Mechanisms of Hormonal Regulation
The endocrine system is composed of various glands located throughout the body (Figure 21-1). These glands are capable of synthesizing and releasing special chemical messengers called hormones. The endocrine system has five general functions:
Hormones convey specific regulatory information among cells and organs and are integrated with the nervous system to maintain communication and control. The mechanisms of communication include autocrine (within cell), paracrine (between local cells), and endocrine (between remote cells).
The endocrine glands respond to specific signals by synthesizing and releasing hormones into the circulation. Although a wide variety of hormones function within the body, they share certain general characteristics:
1. Hormones have specific rates and rhythms of secretion. Three basic secretion patterns are: (1) circadian or diurnal patterns, (2) pulsatile and cyclic patterns, and (3) patterns that depend on levels of circulating substrates (e.g., calcium, sodium, potassium, or the hormones themselves).
4. Steroid hormones are either excreted directly by the kidneys or metabolized (conjugated) by the liver, which inactivates them and renders the hormone more water soluble for renal excretion. Peptide hormones are catabolized by circulating enzymes and eliminated in the feces or urine.
Hormones may be classified according to their structure, gland of origin, effects, or chemical composition. (Table 21-1 categorizes hormones based on structure.) The secretion and mechanisms of action of hormones represent an extremely complex system of integrated responses. Although much has been learned about these complex systems, many of the specific mechanisms of action are not yet understood. The endocrine and nervous systems work together to regulate responses to the internal and external environments.
|Thyroxine (an amine but lipid soluble)||Thyroxine (both thyroxine [T4] and triiodothyronine [T3])|
|Steroids (cholesterol is a precursor for all steroids)||Estrogens|
|Derivatives of arachidonic acid (autocrine or paracrine action)||Leukotrienes|
The release of hormones occurs either in response to an alteration in the cellular environment or in the process of maintaining a regulated level of certain hormones or certain substances. Hormone release is regulated by one or more of the following mechanisms: (1) chemical factors (such as blood glucose or calcium levels); (2) endocrine factors (a hormone from one endocrine gland controlling another endocrine gland); and (3) neural control (such as stress-induced release of catecholamines from the adrenal medulla).
Feedback systems provide precise monitoring and control of the cellular environment. The most common feedback system, negative feedback, occurs because the changing chemical, neural, or endocrine response to a stimulus negates the initiating change that triggered the release of the hormone. An example of hormone negative feedback is shown in Figure 21-2, A. Thyroid-stimulating hormone (TSH) secretion from the anterior pituitary is stimulated by thyrotropin-releasing hormone (TRH) from the hypothalamus. Secretion of TSH stimulates the synthesis and secretion of thyroid hormones. Increasing levels of T4 (thyroxine) and T3 (triiodothyronine) then generate negative feedback on the pituitary and hypothalamus to inhibit TRH and TSH synthesis.
Negative-feedback systems are important in maintaining hormone concentrations within physiologic ranges. The lack of negative-feedback inhibition on hormonal release often results in pathologic conditions. As discussed in Chapter 22, various hormonal imbalances and related conditions are caused by excessive hormone production, which is the result of failure to “turn off” the system. These negative-feedback regulatory systems are diagrammed in Figure 21-2, B.
Once hormones are released into the circulatory system, they are distributed throughout the body. Peptide or protein hormones (pituitary, hypothalamic, and parathyroid hormones; and insulin) are water soluble and circulate in free (unbound) forms. Water-soluble hormones generally have a short half-life because they are catabolized by circulating enzymes. For example, insulin has a half-life of 3 to 5 minutes and is catabolized by insulinases. Lipid-soluble hormones, such as cortisol and adrenal androgens, are transported bound to a carrier or transport protein (Table 21-2) and can remain in the blood for hours to days. Only free hormones (those not bound to the carrier protein) can signal a target cell. Because an equilibrium exists between the concentrations of free hormones and hormones bound to plasma proteins, a significant change in the concentration of binding proteins can affect the concentration of free hormones in the plasma (see Table 21-2). (Mechanisms of hormone binding are discussed in Chapter 1.)
|BINDING PROTEIN||HORMONE||FACTORS THAT INCREASE BINDING PROTEIN LEVELS||FACTORS THAT DECREASE BINDING PROTEIN LEVELS|
|Corticosteroid-binding globulin||Cortisol||Estrogen||Liver disease|
|Sex hormone–binding globulin||Dihydrotestosterone||—||Androgens|
|Thyroid-binding globulin||Thyroxine (T4)||Estrogen||Testosterone|
|Albumin||All lipid-soluble hormones||Estrogen||Liver disease|
When a hormone is released into the circulatory system, it is distributed throughout the body, but only those cells with appropriate hormone receptors for that hormone are affected. The target cell hormone receptors have two main functions: (1) to recognize and bind with high affinity to their particular hormones and (2) to initiate a signal to appropriate intracellular effectors. See Chapter 1 for cell signaling pathways, particularly Figures 1-19 and 1-20 on pp. 21-22.
The sensitivity of the target cell to a particular hormone is related to the total number of receptors per cell: the more receptors, the more sensitive the cell. Low concentrations of hormone increase the number of receptors per cell, called up-regulation (Figure 21-3, A). High concentrations of hormone decrease the number of receptors, called down-regulation (Figure 21-3, B). Thus the cell can adjust its sensitivity to the concentration of the signaling hormone. The receptors on the plasma membrane are continuously synthesized and degraded, so that changes in receptor concentration may occur within hours. Various physiochemical conditions also can affect both the receptor number and the affinity of the hormone for its receptor. Some of these physiochemical conditions are the fluidity and structure of the plasma membrane, pH, temperature, ion concentration, diet, and the presence of other chemicals (e.g., drugs). Finally, mutations in receptor structure can affect target cell activation such that normal cellular responses are increased or decreased. For example, mutations in thyroid hormone receptors can lead to resistance to thyroid hormone and can contribute to the development of tumors.1,2
Hormone receptors may be located in or on the plasma membrane or in the intracellular compartment of the target cell (Figure 21-4). Water-soluble hormones (see Table 21-1) have a high molecular weight and cannot diffuse across the cell membrane. They interact or bind with receptors in or on the cell membrane and mediate short-acting responses.3 Lipid-soluble steroids, vitamin D, retinoic acid, and thyroid hormones diffuse freely across the plasma and nuclear membranes and bind with cytosolic or nuclear receptors (see Figure 21-4). The hormone-receptor complex binds to a specific region in the deoxyribonucleic acid (DNA) and stimulates the expression of a specific gene. Some lipid-soluble hormones (e.g., estrogen) also may bind with plasma membrane receptors. By these mechanisms, lipid-soluble hormones can mediate both long-acting and rapid-acting responses.4
A hormone is the first messenger, is secreted into the bloodstream, and carries a message to a target cell. Signal transduction is the process by which this message is communicated into a cell. In general, signal transduction involves a series of steps that includes receptor activation or binding of a hormone to its receptor, activation of a G protein (transducer) and membrane-associated enzyme (effector enzyme), and production of a second messenger (see Figure 1-22, p. 24, and Figure 21-5). The final event is activation of an intracellular enzyme, such as protein kinase A or C, which causes alterations in gene transcription and the resulting target cell response to the hormone.
Cell surface receptors are usually classified according to how they initiate signal transduction: (1) G-protein–linked receptors, (2) ion-channel receptors, and (3) enzyme-linked receptors (including tyrosine kinase, serine kinase, and the cytokine-receptor superfamily with intrinsic enzyme activity—such as the Janus family of tyrosine kinases [JAK] and signal transducers and activators of transcription [STAT] molecules). With the exception of insulin, growth hormone, and prolactin, most water-soluble hormones—such as adrenocorticotropic hormone (ACTH), glucagon, norepinephrine, and epinephrine—activate G-protein–linked receptors. Other hormones, such as angiotensin II, activate G-protein–linked and ion-channel receptors. Insulin activates a tyrosine kinase receptor. Growth hormones, prolactin, and cytokines—such as interleukins—activate the JAK/STAT receptors.
Second-messenger molecules are the initial link between the first signal (hormone) and the inside of the cell (Table 21-3). For example, binding of epinephrine to a β-adrenergic receptor subtype activates (through a stimulatory G protein [Gs]) the enzyme adenylyl cyclase. Adenylyl cyclase catalyzes the conversion of adenosine triphosphate (ATP) to the second messenger 3′,5′-cAMP. Elevation of cAMP activates the enzyme cAMP-dependent protein kinase A (PKA). PKA phosphorylates and activates nuclear transcription factors (cAMP response element–binding [CREB] proteins) that influence numerous cellular functions.5 For example, CREB proteins associated with the L-type channel in cardiac muscle increase the influx of calcium into the cell, which increases myocardial contractility. Alterations in CREB activity have been implicated in many disease states including diabetes and cancer.6,7 The actions of cAMP are terminated by the enzyme phosphodiesterase (PDE) III, which hydrolyzes cAMP into inactive adenosine monophosphate (AMP).
|SECOND MESSENGER||ASSOCIATED HORMONES|
|Cyclic AMP||Adrenocorticotropic hormone (ACTH)|
|Luteinizing hormone (LH)|
|Human chorionic gonadotropin (hCG)|
|Follicle-stimulating hormone (FSH)|
|Thyroid-stimulating hormone (TSH)|
|Antidiuretic hormone (ADH)|
|Thyrotropin-releasing hormone (TRH)|
|Parathyroid hormone (PTH)|
|Cyclic GMP||Atrial natriuretic peptide|
|Gonadotropin-releasing hormone (GnRH)|
|Antidiuretic hormone (ADH)|
|IP3 and DAG||Angiotensin II|
|Antidiuretic hormone (ADH)|
|Luteinizing hormone–releasing hormone (LHRH)|
AMP, Adenosine monophosphate; DAG, diacylglycerol; GMP, guanosine monophosphate; IP3, inositol triphosphate; JAK, Janus family of tyrosine kinases; STAT, signal transducers and activators of transcription.
Guanylyl cyclase is an enzyme that converts guanosine triphosphate (GTP) to the second-messenger 3′,5′-cGMP. cGMP activates cGMP-dependent kinase (protein kinase G), which in turn activates a number of physiologic processes. The effects of various ligands, such as atrial natriuretic hormone (vascular smooth muscle relaxation) and nitric oxide (e.g., vascular smooth muscle relaxation and platelet inhibition), are mediated by the second-messenger cGMP. Drugs that target the actions of cGMP are being explored for the treatment of vascular and pulmonary disorders.8
In addition to being an important ion that participates in a multitude of cellular actions, Ca++ is considered an important second messenger. The binding of a hormone (such as norepinephrine or angiotensin II) to a surface receptor activates the enzyme phospholipase C through a G protein inside the plasma membrane. This enzyme breaks down membrane phospholipid phosphatidylinositol biphosphate (PIP2) into second-messengers inositol triphosphate (IP3) and diacylglycerol (DAG) (see Figure 1-22, p. 24) IP3 mobilizes Ca++ from intracellular stores (endoplasmic reticulum). Increased intracellular calcium levels can lead to the formation of the calcium-calmodulin complex, which mediates the effects of calcium on intracellular activities that are crucial for cell metabolism and growth. For example, calmodulin-dependent protein kinases control intracellular contractile components (myosin and actin, which cause contraction), alter plasma membrane permeability to calcium, and regulate the intracellular enzyme activity that promotes hormone secretion.
DAG, together with Ca++, activates protein kinase C (PKC). Similar to other kinase enzymes, PKC activates (by phosphorylation) other proteins or enzymes. PKC initiates a variety of cellular responses that are linked to cell metabolism and growth. For example, PKC activates glycogen synthase in liver cells to convert glucose to glycogen. Calcium signaling systems are crucial to healthy functioning of virtually every tissue system in the body including heart, brain, bone, smooth muscle, and many others.9
Some hormones, such as insulin, growth hormone, and prolactin, bind to surface receptors that directly activate tyrosine kinases. These tyrosine kinases include the Janus family of tyrosine kinases (JAK) and signal transducers and activators of transcription (STAT). They regulate a wide range of intracellular processes that contribute to cellular metabolism and growth, and are being targeted in emerging treatments for diabetes.10 An example of first- and second-messenger systems is presented in Figure 21-5.
The lipid-soluble hormones are steroid hormones and are synthesized from cholesterol. They include androgens, estrogens, progestins, glucocorticoids, mineralocorticoids, vitamin D, and retinoid. Thyroid hormones are lipid soluble but are not synthesized from cholesterol (see p. 701). Because these hormones are relatively small, lipophilic, hydrophobic molecules, they can cross the lipid plasma membrane by simple diffusion (see Chapter 1). Some steroid hormones bind to receptor molecules in the cytoplasm and then diffuse into the nucleus, whereas others bind to receptors in the nucleus. The resulting hormone-receptor complex binds to a specific site on the promoter region of DNA. This binding activates ribonucleic acid (RNA) polymerase, which stimulates DNA transcription and increased synthesis of specific proteins (increased gene expression) (Figure 21-6). Modulation of gene expression can take hours to days.
Steroid hormone receptors also may be found in the plasma membrane and are associated with rapid responses (seconds or minutes) that have nongenomic and genomic effects. Crosstalk between gene transcription and nongenomic responses modulate each other, allowing cells to adapt rapidly to environmental changes. Thyroid hormone, a nonsteroid lipid-soluble hormone, also has been found to use a cell surface receptor for its nongenomic actions. It first binds to an integrin receptor on the plasma membrane, and then uses a specific transport mechanism to gain access to its nuclear receptors where it can influence cell division and metabolic function.11
Hormones have two general types of effects on target cells: direct and permissive. Direct effects are the obvious changes in cell function that specifically result from stimulation by a particular hormone. Permissive effects are less obvious hormone-induced changes that facilitate the maximal response or functioning of a cell. For example, insulin has a direct effect on skeletal muscle cells with insulin receptors, causing increased glucose transport into these cells. Insulin also has a permissive effect on mammary cells, facilitating the response of these cells to the direct effects of prolactin.
Some hormones have biphasic pharmacologic effects that are dependent on the concentration of the hormone. For example, low or physiologic levels of antidiuretic hormone (ADH, or arginine-vasopressin) stimulate renal tubular reabsorption of sodium and water. However, at supraphysiologic levels (i.e., those that can be achieved by exogenous administration), ADH acts as a vasoconstrictor.
The hypothalamic-pituitary axis (HPA) forms the structural and functional basis for central integration of the neurologic and endocrine systems, creating what is called the neuroendocrine system. The HPA produces a number of releasing/inhibitory hormones and tropic hormones that affect a number of diverse body functions (Figure 21-7). For example, the functions of the thyroid gland, adrenal gland, and male and female reproductive glands, as well as somatic growth and lactation, are regulated by hormones originating from the HPA.
The hypothalamus is divided into several nuclei and nuclear areas and is located at the base of the brain. The pituitary gland is located at the sella turcica, a saddle-shaped depression on the superior surface of the sphenoid bone (Figure 21-8). The communication or anatomic connection (blood vessels and neural tract) between the hypothalamus and anterior and posterior pituitary is quite elaborate and well described. However, simply described, the hypothalamus is connected to the anterior pituitary by way of portal blood vessels (Figure 21-9), whereas the hypothalamus is connected to the posterior pituitary by way of a nerve tract referred to as the supraopticohypophysial tract (Figure 21-10). These connections are vital to the functioning of the hypothalamus-pituitary system.12
The special cells of the hypothalamus are like other neurons in that they have similar electrical properties, organelles, membranes, and synapses. Hypothalamic neurosecretory cells, however, can synthesize and secrete the hypothalamic-releasing hormones and synthesize the hormones of the posterior portion of the pituitary gland. For example, antidiuretic hormone (ADH) and oxytocin are synthesized in hypothalamic neurons but are stored and secreted by the posterior pituitary. ADH and oxytocin travel to the posterior pituitary by way of the hypothalamohypophysial nerve tract. Releasing/inhibitory hormones also are synthesized in the hypothalamus and are secreted into the portal blood vessels, through which they travel to the anterior pituitary and control the release of tropic hormones. These releasing/inhibitory hormones from the hypothalamus include prolactin-inhibiting factor (PIF), thyrotropin-releasing hormone (TRH), gonadotropin-releasing hormone (GnRH), somatostatin, growth hormone–releasing factor (GRF), corticotropin-releasing hormone (CRH), and substance P. These hormones are summarized in Table 21-4.
|Thyrotropin-releasing hormone (TRH)||Anterior pituitary||Stimulates release of thyroid-stimulating hormone (TSH)|
Modulates prolactin secretion
|Gonadotropin-releasing hormone (GnRH)||Anterior pituitary||Stimulates release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH)|
|Somatostatin||Anterior pituitary||Inhibits release of growth hormone (GH) and TSH|
|Growth hormone–releasing hormone (GHRH)||Anterior pituitary||Stimulates release of GH|
|Corticotropin-releasing hormone (CRH)||Anterior pituitary||Stimulates release of adrenocorticotropic hormone (ACTH) and β-endorphin|
|Substance P||Anterior pituitary||Inhibits synthesis and release of ACTH|
Stimulates secretion of GH, FSH, LH, and prolactin
|Dopamine||Anterior pituitary||Inhibits synthesis and secretion of prolactin|
|Prolactin-releasing factor (PRF)||Anterior pituitary||Stimulates secretion of prolactin|
The anterior pituitary (adenohypophysis) accounts for 75% of the total weight of the pituitary gland. It is composed of three regions: (1) the pars distalis, (2) the pars tuberalis, and (3) the pars intermedia. The pars distalis is the major component of the anterior pituitary and the source of the anterior pituitary hormones. The pars tuberalis is a thin layer of cells on the anterior and lateral portions of the pituitary stalk. The pars intermedia lies between the two. In the adult the distinct intermediate lobe disappears, and the individual cells are distributed diffusely throughout the pars distalis and pars nervosa (neural lobe), which are part of the posterior pituitary.
The posterior pituitary (neurohypophysis) arises embryologically from an outpouching of the floor of the third ventricle within the brain. The posterior pituitary consists of three parts: (1) the median eminence located at the base of the hypothalamus, (2) the pituitary stalk, and (3) the infundibular process, also known as the pars nervosa or neural lobe. The median eminence is composed largely of the nerve endings of axons that arise primarily in the ventral hypothalamus. The median eminence often is designated as part of the posterior pituitary but contains at least 10 biologically active hypothalamic-releasing hormones, as well as the neurotransmitters dopamine, norepinephrine, serotonin, acetylcholine, and histamine. The median eminence therefore might be more appropriately considered part of the hypothalamus. The pituitary stalk contains the axons of neurons that originate in the supraoptic and paraventricular nuclei of the hypothalamus. Axons originating in the hypothalamus terminate in the pars nervosa, which secretes the hormones of the posterior pituitary.
Because of the anatomic location and connection of the pituitary gland to the brain, several neurotransmitters as well as physical and emotional stressors influence the release of specific hypothalamic releasing–inhibitory hormones and their respective tropic hormones. This allows for the integrated and coordinated function of the hypothalamic-pituitary axis. Interestingly, hypothalamic hormones also are synthesized outside the HPA. For example, CRH is synthesized in cells of the immune system, female and male reproductive organs, and the placenta. These peripherally synthesized neuropeptides are thought to play a role in the reproductive and immune responses to stress.13,14
The posterior pituitary secretes two polypeptide hormones: (1) ADH, also called arginine-vasopressin; and (2) oxytocin. These peptide hormones are similar in structure, differing by only two amino acids. They are synthesized, along with their carrier proteins (the neurophysins), in the supraoptic and paraventricular nuclei of the hypothalamus (see Figure 21-10). Once synthesized, these hormones and their neurophysins are packaged in secretory vesicles and are moved down the axons of the pituitary stalk to the pars nervosa for storage. The posterior pituitary thus can be seen as a storage and releasing site for hormones synthesized in the hypothalamus.
The release of ADH and oxytocin is mediated by cholinergic and adrenergic neurotransmitters. The major stimulus to both ADH and oxytocin release is glutamate, whereas the major inhibitory input is through gamma-aminobutyric acid (GABA). Before release into the circulatory system, ADH and oxytocin are split from the neurophysins and are secreted in unbound form.15
The major homeostatic function of the posterior pituitary is the control of plasma osmolality, as regulated by ADH (see Chapter 3). At physiologic levels, ADH acts on the vasopressin 2 (V2) receptors of the renal tubular cells to increase their permeability (see Chapter 37). This increased permeability leads to an increase in water reabsorption into the blood and the production of more concentrated urine. These effects may be inhibited by hypercalcemia, prostaglandin E, and hypokalemia. At pathophysiologically high serum levels, ADH acts on vasopressin 1 (V1) receptors and causes vasoconstriction.
The secretion of ADH is regulated primarily by the osmoreceptors of the hypothalamus, located near or in the supraoptic nuclei. As plasma osmolality increases, these osmoreceptors are stimulated, the rate of ADH secretion increases, more water is reabsorbed from the kidney, and the plasma is diluted to its set-point osmolality (approximately 280 mOsm/kg).15 ADH has no direct effect on electrolyte levels, but by increasing water reabsorption, serum electrolyte concentrations may decrease because of a dilutional effect.
ADH secretion also is increased by changes in intravascular volume, which are monitored by mechanoreceptors in the left atrium and in the carotid and aortic arches. A volume loss of 7% to 25% acts through these receptors to stimulate ADH secretion. Stress, trauma, pain, exercise, nausea, nicotine, exposure to heat, and drugs such as morphine also increase ADH secretion. ADH secretion decreases with a decrease in plasma osmolality; an increase in intravascular volume; hypertension; an increase in estrogen, progesterone, and angiotensin II levels; and alcohol ingestion.
As mentioned previously, ADH at high serum levels acts on the V1 receptors and causes vasoconstriction and a resulting increase in arterial blood pressure. This baroreceptor-mediated response is much less sensitive than the ADH response to changes in osmolarity. Therefore, physiologic levels of ADH do not significantly affect vessel tone. However, significant vasoconstriction may be achieved pharmacologically. For example, high doses of ADH (given as the drug vasopressin) may be administered to achieve hemostasis during hemorrhage and to raise blood pressure in shock states.16
Oxytocin is responsible for contraction of the uterus and milk ejection in lactating women and may affect sperm motility in men. In a woman, oxytocin is secreted in response to suckling and mechanical distention of the female reproductive tract. Stimulated by sucking, oxytocin binds to its receptors on myoepithelial cells in the mammary tissues and causes contraction of those cells. This results in increased intramammary pressure and milk expression (“let down” reflex). In response to distention of the uterus, oxytocin stimulates contractions. Oxytocin functions near the end of labor to enhance the effectiveness of contractions, promote delivery of the placenta, and stimulate postpartum uterine contractions, thereby preventing excessive bleeding. The function of this hormone is discussed in more detail in Chapter 23.
Oxytocin has been implicated in behavior responses, especially in women. It has been suggested that oxytocin and its receptor play a role in the brain’s responsiveness to stressful stimuli, especially in the pregnant and postpartum states. Its potential role in the treatment of maternal child neglect and a variety of anxiety disorders is being explored.17,18
The anterior pituitary is composed of two main cell types: (1) the chromophobes, which appear to be nonsecretory; and (2) the chromophils, which are considered the secretory cells of the adenohypophysis. The chromophils are subdivided into seven secretory cell types, each type secreting one or more specific hormones (Table 21-5). In general, the regulation of the anterior pituitary hormones is achieved by (1) feedback of hypothalamic releasing–inhibitory hormones and factors, (2) feedback from target gland hormones (i.e., cortisol, estrogen), and (3) direct effects of neurotransmitters.
|HORMONE||SECRETORY CELL TYPE||TARGET ORGANS||FUNCTIONS|
|Adrenocorticotropic hormone (ACTH)||Corticotropic||Adrenal gland (cortex)||Increased steroidogenesis (cortisol and androgenic hormones)|
Synthesis of adrenal proteins contributing to maintenance of the adrenal gland
|Melanocyte-stimulating hormone (MSH)||Melanotropic||Anterior pituitary||Promotes secretion of melanin and lipotropin by anterior pituitary; makes skin darker|
|Somatotropic||Muscle, bone, liver||Regulates metabolic processes related to growth and adaptation to physical and emotional stressors, muscle growth, increased protein synthesis, increased liver glycogenolysis, increased fat mobilization|
|Liver||Induces formation of somatomedins, or insulin-like growth factors (IGFs) that have actions similar to insulin|
|Thyrotropic||Thyroid gland||Increased production and secretion of thyroid hormone|
Increased iodide uptake
Promotes hypertrophy and hyperplasia of thymocytes
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