|
Edward Lichten, M.D.,PC |
|||
|
INTRODUCTION Women's migraine are often the most difficult to control with standard medication because of the lack of clinical understanding of the interplay of hormonal factors in precipitating many of these cyclic, premenstrual attacks. Identification of these hormonal factors by appropriate history taking can be a key in identifying which patients may need alternative migraine medication and/or hormonal management. Experience with hormonal suppression of migraine using danazol and leupronide acetate is described. * First migraines associated with a hormonal event: menarche, birth control pills, pregnancy, and/or postpartum
Background Information
Previous demographic studies here and in China[1] document the 1)5:1 ratio of female to male headache sufferers, 2)the peak incidence of first occurrence at age 15-19 (puberty), 3) the rarity of headaches before age 10 or after age 60, and, 4) the correlation of severe migraine attacks to menstruation (60-70% incidence). In fact, while girls under 10 and women over 60 report a similar incidence of migraine, 20% to 30%[2] of all women in their childbearing years describe "an attack of vascular headache of migraine type in the previous year.[3] Physicians recognize that estrogen levels spike at ovulation only to rise in the mid-luteal phase and then drop sharply in the days prior to menses. This hormonal fluctuation has been suggested as a triggering mechanism for the repetitious occurrence of the typically, premenstrual migraine in women. Epidemiological studies point to the strong correlation of migraine with hormonal events. Women report having more headaches while on oral contraceptives and a lessening when discontinued. Typically, these headaches occur during the medication-free part of the cycle, when the serum levels of hormones drops. Migraine headaches usually disappear in pregnancy, almost always by the second trimester, when hormonal stability occurs. What appears to be contradictory information, then, is actually explained by considering the fluctuation in estrogen: when there is a drop in estrogen levels, migraine attacks may occur. And to the contrary, when estrogen levels are stable, migraine attacks do not occur.
PREVIOUS RESEARCH
Somerville next attempted to prevent migraine by using high dose estrogen injections. He rationalized that his failure in maintaining high levels of estrogen contributed to the "impossibility of achieving a truly stable plasma level of estradiol, owing to various factors such as the rate of hepatic detoxification, [and] irregularities of absorption of free hormone from the implantation site.[6]" Thus, his attempts at preventing migraine in women of reproductive age failed when using estrogen injections to elevate estrogen levels. Since his experience with the elevation of estrogen levels seems to provoke a worsening of migraine, Lichten reasoned that headaches might be controlled by maintaining a suppressed, low level of serum estrogen. Following the case report of Burnett, Lichten designed two studies to evaluate the possible role of maintaining low serum estrogen levels in women with migraine unresponsive to standard medical therapy. The first study utilized danazol[7], an ethinyl-testosterone derivative that prevents the rise in both estrogen ad progesterone levels in the luteal phase of the menstrual cycle. The second study was based on lupronide acetate[8], a Gn-RH agonist, which directly suppressed the pituitary-ovarian axis without the androgenic and steroid effect s of danazol. Previously, both drugs had undergone extensive human studies and had been approved for endometriosis, a female medical condition responsive to estrogen suppression. Recent Research Definition of Terms
Migraine refers to a specific type of severe headache. Its characteristics usually include 1)one-sided pain, 2)periodicity, that is the headache is not present all the time, 3)association with photophobia, phonophobia and 4)the systemic symptoms of nausea, facial pallor, and the interruption of the person’s normal activities. Migraine, by definition, cannot be associated with any physical or organic lesion.
All the patients studied were free of neurologic and endocrine disease, not taking hormonal medication, experiencing more than one day of severe and incapacitating migraine each month, and reporting no improvement with standard medical treatments.
PROTOCOL A group of women between the ages of 20 and 51 years with a primary diagnosis if migraine, as defined by the Ad Hoc Committee on Classification of Headache[9] were asked to participate in the danazol study. Most women had experienced more than one day of severe and incapacitating migraines per month over the preceding year and sought medical intervention to prevent further episodes, which interfered with work or home function. Each patient had previously been diagnosed by an internist and/or neurologist as experiencing migraine. Each reported no improvement with standard medical treatments. After a complete physical examination, blood count and hormonal profiles, those with a history of psychiatric disorders, drug abuse and underlying medical conditions (menopause, hypo- hyperthyroidism and hyperprolactinemia) were excluded. After the elimination of dietary and medication "triggers" for migraine, 131 women continued to participate in the first study. No volunteer responded to the placebo but after two months of danazol 200 mg taken orally twice daily for 25 days off three, 83 (63%) reported a greater than 75% improvement in their headaches: significantly less medication, less days affected, and less severity. Sixty-seven of the 83 (82.6%) continued the danazol for an additional year remaining relatively migraine free. This first study demonstrated that "danazol, when effective at relieving headaches in the first months of therapy, would remain so throughout the treatment course. Side effects, when present, usually were mild.[7]"
Statistically, there was a significant association between age and the effect of danazol on hormonal migraine. Of women over 40 years of age, 75% confirmed headache relief even though most had migraines for more than ten years. Thus, it appeared than danazol's success was more likely to help the older, more resistant migraine patient.
Of great interest was danazol's success with those women with premenstrual migraine, a complaint of the majority of study participants. Danazol was most effective in this group (75% reported profound relief). In those with a history of migraines occurring during other parts of the reproductive cycle, danazol was totally ineffective.
In the most recent study of 21 similarly affected women with migraine, lupronide acetate, a Gn-RH agonist, was used to suppress the estrogen levels and create an amenorrheic state. In 52% of the 21 participants studied for two years, migraine was effectively controlled by lupronide acetate. Lichten also demonstrated that bilateral oophorectomy (surgical menopause) would be as effective as lupronide, if the lupronide acetate produced a migraine free state. Add back estradiol given continuously in a transdermal delivery system would not aggravate migraine.[8]
DISCUSSION CONCLUSION The complications of hormonal therapy affected approximately 25% of the original participants with varying severity. Of women selected with previously unresponsive migraine and without cervicogenic headaches, approximately 25% found little or no relief with each drug trial. Although less than 100% effective for migraine in this female population, both danocrine and leupronide acetate remain effective in treating moliminal complaints of menstrual pain, metromenorrhagia, and premenstrual syndrome. Our experience definitely establishes that there is a place for hormonal medications in the treatment of hormonal migraine, a distinct and significant clinical entity. Recognition of the importance of hormonal factors and the appropriate initiation of hormonal therapy offers the clinician an additional avenue to migraine control in reproductive aged women.
References
|
||||