Clinical Science and Molecrdar Medicine (1976) SO, 241-247.
Growth hormone secretion in acid-base alterations at rest and
during exercise
J. R. S U T T O N , N. L. J O N E S A N D C. J. TOEWS
Department of Medicine, McMaster University, Hamilton, Ontario, Canada
(Received 1 1 July 1975)
Introduction
Plasma human growth hormone concentration is in1. Seven healthy males were studied during cycle
creased in clinical states associated with metabolic
ergometer exercise at 33%, 66% and 90% of Vo2
acidosis such as renal failure (Horton, Johnson &
max. on three occasions when NH,Cl, NaHC03 or
Lebovitz, 1968;Wright, Lowy, Russell-Fraser, Spitz,
CaC03(as a control substance)were administeredin
Rubenstein & Bersohn, 1968; Samaan t Freeman,
gelatin capsules double blind and in randomized
1970) and diabetes mellitus (Gerich, Martin &
order. Plasma growth hormone (HGH), lactic acid
and hydrogen ionconcentration@
weremeasured
i+])Recant, 1970). Exercise also stimulates HGH(l)
secretion (Roth, Glick, Yalow & Berson, 1963;
at frequent intervals.
Hunter, Fonseka & Passmore, 1965;Schalch, 1967).
2. Ammonium chloride produced highest blood
The magnitude of HGH elevation is related to the
[H+]and NaHC03the lowest. These differences were
duration and intensity of the exercise (Sutton &
maintained during exercise and in recovery. Plasma
Lazarus, 1974), and the ‘fitness’ of the individual,
lactic acid concentrations were similar at rest. At
being greater and sustained for longer in the ‘unfit’
66%, 90% ro2 max. and recovery lactic acid was
(Sutton, Young,Lazarus, Hickie & Maksvytis, 1969;
highest with NaHC03 and lowest with NH4Cl.
Rennie, Jennett & Johnson, 1974).
3.ExercisestimulatedHGH secretionin all studies
Greater increases are found in submaximal exerand the elevation was proportional to the intensity of
cise
during hypoxia (Sutton, 1971). As lactic acid
the exercise. N H X l caused a variable elevation of
levels are higher in hypoxic exercise (Jones, RobertHGH at rest and 33% ko2max. At 66% Vo2max.,
son, Kane & Hart, 1972)and also in unfit individuals
plasma HGH was significantly elevated to similar
during exercise, we have examined the relationship
concentrations in all studies and, at 90% voz max.,
between the lactic acidosis associated with exercise
HGH was highest with NaHC03.
and changes in HGH. By inducingmetabolicacidosis
4.An infusion of sodium L( +)-lactate producing
with ammonium chloride and metabolic alkalosis
plasma lactate concentrations of 3-5 mmol/l did not
with sodium bicarbonate, we have separated the
influence HGH secretion.
effects of increasing plasma lactate concentrations
5. Exercise is a physiological stimulus to HGH
from those of increasing blood hydrogen ion consecretion and the mechanism is independentof blood
centration ([H+]).
IH+] and lactate concentrations.
Y
S
Subjects and methods
Seven healthy males aged 22-42 years, who gave in-
Key words : acid-base, exercise, growth hormone.
formed consent, were studied on three occasions in
Correspondence:Dr J. R.Sutton,Department of Medicine,
McMaster University, Hamilton, Ontario, Canada.
(I) Abbreviation:
241
HOH, human growth hormone.
J. R. Sutton, N . L. Jones and C. J. Toews
242
the space of 6 weeks. The subjects were receiving no
drugs at the time of the study, which was approved
by the hospital ethics committee. Metabolic acidosis
and alkalosis were induced by NH,Cl or NaHC03
and the response of HGH at rest and during exercise
was compared with results of a control study in which
CaC03 was administered. The studies were randomized and conducted double blind by administering
these agents as a powder in gelatin capsules. In a
preliminary study, maximal oxygen uptake ( roz
rnax.) was measured with a progressive exercise test
on a cycle ergometer. After an overnight fast, NH4Cl
(acidosis), NaHC03 (alkalosis) or CaC03 (control)
were given in a dose of 0.3 glkg over 3 h. After the
3 h rest period, the subjects exercised on a cycle ergometer at 33% and 66% of Jho, max., each sustained
for 20 min. After this, the subjects exercised at 90%
of Jho, max. until exhaustion. The individual power
output and time to exhaustion at 90% 30, max. are
shown in Table 1. The electrocardiogram (V,) was
displayed on a multichannel recorder and the heart
rate calculated by averaging five consecutive R-R
intervals. Venous blood was collected from an indwelling intravenous polyethylene catheter inserted
into an antecubital vein. The blood was collected
during the 3 h after the administration of the capsules, with the subjects at rest, during the exercise,
and in the post-exercise period. Venous pH was
measured with a Radiometer Blood Gas analyser
(BMS 3), plasma lactate was determined by enzymic
fluorimetric assay (Toews, Lowy & Ruderman, 1970)
and plasma growth hormone by double antibody
radioimrnunoassay (Molinatti, Massara, Strumia,
Pennisi, Scassellati & Vancheri, 1969). All samples
from the one subject were measured in the same
assay to avoid interassay variance. The mean k2 SD
for low and high control sera in the growth hormone
assay were 0.5 k0.4 ng/ml and 20.0 k4.0nglml.
In a second study, the influence of lactate on HGH
secretion was investigated. Sodium L( +)-lactate, pH
7.4 (1 mmol/ml), was infused intravenously at 0.1
mmol min-I kg-' by a Harvard constant-infusion
syringe pump in six normal fasting subjects at rest
and the response in plasma HGH was measured.
Results
Acidosis and alkalosis produced by the capsule administration regime achieved significant separation
in blood [H+] (P<O.Ol), which was maintained
throughout the study (Fig. 1). Little additional
changes in [H+] occurred with exercise at the two
lower levels of power output, but at 90% vo, max.
a marked increase in [H+]
occurred in all studies and
was greatest in the alkalosis study and least in the
acidosis study.
Plasma lactic acid concentrations were similar at
rest in all studies (Fig. 2). During exercise, lactic acid
was highest with alkalosis and lowest with acidosis
and this difference was accentuated at higher levels
TABLE
1. Clinical and exercise data for subjects
Exhaustion time at 90% voz
Power output (J s-')
Subject
J.M.
R.H.
N.J.
R.R.
J.R.
J.S.
R.T.
Age
(years)
Height
( 4
Weight
(kg)
28
24
42
22
23
33
27
174
177
65
63
98
iaa
185
178
188
185
90
62.5
82
80
33%
66%
65
97
97
114
90
114
82
131
(min)
90%
196")
294"'
270
302
245
311
221
196
196
229
180
229
163
~
Mean
SD
SEM
28.4
7.0
2-7
182
5.7
77-2
14.1
2.2
5.3
946
17.6
6.6
CaC03
189
35.1
13.3
260
4.67
4.55
3.50
1.75
4.18
4.60
~
263
43.8
16.5
(2)
2.02
2.77
2.60
2.58
1.37
2.20
3.07
NaHC03
297
5.33
8-35
5.58
3.80
9.60
5.97
~~
3.69
1.14
0.43
Highest power output = 100% of previous maximum power output.
Different from CaCO, study (P<0005).
(3) Different from CaCO, study (P<0.01).
(')
NH&l
2.37'2)
0.56
0.21
5.94'3)
235
089
Growth hormone in acid-base alterations during exercise
243
Time (mid
FIG. 1. Hydrogen ion concentrations at rest and during exercise at 33%, 66% and 90% of Vo2 max. after
NH4Cl (C -H) and NaHC03 (0- - -0). Results are plotted as mean
administration of CaC03 (.-a),
values+ SEM.
Exercise
,-
66%
33 Yo
-0-
I
I
90%
I
Recovely
10
FIG.2. Plasma lactic acid concentrationsat rest and during exercise with CaC03, NH4Cl and NaHCO,. Symbols,
etc., are the same as in Fig. 1 .
J. R.Sutton, N. L. Jones and C.J. Toews
244
Time ( min)
FIG.3. Plasma growth hormone concentrations at rest and during exercise with CaC03, NH4Cl and NaHC03.
Symbols, etc., are the same as in Fig. 1.
of power output, and maintained in recovery. Lactic
acid concentrations were significantly different from
control at 66%, 90% vo, max. and in recovery
(P<0.01). Heart rates were similar in all studies.
Basal levels of HGH were low and similar in all
studies, although considerable interindividual differences were seen thereafter (Table 2). After capsule
administration, but still at rest, elevations in HGH
occurred in the acidosisstudy in six of seven subjects,
but only in three subjects was the elevation above
10ng/ml. During exercise,HGH levels increased with
increasing power output in all studies (Fig. 3). At
33 % T'oz max., the elevation seen at rest with acidosis was maintained, at 66% t o , max., the level of
HGH was similar in all studies and at exhaustion
was highest with alkalosis and lowest with acidosis.
Peak HGH levels were correlated with peak lactate
levels (P<0.01) (Fig. 4).
to exercise after calcium carbonate, ammonium chloride
and sodium bicarbonate
Mean values are shown _+ SD with SEM in parentheses.
TABLE
2. Plasma growth hormone response
Plasma growth hormone (nglrnl)
Time (min)
CaC03
- 180 Rest
- 120 Rest
- 60 Rest
0 Rest
10 33%
~xercise 20 Vo, m u .
{
Exercise { 2
Exhaustion
10 Recovery
NHaC1
NaHCO,
1.42 2.4 (0.9)
1.2k2.3 (0.9)
1.1f 1.9 (0.7)
0.42 0.2 (0.1)
0.7k 0.5 (0.2)
6.8f 8.6 (3.2)
9.3* 8.8 (3.3)
1.2_f2.1 (0-8)
1.9k2-5(1.0)
0.5k0.3 (0.1)
0.4k0.2 (0.1)
3.4k4.9 (1.8)
5-7k4.6 (1.8)
8.5f 7.9 (3.0)
10*2+8*8(3.3)
3-5+ 6.5 (2.5)
5.6C 7.4 (2.8)
19-6* 11.6 (4.4)
3 0 6 k 14.0 (5.3)
19-4+ 5.8 (2.2)
2 5 4 + 13.4 (5.1)
19*6+ 12.4 (4.7)
29*4+ 10.9 (4.1)
352+ 17.8 (6.7)
21.25-103 (4-0)
28.3+ 13-4 (5.1)
17-4+7-0 (2-7)
36*8+ 7.9 (3.0)
256+ 11.8 (4.5)
5.6k 7.9 (3.0)
Growth hormone in acid-base alterations during exercise
0
y=158+2.23 x
r = 0.6130
0
0
0
0
lot
I
2
0
I
I
I
I
4
6
8
10
Plasma lactic acid (rnrnol/l)
I
I
12
14
FIG. 4. Correlation between peak plasma growth hormone
and peak plasma lactate in all studies.
L
O t ,
I
I
15
30
I
45
Time (mid
FIG. 5. Plasma lactate and growth hormone after sodium
lactate infusion (0.1 mmol min-' kg-' ;horizontal line
between arrowheads).
In the subjects receiving sodium L( +)-lactate infusions at rest, there was no increase in plasma HGH
in spite of significant elevation in plasma lactate to
concentrations found in moderately severe exercise
(Fig. 5).
Discussion
This study confirmed that exercise is a potent physiological stimulusto HGH secretion and that the elevation in plasma HGH concentration is proportional
to the intensity of the exercise. Nevertheless, the
mechanism of such stimulation remains unclear.
245
Lactic acid has been suggested as a possible trigger
to HGH secretion in exercise (Sutton et al., 1969;
Lassarre, Girard, Durand & Raynaud, 1974; Vigas,
Nemeth, Jurcovicova, Mikulaj & Komadel, 1974),
although elevations in HGH have been reported
during submaximal exercise insufficient to elevate
plasma lactic acid (Hartley, Mason, Hogan, Jones,
Kotchen, Mougey, Wherry, Pennington & Ricketts,
1972; Sutton, Coleman, Casey & Lazarus, 1973).
As an increase in plasma [H+]will usually occur if
plasma lactate is elevated, the extent to which elevations in plasma HGH are related to increasesin lactic
acid per se or to concomitant changes in [H+] has
been uncertain.
The design of the present study enabled us to
separate the effects of high lactic acid from those of
high [H+]. The greatest elevation in lactic acid
followed NaHC03 administrationin which [H+]was
lowest, whereas NH4Cl administration led to the
least increase in lactic acid, but highest concentrations of [H+]. Subjects were also able to exercise
longest at 90% Vozmax. after NaHC03,endurance
being least with NH4C1 (Jones, Sutton, Taylor &
Toews, 1975).
The elevation of plasma HGH in the resting state
with NH,Cl but not with CaCOJ or NaHC03 is consistent with [H+]being a stimulus to HGH secretion.
As there were no consistent differences in the symptoms or resting heart rates of the subjects during the
three studies, it is unlikely that this elevation in HGH
could be attributed to non-specific stress reaction
associated with the administration of MI[&l
(Greenwood & Landon, 1966).
It is possible that the increased HGH secretion at
rest with NH4C1 may be related to the secondary
effects of a lowered Pco2 through the ventilatory
effects of acidosis, which may become particularly
important during heavy exercise. A low PCOZmight
influence HGH release directly or via an effect on
cerebral and hypothalamic blood flow. Preliminary
studies during voluntary hyperventilation are consistent with this theory (J. R. Sutton, A. P. Powles
& N. L. Jones, unpublished observations).
Although an increasein blood [H+1at rest appears
to be associated with increased HGH secretion,there
was marked variation among individuals. In four
subjects, the rise was less than 10 n g / d (20 punits/
ml), an increase which is considered to be of doubtful
physiologicalsignificance in normal subjects (Tanner,
Whitehouse, Hughes & Vince, 1971). During exercise at low intensity (33 % Po2max.), the rise in HGH
246
J. R. Sutton, N.L. Jones and C. J. Toews
associated with an increase in [H+]
was maintained,
but at higher levels of power output, [H+] did not
appear to have an effect independent of exercise. If
absolute concentrations of [H+] stimulated HGH
secretion at rest, clearly, other factors must operate
to override the [H+]effect at the higher intensities of
exercise as the highest HGH concentrations were
found at exhaustion in alkalosis and the lowest with
acidosis. As the greatest increase in [H+]and also in
HGH during exercise at 90% Pozo,
max. occurred in
the alkalosis study, it is possible that an acute increase in [H+lmay be a more important HGH stimulus than a persistently elevated [H+].
The correlation between peak HGH levels and
peak lactate levels suggests that the two may be
causally related. However, this hypothesis was not
supported by the study in which an elevation in lactate concentration produced by sodium L( $)-lactate
infusions were not associated with evidence of increased HGH secretion.
These findings are in apparent conflict with a previous study of Sutton et al. (1969), in which infusions
of sodium DL-lactate were stated to provoke HGH
secretion. Although we are unable to explain the
reasons for this discrepancy, the amount of lactate
infused was less than in the present study; only half
was biologically active and the increase in HGH concentration was negligible in two subjects and barely
physiologically significant in the remaining two subjects, i.e. less than 10 nglml. In a similar study, Vigas
et al. (1974) found elevation in serum HGH above
10 ng/ml in only two of seven subjects after an infusion of 150 mmol of sodium lactate and in none of
five subjects after an infusion of 240 mmol of sodium
lactate. Taken in concert with the present findings,
we suggest that HGH secretion during exercise is
independent of lactate.
We have previously emphasized the importance of
work load, duration of exercise and physical fitness
of the subjects in assessing the HGH response to
exercise(Sutton et al., 1969; Sutton & Lazarus, 1974).
The present study has confirmed the effects of intensity and duration of exercise, but by separating the
influences of [H+]and lactate, has shown that the increase in plasma HGH with exercise cannot be explained by changes in blood [H+] or lactate concentrations. Although adrenergic (Sutton & Lazarus,
1974) and serotonergic (Smythe & Lazarus, 1974)
neurotransmission appears important in the growth
hormone secretion with exercise, the exact stimulus
remains unknown.
Acknowledgments
The authors acknowledge the technical assistance of
the following people: Mrs E. Head, Mrs W.Richardson, Mrs K. Gupta, Mr M. Kangalee, Mr G. Lin,
Mr R. Leville, Mr R. Taylor and Mr G. Ward.
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