MENOPAUSAL MIGRAINE

HORMONAL CONSIDERATIONS
OF MIGRAINE MANAGEMENT
IN
POSTMENOPAUSAL WOMEN

Edward Lichten, M.D.,PC
180 East Brown Street
Birmingham, MI 48009 
248.593.9999

 

Introduction
There exists an "estrogen threshold" in menopausal women who experience "hormonal migraine." By recognizing the significance of hormonal factors and by maintaining a stable estrogen milieu, menopausal migraine complaints can usually be eliminated.

EARLY RESEARCH
Folklore, experience and careful epidemiological medical studies have linked the female sex to migraine. Reproductive age women, 15- 50 years of age, experience more than five times as many migraine headaches as men of similar age, worldwide.[1] 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] with 60% to 70% of these women describing most of their headaches just prior to menstruation. Recognizing that estrogen levels fluctuate after ovulation and drop sharply in the days prior to menses, this hormonal change has been implicated as a major factor in the despairing occu rrence of migraine in women.

In fact B.W. Somerville, an Australian neurologist substantiated that a drop in serum estradiol levels near menstruation correlated to the occurrence of migraine. He formulate three postulates to explain the contributing factors of estrogen and migraine[4]:

  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.

There has been little written on estrogen and its role in menopausal migraine. In 1975, Kudrow[5], a neurologist, noted that menopausal migraine sufferers typically reported their migraines occurred the week off oral estrogen replacement therapy. Therefore, he suggested the use of continuous estrogen. In his study, this continuous course of therapy was associated with less migraines. In 1977 Stryker[6], a gynecologist, in analysis of menopausal women followed for several years, noted that the addition of oral estrogen effectively decreased migraine complaints in two-thirds of her forty-nine women who recorded this complaint. Greenblatt,[7] another gynecologist, attested to the relief estradiol pellets had for some of his menopausal migraine patients. Finally, Lichten[8] found that the use of continuous oral or transdermal estrogen replacement was effective in alleviating menopausal migraine in 19 of 24 subjects. However, in none of these studies were serum estradiol levels measured, nor were estradiol injections given in the management of the menopausal migraine.

RECENT RESEARCH
Lichten's most recent study of 28 menopausal women[9] confirmed that 5 mg depo-estradiol injections usually maintained the serum estradiol level above 50 pg/ml for 14, and sometimes 21 days. Varying signficantly from individual to individual, the serum estradiol levels fell below 30 pg/ml by the 28th day. Not every menopausal woman studied developed migraine attacks. All who developed migraine had recorded a fall in serum estradiol levels below 50 pg/ml and had a history of migraine attacks during their reproductive years. It was also interesting to note that half of these women with migraine secondary to "withdrawal estrogen" mentioned severe headaches occurring in a first degree family relative.

DISCUSSION:
The Role of Estrogen and Menopausal Migraine

Because previous literature on the subject of menopausal migraine has been confusing this study helped to focus exclusively on the hormonal aspects of migraine. First, even though there exists no compatibility of estradiol levels between institutions, Kudrow, Stryker and Greenblatt all concluded that there was a positive clinical effect on migraine when estrogen was given continuously. Lichten's study validated Somerville's theory that some menopausal migraines can be seen as a result of "estrogen withdrawal" after a period of estrogen "priming." Whether the estrogen withdrawal affects neuro-receptors in the brain or receptors within the walls of the carotid vessels does not matter. What does matter is that once priming occurs, withdrawal will result in migraine in a select population of women. Not every woman develops migraine in the menopause, but there seems to exist a genetically unique population in whom 100% have noted a history of migraine in the reproductive years and whom experience m igraine under certain conditions of estradiol withdrawal [i.e. depo-estradiol injections]. In our study, 14 of 26 women experienced a severe attack of migraine, 14 to 23 days after a 5 mg estradiol cyprionate injection was given. Their averaged serum estradiol level was 42 +10 pg/ml on the day of the migraine. The 12 who had no complaints of migraine had no personal or family history of headache.

For the clinician, he or she must first recognize that menopausal estrogen replacement can both alleviate and contribute to migraine occurrence. Secondly, the clinician must know that there exists two populations of menopausal women, one that will not usually develop migraine no matter how the estrogen is given, and a second that will be sensitive to conditions that produce "estrogen withdrawal."

Estrogen Replacement in the Menopause
There are three basic estrogen preparations: estrogen oral tablets, estradiol transdermal systems, and estradiol injections. Estradiol is available in all three forms, yet the absorption and half-life of estradiol varies by individual, by dose, and by route of administration. Oral conjugated estrogens and generics contain up to 32 various "chemical compounds" and for that reason are not routinely used by this author.

Estradiol given orally is rapidly metabolized by the liver. Typical dosage is 1 to 2 mg daily. After oral ingestion the peak estradiol level is usually noted at 4-8 hours with a fall back to near baseline levels by 12-16 hours. Therefore, to maintain adequate estradiol levels in the headache patient, oral estradiol probably needs to be given every twelve hours. Even then in my experience, it is more difficult to maintain a stable estradiol milieu with oral estradiol than with either the "patch" or injections.

Estradiol Transdermal System, Estraderm@, contain either .05 mg % or .10 mg % estradiol for parental absorption through the skin. The serum estradiol level reaches a peak within 4 hours of application, and maintain serum levels for approximately 3-4 days. In many cases, the .05 mg % patch is unable to maintain adequate estradiol levels to prevent migraine in our patients so we usually prescribe the .10 mg % patch. Also, many patients seem to need to change the estradiol patch more often, after 2 1/2 or 3 days, to prevent a migraine attack.

As noted in our depo-estradiol study, injections of 5 mg of depo-estradiol cyprionate every two weeks prevent migraine in most menopausal migraine patients. However, some develop a migraine on the day of injections along with breast tenderness. Since no estrogen preparation is perfect for all women, the clinician must recognize the limits of each preparation and treat accordingly.

In 1999, Edward Lichten, M.D. announced that a new formulation of the estradiol subcutaneous pellet would maintain estradiol levels for 6-8 weeks. In a study of 50 women between the ages of 31 and 57, there was an 85% reduction in the use of Imitrex injections and oral tablets. Dr. Lichten explains that the pellet prevented the normal drop in estradiol near menstruation. The patients were elated at this simple method for migraine prevention. For women in their 40s and 50s, many elected to have testosterone pellets inserted at the same time. They had renewed energy, sex drive, and a positive attitude as a direct result of the action of testosterone.

The clinician must first realize that the "old standard" of estrogen replacement with conjugated estrogen for 21-25 days per month is absolutely wrong for the menopausal migraine patient. If a menopausal patient has "hormonal migraine," the treatment courses are as follows:

  1. Continuous estrogen. First try estrogen orally every day. < LI> Next, try the estradiol .10% patch every 3 days.

  2. Then try the 5mg estradiol injections every 7-10 days.

  3. If this fails, then change to estradiol tablets taken orally every 12 hours.

  4. If all fails, the subcutaneous estradiol pellets can be secured by contacting Dr. Lichten's office.

  5. If headaches continue, stop all estrogen.

Progesterone Replacement in the Menopause
Gynecologists usually recognize that there may be no real need to take any progesterone replacement if the woman has had a hysterectomy. Medical studies do show that both synthetic progestin and natural progesterone usually protect against endometrial cancer in menopausal women on estrogen replacement. Progestin and progesterone prevent the build up of the endometrial lining that can be associated with heavy bleeding and both pre- and malignant endometrial change. However, a rarely appreciated fact or is that progesterone and progestin alone can cause migraine!

For example, in the typical estrogen/progestin replacement regimen, the menopausal woman is prescribed .625 to 1.25 mg conjugated estrogen for 21-25 days and medroxyprogesterone acetate 2.5 to 10 mg for 10 to 14 or 25 days. Most women will report their severe headaches either 1) the days off both estrogen and progestin or, 2) the days on progestin. In a number of patients, daily headache are noted on progestin therapy.

I suggest the following steps to determine if the headache condition is caused by progestin therapy.

  1. Stop all progestin for two months. Determine if headaches still continue. If they do, they are not related to progestin therapy.

  2. Shift to the lowest dose of progestin and limit it to 10 days. If headaches continue, discontinue progestin therapy.

  3. Change from synthetic progestin to a natural progesterone. Natural or aqueous progesterone is available in oral preparations and rectal/vaginal suppositories. Doses of 200mg need to be given every 12 hours for the ten days to have a protective effect on the endometrium

  4. Rarely, a woman will still have headache on the natural progesterone preparations. For these women, no progesterone can be prescribed. These women should be followed by a gynecologist experienced in vaginal ultrasound and endometrial sampling.

Natural progesterone can be prescribed for those women who experience pre-menstrual complaints. Use this progesterone for the last 10-14 days of the cycle, increasing the dosage as needed. In a similar fashion, prescribe progesterone for the day or two when migraine or breast tenderness occurs after estradiol injections or upon changing the estradiol patch.

Conclusion
Although family history is an important factor in screening menopausal migraine patients, our research demonstrates that the most significant factors are 1) past history of migraine and 2) estrogen usage. There exists a population of women who are not affected by any hormonal preparation. On the other hand, there is validation of a migraine population sensitive to estrogen/ progesterone preparation, dosage, and continuity of medication delivery.

Based on Somerville's model and our data, these migraine sensitive patients do best by maintaining their serum estradiol levels above our laboratory's 40-50 pg/ml, "estradiol threshold." We found the depo-estradiol injection of 5mg every two weeks worked well. The estradiol .10mg% transdermal patch was somewhat less effective and if clinically indicated, two "patches" might need to be applied and changed every 3 days if the injections are not considered useful in maintaining a stable estradiol milieu.

Also of importance to the menopausal migraine patient is the use of synthetic progesterone replacement. Progestin can cause headaches, probably by competing for estrogen receptors. Natural progesterone does not seem to cause headaches for most women. However, if headaches continue, stop all progestin/progesterone compounds and allow a gynecologist to follow the endometrium for changes while the patient remains on estradiol alone.

The use of continuous estrogen replacement including estrogen injections, in the menopausal migraine patient should, then, not be avoided because of an unfounded fear of exacerbating migraine. Rather, consider migraine in menopausal women to be "hormonal." These attacks may rapidly respond to a continuous estrogen therapy and a "stable estradiol milieu." Physicians treating women patients must recognize that there continues to exists a strong correlation between estrogen, progesterone and migraine. Hormonally influenced menopausal migraine is unquestionably a distinct clinical entity and must be treated as such.

References

  1. Zhao F, Tsay JY, Cheng X, et.al. Epidemiology of migraine: A survey in 21 provicenes of the People's Republic of China, 1985. Headache 28:558, 1988.
  2. Welch KMA, Darnley D, Simkins RT. The role of estrogen in migraine: A review and hypothesis. Cephalgia 1984;4:227-236.
  3. Waters WE,O'Connor PJ. Epidemiology of headache and migraine in women. J. Neurology, Neurosurgery & Psychiatry 1971; 34: 148-153.
  4. Somerville BW. The role of estradiol withdrawal in the etiology of menstrual migraine. Neurology. 1972;22:355-65.
  5. Kudrow L. The relationship of headache frequency to hormone use in migraine. Headache. 1975;15:36-49.
  6. Stryker J. Use of Hormones in Women over 40. Clinics in Obstetrics and Gynecology. 1977:20(1):155-164.
  7. Greenblatt RW. editor Menopausal Syndrome. New York: Medcom Press 1974: 102-110.
  8. Lichten EM. Menopausal Migraine. The Menopausal Migraine. Reid-Rowell Symposium McGraw-Hill, Inc. 1990, p.21.

  9. Lichten EM, Lichten JB, Whitty AR, Piper DM. The Confirmation of a Biochemical Marker for Women's Migraine: The Depo-Estradiol Challenge Test. Headache. 1994;36:367-70