What are hormones?
The definition of the term “hormone” has continued to change over the years. The classic definition is that of an endocrine hormone—that is, one secreted by ductless glands directly into the blood and acting at a distant site. The definition can be expanded to include any chemical substance secreted by any cell of the body that has a specific effect on another cell. A hormone can affect a nearby cell (paracrine action) or the cell that secretes it (autocrine action). Certain hormones are produced by the brain and kidneys, which are not thought of as classic endocrine glands. In fact, the largest producer of hormones is the gastrointestinal tract, which is not usually thought of as an endocrine gland.
Hormones fall into two major categories: peptide hormones, which are derived from amino acids, and steroid hormones, which are derived from cholesterol. The different classes of hormones have different mechanisms of action. Peptide hormones work by interacting with a specific receptor located in the plasma membrane of the target cell. Receptors have different regions, or domains, that perform specialized functions. One part of the receptor has a specific three-dimensional structure similar to a keyhole into which a certain hormone can fit. This design allows a specific action of a hormone despite the fact that the hormone is often circulating in minute quantities in the bloodstream along with myriad other hormones.
There are different classes of plasma membrane receptors. One class is that of the receptor kinases. The insulin receptor is an example. In this case, the part of the receptor molecule that faces the cytoplasm, or inside of the cell, is able to perform a specific function. When insulin interacts with its receptor, a chemical change occurs on the receptor that allows it to activate proteins within the cell. Many hormones use a similar cascade of chemical reactions to control and amplify signals from outside the cell and effect change within the cell itself.
Another class of membrane receptors includes the G-protein coupled receptor. An example is the beta-2 adrenergic receptor. Epinephrine interacts with this receptor, causing the activation of a signal transducer or G protein. This activated G protein then leads to the modification of a specific protein, which leads to a cascade of biochemical events within the cell. This is another example of an amplification mechanism.
Steroid hormones exert their effects by means of a different mechanism. For example, glucocorticoids exert their effects by entering the cell and binding to specific glucocorticoid receptors in the cell nucleus. The glucocorticoid-receptor complex is able to bind specific regulatory DNA sequences, called glucocorticoid response elements. This binding is able to activate gene transcription, which causes an increase in mRNA and, ultimately, the translation of the mRNA to deliver a newly secreted protein. The protein can then act to change the cell’s metabolism in some way. Cortisol, a type of glucocorticoid, is produced by the adrenal glands when a person is under stress. It can lead to changes in blood sugar levels, affect immune system function, and, at high levels, increase fat deposition in characteristic areas of the body.
Most hormones that circulate in the blood are attached to binding proteins. The general binding proteins in the body are albumin and transthyreitin. These two proteins bind many different hormones. There are also specific binding proteins, such as thyroid-binding globulin, which binds thyroid hormone, and insulin-like growth factor-binding proteins, which bind to the family of insulin-like growth factors. The bound hormone is considered the inactive hormone, and the free hormone is the active hormone. Therefore, binding proteins make it possible to control an active hormone precisely, without having to synthesize a new hormone.
Hormones can be secreted in a variety of time frames. Some hormones, such as testosterone, are secreted in a pulsatile fashion that changes over minutes or hours. Other hormones, such as cortisol, are secreted in a diurnal pattern, with levels varying depending on the time of day. Cortisol levels are highest at about 8 a.m. and fall throughout the day, with the lowest levels occurring between midnight and 2 a.m. The menstrual cycle is an example of the weekly to monthly variation of hormone production. For instance, progesterone (a steroid hormone) levels rise throughout the menstrual cycle and fall prior to the onset of menses. The exact control mechanisms that determine the rhythmicity of hormone production are unknown.
The ability to study and utilize hormones in treating human disease has been revolutionized by molecular biology. The first hormone to be synthesized for clinical use was insulin. The need for a secure and steady supply of insulin prompted scientists to look for alternative sources of this hormone in the 1970s. At that time, insulin was isolated and purified from animal pancreas glands, mostly those of cows and pigs. It was suspected, however, that insulin could be made in the laboratory via genetic engineering. Native insulin is produced from a prohormone, proinsulin. Recombinant DNA human insulin is currently made by encoding for the proinsulin molecule and then using enzymes to cut the molecule in the proper places, yielding insulin and a piece of protein called C peptide. This process, which is very similar to the process that the body uses to create insulin, produces high yields of active hormone.
Modern molecular biology techniques were used to identify a hormone and receptor involved in weight regulation. Originally discovered in mice, a gene called ob was identified in human beings that produced a hormone called leptin. Leptin and its receptor are believed to play a role in signaling satiety to the brain. If the leptin signal does not reach the brain as the result of a faulty receptor, the brain will not produce the satiety signal. Appetite will remain high. Thus, a defective leptin system may contribute to obesity in human beings. The functioning of leptin may also be responsible for cycles of weight loss and gain in dieters. As obese individuals lose adipose tissue, less leptin is synthesized and the brain may not send out sufficient signals to indicate satiety, thus increasing appetite and food consumption. The leptin-obesity connection is under intensive study.
The biological roles of hormones are numerous and critical to the normal function of important organ systems in human beings, and there are many examples of medical uses for hormones. In general, any derangements in the amount of hormones made, or in the timing of their production, can result in significant human disease or discomfort. For example, in women who reach menopause, declining levels of estrogen and progesterone from the ovaries can lead to undesirable consequences such as hot flashes, vaginal dryness, and bone mineral density loss. Taking exogenous estrogen and progesterone, in the form of hormone therapy, can reduce or stop these consequences. Another example of exogenous hormone use in human disease is thyroid hormone. People with thyroid disease, such as Hashimoto’s thyroiditis, do not produce adequate levels of thyroid hormone. This condition can lead to intense fatigue and weight gain. These symptoms may be relieved by taking a synthetic thyroid hormone called levothyroxine.
Another example of the medical use of hormones is the role of synthetic erythropoietin in treating and preventing anemia. Normally, erythropoietin is made by the kidneys. It is essential for the differentiation and development of stem cells from the bone marrow into red blood cells. Most patients who develop kidney failure also suffer from severe anemia because the ability to synthesize erythropoietin is lost as the kidneys are destroyed by disease. Giving this hormone to a patient with kidney disease can lead to the restoration of that patient’s red blood cell mass. Correcting the anemia that accompanies chronic renal disease can improve the exercise tolerance and overall quality of life of kidney disease patients. The hormone must be given by injection several times per week. It has been made available to the almost fifty thousand Americans with chronic renal failure who require dialysis. Erythropoietin can also be given to renal failure patients who do not yet require dialysis but who do have anemia.
Another example of a hormone that has been synthesized for treatment of human disease is calcitonin. Calcitonin is a polypeptide hormone secreted by specialized C cells of the thyroid gland (also called parafollicular cells). The parafollicular cells make up about 0.1 percent of the total mass of the thyroid gland, and the cells are dispersed within the thyroid follicles. Calcitonin has been isolated from several different animal species, including salmon, eel, rat, pig, sheep, and chicken. The main physiologic function of the hormone is to lower the serum calcium level. It does this by inhibiting calcium resorption from bone. Calcitonin has been used to treat patients with Paget’s disease, a disorder of abnormal bone remodeling that can lead to deformities, bone pain, fractures, and neurological problems. Calcitonin has also been used in the past to treat patients with osteoporosis, a condition of bone density depletion associated with aging that can lead to bone fractures.
The first and most commonly used form of the hormone in the United States is salmon calcitonin. This form is a more potent inhibitor of bone resorption than the human form. A small number of patients given the drug will develop a resistance to it. The etiology of this resistance may be the development of antibodies to the salmon calcitonin. Subsequently, calcitonin was synthesized via recombinant DNA technology. Although the human form is somewhat less potent, the fact that its amino acid structure is identical to that of the native hormone makes it much less immunogenic than salmon calcitonin, and theoretically less likely to produce resistance. In fact, patients who were resistant to salmon calcitonin may be switched to human calcitonin and achieve a therapeutic effect.
An example of a hormone with multiple medical uses is vasopressin, also known as antidiuretic hormone. Normally, vasopressin is produced in the posterior pituitary gland (located in the brain); it is responsible for water conservation. An increase in plasma osmolality or a decrease in circulating blood volume will normally cause its release. Central diabetes insipidus, a disorder involving an absence or abnormal decrease of vasopressin, is characterized by an inappropriately dilute urine. Central diabetes insipidus can be caused by a variety of factors, including trauma, neurosurgery, brain tumors, brain infections, and autoimmune disorder. The clinical symptoms of the disease are polyuria and polydipsia. The patient may put out up to 18 liters of urine per day. If such large volume deficits are not remedied, more serious symptoms will ensue, including dangerously low blood pressure and coma. The acute treatment of any patient with central diabetes insipidus involves the replacement of body water with intravenous fluids. The chronic therapy involves replacement of the hormone vasopressin.
Several different forms of the hormone may be used, depending on the clinical situation. Aqueous vasopressin is useful for diagnostic testing and for acute management following trauma or neurosurgery. For diagnostic testing, it is often given subcutaneously at the end of the water deprivation test to determine whether the patient will respond to the hormone with a decrease in urine output and an increase in urine osmolality greater than 50 percent. After surgery, vasopressin can be given either intramuscularly, with a duration of action of about four to six hours, or by continuous intravenous infusion to ensure a steady level of the hormone.
In obstetrics, vasopressin is also known as pitocin, a hormone that can cause powerful uterine contractions. It is commonly used to augment labor, as when the mother’s own uterine contractions are not adequate to expel the baby. It is given intravenously and titrated up until regular contractions of the uterus occur. Another use of vasopressin is in the acute setting of advanced cardiac life support, also known as a code situation. A patient noted to have a cardiac arrhythmia such as ventricular fibrillation may receive vasopressin as well as shocks from a defibrillator in an attempt to restore a perfusing cardiac rhythm.
One of the most important uses of hormones in medicine is for contraception, specifically in the form of birth control pills. In the early twentieth century, the observation was made that mice that were fed extracts from ovaries could be rendered infertile. In the 1920s, the critical substance responsible for this infertility was discovered to be sex steroid hormones. The production of birth control pills dates to the 1920s and 1930s, when steroid hormones such as progesterone were isolated from animal sources, such as pigs. By the 1940s, progesterone could be isolated in large quantities from Mexican yams, which caused the prices for progesterone to fall dramatically. With the fall in prices, the idea that progesterone could be sold in the mass market as a birth control pill became more feasible. The first clinical trial of the birth control pill in human beings occurred in 1956. Since then, several generations of progesterones have been mass produced for the purposes of birth control. Each successive generation of progesterone has caused fewer undesirable side effects, and the dosage necessary to achieve a contraceptive effect has been found to be much lower than those found in the original birth control pills.
Birth control pills and the progesterone contained within them have other medical uses besides contraception. Birth control pills can be used to regulate menstrual cycles in women who suffer from irregular menstrual cycles or abnormal vaginal bleeding. They can be used to decrease heavy menstrual periods. They can even be useful in decreasing acne, which can lead to permanent scarring when it is severe.
The study of hormones has been instrumental in understanding how human beings adapt to and live in their environment. Hormones are involved in the regulation of body homeostasis and all critical aspects of the life cycle. The study of hormones has expanded as scientists have produced large amounts of synthetic hormones in the laboratory for use in research.
The history of insulin discovery and production is an example of the rapid scientific progress made in the field of hormone research. In 1889, Joseph von Mering and Oskar Minkowski demonstrated that dogs whose pancreases had been removed exhibited abnormalities in glucose metabolism that were similar to those seen in human diabetes mellitus patients. This fact suggested that some factor made by the pancreas lowered the blood glucose. The search for this factor led to the discovery of insulin in 1921 by Frederick C. Banting and Charles H. Best. They were able to extract the active substance from the pancreas and to demonstrate its therapeutic effects in dogs and humans. The chemistry of insulin progressed with the establishment of the amino acid sequence and three-dimensional structure in the 1960s. In 1960, insulin became the first hormone to be measured by radioimmunoassay. With advances in laboratory techniques in the 1970s, it became the first hormone to be commercially available via recombinant DNA technology, thus ensuring the availability of pure hormone without the need for animal sources.
The ability to synthesize hormones and their receptors has increased greatly. In fact, scientists can clone genes, or parts of genes, and synthesize the associated protein in order to make hormones that are encoded by the body. This method involves amplifying small amounts of DNA isolated from the cell using the technique of polymerase chain reaction (PCR). This allows large amounts of the same piece of DNA to be made in a matter of hours, which can then be transcribed into RNA and translated to yield the hormone. These powerful techniques, developed in the research laboratory, have been applied on a commercial basis and have provided enormous benefits to people. One such example is the production of growth hormone.
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