ARTICLE IN BRIEF
In a small study, researchers found that non-obese men with migraine have higher levels of estrogen compared to similar men without migraine, and they also are more likely to have signs of androgen deficiency.
Estrogen's role in migraine in women has long been scrutinized, but little research attention has been paid to the influence of sex hormones in men with migraine.
Now comes a new study from the Netherlands that found that non-obese men with migraine have higher levels of estrogen compared to similar men without migraine, and they also are more likely to have signs of androgen deficiency.
The study is small and raises many questions, but researchers said it is a step toward better understanding the hormonal influence in migraine. The study appears in the June 27 online edition of Neurology.
“This is the first study to show that differences/changes in sex hormones are associated with migraine in men, too, and not only in women,” said the study's primary author, Willebrordus PJ van Oosterhout, MD, of the department of neurology at Leiden University Medical Center, in an email to Neurology Today. He noted, however: “I think it is too early to have clinical implications yet.”
It's not surprising that migraine research has focused so much on women, given that women are about three times more likely than men to experience migraine, and their attacks are apt to be more frequent and severe, the study authors noted. The cyclical nature of women's hormones, in particular estrogen, at various stages of life makes it easier to study the connection between hormones and migraine in women.
“Fluctuations in female sex hormones during puberty, menstruation, pregnancy, breast-feeding, menopause and post-menopause are associated with changes in attack frequency,” the paper noted. But “it is unknown whether sex hormones might modulate migraine risk and activity in men.”
STUDY DESIGN, FINDINGS
The study, done as part of Leiden University Medical Center's Neuro Analysis Programme, compared 17 men who had episodic migraine without aura (according to the International Classification of Headache Disorders) to 24 non-migraine controls. The men ranged in age from 18 to 74 and were all non-obese (body mass index greater than 20 and less than 28). The study excluded men who were taking medication that could interference with hormone levels. The researchers took blood samples to assess levels of 17B (beta) estradiol and free testosterone and to calculate a ratio of free testosterone to 17B estradiol. Blood samples were taken on a single (for migraineurs) interictal day at 9 a.m., noon, 3 p.m. and 6 p.m. The migraine group was then measured three to four times daily until an attack occurred.
“The males with migraine had an average serum level of estrogen of 96.4 pmol/L (on a day without migraine) compared to 69.1 pmol/L in the control group, reflecting a 40 percent higher blood level of the hormone,” Dr. van Oosterhout said. Serum levels of testosterone were similar between the two groups, though the migraine group had a lower estrogen/ testosterone ratio due to the higher levels of estrogen.
He noted that hormone levels did not fluctuate much throughout for either the men with migraine or controls.
In the migraine group, “there was an increase in testosterone levels visible just before the migraine attack, but only in the subgroup of patients who reported clinical premonitory symptoms,” such as fatigue, yawning and food craving, Dr. Van Oosterhout said.
The researchers also looked at clinical androgen deficiency using two measures, the Androgen Deficiency of Ageing Men (ADAM) questionnaire and the Aging Males' Symptom scale. On the ADAM questionnaire, 61.1 percent of men with migraine reported symptoms of androgen deficiency versus 27.3 percent of non-migraine men. The second scale also indicated more symptoms of androgen deficiency in the migraine group.
The researchers said the study had limitations, including foremost its small size, which made it impossible to say whether hormone levels influenced the frequency, duration or severity of attacks. It's also not possible to say whether the study group, seen at an academic medical center, was typical of male migraine sufferers in the general population, although the general characteristics of the men studied resembled the average male migraine patient.
The precise mechanisms at work are also not known.
“We can only speculate,” Dr. van Oosterhout said. “High estrogen levels might increase susceptibility to spreading depolarization, the underlying mechanism for migraine aura and a putative trigger of migraine headaches.”
He noted that “we know that, in women alteration in (mainly) estrogen, and then most clearly, a fall in pre-menstrual estrogen levels after a mid-cycle rise is considered a trigger for a new migraine attack. We could speculate, that in men, a higher serum level of estrogen makes them more susceptible to get migraines.”
Dr. van Oosterhout said the role of testosterone in migraine in men is less clear, and said it was possible that the rise of testosterone prior to an attack was a result of the stress of knowing an attack was coming, not necessarily a cause of the attack.
The researchers said “further intra-individual follow-up studies over multiple attack cycles” are needed to further elucidate the role of sex hormones in men with migraine.
Nasim Maleki, PhD, a migraine researcher and assistant professor of psychiatry at Massachusetts General Hospital, said the study, while not definitive, was important, in part because “men in general are very much understudied in migraine.”
Dr. Maleki said migraine in women has traditionally been placed in one research box, with much of the focus on hormonal influences, while migraine in men has been put in another box and largely ignored.
She said the new study “provides a different perspective” and “helps us understand the physiology of migraine,” in both sexes.
Vincent Martin, MD, professor of medicine and director of the Headache and Facial Pain Center at the University of Cincinnati, agreed, noting that men are almost completely underrepresented in clinical trials of migraine therapies. Migraine in men is probably an under recognized problem because there may be stigma attached to a man saying he suffers from headaches, he said, and because migraine is less frequent in men than women.
Dr. Martin, who is president of the National Headache Foundation, said it was plausible, based on research involving women, that small changes in serum levels of estradiol could increase migraine risk in men.
In a study he conducted in 2003 in which women were placed in a state of medical menopause and then given an estradiol patch, “We found that even minute changes in estradiol could trigger headache,” he said. He said that in the case of transgender people, transitioning from female to male can decrease migraines as estrogen levels go down and testosterone goes up.
But he cautioned against drawing any firm conclusions from the small Dutch study.
Jelena Pavlovic, MD, PhD, assistant professor of neurology at Albert Einstein College of Medicine and attending neurologist at Montefiore Medical Center, said the new study makes a good case that “the estrogen story in migraine is not just relevant to women,” but said it's too soon to say whether the findings will have clinical relevancy.
“Though the sample size is small, it is an important step in a much needed broader understanding of the influence of sex hormones in migraine in both men and women,” she said. She said she'd like to see a larger follow-up study done in younger men, given that migraine often improves and remits with aging in both men and women. Dr. Pavlovic said the point isn't that there's a set “absolute level” of a given sex hormone that increases migraine risk but rather “how different hormones change over time and how they interplay with each other.”
“Sex hormones don't act in isolation,” she said.