MENOPAUSAL MIGRAINE:
THE ROLE OF HORMONAL REPLACEMENT

Edward Lichten, M.D.,PC
189 Townsend -2nd Floor
Birmingham, MI 48009 
248.593.9999

 

The Menopausal Syndrome. Proceedings from a Symposium. Scottsdale, Arizona January 27, 1990. Reid-Rowell, Inc. Pages 21-24.

 

Many articles have implied a strong correlation between estrogen levels and migraine. Estrogen, the primary hormone of reproductive-age women, has been strongly implicated in migraine because women in this age group experience more than five times as many migraine headaches as men of similar age.[1] Statistically, 20% to 30%[2] of all women of reproductive age describe "an attack of vascular headache of migraine type in the previous year."[3] Klee[4] and Edelson[5] have documented that 60% to 70% of these women report that most of their headaches occur just prior to menstruation. Thus, hormonal fluctuation appears to influence significantly the incidence of migraine.

Additional factors point to a hormonal action, specifically estrogen fluctuations. For example, some women report more headaches while on oral contraceptive agents; typically these headaches occur during the medication-free part of the cycle, when serum estrogen levels drop.[6] Others report a lessening of headaches after discontinuing oral contraceptives.[7] Migraine headaches during pregnancy usually disappear by the second trimesters[8] when estrogen levels rise.

EARLY RESEARCH

Sommerville[9] focused on the role of fluctuating estrogen levels in migraine and was the first to investigate premenstrual estrogen levels in women with menstrually related migraines. He found that migraine attacks resulted from the drop in serum estrogen levels. At the end of his investigations Sommerville concluded that although estrogen levels before ovulation are significantly lower than after ovulation, and a drop in estrogen is necessary to precipitate migraine, "a period of several days of exposure to high estrogen levels may be necessary before withdrawal of estrogen could result in migraine [italics added]."[l0] Because Sommerville reasoned that it was the fluctuations that precipitated migraine, he sought a way of maintaining constant estrogen levels throughout the hormonal cycle. He reported in 1975, however, that he was unsuccessful in establishing an effective therapeutic modality. [11]

Sommerville's three postulates can be summarized as follows:

(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

"Hormonal fluctuation appears to influence
significantly the incidence of migraine"

Recent Research
In a 1-year controlled sequential elimination study, Lichten [12] used danazol, a 17alpha-ethinyl testosterone derivative, to prevent or reduce the frequency and severity of hormonal migraine in premenopausal women.

An earlier study by Greenblatt [13] demonstrated that both menstrual and postmenopausal migraine could be controlled with subcutaneous pellets of estrogen and testosterone. In his study of 85 women, he concluded that estrogen pellets relieved all symptoms in the majority of his menopausal patients, and that maintenance of stable estrogen levels would control menopausal migraine.

Because of the limited information available on menopausal headaches and the relevance of estrogen therapy, the Headache Institute for Women initiated a study to evaluate the efficacy of estrogen therapy in women with menopausal migraine. This study sought to identify women whose menopausal migraines were unresponsive to standard medical therapy, and to determine the role of estrogen on migraine.

MATERIALS AND METHODS
The medical charts of menopausal women, aged 50 to 68 years, were read to establish the primary complaint of migraine and the use of migraine medication. The following information was recorded:

  • age of first occurrence of migraine
  • correlation of migraine to the menstrual cycle
  • monthly migraine frequency and severity
  • change in occurrence/severity of migraine at menopause
  • previous standard headache medication
  • previous hormonal medication
  • side effects of hormonal medication
  • success or failure of present treatment plan.

Of the 136 patients reviewed, 51 (37.5%) described a history of migraine many years prior to menopause. Three of these women were excluded from the study because they had documented migraine relief during, the menopause without therapy. Five women reported migraine only after the onset of menopause. Of these five only two were included in this study. The other three were found to have organic pathology* as the cause of migraine and were eliminated from this study. A total of 50 patients remained in the study for analysis.

*One patient, posterior fossa brain tumor; one patient, a demyelinating disorder; one patient, severe osteoarthritis.

Menopause was confirmed in all patients (serum FSH and LH levels over 40 mIU/ml), Previous headache medications were continued as needed. Of the 50 migraine sufferers, 23 (46%) were diagnosed as having chronic headache with intermittent migraine secondary to long-standing migraine occurrence. Nonhormonal medical management (trigger point injections as described by Travell,[14] coupled with physical therapy) was effective for these women, and they were excluded from further analysis. Three additional women effectively continued nonestrogenic hormonal therapy. Estrogen therapy was evaluated in the remaining 24 patients.

Migraine symptoms in six women had previously not been relieved by cyclic conjugated estrogen therapy. However, four of these women were also receiving progestogen for 1 week per month; as an initial measure to reduce migraines, this medication was discontinued. One of these women had relief of migraine; she was continued on cyclic conjugated estrogen and remained migraine free. The five remaining patients were placed on continuous conjugated estrogen; one woman became migraine free. The four who continued to have migraines were next administered oral estradiol daily, but no change occurred. When they were switched to the transdermal estradiol, however, two reported relief of migraine. Another patient reported migraine relief after placement of subcutaneous pellets of estradiol and testosterone.

In the group of 18 migraine sufferers who had not previously been on estrogen replacement therapy, half (nine) received oral estradiol daily; three of these reported complete relief. The remaining six women were then treated with transdermal estradiol; four experienced relief while two continued to have migraines. The other half (nine) were initially begun on transdermal estradiol; six noted relief of migraine. One of these women switched to estradiol subcutaneous pellets and remained migraine free. One of the remaining three sufferers noted relief with oral estradiol while two reported continuing migraine.

Limited side effects were noted for each medication used. With both oral estrogens and transdermal estradiol, some patients complained of worsening migraine, and the medication was stopped. Progestogen, added to the regimen of six migraine-free patients on continuous estrogen therapy, produced a return of migraine and mood disturbances in four as well. These symptoms disappeared when progestogen was discontinued. Six of 19 patients on transdermal estradiol recorded symptoms severe enough to warrant discontinuation of the hormonal medication: two had worsening of migraine complaints, three described severe allergic skin reactions, and one developed a hepatic tumor (after oral estrogen for 18 months, followed by transdermal estradiol for 18 months).

These statistics demonstrate that estrogen replacement was effective in relieving menopausal migraine in 19 of the original 50 patients studied. However, the limited sample size prevents a clear differentiation between the effectiveness of oral versus parenteral estrogen, or any conclusion with regard to a specific chemical formulation of oral estrogen.

DISCUSSION
A strong correlation exists between menopausal migraine and estrogen levels. Migraine was documented both during the week women were not taking cyclic conjugated estrogen and the week they were administered progestogen. As explained by the Sommerville model of estrogen withdrawal, the drop in serum estrogen level that occurred during the days in which oral estrogen was not taken may serve to trigger neurovascular changes that precipitate migraine. Progestogen, by competing with estradiol receptors within central brain structures, could also cause migraine.[15]

Continuous estrogen therapy, acting through the estradiol receptor mechanism within the central nervous system, may help in the treatment of menopausal migraine. Estradiol restores endogenous opioid activity in postmenopausal women and stabilizes central dopaminergic and serotoninergic systems in the hypothalamus.[16] Estrogen withdrawal and possibly progestogen induction have an opposite effect, decreasing this endogenous opioid activity. This may explain why progestogen contribute to mood disturbances and migraine, whereas estrogens stabilize mood and eliminate migraine.

"Once estrogen levels have been restored, withdrawal for a few days each month could produce the return of migraine."

CONCLUSION
Multiple factors influence menopausal migraine, as evidenced by the fact that approximately half the women (23 of 50) in our study who had migraine prior to menopause developed a pattern of chronic headache with intermittent migraine that responded to nonhormonal therapeutic modalities. Five patients failed to respond to any estrogenic modality and three continued nonestrogenic hormonal medications. Therefore, it appears that 19 (79%) of the remaining 24 with menopausal migraine had an estrogenic component, as evidenced by their positive response to estrogen therapy. Only 5 of 50 (10%) had migraine develop after the onset of menopause and 60% of this group had documented neurologic pathology. This underscores the need to pay specific attention to patients who develop migraine only after menopause; rule out serious pathology before initiating estrogen therapy.

Estrogen withdrawal at menopause does not appear to be a key factor in migraine, as most women experienced migraine prior to menopause. This clinical study showed,however, that estrogen supplementation relieves migraine complaints in some menopausal women. The evidence was further strengthened by the observation that once estrogen levels have been restored, withdrawal for a few days each month could produce the return of migraine. This also explains the group of patients in whom estrogen withdrawal or the addition of progestogen results in cyclic migraine.

The use of continuous estrogen replacement in the menopausal migraine patient should be considered appropriate therapy. It is surprising that this treatment modality has rarely been considered in the past, perhaps because of an unfounded fear of exacerbating migraine. Because of the limited number of patients in this study, further trials are indicated to establish the effectiveness of the various estrogenic compound . For those who cannot tolerate oral estrogenic preparations, a trial of the transdermal estradiol should be substituted.

References

  1. Bono G, Micieli G, Sances G, Calvani M, Nappi G. 5-HTP-treatment in primary headaches: an attempt at clinical identification of responsive patients. Cephalgia 1984;4:159-165.
  2. Welsh KMA, Dannley D, Simkins RT. The role of estrogen in migraine: a review and hypothesis. Cephalgia. 1984;4:227-236.
  3. Watters WE, O'Connor Pj. Epidemiology of headache and migraine in women. Neurology Neurosurg Psychiatry. 1971;34:148-153.
  4. Klee A. Clinical Study of Migraine. Copenhagen:;Munksgaard; 1968
  5. Edelson RN. Menstrual migraine and other hormonal aspects of migraine. Headache. 1985; 25:376-379.
  6. Desrosiers JJJ. Headaches related to contraceptive therapy and their control. Headache. 1973;13:117-124.
  7. Kudrow L. The relationship of headache frequency to hormone use in migraine. Headache. 1975;15:36-40.
  8. Epstein MT, Hockaday JM, Hockaday TDR. Migraine and reproductive hormones throughout the menstrual cycle. Lancet. 1975; 1: 543-548.
  9. Sommerville BW. The role of estradiol withdrawal in the etiology of menstrual migraine. Neurology (Minn). 1972;22:355-362.
  10. Sommerville BW. Estrogen-withdrawal migraine. 1. Duration of exposure required and attempted prophylaxis by premenstrual estrogen administration. Neurology. 1975;25: 239-244.
  11. Sommervile BW. Estrogen withdrawal migraine:II. Attempted prophylaxis by continuous estradiol administration. Neurology. 1975; 25:245-250.
  12. Sommervile BW. Estrogen withdrawal migraine:II. Attempted prophylaxis by continuous estradiol administration. Neurology. 1975; 25:245-250.
  13. Greenblatt RB (ed). Menopausal Syndrome. New York: Medcom Press; 1974:102-110.
  14. Travell JG, Simons DG. Myofascial pain and dysfunction. The Trigger Point Manual. Baltimore;Williams and Wilkins; 1983:165- 330.
  15. Facchinetti A, Nappi G, Genazzani AR. Clinical findings of headache in postmenopausal age. In: Fioretti J, ed. Postmenopausal Hormonal Therapy: Benefits and Risk. New York: Raven Press; 1987:67-70.
  16. Sicutei F, Fanciullacci M. Dopamine as an agonist in opiate and endogenous opioid abstinence. In: Calne DB, McDonald Rj, Horowski R, Wuttke W, eds. Lisuride and Other Dopamine Agonists. New York: Raven Press; 1983:481- 488.

DISCUSSION

Dr. M. Chrystie Timmons: Have you examined the effectiveness of estrogen patches for migraine?

Dr. Lichten: In premenstrual patients the response rate is better than 60%. The patch is used for approximately 3 days before the migraine typically occurs and is used throughout menstruation. Some patients need to use patches for a week after menstruation. In some premenopausal women the continuous use of patches has virtually eliminated migraines.

Dr. Lila Nachtigall: Is there any concern about using a patch in a premenopausal woman who is still making her own estrogen?

Dr. Lichten: The patch adds a relatively low level of estradiol and an even lower level of estrogen. It probably has no significant effect on the endometrium. It only maintains the threshold level.