What is endocrinology?

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The science dealing with how the internal secretions from ductless glands in the body act both in normal physiology and in disease states.
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The rates of metabolic pathways in the body are controlled mainly by the endocrine system, in conjunction with the nervous system. These two systems are integrated in the neuroendocrine system, which controls the secretion of hormones by the endocrine glands. The study of endocrinology deals with the normal physiology and pathophysiology of endocrine glands. The endocrine glands that are typically the main focus of clinical endocrinologists are the hypothalamus, pituitary gland, thyroid, parathyroid, adrenal glands, endocrine pancreas, ovaries, and testes. The endocrine system regulates virtually all activities of the body, including growth and development, homeostasis, energy production, and reproduction.

The hypothalamus is a highly specialized endocrine organ that sits at the base of the brain and that functions as the master gland of the endocrine system. It is the main integrator for the endocrine and nervous systems. The hypothalamus produces a number of chemical mediators that have direct control over the pituitary gland. These chemicals are made in the cells of the hypothalamus and reach the pituitary gland, which sits just below it, by a special hypophyseoportal blood system. In adult humans, the pituitary is divided into two lobes: the anterior lobe (adenohypophysis) and the posterior lobe (neural lobe).

Vasopressin and oxytocin are the two main hormones that are made in the hypothalamus but stored in the posterior lobe of the pituitary for release when needed. Vasopressin (also known as antidiuretic hormone, or ADH) is a hormone that maintains a normal water concentration in the blood and is a regulator of circulating blood volume. Oxytocin is a hormone that is involved in lactation and obstetrical labor.

The hypothalamic-pituitary-thyroid axis is important in the control of basal metabolic rate. There are a number of releasing hormones secreted from the hypothalamus that control the release of anterior pituitary hormones, which then cause the release of hormones at the end organ. Most of these hormones have the chemical structures of peptides. Thyrotropin-releasing hormone (TRH) was the first hypothalamic releasing hormone that was synthesized and used clinically. TRH, secreted in nanogram quantities, is a cyclic tripeptide that causes the release of thyrotropin-stimulating hormone (TSH) from the thyrotropic cells of the anterior pituitary gland. The release of TSH is in microgram quantities and leads to an increase in thyroid hormone release by the thyroid gland. The amount of thyroid hormone synthesized is on the order of milligrams. Therefore, the secretion of minute amounts of TRH allows for the production of thyroid hormone that is a millionfold greater than the amount of TRH itself. This is an example of an amplifying cascade, a system by which the central nervous system can control all metabolic processes with the secretion of very small amounts of hypothalamic releasing hormones. This intricate system possesses controls to stop the production of too much hormone as well. Such negative feedback is an important concept in endocrinology.

In the case of the thyroid, an increased amount of thyroid hormone produced by the thyroid gland will cause the pituitary and hypothalamus to decrease the amounts that they produce of TSH and TRH, respectively. Many hormones are subject to the laws of negative feedback control. TRH also causes potent release of the anterior pituitary hormone called prolactin. Thyroid hormone is important in determining basal metabolism and is needed for proper development in the newborn child. The thyroid gland produces both thyroxine (T4), also called tetraiodothyronine) and triiodothyronine (T3), both of which it synthesizes from iodine and the amino acid tyrosine.

The hypothalamic-pituitary-adrenal axis is critical in the reaction to stress, both physical and emotional. Corticotropin-releasing hormone (CRH) is a polypeptide, consisting of forty-one amino acids, that causes the production of the proopiomelanocortin molecule by the corticotropic cells of the anterior pituitary. The proopiomelanocortin molecule is cleaved by proteolytic enzymes to yield adrenocorticotropic hormone (ACTH, also called corticotropin), melanocyte-stimulating hormone, and lipotropin. It is ACTH made by the anterior pituitary, which then stimulates the adrenal cortex to produce steroid hormones. The main stress hormone produced by the adrenal cortex in response to ACTH is the glucocorticoid cortisol. ACTH also has some control over the production of the mineralocorticoid aldosterone and the androgens dehydroepiandrosterone and testosterone. These steroids are synthesized from cholesterol. The production of cortisol (also known as hydrocortisone) is subject to negative feedback by CRH and ACTH.

The hypothalamic-pituitary-gonadal axis is involved in the control of reproduction. Gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LHRH), is produced by the hypothalamus and stimulates the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the gonadotrophic cells of the anterior pituitary. LH and FSH have different effects in men and women. In men, LH controls the production and secretion of testosterone by the Leydig cells of the testes. The release of LH is regulated by negative feedback from testosterone. FSH along with testosterone acts on the Sertoli cells of the seminiferous tubule of the testis at the time of puberty to start sperm production. In women, LH controls ovulation by the ovary and also the development of the corpus luteum, which produces progesterone. Progesterone is a steroid hormone that is critically important for the maintenance of pregnancy. FSH in women stimulates the development and maturation of a primary follicle and oocyte. The ovarian follicle in the nonpregnant woman is the main site of production of estradiol. Estradiol is the principal estrogen made in the reproductive years by the ovary and is responsible for the development of female secondary sexual characteristics.

Growth hormone-releasing hormone (GHRH) is a polypeptide with forty-four amino acids that stimulates the release of growth hormone (GH) from the somatotrophic cells of the anterior pituitary. The regulation of GH secretion is under dual control. While GHRH positively releases GH, somatostatin (a polypeptide with fourteen amino acids, also released from the hypothalamus) inhibits the release of GH. Somatostatin has a wide variety of functions, including the suppression of insulin, glucagon, and gastrointestinal hormones. GH released from the pituitary circulates in the bloodstream and stimulates the production of somatomedins by the liver. Several somatomedins are produced, all of which have a profound effect on growth, with the most important one in humans being somatomedin C, also called insulin-like growth factor I (IGF I). Molecular biological techniques have shown that many cells outside the liver also produce IGF I; in these cells, IGF I acts in autocrine or paracrine ways to cause the growth of the cells or to affect neighboring cells.

Prolactin is a peptide hormone that is secreted by the lactotrophs of the anterior pituitary. It is involved in the differentiation of the mammary gland cells and initiates the production of milk proteins and other constituents. Prolactin may also have other functions, as a stress hormone or growth hormone. Prolactin is under tonic negative control. The inhibition of prolactin release is caused by dopamine, which is produced by the hypothalamus. Thus, while dopamine is normally considered to be a neurotransmitter, in the case of prolactin release it acts as an inhibitory hormone. Serotonin, also classically thought of as a neurotransmitter, may cause the stimulation of prolactin release from the anterior pituitary.

Diagnostic and Treatment Techniques

One of the most common medical problems seen by specialists in the field of endocrinology is a patient with type 1 diabetes mellitus, sometimes also called juvenile-onset or insulin-dependent diabetes mellitus. “Insulin-dependent” is probably more appropriate, as not all patients with type 1 diabetes mellitus develop the disease in childhood. Type 1 diabetes is an autoimmune disease in which antibodies to different parts of the pancreatic beta cell, the cell that normally produces insulin, are produced. Some of these antibodies are cytotoxic; that is, they actually destroy the pancreatic beta cell. The most striking characteristic of patients with type 1 diabetes is that they produce very little insulin. The symptoms of type 1 diabetes include increased thirst, increased urination, blurring of vision, and weight loss. A doctor would confirm the diagnosis by running blood tests for glucose and insulin. The glucose level would be high, and the insulin level would be low. The treatment includes controlled diet, exercise, insulin therapy, and self-monitoring of blood glucose. With proper control of blood glucose, patients with type 1 diabetes can lead normal, productive lives.

Graves’ disease is another autoimmune disease that is commonly seen by endocrinologists. Graves’ disease is caused by the production of thyroid-stimulating immunoglobulin antibodies that bind to and activate TSH receptors. As a result, the thyroid gland produces too much thyroid hormone and the thyroid gland enlarges in size. The antibodies also commonly affect the eyes, causing a characteristic bulging. The clinical symptoms of hyperthyroidism include increased heart rate, anxiety, heat sensitivity, sleeplessness, diarrhea, and abdominal pain. Patients often lose considerable weight, despite having a great appetite and eating large amounts of food. Sometimes, the diagnosis is missed, leading to an extensive evaluation for a variety of other diseases. Often, a family history of thyroid disease or other endocrine disease can be found.

The usual method of screening for Graves’ disease is with a simple blood test for thyroid function, which includes testing for T4, T3, and TSH. In patients with Graves’ disease, both T4 and T3 will be elevated, and TSH will be very low. If the blood test reveals this pattern, the next usual step is to proceed to a radioactive iodine uptake and scan test, which involves giving a very small amount of radioactive iodine by mouth and having the patient return twenty-four hours later for a scan. The thyroid gland normally accumulates iodine and thus will accumulate the radioactive iodine as well. The radioactive iodine emits a gamma-ray energy that can be picked up by a solid-crystal scintillation counter placed over the thyroid gland. With this device, one can determine the percentage of iodine uptake and also obtain a picture of the thyroid gland. The normal radioactive iodine uptake is about 10 to 30 percent of the dose, depending somewhat on the amount of total body iodine, which is derived from the diet. Patients with Graves’ disease will have high radioactive iodine uptakes.

Those who suffer from Graves’ disease can be treated by three different means, depending on the circumstances. The first treatment that is often tried is antithyroid drugs, either propylthiouracil or methimazole. These drugs belong to the class of sulfonamides and inhibit the production of new thyroid hormone by blocking the attachment of iodine to the amino acid tyrosine. Another mode of therapy is the use of radioactive iodine. A dose of radioactive iodine (on the order of five to ten millicuries) is used to destroy part of the thyroid gland. The gamma-ray energy emitted from the iodine molecule that has traveled to the thyroid gland is enough to kill some thyroid cells. An alternative way to destroy the thyroid gland is to remove it surgically (thyroidectomy). Endocrinologists rarely send patients for surgery, as the other therapies are often effective. The goal of all treatments is to bring the level of thyroid hormone into the normal range, as well as to shrink the thyroid gland. After treatment, the patient’s level of thyroid hormone sometimes falls to levels that are below normal. The symptoms of hypothyroidism are the opposite of hyperthyroidism and include fatigue, weight gain, cold sensitivity, constipation, and dry skin. If this happens, the patient is treated with thyroid hormone replacement. The dose is adjusted for each individual to produce normal levels of T4, T3, and TSH.

A less common but important endocrine disorder is the existence of a pituitary tumor that secretes prolactin, called a prolactinoma. Prolactinomas are diagnosed earlier in women than in men, as women with the disorder often complain of a lack of menstrual periods and spontaneous milk production from the breasts, known as galactorrhea. These tumors, which can be quite small, are called microadenomas because they are less than ten millimeters in size. They can affect men as well, causing decreased sex drive and impotence. Macroadenomas are tumors greater than ten millimeters in size. When the tumors increase in size, they can cause symptoms such as headache and decreased vision. It is important to note that most microadenomas never progress to macroadenomas. Vision loss and/or decreased eye movement can be seen with a macroadenoma and are reason for immediate treatment.

Doctors screen patients for a prolactinoma by running a blood test for prolactin. There are other reasons for mild elevations in prolactin levels, including the use of certain psychiatric drugs such as phenothiazines or the antihypertensive drugs reserpine and methyldopa, primary hypothyroidism, cirrhosis, and chronic renal failure. If a pituitary tumor is suspected, then other biochemical tests of pituitary function are conducted to determine if the rest of the gland is functioning normally. At that time, imaging tests are often done to get a picture of the hypothalamic-pituitary area; this can be done with either computed tomography (CT) scanning or magnetic resonance imaging (MRI). Patients with macroadenomas will require treatment. In patients with little neurological involvement, medical therapy may be initiated. Bromocriptine, a semisynthetic ergot alkaloid that is an inhibitor of prolactin secretion, may be used. It has been shown that patients treated with this drug have a reduction in tumor size. Patients can be maintained on the drug indefinitely because prolactin levels return to pretreatment levels when the drug is stopped. If there is severe neurologic involvement, with loss of vision and other eye problems, immediate surgery may be indicated. There is a very high incidence of tumor recurrence after surgery, requiring medical and/or radiation therapy.

Perspective and Prospects

The field of endocrinology is a continuously evolving one. Advances in biomedical technology, including molecular biology and cell biology, have made it a demanding job for the clinician to keep up with all the breakthroughs in the field. The challenge for endocrinology will be to apply many of these new technologies to novel treatments for patients with endocrine diseases.

An example of the progression of the field of endocrinology can be seen in the history of pituitary diseases. The start of pituitary endocrinology is attributed to Pierre Marie, the French neurologist who in 1886 first described pituitary enlargement in a patient with acromegaly (enlargement of the skull, jaw, hands, and feet) and linked the disease to a pituitary abnormality. During the first half of the twentieth century, many of the hypothalamic and pituitary hormones were isolated and characterized. The field of endocrinology was revolutionized by the development of radioimmunoassay, which allows sensitive and specific measurements of hormones. Radioimmunoassay replaced bioassay techniques, which were laborious, time-consuming, and not always precise. This technique has allowed for rapid measurement of hormones and improved screening for endocrine diseases involving hormone deficiency or hormone excess.

The development of new hormone assays has been complemented by the development of noninvasive imaging techniques. Before the advent of CT scanning in the late 1970s, it was an ordeal to diagnose a pituitary tumor. Pneumoencephalography was often performed, which involved injecting air into the fluid-containing structures of the brain, with associated risk and discomfort to the patient. In the 1980s, with new generations of high-resolution CT scanners that were more sensitive than early scanners, smaller pituitary lesions could be detected and diagnosed. That decade also ushered in the use of MRI to diagnose disorders of the hypothalamic-pituitary unit. MRI has allowed doctors to evaluate the hypothalamus, pituitary, and nearby structures very precisely; it has become the method of choice for evaluating patients with pituitary disease. MRI can easily visualize the optic chiasm in the forebrain and the vascular structures surrounding the pituitary.

In patients who require surgery, advances have helped decrease mortality rates. Harvey Cushing pioneered the transsphenoidal technique in 1927 but abandoned it in favor of the transfrontal approach. This involves reaching the pituitary tumor by retracting the frontal lobes to visualize the pituitary gland sitting underneath. The modern era of transsphenoidal pituitary surgery was developed by Gérard Guiot and Jules Hardy in the late 1960s. Transsphenoidal surgery done with an operating microscope to visualize the pituitary contents allows for selective removal of the tumor, leaving the normal pituitary gland intact. The advantage of this approach from below, instead of from above, includes minimal movement of the brain and less blood loss. This technique requires a neurosurgeon with much skill and experience. There are also new drug treatments for patients with pituitary diseases, such as bromocriptine for use in patients with prolactinomas and octreotide (a somatostatin analogue) to lower growth hormone levels in patients with acromegaly.

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