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Long feedback loop

Growth Hormone Release Cascade

FIGURE 3-1 Many hormonal systems involve the hypothalamus. This figure shows a cascade of hormonal signals starting with an external or internal environmental signal. This is transmitted first to the CNS and may involve components of the limbic system, such as the hippocampus and amygdala. These structures innervate the hypothalamus in a specific region, which responds with secretion of a specific releasing hormone, usually in nanogram amounts. Releasing hormones are transported down a closed portal system connecting the hypothalamus and the anterior pituitary cell membrane receptor and cause the secretion of specific anterior pituitary hormones, usually in microgram amounts. These access the general circulation through fenestrated local capillaries and bind to specific target gland receptors. The interactions trigger the release of an ultimate hormone in microgram to milligram daily amounts, which generates the hormonal response by binding to receptors in several target tissues. In effect, this overall system is an amplifying cascade. Releasing hormones are secreted in nanogram amounts, and they have short half-lives on the order of a few minutes. Anterior pituitary hormones are often produced in microgram amounts and have longer half-lives than releasing hormones. Ultimate hormones can be produced in milligram daily amounts with much longer half-lives. Thus, the products of mass X half-life constitute an amplifying cascade mechanism. With respect to differences in the mass of hormones produced from hypothalamus to target gland, the range is nanograms to milligrams, or as much as 1 million-fold. When the ultimate hormone has receptors in nearly every cell type, it is possible to affect the body chemistry of virtually every cell by a single environmental signal. Consequently, the organism is in intimate association with the external environment, a fact that we tend to under emphasize. Arrows with a black dot at the origin indicate a secretory process. Long arrows studded with black or open dots indicate feedback pathways. Reproduced from "Textbook of Biochemistry" (Devlin, T. M., ed.), 3rd edition. Wiley-Liss, New York (1992).

hormone is released into the bloodstream, gaining access to the circulation through fenestrations in nearby blood vessels. Subsequently, it binds to a specific receptor on the cell membrane of a target gland cell. Within the target cell, a chain of events similar to those following the binding of releasing hormone to anterior pituitary cell occurs, culminating in the release of the ultimate hormone. The ultimate hormone has receptors in many tissues and produces the systemic hormonal response.

Hypothalamic neurons synthesize and release the releasing hormones and the release-inhibiting hormones. The signals to the hypothalamus may be either electrical or chemical or both, and often amine neurotransmitters are involved. The locations of the hypothalamic peptidergic neurons that secrete the releasing

Hypothalamic releasing hormones

Cell bodies of releasing hormonergic neurons

Hypothalamic artery

Posterior pituitary

Superior hypophyseal artery

Stalk

pituitary

Anterior pituitary cells, secrete hormones into 11° plexus through fenestrations to general circulation r plexus of hypophyseal closed portal system, releasing hormones enter through fenestrations

11° plexus; releasing hormones exit through fenestrations

General circulation (AVP, OT(

(demarcated in rat, not in human)

General circulation (ACTH, 0-LPH, FSH, LH. PRL, GH. TSH)

Hypothalamic releasing hormones

Cell bodies of releasing hormonergic neurons

General circulation (AVP, OT(

(demarcated in rat, not in human)

General circulation (ACTH, 0-LPH, FSH, LH. PRL, GH. TSH)

Hypothalamic artery

Posterior pituitary pituitary

Anterior pituitary cells, secrete hormones into 11° plexus through fenestrations to general circulation

Superior hypophyseal artery

Stalk r plexus of hypophyseal closed portal system, releasing hormones enter through fenestrations

11° plexus; releasing hormones exit through fenestrations

General circulation

FIGURE 3-2 Diagram showing the hypothalamus with nuclei in various places in which the hypothalamic releasing hormones are synthesized. Also shown is the major vascular network consisting of a primary plexus, where releasing hormones enter circulation through fenestrated vessels, and the secondary plexus in the anterior pituitary, where the releasing hormones are transported out of circulation again through fenestrations in the vessels to the region of the anterior pituitary target cells. This figure also shows the resultant effects of the actions of the hypothalamic releasing hormones, causing the release into general circulation of the anterior pituitary hormones.

hormones will be summarized later. Once stimulation to a specific region of the hypothalamus has occurred, a specific releasing hormone will be secreted from a neuronal nerve ending, often in the area of the primary plexus of the closed portal system connecting the hypothalamus with the anterior pituitary. The primary plexus is a group of capillaries with fenestrations or functional "openings" that allow the passage of releasing hormone peptides that range from 3 to more than 40 amino acids in size into the closed portal circulation. In addition to the peptidic releasing hormones, dopamine may function in a primary or secondary role as a regulator of prolactin release, and dopamine may affect the release of other pituitary hormones. Once inside the plexus, the releasing hormones circulate down the portal vessel to the secondary plexus, which, analogously to the primary plexus, allows for outward passage of the releasing hormone peptides via fenestrations into the extracellular space in the vicinity of the anterior pituitary cells containing the anterior pituitary hormones. Specific receptors for the releasing hormones are located on the surface of specific cells of the anterior pituitary. After binding of the specific releasing hormone to its cognate receptor, signal transduction events take place that culminate in the release of the appropriate pituitary hormone(s). The closed portal circulation is needed to maintain the concentration of the releasing hormones, which are secreted in nanogram amounts from the hypothalamus following the central nervous system signal. The appropriate anterior pituitary hormone released in response to the action of the releasing hormone is secreted into the extra cellular space and subsequently gains access to the general circulation; here fenestrations in local small vessels are also needed to pass the fairly large hormonal proteins. These are secreted in microgram amounts and then circulate until they reach a distant target cell containing a specific receptor in its cell membrane for the anterior pituitary hormone. The interaction of pituitary hormone and cognate receptor on the target cell is followed by signal transduction processes, which culminate in the release of the target gland cell hormone, usually in milligram or high microgram quantities. The terminal hormone then circulates in the blood until it finds target cells that contain receptors either in the cell membrane (polypeptide hormones) or in the cellular cytoplasm or nucleus (steroid hormones). The anterior pituitary hormones and the terminal hormones both feed back negatively to inhibit further release of pituitary and hypothalamic hormones in the cascade (Figure 3-1) and may also shut down the initial signaling mechanism in the central nervous system. When the cycle has been completed and the terminal hormone has generated its cellular and systemic effects, the entire system is once again poised for a subsequent round of activity.

The anterior pituitary (trophic) hormone may be a growth factor for the terminal gland cells. For example, the anterior pituitary hormone, ACTH (adrenocorticotropic hormone), in addition to causing the subsequent secretion of Cortisol from the adrenal gland, is also required for the survival of the cells of the adrenal (zona fasciculata cells) that produce Cortisol. Thus, if a patient is treated with pharmacological doses of Cortisol, there is the risk of destroying adrenal gland cells by way of the negative feedback effects of the administered Cortisol (or other glucocorticoid) on the anterior pituitary and higher functions in the cascade (Figure 3-1). As a result of the negative feedback effects of administered Cortisol, the circulating levels of ACTH will fall dramatically. A fall in the circulating level of ACTH would deprive adrenal cortical cells of their growth factor, resulting in the destruction of the cortisol-producing cells. It is for this reason that glucocorticoid therapy is usually given on alternate days with the expectation that the negative feedback on ACTH release will recover during the time the treatment is discontinued and the cortisol-producing adrenal cells will survive. It is not certain whether this protection always occurs, especially when large amounts of the drug are given over a long period.

Proceeding down the cascade (Figure 3-1) from the central nervous system to the terminal hormone, there are increasing masses of the hormones released. The releasing hormones from the hypothalamus are secreted in nanogram amounts, the anterior pituitary hormones in microgram amounts, and the terminal hormone in microgram to milligram amounts. In addition, the stability of these hormones, proceeding down the cascade, seems to increase, as the releasing hormones have half-lives in the range of 3-10 min, the anterior pituitary hormones have half-lives of 20 min or longer, and the terminal hormones are usually quite stable in blood. The product of the increasing mass and increasing stability of the hormones produced proceeding downward in this system suggests a high degree of amplification stemming from a unique event, from either the external or internal environment.

The posterior pituitary hormones, which will be discussed in a subsequent chapter, also derive from the hypothalamus (Figure 3-1). The main hormones are oxytocin and vasopressin, and they are synthesized in cell bodies in the hypothalamus and transported to the nerve endings located in the posterior pituitary awaiting release, which is triggered by appropriate signals to be discussed later. Of particular interest are suggestions that oxytocin may be degraded to form active compounds and that some of these may function as releasing factors. For this to be true, the axons from some of the neurons producing oxytocin would have to end close to the secondary plexus of the anterior pituitary. Also, it is known that arginine vasopressin plays an auxiliary role in the release of ACTH from the anterior pituitary in conjunction with CRH, and the axons from vasopressinergic neurons would be expected to end in the same region, in addition to the posterior pituitary. The main roles of oxytocin and vasopressin in regulating uterine contraction and lactation and water balance, respectively, will be discussed later.

Unfortunately, modern literature has introduced a plethora of new names for the releasing hormones. Such names as gonadorelin, buserelin, goserelin, leuprolide, nafarelin, and triptorelin refer to GnRH. Pro-tirelin refers to PRF/TRH. Somatoliberin and somato-crinin refer to GRH, and corticoliberin refers to CRH. For simplicity, the contractions are used as well as their equivalents, e.g., corticotropin-releasing hormone or CRH.

II. ANATOMICAL, MORPHOLOGICAL, AND PHYSIOLOGICAL RELATIONSHIPS

A. Hypothalamus

As seen from Figure 3-3, the hypothalamus is located below the third ventricle of the brain, just above the median eminence. The functions of the hypothalamus are intimately connected to the pituitary, which

Anterior

Third ventricle

Pineal bodv

Mammillae bodv

Median eminence area

Op he chiasm

Pituitary

FIGURE 3-3 Lateral view of the brain showing the relationship of the pituitary gland to the hypothalamus. Reproduced from Krieger, D. T. (1980). The hypothalamus and neuroendo-crinology. In "Neuroendocrinology" (D. T. Krieger and J. C. Hughes, eds.), pp. 3-12. Sinauer Associates, Sunderland, Massachusetts.

Third ventricle

Pineal bodv

Anterior

Mammillae bodv

Op he chiasm

Pituitary

Median eminence area

FIGURE 3-3 Lateral view of the brain showing the relationship of the pituitary gland to the hypothalamus. Reproduced from Krieger, D. T. (1980). The hypothalamus and neuroendo-crinology. In "Neuroendocrinology" (D. T. Krieger and J. C. Hughes, eds.), pp. 3-12. Sinauer Associates, Sunderland, Massachusetts.

lies below the hypothalamus at the end of the delicate infundibular stalk.

In the process of development of the brain, a structure known as the diencephalon appears. It is referred to as the second division of the brain and is a relay center for the cerebral hemispheres. It has a central cavity known as the third ventricle (Figure 3-3). The diencephalon, the thalamus, is a relay center for tracts connecting the cerebral hemisperes. The hypothalamus contains optic chiasma where the optic nerves cross at their entrance to the brain, tuber cinerium, infundibu-lum, hypophysis, and mammillary region. The tuber cinerium contains gray matter behind the optic chiasma involved with olfaction. It continues ventrally as the infundibular stalk whose cavity is an extension of the third ventricle connecting the pituitary (see Chapter 5).

B. Blood Supply of Hypothalamus

Small branches of the anterior cerebral artery and the posterior communicating artery extend to form a network within the hypothalamic region. The supraoptic and paraventricular nuclei are situated in a dense capillary network supplied by branches of the supraoptic-paraventricular arteries. Small branches from the superior hypophyseal artery also serve the supraoptic nucleus. The nuclei of the tuber cinerium have a less dense vasculature, partly supplied by the posterior communicating arteries. Thus, two large pairs of arteries supply this region. There are no direct connections between vessels of the hypothalamic nuclei and the pituitary. The hypophysis is supplied by the superior and inferior hypophyseal arteries, which are branches of the internal carotid (Figure 3-2). The vasculature of the hypothalamus and pituitary is shown vividly in Figure 3-4.

C. Electrical Connections from the Brain to the Hypothalamus

The systems and circuitry between the brain and the hypothalamus (afferent) and the electrical connections from the hypothalamus to other structrures (efferent) are extremely complex and probably unnecessary to the subject matter of this book. Naturally, many of the electrical signals conducted by these fibers will either stimulate or depress the release of releasing hormones from the nerve endings of the peptidergic nerve terminals in which they are stored.

D. The Neuron

Neurons, whether they manufacture small molecular neurotransmitters such as norepinephrine or polypeptides, have the general structure diagrammed in Figures 3-5 and 3-6. The cell body is the site of synthesis and packaging of the releasing hormones. Some of the amine neurotransmitters may be synthesized in the nerve endings. The secretory granules are transported down the axon, which in some cases may be extremely long, into the nerve ending where a signal will cause the exocytotic release of the granules (defined in Chapter 4). The signal can be electrical, presumably trans-

Optic chiasm

Median eminence

Pituitary stalk

Pars distaiis

Optic chiasm

Median eminence

Pituitary stalk

Pars distaiis

FIGURE 3-4 Schematic representation of the hypothalamic-hypophyseal portal vasculature of the rat. Reproduced from Porter, J. C. et al. (1983). Vitam. Horm. 40; 145-174 with permission.

Superior hypophyseal artery

Primary capillary plexus of the hypophysial portal vessels

Medial portal vessel Lateral portal vessel

Secondary capillary texus of the hypophyseal portal vessels

FIGURE 3-4 Schematic representation of the hypothalamic-hypophyseal portal vasculature of the rat. Reproduced from Porter, J. C. et al. (1983). Vitam. Horm. 40; 145-174 with permission.

mitted through fibers traveling the length of the axon and causing depolarization at the nerve ending and Ca2+ uptake there, which appears to be essential in the exocytosis process.

The nerve endings may also be regulated by an interneuron forming a synapse with the nerve ending, as shown in Figure 3-7. In this case, receptors for the neurotransmitter, such as enkephalin in this example, would be located on the surface of the nerve ending in the synaptic region. Through a second messenger, an action would occur in the nerve ending that influences, positively or negatively, the release of the secretory material stored there.

The targets of the releasing hormones are the cells of the adenohypophysis in the anterior pituitary, which secrete the anterior pituitary hormones. The anatomy and cellular characteristics of the anterior pituitary are presented in Chapter 5.

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