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OVERNIGHT
CORTICOTROPIN LEVELS
ELEVATED IN NOCTURNAL
ASTHMA
DENVER—Although
researchers have studied nocturnal asthma for years, little
is known about the hypothalamic-mediated or pituitary-mediated
changes in cortisol secretion that may contribute to nighttime
symptoms. Exogenous corticotropin-releasing hormone reportedly
improves overnight airflow, but no significant difference
in endogenous corticotropin levels has been observed between
asthma patients and nonasthmatic controls. In an attempt
to see how (or whether) the adrenal-pituitary axis differs
in patients with nocturnal asthma, a group of researchers
in Denver found that levels of corticotropin—but not
cortisol—are increased.[1]
Seven
patients with nocturnal asthma, 13 with nonnocturnal asthma,
and 11 nonasthmatic controls took part in the study. All
participants had an intravenous catheter in place for 24
hours, and blood was withdrawn every two hours to measure
plasma corticotropin and serum cortisol levels. Participants
also underwent low-dose corticotropin stimulation at 7 AM
to assess production of adrenal cortisol.
GROUP
DIFFERENCES OBSERVED
Patients
with nocturnal asthma had significantly lower FEV1 at bedtime
and a greater overnight decrease in FEV1 than did the other
two groups. All three groups experienced a similar circadian
pattern of peak and trough corticotropin and cortisol levels.
However, peak corticotropin levels were highest in the patients
with nocturnal asthma, and the difference in peak levels
between this group and the other two groups was significant
at 4 AM, 6 AM,
8 AM, and 10 AM.
In
contrast, peak cortisol levels were highest in the patients
with nonnocturnal asthma, and these levels were significantly
higher than those in patients with nocturnal asthma at 8
AM and 10 AM.
Neither
bedtime nor morning FEV1 correlated significantly with peak
corticotropin or cortisol levels. Thus, peak hormone levels
were not associated with degree of physiologic impairment.
After
low-dose corticotropin stimulation, there was no significant
between-group difference in cortisol levels in response
to treatment at any time. This finding surprised the investigators.
ADRENAL
GLAND NOT RESPONDING
Despite
the increased corticotropin levels in the patients with
nocturnal asthma, their adrenal glands did not respond with
an increase in serum cortisol. The investigators speculated
that this may be part of a response—either inhibitory
(in nocturnal asthma) or enhanced (in nonnocturnal asthma)—to
the increase in corticotropin.
“Our
study suggests that in people with nocturnal asthma, the
body is trying to increase endogenous cortisol levels
by increasing corticotropin levels,” said E. Rand Sutherland,
MD, MPH, Assistant Professor of Medicine at National Jewish
Medical and Research Center and the University of Colorado
Health Sciences Center, both in Denver. Although corticotropin
levels are increased, he explained, “the adrenal gland
is not responding. There appears to be a deficit in the
adrenal response.”
Interestingly,
peak and trough cortisol concentrations occurred about 90
minutes earlier in the patients with nocturnal asthma than
in the other two groups. The 90-minute phase advance could
theoretically have affected the patients’ response
to corticotropin stimulation in the early morning hours.
But, it is also possible that because of phase advance,
the increase in endogenous corticotropin at 7 AM
was already fully stimulating the patients’ adrenal
glands and thus no differences would be detectable. However,
Dr. Sutherland remarked, even though the dose of corticotropin
used was low, it was still greater than what is normally
found in the body; this comparatively high dose could have
served to diminish the investigators’ ability to detect
between-group differences.
The
90-minute phase advance in cortisol levels has a second
implication, he added. It could in part explain why chronotherapeutic
dosing with corticosteroids improves nocturnal asthma symptoms.
TIMING
IS EVERYTHING
In
a Brazilian study,[2] patients with nocturnal asthma were
given either 1,000 µg of fluticasone, 1,000 µg of
beclomethasone, or placebo as a single dose at 4 PM.
The dosing was alternated weekly for three weeks, so that
all patients got all three treatments.
After
placebo administration, the mean overnight decrease in FEV1
was 0.65. After fluticasone use, it was –0.02, and
after beclomethasone treatment, 0.23. Both of the results
obtained with the corticosteroids were significantly different
from those attained with placebo; there was no significant
difference between the results achieved with the corticosteroids.
This
demonstrated that a single dose of inhaled corticosteroids
given late in the afternoon was enough to prevent nocturnal
worsening of asthma. The authors proposed that the benefit
was due to a direct effect of corticosteroids on the lungs
rather than a systemic effect. In addition, they noted,
the acute effects of inhaled corticosteroids correlate with
long-term improvement in symptoms.
Dr.
Sutherland also stressed the importance of timing the dosing
of medications in patients with nocturnal asthma so they
will be effective at around 3 or 4 AM,
when the increase in corticotropin levels begins. “For
example,” he said, “oral corticosteroids should
be taken late in the afternoon, and long-acting ß-agonists
should be timed so that they will be effective through the
night.”
Still,
“we need to establish the mechanism by which the adrenal
gland is not responding to corticotropin,” Dr. Sutherland
concluded.
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Melatonin
May Affect Nocturnal Asthma
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DENVER—While
the mechanisms of nocturnal asthma remain unclear,
data from the National Jewish Medical and Research
Center’s study of the adrenal-pituitary axis
have identified another potential cause of nocturnal
asthma symptoms: melatonin.[1]
Twenty-four–hour serum melatonin levels were
studied in seven patients with nocturnal asthma, 13
with nonnocturnal asthma, and 11 healthy controls.
Peak melatonin levels were significantly higher in
the patients with nocturnal asthma than in either
of the other two groups. Additionally, peak melatonin
levels were significantly and inversely correlated
with overnight change in FEV1 in the nocturnal asthma
group but not in the other two groups.
In patients with asthma, melatonin is proinflammatory,
increasing the production of interleukin 1, interleukin
16, and tumor necrosis factor alpha. The authors suggested
that systemic corticosteroids may alter the melatonin
circadian rhythm—a possible reason why corticosteroids
given at the appropriate time of day reduce symptoms
in nocturnal asthma.
The authors also observed that melatonin is used
by many people as a sleep aid. In patients with nocturnal
asthma, taking melatonin supplements could worsen
nocturnal symptoms. They noted that until further
studies have been performed on the clinical effects
of melatonin on asthma, patients with nocturnal asthma
should refrain from using it.
—Gale Jurasek
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Reference
1. Sutherland ER, Ellison MC, Kraft M, Martin RJ.
Elevated serum melatonin is associated with the nocturnal
worsening of asthma. J Allergy Clin Immunol.
2003;112:513-517.
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—Gale
Jurasek
References
1. Sutherland ER, Ellison MC, Kraft M, Martin RJ. Altered
pituitary-adrenal interaction in nocturnal asthma. J
Allergy Clin Immunol. 2003;112:52-57.
2. Frezza G, Terra-Filho J, Martinez JAB,
Vianna EO. Rapid effect of inhaled steroids on nocturnal
worsening of asthma. Thorax. 2003;58:632-633.
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