Estrogens and migraine

Author: Francesca Bar
Date: 08/10/2007


Tiziana Ruggiero (238561) & Francesca Bar (239273)

The normal female life cycle is associated with hormonal fundamental moments including menarche, pregnancy, OC use, menopause, and the use of HRT.

Menarche marks the onset of menses and cyclic changes in hormone levels.
Pregnancy is associated with rising noncyclic levels of sex hormones.
Menopause is associated with declining noncyclic levels.
Hormonal OC use during the reproductive years and HRT in menopause are therapeutic hormonal interventions that alter the levels and cycling of sex hormones.

These events and interventions may cause a change in the prevalence or intensity of headache. Headaches associated with OC use or menopausal HRT may be related, in part, to periodic discontinuation of oral sex hormone preparations. The treatment of migraine associated with changes in sex hormone levels is difficult, and patients often are refractory to therapy.

Ovarian hormones have variable effects on the central nervous system of women:
● The predominant effect of estrogen appears to be facilitation of the glutamatergic and serotonergic systems as well as inhibition of the sympathetic nervous system.
● It has both facilitory and inhibitory effects on the opiatergic,GABAergic and noradrenergic systems.

The main effect of progesterone and its metabolites seems to be:
● activation of GABAergic systems
● modulation of the actions of estrogen on the central nervous system.

In addition, estrogen and progesterone:
● influence the pain processing networks and vascular endothelium, which are believed to be involved in the pathophysiology of migraine headache.

We could argue that neurotransmission within the trigeminal nucleus caudalis is the best measure of the net effect of all the changes induced by ovarian hormones within neurotransmitter systems.

Estrogen increases fos expression and neuronal response properties within the trigeminal nucleus after peripheral activation and cutaneous receptor fields of trigeminal neurons are increased after administration of estrogen. This would suggest that the administration of estrogen leads to neuronal hyper-responsiveness within the trigeminal nucleus. Viceversa, progesterone reduces fos expression within the trigeminal nucleus after electrical stimulation of the trigeminal nerve would lead to neural hyporesponsiveness.

Clinical data would suggest that the activity of specific neurotransmitter systems varies during different phases of the menstrual cycle.
● During the mid-cycle (high estrogen, low progesterone), there is likely up-regulation of the serotonergic and glutamatergic systems and down-regulation of the sympathetic nervous system.
● During the midluteal phase (high estrogen/high progesterone), there is up-regulation of GABAergic and sympathetic systems and down-regulation of the serotonergic system.
● During the late luteal and early follicular phases, there is up-regulation of the sympathetic system and down-regulation of serotonergic and GABAergic systems.
It is unknown if the above changes involve trigeminal pain pathways, but if present could play an important role in the pathogenesis of migraine headache.

Maybe the risk for migraine headache varies during different phases of the menstrual cycle based on a delicate balance of neurotransmitter systems.
Increasing serum levels of estrogen during the mid-cycle could enhance neurotransmission in the trigeminal nucleus by enhancing glutamatergic tone and predispose to mid-cycle migraine headaches.
Tone within neuroinhibitory systems could be maintained by the high serum estrogen levels. This may be the reason why mid-cycle migraines occur less frequently than menstrual migraines. Progesterone and its metabolites rise during the mid-luteal phase and could decrease neurotransmission within the trigeminal secondary to enhanced GABAergic tone. So migraine headache would be less frequent during this time.
During the late luteal and early follicular phases, estrogen and progestereone levels decline precipitously. Structural changes in the trigeminal nucleus induced by estrogen could not reverse immediately with a decrease of estrogen and neuroexcitation could remain despite falling estrogen levels. At the same time, tone within inhibitory neurotransmitter systems is at its least. So, a delay in recovery of the glutamatergic system along with decreased tone of inhibitory neurotransmitter systems could make the late luteal and early follicular phases of the menstrual cycle ( perimenstrual time) a particularly vulnerable time for migraine headache.

The influence of gender and sex steroids on craniofacial nociception.

The influence of estrogen on migraine: a systematic review

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