Hormone Secretion, Transport, and Clearance from the Blood
Onset of Hormone Secretion After a Stimulus, and Duration of Action of Different Hormones. Some hormones, such asnorepinephrine and epinephrine, are secreted within seconds after the gland is stimulated, and they may develop full action within another few seconds to minutes; the actions of other hormones, such as thy-roxine or growth hormone, may require months for full effect. Thus, each of the different hormones has its own characteristic onset and duration of action—each tailored to perform its specific control function.
Concentrations of Hormones in the Circulating Blood, and Hor-monal Secretion Rates. The concentrations of hormonesrequired to control most metabolic and endocrine functions are incredibly small. Their concentrations in the blood range from as little as 1 picogram (which is one millionth of one millionth of a gram) in each mil-liliter of blood up to at most a few micrograms (a few millionths of a gram) per milliliter of blood. Similarly, the rates of secretion of the various hormones are extremely small, usually measured in micrograms or milligrams per day. We shall see later that highly specialized mechanisms are available in the target tissues that allow even these minute quantities of hormones to exert powerful control over the phys-iological systems.
Negative Feedback Prevents Overactivity of Hormone Systems.
Although the plasma concentrations of many hor-mones fluctuate in response to various stimuli that occur throughout the day, all hormones studied thus far appear to be closely controlled. In most instances, this control is exerted through negative feedback mech-anisms that ensure a proper level of hormone activityat the target tissue. After a stimulus causes release of the hormone, conditions or products resulting from the action of the hormone tend to suppress its further release. In other words, the hormone (or one of its products) has a negative feedback effect to prevent oversecretion of the hormone or overactivity at the target tissue.
The controlled variable is often not the secretory rate of the hormone itself but the degree of activity of the target tissue. Therefore, only when the target tissue activity rises to an appropriate level will feedback signals to the endocrine gland become powerful enough to slow further secretion of the hormone. Feedback regulation of hormones can occur at all levels, including gene transcription and translation steps involved in the synthesis of hormones and steps involved in processing hormones or releasing stored hormones.
Surges of Hormones Can Occur with Positive Feedback. In afew instances, positive feedback occurs when the bio-logical action of the hormone causes additional secre-tion of the hormone. One example of this is the surge of luteinizing hormone (LH) that occurs as a result of the stimulatory effect of estrogen on the anterior pitu-itary before ovulation. The secreted LH then acts on the ovaries to stimulate additional secretion of estro-gen, which in turn causes more secretion of LH. Even-tually, LH reaches an appropriate concentration, and typical negative feedback control of hormone secre-tion is then exerted.
Cyclical Variations Occur in Hormone Release. Superim-posed on the negative and positive feedback control of hormone secretion are periodic variations in hormone release that are influenced by seasonal changes, various stages of development and aging, the diurnal (daily) cycle, and sleep. For example, the secre-tion of growth hormone is markedly increased during the early period of sleep but is reduced during the later stages of sleep. In many cases, these cyclical variations in hormone secretion are due to changes in activity of neural pathways involved in controlling hormone release.
Water-soluble hormones (peptides and cate-cholamines) are dissolved in the plasma and trans-ported from their sites of synthesis to target tissues, where they diffuse out of the capillaries, into the inter-stitial fluid, and ultimately to target cells.
Steroid and thyroid hormones, in contrast, circulatein the blood mainly bound to plasma proteins. Usually less than 10 per cent of steroid or thyroid hormones in the plasma exist free in solution. For example, more than 99 per cent of the thyroxine in the blood is bound to plasma proteins. However, protein-bound hor-mones cannot easily diffuse across the capillaries and gain access to their target cells and are therefore bio-logically inactive until they dissociate from plasma proteins.
The relatively large amounts of hormones bound to proteins serve as reservoirs, replenishing the concen-tration of free hormones when they are bound to target receptors or lost from the circulation. Binding of hormones to plasma proteins greatly slows their clearance from the plasma.
Two factors can increase or decrease the concentration of a hormone in the blood. One of these is the rate of hormone secretion into the blood. The second is the rate of removal of the hormone from the blood, which is called the metabolic clearance rate. This is usually expressed in terms of the number of milli-liters of plasma cleared of the hormone per minute. To calculate this clearance rate, one measures (1) the rate of disappearance of the hormone from the plasma per minute and (2) the concentration of the hormone in each milliliter of plasma. Then, the meta-bolic clearance rate is calculated by the following formula:
Metabolic clearance rate = Rate of disappearance of hormone from the plasma/Concentration of hormone in each milliliter of plasma
The usual procedure for making this measurement is the following: A purified solution of the hormone to be measured is tagged with a radioactive substance. Then the radioactive hormone is infused at a constant rate into the blood stream until the radioactive con-centration in the plasma becomes steady. At this time, the rate of disappearance of the radioactive hormone from the plasma equals the rate at which it is infused, which gives one the rate of disappearance. At the same time, the plasma concentration of the radioactive hormone is measured using a standard radioactive counting procedure. Then, using the formula just cited, the metabolic clearance rate is calculated.
Hormones are “cleared” from the plasma in several ways, including (1) metabolic destruction by the tissues, (2) binding with the tissues, (3) excretion by the liver into the bile, and (4) excretion by the kidneys into the urine. For certain hormones, a decreased metabolic clearance rate may cause an excessively high concen-tration of the hormone in the circulating body fluids. For instance, this occurs for several of the steroid hor-mones when the liver is diseased, because these hor-mones are conjugated mainly in the liver and then “cleared” into the bile.
Hormones are sometimes degraded at their target cells by enzymatic processes that cause endocytosis of the cell membrane hormone-receptor complex; the hormone is then metabolized in the cell, and the recep-tors are usually recycled back to the cell membrane.
Most of the peptide hormones and catecholamines are water soluble and circulate freely in the blood. They are usually degraded by enzymes in the blood and tissues and rapidly excreted by the kidneys and liver, thus remaining in the blood for only a short time. For example, the half-life of angiotensin II circulating in the blood is less than a minute.
Hormones that are bound to plasma proteins are cleared from the blood at much slower rates and may remain in the circulation for several hours or even days.The half-life of adrenal steroids in the circulation, for example, ranges between 20 and 100 minutes, whereas the half-life of the protein-bound thyroid hor-mones may be as long as 1 to 6 days.
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