Chronic migraine (CM) is a
débilitating disorder that affects 2.4%
of the general population and accounts for most
consultations in headache clinics 40% to 65%.
Because CM affects people during their peak
productive years, it imposes a significant
decrease in their quality of life and
considerable economical burden to society.
Patients with CM often have a history of
episodic migraine beginning in their teenage
years. The headache frequency increases over
months or years, and the associated symptoms of
nausea, vomiting, photophobia, and phonophobia
become less prominent. Chronic migraine is a
complex: syndrome with many associated
conditions including acute medication overuse,
generalised anxiety disorder (70%), major
depression (80%), and insomnia (71%).
Little is known about the causes and
mechanisrns of CM. The transformation of
episodic migraine to CM (> 15 days/month)
remains an enigma. Several mechanisms have been
alleged to be the cause of the change in
frequency and symptoms, including chronic
neurogenic inflammation central sensitisation,
defective central pain modulation, hypothalamic
dysfunction, or a combination of these.
Hypothalamic involvement in the pathogenesis
of cluster headache is well known,whereas the
role of the hypothalamus in the pathophysiology
of chronic migraine has never been studied. For
this reason we chose to explore the
hypothalamic-tuber-infundibular system
(prolactin, growth hormone), the hypothalamic
hypophyseal-adrenal axis (cortisol), and pineal
gland function (melatonin) in CM.
[...]
Discussion
Prolactin, growth hormone, cortisol, and
melatonin concentrations were determined every
hour for 12 hours to investigate the role of the
hypothalamus in chronic migraine. The hormones
were measured during the night as the highest
concentrations are usually at this time. We
found decreased prolactin peak secretion,
increased cortisol concentrations, a phase delay
in the melatonin peak, and lower melatonin
concentrations in patients with CM with
insomnia.
MELATONIN Lower melatonin
concentrations have been reported in episodic
migraine, menstrual migraine, and cluster
headache. This is the first study of melatonin
in patients with CM. Forty seven per cent of
patients with CM had a significant phase delay
in the melatonin peak, and half had insomnia.
Melatonin concentrations, peak secretion, and
AUCs were significantly lower in patients with
CM who had insomnia than in controls and
patients with CM without insomniaLower melatonin
concentrations, but not a phase shift in the
nocturnal peak, have been reported in patients
with insomnia. A phase delay in the nocturnal
melatonin peak has been reported in patients
with delayed sleep phase syndrome (DSPS), and
these patients treated with 5 mg melatonin had a
great improvement of both sleep and its
associated headaches.
The circadian rhythm of melatonin secretion
is regulated by the suprachiasmatic nucleus in
the hypothalamus. The phase delay in the
melatonin peak found in patients with CM
supports the theory that hypothalamic
involvement in CM leads to a chronobiological
dysfunction; however, it is not known whether it
is a cause or a consequence of the disease. It
could also be due to an underlying delayed sleep
phase syndrome and other sleep disorder
comorbidity.
Melatonin is a potent endogenous scavenger of
reactive oxygen species acting as a
neuroprotective agent in processes involving
free radical formation and excitatory amino acid
release. Evidence in laboratory animals shows
that this neuroprotective action is probably
mediated through inhibition of NF-kappaB, a
peptide upstream of tumour necrosis factor
(TNFalpha), which is known to be involved in
inflammatory processes and sensitisation. It is
hypothesised that dysfunction in melatonin
secretion can favour sensitisation and
persistence of inflammatory products. Melatonin
receptors have also been found in cerebral
arteries and in the hypothalamus.
Melatonin may have a role in the treatment of
CM, particularly in those patients with
insomnia, but further studies are necessary to
confirm this. Its other favourable qualities for
CM treatment include its analgesic properties,
and the fact that it potentiates a GABA
inhibitory effect and inhibits prostaglandin E
synthesis. Melatonin is a sensitive marker of
endogenous rhythms24 and is thought to play an
important part in the adaptative mechanisms to
changing enviromental and endogenous stimuli
PROLACTIN Patients with chronic
migraine show a decreased nocturnal prolactin
peak. Studies have reported normal prolactin
values in episodic migraine, but none of them
analyzed the nocturnal prolactin profile. This
is the first study on prolactin concentrations
in CM.
Based on the hypersensitivity of dopamine
receptors that some migraineurs manifest,
modulating dopaminergic neurotransmission has
been a therapeutic target. This is demonstrated
by the induction of yawning, nausea,
vomiting, and hypotension by dopaminergic
agonists. In addition, some migraineurs show
allelic variations within the DRD2 gene that has
been hypothesised to predispose to a
hypersensitive state to dopamine. Prolactin
secretion is one measure of dopaminergic
function, as dopamine is its main inhibitory
factor. The measurement of prolactin can
indirectly provide information on the
dopaminergic system in CM.
We hypothesise that there is a sustained
nocturnal inhibition of prolactin by dopamine
and, therefore, an indirect increase in dopamine
secretion. Many antidopaminergic agents have
been successfully used in acute (droperidol,
chlorpromazine, prochlorperazine,
metoclopramide, domperidone, haloperidol), and
preventive (flunarizine, olanzapine) headache
treatment. Our findings support the use of these
drugs in CM, but clinical trials are needed to
confirm their efficacy.Tumour necrosis
factor-alpha, a potent proinflammatory cytokine
involved in pain andinflammatory disorders such
as multiple sclerosis, psoriasis, meningitis,
and migraine,has been shown to inhibit prolactin
release. Its algesic effects are due to
sensitising actions on nociceptive afferents,
upregulation of other proinflammatory and
algesic proteins, and a triggering of
cyclooxygenase dependent pathways to synthesise
prostaglandins. If we consider neurogenic
inflammation as part of the pathogenesis of
migraine, it is possible that the suppressed
peak of prolactin could also be due to an
increase in TNFalpha.
CORTISOL Cortisol concentrations are
raised in many conditions related to CM, such as
depression, anxiety, insomnia, fibromyalgia, and
chronic pain. This is the first study of
cortisol concentrations in patients with CM.We
found higher concentrations of cortisol,
suggesting that the hypophyseal-adrenal axis is
activated in patients with CM compared with
controls. Glucocorticoids exert numerous effects
on metabolism, inflammation, and immunity, and
play an important part in pain inhibitor
mechanisms.
It is also important to consider the long
term effect of a hypercortisol state in patients
with CM. Arterial hypertension was found by
Mathew in the transformation of episodic to
chronic daily headache. The increase in cortisol
concentrations could be the biological basis for
this finding, although patients with
hypertension were excluded from our study.
Cortisol concentrations should be studied in
patients with CM and arterial hypertension in
the future.
GROWTH HORMONE Growth hormone
regulation is complex; neuropeptides,
neurotransmitters, and opioids are involved.
Dopamine also inhibits growth hormone secretion
in the hypophysis, and the study of this hormone
is another indirect way to address the
dopaminergic system. Our data did not show any
significant difference in the analysis of growth
hormone. However, any differences may not have
been great enough to be detected with the small
sample studied. The role of growth hormone in
headaches remains unknown.
Conclusion
We found an abnormal pattern of hypothalamic
hormonal secretion in CM. This comprised: (1) a
decreased nocturnal prolactin peak, (2)
increased cortisol concentrations, (3) a delayed
nocturnal melatonin peak in patients with CM,
and (4) lower melatonin concentrations in
patients with CM with insomnia.
Secretion of growth hormone did not differ
from controls. Overall, these results support
the involvement of the hypothalamus in the
pathophysiology of CM as shown by a
chronobiological dysregulation, and a possible
hyperdopaminergic state in patients with
CM.
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