Stimulate Growth Hormone Secretion
Decreased blood glucose Decreased blood free fatty acids
Starvation or fasting, protein deficiency Trauma, stress, excitement Exercise
Testosterone, estrogen Deep sleep ( stages II and IV) Growth hormone-releasing hormone
Inhibit Growth Hormone Secretion
Increased blood glucose Increased blood free fatty acids Agmg Obesity
Growth hormone inhibitory hormone (somatostatin) Growth hormone (exogenous) Somatomedins (insulin-like growth factors)
Effect of extreme protein deficiency on the plasma concentration of growth hormone in the disease kwashiorkor. Also shown is the failure of carbohydrate treatment but the effectiveness of protein treatment in lowering growth hormone concentration. (Drawn from data in Pimstone BL, Barbezat G, Hansen JD, Murray P: Studies on growth hormone secretion in protein-calorie malnutrition. Am J Clin Nutr 21:482, 1968.)
Figure 75-7 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.
Role of the Hypothalamus, Growth Hormone-Releasing Hormone, and Somatostatin in the Control of Growth Hormone Secretion
From the preceding description of the many factors that can affect growth hormone secretion, one can readily understand the perplexity of physiologists as they attempt to unravel the mysteries of regulation of growth hormone secretion. It is known that growth hormone secretion is controlled by two factors secreted in the hypothalamus and then transported to the anterior pituitary gland through the hypothalamic-hypophysial portal vessels. They are growth hormone-releasing hormone and growth hormone inhibitory hormone (also called somatostatin). Both of these are polypeptides; GHRH is composed of 44 amino acids, and somatostatin is composed of 14 amino acids.
The part of the hypothalamus that causes secretion of GHRH is the ventromedial nucleus; this is the same area of the hypothalamus that is sensitive to blood glucose concentration, causing satiety in hyper-glycemic states and hunger in hypoglycemic states. The secretion of somatostatin is controlled by other nearby areas of the hypothalamus. Therefore, it is reasonable to believe that some of the same signals that modify a person's behavioral feeding instincts also alter the rate of growth hormone secretion.
In a similar manner, hypothalamic signals depicting emotions, stress, and trauma can all affect hypothala-mic control of growth hormone secretion. In fact, experiments have shown that catecholamines, dopamine, and serotonin, each of which is released by a different neuronal system in the hypothalamus, all increase the rate of growth hormone secretion.
Most of the control of growth hormone secretion is probably mediated through GHRH rather than through the inhibitory hormone somatostatin. GHRH stimulates growth hormone secretion by attaching to specific cell membrane receptors on the outer surfaces of the growth hormone cells in the pituitary gland. The receptors activate the adenylyl cyclase system inside the cell membrane, increasing the intracellular level of cyclic adenosine monophosphate (cAMP). This has both a short-term and a long-term effect. The short-term effect is to increase calcium ion transport into the cell; within minutes, this causes fusion of the growth hormone secretory vesicles with the cell membrane and release of the hormone into the blood. The long-term effect is to increase transcription in the nucleus by the genes to stimulate the synthesis of new growth hormone.
When growth hormone is administered directly into the blood of an animal over a period of hours, the rate of endogenous growth hormone secretion decreases. This demonstrates that growth hormone secretion is subject to typical negative feedback control, as is true for essentially all hormones. The nature of this feedback mechanism and whether it is mediated mainly through inhibition of GHRH or enhancement of somatostatin, which inhibits growth hormone secretion, are uncertain.
In summary, our knowledge of the regulation of growth hormone secretion is not sufficient to describe a composite picture. Yet, because of the extreme secretion of growth hormone during starvation and its important long-term effect to promote protein synthesis and tissue growth, we can propose the following: the major long-term controller of growth hormone secretion is the long-term state of nutrition of the tissues themselves, especially their level of protein nutrition.That is, nutritional deficiency or excess tissue need for cellular proteins—for instance, after a severe bout of exercise when the muscles' nutritional status has been taxed—in some way increases the rate of growth hormone secretion. Growth hormone, in turn, promotes synthesis of new proteins while at the same time conserving the proteins already present in the cells.
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