Henry Ford Hospital Medical Journal

Volume 18 | Number 2 Article 9

6-1970

Hypophyseal Growth Hormone: I. Control ofSecretionM. Saeed Zafar

Raymond C. Mellinger

Lewis B. Morrow

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Recommended CitationZafar, M. Saeed; Mellinger, Raymond C.; and Morrow, Lewis B. (1970) "Hypophyseal Growth Hormone: I. Control of Secretion,"Henry Ford Hospital Medical Journal : Vol. 18 : No. 2 , 143-148.Available at: https://scholarlycommons.henryford.com/hfhmedjournal/vol18/iss2/9

Hemy Ford Hosp. Med. Journal Vol. 18, No. 2, 1970

Hypophyseal Growth Hormone

I. Contro l o f Secretion

M. Saeed Zafar, M.D., Raymond C. Mellinger, M.D. and Lewis B. Morrow, M.D.*

Growth hormone (GH) is a major hormone of the anterior pituitary gland. Once established, its secretion continues throughout life. GH was first recognized in 1866 as a factor controlling growth. More recently, it has been demonstrated as a vital regulator of fat, carboyhdrate and protein metabolism. In fact, GH in­fluence on the intermediary metabolism is the major mechanism by which growth and development are regulated. Numerous hormonal and nonhormonal factors have been shown to modify the basic pattern of GH synthesis and secretion. In this article we have reviewed some of these nonhormonal factors.

Human growth hormone (GH), a polypeptide of 188 amino acids with a molecular weight of 21,500, shares with melanocyte-stimulating hormone the distinction of being an anterior pituitary factor having no target endo­crine gland.i An association between the pituitary and growth was first rec­ognized in 1866 by Marie, who ob­served pathologic changes in the hypo­physis of patients with acromegaly. Subsequently, Aschner demonstrated that hypophysectomy of young animals resulted in dwarfism, and in 1921 Long and Evans made the first success­ful attempt to influence growth with hormones when they produced giant rats by prolonged daily injections of ox pituitary extract.

Synthesis and release of growth hor­mone is controlled by a hypothalamic

* Division of Endocrinology, Department of Medicine

secretion called growth hormone re­leasing factor (GHRF). Produced in or around the ventro-medial nucleus, GHRF travels via the hypothalamo-hypophyseal portal system to the an­terior pituitary. Existence of this hypo­thalamic factor was demonstrated when Deuben and Meites showed that rat hypothalamic extract caused the se­cretion of GH in a tissue culture of rat anterior pituitaries.* Shortly thereafter, similar activity was demonstrated in bovine and porcine hypothalamic ex­tracts incubated with rat pituitaries. * Pecile et aF first studied the effects of hypothalamic GHRF in vivo and the factor has been identified in the hypo­thalami of various species including man. -i"

Localization of GHRF in the ventro­medial nucleus of the hypothalamus is documented by experiments in which monkeys with isolated lesions of this

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region fail to release GH in response to hypoglycemia.il uj^n also, an in­tact hypothalamo-hypophyseal system is essential for release of GH; patients with pituitary stalk section have no GH response to hypoglycemia.Experi­mental evidence in rats indicates that GHRF acts directly on the pituitary to promote GH synthesis as well as its release.''•i^i^

Many factors, both hormonal and non-hormonal, influence the secretion of growth hormone. The plasma GH level fluctuates rapidly and widely under the influence of various known stimuli and at times without any known stimulus. Accordingly, growth hormone must be studied under controUed con­ditions and initial plasma levels deter­mined with the subject in the basal state. Thereafter, GH response to modi­fying conditions may be evaluated.

Non-Hormonal Factors Affecting GH Secretion

Age. Basal growth hormone values vary little with age. In the newborn, umbilical vein blood levels are high^' but by the age of four years, the lower adult levels have been reached and no consistent change in basal values is evident thereafter. - ^ Although no in­crease in basal GH levels has been demonstrated during the adolescent growth spurt, both estrogens * and an­drogens^* can be shown to cause an in­creased GH response to other stimuli.

Glucose. In normal subjects, a 50% fall in blood sugar can cause a fivefold or greater elevation in plasma GH.^^ The increase occurs 15 to 30 minutes after the nadir in blood glucose concen­tration and persists for several hours. Since the plasma half-life of GH is no more than 30 minutes22,2. j g persis­

tence of high concentrations for several hours during prolonged hypoglycemia suggests sustained GH hypersecretion. This pattern of response differs from that of the catecholamines^* and corti­costeroids^^ whose blood levels also in­crease with acute hypoglycemia but are not sustained, despite persistent low blood sugar. 22

A fall in blood glucose is a powerful stimulus for GH release whether in­duced by insulin, tolbutamide or fruc-tose.i -22'28 Actual hypoglycemia is not essential to the reaction inasmuch as a rise in GH may occur after the third hour of a glucose tolerance test when the elevated sugar is falling to control values.22 On the other hand, ethanol-induced hypoglycemia may not provoke a rise in GH, possibly because there is associated central suppression of the GH releasing mechanism.29 Overnight fasting is accompanied by a continued GH rise but the levels do not reach the height induced by acutely lowered glu­cose concentration.22

The mechanism by which hypogly­cemia provokes release of GH is not entirely established but a fall in intra­cellular glucose utilization is con­sidered the essential stimulus. The rise in plasma GH can be prevented by the simultaneous administration of glucose with insulin or even by the administra­tion of glucose 20 minutes after the in­sulin injection, hypoglycemia having already ensued.22 Furthermore, the ad­ministration of 2-deoxy-D glucose, an inhibitor of intracellular glucose utiliza­tion, causes a rise in plasma GH even in the presence of elevated blood sugar.3*

It may be concluded, therefore, that a decrease in glucose available for util­ization at a critical intracellular site in

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the median eminence of the hypothal­amus provokes release of GHRF. This factor is carried through the hypo­thalamo-hypophyseal portal system to the acidophilic cells of the anterior hy­pophysis where it stimulates GH syn­thesis and secretion.

Contrary to the provocative action of hypoglycemia, hyperglycemia sup­presses GH release.12.21,22,30,31 PQJ- ^JJ. known reasons the GH level is variable during the first half hour after glucose administration but declines thereafter to a nadir at three hours, followed by a rise between the 4th and 6th hour.22 Normally, glucose-induced suppression does not occur in acromegaly, in some patients with intracranial tumor and in infants.^2

Protein. Consistent elevation of plas­ma GH following ingestion of beef has been reported in female subjects. The extent and time of the response is vari­able but elevation occurs most fre­quently three hours after oral feed-ijig 33,3B Knopf et aF° proved that in­fusion of various L-amino acids also simulates GH release and arginine was found to have the most potent action. Inexplicably, the GH rise to amino acid stimulus was inconsistent in males but after pre-treatment with stilbestrol, unresponsive male subjects reacted sensitively.^* Amino acid infusion also causes changes in blood glucose and stimulates secretion of insulin but the extent and time relationship of these changes are such that GH release is not considered to be a secondary pheno­menon. In fact, even during hypergly­cemia, arginine infusion can induce a rise in plasma GH."*

Parker et aW analyzed the response of 49 persons age 4 to 65 to arginine infusion. In the 28 males and 21 fe­

males, maximum GH level was reached by 40 minutes to an hour and the mean peak was 21 m/ig/ml. In a control group studied during insulin testing the mean peak was 17 m/xg/ml. The re­sponse to arginine was higher in post­pubertal individuals than in children. In the study of growth retarded chil­dren, both insulin and arginine stimu­lation is advocated because of the oc­casional failure of normal subjects to respond to either test situation.

Fat. Ingestion of fat has not been shown to affect plasma GH. No rise in plasma GH occurs with increased plas­ma free fatty acids (FFA),*« * i and GH levels of human subjects do not change following administration of 50 gm of olive oil.22 Moreover, heparin-induced elevation of FFA does not alter plasma GH levels.** On the other hand, Black-ard et al*2 demonstrated that lipid in­fusion in monkeys completely inhibits the anticipated rise in GH following insulin-induced hypoglycemia. Infu­sions of soybean oil emulsion or sodium octanoate were equally effective al­though the large doses used produced plasma FFA levels far above the phy­siologic range.

Sleep. Serial determinations of plas­ma GH levels indicate that secretion oc­curs in intermittent bursts. Such fluctu­ations are more prominent at night. A marked elevation which occurs with the onset of deep sleep* ** soon subsides and is foUowed by additional GH peaks of decreased magnitude. When a state of fuU wakefulness is maintained at night, plasma GH does not fluctuate. The secretion pattern is closely related to the depth and course of sleep. Honda et al believe that activation of the neo­cortex inhibits GH secretion whereas slow-wave sleep is associated with re-

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lease of GHRF and consequently, with growth hormone.*''

Exercise. Roth et aP" observed that moderate exercise stimulates GH se­cretion. Thirty minutes of walking at moderate speed is regularly followed by an elevation of plasma GH although this rise can be blunted by ingestion of glucose prior to the exercise.22

Surgery. An increase in GH paraUel to the rise of Cortisol occurs during surgical stress.* '* Recently, Charters studied anterior pituitary function in 13 patients during surgery and convales­cence.*" Plasma GH concentration rose from a control of 2.0 to a mean peak of 16 m^g/ml during the first hour of the operation, but decreased toward control levels at two hours despite con­tinued surgical stress. In contrast, cor­ticosteroid concentration increased con­comitantly with the GH rise but re­mained elevated throughout the oper­ation. During convalescence, plasma GH varied greatly on the first post­operative day and stabilized in the nor­mal range subsequently.

Summary

Regulation of growth is the primary but not the only function of growth hormone. GH levels in the premature infant and in the cord blood of new-boms are very high, and the widely held concept that GH is not essential for growth in the first year of life has recently been challenged.-'* During the time of accelerated pubertal growth, basal GH levels are not elevated but the overall secretion may be aug­mented, consistent with the increased GH response to various stimuli which follows administration of sex steroids.

Because somatic growth requires protein synthesis, nitrogen storage is

considered the fundamental biologic GH effect. This anabolic activity is ac-comphshed by complex alterations of the intermediary metabolism of fats and carbohydrates, sparing protein for tissue synthesis. GH secretion, func­tioning as a metabolic regulator, per­sists even after potential growth is at­tained. Just as growth hormone regu­lates metabolism of proteins, fat ,and carbohydrates, the available concentra­tions of these factors in turn regulate GH secretion. This relationship sug­gests the "negative feedback" which exists between pituitary tropic hor­mones and their target gland secretions. In the presence of high glucose concen­tration (meals) GH secretion is inhib­ited; during relative glucose deficiency (fasting and exercise) GH secretion is stimulated. The increased hormone re­duces glucose utilization, tending to maintain the blood sugar level. Con­comitantly, GH-induced hpolysis pro­vides fatty acids to be utilized for energy and gluconeogenesis, whfle catabolism of proteins is proportionate­ly diminished. Increased concentration of amino acids also stimulates GH re­lease, the increased hormonal levels serving to enhance amino acid transport and protein synthesis.

The physiologic significance and possible utility of the alterations in­duced by deep sleep are speculative, but the biologic value of increased growth hormone during exercise and physical stress is readily appreciated.

In this article we have reviewed some of the effects of nonhormonal factors regulating GH secretion. Sub­sequently, we will discuss the signifi­cance to the body economy of the in­terplay between GH and other hor­mones.

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