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Augmented growth hormone (GH) secretory burst frequency and amplitude mediate enhanced GH secretion during a two-day fast in normal men

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Serum GH concentrations are increased in fasted or malnourished human subjects. We investigated the dynamic mechanisms underlying this phenomenon in nine normal men by analyzing serum GH concentrations measured in blood obtained at 5-min intervals over 24 h on a control (fed) day and on the second day of a fast with a multiple-parameter deconvolution method to simultaneously resolve endogenous GH secretory and clearance rates. Two days of fasting induced a 5-fold increase in the 24-h endogenous GH production rate [78 +/- 12 vs. 371 +/- 57 micrograms/Lv (Lv, liter of distribution volume) or 0.24 +/- 0.038 vs. 1.1 +/- 0.16 mg/m2 (assuming a distribution volume of 7.9% body weight), P = 0.0001]. This enhanced GH production rate was accounted for by 2-fold increases in the number of GH secretory bursts per 24 h (14 +/- 2.3 vs. 32 +/- 2.4, P = 0.0006) and the mass of GH secreted per burst (6.3 +/- 1.2 vs. 11 +/- 1.6 micrograms/Lv, P = 0.002). The latter was a result of increased secretory-event amplitudes (maximal rates of GH release attained within a burst) with unchanged secretory burst durations. GH was secreted in complex volleys composed of multiple discrete secretory bursts. These secretory volleys were separated by shorter intervals of secretory quiescence in the fasted than fed state (respectively, 88 +/- 4.2 vs. 143 +/- 14 min, P = 0.0001). Similarly, within volleys of GH release, constituent individual secretory bursts occurred more frequently during the fast [every 33 +/- 0.64 (fasted) vs. every 44 +/- 2.0 min (fed), P = 0.0001]. The t1/2 of endogenous GH was not significantly altered by fasting [18 +/- 2.2 (fasted) vs. 20 +/- 1.5 min (fed), P = 0.47]. Serum insulin-like growth factor I concentrations were unchanged after 56 h of fasting. In conclusion, the present data suggest that starvation-induced enhancement of GH secretion is mediated by an increased frequency of GHRH release, and longer and more pronounced periods of somatostatin withdrawal.
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Journal of Clinical Endocrinology and Metabolism
Copyright 0 1992 by The Endocrine Society Vol. 74, No. 4
Printed in U.S.A.
Augmented Growth Hormone (GH) Secretory Burst
Frequency and Amplitude Mediate Enhanced GH
Secretion during a Two-Day Fast in Normal Men*
MARK L. HARTMAN, JOHANNES D. VELDHUIS, MICHAEL L. JOHNSON,
MARY M. LEE?, K. G. M. M. ALBERTI, EUGENE SAMOJLIK,
AND
MICHAEL 0. THORNER
Departments
of
Medicine (M.L.H., J.D. V., M.O.T.) and Pharmacology (M.L.J.), University
of
Virginia
National Science Foundation Science and Technology Center
for
Biological Timing (J.D. V., M.L.J., M.O.T.),
University
of
Virginia Health Sciences Center, Charlottesville, Virginia 22908; the Department
of
Pediatrics,
University
of
Pennsylvania School
of
Medicine (M.M.L.), Philadelphia, Pennsylvania 19104;
the Department
of
Medicine, University
of
Newcastle Upon Tyne (K.G.M.M.A.), Newcastle Upon Tyne,
Great Britain; and the Department
of
Medicine, Newark Beth Israel Medical Center, University
of
Medicine
and Dentistry
of
New Jersey, New Jersey Medical School (E.S.), Newark, New Jersey 07112
ABSTRACT.
Serum GH concentrations are increased in
fasted or malnourished human subjects. We investigated the
dynamic mechanisms underlying this phenomenon in nine nor-
mal men by analyzing serum GH concentrations measured in
blood obtained at 5-min intervals over 24 h on a control (fed)
day and on the second day of a fast with a multiple-parameter
deconvolution method to simultaneously resolve endogenous GH
secretory and clearance rates. Two days of fasting induced a 5-
fold increase in the 24-h endogenous GH production rate [78 +
12 us. 371 + 57 uelL, (L,. liter of distribution volume) or 0.24 f
-,
0.038 vs. 1.1 f 0.16 mg/m’ (assuming a distribution volume of
7.9% body weight), P = O.OOOl]. This enhanced GH production
rate was accounted for by 2-fold increases in the number of GH
secretory bursts per 24 h (14 + 2.3 vs. 32 f 2.4,
P
= 0.0006) and
the mass of GH secreted per burst (6.3 + 1.2 vs. 11 + 1.6 pg/Lv,
P = 0.002). The latter was a result of increased secretory-event
amplitudes (maximal rates of GH release attained within a burst)
with unchanged secretory burst durations. GH was secreted in
complex volleys composed of multiple discrete secretory bursts.
These secretory volleys were separated by shorter intervals of
secretory quiescence in the fasted than fed state (respectively,
88 f 4.2 vs. 143 + 14 min, P = 0.0001). Similarly, within volleys
of GH release, constituent individual secretory bursts occurred
more frequently during the fast [every 33 f 0.64 (fasted) vs.
every 44 + 2.0 min (fed), P = O.OOOl]. The tllz of endogenous
GH was not significantly altered by fasting [18 + 2.2 (fasted) vs.
20 f 1.5 min (fed),
P
= 0.471. Serum insulin-like growth factor
I concentrations were unchanged after 56 h of fasting. In con-
clusion, the present data suggest that starvation-induced en-
hancement of GH secretion is mediated by an increased fre-
quency of GHRH release, and longer and more pronounced
periods of somatostatin withdrawal.
(J Clin Endocrinol Metub
74: 757-765, 1992)
G
ROWTH failure occurs in the setting of increased
serum GH and decreased insulin-like growth factor
I (IGF-I) concentrations in patients with various forms
Received April 8, 1991.
Address requests for reprints to: Michael 0. Thorner, Division of
Endocrinology and Metabolism, Department of Medicine, Box 511,
University of Virginia Health Sciences Center, Charlottesville, Virginia
22908.
* Presented in part at the Second International Pituitary Congress,
Palm Desert, CA, June 25-28,1989. This work was supported by NIH
Grants RR-00847 (to the University of Virginia General Clinical Re-
search Center and CLINFO laboratory), Clinical Investigator Award
l-K08-HD-00860 (to M.L.H.), Research Career Development Award l-
K04-HD-00634 (to J.D.V.), GM-28928 (to M.L.J.), DK-32632 (to
M.O.T.), DK-38942 (to the University of Virginia Diabetes Endocri-
nology Research Center), grants from the University of Virginia Com-
puter Services, Pratt Fund, and Academic Enhancement Program, and
the NSF Science and Technology Center for Biological Timing.
t Current address: Department of Pediatrics, Massachusetts General
Hospital, Boston, MA 02114.
of nutrient deprivation, such as kwashiorkor and maras-
mus (1, 2). In healthy subjects, serum IGF-I levels de-
crease significantly after 5 days of fasting (2). Early
studies of fasting observed inconsistent changes in serum
GH concentrations and thus concluded that GH was
unimportant in the regulation of altered metabolism in
starvation (3-5). However, frequent blood sampling of
fasted normal subjects indicates that pulsatile GH re-
lease is enhanced by fasting (6). This dissociation of the
normal relationship between circulating levels of GH and
IGF-I suggests that impaired somatic growth in mal-
nourished patients is related to reduced IGF-I synthesis
or action while GH, with its known actions to promote
hepatic glucose production, lipolysis, and nitrogen con-
servation, may mediate, at least in part, the metabolic
adaptation to starvation (7). Pulsatile GH release is
757
758 HARTMAN
ET AL.
JCE & M. 1992
decreased in obese subjects and increased in patients
with insulin-dependent diabetes mellitus, providing fur-
ther evidence that nutrition and the metabolic milieu
are important determinants of spontaneous GH release
(8, 9).
The importance of frequent blood sampling over an
extended period of time to characterize the pulsatile
release of hormones is now well known. Approximately
twice as many GH pulses are detected in normal subjects
when blood samples are obtained every 5 min us. every
20 min, most likely because of the relatively short t1/2 of
GH disappearance from serum (-19 min) (10,ll). How-
ever, changes in GH secretory events cannot be directly
inferred from such data because of the confounding
influence of ongoing metabolic clearance which is vari-
able among individuals (11, la), and in different patho-
physiological contexts (8, 13). Thus, the increase in
circulating GH concentrations reported in fasted subjects
may be attributable to either an increase in GH secretion
or a decrease in the metabolic clearance of GH or both.
In this study we have measured GH in blood collected at
5-min intervals for 24 h and used deconvolution analysis
to demonstrate that fasting increases the frequency and
amplitude of GH secretory bursts without changing the
GH MCR (14).
Materials and Methods
Subjects and study design
The study was approved by the Human Investigation and
General Clinical Research Center Advisory Committees of the
University of Virginia. Nine healthy men (ages 24-28) of nor-
mal body weight [body mass indices (BMI) 21-25 kg/m2) were
studied after written informed consent. All were nonsmokers,
were taking no medications, had not undertaken transmeridian
travel for at least 4 weeks, and had unremarkable clinical
histories and physical examinations. All had normal biochem-
ical indices of renal, hepatic, and hematologic function and
normal fasting serum concentrations of glucose, Tq, TSH, PRL,
testosterone, IGF-I, and immunoactive LH and FSH. The
subjects were studied on the General Clinical Research Center
on two occasions: 1) a control fed day during which a weight-
maintenance diet was served at 0900, 1300, and 1800 h; and 2)
day 2 of a fast (32-56 h after the last meal) during which the
subjects ingested only water, potassium chloride (20 meq/day),
and a multivitamin tablet. Compliance with the fast was mon-
itored by daily weights and measurement of urine ketones. The
two admissions were separated by at least 30 days and their
order was randomized. On each study day a cannula was in-
serted into a forearm vein at 0700 h; blood samples were
obtained from 0800-0800 h at 5-min intervals for measurement
of GH and at 6-h intervals for measurement of gonadal steroids.
A 24-h urine was collected for measurement of urine free
cortisol. Daily blood samples (0800 h) were obtained for com-
plete blood count, serum chemistries, hepatic enzymes, serum
/3-hydroxybutyrate (BOH), acetoacetate (AcAc), FFA, and IGF-
Vol74.No4
I. Volunteers were permitted to ambulate but were not allowed
to nap or sleep until 2200 h. All serum samples were frozen at
-20 C until analyzed.
Assays
Serum GH concentrations were measured in duplicate by
immunoradiometric assay (IRMA; Nichols Institute, San Juan
Capistrano, CA) using standards diluted in equine serum. Our
results were multiplied by a factor of 0.5 to correct for the
parallel shift in the IRMA standard curve caused by equine
serum matrix relative to results obtained with human serum
(12, 15, 16). The sensitivity of the assay was taken as 0.25 pg/
L; undetectable samples were assigned this value. The median
intraassay coefficient of variation calculated from all 289 du-
plicated samples in each subject averaged 7.4% (range 2.9-
26.4%). IGF-I was measured in unextracted serum in the pres-
ence of heparin which causes IGF-I to dissociate from its
binding proteins (17). Commercially available RIAs, adapted
by E. Samojlik, were used to measure testosterone (RSL, Los
Angeles, CA) and estradiol (Diagnostics Products Corporation,
Los Angeles, CA) (Samojlik, E., Kirschner, M. A., Ribot, S.,
and Szmal, E., submitted for publication). Serum free testos-
terone and estradiol were measured by ultracentrifugation di-
alysis (18). Urine free cortisol was measured by RIA after
methylene chloride extraction (y-Coat Cortisol, Clinical As-
says, Cambridge, MA). Serum concentrations of Tq, LH, FSH,
PRL, BOH, AcAc, FFA were measured by previously described
methods (16, 19,20).
Deconvolution analysis
Multiple-parameter deconvolution derives quantitative esti-
mates of attributes of hormone secretory events from measured
peripheral serum hormone concentrations while simultaneously
estimating the endogenous subject-specific hormone MCR (14).
Serum GH concentrations were considered to arise from a series
of discrete secretory bursts of determinable locations, durations
and amplitudes, acted upon by metabolic clearance kinetics. A
distinct secretory burst was defined as a random (Gaussian)
distribution of instantaneous molecular secretory rates, whose
fitted amplitude could be distinguished from zero
(i.e.
pure
noise) with 95% statistical certainty. A tonic secretion function
was not required to model the present data. Clearance of GH
was modeled as a monoexponential function with a unique rate
constant for each subject. Serum GH concentrations were as-
sumed to decay to the sensitivity of the IRMA. The convolution
integrals relating the secretion and elimination functions were
solved by a numerical deconvolution technique (12, 14).
The following independent parameters were calculated for
each subject: amplitudes (maximal secretory rate) and temporal
positions of all GH secretory bursts; GH secretory burst half-
duration (duration at half-maximal amplitude); and the tllz of
GH disappearance. The latter two parameters and the GH
distribution volume were assumed to be constant throughout
the 24-h period for each individual (12). The mass of GH
secreted per burst was estimated as the area of the re-
solved secretory burst [in units of pg/L” (L,, L of distribution
volume)]. The 24-h endogenous GH production rate was esti-
GH SECRETORY BURSTS DURING FASTING 759
mated as the product of the number of secretory bursts and the occurred in serum levels of IGF-I or activities of hepatic
mean GH secretory burst mass. enzymes.
Statistical analyses Effects on gonadal and adrenal steroids
Results are expressed as means +
SE,
except where noted
otherwise. Comparisons among mean parameter estimates were
made by Duncan’s multiple range test after analysis of variance
or by paired two-tailed t tests. Non-Gaussian distributed pa-
rameters were logarithmically transformed before analysis. The
randomness of individual subjects’ serial interburst intervals
and secretory burst mass estimates was examined by autocor-
relation analysis with one time lag. The autocorrelation was
considered significant for the group of subjects if the distribu-
tion of Z-scores
(r/SE)
was nonrandom by the Kolmogorov-
Smirnov test (12). Correlations between properties of GH se-
cretion and BMI, and serum levels of IGF-I, BOH, AcAc, and
gonadal steroids were sought with linear regression analysis.
Statistical significance was assumed for P less than or equal to
0.05. If multiple comparisons were made the overall per-study
error rate was limited by restricting the per-comparison P value
to less than or equal to 0.01 (16).
Pooled specimens were analyzed for gonadal steroid
concentrations. Serum free testosterone concentrations
decreased significantly from 0.42 f 0.066 to 0.34 + 0.046
nmol/L after 2 days of fasting (P < 0.05). Fasting-
associated decreases in serum concentrations of total
testosterone (20 + 1.4 us. 18 + 1.9 nmol/L), total estradiol
(94 f 45 us. 69 + 14 pmol/L) and free estradiol (4.8 +-
2.4 us. 3.9 + 1.0 pmol/L) were not statistically significant.
Urinary excretion of free cortisol was not significantly
increased by the 2-day fast (230 f 40 us. 370 f 150 nmol/
day).
Mean serum GH concentrations
Results
Biochemical effects of fasting
Fasting-induced changes in serum concentrations of
IGF-I and selected metabolites are shown in Table 1.
After 32 h of fasting (start of frequent blood sampling)
significant increases in serum concentrations of BOH (4-
fold), AcAc (6-fold), FFA (3-fold), bilirubin (3-fold), and
uric acid were observed. After 56 h of fasting, further
increases above basal levels were observed for BOH (9-
fold), AcAc (&fold), FFA, uric acid, and creatinine, and
significant decreases in serum levels of glucose and bi-
carbonate occurred. These metabolic alterations were
reversed with refeeding. All subjects were ketonuric by
the evening of day 2 of the fast. No significant changes
The 2-day fast resulted in a more than 3-fold increase
in 24-h mean serum GH concentrations (2.0 Z!Z 0.29 vs.
6.7 + 1.1 r.Lg/L, P = 0.0004). The percent of samples with
undetectable GH concentrations was 29 + 8.5% (range
O-74%) on the control day, and 3.0 f 2.0% (range O-
18%) on the fasting day (P = 0.01).
Deconvolution analysis of endogenous GH secretion
and clearance
Twenty-four hour profiles of pulsatile serum GH con-
centrations and deconvolution-resolved GH secretory
rates from two normal men on the control and fasting
days are shown in Fig. 1. The quantitative changes in
specific attributes of endogenous GH secretory bursts
and the tIlz of GH disappearance are illustrated in Fig.
2. Twenty-four hour endogenous GH production rates
were increased 5-fold by 2 days of fasting (78 f 12 us.
TABLE
1. Effect of a P-day fast on the serum concentrations of IGF-I and selected metabolites in normal men
Day 04
of fast Glucose
(mmol/L) fi-Hydroxy-
butyrate
(mmol/L) Acetoacetate
(mmol/L) FFA IGF-I
(mmol/L) W/ml)
Day 1 (8 h) 4.3 + 0.22 0.21 f 0.11 0.075 5 0.023 0.37 2 0.10 1.7 * 0.21
Day 2 (32 h) 4.1 + 0.20 0.80 zk 0.28" 0.43 + 0.16" 1.0 f 0.25” 1.6 + 0.21
Day 3 (56 h) 3.2 + 0.17" 1.8 f 0.39 0.58 + 0.10 1.2 + 0.14” 1.5 + 0.25
Uric
acid Bicarbonate Creatinine Bilirubin
(moW (mmol/L) (mWL) GmWL)
Day 1 (8 h) 38Ok 19
Day 2 (32 h) 450f15
Day 3 (56 h) 550 + 18"
Blood samples were taken at 0800 h on each day.
26 + 0.80 92 f 5.1 8.0 2~ 0.80
24 k 1.2 99 _+ 6.7 22 f 1.2"
20 + 1.3" 116 + 6.0" 24 + 1.9”
“P < 0.05 us. day 1 by analysis of variance and Duncan’s multiple range test; non-Gaussian distributed parameters were logarithmically
transformed before analysis. Control day values
are
not shown since these were not different from those obtained on day 1 after 8 h of fasting.
Serum concentrations of BOH, AcAc, and FFA were not measured on the control day.
HARTMAN
ET AL.
JCE & M. 1992
760
TIME (ttwa)
FAST
7
1
FIG. 1. Twenty-four hour profiles of serum GH concentrations and
deconvolution-resolved GH secretory rates in two normal men, aged 26
(A) and 25 (B), on a control fed day (l&panels) and the second day of
a fast (right panels). For each individual, the upper panels depict serial
serum GH concentrations measured in blood collected at 5-min inter-
vals over 24 h. The intrasample SDS are denoted by vertical marks.
The continuous line through the data represents the calculated recon-
volution curve predicted by the multiple-parameter convolution model
(see Materials and Methods). In the louver panels, the calculated GH
secretory rate is plotted US. time. The secretory rate is derived by
removing the influence of subject-specific endogenous GH clearance
on the GH concentration profile. Serum GH concentrations and secre-
tory rates were increased on the fasting day. Differing scales for the
vertical axes are used because of the wide range of serum GH concen-
trations. Note that the resolved GH secretory pattern consists of volleys
of multiple secretory bursts. L, = L of distribution volume.
371 + 57 pg/LV,
P =
0.0001; Fig. 2A). These 24-h GH
production rates correspond to approximately 0.24 +
0.038 and 1.1 + 0.16 mg/m’, respectively, assuming a
mean GH distribution volume of 7.9% body weight (13).
This enhanced GH production rate was accounted for by
a 2-fold increase in the number of GH secretory bursts/
24 h (14 f 2.3 us. 32 f 2.4,
P
= 0.0006; Fig. 2B) and the
mass of GH secreted per burst (6.3 f 1.2 vs. 11 + 1.6 pg/
L,,
P
= 0.002; Fig. 2C). The latter was a result of
Vol74.No4
increased secretory burst amplitudes (0.24 + 0.053 us.
0.45 + 0.052 pg. L,-’ . min-‘,
P
= 0.0004; Fig. 2D) with
unchanged secretory burst half-durations [27 + 2.5 (fed)
US. 24 + 1.4 (fasted) min,
P
= 0.36; Fig. 2E]. Based on
the GH secretory burst frequencies and half-durations,
we estimated that 95% of daily GH secretion occurred
during 45% (11 h) of the control days and 91% (22 h) of
the fasting days. The mean tllz of endogenous GH was
not significantly altered by fasting [20 + 1.5 (fed) vs. 18
f 2.2 (fasted) min,
P
= 0.47; Fig. 2F), although based on
the individual statistical confidence limits of their tllz
estimates, three subjects had individually significant de-
creases and two subjects had individually significant
increases.
The increased number of GH secretory bursts/24 h on
the fasted day was also reflected by a decrease in the
mean interval between secretory burst centers (106 f 17
us. 45 f 3.9 min,
P
= 0.0004). On both days of study, two
types of interburst intervals were apparent: 1) those that
separated individual secretory bursts within a cluster or
volley of multiple secretory events (intravolley intervals);
and 2) those that spanned periods of secretory quiescence
during which secretory rates approached zero (intervolley
intervals). A histogram of the two types of interburst
intervals on the control and fasting days is shown in Fig.
3. On both study days, the distributions of these two
types of interburst intervals were significantly different.
On the control day, volleys of GH secretion were sepa-
rated by a mean interburst interval of 143 f 14 (median
= 106) min, whereas constituent individual secretory
events within secretory volleys occurred every 44 f 2.0
(median = 41) min
(P
= 0.0001). On the fasting day,
mean inter- and intravolley interburst intervals were 88
+ 4.2 (median = 80) and 33 + 0.64 (median = 32) min,
respectively
(P
= 0.001). The decrease in these two types
of interburst intervals with fasting was significant
(P =
0.0001). Intravolley interburst intervals accounted for
60% and 82% of the total number of interburst intervals
on the control and fasting days, respectively.
A significantly positive autocorrelation existed be-
tween the mass of GH secreted in successive secretory
bursts on both the control and fasting days
(P <
0.01).
The individual autocorrelation coefficients (r values) in
the nine subjects ranged from -0.31 to 0.70 (median =
0.32) on the control days and from 0.10 to 0.54 (median
= 0.41) on the fasting days. Successive interburst inter-
vals were not significantly autocorrelated.
Relationship between GH secretion and BMI (kg/m’),
and serum concentrations
of
IGF-I and gonadal steroids
The correlation of BMI and the endogenous GH pro-
duction rate on the control and fasting days is shown in
Fig. 4. The amount of GH secreted on the fasting day
GH SECRETORY BURSTS DURING FASTING
761
CONlROL FAFT CONT’WL FAST
30 1.0
0.83
20
M&S OF GH GH SECRl3ORY 0.6
BURST
SECRETED/WRSl , o AMPLITUDE o.4
bdb) (pg*L,-l .minql)O.Z
0 0.0
CONll?lX FM CONTROL FAST
so IE 1 40
- P-0.3l 1F o-n ‘7
r -Y.-I
4a
30..
‘3 SECRETORY 3.
BURST GH ti4.F~LIFE
EE 2. ‘, ZE
HALF-oURAnON 2o hi4 FE
4
01 OL
CONTROL FEZ CONTROL FAST
FIG. 2. Quantitative changes in specific attributes of endogenous GH secretory bursts and t iI2 of GH disappearance resulting from 2 days of
fasting as derived from deconvolution analysis of serum GH concentrations measured at 5-min intervals for 24 h in 9 normal men (see Materials
and Methods). For each individual, the 24-h endogenous GH production rate (A) was estimated as the product of the total number of GH secretory
bursts (B) and the mean mass of GH secreted per burst (C). The mean 24-h GH production rates correspond to approximately 0.24 + 0.038
(control) and 1.1 f 0.16 (fast) mg/m’ assuming a mean GH distribution volume of 7.9% body weight (13) and correcting for the subjects’ body
surface areas. The GH secretory burst amplitude (D) is the maximal secretory rate attained during a secretory burst and the GH secretory burst
half-duration (E) is the duration of a secretory burst at half-maximal amplitude. The GH tljz (F) for each subject was derived from a single-
component disappearance rate constant. In each panel, the changes for each individual are shown by connecting lines and the mean + SE for each
group
are shown adjacent to the individual data. Differences between attributes on the control and fasting days were tested by paired two-tailed t
tests. L, = L of distribution volume.
was inversely correlated with BMI (r = -0.90, P < 0.001).
This relationship was not observed on the control day in
these subjects. Serum concentrations of IGF-I, and total
and free concentrations of testosterone and estradiol
were not significantly correlated with GH production
rates, the mass of GH secreted per burst, or the number
of GH secretory bursts/24 h on either the control or
fasting days.
Discussion
We have investigated the mechanisms underlying aug-
mented serum GH concentrations during nutrient dep-
rivation using a multiple-parameter deconvolution tech-
nique and frequent blood sampling. Our results demon-
strate that endogenous GH secretion rates are enhanced
&fold by a a-day fast in normal young men. A doubling
of both GH secretory burst frequency and the mass of
GH secreted per burst fully accounted for the observed
increase in serum GH concentrations as the GH MCR
was not significantly altered by fasting. Fasting increased
the amplitude but not the half-duration (width) of GH
secretory bursts. It is unlikely that GH distribution vol-
umes were significantly altered since plasma volumes
estimated by infusions of lz51-labeled albumin in six other
normal men were unchanged by a &day fast (Vance, M.
L., Thorner, M. O., and Veldhuis, J. D., unpublished
data). Although GH secretion became virtually continu-
ous with fasting, serum GH concentrations were modeled
adequately by pulsatile secretion without measurable
intervening tonic secretion (12). Since serum GH con-
centrations below the limit of detection of conventional
GH immunoassays are also pulsatile (21), it is possible
that we have underestimated the number of GH secretory
bursts in the fed state. However, the GH secretory burst
frequency was still increased 2-fold by fasting in three
subjects in whom GH was measurable in 94-100% of
samples on the control day.
Food restriction increases GH secretion in sheep (22),
steers (23), pigs (24), dogs (25), rabbits (26), and chickens
(27), but decreases GH release in rats (28). In dogs (25)
both serum GH concentration pulse frequency and am-
762 HARTMAN ET AL.
JCE & M. 1992
FAST
0 20 40 60 .a0
loil50
350 550
INTERBURST INTERVALS (mini
FIG. 3. Histograms of the GH interburst intervals derived from decon-
volution analysis. An interburst interval is a general term defined as
the time in minutes between designated secretory burst centers. A
volley is defined as a cluster of two or more secretory bursts, between
which the secretory rate does not fall to 0. Accordingly, an intravolley
interval separates secretory bursts within a volley. Intervolley intervals
separate consecutive volleys or solitary secretory bursts; during these
intervals, the secretory rate approaches zero asymptotically. The dis-
tributions of these two types of structurally distinct interburst intervals
were significantly different on both study days by the Wilcoxon rank
sum test (P 5 0.001). Both types of interburst intervals were signifi-
cantly shorter on the fasting day compared to the control day (P =
0.0001). Thus, fasting prolonged the duration of GH secretory volleys,
shortened the intervening periods of secretory quiescence, and in-
creased the frequency of individual secretory bursts within the volleys.
The mean + SE (median) is shown above each distribution.
-S
< 800 CONTROL *
cn I?- -0.22. P- 0.56
4
.I5 F*sT
0
Y
600..
O0 0 R- -0.90. PC 0.001
$ 400.. 0
8 0
i? 200..
6 A
r 0.
:-‘h 0
A
20 21 22 23 24 25 26
G.4
BODY MASS INDEX (kg/m2)
FIG. 4. Correlations of the 24-h endogenous GH production rate with
body mass index on the control and fasting days. A significantly
negative correlation was observed on the fasting day indicating that
subjects with higher body mass indices secreted less GH at this time.
No correlation was observed on the control days. The correlation
coefficients and P values are shown in the figure. L, = L of distribution
volume.
plitude are increased, whereas in sheep (22) and steers
(23) only the latter is increased. Most investigators have
assumed that increased serum GH concentrations in
fasting reflect enhanced GH secretion and have not
Vol’74.No4
calculated the GH MCR. This assumption may not al-
ways be valid. Nutritional restriction has been reported
to increase the GH tl,n in sheep and calves (29) but not
in chickens (30). In our study, the individual increases
and decreases in GH tljz observed with fasting are attrib-
utable to the variability inherent in such estimates since
no significant overall change was observed. All of the
calculated GH tl,z were within the range of previously
reported values for exogenous and endogenous GH tliz
in normal subjects (reviewed in 11, 12). In contrast,
deconvolution estimates of GH tliz are significantly
shorter in obese subjects (8).
Pulses of GH secretion arise from the interactions of
GHRH and SRIH released into the hypophyseal-portal
circulation (31). In rats, GHRH peaks in hypophyseal-
portal. blood occur during periods of decreased SRIH
concentrations (32) whereas this relationship has not
been evident in sheep (22). Since such measurements are
impossible in humans, we have analyzed the intervals
between GH secretory bursts to make inferences about
the mechanisms by which fasting enhances GH secretion
in man. On both study days, the distributions of intra-
and intervolley intervals were significantly different, sug-
gesting that these two types of intervals may relate to
distinct physiological phenomena. We hypothesize that
intravolley intervals reflect the frequency of bursts of
GHRH secretion, whereas intervolley intervals represent
the time between nadirs of SRIH secretion (12). Accord-
ing to this model (Fig. 5), volleys of GH secretory activity
might arise from secretion of multiple discrete bursts of
GHRH into the hypophyseal-portal blood during a sus-
tained period of decreased SRIH secretion. Fasting sig-
nificantly decreased both types of intervals so that vol-
leys of GH secretion were prolonged and the frequency
of GH secretory bursts within volleys was increased.
Since serum GH concentrations do not decay to unde-
tectable levels within secretory volleys (in either the fed
or fasted state), the increased frequency of GH release
episodes within such volleys suggests that the GH pulse
frequency is truly accelerated by fasting. Based on these
findings, we speculate that in fasting men the frequency
of GHRH release is increased and nadirs of SRIH secre-
tion are prolonged, resulting in increased GH secretory
burst amplitude and frequency. Nutritional restriction
increases the amplitude but not the frequency of GH
pulses in sheep and this is associated with a 50% decrease
in hypophyseal-portal blood concentrations of SRIH
with no change in GHRH pulse amplitude or frequency
(22). These data support our human model of modulation
of GH pulse amplitude by SRIH and a coupling of GHRH
and GH secretory bursts. However, our analysis suggests
that in man fasting alters both SRIH and GHRH secre-
tion.
The metabolic and hormonal mechanisms by which
GH SECRETORY BURSTS DURING FASTING
763
FED FASTED
AAA 0 0 AAA B
-- IP-?
AAA AM
- LI
HYPOTHETICAL
GHRH
SECRETORY
RATE
FIG.
5. Hypothetical model for the physiological basis of fasting-in-
duced increases in burst-like volleys of GH secretion in man. The top
panels depict typical patterns of GH secretory rates derived by decon-
volution analysis on a fed day (left) and on the second day of a fast
(right). Intervals between GH secretory bursts are defined as either
intravolley (denoted by “A”) or intervolley (denoted as “B”) intervals,
as defined in Fig. 3. The middle and bottom panels illustrate hypothet-
ical patterns of somatostatin (SRIH) and GHRH secretion, derived
from analysis of the GH interburst intervals. Intravolley interburst
intervals are considered to reflect the frequency of bursts of GHRH
secretion, whereas intervolley interburst intervals represent periods of
time separating nadirs of SRIH secretion. Thus multiple GHRH bursts
during an interval of decreased SRIH secretion may give rise to volleys
of GH secretion. During periods of increased SRIH secretion, GH
response to GHRH is inhibited. We hypothesize that decreased mean
intra- and intervolley interburst intervals observed in fasting subjects
(Fig. 3) reflect an increased frequency of GHRH release and prolonged
nadirs of SRIH secretion. The frequency of GHRH is illustrated here
as constant, although some physiologic variability probably occurs
based on mean intravolley interburst interval coefficients of variation
of 23% (control) and 26% (fasting).
nutritional deprivation signals the hypothalamic-soma-
totroph axis are not known although it is likely that
IGF-I and insulin are involved. Since IGF-I directly
inhibits pituitary GH secretion and also stimulates hy-
pothalamic SRIH release (33), fasting-associated de-
creases in IGF-I concentrations may mediate increased
GH secretion (2). However, as previously shown (6),
pulsatile GH secretion increased before significant de-
creases in total serum IGF-I concentrations occurred.
This may reflect the stability of IGF-I bound to its
binding proteins since the bound fraction accounts for
the vast majority of circulating IGF-I (17). Nevertheless,
fasting may decrease free IGF-I concentrations more
rapidly by increasing concentrations of IGF-I binding
proteins. Preliminary results suggest that serum concen-
trations of GH and IGF binding protein-l (IGFBP-1)
increase with fasting and decrease with refeeding with
similar time courses (34, 35). Furthermore, small in-
creases in free IGF-I concentrations achieved by a low-
dose infusion of recombinant human IGF-I rapidly sup-
pressed fasting-enhanced pulsatile GH secretion (36).
Fasting may also decrease the direct inhibitory effect of
insulin on somatotroph secretion (37). Decreased IGF-I
synthesis in the hypothalamus or pituitary may increase
GH secretion by paracrine mechanisms (38). Finally,
inhibitors of IGF-I bioactivity, identified in the serum of
malnourished children and diabetics, may attenuate IGF-
I negative feedback on the somatotrophic axis (1).
Several other hormones and metabolites must be con-
sidered as possible mediators of the effect of fasting to
stimulate GH secretion. Although infusions of sodium p-
hydroxybutyrate modestly stimulate GH secretion, this
effect is blocked by increases in serum FFA which inhibit
the GH response to GHRH (39, 40). Thus, it is unlikely
that fasting-associated increases in serum concentrations
of BOH, AcAc, and FFA stimulate GH secretion. In this
study, fasting significantly decreased serum concentra-
tions of free testosterone but total testosterone, total and
free estradiol, and urine free cortisol were unchanged.
Fasting has previously been reported to decrease serum
TB and increase serum cortisol concentrations (5, 41).
However, it is unlikely that these hormones regulate the
GH response to fasting since the observed changes are
in the opposite direction of what would be expected if
they were responsible for the stimulation of GH secretion
(42). Finally, glucagon and branched-chain amino acids,
which are capable of stimulating GH release, increase
during the first few days of fasting (5, 42-44).
Linear regression analysis revealed that the amount of
GH secreted during the fast was negatively correlated
with the degree of adiposity, as estimated by the BMI.
The lack of correlation in the fed state probably reflects
the narrow range of BMIs in these men since a negative
correlation has previously been observed in obese and
nonobese fed subjects (8, 45). A negative correlation of
BMI and the GH response to GHRH, measured with the
same GH IRMA, has also been evident in nonobese men
(46). More sensitive GH assays and accurate measure-
ments of fat mass may strengthen this correlation in fed
normal-weight subjects.
In summary, fasting increases the amplitude and fre-
quency of GH secretory bursts in normal men without
altering their duration or the GH MCR. Somatotroph
secretion becomes virtually continuous during fasting
but the pattern remains pulsatile without measurable
tonic secretion. Volleys of GH secretion are prolonged
and constituent individual secretory bursts occur more
frequently than in the fed state. This pattern is consist-
ent with an increased frequency of GHRH release and
prolonged periods of reduced SRIH secretion. Increases
in GH secretion with fasting are inversely related to the
degree of adiposity of normal-weight subjects. Although
764 HARTMAN
ET AL.
JCE & M. 1992
Voll4.No4
enhanced GH release during starvation may promote
lipolysis and nitrogen conservation, further investigation
is required to elucidate the metabolic and hormonal
responses to, and mechanisms which mediate, increased
GH secretion during fasting.
Acknowledgments
We thank Ms. Sandra W. Jackson and the staff of the General
Clinical Research Center of the University of Virginia for their expert
assistance. We also thank Ms. Ginger Bauler, Ms. Catherine Kern, and
Ms. Marjorie Gingell for performing the GH assays, Ms. Suzan Pezzoli
for technical and artistic assistance, and Mr. David G. Boyd for
assistance with CLINFO.
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... We have previously shown that in humans it is the nadir GH concentrations that determine the magnitude of plasma IGF-1 concentrations (mainly of the hepatic origin) as well as muscle IGF-1 mRNA abundance [9,10] . The current study was not designed to revisit this question since the model of prolonged fasting is not appropriate to address that issue: fasting per se decreases plasma IGF-1 levels [22] and would be a major confounding factor in analyzing a model of central GH inhibition. ...
... The mechanism(s) regulating the increased GH pulsatile component during fasting are still unclear. Fastinginduced decrease in circulating IGF-1 concentrations [22] is likely to be involved, since the negative feedback of IGF-1 on GH secretion specifically suppresses GH pulse amplitude [22][23][24]. Also, the reduction in insulin secretion with fasting may also play an important role, because elevated insulin concentration during overeating rapidly and specifically suppressed GH pulse amplitude [25]. ...
... The mechanism(s) regulating the increased GH pulsatile component during fasting are still unclear. Fastinginduced decrease in circulating IGF-1 concentrations [22] is likely to be involved, since the negative feedback of IGF-1 on GH secretion specifically suppresses GH pulse amplitude [22][23][24]. Also, the reduction in insulin secretion with fasting may also play an important role, because elevated insulin concentration during overeating rapidly and specifically suppressed GH pulse amplitude [25]. ...
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... 25 Heilbronn L K, et 2005. 26 Ho K Y, et al 1988; Hartman ML, et al. 1992.; Rudman D, et al. 1990. 27 Mehrdad A, et al, 2010. ...
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Para vivir plenamente hay que desarrollar adecuadamente nuestras emociones e imaginación, y dejar de guiarnos solo por lo racional. Pero dada nuestra educación, no es fácil de hacer. Basado en neurobiología, psicología y filosofía, y utilizando evidencia empírica reciente, este libro presenta seis pasos para lograrlo: 1) moverse todo el tiempo, estar alerta, desafiarse física y mentalmente; 2) satisfacer nuestros instintos guiados por la pertenencia, ser instintivo; 3) desenvolver nuestra pertenencia potencial por tres vías: a los seres cercanos, al grupo social y al universo existencial; 4) desarrollar nuestras emociones e imaginación, fluir; 5) estar consciente del aquí y del ahora, de la importancia de vivir y de la maravilla del universo que nos rodea; y 6) usar nuestra mente para leer adecuadamente nuestras emociones, mirar con perspectiva el pasado y el presente, y en base lo que sentimos tomar decisiones en relación al futuro. El doctor Obregón es especialista en psicología y ciencias sociales. Y ha sido profesor visitante en el MIT, Massachusetts Institute of Technology, y en la Universidad de Colorado; e invitado como Post Doctoral Fellow por la Universidad de Harvard. Es autor de diversos artículos y libros, entre los que se encuentran: El camino a la libertad (2013) y ¿Quiénes somos realmente? La historia del yo (2017).
... However, nutrition guidelines recommend the early initiation of enteral feeding (EN) in most patients (91,92), recent RCTs have questioned the ideal time to start parenteral nutrition (PN) if enteral feeding fails to meet the prespecified nutritional target (30,31,93,94). Interestingly, most neuroendocrine changes in the acute phase of critical illness resemble those during fasting in healthy individuals: an increase in GH in face of low levels of IGF-I, a decrease in T3 with concomitant rise in rT3 despite relatively normal levels of TSH and T4 (NTI), a rise in systemic cortisol availability and a decrease in gonadal steroid hormones (29,95). In this view, it is likely that the neuroendocrine adaptations in the acute phase of critical illness are beneficial or at least evolutionary selected and may enhance chances of survival and recovery. ...
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Critical illness is hallmarked by major changes in all hypothalamic-pituitary-peripheral hormonal axes. Extensive animal and human studies have identified a biphasic pattern in circulating pituitary and peripheral hormone levels throughout critical illness. In the acute phase of critical illness, following a deleterious event, rapid neuroendocrine changes try to direct the human body towards a catabolic state to ensure provision of elementary energy sources, whereas costly anabolic processes are postponed. Thanks to new technologies and improvements in critical care, the majority of patients survive the acute insult and recover within a week. However, an important part of patients admitted to the ICU fail to recover sufficiently, and a prolonged phase of critical illness sets in. This prolonged phase of critical illness is characterized by a uniform suppression of the hypothalamic-pituitary-peripheral hormonal axes. Whereas the alterations in hormonal levels during the first hours and days after the onset of critical illness are evolutionary selected and are likely beneficial for survival, endocrine changes in prolonged critically ill patients could be harmful and may hamper recovery. Most studies investigating the substitution of peripheral hormones failed to show benefit for morbidity and mortality. Research on treatment with selected and combined hypothalamic hormones has shown promising results. Well controlled RCTs to corroborate these findings are needed.