Hormones are secreted into extracellular fluid and readily enter the blood by passive diffusion driven by steep concentration gradients. Diffusion through pores in capillary endothelium also largely accounts for delivery of hormones to the extracellular fluid that bathes both target and nontarget cells. Receptor-mediated transfer across capillary endothelial cells may facilitate delivery of insulin, and perhaps other hormones, to target cells, but the importance of this mechanism of hormone delivery has not been established. In general, hormones distribute rapidly throughout the extracellular fluid and are not preferentially directed toward their target tissues.
Most hormones are cleared from the blood soon after secretion and have a half-life in blood of less than 30 min. The half-life of a hormone in blood is defined as that period of time needed for its concentration to be reduced by half. Clearance of a hormone from the blood depends on the rapidity with which it can escape from the circulation to equilibrate with extravascular fluids as well as on its rate of degradation. Some hormones, for example, epinephrine, have half-lives of the order of seconds, whereas thyroid hormones have half-lives of the order of days.
The half-life of a hormone in blood must be distinguished from the duration of its hormonal effect. Some hormones produce effects virtually instantaneously, and the effects may disappear as rapidly as the hormone is cleared from the blood. Other hormones produce effects only after a lag time that may last minutes or even hours, and the time the maximum effect is seen may bear little relation to the time of maximum hormone concentration in the blood. The time for decay of a hormonal effect is also highly variable; it may be only a few seconds, or it may require several days. Some responses persist well after hormonal concentrations have returned to basal levels. Understanding the time course of a hormone's survival in blood as well as the onset and duration of its action is obviously important for understanding normal physiology, endocrine disease, and the limitations of hormone therapy.
Most hormones are quite soluble, and they circulate completely dissolved in plasma water. Steroid hormones and thyroid hormones, whose solubility in water is limited, circulate bound specifically to large carrier proteins with only a small fraction, sometimes less than 1%, present in free solution. Some peptide hormones also bind to specific proteins in plasma. Protein binding is reversible; free and bound hormone are in equilibrium. However, only free hormone can cross the capillary endothelium and reach its receptors in target cells. Protein binding protects against loss of hormone by the kidney, slows the rate of hormone degradation by decreasing cellular uptake, and buffers changes in free hormone concentrations. In some cases hormone binding may facilitate or impede hormone delivery to target cells.
Implicit in any regulatory system involving hormones or any other signal is the necessity for the signal to disappear once the appropriate information has been conveyed. Recall that neurotransmitters are either rapidly destroyed in the synaptic cleft or taken up by nerve endings. Little hormone is destroyed in association with production of its biologic effects, and the remainder must therefore be inactivated and excreted. Degradation of hormones and their subsequent excretion are processes that are just as important as secretion. In general, rates of hormone degradation are characteristic for each hormone and follow first-order kinetics. That is, a constant percentage of hormone present in blood is destroyed per unit time by processes that are not usually subject to regulation. Inactivation of hormones occurs enzymatically in blood or intercellular spaces, in liver or kidney cells, or in target cells. Inactivation may involve complete metabolism so that no recognizable product appears in urine, or it may be limited to some simple one- or two-step process such as addition of a methyl group or glucuronic acid. In the latter cases, recognizable degradation products are found in urine and can be measured to obtain a crude index of the rate of hormone production.
Hormone concentrations in plasma fluctuate from minute to minute and may vary widely in the normal individual over the course of a day. Because rates of degradation usually do not vary, changes in concentration reflect changes in secretion rates. Hormone secretion may be episodic, pulsatile, or follow a daily rhythm (Fig. 2). In most cases, it is necessary to make multiple
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