Pauline Anderson

June 26, 2014

LOS ANGELES — A new survey confirms what many headache specialists see in their practice: an increase in headache frequency for perimenopausal women.

A new study shows that the risk of having 10 or more headaches a month increases by up to 50% as estrogen levels drop and women enter perimenopause, said Vincent T. Martin, MD, co-director, Headache and Facial Pain Program, and professor, internal medicine, University of Cincinnati, Ohio.

"The time period which was the absolute worst as judged by headache frequency and disability was during the perimenopause, and that's something that is new, has never been shown before," said Dr. Martin, who was lead researcher for the study.

"Patients often tell us that their headaches tend to worsen when going through perimenopause, but there has never been a published study to demonstrate this."

However, he added, the results are not unexpected, "simply because perimenopause is such a turbulent time period for hormonal changes in women."

Dr. Martin will present the results at the American Headache Society (AHS) 56th Annual Scientific Meeting.

Menopause Stages

The study used data from the 2006 American Migraine Prevalence & Prevention Study, a national survey that incorporated detailed questions about the menstrual cycle. It included 3603 women aged 35 to 65 years (mean age, 45 years) who met International Classification of Headache Disorders criteria for migraine.

Premenopause was defined by having regular menstrual cycles without variation in length. Perimenopause entailed cycles that varied by 7 or more days or periods of amenorrhea lasting 2 to 11 months. Postmenopause included amenorrhea persisting for 12 or more months.

Researchers used a cutoff of 10 or more headache days per month to separate high vs low headache frequency, which was the primary outcome.

The study showed that 8.0% of the premenopausal, 12.2% of the perimenopausal, and 12.0% of postmenopausal women were in the high-frequency headache category.

Compared with premenopausal women, the odds of being in the high-frequency group were 1.5 (95% confidence interval [CI], 1.1 - 2.0) for perimenopausal women and 1.6 (95% CI, 1.1 - 2.3) for postmenopausal women, after adjustment for stage of menopausal transition, age, income, body mass index, preventive mediation use, and smoking.

After additional adjustment for cutaneous allodynia (with a cutoff score of 3 on the Allodynia Symptom Checklist, and depression (cutoff score of 10 on the Patient Health Questionnaire), the results were slightly altered but remained statistically significant.

The concept of "estrogen withdrawal" — in which declining estrogen levels trigger headaches — is well known for menstrual periods. But these new data suggest "this concept of estrogen withdrawal can extend much longer than just the 5 to 7 days; it can extend for years in some women," said Dr. Martin.

Women and doctors need to be aware of this, he added. "In the past, there just hasn't been this recognition that hormones have any effect on migraines at all."

Dr. Martin noted that the study looked at the presence or absence of headache, not migraine. However, in an analysis that wasn't included in his poster, he and his colleagues found that disability was increased in the perimenopausal women experiencing a lot of headaches.

"This suggests that these women were probably having more frequent migraines because it's the migraines that cause disability," said Dr. Martin.

Trigeminal Nerve

The mechanism by which falling estrogen levels might affect headache frequency probably involves complex biological systems, the researchers note. Rat studies suggest that the mechanism involves the trigeminal nerve, which is the largest cranial nerve. "In these experiments, the trigeminal nerve actually became sensitized during declines of estrogen," said Dr. Martin.

Because there are estrogen receptors in different areas of the brain, falling or declining estrogen levels likely affect other functions, such as the limbic system, which, among other roles, is responsible for emotions, and cortisol status, which affects stress, said Dr. Martin.

Hormone replacement therapy (HRT) might be a viable option for women in the later phases of perimenopause when they have more estrogen "withdrawal" and start having more frequent headaches, said Dr. Martin.

But he stressed that it's important to use "the right type" of HRT preparation. Studies suggest that conjugated estrogens (Premarin, Pfizer) probably worsen headaches in most women, he said, while the estrogen patch, which uses a more natural form of estrogen (β-estradiol), might be preferable.

In a study he and others carried out several years ago (Headache. 2003;43:309-321) in which they used a subcutaneous goserelin implant, a gonadotropin-releasing hormone agonist, to induce medial oophorectomy in premenopausal women, those who got an estrogen patch afterward as opposed to a placebo had about a 33% improvement in headache outcome measures.

"The bottom line is that if you throw women into menopause abruptly, you have to replace the estrogen," said Dr. Martin.

The logical next step for Dr. Martin and his fellow researchers is to look at different subgroups to determine in which women headaches worsen around perimenopause, information that may shed light on who may most benefit from HRT.

"What it probably comes down to is genetics of receptors, the estrogen receptors and maybe the progesterone receptors, in how women respond to hormones," said Dr. Martin.

No Secret

Elizabeth Loder, MD, past president, AHS, and an internist in the Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, said the study "validates what we see and hear in the clinic all the time."

"It's no secret to people who treat headache that for many women with migraine, but not all, things can get worse during the perimenopausal transition," Dr Loder told Medscape Medical News.

This study is important "because it's very large and done by an excellent research group" who "went to a lot of trouble to correctly classify women in terms of what stage they were in" with regard to menopause, said Dr. Loder.

Although menopause status was self-reported, "unlike reporting their weight, I think women are pretty accurate and honest about where they stand with regard to menopause, so I have a lot of confidence in the accuracy of the classification and in the findings themselves."

She did point out, though, that while the relative change in headache frequency went up 50% or more from premenopause to postmenopause, the absolute differences could be quite small.

According to Dr. Loder, attributing increased headaches approaching menopause to just hormones is an "oversimplification." In her experience, headaches do get better with age in many women, although this is sometimes delayed and may occur gradually several years after menopause.

American Headache Society (AHS) 56th Annual Scientific Meeting. Abstract 1957555.

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