0021-972X/01/$03.00/0
6
The Journal of Clinical Endocrinology & Metabolism
Copyright © 2001 by The Endocrine Society
Increased Vasopressin and Adrenocorticotropin
Responses to Stress in the Midluteal Phase of the
Menstrual Cycle
MARGARET ALTEMUS, CATHERINE ROCA, ELISE GALLIVEN,
CATHERINE ROMANOS, AND PATRICIA DEUSTER
Department of Psychiatry, Weill Medical College, Cornell University (M.A., C.R.), New York, New York
10021; Behavioral Endocrinology Branch, National Institute of Mental Health, National Institutes of
Health (C.R.), Bethesda, Maryland 20892; and Department of Military and Emergency Medicine,
Uniformed Services University of the Health Sciences (E.G., P.D.), Bethesda, Maryland 20814
ABSTRACT
Accumulating evidence indicates that gonadal steroids modulate
functioning of the hypothalamic-pituitary-adrenal (HPA) axis, which
has been closely linked to the pathophysiology of anxiety and depres-
sion. However, the effect of the natural menstrual cycle on HPA axis
responsivity to stress has not been clearly described. In nine healthy
women, metabolic and hormonal responses to treadmill exercise
stress during the early follicular phase of the menstrual cycle, when
gonadal steroid levels are low, were compared with responses in the
midluteal phase of the cycle, when both progesterone and estrogen
levels are relatively high. Exercise intensity was gradually increased
C LINICAL OBSERVATIONS suggest that fluctuations in
reproductive hormones influence the course of de-
pression and anxiety disorders, but the biological mecha-
nisms that may mediate the effects of reproductive hormones
on emotional regulation have not been identified. Accumu-
lating evidence suggests that gonadal steroids modulate
functioning of the hypothalamic-pituitary-adrenal (HPA)
axis, which has been closely linked to the pathophysiology
of anxiety and depression. On the one hand, HPA axis re-
sponses to acute stress can reflect the sensitivity of the in-
dividual to a physical or emotional stress. On the other hand,
glucocorticoids secreted during stress may, in turn, act in the
central nervous system to regulate mood and other mental
processes (1). Glucocorticoids are also the primary endocrine
feedback signal for suppression of the HPA axis and nor-
adrenergic responses to stress (2– 4). Alterations in glucocor-
ticoid secretion and glucocorticoid receptor sensitivity are
postulated to play a role in the development of psychiatric
disorders (4) and the mechanism of action of antidepressant
medication (5, 6).
Our previous clinical studies have shown enhanced sen-
sitivity of the HPA axis to dexamethasone suppression and
increases in type II glucocorticoid receptor messenger ribo-
nucleic acid (mRNA) expression in circulating mononuclear
Received September 12, 2000. Revision received December 14, 2000.
Accepted December 23, 2000.
Address all correspondence and requests for reprints to: Dr. Margaret
Altemus, Box 244, Weill Medical College, Cornell University, 1300 York
Avenue, New York, New York 10021. E-mail: maltemus@mail.med.
cornell.edu.
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Vol. 86, No.
Printed in U.S.A.
over 20 min to reach 90% of each subject’s maximal oxygen consump-
tion during the final 5 min of exercise. Basal plasma lactate, glucose,
ACTH, vasopressin, oxytocin, and cortisol levels were similar in the
two cycle phases. However, in response to exercise stress, women in
the midluteal phase had enhanced ACTH (P ⬍ 0.0001), vasopressin
(P ⬍ 0.01), and glucose (P ⬍ 0.001) secretion. These findings suggest
that relatively low levels of gonadal steroids during the early follicular
phase of the menstrual cycle provide protection from the impact of
stress on the HPA axis. (J Clin Endocrinol Metab 86: 2525–2530,
2001)
cells during the early follicular phase of the menstrual cycle
relative to the midluteal phase (7). The study described here
was designed to test whether HPA axis responsivity to stress
is restrained in the early follicular, compared with the mid-
luteal phase of the menstrual cycle. Restrained HPA axis
reactivity in the early follicular phase would be expected as
a consequence of increased glucocorticoid receptor sensitivity.
We chose to deliver exercise as an HPA axis stressor across
the menstrual cycle because it is a reproducible, quantifiable
stressor that elicits neuroendocrine and metabolic responses
proportional to the intensity and duration of the exercise (8,
9). The relative intensity of the exercise can be standardized
across subjects who have different levels of physical condi-
tioning by setting each subject’s exercise intensity to elicit a
specific percentage of that individual’s maximal aerobic ca-
pacity (VO2max). Exercise stress stimulates release of cortisol,
ACTH, and vasopressin, which, in turn, promotes mobili-
zation of the energy stores needed to meet the exercise stress.
Subjects and Methods
Subjects
Nine healthy women participated in the study after giving written
informed consent. The protocol had been approved by the intramural
institutional review boards of the NIMH and the Uniformed Services
University of the Health Sciences. Subjects were recruited by local ad-
vertisements for paid participation in an exercise study. Subjects were
34.2 ⫾ 1.8 (range, 25– 42) yr of age. All subjects were Caucasian, were
in good physical health, had regular menstrual cycles, were nonsmokers,
and were not taking any medications other than vitamins. All subjects
completed a medical history and underwent a physical examination and
screening laboratory tests, including complete blood count, chemistry
panel, thyroid function tests, toxicology screen, urinalysis, and preg-
2526 ALTEMUS ET AL. JCE & M • 2001
Vol. 86 • No. 6

nancy test. No subject was suffering from anxiety disorders, depression,
or other mental illnesses, as assessed by a structured diagnostic inter-
view (10). No subject suffered from premenstrual dysphoric disorder, as
assessed by clinical interview and 3 months of daily mood ratings
(10, 11).
Experimental protocol
Exercise testing was performed in both the early follicular (3– 6 days
after the onset of menses) and midluteal (7–10 days after the LH surge)
phases of the menstrual cycle. Each woman determined the time of her
LH surge by using a home urine test kit (Clearplan Easy, Unipath Ltd.,
Bedford, UK). Four women performed the follicular phase exercise test
first, and five women started with the luteal phase exercise test. Five of
the nine subjects completed exercise testing within one menstrual cycle.
The other subjects required up to three cycles to complete testing due
to scheduling difficulties and failure to detect an LH surge needed for
scheduling of the luteal test.
Details of the exercise protocol have been reported previously (12).
Subjects were instructed not to eat on the morning before the exercise
tests and to abstain from caffeine and alcohol consumption and from
running or other strenuous activity during the 24 h before testing.
VO2max was determined once by a progressive treadmill exercise
protocol conducted to volitional exhaustion. Oxygen consumption and
carbon dioxide production during the maximal exercise test and the two
subsequent follicular and luteal exercise test sessions were measured
with a Metabolic Measurement Cart 2900c (SensorMedics, Inc., Yorba
Linda, CA). Electrocardiogram and heart rate were also monitored con-
tinuously during all exercise tests.
For the follicular and luteal exercise test sessions, subjects reported
to the laboratory between 0700 – 0800 h. On arrival, all subjects had an
iv catheter inserted into an antecubital vein and then consumed 5 mL/kg
BW water to ensure uniform hydration. The exercise test began 60 min
after the subject finished drinking. The treadmill exercise test consisted
of 5 min of exercise at 50% of VO2max, 5 min at 70%, a 2-min break for
blood drawing, another 5 min at 70%, and 5 min at 90% of VO2max.
Exercise intensities of 50%, 70%, and 90% of VO2max were enforced by
adjusting the slope and speed of the treadmill. The exercise was followed
by a cool-down period of 5 min at a minimal workload, then 35 min of
rest in a semirecumbent position. Expired oxygen and carbon dioxide,
electrocardiogram, and heart rate were monitored throughout the ex-
ercise test and for the first 15 min of the recovery period.
Subjects stood for at least 15 min before the first baseline blood sample
was drawn. Samples were collected before exercise (⫺10 and 0 min),
during exercise (⫹10 min), and immediately after exercise (⫹20 min) in
a standing position and subsequently (⫹30, ⫹40, ⫹50, and ⫹60 min) in
a semirecumbent position. Blood was collected into a syringe and dis-
pensed into chilled tubes containing ethylenediamine tetraacetate for
ACTH, cortisol, vasopressin, oxytocin, estradiol, and progesterone as-
says and into tubes containing heparin and fluoride for lactate and
glucose measurements. Chilled tubes were stored on ice until plasma
was separated by centrifugation at 4 C (within 30 min). Plasma for
ACTH, vasopressin, and cortisol determinations was stored frozen at
⫺80 C until assayed, whereas plasma for lactate, glucose, estrogen, and
progesterone determinations was refrigerated and assayed on the day
of the exercise test.
3-fold concentration during the extraction procedure. The intraassay
CVs were less than 10% for vasopressin and oxytocin. The interassay CV
for vasopressin was 13%. The detection limit was 0.60 pmol/L for
vasopressin and 1.0 pmol/L for oxytocin. Oxytocin levels were not
measured in one subject. Basal estradiol and progesterone were mea-
sured by RIA at the NIH Clinical Center Laboratory at the time of
exercise testing. The intraassay CVs were less than 5% for the estradiol
and progesterone assays. Detection limits were 37 pmol/L for estradiol
and 1.27 nmol/L for progesterone.
Statistical analyses
Data are presented as the mean ⫾ sem. Two-way repeated measures
ANOVA was used to investigate the effects of exercise and cycle phase
on hormonal variables. ACTH data were log transformed before the
ANOVA because the distribution among subjects was not normal. If
significant differences were indicated by ANOVA, post-hoc contrasts
were used to evaluate differences at each time point. Single time point
data were compared using two-tailed Student’s t-tests. Relationships
among variables were evaluated using Pearson’s correlation coefficient.
The area under the curve was used for correlational analyses of multiple
time point hormonal data and was calculated by the trapezoidal method
with subtraction of the baseline. Significance was set at the 0.05 level.
Results
Basal hormone levels
As expected, basal plasma estradiol and progesterone lev-
els were lower in the early follicular compared with the
midluteal phase of the menstrual cycle [estradiol, 242 ⫾ 48
vs. 580 ⫾ 48 pmol/L (P ⬍ 0.001); progesterone, 2.9 ⫾ 1.3 vs.
47.7 ⫾ 5.1 nmol/L (P ⬍ 0.0001)]. Basal plasma lactate, glu-
cose, ACTH, vasopressin, oxytocin, and cortisol levels were
similar in the early follicular and midluteal phases of the
cycle (Table 1).
Hormonal responses during exercise
Hormonal responses to exercise are shown in Fig. 1. In-
duction of anaerobic metabolism during exercise was indi-
cated by marked increases in plasma lactate levels over time
[F(6,48) ⫽ 29.3; P ⬍ 0.0001]; values did not differ between
phases of the menstrual cycle [F(6,48) ⫽ 0.94; P ⫽ 0.47].
As expected, there was a significant increase in ACTH
during the exercise test [F(7,56) ⫽ 12.2; P ⬍ 0.0001]. In ad-
dition, there was a significant interaction of ACTH response
with cycle phase [F(7,56 ⫽ 13.85; P ⬍ 0.0001], with the ACTH
response enhanced in the luteal phase.
A significant increase in vasopressin during the exercise
test was also found [F(7,56) ⫽ 5.8; P ⬍ 0.0001] along with a
significant menstrual cycle phase interaction [F(7,56) ⫽ 3.0;

Biochemical assays
TABLE 1. Basal hormone in the early follicular and midluteal
Plasma lactate and glucose concentrations were determined in du- phases
plicate (analyzer model 27, YSI, Inc., Yellow Springs, OH). The intra- and
interassay coefficients of variation (CVs) for lactate and glucose were less Variable Early follicular Midluteal
than 5%. ACTH, vasopressin, and cortisol were assayed in three batches,
ACTH (pmol/L) 2.78 ⫾ 0.57 2.66 ⫾ 0.96
with follicular and luteal samples from individual subjects run in the
Cortisol (nmol/L) 521 ⫾ 25 552 ⫾ 50
same batch to minimize effects due to interassay variation. All oxytocin
Vasopressin (pmol/L) 0.80 ⫾ 0.13 0.73 ⫾ 0.11
samples were run in one assay. Commercial RIA kits were used to
Oxytocin (pmol/L) 1.66 ⫾ 0.10 1.95 ⫾ 0.45
measure ACTH (immunoradiometric assay, Nichols Institute Diagnos-
Glucose (mmol/L) 5.0 ⫾ 0.3 5.2 ⫾ 0.3
tics, San Juan Capistrano, CA) and cortisol (Coat-a-Count, Diagnostic
Lactate (mmol/L) 1.0 ⫾ 0.1 0.9 ⫾ 0.1
Products, Los Angeles, CA). The limits of detection for these kits in our
Estradiol (pmol/L) 242 ⫾ 48 580 ⫾ 48a
laboratory are 0.55 pmol/L for ACTH and 27 nmd/L for cortisol. The
Progesterone (nmol/L) 2.86 ⫾ 1.27 47.7 ⫾ 5.09a
intraassay CV averaged 5% for cortisol and ACTH, and the interassay
CV was 12% for ACTH and 8% for cortisol. Arginine vasopressin and Values are the means ⫾ SEM.
oxytocin RIAs were performed as previously described (13, 14) with a a
P ⬍ 0.01.

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 ENHANCED MIDLUTEAL ARGININE VASOPRESSIN AND ACTH RELEASE 2527

FIG. 1. Hormonal and metabolic re-

sponses to 20 min of graded treadmill
exercise in the early follicular and mid-
luteal phases of the menstrual cycle.
ACTH, vasopressin, and glucose re-
sponses were significantly increased in
the midluteal phase by ANOVA. *, Sig-
nificant differences (P ⬍ 0.05) by post
hoc contrasts at single time points.

P ⬍ 0.01]. As noted for ACTH, the vasopressin response was
enhanced in the luteal phase.
As expected, a significant change in plasma glucose oc-
curred during the exercise [F(6,48) ⫽ 6.0; P ⬍ 0.0001]. As
noted for ACTH and vasopressin, there was a significant
interaction of glucose response to exercise and cycle phase
[F(6,48) ⫽ 2.5; P ⬍ 0.04], with exercise-induced glucose levels
being higher in the luteal phase.
There was only a trend toward an effect of exercise on
plasma cortisol release during the exercise test [F(7,56) ⫽ 2.2;
P ⬍ 0.06], and no interaction between the cortisol response
to exercise and cycle phase [F(7,56) ⫽ 1.1; P ⫽ 0.40]. There
also was no main effect of cycle phase on cortisol levels
[F(1,8) ⫽ 1.2; P ⫽ 0.29].
In contrast to the other metabolic and hormonal param-
eters, there was no effect of exercise on plasma oxytocin
[F(7,42) ⫽ 0.617; P ⫽ 0.74]. Moreover, oxytocin secretion was
not affected by cycle phase [F(1,6) ⫽ 0.016; P ⫽ 0.90], and
there was no interaction between the oxytocin response to the
exercise test and cycle phase [F(7,42) ⫽ 0.954; P ⫽ 0.48].
A significant positive correlation was found between basal
plasma progesterone and the AUC for both ACTH (r ⫽ 0.54)
and cortisol (r ⫽ 0.56) in the luteal phase. Basal estradiol
levels correlated positively with AUC for ACTH (r ⫽ 0.80),

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2528 ALTEMUS ET AL.
cortisol (r ⫽ 0.55), and glucose (r ⫽ 0.75) in the follicular
phase and the AUC for cortisol (r ⫽ 0.50) and glucose (r ⫽
0.82) in the luteal phase.
Discussion
We found increased ACTH, vasopressin, and glucose re-
sponses to treadmill exercise in the midluteal compared with
the early follicular phase of the menstrual cycle. The results
of this study are compatible with those of a few human
studies of HPA axis responsivity across the menstrual cycle,
including two studies that found increased cortisol response
to psychological stress in the luteal phase (15, 16), another
study that reported increased cortisol response to prolonged
(90-min) submaximal exercise in the luteal phase (17), and a
fourth study that found a significant rise in cortisol after 30
min of submaximal exercise stress only the in midluteal
phase of the cycle (18). However, many stress studies have
not found menstrual cycle-related differences in HPA axis
responsivity, including studies using intense (19) and mod-
erate physical exercise (20, 21), endotoxin infusion stress (22),
or psychological stressors (23, 24). The lack of a menstrual
cycle effect on ACTH secretion in an earlier exercise stress
study from our laboratory (21) and in an exercise study from
another laboratory (20), both using lower intensity exercise,
suggests that cycle phase differences in ACTH secretion are
evident only during high intensity exercise. Our use of nar-
row windows for timing of tests, our choice of testing times
to maximize differences in gonadal steroid levels, measure-
ment of ACTH and vasopressin secretion in addition to cor-
tisol secretion, and use of a relatively severe stress stimulus
may have increased our ability to detect these cycle-related
differences. Our finding of increased HPA axis responsivity
in the luteal phase parallels our previous report of enhanced
HPA axis responses to exercise in nonlactating postpartum
women compared with lactating women who are in a state
of relative gonadal steroid suppression (12).
The less robust cycle-related difference in cortisol secretion
in response to the exercise testing is surprising in light of the
enhanced ACTH and vasopressin responses in the luteal
phase, both of which stimulate cortisol secretion, and in light
of reports that adrenal sensitivity to ACTH is enhanced in the
luteal phase (16, 25). This discrepancy most likely is due to
the circadian fall in cortisol, which continued through the
early morning testing. The circadian fall completely ob-
scured any rise in plasma cortisol in response to the exercise
test in half of the subjects. In contrast, cortisol responses were
larger and more distinct in an exercise study that was per-
formed in postpartum women in our laboratory using the
same protocol but at midday, when ambient cortisol levels
are lower (12).
The physiological mechanism that produces the increase
in glucose level at baseline and throughout testing during the
luteal phase is unclear. An earlier study from our laboratory
using moderate intensity exercise during the follicular and
luteal phases of the cycle also demonstrated higher glucose
levels during the luteal phase (21). Another study noted the
typical drop in glucose in response to submaximal exercise
only in the luteal phase (17); this finding also suggests that
glucose responses to stress are enhanced in the luteal phase.
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JCE & M • 2001
Vol. 86 • No. 6
However, several other exercise studies found no difference
in glucose levels across the menstrual cycle (19, 26). Impair-
ment of glucose uptake and increases in fasting glucose in the
luteal phase have been described in two studies that more
directly focused on glucose regulation across the menstrual
cycle (27, 28). Increased glucose responsivity noted in the
luteal phase in our current study may be a consequence of
increased vasopressin and cortisol responses in the luteal
phase, as both of these hormones mobilize glucose. The lack
of cycle phase differences in glucose response in other studies
may result from less robust cycle-related differences in hor-
mones that mobilize glucose.
The failure of exercise to stimulate oxytocin release in
healthy women is consistent with the findings of other ex-
ercise and psychological stress studies (12, 29, 30). On the
other hand, massage (31) and breast stimulation in the luteal
phase (32) have been shown to provoke oxytocin release in
women. The lack of oxytocin response to exercise in women
stands in contrast to the oxytocin release in rats that occurs
in response to a wide variety of physiological stressors (33).
This species difference parallels observations that oxytocin
increases plasma ACTH release in rats (33) and inhibits
plasma ACTH release in humans (34, 35).
Menstrual cycle-related changes in several different reg-
ulatory elements of the HPA axis may contribute to the
increased HPA axis responsivity in the luteal phase. Perhaps
most important, gonadal steroids appear to regulate glu-
cocorticoid receptor activity in the limbic-hypothalamic-
pituitary-adrenal axis and are likely to thereby modulate
feedback sensitivity of the HPA axis. In a prior study using
the same sampling windows across the menstrual cycle, we
found decreased lymphocyte glucocorticoid receptor mRNA
expression in the midluteal compared with the early follic-
ular phase. Reduced glucocorticoid receptor mRNA expres-
sion in the luteal phase was accompanied by reduced sen-
sitivity to dexamethasone suppression of plasma cortisol (7).
Animal studies are consistent with these observations, show-
ing increases in HPA axis feedback sensitivity after ovari-
ectomy (36). Enhanced plasma vasopressin release in the
midluteal phase may also contribute to the enhanced ACTH
response found in the midluteal phase by stimulating pitu-
itary vasopressin receptors (37, 38). In addition, catechol-
amine activity is enhanced in the luteal phase (39, 40) and
may contribute to enhanced HPA axis responsivity. Central
serotonergic activity also may fluctuate across the menstrual
cycle and contribute to changes in HPA axis regulation
(41– 43).
Because of the naturalistic design of this study, it was not
possible to definitely sort out the differential effects of spe-
cific gonadal steroids on HPA axis responsivity. Both estra-
diol and progesterone levels correlated positively with at
least some components of HPA axis responsivity. Although
correlations between estradiol and HPA axis responses were
seen in both the follicular and luteal phases of the cycle,
progesterone levels all were close to the detection limit of the
assay in the follicular phase; this prevented any meaningful
associations with hormonal responses. Further studies using
specific estrogen and progesterone receptor antagonists or
single hormone replacement strategies in postmenopausal
 ENHANCED MIDLUTEAL ARGININE VASOPRESSIN AND ACTH RELEASE
women should help to clarify the roles of individual gonadal
steroid hormones in regulation of the HPA axis in humans.
Numerous studies of ovariectomized rats have found a
stimulatory effect of estradiol on HPA axis responsivity (44,
45) and an inhibitory effect of estradiol on HPA axis feedback
sensitivity (44, 46), but effects of progesterone on HPA axis
regulation are less clear (44, 45, 47– 49). Studies in ovariec-
tomized primates have shown that ACTH and cortisol re-
sponses to interleukin-1 challenge were enhanced during
replacement of late follicular compared with early follicular
levels of estradiol (50, 51). The effects of estrogen on HPA axis
responsivity in humans have been mixed, with increased
HPA axis responsivity after 1 day of estradiol treatment in
men (52), reduced responsivity after 6 – 8 weeks of estrogen
treatment in postmenopausal women (53, 54), and no effect
on HPA responses to stress after longer term treatment (55).
Also, a recent study in men showed that 24-h administration
of exogenous estrogen significantly enhanced HPA axis re-
sponses to interview stress. These effects of estrogen and
progesterone on HPA axis regulation may be mediated by
the effects of these gonadal steroids on glucocorticoid re-
ceptor feedback sensitivity. Preclinical data indicate that pro-
gesterone serves as an antagonist at glucocorticoid receptors
(56, 57) and that short-term estrogen treatment in ovariec-
tomized rats can down-regulate glucocorticoid receptors in
the hippocampus, hypothalamus, and pituitary (47, 58 – 60).
Preclinical data also indicate that estrogen may enhance the
magnocellular release of vasopressin. In rats ovariectomy
prevented the release of vasopressin into the systemic cir-
culation in response to salt loading and also attenuated the
induction of vasopressin mRNA expression in the magno-
cellular cells of the supraoptic and paraventricular nuclei of
the hypothalamus (61). In addition, arginine vasopressin
mRNA in the magnocellular division of the paraventricular
nucleus was increased in ovariectomized rats in response to
estrogen treatment (59).
Changes in HPA axis and plasma vasopressin responsivity
across the menstrual cycle may be linked to fluctuations in
mood and somatic symptoms. Multiple studies in nonclinical
populations have documented increases in irritability, anx-
iety, and depression symptoms in the mid- and late luteal
phases of the menstrual cycle (23, 62, 63). In addition, 3– 8%
of women are particularly sensitive to menstrual cycle hor-
monal changes and experience severe mood worsening in the
luteal phase, with significant impairment of social and oc-
cupational functioning (11, 63– 65). Suppression of HPA axis
activation during the follicular phase of the menstrual cycle
may be a reflection at least in part of suppression of central
neuropeptides that drive the axis, particularly CRH and
vasopressin. These peptides have arousal-producing, anxio-
genic effects and have been argued to play an important role
in the generation of depression and anxiety disorder symp-
toms (66). In addition, increased vasopressin responsivity in
the midluteal phase of the menstrual cycle may contribute to
subjective sensations of fluid retention premenstrually.
In summary, this study demonstrates suppression of HPA
axis and plasma vasopressin reactivity to exercise stress in
the early follicular compared with the midluteal phase of the
menstrual cycle. These findings in combination with prior
findings of reduced HPA axis and vasopressin responses to
Downloaded from jcem.endojournals.org by on July 26, 2009
2529
exercise in lactating women suggest that relatively low levels
of gonadal steroids in premenopausal women may reduce
the effects of stress on the HPA axis.
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