thyroid. It prevents excessive calcium levels from appearing in the blood and acts as an antagonist to the parathyroid hormone.

The Parathyroid Glands

The parathyroid glands are small, pea-like glands located on the surface of the thyroid gland BUT they are distinct glands in their own right.

The parathyroid hormone is a small protein derived hormone that acts through a second messenger system and effects regulation of the calcium-phosphate balance between the blood and other tissues.

Hypoparathyroidism is quite rare. If the parathyroids are accidentally removed during a surgical procedure on the thyroid, however, profound problems arise. The level of phosphate in the blood rises as the level of calcium falls. This change in the environment of the cells produces serious disturbances. Muscles and nerves become very irritable and respond to the smallest of stimuli with tremors, cramps and tetany. The tetany includes a tetany of the muscles of the larynx and can cause an obstruction of the airway. Complete absence of the parathyroid hormone eventually results in death.

The Anterior Pituitary Gland

At least six hormones are secreted by the anterior pituitary gland. All are hydrophilic and work in some second messenger system.

Of the hormones produced, prolactin is the most versatile. It stimulates milk production by female mammary glands shortly after childbirth. In its absence milk production quickly ceases. It also has roles in metabolism of fats and carbohydrates.

Human growth hormone does not directly produce growth but induces other tissues to secrete a number of protein growth factors which have an affect skeletal and muscle growth. There is epidermal growth factor, nerve growth factor, ovarian growth factor.

A deficiency of human growth factor will stunt the growth of a child and result in a midget. Until recently, the only source of hGF was from cadavers making it one of the most expensive of materials. In the early 1980s, the gene for the hormone was cloned and expressed in E. coli. In 1985, Genentech began marketing hGF produced by these recombinant bacteria. Although still quite expensive, it has great use in the treatment of pituitary dwarfs. It can also be used on normal children to make them great basketball player candidates. Physicians are quite concerned about such use but hGF still finds its way to the Black Market.

An oversupply of hGF results in a condition known as acromegaly. They become giants. Their proportions are OK, but they have several large hands and distorted facial features.

The anterior pituitary also produces tropic hormones that control other endocrine organs. Several of these will be treated when I discuss human reproduction.

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