1. Control of Synthesis and Secretion
The production and/or secretion of most hormones are regulated by the homeostatic mechanisms operative in that particular endocrine system. The secretion or release of the hormone is normally (in the absence of an endocrine disease related to hormone secretion) related to the requirement for the biological response(s) generated by the hormone in question. Once this requirement has been met, the secretion of the hormone is curtailed to prevent an overresponse. Thus, a characteristic feature of most endocrine systems is the existence of a feedback loop that limits or regulates the secretion of the hormonal messenger.
Two general categories of endocrine feedback systems are illustrated in Figure 1: those in which the function achieved by the hormone (e.g., elevated serum Ca2+ or elevated blood glucose) directly feeds back upon the endocrine gland that secretes the hormone; and those involving the central nervous system (CNS) and hypo thalamus. On the left is shown the first case, a simple but effective system, in which changes in the circulating amount of something of physiological importance, in this case serum Ca2+, is both the biological response and the agent that exerts negative feedback inhibition on the gland producing the hormone that caused its increase. Although the actual control of parathyroid hormone (PTH) is considerably more complex than shown in this figure, the secretion of the hormone in response to low serum Ca2+ and its cessation when this cation returns to normal levels is at the heart of the regulation of PTH. Another example of this type of control is the stimulation of insulin by elevated levels of blood glucose and the fall of the hormone when glucose levels fall in response to its actions.
Fig1. Models of the regulation of hormone secretion. Two general models of the physiological homeostatic control of hormone secretion are shown. On the left is the type of negative feedback exemplified by the secretion of parathyroid hormone (PTH) by the parathyroid gland. The stimulus for the secretion of PTH is a drop in serum Ca2+ below the threshold of normality. A calcium sensor in the parathyroid gland cell detects this drop and sets into motion events leading to increased synthesis of PTH and its secretion into the bloodstream. At its target cells PTH stimulates the movement of Ca2+ into the blood and the negative feedback effect of normal circulating levels of the cation result in reduced production and secretion of PTH. On the right is a generic version of the hypothalamic-pituitary-peripheral organ axis seen for the hormones of the thyroid gland, gonads, adrenal cortex, and other pituitary hormones. In these systems, the hypothalamus receives input from many different areas of the central nervous system (CNS) and responds by secreting a hormone (releasing hormone, RH, or, in some cases a release-inhibiting hormone) that stimulates specific cells of the pituitary to secrete a peptide hormone that stimulates a peripheral gland (SH). This peripheral gland secretes another hormone, PH, which acts on its target cells to bring about the appropriate biological response and at the same time exerts negative feedback effects on the hypothalamus and/or the pituitary to turn off the system. As will be seen in the chapters devoted to these systems, the actual controls are considerably more complex than depicted here, but the underlying blueprint for them is constant.
On the right side of Figure 1 is shown a generalized version of a hypothalamic-pituitary-peripheral gland axis, of which several will be encountered in the following chapters. Under the control of numerous areas in the central nervous system, specific neurons of the hypothalamus secrete a given hormone (e.g., thyrotrophin releasing hormone, TRH) that, rather than entering the general circulation, enters the hypothalamic pituitary portal system and stimulates the secretion of a particular peptide hormone (e.g., thyroid stimulating hormone, TSH). This hormone is released into the circulation and travels to its target peripheral endocrine gland (e.g., the thyroid) where it stimulates the release of that gland’s hormone (e.g., thyroid hormone). Thyroid hormone has many target tissues in which it brings about biological responses, but most important in the context of the current discussion are its feedback effects on the hypothalamus and pituitary to shut off the stimulatory hormones from these glands. Again, there are many variations on this basic theme which will be encountered in the consideration of the thyroid gland, the gonads, and the adrenal cortex.
The cellular and molecular details of how the syn thesis and secretion of hormones is regulated by the players described above and others will be covered in the relevant chapters. Here it is important to note that, while usually the emphasis is on the increased syn thesis of hormones as a point of regulation, there are many other possible regulatory points and these vary with the type of hormone. For example the steroid hormones (excluding vitamin D metabolites) are regulated primarily at the first step in their synthesis (the cleavage of the side chain of cholesterol; see Chapter 2) and are released as synthesized, not stored in the gland. Thyroid hormone, on the other hand, is stored in large quantities within the thyroid gland. The short-term regulation of its secretion is on the secretory process, while the synthetic process takes place over a longer time frame. Peptide hormones, such as insulin, PTH, and the trophic hormones of the pituitary, are stored in varying amounts in the glands, so the relative roles of synthesis and secretion in the regulatory processes also vary among these hormones.
Two other contributors to the biological availability of hormones deserve mention here. One is the conversion of a relative inactive hormone to an active one in its target glands as occurs with thyroid hormone and, in some cases, testosterone. Secondly, removal of active hormone from the blood must occur as part of the attenuation of its effect (in addition to shutting off the flow of new hormone into the blood). Thus, the half-life of an active hormone in the blood, which can vary from seconds to days, is important in understanding its regulatory dynamics.
2. Binding Proteins
As discussed in Chapter 2, most steroid hormones have limited solubility in plasma due to their intrinsic hydrophobic character; accordingly, steroid hormones as well as thyroid hormone, are largely (99%) bound to specific plasma trans port proteins (PTP), which are synthesized in the liver. Each transport protein has a specific ligand-binding domain for its cognate hormone. These ligand domains display little amino acid sequence homology with the ligand binding of the cognate receptors. Nevertheless, the PTP ligand-binding domain also displays a high affinity (see section II.D following) for its ligand: usually the Kd for the PTP ligand is 10–100× lower than the Kd of the hormone’s receptor.
The current view is that it is the “free” form of steroid hormones and not the complex of the hormone with its PTP that interacts with receptors in or on the target cells to begin the sequence of steps that results in the generation of a biological response. For some endocrine systems, the concentration of the plasma transport protein can be subject to physiological regulation; that is, the concentration of PTP can be either increased or decreased. Thus, changes in the amount of PTP can alter the amount of free hormone in the blood, as well as affect the total amount of hormone in the blood. This role of the binding proteins in the availability of steroid and thyroid hormones can be of considerable physiological relevance in clinical situations.
