0021-972X/00/$03.00/0 Vol. 85, No.

1
The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A.
Copyright © 2000 by The Endocrine Society

A Paradoxical Gender Dissociation within the Growth

Hormone/Insulin-Like Growth Factor I Axis during
Protracted Critical Illness*
G. VAN DEN BERGHE, R. C. BAXTER, F. WEEKERS, P. WOUTERS, C. Y. BOWERS,
AND J. D. VELDHUIS

Department of Intensive Care Medicine, University Hospital Gasthuisberg, University of Leuven

(G.V.d.B., F.W., P.W.), B-3000 Leuven, Belgium; Kolling Institute of Medical Research, Royal North

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Shore Hospital, Sydney University (R.C.B.), St. Leonards, New South Wales 2065, Australia; the
Department of Medicine, Division of Endocrinology, Tulane University Medical Center (C.Y.B.), New
Orleans, Louisiana 70112-2699; and the General Clinical Research Center and Department of
Medicine, Division of Endocrinology, University of Virginia Health Sciences Center (J.D.V.),
Charlottesville, Virginia 29908

ABSTRACT revealing lower IGF-I (P 5 0.01) and ALS (P 5 0.005) concentrations

Female gender appears to protect against adverse outcome from than female patients. Correspondingly, circulating IGF-I and ALS
prolonged critical illness, a condition characterized by blunted and levels correlated positively with pulsatile (but not with nonpulsatile)
disorderly GH secretion and impaired anabolism. As a sexual dimor- GH secretion. Circulating levels of GH-binding protein and IGFBP-1,
phism in the GH secretory pattern of healthy humans and rodents -2, and -6 were higher in patients than controls, without a detectable
determines gender differences in metabolism, we here compared GH gender difference. In female patients, PRL levels were 3-fold higher,
secretion and responsiveness to GH secretagogues in male and female and TSH and cortisol tended to be higher than levels in males. In both
protracted critically ill patients. GH secretion was quantified by de- genders, estrogen levels were more than 3-fold higher than normal,
and testosterone (2.25 6 1.94 vs. 0.97 6 0.39 nmol/L; P 5 0.03) and
convolution analysis and approximate entropy estimates of 9-h noc-
dehydroepiandrosterone sulfate concentrations were low. In male
turnal time series in 9 male and 9 female patients matched for age patients, low testosterone levels were related to reduced GH pulse
(mean 6 SD, 67 6 11 and 67 6 15 yr), body mass index, severity and amplitude (r 5 0.91; P 5 0.0008). GH responses to GHRH were
duration of illness, feeding, and medication. Serum concentrations of relatively low and equal in critically ill men and women (7.3 6 9.4 vs.
PRL, TSH, cortisol, and sex steroids were measured concomitantly. 7.8 6 4.1 mg/L; P 5 0.99). GH responses to GHRP-2 in women (93 6
Serum levels of GH-binding protein, insulin-like growth factor I (IGF- 38 mg/L) were supranormal and higher (P , 0.0001) than those in men
I), IGF-binding proteins (IGFBPs), and PRL were compared with (28 6 16 mg/L). Combining GHRH with GHRP-2 nullified this gender
those of 50 male and 50 female community-living control subjects difference (77 6 58 in men vs. 120 6 69 mg/L in women; P 5 0.4).
matched for age and body mass index. In a second study, GH re- In conclusion, a paradoxical gender dissociation within the GH/
sponses to GHRH (1 mg/kg), GH-releasing peptide-2 (GHRP-2; 1 mg/ IGF-I axis is evident in protracted critical illness, with men showing
kg) and GHRH plus GHRP-2 (1 and 1 mg/kg) were examined in com- greater loss of pulsatility and regularity within the GH secretory
parable, carefully matched male (n 5 15) and female (n 5 15) patients. pattern than women (despite indistinguishable total GH output) and
Despite identical mean serum GH concentrations, total GH output, concomitantly lower IGF-I and ALS levels. Less endogenous GHRH
GH half-life, and number of GH pulses, critically ill men paradoxically action in severely ill men compared with women, possibly due to
presented with less pulsatile (mean 6 SD pulsatile GH fraction, 39 6 profound hypoandrogenism, accompanying loss of the putative en-
14% vs. 67 6 20%; P 5 0.002) and more disorderly (approximate dogenous GHRP-like ligand action with prolonged stress in both gen-
entropy, 0.946 6 0.113 vs. 0.805 6 0.147; P 5 0.02) GH secretion than ders may explain these novel findings. (J Clin Endocrinol Metab 85:
women. Serum IGF-I, IGFBP-3, and acid-labile subunit (ALS) levels 183–192, 2000)
were low in patients compared with controls, with male patients

P ROTRACTED critical illness is characterized by ongoing

wasting of lean body mass despite feeding, whereas fat
is paradoxically accrued (1), and by dependency on intensive
medical care for weeks or months with an attendant consider-
able morbidity and mortality. The metabolic dysfunction was
found to be at least in part evoked by a uniform suppression of
pulsatility and regularity in the secretory patterns of anterior
pituitary hormones, which seems largely due to impaired
Received July 29, 1999. Revision received September 22, 1999. Ac- and/or asynchronous hypothalamic stimulation (2–6). A gen-
cepted October 15, 1999. der survival benefit for female intensive care patients has been
Address all correspondence and requests for reprints to: Greet Van
den Berghe, M.D., Ph.D., Department of Intensive Care Medicine Uni-
suggested (7, 8) and was observed for the protracted critically
versity Hospital Gasthuisberg, University of Leuven, B-3000 Leuven, ill patients treated in our own intensive care department,1 for
Belgium. E-mail: [email protected]. which a solid explanation is still lacking.
* Presented in part at the 81st Annual Meeting of The Endocrine Stress responses within the immune system appear to dif-
Society, San Diego, California, 1999. This work was supported by the fer in male and female experimental animals (9, 10), which
National Science Foundation Center for Biological Timing and NIH
Grant ROI-AG-14799 (to J.D.V.); the National Health and Medical Re-
1
search Council of Australia, Grant 940447 (to R.C.B.); the Fund for From 1996 to 1998, only 36% of the 562 protracted critically ill
Scientific Research Flanders Belgium, Grants G.0162.96, G.0144.00, and patients (with an age of 33 yr or more and an ICU stay of at least 21 days)
G.3C05.95N (to G.V.d.B.); the Research Council of the University of treated in our intensive care department were women, revealing a 6%
Leuven, Grants OT 95/24 and OT 99/32 (to G.V.d.B.); and the University survival benefit (20% vs. 26%; P 5 0.057, by x2 test) over the protracted
of Leuven 1998 –1999 VKG grant for medical research (to F.W.). critically ill men (unpublished data).

183
184 VAN DEN BERGHE ET AL. JCE & M • 2000
Vol 85 • No 1

has been attributed in part to distinct alterations within the TABLE 1. Male and female patients included in both studies and
hypothalamic-pituitary-adrenal axis and/or effects of sex community-living controls were matched for relevant clinical and
demographic characteristics
steroids (10, 11). Moreover, in healthy rodents and humans,
a sexual dimorphism in the GH secretory pattern is thought Females Males
P value
to determine gender differences in metabolism. Female rats (mean 6 SD) (mean 6 SD)
exhibit a more irregular and less pulsatile GH secretory pat- Controls n 5 50 n 5 50
tern compared with males (12, 13), a difference that may be Age (yr) 67 6 11 67 6 8 0.9
related to lower insulin-like growth factor I (IGF-I) gene BMI (kg/m2) 25 6 4 26 6 3 0.4
Study I n59 n59
expression and serum levels in the female, in turn contrib- Age (yr) 67 6 15 67 6 11 0.9
uting to the gender differences in growth (13–16). Women, BMI (kg/m2) 29 6 7 25 6 3 0.1
both premenopausal and elderly, also display more disor- Cal/kg/24 h 27 6 7 27 6 6 0.9
derliness in the GH secretory pattern compared with men of Apache II score 17 6 5 16 6 7 0.6
ICU stay (days) 21 6 6 35 6 25 0.1
the same age, which may determine differences in body

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Blood glucose (mmol/L) 7.7 6 2.2 7.1 6 0.7 0.4
composition (17–21). In both genders, aging is associated Study II n 5 15 n 5 15
with a progressive loss of regular, pulsatile GH secretion (19). Age (yr) 70 6 2 67 6 8 0.5
Sexual dimorphism appears largely dependent upon prim- BMI (kg/m2) 24 6 5 24 6 3 0.9
ing effects of androgens on hypothalamic signaling and on Cal/kg/24 h 28 6 5 26 6 3 0.5
Apache II score 13 6 6 13 6 4 0.9
the modifying influences of available estrogens and andro- ICU stay (days) 18 6 11 13 6 7 0.2
gens during adult life. Blood glucose (mmol/L) 8.2 6 1.5 8.5 6 1.8 0.7
In view of the specific metabolic dysfunction in protracted P values were obtained with unpaired Student’s t test.
critical illness and the apparent survival benefit associated
with female gender, we here investigated whether a gender
dissociation is evident within the GH/IGF-I axis in this par- IGFBP-6 were determined at or near midnight, and serum concentra-
tions of IGF-I, androstenedione, estrone (E1), estradiol (E2), dehydro-
ticular condition of chronic severe stress. The hypothesis was epiandrosterone sulfate (DHEAS), testosterone, and PRL were mea-
tested by comparison of nocturnal GH secretory patterns and sured at 0600 h.
levels of GH-binding protein (GHBP), IGF-I, and IGF-bind- For measures of GHBP, IGF-I, IGFBPs, and PRL, patients were com-
ing proteins (IGFBPs) in matched male and female patients pared with a healthy, community-living, age- and body mass index-
matched control group consisting of 50 men and 50 women (Table 1).
with protracted critical illness. To aid in interpretation, we Exclusion criteria for participation as a healthy control were acute and
also measured sex steroids and other anterior pituitary hor- chronic illnesses, including neurological, psychiatric, metabolical, or
mones, and we assessed GH secretory responses to the single endocrine diseases, and use of the drugs mentioned above as exclusive
and combined administration of GHRH and GH-releasing for the patients.
peptide-2 (GHRP-2). In a second study, we investigated GH, PRL, TSH, and cortisol re-
sponses to GH secretagogues [random iv administration of a bolus of
GHRH (1 mg/kg), GHRP-2 (1 mg/kg), or GHRH plus GHRP-2 (1 plus
1 mg/kg)] in a comparable group of prolonged critically ill (15 male and
Subjects and Methods 15 female) patients (age, 67 6 9 yr), with each secretagogue group
Study design consisting of 5 men and 5 women carefully matched as described above
(Table 1). GH, PRL, TSH and cortisol concentrations were measured
In a first dynamic study, patterns of nocturnal GH secretion were before and 20, 40, 60, and 120 min after administration of the GH
compared in nine male and nine female patients experiencing prolonged secretagogues.
critical illness, matched for age (mean 6 sd age, 67 6 11 and 67 6 15 yr),
body mass index (25 6 4 and 29 6 7 kg/m2), type, severity (Apache II
score, 16 6 7 and 17 6 5), and duration (35 6 24 and 21 6 6 day) of illness, Ethical aspects
type and caloric load (27 6 6 and 27 6 7 Cal/kgz24 h) of continuously Informed consent was obtained from volunteers and from a first
administered feeding, blood glucose (7.1 6 0.7 and 7.7 6 2.2 mmol/L), degree relative of patients before inclusion. The study protocols were
and triglycerides (2.1 6 0.8 and 2.3 6 1.8 mmol/L) as well as any approved by the ethical review board of the University of Leuven School
concomitant medications (Table 1). Patients depending on intensive care of Medicine (Leuven, Belgium).
(including mechanical ventilatory support) for at least 2 weeks and with
an expected stay in the intensive care unit of at least another 2 weeks Blood sampling
were eligible for participation in this study. Further inclusion criteria
were a stable condition without dopamine treatment for at least 72 h, in Blood samples were collected through an arterial line inserted in
view of the pronounced suppressive effect dopamine exerts on GH patients for clinical purposes independently of this study. The Edwards
secretion in such patients (22). Exclusion criteria were age less than 18 VAMP system (Baxter Healthcare Corp., Irvine, CA) was used, which
yr; preexisting neurological, psychiatric, metabolic, or endocrine dis- permitted withdrawal of undiluted blood samples from an indwelling
ease; intracranial lesions; clinically significant liver failure (prothrombin catheter without undue blood loss. Healthy volunteers were sampled by
time, ,30%); renal failure requiring replacement therapy; concomitant venous puncture. Blood was collected into Vacutainer (Becton Dickinson
treatment with glucocorticoids, estrogens, somatostatin, thyroid hor- Vacutainer Systems Eur.; Meylan Cedex, France) tubes; after clotting
mones, Ca21 entry blockers, clonidine, amiodarone, etomidate, dopa- and centrifugation, the serum was kept frozen at 220 C until assay.
mine agonists, or antagonists; and the use of iodine in antiseptic dress-
ings or as iv contrast agents. Assays
GH secretion was quantified by deconvolution analysis of nocturnal
serum GH concentration time series (23) obtained by sampling blood Samples from the same patient were always processed within one
every 20 min between 2100 – 0600 h, and approximate entropy (ApEn) assay run. In the nocturnal profiles of the first study, the serum con-
was used as a measure of the irregularity of GH release patterns (24). In centrations of GH were measured by immunoradiometric assay (IRMA),
addition, mean nocturnal (2100 – 0600 h) PRL, TSH, and cortisol con- using the Nichols Institute Diagnostics hGH immunoassay 100T kit
centrations and mean (2100 – 0200 h) levels of IGFBP-1 were determined. (40 –2155, San Juan Capistrano, CA). The intraassay coefficient of vari-
Serum levels of GHBP, IGFBP-3, acid-labile subunit (ALS), IGFBP-2, and ation was 4.2% at 1.4 mg/L and 2.8% at 12.2 mg/L. The detection limit
 GENDER DIFFERENCE IN GH/IGF-I AXIS IN CRITICAL ILLNESS 185

of this immunoradiometric assay was 0.2 mg/L. In the second study (GH secretion (percentage) was calculated as the pulsatile production over
responses to GH secretagogues), GH was measured by RIA, using a 9 h divided by the total nocturnal GH production, multiplied by 100. In
polyclonal antibody (25). The intraassay coefficient of variation was 7.3% healthy humans, both males and females, more than 90% of GH is
at 6.7 mg/L and 4.6% at 14.4 mg/L. The detection limit was 1.2 mg/L. All released in a pulsatile fashion (28, 29).
processed samples had detectable GH values using these assays. As an approximate measure of IGF-I and ALS responsiveness to GH,
The serum concentrations of total IGF-I were measured by RIA, after the IGF-I/GH and ALS/GH ratios [either IGF-I (ALS)/total GH output
acid-ethanol extraction. The intraassay coefficient of variation was 10.1% ratio or IGF-I (ALS)/pulsatile GH ratio) were calculated, while recog-
at 95 mg/L and 5.5% at 474 mg/L. The between-assay coefficient of nizing that the dynamics of the two analytes, and the volume base on
variation was 14.8% at 109 mg/L and 10.1% at 389 mg/L. which their concentrations were calculated, are different.
Serum concentrations of IGFBP-1, IGFBP-2, IGFBP-3, IGFBP-6, and The regularity in the GH secretory pattern was quantified by the
ALS were determined by RIA, as previously described (26). ApEn statistic (24). ApEn measures the logarithmic likelihood that runs
The serum GHBP levels were measured by enzyme-linked immu- of patterns that are similar remain similar on next incremental compar-
nosorbent assay (DSL Kit, Diagnostics Systems Laboratories, Inc., Web- isons. ApEn assigns a single nonnegative number to a time series with
ster, TX). The intraassay coefficient of variation was 5.4% at 0.82 mg/L, larger values corresponding to greater irregularity. ApEn is stable to
1.8% at 3.83 mg/L, and 5.1% at 10.4 mg/L. small changes in noise characteristics and to infrequent and significant

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The serum TSH concentrations were measured by IRMA using the artifacts. It detects variations in episodic behavior not necessarily re-
TSH Riabead II (Abbott Laboratories, North Chicago, IL). The intraassay flected in changes in peak occurrences or amplitudes. Additionally,
coefficient of variation was 4.3% at 1.2 mIU/L and 2.2% at 7.0 mIU/L. ApEn provides a direct barometer of feedback system changes in many
The detection limit was less than 0.02 mIU/L. Normal nocturnal values coupled systems. The calculation of ApEn was performed as previously
ranged between 1–7 mIU/L. reported (24). As ApEn will generally increase with increasing process
The serum concentrations of PRL were measured by immunoradio- noise (and increasing intraassay variation), it is important to compare
metric assay using the PRL IRMA kit (Medgenix, Fleurus, Belgium). The datasets with similar assay coefficients of variation, as performed here.
intraassay coefficient of variation was 6.2% at 6.6 mg/L and 4.7% at 46.4 To this end, we used a tolerance/threshold for ApEn of 0.2 times the
mg/L. Normal values are less than 25 mg/L. individual series between-sample sd and a window/range of m 5 1
The serum concentrations of cortisol were measured by RIA after consecutive samples over which to test for pattern reproducibility, as is
extraction with dichloromethane. The intraassay coefficient of variation appropriate for time series of less than 150 samples (30). A normal
was 3.1% at 417 nmol/L. Normal morning values are 200 –700 nmol/L, mean 6 sd ApEn scores of 0.60 6 0.20 has been calculated for age-
and normal nocturnal values when asleep are less than 50 nmol/L. matched men, and a score of 0.81 6 0.23 has been calculated for age-
Serum concentrations of E2 were determined by a heterogeneous matched women (21).
competitive magnetic separation assay (Technicon Immuno 1 System, Results are presented as the mean 6 sd unless indicated otherwise.
Bayer Corp., Tarrytown, NY). The intraassay coefficient of variation was Single measurements were compared between males and females using
3.9% at 268 pmol/L (n 5 114). The detection limit was 37 pmol/L. unpaired Student’s t test, performed after log transformation if values
Normal mean 6 sd (median and ranges) values are 74.5 6 28.1 (72.4 and were nonnormally distributed or with a one-way ANOVA with post-hoc
8.2–146) pmol/L for age-matched men and 71.8 6 30.1 (57.2 and 10.5– Fisher’s protected least significant difference testing when appropriate.
104) pmol/L for age-matched women (21). Analysis of the effects of gender and critical illness (and the interaction
Serum concentrations of E1 were determined by RIA (DSL-8700 Es- between these two factors) was performed using a two-way ANOVA.
trone RIA kit, Diagnostics Systems Laboratories, Inc.). The intraassay Linear regression analysis was used to evaluate relationships between
coefficient of variation was 5.6% at 376 pmol/L (n 5 10). The detection paired measures of interest. The changes over time (increments above
limit was 4.4 pmol/L. Normal values for age-matched men and women baseline) in response to GH secretagogues were compared using re-
range between 52–379 pmol/L, with a median of 120 pmol/L. peated measures ANOVA. P , 0.05 was construed as significant.
The serum DHEAS concentrations were measured by RIA using the
DSL DHEAS RIA Kit (Diagnostics Systems Laboratories, Inc.). The in- Results
traassay coefficient of variation was 5.1% at 0.6 mmol/L and 4.1% at 6.1
mmol/L. The detection limit was 0.05 mmol/L. Normal values in men Study 1 (Table 2 and Figs. 1– 6)
range between 2–10 mmol/L and in women between 3–12 mmol/L.
Serum concentrations of androstenedione and testosterone were de- GH secretory pattern. Critically ill men and women presented
termined by RIA, as previously described (27). Normal values for tes- with comparable mean nocturnal GH concentrations, GH
tosterone in men range between 9 –35 nmol/L (mean, 16.2 nmol/L) (21) half-life, total nocturnal pituitary GH output, and number of
and in women between 0.5–3 nmol/L (mean, 1.3 nmol/L) (21). GH pulses over the studied 9 h (Table 2). In contrast, men had
a lower fraction of GH released in a pulsatile fashion com-
Data analysis pared with women (and conversely a higher nonpulsatile
The time series of sequential serum GH concentrations measured component; Figs. 1 and 2). In addition, men released GH with
overnight was transformed into pituitary secretion profiles by adjusting more irregularity than women, as indicated by a higher
for endogenous GH half-life using multiple parameter deconvolution ApEn (Table 2).
analysis (23). This method is designed to compute hormonal half-life and
the number, amplitude, and mass of underlying pituitary secretory IGF-I and ternary complex IGFBPs. Serum IGF-I, IGFBP-3, and
bursts and to estimate tonic (basal or nonpulsatile) secretion (23). Besides ALS levels were low in patients compared with controls (Fig.
mean serum concentrations, the following parameters were calculated
for each hormonal profile in each subject: basal secretion rate (estimated 3), with a gender difference in IGF-I and ALS (men had lower
as the amount of hormone continuously released from the pituitary to values than women) in the face of critical illness (Table 2 and
achieve serum concentrations approximating the mean of the lowest 5% Fig. 3). The serum concentrations of IGF-I and ALS normal-
of all serum GH values observed [micrograms per L of distribution ized per total amount of GH released in male patients were
volume (Lv) and per min], amplitudes (maximal secretory rate; micro-
only half those observed in female patients, whereas IGF-I
grams per Lv and per min) and temporal positions of all secretory bursts,
mass of hormone secreted per burst (estimated as the area of the resolved and ALS normalized per amount of pulsatile GH secretion
secretion burst; micrograms per Lv), and pulsatile production (calcu- were identical in both genders (Fig. 2). Correspondingly,
lated as the product of the number of secretory bursts and the mean there was a positive correlation between circulating IGF-I
secretory burst mass over the time interval considered; micrograms per and ALS levels and pulsatile (but not nonpulsatile) GH se-
Lv over 9 h). Total nocturnal GH production (micrograms per Lv) was
calculated as the sum of pulsatile GH production (micrograms per Lv) cretion (Fig. 4).
over 9 h and the nonpulsatile GH secretion over 9 h [basal GH secretion Age was negatively correlated, in both patients and con-
rate (micrograms per Lv/min) 3 540 min]. The proportion of pulsatile trols, with serum levels of IGF-I (r 5 20.81; P , 0.0001 and
186 VAN DEN BERGHE ET AL. JCE & M • 2000
Vol 85 • No 1

TABLE 2. Results from all measurements (mean 6 SD) in male and female patients

Female patients Male patients

P value
(mean 6 SD) (mean 6 SD)
Study I n59 n59
Mean (2100 – 0600 h) GH conc. (mg/L) 1.6 6 1.2 1.8 6 0.7 0.7
GH half-life (min) 16.5 6 3.7 17.1 6 5.5 0.7
Total GH output (mg/Lv) z 9 h 38.2 6 29.4 39.9 6 15.2 0.9
No. of GH pulses z 9 h 5.7 6 1.3 5.3 6 1.5 0.5
Pulsatile GH production (mg/Lv) z 9 h 22.3 6 13.5 15.5 6 7.9 0.1
% Pulsatile GH secretion 67 6 20 39 6 14 0.002
Nonpulsatile GH release (mg/Lv) z 9 h 15.9 6 19.5 24.4 6 12.1 0.05
% Nonpulsatile GH release 33 6 19 61 6 14 0.002
GH ApEn 0.805 6 0.147 0.946 6 0.113 0.02
GHBP (mg/L) 2.73 6 2.59 2.61 6 1.25 0.9

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IGF-I (mg/L) 117 6 50 81 6 40 0.01
IGF-I (mg/L)/total GH output (mg/Lv) 4.6 6 2.6 2.3 6 1.4 0.019
IGF-I (mg/L)/pulsatile GH production (mg/Lv) 6.9 6 3.4 6.5 6 3.8 0.8
ALS (mg/L) 7.4 6 3.8 5.1 6 2.7 0.005
ALS (mg/L)/total GH output (mg/Lv) 0.31 6 0.21 0.15 6 0.09 0.027
ALS (mg/L)/pulsatile GH production (mg/Lv) 0.46 6 0.29 0.39 6 0.21 0.6
IGFBP-3 (mg/L) 2.5 6 0.9 2.3 6 0.7 0.6
IGFBP-1 (mg/L), mean nocturnal 30.3 6 21.2 37.1 6 24.9 0.5
IGFBP-2 (mg/L) 898 6 502 1024 6 418 0.6
IGFBP-6 (mg/L) 593 6 234 636 6 239 0.5
Mean nocturnal PRL (mg/L) 24 6 18 863 0.009
Mean nocturnal TSH (mIU/L) 1.59 6 1.51 0.77 6 0.63 0.08
Mean nocturnal cortisol (nmol/L) 483 6 110 403 6 178 0.07
E2 (pmol/L) 224 6 89 246 6 133 0.7
E1 (pmol/L) 397 6 266 397 6 318 0.99
Androstenedione (nmol/L) 4.29 6 2.02 4.74 6 3.32 0.7
Testosterone (nmol/L) 0.97 6 0.39 2.25 6 1.94 0.03
DHEAS (mmol/L) 1.2 6 1.3 1.2 6 1.0 0.9
P values indicate the level of significance of the gender differences as determined by unpaired Student’s t test or by one-way ANOVA with
post-hoc testing using Fisher’s protected least significant difference test when appropriate.

double the control values (P , 0.0001) without an effect of

gender (Fig. 3). Serum IGFBP-2 was positively correlated to
IGFBP-1 (r 5 0.57; P 5 0.01) and inversely correlated to IGF-I
(r 5 20.50; P 5 0.03), IGFBP-3 (r 5 20.51; P 5 0.03), ALS (r 5
20.56; P 5 0.01).
Serum IGFBP-6 concentrations in patients were higher
than values in matched controls (P , 0.0001) without an
effect of gender (Fig. 3). Serum IGFBP-6 levels were unrelated
to any other studied endocrine parameter.
In healthy controls, IGFBP-2 (r 5 0.43; P , 0.0001) and
IGFBP-6 (r 5 0.30; P 5 0.003) correlate to age, as did mean
nocturnal IGFBP-1 levels in the patients (r 5 0.67; P 5 0.002).
FIG. 1. The more feminized pattern of GH secretion (more irregular
and less pulsatile GH secretory pattern for an identical mean noc-
turnal GH level) in critically ill men compared to women is illustrated GHBP. Serum GHBP levels were higher in patients than
by the representative nocturnal (2100 – 0600 h) GH serum concen- controls (2.67 6 1.97 vs. 1.95 6 1.16 mg/L; P 5 0.03) without
tration series (sampling every 20 min) obtained in one male (squares) a detectable gender difference (Table 2 and Fig. 3). In criti-
and one matched female (circles) patient. cally ill female patients, GHBP levels were positively corre-
r 5 20.32; P 5 0.001, respectively), IGFBP-3 (r 5 20.85; P , lated to mean nocturnal GH concentrations and to nonpul-
0.0001, and r 5 20.21; P 5 0.03, respectively) and ALS (r 5 satile GH release, but not to pulsatile GH secretion (Fig. 5).
20.81; P , 0.0001 and r 5 20.38; P 5 0.0001, respectively).
Other anterior pituitary hormones and steroids. Measured in a
Other IGFBPs. Mean nocturnal serum IGFBP-1 concentra- single daytime sample, PRL levels were 5-fold higher in
tions (measured with blood glucose clamped below 9 patients than in controls (mean 6 sd, 22 6 23 vs. 4 6 3 mg/L;
mmol/L) were not detectably different (37 6 24 vs. 30 6 21 medians, 15 vs. 3 mg/L; P , 0.0001) without a gender dif-
mg/L; P 5 0.5) in male and female patients and correlated ference in healthy subjects, but with critically ill men reveal-
inversely with circulating levels of IGF-I (r 5 20.63; P 5 ing lower mean nocturnal (Table 2) and single daytime PRL
0.005), IGFBP-3 (r 5 20.58; P 5 0.01), and ALS (r 5 20.62; concentrations (median, 10 vs. 21 mg/L; P 5 0.01) than sick
P 5 0.006) and tended to relate positively to ApEn (r 5 0.45; women. In patients, PRL was positively correlated to max-
P 5 0.06). imal nocturnal GH concentration (r 5 0.77; P 5 0.0002), GH
Serum IGFBP-2 concentrations in patients were more than pulse amplitude (r 5 0.21; P 5 0.05), and mass (r 5 0.61; P 5
 GENDER DIFFERENCE IN GH/IGF-I AXIS IN CRITICAL ILLNESS 187

testosterone and E2 (r 5 0.76; P 5 0.017) correlated positively

with GH pulse amplitude (Fig. 6).

Endocrine parameters and outcome. Four of 9 male and 3 of 9

female patients died. Among all of the studied endocrine
parameters, serum IGFBP-1 concentration and GH half-life
were the only parameters related to outcome; IGFBP-1 con-
centrations were higher (P 5 0.01) in nonsurvivors (49 6 21
mg/L) compared to survivors (23 6 18 mg/L) in the presence
of identical (clamped) blood glucose levels. GH half-life was
longer (P 5 0.01) in nonsurvivors (20 6 5 min) compared to
survivors (15 6 3 min).

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Study 2 (Fig. 7)
The peak serum GH concentration responses (increments
above baseline) to GHRH were relatively low (31) and sta-
tistically identical (P 5 0.99) in men and women (mean peak
GH increment, 7.3 6 9.4 vs. 7.8 6 4.1 mg/L; Fig. 7). In contrast,
the GH responses to GHRP-2 in women (mean peak GH
increment, 93 6 38 mg/L) were supranormal (31) and much
higher (P , 0.0001, respectively) than those in men (mean
peak GH increment, 28 6 16 mg/L). Combining GHRH with
GHRP-2 eliminated this gender difference (P 5 0.4); both
men (mean peak GH increment, 77 6 58 mg/L) and women
(mean peak GH increment, 120 6 69 mg/L) revealed sub-
stantially elevated peak GH responses compared to healthy
subjects (31).
Apart from a slightly higher incremental rise in PRL in
women in response to GHRH plus GHRP-2 (7.01 6 2.87 vs.
2.68 6 3.13 mg/L; P 5 0.03), the PRL, TSH, and cortisol
responses to the GH secretagogues were comparable in both
genders (Fig. 7).

FIG. 2. Protracted critically ill men reveal a lower pulsatile GH frac-

Discussion
tion despite an identical total GH output compared to sick women. Protracted critical illness was previously characterized by a
This was associated with a lower serum IGF-I and ALS normalized
blunted and irregular pattern of GH secretion, due to reduced
for total GH output (micrograms per L IGF-I and ALS per mg/Lv GH
release), but an identical serum IGF-I and ALS normalized for pul- hypothalamic stimulation, possibly involving the putative en-
satile GH secretion (micrograms per L IGF-I and ALS per mg/Lv GH dogenous GHRP-like ligand, along with low levels of IGF-I and
release). Results are presented as the mean 6 SEM. P values were ALS and impaired anabolism (2–6, 32). The current comparison
obtained with unpaired Student’s t test. between matched male and female patients with protracted
critical illness revealed that despite a similar total nocturnal GH
0.008) and inversely correlated to GH ApEn (r 5 20.60; P 5 output and an identical GH pulse frequency and GH half-life,
0.009). Mean nocturnal cortisol and TSH levels also tended male patients presented with an even more irregular pattern
to be lower in sick men than women (Table 2). and a more profoundly suppressed pulsatile fraction of GH
Serum levels of E2 and E1 were positively interrelated (r 5 release than female patients and concomitantly lower IGF-I and
0.64; P 5 0.006) and more than 3-fold elevated in male and ALS levels. The GH responses to bolus administration of
female patients (Table 2) compared to age-matched healthy GHRH, GHRP, and the combination of both releasing factors
subjects (mean 6 sd E2 value, 74.5 6 28.1 pmol/L for healthy indicated that at least part of this gender dissociation originates
age-matched men and 71.8 6 30.1 pmol/L for age-matched within the GHRH response pathway, with critically ill men
women) (21). Serum androstenedione concentrations were revealing a lesser GHRH effect than women. The pronounced
high normal and comparable in men and women, whereas hypoandrogenism in protracted critically ill men is thought to
serum levels of DHEAS and testosterone were low in both play a role.
genders (Table 2). Serum testosterone levels in male patients, The less pulsatile and more irregular, and therefore more
although statistically slightly higher than those in females, ‘feminized’ (13, 14, 21, 33), pattern of GH secretion paradox-
were only 13.8% of the normal mean for age-matched men ically observed in male patients was striking. It could be
(21), reflecting pronounced hypoandrogenism. hypothesized that the exaggerated nonpulsatile (vs. pulsa-
Circulating E2 and GH half-lives were positively interre- tile) GH secretion in critically ill men is due to reduced
lated (r 5 0.49; P 5 0.04). In men only, serum testosterone inhibitory somatostatin tone between pulses. Indeed, in ex-
levels (r 5 0.91; P 5 0.0008) and the molar ratio between perimental animals intermittent somatostatin suppression of
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FIG. 3. Effects of gender and critical illness on serum concentrations of IGF-I, IGFBP-3, ALS, IGFBP-2, IGFBP-6, and GHBP. Results are
presented as the mean 6 SD. Open bars represent males, and filled bars represent females. P values were determined using a two-way
(male/female and patient/control) ANOVA. Protracted critically ill patients have low circulating levels of IGF-I, IGFBP-3, and ALS and high
levels of GHBP, IGFBP-2, and IGFBP-6 compared to controls. A gender difference in IGF-I was evoked by protracted critical illness. ****, P ,
0.0001; ***, P , 0.001; **, P , 0.01 (determined by one-way ANOVA with post-hoc testing for multiple comparisons using Fisher’s protected
least significant difference test).

FIG. 4. Circulating IGF-I and ALS levels during protracted critical illness correlated positively with pulsatile, but not with nonpulsatile, GH
secretion in both genders.

the somatotropes determines the depth of the troughs and rather than to determine nonpulsatile GH release (35, 36).
the frequency of GH pulses (34). In the human, however, Therefore, in the face of reduced somatostatin tone, higher
somatostatin seems to primarily blunt GH pulse amplitude GH pulses would be anticipated (35) as well as a more pro-
 GENDER DIFFERENCE IN GH/IGF-I AXIS IN CRITICAL ILLNESS 189

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FIG. 6. Only in male patients was GH pulse amplitude positively
correlated with serum testosterone concentrations and with the molar
ratio between circulating testosterone and estradiol.

may explain the relatively smaller amount of GH released in

pulses in critically ill men than women.
The higher GH ApEn scores in critically ill men indicate a
more irregular GH secretory pattern and, inferentially, less syn-
chrony between somatostatin withdrawal and GHRH release
(12). This also is a feminine characteristic of the GH axis, as
FIG. 5. Serum GHBP concentrations seemed to be controlled differ- females, both rodents and healthy young and elderly humans,
ently in male and female critically ill patients. In female patients only, display greater irregularity in GH secretion than males (21, 12).
circulating levels of GHBP were significantly and positively corre- In both genders, disorderliness increases with age (38).
lated with mean GH concentrations and with nonpulsatile, but not Sex steroids are known to influence GH secretion. Estro-
with pulsatile, GH release.
gens stimulate GH release (39) directly through modulation
of both GH pulse frequency and amplitude in lower doses (40)
nounced GH response to the injection of GHRH (37), whereas as well as indirectly in higher doses, the latter by reducing IGF-I
the latter was found to be relatively low and equal in male negative feedback due to suppression of hepatic IGF-I synthesis
and female patients. The tendency for lower TSH concen- (41). Serum testosterone levels correlate with measures of GH
trations in critically ill men compared with women was in- secretion in healthy men (42, 43), and administration of andro-
deed not consistent with a reduced somatostatin effect. Al- gens selectively stimulates GH pulse amplitude and mass (43).
ternatively, as exogenous dopamine profoundly suppresses The effects of testosterone are thought to be at least partially
PRL, TSH, and GH pulses in critically ill patients (22), the mediated by aromatization to E2 (20, 44) and have been inter-
substantially lower PRL levels in sick men compared to preted as reflecting a relatively greater ratio of GHRH vs. so-
women and the positive correlation between PRL and the matostatin actions on responsive somatotropes (45). However,
size of the GH pulses as well as the regularity with which the tight correlation observed in the current study between GH
they occur may point to a dopaminergic mechanism. The pulse amplitude and levels of testosterone, but not E2, in men
results for critically ill women strongly indicated an endog- favor a direct suppressive effect of hypoandrogenism on pul-
enous GHRP-like ligand deficiency, with GHRH secretion satile GH secretion. The latter is in line with enhancement of
being maintained, as evidenced by the extremely high GH GHRH-induced GH release by testosterone in vitro (46). Estro-
responses to exogenous GHRP, but not to GHRH, when gens exert a negative effect on the regularity of GH secretion in
administered alone (31). The foregoing and the observation the human, inferentially by impairing the synchrony of firing
that adding a high dose of GHRH to the GHRP injection between somatostatin and GHRH neuronal networks (12). To
nullified the gender difference in the GHRP response, al- account for less orderly GH release in the ill men than women,
lowing men also to release supranormal amounts of GH reduced testosterone antagonism of estrogen and/or higher
during combined stimuli, could indicate that 1) critically ill sensitivity of the male hypothalamus to the estrogenized sex
men have less endogenous GHRH activity than women; and steroid environment during protracted critical illness could be
2) both genders have an inferred reduced GHRP-like ligand hypothesized.
availability with a potentially even greater deficiency in As high estrogen and low androgen levels were present in
women. This subtle difference in hypothalamic regulation both genders, however, an alternative explanation for the
190 VAN DEN BERGHE ET AL. JCE & M • 2000
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FIG. 7. Responses (increments above baseline) of GH, PRL, TSH, and cortisol obtained 20, 40, 60, and 120 min after iv bolus administration
of GHRH (1 mg/kg), GHRP-2 (1 mg/kg), and GHRH plus GHRP-2 (1 plus 1 mg/kg) in matched male and female protracted critically ill patients
are depicted. Five men and five women were randomly allocated to each secretagogue group. Results are presented as the mean 6 SEM. Circles
depict results from female patients, and squares show results from male patients. P values were obtained using repeated measures ANOVA.

observed gender dissociation in the GH/IGF-I axis could be myocardial infarction (55) in both male and female patients.
an intrinsic underlying difference in hypothalamic signaling In view of the hypogonadotropic hypogonadism in pro-
between men and women (e.g. lower endogenous GHRH tracted critical illness and the postmenopausal age of most of
effect in the male), which is only unveiled when the impact the studied women here, it is unlikely that the elevated
of sex steroids is identical. A tendency to equalize sex ste- estrogen levels originate from the gonads. Indeed, the find-
roids in men and women occurs in protracted critical illness, ing that serum concentrations of E2 and E1 are elevated
unlike in normal aging, where circulating testosterone levels proportionately is consistent with increased aromatase ac-
remain substantially higher in men (21). tivity either in adipose tissue or in muscle. The latter could
The mechanisms underlying the profound alterations in be explained by the concomitantly elevated cortisol (56) and
circulating sex steroids during critical illness remain incom- PRL (57) levels, by effects of endotoxin (58), endogenous
pletely understood. Leydig cell dysfunction and hypogona- catecholamines (59), and/or increased fat storage as a result
dotropism in critically ill men have repeatedly been reported of feeding during critical illness (1, 60). Conversely, altered
(2, 47–53). Elevated levels of E2 and E1 have been previously pulsatility of GH secretion could contribute to changes in
documented in sepsis (52), in burn injury (54), and after hepatic steroid metabolism (61– 63).
 GENDER DIFFERENCE IN GH/IGF-I AXIS IN CRITICAL ILLNESS 191

A less pulsatile and more disorderly GH secretory pattern for Acknowledgments

a comparable mean serum GH concentration appeared to de- We thank the medical and nursing staff of the Intensive Care Unit for
termine more severely impaired somatotropic GH effects, as their cooperation, in particular Drs. M. Schetz, C. Verwaest, D. Vlas-
evidenced by lower serum IGF-I and ALS concentrations in selaers, P. Ferdinande, P. Vranckx, L. De Bolle, J. Hermans, S. Allaert,
male compared to female patients. Indeed, IGF-I and ALS cor- and C. Ingels for the clinical patient management. Dr. J. Billen is ac-
knowledged for the TSH and estrogen determinations. We thank Sri
related positively with pulsatile, but not with nonpulsatile, GH Meka, Kevin Hardman, Paula Azimi, Viviane Celis, Tina Schreurs,
production. These data support the hypothesis that in the hu- Myriam Smets, Christiane Eyletten, Marianne Aerts, Marleen Foriers,
man distinct components of the pulsatile signal are involved in and Willy Coopmans for expert technical assistance. We thank Dr. Je-
diverse biological GH effects, as shown in rodents (15). hangir Mistry (Diagnostic Systems Laboratories, Inc., Webster, TX) for
In contrast with the low GHBP levels observed in acute the donation of the GHBP enzyme-linked immunosorbent assay kits,
and Mr. J. Hellers (Baxter, Belgium) for generously providing the Vamp
stress (64), the prolonged critically ill patients studied here systems. Drs. J. Victor, A. Mirzabekiantz, B. Meyns, A. Creemers, and
displayed 37% higher GHBP levels than matched controls. P. J. Durnez and Mr. F. Vandenbussche and E. Vanderheyden are es-
Assuming that serum concentrations of GHBP reflect GH pecially acknowledged for their help with the collection of samples from

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receptor expression in peripheral tissues, as has been dem- healthy matched volunteers. We also thank the senior members of the
Royal Pharmacists Association of Antwerp for the willingness to par-
onstrated in the acute catabolic state evoked by elective sur- ticipate in the healthy control study.
gery (64), this observation is consonant with our earlier find-
ing of recovered responsiveness of IGF-I and ALS to References
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