Rapid Estrogen Decline Confirmed as Migraine Contributor

June 03, 2016

A new study has clarified how hormonal changes may contribute to migraine in women.

The study, published online in Neurology on June 1, was led by Jelena Pavlovic, MD, Albert Einstein College of Medicine/Montefiore Medical Center in Bronx, New York.

"We have shown definitely that women with migraine have a different hormone profile to women without a history of migraine — specifically they have a more rapid decline in estrogen in the late luteal phase of the menstrual cycle," Dr Pavlovic commented to Medscape Medical News. "Our results suggest that a 'two-hit' process may link estrogen withdrawal to migraine."

She added: "This more rapid estrogen decline in women who experience migraine may push them over the edge into a migraine when they experience one of these other triggers. So our recommendation to women with migraine is to be extra cautious to avoid triggers in the few days prior to menstruation. They need to take extra care of themselves in those few days as they appear to be biologically predisposed to be more susceptible at that time."

Commenting on the study for Medscape Medical News, Professor Anne MacGregor, MD, Centre for Neuroscience & Trauma, Barts and the London School of Medicine and Dentistry, United Kingdom, one of the leaders in the field of hormonal migraine, said, "This is an excellent study that builds on our suspicions that rate of change of estrogen in the late luteal phase is more important than absolute levels. More recent technology has enabled a study such as this to be done — it's always nice to see a hypothesis proved."

Professor MacGregor pointed out that the study was looking at women with migraine generally, not women specifically with menstrual migraine.

"We know that for some women menstruation is an addition to nonhormonal triggers, ie as the authors state, it makes a woman more vulnerable to migraine at that time of the month. It may be because the neuroendocrine changes increase vulnerability to other triggers, but it may be because it is an additional trigger. In these women, suppressing the menstrual trigger may change the regular pattern of migraine but doesn't affect the frequency.

However, there are also women for whom the menstrual trigger is the sole trigger for migraine and suppressing the hormone trigger prevents migraine. In these women, nonhormonal triggers are irrelevant. So the 2 step process may be relevant to some women, but not others."

Hormone Levels Measured Every Day

Dr Pavlovic explained that it is well known that hormone levels are important in women with migraine and perimenstrual migraine is common. "The theory is that it is related to estrogen withdrawal, but prior studies have not consistently shown differences in hormone variations between women with migraine and women without migraine."

She noted that few studies have actually compared hormone levels between women with migraine and women without migraine. "Such studies are very labour intensive, with urine samples needing to be collected every day. We have done this in this study in an effort to really understand the day-to-day changes throughout the cycle and how they relate to migraine."

For the study, the researchers recorded history of migraine, daily headache diaries, and daily hormone data in one ovulatory cycle in 114 premenopausal or early perimenopausal women with history of migraine and 223 controls without a history of migraine.

Peak hormone levels, average daily levels, and within-woman day-to-day rates of decline over the 5 days after each hormone peak were calculated in ovulatory cycles for conjugated urinary estrogens (E1c), pregnanediol-3-glucuronide, luteinizing hormone, and follicle-stimulating hormone.

Results showed that E1c decline over the 2 days after the luteal peak was greater in migraineurs for both absolute rate of decline (33.8 pg/mgCr vs 23.1 pg/mgCr; P = .002) and percentage change (40% vs 30%; P = .001).

There was no significant difference between migraineurs and controls in absolute peak or daily E1c, pregnanediol-3-glucuronide, luteinizing hormone, or follicle-stimulating hormone levels. Secondary analyses demonstrated that, among migraineurs, the rate of E1c decline did not differ according to whether a headache occurred during the cycle studied.

Dr Pavlovic said, "We didn't show a significant difference in absolute levels of estrogen, but we did find that women with migraine had a more rapid decline in estrogen levels in the late luteal phase (before menstruation) than those without migraine."

She explained that estrogen levels fluctuate twice during the monthly cycle: once around ovulation and again in the late luteal phase. "During both these phases, estrogen levels peak and then fall sharply. We only found a difference in the rate of estrogen decline between women with migraine and those without migraine in the late luteal phase. We did not see a difference in the ovulatory period."

"Before this study we thought menstrual migraine was caused by estrogen withdrawal but we did not understand why this we did not see the same thing happening with the oestrogen decline after ovulation. Our results give us some explanation of this."

Dr Pavlovic reported that 25% of women of reproductive age have migraine, and the majority have less than one migraine per month. "In our sample of women with migraine, they didn't all have specific menstrual migraine and they didn't all have a migraine during the cycle studied. But they still had the same profile of a more rapid decline of estrogen in the late luteal phase. This seems to be a profile inherent to women with migraine."

Neurology. Published online June 1, 2016. Abstract

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