Pituitary Hormones and Their Control by the Hypothalamus

Hypothalamic-Hypophysial Portal Blood Vessels of the Anterior Pituitary Gland

The anterior pituitary is a highly vascular gland with extensive capillary sinuses among the glandular cells. Almost all the blood that enters these sinuses passes first through another capillary bed in the lower hypothalamus. The blood then flows through small hypothalamic-hypophysial portal blood vessels into the anterior pituitary sinuses. Figure 76-4 shows the lowermost portion of the hypothalamus, called the median eminence, which connects inferiorly with the pituitary stalk. Small arteries penetrate into the median eminence and then additional small vessels return to its surface, coalescing to form the hypothalamic-hypophysial portal blood vessels. These vessels pass downward along the pituitary stalk to supply blood to the anterior pituitary sinuses.

Growth Hormone Promotes Growth of Many Body Tissues

Growth hormone, also called somatotropic hormone or somatotropin, is a small protein molecule that contains 191 amino acids in a single chain and has a molecular weight of 22,005. It causes growth of almost all tissues of the body that are capable of growing. It promotes increased sizes of the cells and increased mitosis, with development of greater numbers of cells and specific differentiation of certain types of cells such as bone growth cells and early muscle cells.

Figure 76-5 shows typical weight charts of two growing littermate rats; one received daily injections of growth hormone, and the other did not receive growth hormone. This figure shows marked enhancement of growth in the rat given growth hormone, in the early days of life and even after the two rats reached adulthood. In the early stages of development, all organs of the treated rat increased proportionately in size; after adulthood was reached, most of the bones stopped lengthening, but many of the soft tissues continued to grow. This outcome results from the fact that once the epiphyses of the long bones have united with the shafts, further lengthening of bone cannot occur, even though many other tissues of the body can continue to grow throughout life.

Growth Hormone Has Several Metabolic Effects

Aside from its general effect in causing growth, growth hormone has multiple specific metabolic effects, including (1) increased rate of protein synthesis in most cells of the body; (2) increased mobilization of fatty acids from adipose tissue, increased free fatty acids in the blood, and increased use of fatty acids for energy; and (3) decreased rate of glucose utilization throughout the body. Thus, in effect, growth hormone enhances body protein, decreases fat stores, and conserves carbohydrates.

Growth Hormone Stimulates Cartilage and Bone Growth

Although growth hormone stimulates increased deposition of protein and increased growth in almost all tissues of the body, its most obvious effect is to increase growth of the skeletal frame. This results from multiple effects of growth hormone on bone, including (1) increased deposition of protein by the chondrocytic and osteogenic cells that cause bone growth, (2) increased rate of reproduction of these cells, and (3) a specific effect of converting chondrocytes into osteogenic cells, thus causing deposition of new bone.

There are two principal mechanisms of bone growth. First, in response to growth hormone stimulation, the long bones grow in length at the epiphyseal cartilages, where the epiphyses at the ends of the bone are separated from the shaft. This growth first causes deposition of new cartilage, followed by its conversion into new bone, thus elongating the shaft and pushing the epiphyses farther and farther apart. At the same time, the epiphyseal cartilage is progressively used up, so by late adolescence, no additional epiphyseal cartilage remains to provide for further long bone growth. At this time, bony fusion occurs between the shaft and the epiphysis at each end, so no further lengthening of the long bone can occur.

Second, osteoblasts in the bone periosteum and in some bone cavities deposit new bone on the surfaces of older bone. Simultaneously, osteoclasts in the bone (discussed in detail in Chapter 80) remove old bone. When the rate of deposition is greater than that of resorption, the thickness of the bone increases. Growth hormone strongly stimulates osteoblasts. Therefore, the bones can continue to become thicker throughout life under the influence of growth hormone; this is especially true for the membranous bones. For instance, the jaw bones can be stimulated to grow even after adolescence, causing forward protrusion of the chin and lower teeth. Likewise, the bones of the skull can grow in thickness and give rise to bony protrusions over the eyes.

Growth Hormone Exerts Much of Its Effect Through Intermediate Substances Called Somatomedins

When growth hormone is supplied directly to cartilage chondrocytes cultured outside the body, proliferation or enlargement of the chondrocytes usually fails to occur. Yet, growth hormone injected into the intact animal does cause proliferation and growth of the same cells.

In brief, growth hormone causes the liver (and, to a much less extent, other tissues) to form several small proteins called somatomedins that have the potent effect of increasing all aspects of bone growth. Many of the somatomedin effects on growth are similar to the effects of insulin on growth. Therefore, the somatomedins are also called insulin-like growth factors (IGFs).

At least four somatomedins have been isolated, but by far the most important of these is somatomedin C (also called insulin-like growth factor-1, or IGF-I). The molecular weight of somatomedin C is about 7500, and its concentration in the plasma closely follows the rate of growth hormone secretion.

The pygmies of Africa have a congenital inability to synthesize significant amounts of somatomedin C. Therefore, even though their plasma concentration of growth hormone is either normal or high, they have diminished amounts of somatomedin C in the plasma, which apparently accounts for the small stature of these people. Some other dwarfs (e.g., Laron syndrome) have a similar problem.

It has been postulated that most, if not all, of the growth effects of growth hormone result from somatomedin C and other somatomedins, rather than from direct effects of growth hormone on the bones and other peripheral tissues. Even so, experiments have demonstrated that injection of growth hormone directly into the epiphyseal cartilages of bones of living animals causes growth of these cartilage areas, and the amount of growth hormone required for this growth to occur is minute. Some aspects of the somatomedin hypothesis are still questionable. One possibility is that growth hormone can cause the formation of enough somatomedin C in the local tissue to cause local growth. It is also possible that growth hormone is directly responsible for increased growth in some tissues and that the somatomedin mechanism is an alternative means of increasing growth but not always a necessary one.

Short Duration of Action of Growth Hormone but Prolonged Action of Somatomedin C.

Growth hor­mone attaches only weakly to the plasma proteins in blood. Therefore, it is released from the blood into the tissues rapidly, having a half-time in blood of less than 20 minutes. By contrast, somatomedin C attaches strongly to a carrier protein in the blood that, like somatomedin C, is produced in response to growth hormone. As a result, somatomedin C is released only slowly from the blood to the tissues, with a half-time of about 20 hours. This slow release greatly prolongs the growth-promoting effects of the bursts of growth hormone secretion shown in Figure 76-6.

Regulation of Growth Hormone Secretion

After adolescence, secretion decreases slowly with aging, finally falling to about 25 percent of the adolescent level in very old age.

Growth hormone is secreted in a pulsatile pattern, increasing and decreasing. The precise mechanisms that control secretion of growth hormone are not fully understood, but several factors related to a person's state of nutrition or stress are known to stimulate secretion: (1) starvation, especially with severe protein deficiency; (2) hypoglycemia or low concentration of fatty acids in the blood; (3) exercise; (4) excitement; (5) trauma; and (6) ghrelin, a hormone secreted by the stomach before meals. Growth hormone also characteristically increases during the first 2 hours of deep sleep, as shown in Figure 76-6. Table 76-3 summarizes some of the factors that are known to influence growth hormone secretion.

The normal concentration of growth hormone in the plasma of an adult is between 1.6 and 3 ng/ml; in a child or adolescent, it is about 6 ng/ml. These values may increase to as high as 50 ng/ml after depletion of the body stores of proteins or carbohydrates during prolonged starvation.

Under acute conditions, hypoglycemia is a far more potent stimulator of growth hormone secretion than is an acute decrease in protein intake. Conversely, in chronic conditions, growth hormone secretion seems to correlate more with the degree of cellular protein depletion than with the degree of glucose insufficiency. For instance, the extremely high levels of growth hormone that occur during starvation are closely related to the amount of protein depletion.

Figure 76-7 demonstrates the effect of protein deficiency on plasma growth hormone and then the effect of adding protein to the diet. The first column shows very high levels of growth hormone in children with extreme protein deficiency during the protein malnutrition condition called kwashiorkor; the second column shows the levels in the same children after 3 days of treatment with more than adequate quantities of carbohydrates in their diets, demonstrating that the carbohydrates did not lower the plasma growth hormone concentration. The third and fourth columns show the levels after treatment with protein supplements for 3 and 25 days, respectively, with a concomitant decrease in the hormone.

These results demonstrate that under severe conditions of protein malnutrition, adequate calories alone are not sufficient to correct the excess production of growth hormone. The protein deficiency must also be corrected before the growth hormone concentration will return to normal.

Abnormalities of Growth Hormone Secretion

Panhypopituitarism.

Panhypopituitarism means decreased secretion of all the anterior pituitary hormones. The decrease in secretion may be congenital (present from birth), or it may occur suddenly or slowly at any time during life, most often resulting from a pituitary tumor that destroys the pituitary gland.

Panhypopituitarism in the Adult.

Panhypopituitarism first occurring in adulthood frequently results from one of three common abnormalities. Two tumorous conditions, craniopharyngiomas or chromophobe tumors, may compress the pituitary gland until the functioning anterior pituitary cells are totally or almost totally destroyed. The third cause is thrombosis of the pituitary blood vessels. This abnormality occasionally occurs when a new mother experiences circulatory shock after the birth of her baby.

The general effects of adult panhypopituitarism are (1) hypothyroidism, (2) depressed production of glucocorticoids by the adrenal glands, and (3) suppressed secretion of the gonadotropic hormones so that sexual functions are lost. Thus, the picture is that of a lethargic person (from lack of thyroid hormones) who is gaining weight (because of lack of fat mobilization by growth, adrenocorticotropic, adrenocortical, and thyroid hormones) and has lost all sexual functions. Except for the abnormal sexual functions, the patient can usually be treated satisfactorily by administering adrenocortical and thyroid hormones.

Dwarfism.

Most instances of dwarfism result from generalized deficiency of anterior pituitary secretion (panhypopituitarism) during childhood. In general, all the physical parts of the body develop in appropriate proportion to one another, but the rate of development is greatly decreased. A child who has reached the age of 10 years may have the bodily development of a child aged 4 to 5 years, and the same person at age 20 years may have the bodily development of a child aged 7 to 10 years.

A person with panhypopituitary dwarfism does not pass through puberty and never secretes sufficient quantities of gonadotropic hormones to develop adult sexual functions. In one third of such dwarfs, however, only growth hormone is deficient; these persons do mature sexually and occasionally reproduce. In one type of dwarfism (the African pygmy and the Laron dwarf), the rate of growth hormone secretion is normal or high, but there is a hereditary inability to form somatomedin C, which is a key step for the promotion of growth by growth hormone.

Treatment with Human Growth Hormone.

Growth hormones from different species of animals are sufficiently different from one another that they will cause growth only in the one species or, at most, closely related species. For this reason, growth hormone prepared from lower animals (except, to some extent, from primates) is not effective in human beings. Therefore, the growth hormone of the human being is called human growth hormone to distinguish it from the others.

In the past, because growth hormone had to be prepared from human pituitary glands, it was difficult to obtain sufficient quantities to treat patients with growth hormone deficiency, except on an experimental basis. However, human growth hormone can now be synthesized by Escherichia coli bacteria as a result of successful appli­cation of recombinant DNA technology. Therefore, this hormone is now available in sufficient quantities for treatment purposes. Dwarfs who have pure growth hormone deficiency can be completely cured if treated early in life. Human growth hormone may also prove to be beneficial in other metabolic disorders because of its widespread metabolic functions.

Gigantism.

Occasionally, the acidophilic, growth hormone–producing cells of the anterior pituitary gland become excessively active, and sometimes even acidophilic tumors occur in the gland. As a result, large quantities of growth hormone are produced. All body tissues grow rapidly, including the bones. If the condition occurs before adolescence, before the epiphyses of the long bones have become fused with the shafts, height increases so that the person becomes a giant—up to 8 feet tall.

The giant ordinarily has hyperglycemia, and the beta cells of the islets of Langerhans in the pancreas are prone to degenerate because they become overactive owing to the hyperglycemia. Consequently, in about 10 percent of giants, full-blown diabetes mellitus eventually develops.

In most giants, panhypopituitarism eventually develops if they remain untreated because the gigantism is usually caused by a tumor of the pituitary gland that grows until the gland is destroyed. This eventual general deficiency of pituitary hormones usually causes death in early adulthood. However, once gigantism is diagnosed, further effects can often be blocked by microsurgical removal of the tumor or by irradiation of the pituitary gland.

Acromegaly.

If an acidophilic tumor occurs after adolescence—that is, after the epiphyses of the long bones have fused with the shafts—the person cannot grow taller, but the bones can become thicker and the soft tissues can continue to grow. This condition, shown in Figure 76-8, is known as acromegaly. Enlargement is especially marked in the bones of the hands and feet and in the membranous bones, including the cranium, nose, bosses on the forehead, supraorbital ridges, lower jawbone, and portions of the vertebrae, because their growth does not cease at adolescence. Consequently, the lower jaw protrudes forward, sometimes as much as half an inch, the forehead slants forward because of excess development of the supraorbital ridges, the nose increases to as much as twice normal size, the feet require size 14 or larger shoes, and the fingers become extremely thickened so that the hands are almost twice normal size. In addition to these effects, changes in the vertebrae ordinarily cause a hunched back, which is known clinically as kyphosis. Finally, many soft tissue organs, such as the tongue, the liver, and especially the kidneys, become greatly enlarged.

Possible Role of Decreased Growth Hormone Secretion in Causing Changes Associated with Aging

In people who have lost the ability to secrete growth hormone, some features of the aging process accelerate. For instance, a 50-year-old person who has been without growth hormone for many years may have the appearance of a person aged 65 years. The aged appearance seems to result mainly from decreased protein deposition in most tissues of the body and increased fat deposition in its place. The physical and physiological effects are increased wrinkling of the skin, diminished rates of function of some of the organs, and diminished muscle mass and strength.

As one ages, the average plasma concentration of growth hormone in an otherwise normal person changes approximately as follows:

Chemical Structures of Antidiuretic Hormone and Oxytocin

Both oxytocin and ADH (vasopressin) are polypeptides, each containing nine amino acids. Their amino acid sequences are the following:

Vasopressin: Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-GlyNH₂

Oxytocin: Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-GlyNH₂

Note that these two hormones are almost identical except that in vasopressin, phenylalanine and arginine replace isoleucine and leucine of the oxytocin molecule. The similarity of the molecules explains their partial functional similarities.

Physiological Functions of Antidiuretic Hormone

The injection of extremely minute quantities of ADH—as small as 2 nanograms—can cause decreased excretion of water by the kidneys (antidiuresis). This antidiuretic effect is discussed in Chapter 29. Briefly, in the absence of ADH, the collecting tubules and ducts become almost impermeable to water, which prevents significant reabsorption of water and therefore allows extreme loss of water into the urine, also causing extreme dilution of the urine. Conversely, in the presence of ADH, the permeability of the collecting ducts and tubules to water increases greatly and allows most of the water to be reabsorbed as the tubular fluid passes through these ducts, thereby conserving water in the body and producing very concentrated urine.

Without ADH, the luminal membranes of the tubular epithelial cells of the collecting ducts are almost impermeable to water. However, immediately inside the cell membrane are a large number of special vesicles that have highly water-permeable pores called aquaporins. When ADH acts on the cell, it first combines with membrane receptors that activate adenylyl cyclase and cause the formation of cAMP inside the tubular cell cytoplasm. This formation causes phosphorylation of elements in the special vesicles, which then causes the vesicles to insert into the apical cell membranes, thus providing many areas of high water permeability. All this occurs within 5 to 10 minutes. Then, in the absence of ADH, the entire process reverses in another 5 to 10 minutes. Thus, this process temporarily provides many new pores that allow free diffusion of water from the tubular fluid through the tubular epithelial cells and into the renal interstitial fluid. Water is then absorbed from the collecting tubules and ducts by osmosis, as explained in Chapter 29 in relation to the urine-concentrating mechanism of the kidneys.

Regulation of Antidiuretic Hormone Production