FIGURE 4 Principal hypothalamic nuclei (in midsagittal section) and their relationship to the pituitary gland. (From Netter, F.H. Atlas of Human Anatomy, 2nd ed., Summit, NJ: Novartis, 1989. Reprinted with permission from Icon Learning Systems, LLC, a subsidiary of Multimedia USA, Inc.)

FSH secretion. The frequency of pulses of GnRH release determines the ratio of FSH and LH secreted. In addition, target glands secrete hormones that selectively inhibit secretion of either FSH or LH. These complex events are discussed in detail in Chapters 45 and 46.

The GnRH gene encodes a 92-amino-acid prepro-hormone that contains the 10-amino-acid GnRH peptide and an adjacent 56-amino-acid GnRH associated peptide (GAP), which may also have some biological activity. GAP is found along with GnRH in nerve terminals and may be cosecreted with GnRH. Cell bodies of the neurons that release GnRH into the hypophysial portal circulation reside primarily in the arcuate nucleus in the anterior hypothalamus, but GnRH-containing neurons are also found in the preop-tic area and project to extrahypothalamic regions where GnRH release may be related to various aspects of reproductive behavior. GnRH is also expressed in the placenta. Curiously, humans and some other species have a second GnRH gene that is expressed elsewhere in the brain and appears to have no role in gonadotropin release.

Growth hormone secretion is controlled by the growth hormone-releasing hormone (GHRH) and a GH release-inhibiting hormone, somatostatin, which is also called somatotropin release-inhibiting factor (SRIF). In addition, a newly discovered peptide called ghrelin may act both on the somatotropes to increase GH secretion by augmenting the actions of GHRH and on the hypothalamus to increase secretion of GHRH. The physiologic role of this novel peptide, which is synthesized both in the hypothalamus and the stomach, has not been established. GHRH is a member of a family of gastrointestinal and neurohormones that includes vasoactive intestinal peptide (VIP), glucagon (see Chapter 41), and the probable ancestral peptide in this family, called PACAP (pituitary adenylate cyclase activating peptide). GHRH-containing neurons are found predominantly in the arcuate nuclei, and to a lesser extent in the ventromedial nuclei of the hypothalamus. Curiously, GHRH was originally isolated from a pancreatic tumor and is normally expressed in the pancreas, the intestinal tract, and other tissues, but the physiologic role of extrahypothalamically produced GHRH is unknown.

Somatostatin was originally isolated from hypotha-lamic extracts based on its ability to inhibit GH secretion. The somatostatin gene codes for a 118-amino-acid preprohormone from which either a 14-amino-acid or a 28-amino-acid form of somatostatin is released by proteolytic cleavage. Both forms are similarly active. The remarkable conservation of the amino acid sequence of the somatostatin precursor and the presence of processed fragments that accompany soma-tostatin in hypothalamic nerve terminals have suggested to some investigators that additional physiologically active peptides may be derived from the somatostatin gene. The somatostatin gene is widely expressed in neuronal tissue as well as in the pancreas (see Chapter 41) and the gastrointestinal tract. The somatostatin that regulates GH secretion originates in neurons present in the preoptic, periventricular, and paraventricular nuclei. It appears that somatostatin is secreted nearly continuously and that it restrains GH secretion except during periodic brief episodes that coincide with increases in GHRH secretion. Coordinated episodes of decreased somatostatin release and increased GHRH secretion produce a pulsatile pattern of GH secretion.

Corticotropin releasing hormone is a 41-amino-acid polypeptide derived from a preprohormone of 192 amino acids. CRH is present in greatest abundance in the parvocellular neurons in the paraventricular nuclei whose axons project to the median eminence. About half of these cells also express arginine vasopressin (AVP), which also acts as a corticotropin releasing hormone. AVP has other important physiologic functions and is a hormone of the posterior pituitary gland (see later discussion). The wide distribution of CRH-containing neurons in the central nervous system suggests that it has other actions besides regulation of ACTH secretion.

The simple monoamine neurotransmitter dopamine appears to satisfy most of the criteria for a PRL inhibitory factor whose existence was suggested by the persistent high rate of PRL secretion by pituitary glands transplanted outside the sella turcica. It is possible that there is also a PRL releasing hormone, but although several candidates have been proposed, general agreement on its nature or even its existence is still lacking.

Although, in general, the hypophysiotropic hormones affect the secretion of one or another pituitary hormone specifically, TRH can increase the secretion of PRL at least as well as it increases the secretion of TSH. The physiologic meaning of this experimental finding is not understood. Under normal physiologic conditions, PRL and TSH appear to be secreted independently, and increased PRL secretion is not necessarily seen in circumstances that call for increased TSH secretion. However, in laboratory rats and possibly human beings as well, suckling at the breast increases both PRL and TSH secretion in a manner suggestive of increased TRH secretion. In the normal individual, somatostatin may inhibit secretion of other pituitary hormones in addition to GH, but again the physiologic significance of this action is not understood. In disease states, specificity of responses of various pituitary cells for their own hypophysiotropic hormones may break down, or cells might even begin to secrete their hormones autonomously.

The neurons that secrete the hypophysiotropic hormones are not autonomous. They receive input from many structures within the brain as well as from circulating hormones. Neurons that are directly or indirectly excited by actual or impending changes in the internal or external environment, from emotional changes, and from generators of rhythmic activity signal to hypophysiotropic neurons by means of classical neurotransmitters as well as neuropeptides. In addition, their activity is modulated by hormonal changes in the general circulation. Integration of responses to all of these signals may take place in the hypophysiotropic neurons themselves or information may be processed elsewhere in the brain and relayed to the hypophysio-tropic neurons. Conversely, hypophysiotropic neurons or neurons that release hypophysiotropic peptides as their neurotransmitters communicate with other neurons dispersed throughout the central nervous system to produce responses that presumably are relevant to the physiologic circumstances that call forth pituitary hormone secretion.

Hypophysiotropic hormones increase both secretion and synthesis of pituitary hormones. All appear to act through stimulation of G-protein-coupled receptors (see Chapter 2) on the surfaces of anterior pituitary cells to increase the formation of cyclic AMP or inositol-trisphosphate-diacylglyceride second messenger systems. Release of hormone almost certainly is the result of an influx of calcium, which triggers and sustains the process of exocytosis. The actions of hypophysiotropic hormones on their target cells in the pituitary are considered further in later chapters.

Feedback Control of Anterior Pituitary Function

We have already indicated that the primary drive for secretion of all of the anterior pituitary hormones except PRL is stimulation by the hypothalamic releasing hormones. In the absence of the hormones of their target glands, secretion of TSH, ACTH, and the gonadotropins gradually increases manyfold. Secretion of these pituitary hormones is subject to negative feedback inhibition by secretions of their target glands. Regulation of secretion of anterior pituitary hormones in the normal individual is achieved through the interplay of stimulatory effects of releasing hormones and inhibitory effects of target gland hormones (Fig. 5). Regulation of the secretion of pituitary hormones by hormones of target glands could be achieved equally well if negative feedback signals acted at the level of (1) the hypothalamus to inhibit secretion of hypo-physiotropic hormones or (2) the pituitary gland to blunt the response to hypophysiotropic stimulation. Actually some combination of these two mechanisms applies to all of the anterior pituitary hormones except PRL.

In experimental animals it appears that secretion of GnRH is variable and highly sensitive to environmental influences, e.g., day length, or even the act of mating. In humans and other primates, secretion of GnRH after puberty appears to be somewhat less influenced by changes in the internal and external environment, but there is ample evidence that GnRH secretion is modulated by factors in both the internal and external environment. It has been shown experimentally in environmental factors

hypothalamus tropic hormone hypothalamus tropic hormone

target gland hormone target gland

FIGURE 5 Regulation of anterior pituitary hormone secretion. Environmental factors may increase or decrease pituitary activity by increasing or decreasing hypophysiotropic hormone secretion. Pituitary secretions increase the secretion of target gland hormones, which may inhibit further secretion by acting at either the hypothalamus or the pituitary. Pituitary hormones may also inhibit their own secretion by a short feedback loop. (From Goodman HM. The pituitary gland. In Mountcastle VB, ed., Medical physiology, 14th ed. St. Louis: Mosby, 1980.)

target gland hormone target gland

FIGURE 5 Regulation of anterior pituitary hormone secretion. Environmental factors may increase or decrease pituitary activity by increasing or decreasing hypophysiotropic hormone secretion. Pituitary secretions increase the secretion of target gland hormones, which may inhibit further secretion by acting at either the hypothalamus or the pituitary. Pituitary hormones may also inhibit their own secretion by a short feedback loop. (From Goodman HM. The pituitary gland. In Mountcastle VB, ed., Medical physiology, 14th ed. St. Louis: Mosby, 1980.)

rhesus monkeys and human subjects that all of the complex changes in the rates of FSH and LH secretion characteristic of the normal menstrual cycle can occur when the pituitary gland is stimulated by pulses of GnRH delivered at an invariant frequency and amplitude. For such changes in pituitary secretion to occur, changes in secretion of target gland hormones that accompany ripening of the follicle, ovulation, and luteinization must modulate the responses of gonado-tropes to GnRH (see Chapter 46). However, in normal humans it is evident that target gland hormones also act at the level of the hypothalamus to regulate both the amplitude and frequency of GnRH secretory bursts.

Adrenal cortical hormones exert a negative feedback effect both on pituitary corticotropes where they decrease transcription of POMC and on hypothalamic neurons where they decrease CRH synthesis and secretion (see Chapter 40). The rate of CRH secretion is also profoundly affected by changes in both the internal and external environment. Physiologically, CRH is secreted in increased amounts in response to nonspecific stress. This effect is seen even in the absence of the adrenal glands, and hence the inhibitory effects of its hormones, indicating that CRH secretion must be controlled by positive inputs as well as the negative effects of adrenal hormones.

Control of GH secretion is more complex because it is under the influence of a releasing hormone, GHRH, probably a release-enhancing hormone, ghrelin, and a release-inhibiting hormone, somatostatin. In addition, GH secretion is under negative feedback control by products of its actions in peripheral tissues. As discussed in detail in Chapter 44, GH evokes production of a peptide called insulin-like growth factor-I (IGF-I), which mediates the growth-promoting actions of GH. IGF-I exerts powerful inhibitory effects on GH secretion by decreasing the sensitivity of somatotropes to GHRH. It also acts on the somatostatin-secreting neurons to increase the release of somatostatin and to inhibit the release of GHRH. GH is also a metabolic regulator, and products of its metabolic activity such as increased glucose or free fatty acid concentrations in blood may also inhibit its secretion.

Modulating effects of target gland hormones on the pituitary gland are not limited to inhibiting secretion of their own provocative hormones. Target gland hormones may modulate pituitary function by increasing the sensitivity of other pituitary cells to their releasing factors or by increasing the synthesis of other pituitary hormones. Hormones of the thyroid and adrenal glands are required for normal responses of the somatotropes to GHRH. Similarly, estrogen secreted by the ovary in response to FSH and LH increases PRL synthesis and secretion.

In addition to feedback inhibition exerted by target gland hormones, there is evidence that pituitary hormones may inhibit their own secretion. In this so-called short-loop feedback system, pituitary cells respond to increased concentrations of their own hormones by decreasing further secretion. The physiologic importance of short-loop feedback systems has not been established, nor has that of the postulated ultrashortloop feedback in which high concentrations of hypophy-siotropic hormones may inhibit their own release.

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