Edward Lichten, M.D.,PC
180 East Brown Street
Birmingham, MI 48009 



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
* Worse headaches occur near menstruation
* Birth controls often make headaches worse; discontinuation may bring some relief.
* Headache typically occur the week off birth control pills.
* Absence of migraine noted in second & third trimesters of pregnancy.
* Presence of other premenstrual complaints: mood swings, depression, food cravings, fluid retention and breast pain

Background Information
Headache is one of the most common complaints of patients in a doctorís practice. Even though more than 80 percent of the intense, periodic headaches of migraine are experienced by women, very little literature has been directed to the hormonal forces that may trigger these attacks. The standard medical approach in treating migraine is to first use a non-steroidal anti-inflammatory agent and a prophylactic agent, typically a beta-blocking or calcium-channel blocking agent; then, add an anti-depressant such as imipramine for its central nervous system effects. Should this fail, the secondary treatment focuses on interrupting or aborting the migraine attack. These medications act as vasoconstrictive agents: caffeine, cafergot, ergotamine, isometheptene mucate, and methylsergide maleate. However, even with multiple drug therapies, migraine at or near menstruation remains extremely difficult to treat effectively. Multi-center studies of migraine prophylaxis in women report a success rate of no more than 40% in decreasing headache frequency and severity.

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.

Few researchers have measured hormonal levels in women with migraine and less have attempted to control migraines in women by using hormonal preparations. Until 1972, no research had focused on the role of estrogen and progesterone levels in migraine. Somerville[4] in that year, published the first elegantly performed studies. He identified 5 women whose migraines occurred on the first day of menstruation. He first gave progesterone injections just prior to the anticipated menses/migraine. This delayed the menses but had no effect on the scheduled occurrence of migraine. He next gave these same 5 women an injection of estradiol valerate again, just prior to menstruation. Four women reported their menses occurring at the proper time but the migraine was delayed for up to 8 days. In each case when the estrogen level finally fell, the migraine occurred in a more severe form than before the estradiol injection. Furthermore, he described that when a very short acting estradiol was utilized at ovulation, there was no change in migraine occurrence, timing, or severity. He reasoned that this may explain why ovulation or mid cycle migraine is infrequent while menstrual and premenstrual migraine is common since "a period of several days of exposure to high estrogen levels may be necessary before withdrawal of estrogen could result in migraine." He formulated three postulates to explain the contributing factors of estrogen and migraine[5]:

  1. A drop in estrogen levels precipitates migraine attacks.

  2. A period of estrogen priming is a necessary precursor to the hormonal migraine.

  3. Migraine attacks may be prevented by a stable estrogen milieu.

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
Prior to the publication of these research studies, Lichten[7] defines hormonal migraine as those occurring during the luteal phase of the menstrual cycle. Typically, they occur within 7-10 days before menstruation. But this also includes, menstrual migraine, those attacks that occur within the first two days after the onset of menstruation.

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 personís 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.

Danazol and lupronide acetate studies

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]

Although much has been written about the interplay of womenís hormones, specifically estrogen with migraine attacks, few researchers have been able to establish a scientific basis for this phenomenon. Somerville clearly presented the concept that the menstrual migraine attack was precipitated by the fall in estrogen levels at menstruation, but his attempts to prevent migraine by maintaining elevated estrogen levels failed. Lichten's study plan for evaluating the role of estrogen suppression to control migraine encompassed three separate trials: first, danazol, with its success for one year; secondly, lupronide acetate's success for up to 24 months, and: lastly, oophorectomy with permanent effectiveness for women migraineurs. With a greater than 50% response, these publications validate the concept that a stable, low level of estrogen, may be effective in controlling hormonal migraine, no matter which modality is ultimately selected (danazol, Gn-RH agonist, or bilateral oophorectomy).

Many migraines in women appear to be hormonally related events, based on both demographic and large cohort studies. Lichten's two studies support Somerville's concept that the fluctuation and fall of premenstrual estrogen levels trigger some womenís migraine attacks. Respectively both danazol and lupronide acetate, by suppressing estrogen levels, prevented the most severe migraine attacks in slightly more than 50% of women study participants unresponsive to all previous medical interventions. As reported previously, hormonal suppression therapy seems to work best for those with migraine in the week before and the first few days of menstruation. In six (now 15) selective cases, surgical removal of ovarian tissue was effective. Maintaining const ant estrogen levels with an estradiol transdermal delivery system while on lupronide acetate and/or after oophorectomy was effective in relieving menopausal symptoms without precipitating a recurrence of migraines.

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.


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  2. Welch KMA, Dannley D, simkins RT. The role of estrogen in migraine: A review and hypothesis. Cephalgia1984; 4:159.
  3. Watters WE, O'Connor PJ. Epidemiology of headache and migraine in women. Journal of Neurology, Neurosurgery & Psychiatry1971; 34:148.
  4. Somerville BW. The role of estradiol withdrawal in the etiology of menstrual migraine. Neurology 1972; 22:355.
  5. Somerville BW. Estrogen withdrawal migraine: I. Duration of exposure required and attempted prophylaxis by premenstrual estrogen administration. Neurology1975; 25:239.
  6. Somerville BW. Estrogen withdrawal migraine: II. Attempted prophylaxis by continuous estradiol administration. Neurology , 1975; 25:245.

  7. Lichten EM, Bennett RS, Whitty AJ, Daoud Y. Efficacy of Danazol in the Control of Hormonal Migraine. Journal of Reproductive Medicine 1991; 36(6):419-24.

  8. Lichten EM, Lichten JB, Whitty AJ, Pieper D. The Use of Leuprolide Acetate in the Diagnosis and Treatment of Menstrual Migraine: The Role of Artificially-Induced Menopause. Headache Quarterly 1995;6(4):313-317.

  9. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalgia 1988; 8 Suppl 7:10-73.