Once a hormone has acted on the target tissue, the concentration of the hormone in the blood must be restored to normal. This is necessary to prevent excessive, possibly harmful actions of prolonged exposure of target cells to hormones. A hormone’s concentration in the plasma depends upon (1) its rate of secretion by the endocrine gland, and (2) its rate of removal from the blood. Removal, or "clearance," of the hormone occurs either by excretion or by metabolic transformation. The liver and the kidneys are the major organs that excrete or metabolize hormones. The liver and kidneys, however, are not the only routes for eliminating hormones. Sometimes the hormone is metabolized by the cells upon which it acts. Very importantly, in the case of peptide hormones, endocytosis of hormone-receptor complexes on plasma membranes enables cells to remove the hormones rapidly from their surfaces and catabolize them intracellularly. The receptors are then often recycled to the plasma membrane.
In addition, catecholamine and peptide hormones are excreted rapidly or attacked by enzymes in the blood and tissues. These hormones therefore tend to remain in the bloodstream for only brief periods —minutes to an hour. In contrast, because protein-bound hormones are less vulnerable to excretion or metabolism by enzymes, removal of the circulating steroid and thyroid hormones generally takes longer, often several hours (with thyroid hormone remaining in the plasma for days). In some cases, metabolism of the hormone after its secretion activates the hormone rather than inactivates it. In other words, the secreted hormone may be relatively or completely unable to act upon a target cell until metabolism transforms it into a substance that can act. One example is provided by testosterone, which is converted either to estradiol or dihydrotestosterone in certain of its target cells. These molecules, rather than testosterone itself, then bind to receptors inside the target cell and elicit the cell’s response.
There is another kind of "activation" that applies to a few hormones. Instead of the hormone itself being activated after secretion, it acts enzymatically on a completely different plasma protein to split off a peptide that functions as the active hormone. The best known example of this is the renin-angiotensin system; renin is not technically a hormone but an enzyme that participates in the generation of the hormone angiotensin.