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mise à jour du 13 mars 2003
J Neurol Neurosurg Psychiatry 2001;71:747-751
Hypothalamic involvement in chronic migraine
Peres MF, M Sanchez del Rio, M Seabra, S Tufik, J Abucham, J Cipolla-Neto, S Silberstein, E Zuckerman
SaoPaulo Headache Center Brazil
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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. [...]


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.


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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