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The physiology of growth hormone regulation: Pre- and postimmunoassay eras
The Physiology of Growth Hormone Pre- and Postimmunoassay By Seymour
Regulation Eras
:
Reichlin
A
SHARP dividing line separates two eras of study of growth hormone regulation. The first era began with the discovery of the growth hormone by Evans and Long and was carried forward by histologic, gross functional. and bioassay techniques. The second began with the introduction of practical plasma radioimmunoassay methods by Glick, Roth, Berson. and Yalow.’ by Hunter and Greenwood,’ and by Utiger et al.,3 a technique that has now become the indispensable tool for the majority of workers studying the control of growth hormone secretion. Comprehensive reviews of growth hormone regulation4.5 summarize the ma.. jar facts known or suspected in the preimmunoassay era. This skimpy knowledge was summarized in a review completed in l9634 (the year in which Roth et al.” reported the effects of hypoglycemia in man) but not published until 1967. (I )
Alteration
!lon in growth
in growth at different
hormone
secretion rate is probably
ages. The etfect of maturation
not the major
on growth
cause of vart:t-
hormone
release IS un-
known. (2,
Skimpy
histologic
evidence suggests that the secretion of growth
Hltenced directly or indirectly (2)
Extreme
by growth hormone
degrees of thyroxine
hormone
may be tn-
blood levels.
deficiency interfere with GH
synthesis. Estrogens
ma,
also
inhibit secretion of GH. (4) The adrenal
carticoids.
glucagon
and
epinephrine.
have
no known
effects
on
secre!ron (5)
Pituilary
at a reduced
tissue separated
plant preparations, (6) Cer:ain acidophil
from
rate. This deficiency
the brain
retains
or to loss of specific effects mediated
hypothalamic
cells. decrease
lesions cause a depression in fasting
to nl>rmal by the administration T‘hese may be interpreted
its capacity
may be due to a decreased
blood
ofgrowth
to indicate
sugar.
by the hypophysial in growth,
increased
hormone),
to stimulate
but
portal vessels.
degranulation
sensitivity is involved
of pituitary
to insulin
and a decrease in pituitary
that the hypothalamus
growth
mass of tissue in these trans-
(restored
GH
content.
in the regulation
of
C;H secretion. (7) (SRf‘)
Fragmentary
and contradictory
analogous to CRF
(X) Iisinp the crude of the literature
data about
a somatrotrophic
hormone
releasing
factor
have been accumulated.
criteria
that the growth
of effects on growth. hormone
secretory
the impression function
is gained
of the pituitary
from
is more
perusal auton-
omous than that of any other trophic activity.
The introduction of radioimmunoassay brought about a true revolution in understanding of the physiology of GH regulation. Following the introduction of these procedures for the measurement of growth hormone (GH) in plasma
Krrrived Seymour
fi~rpublication Reichlin,
Profesror of Medicine.
December
M.D..
I I, 1972. Senior Physician.
Neu, England
Tufts L’niversiiy School o/ Medicine.
c IV’.< hb, Grune & Stratton.
Metabolism.
Ph.D.:
Medical
Center
Hospital.
and
Boston. Mass.
Inc
Vol 22. No 8 (August). 1973
987
988
SEYMOUR
REICHLIN
it was recognized that growth hormone secretion was a highly labile function, reacting to an intrinsic neural cycle related to sleep, to altered intake of food, to exercise, to psychologic stimuli, and to a host of stressful, hormonal, and metabolic controls (see reviews’-i4). It also became possible to prove the hypothesis previously advanced on the basis of bioassay datai that the secretion of growth hormone was controlled by the brain through the mediation of one or more hypothalamic hypophysiotropic hormones. The study of GH secretion gained momentum during an era which saw the development of knowledge of the central neurotransmitter control of hypophysiotropic neurone function, of the “second messenger” hypothesis of cell regulation, and of the “stimulusSecretion” coupling hypothesis for glandular regulation; with each of these major biologic advances, new insight and relevance to GH secretory control mechanisms have emerged. The major areas of knowledge of GH regulation (all derived from immunoassay studies) in which there appears to be general agreement are reviewed in detail. I4 These may be summarized. Only a few of the pertinent references are cited; for complete listing see Reichlin.14 (1) GH is secreted spontaneously by the adult human in an irregular manner almost constantly associated with onset of deep s1eep,16 with exercise, and usually during the postprandial fall in blood glucose level. In addition occasional bursts of GH secretion occur with no obvious antecedent stimulus.‘7 Nocturnal growth hormone secretion is greater in the young than in adults. To the limited extent that studies have been carried out in other primates, regulation in these species resembles those of man. Secretory patterns in relation to normal activities have not been well established in nonprimate species. (2) Although GH is detectable in the human fetus and the newborn, growth during these periods is relatively independent of growth hormone secretion. Fetal GH is altered by glucose administration as in the adult. During early postnatal life, GH levels are very high and respond “paradoxically” to glucose loading.” Normal growth in children requires the presence of growth hormone. Tissue responsiveness to growth hormone and to other hormones is important in determining the pattern of childhood growth. Variations in growth rates may be related to subnormal GH secretory patterns; these have not been established with certainty, and there are a few instances in which apparently normal growth occurred without evidence of GH secretion. Only in the rat among laboratory animals has GH secretion in relation to age been studied in any detail. In this species, GH is found in the fetus, the concentration rises with age, but the secretory status in relation to age has not been established. (3) In the human, androgens and estrogens are both capable of increasing the responsiveness of the GH secretory mechanism to certain stimuli, such as exercise and arginine infusion.‘gm2’ This effect probably accounts for the differences between responses in children and adults. The estrogen effects in the normal woman are apparently greater than are androgen effects in the normal man. There are no apparent sex differences in prepubertal children. In the rat, the only other species studied in any detail, plasma and pituitary GH levels differ in the adult, an effect due to gonadal secretions, but the effects on secretory rates and on intrapituitary compartments and turnover of GH are unknown. (4) In primates, hypoglycemia induces GH hypersecretion,“.** and in man it
PHYSIOLOGY
OF GROWTH
HORMONE
989
REGULATION
has additionally been shown that a falling plasma glucose level, even within normal base-line glucose levels, will induce the release of GH.” Rapid fall in glucose level, rather than a specific level of glucose appears to be a more important stimulus to the secretion of GH. Otherwise, a rising glucose level or sustained hyperglycemia over a few hours will inhibit spontaneous GH secretion, and some, but not all types of induced GH discharges. These are evidence of the “glucoreceptor” function in the regulation of GH secretion. Though still a somewhat controversial issue, the bulk of evidence suggests that minor variations in plasma glucose that occur under normal basal conditions or in fasting are not an effective homeostatic regulator of GH secretion. It appears more likely that other neurogenic, exercise-induced, and postprandial GH hypersecretory responses provide the basal level of GH effectiveness at the tissue level. Although GH is secreted episodically, the biologic effects on tissue are probably “smoothed out” through the intermediation of the “sulfation factor,” “somatomedin,” a circulating substance believed to be GH dependent and to have a long time course of effect. ” Reflex GH release in hypoglycemia may function as an “emergency” measure in adults. On the other hand, hypoglycemia-induced GH discharge may be an important mechanism in immature humans, but this assumption has not been adequately tested. Central nervous system components sensitive to low glucose (induced by 2-deoxyglucose)24 or to systemic hypoglycemia 25have been identified: the likely ones are, but with some reservations, the receptors for regulation of GH secretion by the brain. Immunoassay has shown that wide and inexplicable variations exist in patterns of glucose control of GH secretion in subprimates. The dog is like the human; the pig resembles the obese human in the sluggishness in its responses to altered glucose level; GH secretion in the rabbit and mouse is apparently relatively independent of glucose perturbation, and in the rat, hypoglycemia induces a fall in plasma GH levels. (5) A variety of amino acids in relatively large amounts, administered intravenously, or following ingestion of a high protein meal, bring about the release of GH.27*28 The teleologic importance of this phenomenon has not been fully established since it is altered by glucose administration and is sex hormone dependent. Paradoxically, severe protein malnutrition also induces high, sustained plasma GH levels. (6) In early reports, lipids were found to play little or no role in GH regulation.” Recently, it was reported elsewhere that fatty acids inhibit nocturnal GH secretion.* (7) Starvation in the human induces a rise in GH; changes in other animals are highly variable, some showing a rise. others a fall, and still others no change. Thus, though contributing to the metabolic adjustments of fasting in the human, alteration in GH secretion is not crucial for the normal response. The metabolic response to fasting in animals is also relatively independent of starvation-induced GH release.26 (8) In obese humans, GH secretion and secretory responses to a variety of *In
1971, Blackard
Secretion
s7
and assoc~;lta
reported
that
infusion
of fatty
acids
inhibits
nocturnal
C;H
990
SEYMOUR
REICHLIN
stimuli are “blunted,” an effect secondary to obesity, since these effects are reversed by weight reduction. 9~30Comparable studies in laboratory animals have not been carried out. (9) A wide variety of acute physical and psychologic stress stimuli bring about the release of GH in the human and monkey (cf. Ref. 8). In the rat, the only other species extensively studied from this point of view, plasma GH levels fall in response to stress,31 and in some instances, pituitary GH content as determined by bioassay, but not by immunoassay is decreased. Human responses may be specifically related to the type of the psychologic experience (cf. Ref. 8). The teleologic significance of the stress effect has not been established. (10) Chronic physical stress in certain instances alters GH secretion. In the human, protein or proteincalorie malnutrition and chronic liver failure, and in the rat, chronic renal failure all lead to a sustained increase in plasma GH levels. The child exposed to a psychologically inadequate environment may develop a prolonged though potentially reversible inhibition of GH secretion and GH secretory responses. 32 The rat subjected to systematic fondling displays an increase in plasma GH levels.‘6q33 (11) Secretion of GH is influenced by interactions with the other hormones.34,35 Thyroid hormone stimulates the synthesis of GH in the rat, but in this species, effects on secretion as inferred from plasma hormone changes have not been established. In the human, thyroid deficiency blunts or inhibits GH responsiveness in the majority of individuals. Estrogens36 and androgen$’ both enhance pituitary GH responsiveness in the human; the mechanism of this effect is not well understood, but in at least one system it has been shown that estrogens increase pituitary sensitivity to the effects of hypothalamic releasing factor.3s In the human, progestins 39 inhibit some, but not all, GH secretory responses; for example, hypoglycemia-induced responses are blunted or blocked but effects on nocturnal GH discharge are unaltered. High dosages of adrenal corticoids in most instances appear to inhibit reflex GH secretion in the human. Corticoid effects have not been uniformly observed in all studies, and in the monkey cannot be demonstrated. (12) GH probably is capable of regulation of GH secretion though the operation of a “short loop” feedback mechanism .40,4’ (13) Both ablative experiments in monkeys4’ and ablative and stimulation experiments in rats (cf. Refs. 43 47) indicate that the ventromedial nucleus and ventral basal hypothalamus are part of the major neural pathway of control of GH secretion. To the extent that anatomic studies have been made in humans, there is clear evidence that the neural stalk and basal hypothalamus are involved in GH regulation in this species as well. The function of the hypothalamic component of GH regulation is altered by neural stimuli arising in the hippocampus, interpeduncular nucleus, posterior hypothalamus, and latareas clearly related to the limbic eral amygdaloid nucleus. 47 These anatomic system presumably provide the neural substrate of emotional and sleep-induced alterations in GH secretion. (14) The portal vessel chemotransmitter hypothesis of anterior pituitary control is applicable to the regulation of GH secretion. GH releasing materials
PHYSIOLOGY
OF GROWTH
HORMONE
991
REGULATION
have been isolated from hypothalamic extracts and from the hypophysial portal blood (see review38). The chemical nature of the GH releasing factor (GHRF) has not been established, but most work suggests that it is a peptide substance, distinct from the other releasing factors and from vasopressin and oxytocin. Growth hormone inhibitory substances have been identified in hypothalamic extracts as welL4’ but the physiologic significance of GHIF is unknown. Uncertainties about the significance of certain assays used to establish the existence of GHRF have been in part accountable for the difficulties in establishing the identity of this material. (I 5) The function of the putative peptidergic GHRF (and GHIF) secreting neurone is probably altered by catecholaminergic neurones. The predominant stimulatory component is under alpha adrenergic control,49 and an inhibitory component under beta adrenergic control. L-dopa, a dopamine precursor (which also is a noradrenaline precursor), is capable of releasing GH.50 A number of drugs which alter the central neurotransmitter function are capable of altering spontaneous and reflex GH secretory responses. (I 6) At the cellular level, GH secretion is modified by releasing factors possibly through the intermediation of altered intracellular 3’. 5’-cyclic AMP.5’J2 Intracellular Ca++ transport may also be important in determining the secretory responses2*53 thus suggesting that the releasing factor may act primarily on cell membrane function. Prostaglandins and cyclic guanyl adenyl monophosphates4 may also be important intermediary effecters in regulating GH secretion. (17) Paradoxical GH secretory responses to glucose loading in the human have been observed in individuals under chronic stress of several types or with a variety of brain disorder?’ and in acronlegaly.56 The physiologic basis of these reactions in unknown. SUMMARY
This paper is a review of the currently accepted knowledge sonably established about growth hormone secretion.
that seems
rea-
REFERENCES I. Cillck SM, Roth J. Yalow KS, et al: Immunoassay of human growth in plasma. Nature (London) 199:784-787, 1963 2. Hunter WM, Greenwood FC: Studies on the secretion of growth hormone. Br Med J L, 804. 1964 3. Utiger RD. Parker ML, Daughaday WH: Studies on human growth hormone, I. A radioimmunoassay for human growth hormone. J Clin Invest41:254. 1962 4. Retchlin S: Regulation of somatotrophic hormone secretion, in The Pituitary Gland. 1966. pp 270 298 5. Pecile A, Mtiller EE: Control of growth hormone secretion, in Martini L. Ganong, WF (eds): Neuroendocrinology. New York. Academic Press, 1967, p 537
6. Roth J, Click SM. Yalow RS et al: Hypoglycemia: a potent stimulus to secretion of growth hormone. Science 140:987 988, 1963a 7. Bala RM. Burgus R, Ferguson KA, et al: Control of growth hormone secretion, Martrni L. Motta M, Fraschini F (eds): The Hypothalamus. New York. Academic Press, 1970, pp I -48 8. Brown GM. Reichlin S: Psychologrcal and neural regulation of growth hormone secretion. Psychomatic Med 34:45 61. 1972 9. Glick SM: The regulation of growth hormone secretion. in Ganong WF. Martin1 L (eds): Frontiers in Neuroendocrinology. London. Oxford Univ Pr, 1969. pp 141-182 IO. Glick SM. Roth J, Yalow RS. et al:
992
The regulation of growth hormone secretion. Recent Prog Horm Res 21:241-283, 1965 11. Knobil E: The pituitary growth hormone: an adventure in physiology. Physiologist 9:25-44, 1966 12. Pecile A, Mtiller EE: Growth Hormone. international Congress Series no 236. Amsterdam, Excerpta Medica, 1971 13. Pecile A, Miiller EE: Control of growth hormone secretion, in Martini L, Ganong W (eds): Neuroendocrinology. London, Oxford Univ Pr, 1967, p 537 14. Reichlin S: Regulation of somatatrophic hormone secretion. Handbook of Physiology, in press 15. Reichlin S: Growth and the hypothalamus. Endocrinology 67:760, 1960 16. Takahashi Y, Daughaday WH, Kipnis DM: Regulation of immunoreactive growth hormone secretion in male rats. Endocrinology 88:909, 1971 17. Glick SM: Normal and abnormal secretion of growth hormone. Ann N Y Acad Sci 148:471, 1968 18. Cornblath M, Parker ML. Reisner SH, et al: Secretion and metabolism of growth hormone in premature and full term infants. .I Clin Endocrinol Metab 25:209-218, 1965 19. Frantz AC, Rabkin MT: EtTects of estrogen and sex difference on secretion of human growth hormone. J Clin Endocrinol Metab 25: 1470, 1965 20. Merimee TJ, Burgess JA. Rabinowitz D: Sex-determined variation in serum insulin and growth hormone response to amino acid stimulation. J Clin Endocrinol Metab 26:791, 1966 21. Click SM. Goldsmith S: The physiology of growth hormone secretion. in Pecile A, Mtiller EE (eds): Growth Hormone. Amsterdam, Excerpta Medica, International Congress Series No. 158, 1968, pp 84-88 22. Abrams RL, Parker MD, Blanc0 S. et al: Hypothalamic regulation of growth hormone secretion. Endocrinology 78:605-613, 1966 23. Daughaday WH: Sulfation factor regulation of skeletal growth. A stable mechanism dependent on intermittent growth hormone secretion. Am J Med 50:277, 1971 24. Himsworth RL. Carmel RW, Frantz AC: The location of the chemotransmitter controlling growth hormone secretion during hypoglycemia in primates. Endocrinology 91: 217-226, 1972 25. Blanc0 S, Schalch DS, Reichlin S: Control of growth hormone secretion by glucoreceptors in the hypothalamic pituitary unit. Fed Proc 25: 19 I, I966
SwvtouR
REICHLIN
26. Kipnis DN, Hertelendy F. Machlin LD: Studies of growth hormone secretion. Amsterdam, Excerpta Medica, International Congress Series No. 184, 1968, pp 601- 609 27. Knopf RF, Conn JW, Fajans S’S, et al: Plasma growth hormone response to intravenous administration of amino acids. J Clin Endocrinol Metab 25: 1140, 1965 28. Rabinowitz D. Merrmee TJ. Nelson J. et al: The influence of proteins and amino acids on growth hormone release in man, tn Pecile A, Mtiller EE (eds): Growth Hormone. Amsterdam, Excerpta Medica. International CongressSeriesNo. 158, 1968,~~ 105-115 29. Schalch DS, Kipnis DM: Abnormalities in carbohydrate tolerance associated with elevated plasma nonesterified fatty acids. J Clin Invest 44:2010, 1965 30. London0 H. Gallaher TF, Bray GA: Effect of weight reduction, triiodethyronine, and diethylstilbestrol on growth hormone in obesity. Metabolism 18:986-992, 1969 31. Schalch DS, Reichlin S: Plasma growth hormone concentration in the rat determined by radioimmunoassay: influence of sex. pregnancy, lactation, anesthesia, hypophysectomy and extracellular pituitary transplants. Endocrinology 79:275, 1966 32. Powell CF. Brasel JA. Blizzard RM: Emotional deprivation and growth retardation stimulating idiopathic hypopituitarism I. N Engl J Med 276:1271 -1278. 1967 33. Schalch DS. Reichlin S: Stress and growth hormone release, m Pecile A. Mtiller EE (eds): Growth Hormone. Amsterdam, Excerpta Medica, International Congress Series No. I58 1968 34. lwatsubo H, Omori J, Okada Y, et al: Human growth hormone secretion in primary hypothyroidism before and after treatment. J Clin Endocrinol Metab 27:1751-1754. 1967 35. Katz HP, Youlton R. Kaplan SL, et al: Growth and growth hormone III. Growth hormone release in children with primary hypothyroidism and thyrotoxicosis. J Clin Endocrinol Metab 29:346-351. 1969 36. Merimce TJ. Fineberg SE, Tyson JE: Fluctuations of human growth hormone secretion during menstrual cycle: Response to arginine. Metabolism 18:606 608. 1969 37. Deller JJ Jr: Growth hormone response patterns to sex hormone admimstratton in growth retardatton. Am J Med Sci 259:292~ 297, 1970 3X. Malacara JM. Valverde RC. Bollenger J, et al: Elevation in plasma radioimmunassayable GH in the rat by porcine hypothalamic extracts. Endocrinology (in press)
PHYSIOLOGY
39
OF GROWTH
SIrnon
ElTect
of
S. Schiffer
Metab
Ahrams
The efftct
RL.
dence
l’or
man
acid
growth
J Clin
41
Kaplan
on the plasma
l’ree fatty
Sakumz
cndopenous exogenous Rhesu\
N:
glucose,
to
Insulin:
tvl-
autoregulatlon
in
E:
hormone
InhIbition
of
secretion
by
infuclon
Endocrinology
in
the
86:890
894.
42.
Ahrams
Hypothalamic sccretlon. 13.
RL, Parker
ML.
regulation
of
Endocrinology
Reichhn
cmlnencc 44
S:
gland.
Reichlin
secretIon, The
ter*(lrth.
Broun
H!p~,thalamic
in
the
median
secretion AE
of human
GM.
GW,
stress
I966
LA.
Bur-
I response
growth
Bernardis
squirrel
tary
cyclic
mation
Plasma
L,
growth
stimulation.
Kant
K:
Krulich
Inhihltion
of
growth
53.
RW.
hormone
SA:
Ad141-l.
Pf’eitTer JB-
hormone
secre-
2X3:1425
l42Y,
(GH)
CT.
release
Effect
action
ol
Neuroendocrin-
of cations 210:973
Daughaday
(GRf’):
(GH)
cyclase of
Dhariwal
factor
hormone
Meeting
987, 1970
WH,
releasing
adenyl
on prolac-
by rat adeno-
release
system. the
Pro-
Endocrine
A 8 I. I97 I MD.
Cook
elevation
chronic
in response 26:1463
1970 of
secretion
hormone
55. Becker active
in
in r*itro J Physiol
Fifty-Third
56. Beck
APS:
hormone
pituitary
Paradoxical
Dhariwal
245:2883-288X,
IFrontiers
lorpr~>~ta-
I969. pp 389 43 I
and the Society.
et al. pitul-
and
Mechanism
Parsons JA: Effects
hormone
or extrahypo-
extract
effects on in vilru growth gram,
HPG.
of anterior
3’,5’monophosphatc
II:
factors.
1969
Endocrinology
T. Schneider
J Biol Chem
APS: Growth
57.
I.. Lackey
hype-
for grouth
HE.
J Med
hypothalamic
52. Geschwind
hormone
115.19?’
90.107
Engl
adenosine
by
Paradoxical
1968
to hypothalamic
electrIca
S:
hormone
the
of growth
162:5X0-582.
JR:
Reichlin
in
by 1967
47: 1407
growth
studies of stimulation
54. Peake
89:694 ~703. 1971
stimulation
Science
Martin
thalamlc
of
N
Invest
Lebovitz
51. Zor U. Kaneko Further
hypophysis
Donovan
London,
DS.
response
Fndocrinology
Hypothalamic secretInn.
Schalch
III.
I.-DOPA.
vi/m
mechanism
J Clin
Stimulation tion
in
Heidingsfelder
control
1968 50. Boyd
tin and growth
of somatotrophlc
Gland.
WC;.
receptor
hormone
gland
Fed Proc 26:316.
Blackard
ology.
613. 1966 of
Harris
Pituitary
Frohman
47
78:605
Functions
mediation
adrenal
monkch.
4X
49.
pituitary extracts.
releasing
hormone
1966. pp 270-29X
45.
46
S, et al:
N Engl J Med 275:600,
87
(eds):
Blanco growth
S: Regulation
hormone
((;H
the
glandins.
I’)70
;tntl
from
thalamic
1970
1971
hormone
993
renerglc
cortisol.
GH,
Knobil
growth monkey.
in man.
1636. 1967 growth
50:940-950.
M.
upon
S. Grumhach
response
growth
et al:
of human
hormone
In\‘est
SM. acetate
hormone
27:1633~
of adminlstration
hormone
REGULATION
Click
release of growth
J Chn Endl)crinol
and
M.
medroxyprogesterone
stimulated 40
HORMONE
of
hepatitis.
P. Parker
CC.
AD.
hormone
Lancet
2: 1035
MD,
hypersecretion to glucose.
Wright
growth
J Clin
Daughaday of growth
in 1031). WH-
hormone
Endocrinol
Metah
1469. 1966 Blackard
WC;.
of lipids
on groath
in humans.
J Clin
Hull
Invest
EW,
Loper-l-
hormone 50:1439
A:
secretion 1443.
lY71
Regulation Eras
:
Reichlin
A
SHARP dividing line separates two eras of study of growth hormone regulation. The first era began with the discovery of the growth hormone by Evans and Long and was carried forward by histologic, gross functional. and bioassay techniques. The second began with the introduction of practical plasma radioimmunoassay methods by Glick, Roth, Berson. and Yalow.’ by Hunter and Greenwood,’ and by Utiger et al.,3 a technique that has now become the indispensable tool for the majority of workers studying the control of growth hormone secretion. Comprehensive reviews of growth hormone regulation4.5 summarize the ma.. jar facts known or suspected in the preimmunoassay era. This skimpy knowledge was summarized in a review completed in l9634 (the year in which Roth et al.” reported the effects of hypoglycemia in man) but not published until 1967. (I )
Alteration
!lon in growth
in growth at different
hormone
secretion rate is probably
ages. The etfect of maturation
not the major
on growth
cause of vart:t-
hormone
release IS un-
known. (2,
Skimpy
histologic
evidence suggests that the secretion of growth
Hltenced directly or indirectly (2)
Extreme
by growth hormone
degrees of thyroxine
hormone
may be tn-
blood levels.
deficiency interfere with GH
synthesis. Estrogens
ma,
also
inhibit secretion of GH. (4) The adrenal
carticoids.
glucagon
and
epinephrine.
have
no known
effects
on
secre!ron (5)
Pituilary
at a reduced
tissue separated
plant preparations, (6) Cer:ain acidophil
from
rate. This deficiency
the brain
retains
or to loss of specific effects mediated
hypothalamic
cells. decrease
lesions cause a depression in fasting
to nl>rmal by the administration T‘hese may be interpreted
its capacity
may be due to a decreased
blood
ofgrowth
to indicate
sugar.
by the hypophysial in growth,
increased
hormone),
to stimulate
but
portal vessels.
degranulation
sensitivity is involved
of pituitary
to insulin
and a decrease in pituitary
that the hypothalamus
growth
mass of tissue in these trans-
(restored
GH
content.
in the regulation
of
C;H secretion. (7) (SRf‘)
Fragmentary
and contradictory
analogous to CRF
(X) Iisinp the crude of the literature
data about
a somatrotrophic
hormone
releasing
factor
have been accumulated.
criteria
that the growth
of effects on growth. hormone
secretory
the impression function
is gained
of the pituitary
from
is more
perusal auton-
omous than that of any other trophic activity.
The introduction of radioimmunoassay brought about a true revolution in understanding of the physiology of GH regulation. Following the introduction of these procedures for the measurement of growth hormone (GH) in plasma
Krrrived Seymour
fi~rpublication Reichlin,
Profesror of Medicine.
December
M.D..
I I, 1972. Senior Physician.
Neu, England
Tufts L’niversiiy School o/ Medicine.
c IV’.< hb, Grune & Stratton.
Metabolism.
Ph.D.:
Medical
Center
Hospital.
and
Boston. Mass.
Inc
Vol 22. No 8 (August). 1973
987
988
SEYMOUR
REICHLIN
it was recognized that growth hormone secretion was a highly labile function, reacting to an intrinsic neural cycle related to sleep, to altered intake of food, to exercise, to psychologic stimuli, and to a host of stressful, hormonal, and metabolic controls (see reviews’-i4). It also became possible to prove the hypothesis previously advanced on the basis of bioassay datai that the secretion of growth hormone was controlled by the brain through the mediation of one or more hypothalamic hypophysiotropic hormones. The study of GH secretion gained momentum during an era which saw the development of knowledge of the central neurotransmitter control of hypophysiotropic neurone function, of the “second messenger” hypothesis of cell regulation, and of the “stimulusSecretion” coupling hypothesis for glandular regulation; with each of these major biologic advances, new insight and relevance to GH secretory control mechanisms have emerged. The major areas of knowledge of GH regulation (all derived from immunoassay studies) in which there appears to be general agreement are reviewed in detail. I4 These may be summarized. Only a few of the pertinent references are cited; for complete listing see Reichlin.14 (1) GH is secreted spontaneously by the adult human in an irregular manner almost constantly associated with onset of deep s1eep,16 with exercise, and usually during the postprandial fall in blood glucose level. In addition occasional bursts of GH secretion occur with no obvious antecedent stimulus.‘7 Nocturnal growth hormone secretion is greater in the young than in adults. To the limited extent that studies have been carried out in other primates, regulation in these species resembles those of man. Secretory patterns in relation to normal activities have not been well established in nonprimate species. (2) Although GH is detectable in the human fetus and the newborn, growth during these periods is relatively independent of growth hormone secretion. Fetal GH is altered by glucose administration as in the adult. During early postnatal life, GH levels are very high and respond “paradoxically” to glucose loading.” Normal growth in children requires the presence of growth hormone. Tissue responsiveness to growth hormone and to other hormones is important in determining the pattern of childhood growth. Variations in growth rates may be related to subnormal GH secretory patterns; these have not been established with certainty, and there are a few instances in which apparently normal growth occurred without evidence of GH secretion. Only in the rat among laboratory animals has GH secretion in relation to age been studied in any detail. In this species, GH is found in the fetus, the concentration rises with age, but the secretory status in relation to age has not been established. (3) In the human, androgens and estrogens are both capable of increasing the responsiveness of the GH secretory mechanism to certain stimuli, such as exercise and arginine infusion.‘gm2’ This effect probably accounts for the differences between responses in children and adults. The estrogen effects in the normal woman are apparently greater than are androgen effects in the normal man. There are no apparent sex differences in prepubertal children. In the rat, the only other species studied in any detail, plasma and pituitary GH levels differ in the adult, an effect due to gonadal secretions, but the effects on secretory rates and on intrapituitary compartments and turnover of GH are unknown. (4) In primates, hypoglycemia induces GH hypersecretion,“.** and in man it
PHYSIOLOGY
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HORMONE
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REGULATION
has additionally been shown that a falling plasma glucose level, even within normal base-line glucose levels, will induce the release of GH.” Rapid fall in glucose level, rather than a specific level of glucose appears to be a more important stimulus to the secretion of GH. Otherwise, a rising glucose level or sustained hyperglycemia over a few hours will inhibit spontaneous GH secretion, and some, but not all types of induced GH discharges. These are evidence of the “glucoreceptor” function in the regulation of GH secretion. Though still a somewhat controversial issue, the bulk of evidence suggests that minor variations in plasma glucose that occur under normal basal conditions or in fasting are not an effective homeostatic regulator of GH secretion. It appears more likely that other neurogenic, exercise-induced, and postprandial GH hypersecretory responses provide the basal level of GH effectiveness at the tissue level. Although GH is secreted episodically, the biologic effects on tissue are probably “smoothed out” through the intermediation of the “sulfation factor,” “somatomedin,” a circulating substance believed to be GH dependent and to have a long time course of effect. ” Reflex GH release in hypoglycemia may function as an “emergency” measure in adults. On the other hand, hypoglycemia-induced GH discharge may be an important mechanism in immature humans, but this assumption has not been adequately tested. Central nervous system components sensitive to low glucose (induced by 2-deoxyglucose)24 or to systemic hypoglycemia 25have been identified: the likely ones are, but with some reservations, the receptors for regulation of GH secretion by the brain. Immunoassay has shown that wide and inexplicable variations exist in patterns of glucose control of GH secretion in subprimates. The dog is like the human; the pig resembles the obese human in the sluggishness in its responses to altered glucose level; GH secretion in the rabbit and mouse is apparently relatively independent of glucose perturbation, and in the rat, hypoglycemia induces a fall in plasma GH levels. (5) A variety of amino acids in relatively large amounts, administered intravenously, or following ingestion of a high protein meal, bring about the release of GH.27*28 The teleologic importance of this phenomenon has not been fully established since it is altered by glucose administration and is sex hormone dependent. Paradoxically, severe protein malnutrition also induces high, sustained plasma GH levels. (6) In early reports, lipids were found to play little or no role in GH regulation.” Recently, it was reported elsewhere that fatty acids inhibit nocturnal GH secretion.* (7) Starvation in the human induces a rise in GH; changes in other animals are highly variable, some showing a rise. others a fall, and still others no change. Thus, though contributing to the metabolic adjustments of fasting in the human, alteration in GH secretion is not crucial for the normal response. The metabolic response to fasting in animals is also relatively independent of starvation-induced GH release.26 (8) In obese humans, GH secretion and secretory responses to a variety of *In
1971, Blackard
Secretion
s7
and assoc~;lta
reported
that
infusion
of fatty
acids
inhibits
nocturnal
C;H
990
SEYMOUR
REICHLIN
stimuli are “blunted,” an effect secondary to obesity, since these effects are reversed by weight reduction. 9~30Comparable studies in laboratory animals have not been carried out. (9) A wide variety of acute physical and psychologic stress stimuli bring about the release of GH in the human and monkey (cf. Ref. 8). In the rat, the only other species extensively studied from this point of view, plasma GH levels fall in response to stress,31 and in some instances, pituitary GH content as determined by bioassay, but not by immunoassay is decreased. Human responses may be specifically related to the type of the psychologic experience (cf. Ref. 8). The teleologic significance of the stress effect has not been established. (10) Chronic physical stress in certain instances alters GH secretion. In the human, protein or proteincalorie malnutrition and chronic liver failure, and in the rat, chronic renal failure all lead to a sustained increase in plasma GH levels. The child exposed to a psychologically inadequate environment may develop a prolonged though potentially reversible inhibition of GH secretion and GH secretory responses. 32 The rat subjected to systematic fondling displays an increase in plasma GH levels.‘6q33 (11) Secretion of GH is influenced by interactions with the other hormones.34,35 Thyroid hormone stimulates the synthesis of GH in the rat, but in this species, effects on secretion as inferred from plasma hormone changes have not been established. In the human, thyroid deficiency blunts or inhibits GH responsiveness in the majority of individuals. Estrogens36 and androgen$’ both enhance pituitary GH responsiveness in the human; the mechanism of this effect is not well understood, but in at least one system it has been shown that estrogens increase pituitary sensitivity to the effects of hypothalamic releasing factor.3s In the human, progestins 39 inhibit some, but not all, GH secretory responses; for example, hypoglycemia-induced responses are blunted or blocked but effects on nocturnal GH discharge are unaltered. High dosages of adrenal corticoids in most instances appear to inhibit reflex GH secretion in the human. Corticoid effects have not been uniformly observed in all studies, and in the monkey cannot be demonstrated. (12) GH probably is capable of regulation of GH secretion though the operation of a “short loop” feedback mechanism .40,4’ (13) Both ablative experiments in monkeys4’ and ablative and stimulation experiments in rats (cf. Refs. 43 47) indicate that the ventromedial nucleus and ventral basal hypothalamus are part of the major neural pathway of control of GH secretion. To the extent that anatomic studies have been made in humans, there is clear evidence that the neural stalk and basal hypothalamus are involved in GH regulation in this species as well. The function of the hypothalamic component of GH regulation is altered by neural stimuli arising in the hippocampus, interpeduncular nucleus, posterior hypothalamus, and latareas clearly related to the limbic eral amygdaloid nucleus. 47 These anatomic system presumably provide the neural substrate of emotional and sleep-induced alterations in GH secretion. (14) The portal vessel chemotransmitter hypothesis of anterior pituitary control is applicable to the regulation of GH secretion. GH releasing materials
PHYSIOLOGY
OF GROWTH
HORMONE
991
REGULATION
have been isolated from hypothalamic extracts and from the hypophysial portal blood (see review38). The chemical nature of the GH releasing factor (GHRF) has not been established, but most work suggests that it is a peptide substance, distinct from the other releasing factors and from vasopressin and oxytocin. Growth hormone inhibitory substances have been identified in hypothalamic extracts as welL4’ but the physiologic significance of GHIF is unknown. Uncertainties about the significance of certain assays used to establish the existence of GHRF have been in part accountable for the difficulties in establishing the identity of this material. (I 5) The function of the putative peptidergic GHRF (and GHIF) secreting neurone is probably altered by catecholaminergic neurones. The predominant stimulatory component is under alpha adrenergic control,49 and an inhibitory component under beta adrenergic control. L-dopa, a dopamine precursor (which also is a noradrenaline precursor), is capable of releasing GH.50 A number of drugs which alter the central neurotransmitter function are capable of altering spontaneous and reflex GH secretory responses. (I 6) At the cellular level, GH secretion is modified by releasing factors possibly through the intermediation of altered intracellular 3’. 5’-cyclic AMP.5’J2 Intracellular Ca++ transport may also be important in determining the secretory responses2*53 thus suggesting that the releasing factor may act primarily on cell membrane function. Prostaglandins and cyclic guanyl adenyl monophosphates4 may also be important intermediary effecters in regulating GH secretion. (17) Paradoxical GH secretory responses to glucose loading in the human have been observed in individuals under chronic stress of several types or with a variety of brain disorder?’ and in acronlegaly.56 The physiologic basis of these reactions in unknown. SUMMARY
This paper is a review of the currently accepted knowledge sonably established about growth hormone secretion.
that seems
rea-
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6. Roth J, Click SM. Yalow RS et al: Hypoglycemia: a potent stimulus to secretion of growth hormone. Science 140:987 988, 1963a 7. Bala RM. Burgus R, Ferguson KA, et al: Control of growth hormone secretion, Martrni L. Motta M, Fraschini F (eds): The Hypothalamus. New York. Academic Press, 1970, pp I -48 8. Brown GM. Reichlin S: Psychologrcal and neural regulation of growth hormone secretion. Psychomatic Med 34:45 61. 1972 9. Glick SM: The regulation of growth hormone secretion. in Ganong WF. Martin1 L (eds): Frontiers in Neuroendocrinology. London. Oxford Univ Pr, 1969. pp 141-182 IO. Glick SM. Roth J, Yalow RS. et al:
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The regulation of growth hormone secretion. Recent Prog Horm Res 21:241-283, 1965 11. Knobil E: The pituitary growth hormone: an adventure in physiology. Physiologist 9:25-44, 1966 12. Pecile A, Mtiller EE: Growth Hormone. international Congress Series no 236. Amsterdam, Excerpta Medica, 1971 13. Pecile A, Miiller EE: Control of growth hormone secretion, in Martini L, Ganong W (eds): Neuroendocrinology. London, Oxford Univ Pr, 1967, p 537 14. Reichlin S: Regulation of somatatrophic hormone secretion. Handbook of Physiology, in press 15. Reichlin S: Growth and the hypothalamus. Endocrinology 67:760, 1960 16. Takahashi Y, Daughaday WH, Kipnis DM: Regulation of immunoreactive growth hormone secretion in male rats. Endocrinology 88:909, 1971 17. Glick SM: Normal and abnormal secretion of growth hormone. Ann N Y Acad Sci 148:471, 1968 18. Cornblath M, Parker ML. Reisner SH, et al: Secretion and metabolism of growth hormone in premature and full term infants. .I Clin Endocrinol Metab 25:209-218, 1965 19. Frantz AC, Rabkin MT: EtTects of estrogen and sex difference on secretion of human growth hormone. J Clin Endocrinol Metab 25: 1470, 1965 20. Merimee TJ, Burgess JA. Rabinowitz D: Sex-determined variation in serum insulin and growth hormone response to amino acid stimulation. J Clin Endocrinol Metab 26:791, 1966 21. Click SM. Goldsmith S: The physiology of growth hormone secretion. in Pecile A, Mtiller EE (eds): Growth Hormone. Amsterdam, Excerpta Medica, International Congress Series No. 158, 1968, pp 84-88 22. Abrams RL, Parker MD, Blanc0 S. et al: Hypothalamic regulation of growth hormone secretion. Endocrinology 78:605-613, 1966 23. Daughaday WH: Sulfation factor regulation of skeletal growth. A stable mechanism dependent on intermittent growth hormone secretion. Am J Med 50:277, 1971 24. Himsworth RL. Carmel RW, Frantz AC: The location of the chemotransmitter controlling growth hormone secretion during hypoglycemia in primates. Endocrinology 91: 217-226, 1972 25. Blanc0 S, Schalch DS, Reichlin S: Control of growth hormone secretion by glucoreceptors in the hypothalamic pituitary unit. Fed Proc 25: 19 I, I966
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REICHLIN
26. Kipnis DN, Hertelendy F. Machlin LD: Studies of growth hormone secretion. Amsterdam, Excerpta Medica, International Congress Series No. 184, 1968, pp 601- 609 27. Knopf RF, Conn JW, Fajans S’S, et al: Plasma growth hormone response to intravenous administration of amino acids. J Clin Endocrinol Metab 25: 1140, 1965 28. Rabinowitz D. Merrmee TJ. Nelson J. et al: The influence of proteins and amino acids on growth hormone release in man, tn Pecile A, Mtiller EE (eds): Growth Hormone. Amsterdam, Excerpta Medica. International CongressSeriesNo. 158, 1968,~~ 105-115 29. Schalch DS, Kipnis DM: Abnormalities in carbohydrate tolerance associated with elevated plasma nonesterified fatty acids. J Clin Invest 44:2010, 1965 30. London0 H. Gallaher TF, Bray GA: Effect of weight reduction, triiodethyronine, and diethylstilbestrol on growth hormone in obesity. Metabolism 18:986-992, 1969 31. Schalch DS, Reichlin S: Plasma growth hormone concentration in the rat determined by radioimmunoassay: influence of sex. pregnancy, lactation, anesthesia, hypophysectomy and extracellular pituitary transplants. Endocrinology 79:275, 1966 32. Powell CF. Brasel JA. Blizzard RM: Emotional deprivation and growth retardation stimulating idiopathic hypopituitarism I. N Engl J Med 276:1271 -1278. 1967 33. Schalch DS. Reichlin S: Stress and growth hormone release, m Pecile A. Mtiller EE (eds): Growth Hormone. Amsterdam, Excerpta Medica, International Congress Series No. I58 1968 34. lwatsubo H, Omori J, Okada Y, et al: Human growth hormone secretion in primary hypothyroidism before and after treatment. J Clin Endocrinol Metab 27:1751-1754. 1967 35. Katz HP, Youlton R. Kaplan SL, et al: Growth and growth hormone III. Growth hormone release in children with primary hypothyroidism and thyrotoxicosis. J Clin Endocrinol Metab 29:346-351. 1969 36. Merimce TJ. Fineberg SE, Tyson JE: Fluctuations of human growth hormone secretion during menstrual cycle: Response to arginine. Metabolism 18:606 608. 1969 37. Deller JJ Jr: Growth hormone response patterns to sex hormone admimstratton in growth retardatton. Am J Med Sci 259:292~ 297, 1970 3X. Malacara JM. Valverde RC. Bollenger J, et al: Elevation in plasma radioimmunassayable GH in the rat by porcine hypothalamic extracts. Endocrinology (in press)
PHYSIOLOGY
39
OF GROWTH
SIrnon
ElTect
of
S. Schiffer
Metab
Ahrams
The efftct
RL.
dence
l’or
man
acid
growth
J Clin
41
Kaplan
on the plasma
l’ree fatty
Sakumz
cndopenous exogenous Rhesu\
N:
glucose,
to
Insulin:
tvl-
autoregulatlon
in
E:
hormone
InhIbition
of
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infuclon
Endocrinology
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the
86:890
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Hypothalamic sccretlon. 13.
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ML.
regulation
of
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S:
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Reichlin
secretIon, The
ter*(lrth.
Broun
H!p~,thalamic
in
the
median
secretion AE
of human
GM.
GW,
stress
I966
LA.
Bur-
I response
growth
Bernardis
squirrel
tary
cyclic
mation
Plasma
L,
growth
stimulation.
Kant
K:
Krulich
Inhihltion
of
growth
53.
RW.
hormone
SA:
Ad141-l.
Pf’eitTer JB-
hormone
secre-
2X3:1425
l42Y,
(GH)
CT.
release
Effect
action
ol
Neuroendocrin-
of cations 210:973
Daughaday
(GRf’):
(GH)
cyclase of
Dhariwal
factor
hormone
Meeting
987, 1970
WH,
releasing
adenyl
on prolac-
by rat adeno-
release
system. the
Pro-
Endocrine
A 8 I. I97 I MD.
Cook
elevation
chronic
in response 26:1463
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secretion
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55. Becker active
in
in r*itro J Physiol
Fifty-Third
56. Beck
APS:
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Paradoxical
Dhariwal
245:2883-288X,
IFrontiers
lorpr~>~ta-
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et al. pitul-
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Mechanism
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52. Geschwind
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renerglc
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REGULATION
Click
release of growth
J Chn Endl)crinol
and
M.
medroxyprogesterone
stimulated 40
HORMONE
of
hepatitis.
P. Parker
CC.
AD.
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Lancet
2: 1035
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Wright
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Endocrinol
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Invest
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lY71