As a general rule, hormones are produced by their gland or tissue of origin in an active form. However, for a few notable exceptions, the peripheral transformation of a hormone plays a very important role in its action.
Peripheral Transformation of Hormones. Specific hormone transformations may be impaired because of a congenital enzyme deficiency or drug-induced inhibition of enzyme activity, resulting in endocrine abnormalities. Well-known transformations are the conversion of testosterone to dihydrotestosterone (see Chapter 37) and the conversion of thyroxine to triiodothyronine (see Chapter 33). Other examples are the formation of the octapeptide angiotensin II from its precursor, angiotensinogen (see Chapter 34), and the formation of 1,25-dihydroxychole-calciferol from cholecalciferol (see Chapter 36).
As in any regulatory control system, it is necessary for the hormonal signal to dissipate or disappear once appropriate information has been transferred and the need for further stimulus has ceased. As described earlier, steady-state plasma concentrations of hormone are determined not only by the rate of secretion but also by the rate of degradation. Thus, any factor that significantly alters the degradation of a hormone can potentially alter its circulating concentration. Commonly, however, secretory mechanisms can compensate for altered degradation such that plasma hormone concentrations remain within the normal range. Processes of hormone degradation show little, if any, regulation,- alterations in the rates of hormone synthesis or secretion in most cases provide the primary mechanism for altering circulating hormone concentrations.
For most hormones, the liver is quantitatively the most important site of degradation, for a few others, the kidneys play a significant role as well. Diseases of the liver and kid neys may, therefore, indirectly influence endocrine status as a result of altering the rates at which hormones are removed from the circulation. Various drugs also alter normal rates of hormone degradation,- thus, the possibility of indirect drug-induced endocrine abnormalities also exists. In addition to the liver and kidneys, target tissues may take up and degrade quantitatively smaller amounts of hormone. In the case of peptide and protein hormones, this occurs via receptor-mediated endocytosis.
The nature of specific structural modification(s) involved in hormone inactivation and degradation differs for each hormone class. As a general rule, however, specific enzyme-catalyzed reactions are involved. Inactiva-tion and degradation may involve complete metabolism of the hormone to entirely different products, or it may be limited to a simpler process involving one or two steps, such as a covalent modification to inactivate the hormone. Urine is the primary route of excretion of hormone degradation products, but small amounts of intact hormone may also appear in the urine. In some cases, measuring the urinary content of a hormone or hormone metabolite provides a useful, indirect, noninvasive means of assessing endocrine function.
The degradation of peptide and protein hormones has been studied only in a limited number of cases. However, it appears that peptide and protein hormones are inactivated in a variety of tissues by proteolytic attack. The first step appears to involve attack by specific peptidases, resulting in the formation of several distinct hormone fragments. These fragments are then metabolized by a variety of nonspecific peptidases to yield the constituent amino acids, which can be reused.
The metabolism and degradation of steroid hormones has been studied in much more detail. The primary organ involved is the liver, although some metabolism also takes place in the kidneys. Complete steroid metabolism generally involves a combination of one or more of five general classes of reactions: reduction, hydroxylation, side chain cleavage, oxidation, and esterification. Reduction reactions are the principal reactions involved in the conversion of biologically active steroids to forms that possess little or no activity. Esterification (or conjugation) reactions are also particularly important. Groups added in esterification reactions are primarily glucuronate and sulfate. The addition of such charged moieties enhances the water solubility of the metabolites, facilitating their excretion. Steroid metabolites are eliminated from the body primarily via the urine, although smaller amounts also enter the bile and leave the body in the feces.
At times, quantitative information concerning the rate of hormone metabolism is clinically useful. One index of the rate at which a hormone is removed from the blood is the metabolic clearance rate (MCR). The metabolic clearance of a hormone is analogous to that of renal clearance (see Chapter 23). The MCR is the volume of plasma cleared of the hormone in question per unit time. It is calculated from the equation:
MCR = Hormone removed per unit time (mg/min) (1) Plasma concentration (mg/mL)
and is expressed in mL plasma/min.
One approach to measuring MCR involves injecting a small amount of radioactive hormone into the subject and then collecting a series of timed blood samples to determine the amount of radioactive hormone remaining. Based on the rate of disappearance of hormone from the blood, its half-life and MCR can be calculated. The MCR and halflife are inversely related—the shorter the half-life, the greater the MCR. The half-lives of different hormones vary considerably, from 5 minutes or less for some to several hours for others. The circulating concentration of hormones with short half-lives can vary dramatically over a short period of time. This is typical of hormones that regulate processes on an acute minute-to-minute basis, such as a number of those involved in regulating blood glucose. Hormones for which rapid changes in concentration are not required, such as those with seasonal variations and those that regulate the menstrual cycle, typically have longer half-lives.
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