I.               INTRODUCTION

Endocrine glands are composed of cells that produce chemical messengers called hormones, from the Greek word meaning "to set in motion." Exocrine glands dump their secretions into ducts. Endocrine glands secrete their products into the blood, where they can travel to and act upon distant organs.

Hormones must interact with target cells. Fat-soluble hormones (e.g., steroids) have receptors within cells. Receptors for water-soluble hormones (e.g., insulin) are located on the outer surface of the cell’s plasma membrane. Binding of a hormone to a receptor sets off a biochemical signaling cascade within the cell that directs it to behave in a particular way.

The endocrine system is regulated by feedback inhibition, also known as a negative feedback loop. What these terms mean is that a hormone causes its target to secrete a second hormone. This second hormone, in turn, acts back to shut off production of the first hormone.

II.             THE PITUITARY GLAND

The pituitary is a very small (~0.5 g) gland located in the brain in the sella turcica. It is attached by a stalk to the hypothalamic area. It is also located close to the optic chiasm, the point where the optic nerves cross. It is composed of anterior and posterior lobes.

The hypothalamus produces oxytocin, which is responsible for uterine contractions during birth, and antidiuretic hormone (ADH; also known as vasopressin), which regulates water retention by the kidneys. These are delivered to the posterior lobe of the pituitary directly from the hypothalamus.

The anterior lobe of the pituitary synthesizes six hormones that are secreted in response to blood-borne releasing factors produced by the hypothalamus. These are:

1.     Growth hormone (GH)

2.     Prolactin: stimulates production of milk

3.     Adrenocorticotropic hormone (ACTH): stimulates adrenal cortex

4.     Luteinizing hormone (LH):  acts on the ovary and testes

5.     Follicle-stimulating hormone (FSH):  acts on the ovary and testes

6.     Thyroid-stimulating hormone (TSH): acts on the thyroid

Hyperfunction of the pituitary can result from benign tumors called pituitary adenomas. These tumors are composed of cells that overproduce particular hormones. The tumors can produce local symptoms, such as headache or loss of visual field (remember the pituitary’s location near the optic chiasm). An enlargement of the sella turcica may be noted on x-ray. The hormones produced by these tumors may also have manifestations that vary according to the particular hormone that is overexpressed. Overproduction of growth hormone in adults produces acromegaly, due to excessive growth of bone and soft tissue. Patients with acromegaly have prominent jaws and brows and large hands with a soft, doughy consistency. They may have postural problems due to formation of bony spurs in the vertebral column.  Sixty-five percent also have hypermetabolic problems. When the same tumor occurs in a child, it produces a pituitary giant. The epiphyses in the bones of children have not yet closed, so the bones grow in length in response to the hormone. Overproduction of GH may also result in kidney disease or diabetes, as GH antagonizes the effects of insulin. These patients do not have a normal life span.

Hypofunction of the pituitary may result from a nonsecretory pituitary adenoma, which compresses and destroys the normal tissue of the gland. Another cause is Sheehan’s pituitary necrosis, which is associated with pregnancy. During pregnancy, the pituitary becomes highly vascularized. During birth, an excessive loss of blood may lead to an infarct in the pituitary. This situation is a medical emergency.

III.           THE THYROID

The thyroid is located in the lower part of the neck and consists of two lobes. Sometimes, a vestigial third lobe is present. Four (or as many as 8) parathyroid glands are located posteriorly. The functioning unit of the thyroid is called a thyroid follicle. It contains colloid consisting of thyroglobulin, from which hormones are made. Tetraiodothyronine (also known as T4 or thyroxine) is the most common form of thyroid hormone. Other forms are iodinated to different extents. Epithelium surrounding the follicles contains C cells, which make calcitonin. Calcitonin plays an important role in the metabolism of calcium.

Thyroid-releasing hormone (TRH) made by the hypothalamus acts on the anterior pituitary to stimulate secretion of TSH. TSH then acts on the thyroid to promote secretion of T3 and T4. T3 and T4 act on target organs and also act back on the hypothalamus to shut down production of TRH. (This is a good example of feedback inhibition).

Women have a much higher incidence of thyroid disease than do men. The term goiter refers only to an enlargement of the thyroid; it says nothing about its functional state.

An example of hyperfunction of the thyroid is Graves' disease, which is an autoimmune disease in which antibodies constantly stimulate the gland to produce hormone. The entire gland becomes hyperplastic and diffusely enlarged. This disease results in a hypermetabolic state that presents with a classic triad of clinical signs: exophthalmos (bulging eyes); rapid heartbeat with arrhythmias, and indurated (hardened), "woody" skin. The bulging eyes are due to infiltration of the extraocular muscles with fluid.

Hypofunction of the thyroid may occur upon surgical removal of the gland (e.g., to remove a tumor), following radiation therapy (e.g., for Hodgkin’s disease), or in Hashimoto’s thyroiditis. Like Grave’s disease, Hashimoto’s thyroiditis is caused by an autoimmune attack. In this case, however, the gland is destroyed rather than stimulated. Early in the course of the disease, the gland may become diffusely enlarged due to infiltration by lymphocytes.  Symptoms result from a slowing of metabolism and include: sluggishness, thin eyebrows, edema in the tongue, puffiness around the eyes and lips, cold intolerance, dry skin, and chipping of the nails. In a child, hypofunction of the thyroid can lead to retardation (thyroid cretin).

Sometimes the thyroid enlarges but functions normally, as in multinodular goiter. Here individual nodules are enlarged, rather than a diffuse enlargement. The follicles appear quite variable in size.

Neoplasms of the thyroid usually form a single mass. A benign tumor is follicular adenoma, which usually does not affect function of the gland. Malignant tumors include:

• Papillary carcinoma: a very indolent, nonaggressive tumor; patients may live for 20 years with it.
• Follicular carcinoma
• Anaplastic carcinoma: an extremely aggressive tumor that usually kills within 4 to 5 months.
• Medullary carcinoma: which arises from C cells; the other three types arise from the follicular epithelium

The thyroid therefore gives rise to one of the least and one of the most aggressive malignancies in the body.

IV.           THE ADRENALS

The adrenal glands are small (~4 g) and sit atop the kidneys. Each adrenal gland has an outer cortex and an inner medulla with a large adrenal vein. The medulla synthesizes catecholamines (epinephrine and norepinephrine).  The cortex has three layers: the glomerulosa, which produces mineralocorticoids (the most important being aldesterone) that are important for regulating metabolism of sodium and potassium; the fasciculata, which produces glucocorticoids (principally cortisol); and the reticularis, which produces sex steroids (androgens and estrogens).

The adrenals are under control of the hypothalamus and the anterior pituitary according to the following scheme. Note the feedback inhibition that regulates release!

Hyperfunction of the adrenal cortex resulting in overproduction of cortisol causes Cushing’s syndrome. There are two types:

1. ACTH-dependent: About 68% of patients with Cushing’s syndrome have Cushing’s disease, which is due to a pituitary adenoma that produces too much ACTH. Another 15% have disease due to ectopic ACTH syndrome, e.g., some lung cancers inappropriately produce ACTH.

2. ACTH-independent: Another 9% of cases of Cushing’s syndrome are due to adrenal adenomas and 8% to adrenal carcinomas. These tumors sometimes (not always) produce excessive amounts of cortisol.

Symptoms of Cushing’s syndrome include:

• Redistribution of fat, which increases in the trunk, back of neck, and face ("moon face" and "buffalo hump")
• Wasting of extremities due to muscle breakdown, resulting in fatigue
• Thin, fragile, easily bruised skin
• Immune suppression
• Poor wound healing
• Osteoporosis, due to increased resorption of bone

Hypofunction of the adrenal cortex may result in Addison’s disease. About 80% of cases of Addison’s disease are due to autoimmune destruction of the adrenal gland and 20% to tuberculosis. A very rare cause is bilateral adrenal hemorrhages following bacterial sepsis, usually due to meningococci. Adrenal hypofunction in this setting is called the Waterhouse-Friderichsen syndrome and is a medical emergency that is difficult to treat.

Symptoms of Addison’s disease include:

• A diffuse increase in body pigmentation. This occurs because the pituitary gland overproduces ACTH due to the lack of feedback inhibition by cortisol. ACTH is similar to a hormone (melanocortin) that stimulates the pigment-producing melanocytes in the skin.
• Hypotension; problems with water and electrolyte balance

V.             THE PANCREAS

The pancreas is composed of a head, a body, and a tail. Located within the Islets of Langerhans are a cells, which make glucagon, and b cells, which make insulin. Insulin promotes the uptake of glucose by liver cells, which convert it into glycogen for storage. Glucagon causes breakdown of glycogen, causing glucose to be released into the blood. Insulin is also needed for cells (e.g., muscle cells) to take up glucose and use it to generate energy. The term gluconeogenesis refers to the process whereby liver cells make glucose from amino acids or other non-glucose precursors.

Insulin has a number of functions that are considered anabolic (building up):

• Reduces blood glucose levels by:
• Increasing synthesis and storage of glycogen in liver and muscle
• Increasing lipogenesis (formation of lipids) by stimulating fat cells to take up glucose and free fatty acids
• Increasing synthesis of proteins by stimulating the uptake of amino acids
• Decreasing gluconeogenesis in the liver (by decreasing the availability of amino acids)

Glucagon, on the other hand, has functions that are generally catabolic (breaking down):

• Increases blood glucose levels by:
• Increasing the breakdown of glycogen (glycogenolysis)
• Increasing the breakdown of lipids.  As a result, glycerol, which can be used for gluconeogenesis in the liver, is released.
• Increasing the breakdown of proteins to amino acids, which can be used by the liver for gluconeogenesis
• Increasing gluconeogenesis in the liver
• Promoting ketogenesis: this occurs when fatty acids are produced (due to breakdown of lipids) in excessive amounts and, as a result, cannot be fully processed by the liver. Consequently, ketoacids (also called ketone bodies) are released into the blood.  This process occurs when the action of glucagon is unopposed.

Diabetes mellitus is defined as glucose intolerance due to a relative or actual inadequacy of b cells to meet the needs of the body for insulin.

Type I diabetes:

• Called insulin-dependent or juvenile onset
• Abrupt onset at a young age (often before age 20)
• Marked tendency for ketoacidosis (diabetic coma)
• Accounts for 10-20% of cases
• Caused by autoimmune attack on b cells.  Antibodies to islet cells are usually present at the onset of disease.
• Genetic tendency to develop; associated with certain HLA (MHC) types.  Viral and/or environmental factors are probably also involved.
• Treated with insulin, diet
• Greatly reduced secretion of insulin
• Obesity less common than for type II
• Significant reduction in lifespan

Type II diabetes:

• Called non-insulin-dependent or adult onset
• Slow onset, typically at 40 or older
• Ketoacidosis is rare
• Accounts for 80-90% of cases
• Causation is defective receptors for insulin (not autoimmune).   There is a progressive loss of functional insulin receptors in the peripheral tissues.
• Genetic tendency, but no HLA association
• Usually managed by diet, weight reduction, and, as a last resort, drugs
• Insulin is secreted but is insufficient and/or ineffective
• Obesity is a factor
• Reduction in lifespan is usually slight

The symptoms of type I diabetes typically include polyuria (production of abnormally large amounts of urine) and thirst, since excessive levels of glucose in the blood dehydrate cells; weakness and fatigue due to inefficient metabolism; and polyphagia (ingestion of large amounts of food) combined with weight loss, due to breakdown of lipids, proteins, glycogen, etc., by the unopposed action of glucagon. The symptoms of type II diabetes are more insidious and harder to recognize. They may include blurred vision, infections, and peripheral neuropathy (tingling in hands and feet).

Gestational diabetes most commonly occurs in the third trimester of pregnancy; obesity is a risk factor. It often resolves after birth, but these women are prone to develop Type II diabetes later in life.

Laboratory diagnosis of diabetes is by measuring fasting levels of blood glucose. An oral glucose tolerance test is often used, in which a patient ingests a measured amount of glucose. The patient is then monitored over time to see if the blood glucose levels fall appropriately. Glucose can bind to hemoglobin to form a modified molecule called hemoglobin A_1c. Measurement of hemoglobin A_1c levels can be used to follow the success of therapy over the long term (weeks or months).

Diabetes results in both acute and chronic complications. Acute complications include:

• Hypoglycemia: which may result from taking too much insulin, drinking alcohol (which inhibits gluconeogenesis by the liver), or excessive exercise (which can increase the number of functional insulin receptors in type II diabetics).
• Diabetic ketoacidosis (DKA): associated with type I diabetes
• Hyperglycemic hyperosmolar nonketotic coma (HHNC): associated with type II diabetes. In this condition, very high glucose levels in the blood lead to severe dehydration of cells, but the patient is not thirsty. HHNC can be a dire emergency. It is difficult to treat and can prove fatal.  This condition causes significantly more deaths than does DKA.

Chronic complications are many, including:

• Microangiopathy, a term referring to disease of small blood vessels. In diabetes, the basement membranes surrounding capillaries tend to get very thick but also leaky. Eventually, the capillary may become occluded, leading to impaired circulation in the affected tissue.
• Nephropathy (kidney disease), including:
• Glomerulopathy:
• Diffuse glomerulosclerosis: a fairly common condition in a number of diseases
• Nodular glomerulosclerosis: very specific to diabetes
• Exudative lesions
• Arteriosclerosis
• Pyelonephritis: urinary tract infections are more likely to flourish in a glucose-rich environment.
• Tubular cell changes
• Ocular disease:
• Nonproliferative retinopathy: Microangiopathy and ischemia may result in infarcts, aneurysms, hemorrhages, and exudate in the retina. These, in turn, may lead to scarring and to:
• Proliferative retinopathy: a condition that is marked by growth of new blood vessels (neovascularization). The scar tissue may squeeze these new vessels, causing them to hemorrhage. This, in turn, may lead to detachment of the retina.
• Rubeosis iridis diabetica: refers to retinopathy in the iris of the eye. The canal that drains fluid from the eye may become clogged, leading to glaucoma.
• Cataracts: opacities in the lens due to poor water balance
• Neuropathy: is due to occlusion of small blood vessels that supply the nerves. It usually is symmetrical and tends to be worse in the lower extremities. It usually affects sensory nerves more than motor nerves, resulting in tingling, numbness, and loss of sense of position. Ulcers may develop, since the patients do not feel small cuts, infections, etc. and may tend to ignore them until they ulcerate. These ulcers may become gangrenous.
• Macroangiopathy: refers to disease of large vessels. Diabetics are at greater risk for developing atherosclerosis. They may fall victim to ischemia, myocardial infarction, aortic aneurysms, strokes or other cerebrovascular disease, or develop gangrene and ulcers (which may require amputation of the affected part).

Atherosclerotic heart disease and renal disease are the most common causes of death in diabetics.  Note that nephropathy, retinopathy, and neuropathy are largely due to microangiopathy.