Modifying Aminergic And Peptidergic Hormones

Pituitary Hormones And Trophs

FIGURE 5-1 Overview of the anterior pituitary hormones showing the connections between the aminergic hormones and neurotransmitters of the CNS, the releasing hormones from the hypothalamus, and the anterior pituitary hormones together with the organs upon which they act and their general effects. GRH, Growth hormone releasing hormone, or somatocrinin; GIH, growth hormone release-inhibiting hormone, or somatostatin; TRH, thyroid-stimulating hormone releasing hormone; CRH, corticotropic releasing hormone; PRF, prolactin releasing factor, PIF, prolactin release-inhibiting factor; GnRH, gonadotropic releasing factor; GH, growth hormone; TSH, thyrotropic stimulating hormone; ACTH, adrenocorticotropic hormone; MSH, mela-nocyte-stimulating hormone; PRL, prolactin; FSH, follicle-stimulating hormone; LH, luteotropic hormone; CHO, carbohydrate; IGFs, insulin-like growth factors; T3, triiodothyronine; T4, thyroxine. Superscript plus or minus signs or encircled plus or minus signs refer to positive or negative actions.

FIGURE 5-1 Overview of the anterior pituitary hormones showing the connections between the aminergic hormones and neurotransmitters of the CNS, the releasing hormones from the hypothalamus, and the anterior pituitary hormones together with the organs upon which they act and their general effects. GRH, Growth hormone releasing hormone, or somatocrinin; GIH, growth hormone release-inhibiting hormone, or somatostatin; TRH, thyroid-stimulating hormone releasing hormone; CRH, corticotropic releasing hormone; PRF, prolactin releasing factor, PIF, prolactin release-inhibiting factor; GnRH, gonadotropic releasing factor; GH, growth hormone; TSH, thyrotropic stimulating hormone; ACTH, adrenocorticotropic hormone; MSH, mela-nocyte-stimulating hormone; PRL, prolactin; FSH, follicle-stimulating hormone; LH, luteotropic hormone; CHO, carbohydrate; IGFs, insulin-like growth factors; T3, triiodothyronine; T4, thyroxine. Superscript plus or minus signs or encircled plus or minus signs refer to positive or negative actions.

of the principal mediators of the stress adaptation mechanism in its tropic stimulation of adrenocortical hormones; (6) prolactin (PRL), which is important for the synthesis of milk constituents during lactation and may have other actions somewhat similar to those of growth hormone as well as being secreted during stress; (7) melanocyte-stimulating hormone (melano-tropin, MSH), which plays a role in skin-darkening reactions and influences important CNS functions, such as memory and learning;1 (8) /3-lipotropin {(i-LPH), through its proteolytic products (9) /3-endorphin and (10) Met-enkephalin, may promote analgesia in stress and act as a neurotransmitter in signaling the release of other hormones or affect ion flux. Thus, through the effects of all of these hormones in the anterior pituitary, the processes of somatic cell growth, metabolic rate, reproductive function, stress adaptation, mammary gland development and function, skin

1 MSH and ACTH derive from the same precursor polypeptide and share homologous sequences, but they have distinct receptors. MSH is thought to derive mainly from pars intermedia-like cells under the influence of an aminergic signal. Although there are separate receptors for ACTH and MSH, it has become apparent that ACTH in higher than normal blood concentrations may induce skin darkening, and it may accomplish this by binding to the MSH receptor.

darkening, and CNS reactions are regulated. The importance of these hormones is all too evident in cases of their inadequate production, such as occurs when tumors or other physical pressures reduce the output of one or more of these hormones, or during their overproduction when tumors may secrete them in large quantities ec-topically. All of the anterior pituitary hormones are proteins or polypeptides. They are substantially larger (1500-35,000 Da) than many of the hypothalamic releasing hormones recognized earlier, but not larger than CRH and GRH. Anterior pituitary hormones seem to have longer half-lives in the bloodstream than the releasing hormones. As already indicated in Chapter 3, the secretion of anterior pituitary hormones is under the control of the releasing hormones and is sometimes directly or indirectly under neuronal control. The secretion of anterior pituitary hormones also is regulated by an elaborate feedback control by terminal target gland hormones. Thus, for example, Cortisol inhibits further output of ACTH (see Table 5.1).

We then focus upon the explanation of the effects of the anterior pituitary hormones. Some mechanisms are better understood than others. The actions of ACTH and TSH are clearer at this point than the actions of the rest; prolactin, growth hormone, and MSH are less well understood. Accordingly, more emphasis will be allocated here to prolactin, growth hormone, and /3-lipotropin since ACTH actions are covered in Chapter 10, TSH actions are emphasized in Chapter 6, and LH and FSH actions are reported in Chapters 11 and 12.

II. ANATOMICAL, MORPHOLOGICAL, AND PHYSIOLOGICAL RELATIONSHIPS

The location and anatomy of the pituitary are described in Chapter 3 (see Figure 3-2). It is appropriate here to begin with the localization of the anterior pituitary hormones into discrete cell types. The anterior pituitary can be discussed in terms of cells localized to the pars distalis, which occupies the major part of the gland, as shown in Figure 5-2.

TSH is located in the thyrotrope (thyrotropic cells of the pars distalis). This is a basophilic large cell type with very small granules of the hormone. The granule size, measured by electron microscopy, is 120-200 nm. LH and FSH are located in the gonadotrope, also baso philic, containing granules of 200-250 nm. ACTH is located in the corticotropic cell of the pars distalis, a highly staining basophil, with granules 100-200 nm in diameter. This cell also appears to be present in the pars intermedia (Figure 5-2). The pars intermedia is less distinct in the human than in the rat. MSH is located in the melanotrope, a weakly basophilic cell with granules of 200-300 nm. MSH antisera interact with cells of the pars distalis and pars intermedia. GH is in the somatotrope of the pars distalis, an acidophilic cell containing large numbers of granules of 300-400 nm.

Prolactin is in the mammotrope, an acidophilic cell of the pars distalis containing large, dense, and variable secretory granules in the size range of 400-700 nm. ß-Lipotropin is also in the pars distalis, presumably in corticotropes, and its processing to /3-endorphin can also occur in these cells. MSH is a breakdown product of ACTH, and this breakdown probably does not occur when the corticotrope is stimulated by CRH, resulting in the primary release of ACTH and /3-endorphin. The latter is derived from the enzymatic breakdown of ß-

TABLE 5-1 Summary of Properties of Secretory Cells of the Anterior Pituitary

Cell

Hormone secreted

Staining type

Diameter of secretory granules (/urn)

Distinguishing features

Somatotroph"

Mammotroph

Gonadotroph

Luteotroph

Thyrotroph

Corticotroph

GH Acidophilic

(STH) (stains with acid dye)

PRL Acidophilic

FSH Basophilic

(stains with basic dye)

LH Basophilic

TSH Basophilic

ACTH Basophilic

Melanocyte-stimulating MSH Basophilic hormone cell

300-350 Typical cell

600-900 Large round, ovoid secretory granules; cells vary in shape; cell number increases in pregnancy and lactation; lysosomes more prominent when secretion is suppressed —200 Large round cell body; rough endoplasmic reticulum

(RER) and Golgi probably play a role in synthesis of carbohydrate moiety of subunits —250 Secretory granules slightly larger than FSH-

containing cells; granules tend to accumulate in one pole of cell near periphery; Golgi apparatus less extensive than FSH cell 120-150 Smaller than other cell types; irregular in shape;

flattened nucleus; smaller granules than in other cell types

—200 Large cell with irregular shape; granules associated with Golgi; gastrin has been reported to occur in these cells

A few layers of cells between pars distalis and pars nervosa; in human cells may extend into neural lobe; cells of pars intermedia are polygonal; morphologically similar to corticotroph; also possible that corticotroph can produce MSH

" The suffix troph is used here to connote a growth function. The suffix trope (e.g., gonadotrope) is used to connote a cell containing a substance that produces change rather than growth. There is some confusion in the usage of these terms since at one stage an anterior pituitary hormone may cause a target cell to grow (act as a mitogen), whereas at another stage the same hormone may cause the same cell to alter its metabolism or produce some change other than growth. Most of the information in this table is summarized from description by Lentz, T. L. (1971). "Cell Fine Structure."

FIGURE 5-2 Pituitary and its structures. Reproduced from Guillemin (1980). Beta lipotro-pin and endorphins: Implications of current knowledge. In "Neuroendocrinology" (D. T. Krieger and J. C. Hughes, eds.), p. 70. Sinauer Associates, Sunderland, Massachusetts, 1980.

Neuroendocrinology

FIGURE 5-2 Pituitary and its structures. Reproduced from Guillemin (1980). Beta lipotro-pin and endorphins: Implications of current knowledge. In "Neuroendocrinology" (D. T. Krieger and J. C. Hughes, eds.), p. 70. Sinauer Associates, Sunderland, Massachusetts, 1980.

lipotropin. a-MSH derives from the proteolytic cleavage of ACTH in pars intermedia-like cells in which the stimulatory signals are different from those of the corti-cotrope that produces ACTH. Thus, the stimulation of MSH secretion occurs through an aminergic signal to pars intermedia-like cells, while ACTH is elicited by CRH action on corticotropes in the pars distalis.

The cells of the pars distalis are recognized in the light microscope on the basis of their affinity for stains. The two types already mentioned are acidophils (acid stainable) and basophils (base stainable) and are easily distinguished. Cells that are not stained by these procedures usually represent degranulated cells that are undergoing recovery after secretion of granular contents.

The adenohypophysis itself consists of three parts: the pars distalis, pars intermedia, and pars tuberalis, as shown in Figure 5-2. Cells of the pars distalis are arranged in anastomosing cords close to fenestrated capillaries in the secondary capillary plexus of the hypophyseal portal system. The pars intermedia, a narrow region separating the pars distalis from the posterior pituitary (pars nervosa), consists of basophils with MSH and possibly some endorphins, with ACTH virtually absent. The situation in humans is not completely clear in relation to the products of the pars intermedia, which, itself, is not well defined anatomically in comparison with lower forms. Thus, in humans, pars intermedia-like cells seem to be scattered throughout the pars dis talis. The pars tuberalis, which is dorsal to the pars distalis and pars intermedia, has no specifically assigned function. The pars distalis has 30-35% acidophils, 15-20 fx,m in diameter, which contain GH and PRL. The basophils, 15-25 fim in diameter, make up about 10-15% of the cells and contain LH, FSH, TSH, and ACTH.

The release of pars distalis hormones is signaled by the action of releasing hormones, and the general mechanism is shown in Figure 3-10. The synthesis of these hormones occurs on ribosomes that are transported within the rough endoplasmic reticulum cister-nae r.nd then concentrated into granules of the Golgi complex. Small granules arise from the Golgi to fuse and form mature secretion granules. At this point the releasing hormones, when triggered, cause the granules to be released by exocytosis.

At the electron microscopic level, there appear to be separate cells for the secretion of each of the six major hormones of the anterior pituitary. However, the total picture is incomplete. One must remember that ACTH and /3-LPH derive from the same gene, and both of these peptides can be further degraded even within the anterior pituitary to the MSH hormones as well as /^-endorphin. However, there does appear to be some segregation in terms of one or two of these hormones being secreted while the others are not. The corticotroph mainly secretes ACTH, /3-lipotropin, and ¿3-endorphin, while the cells in the rat pars intermedia mainly secrete /3-endorphin, corticotropin-like intermediate lobe peptide (CLIP), and MSH. Clearly, the derivatization of hormonal peptide precursors and the specific proteolysis taking place are different in the two distinct cell types.

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