The Confirmation of a Biochemical Marker for Women's Hormonal Migraine: The Depo-Estradiol Challenge Test

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


Reprinted from
THE JOURNAL OF HEADACHE Vol. 36 No. 6, pp. 367-371, June 1996

Edward M. Lichten, MD; Jason B. Lichten, BS; Albert Whitty, Ph.D.; David Pieper, Ph.D.
From Southfield, Mich. (Dr. E.M. Lichten); Thomas Jefferson University, Jefferson Medical College, Philadelphia, PA. (Mr. J.B. Lichten); Sinai Hospital of Detroit (Mich.) (Dr. Whitty); and Providence Hospital, Southfield, Mich. (Dr. Pieper).
Address all correspondence to Dr. Edward M. Lichten, 180 East Brown Street, Birmingham, Michigan 48009 (248.593.9999)
Accepted for publication July 15, 1995.


Precise: Will estrogen withdrawal cause migraines in post-menopausal women?
Objective: To record the changes in serum estradiol and total estrogen levels after an intramuscular estradiol injection in menopausal subjects and then record any subsequent migraine occurrence.
Design: Open selection process, comparative trial.
Patients: Twenty-eight postmenopausal women volunteers were given 5 mg Depo-Estradiol cyprionate as an intramuscular injection. Sixteen (migraine group) had a history of severe, cyclic, menstrually related migraine attacks before becoming menopausal. Twelve (control group) had no history of migraine or headache. All volunteers were on continuous estrogen replacement therapy at the beginning of the study. Progestins were not used in the study.
Main Outcome Measures: Serum estradiol and total estrogen levels were measured prior to the Depo-Estradiol injection and on subsequent days 4, 7, 14, 21, and 28.
Results: Total estrogen and estradiol levels varied greatly at every measured interval. Menopausal complaints of vasomotor symptoms were relieved for at least the first 2 weeks of the study. No member of the control group reported a migraine during the month. However, a severe migraine was reported by all 16 women with a history of migraine. The average day of the migraine occurrence was 18.5 + 2.8. The serum level of estradiol on the day of the worst migraine was 46.4 5.6 pg/mL. The significance of these findings was at the 95% confidence level.
Conclusions: This study confirms two factors about menopausal hormonal migraine: (1) it can be precipitated by a drop in serum estrogen levels, and (2) a period of estrogen priming is a necessary prerequisite. This study also identifies that there are two biologically different populations of postmenopausal women: (1) those who developed migraine after a single depo-estradiol injection, and (2) those who did not. By understanding that in addition to the biological predisposition to migraine there exists the biochemical cofactor of falling estrogen levels, we may better understand this phenomenon and develop means to prevent its occurrence.
Key words: biochemical marker, migraine, depo-estradiol, estrogen withdrawal
(Headache 1996;36:367-371)


Medical literature has linked gender to migraine. This was evident when considering statistical data on the occurrence of migraine. Women of reproductive age, 15 to 50 years, experienced more than five times as many migraine headaches as men of similar age, worldwide.[1] In fact, while girls under 10 years of age and women over 60 reported a similar incidence of migraine, 20% to 30%[2] of all women in their childbearing years described "an attack of vascular headache of migraine type in the previous year.[3] Klee [4] and Edelson[5] went one step further, showing that 60% to 70% of these women described most of their headaches just before menstruation. Since estrogen levels drop sharply prior to menses, this hormonal change has been suggested as a major factor in the occurrence of migraine in women.

Somerville, an Australian neurologist, was the first to substantiate that a drop in serum estradiol levels correlated with the occurrence of migraine.[6-9]In a small study of eight women whose migraine occurred only at the onset of menses, he was able to delay some of the attacks of migraine by 3 to 9 days with intramuscular estradiol valerate injection.[7] Recognizing that estrogen levels spiked at ovulation and then gradually rose and fell during the remainder of the luteal phase, Somerville repeated the study with estradiol injections at ovulation. However, no subject experienced migraine after the injection, nor did any note a change in migraine at the time of menses. Somerville, after considering the different timing of the estradiol injections, concluded that it was not only the drop in the estrogen level that triggered migraine, but rather it was also that 'a period of several days of exposure to high estrogen levels may be necessary before withdrawal of estrogen could result in migraine." [7] Somerville reasoned that migraine could be prevented if the estradiol levels could be maintained above a migraine threshold. However, he was unsuccessful in doing so using the parenteral preparation of estrogen pellets available in 1975.[9]

Somerville's three significant postulates should be noted: (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. Kudrow noted that menopausal migraine sufferers typically reported their migraines 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 fewer migraines.[10], in an analysis of menopausal women she followed for several years, noted that the addition of oral estrogen effectively decreased migraine complaints in two thirds of the 49 patients who recorded this specific complaint.[11] Greenblatt[12] attested to the relief estradiol pellets provided for some of his menopausal migraine patients. Lichten [13] found that the use of continuous oral or transdermal estrogen replacement was effective in alleviating menopausal migraine in 19 of 24 subjects. Dennerstein and coworkers [14] also confirmed that the use of transdermal estradiol patches prevented migraine in some menopausal women. However, in none of these studies were serum estradiol levels measured, nor were estradiol injections given in the management of the menopausal migraine.

This study was initiated to accurately document serum estradiol levels in relation to the occurrence of the menopausal migraine and to determine what influence changing serum estradiol levels might have on migraine attacks. Intramuscular injections were selected as the method of administering estradiol because they are unaffected by patient compliance and variations in oral or transdermal absorption.


The proposed study was approved by the Institutional Review Board of Providence Hospital in Southfield, Michigan. Menopausal women volunteers, with and without present complaints of migraine, were identified from the private medical practice of the primary investigator. Using the definition of migraine as proposed by the Headache Classification Committee of the International Headache Society," the comprehensive history was first recorded by J.B.L. Questions included family history; whether the volunteer experienced migraine and if so, the first onset of migraine; the correlation to menses, pregnancy, onset of menopause, and effects of previous hormonal medication; previous diagnostic testing; nonhormonal medication use; and the degree the headaches interrupted the normal life-style of the patient at the time of the study. Each had documented the severity and frequency of severe headaches for 1 month and the present form of hormonal therapy. All were on continuous estrogen (oral or transdermal). The location and intensity of the migraine, and the association of nausea, vomiting, phonophobia, photophobia, and other visual changes were also noted. For each patient, the follicular stimulating hormone (FSH) and luteinizing hormone (LH) serum levels had to exceed 20 pg/mL; indicative of menopause. The thyroid stimulating hormone (TSH), T3 uptake, free T4 value, prolactin level, complete blood count (CBC), chemistry profile (SMA 12), and lipid profiles had to be within the normal range. None were taking any regular medication for headaches except analgesics, and each volunteered to return for periodic blood tests on days 4, 7, 14, 21, and 28 after the injection.

All volunteers were next examined by E.M.L. Care was taken to insure that migraine was not the result of other factors. As such, each patient was questioned about dietary and sleeping habits that could trigger migraine attacks. The specific intent of the physical examination was to exclude headaches of an organic nature that could mimic migraine. Assessment for the presence of cervicogenic headache was made using the protocol of Sjaastad et a 116 and the trigger point injection techniques of Travell and Simon."

Temporal mandibular joint dysfunction and facial pain of sinus origin were excluded both by historical presentation and when indicated, by selective anesthetic placement. Only when the investigators agreed that the menopausal subject was either headache-free or had suffered exclusively from migraine was she offered participation in this study. Treatment for migraine throughout the study was limited to analgesic agents.

In total, 16 menopausal women reported a past history of severe incapacitating migraine in association with their monthly menses and they comprised the "history of migraine" group. Twelve other women without any migraine or headache history were included as the "control" subjects. It must be noted that no volunteer was having severe migraine at time of entry into the study nor was any taking medication other than the estrogen replacement.

All blood sampling was processed in batch and run in duplicate. Estrogen assays were performed using I.C.N. Biomedicals, Inc, R.S.L. total estrogen radioimmunoassay kits and Diagnostic Systems Laboratories radioimmunoassay estradiol kits. The serum was collected as the supernate after centrifugation at 20g for 5 minutes. All assay tubes were counted on the Packard Crystal Multi-detector RIA System Gamma Counter and run in batch assay mode.

The estradiol preparation was depo-estradiol cyprionate, 5 mg/mL. The injection, consisting of 1 mL, was given in the outer gluteal muscle on day 1 of the study. No other injections or medications were scheduled to be used for the next 28 days.

Data was manually collected from the charts and checked for errors. This information was entered into a Lotus 1-2-3 format for future analysis. After initial tabulation for averages and standard deviation, further analysis was performed using Fox Data Base Statistical software.


The specific and average serum estradiol values for the migraine, control, and combined groups and respective standard deviations for days 0, 4, 7, 14, 21, and 28 of the study period appear in Tables 1, 2, and 3. The averages and standard deviations for the migraine group and the controls show wide variations at every recorded blood draw. There is no statistical difference between the serum estradiol levels for the migraine and control groups (Fiure 1). The only difference between the two groups is the history of migraine (Table 4). Fifty percent of the headache group had a family history of a first-degree relative with migraine. One hundred percent of those experiencing migraine during the study had a personal history of cyclic, menstrually relate migraine before the menopause.

The serum estradiol level on the day of migraine were found to average 46.4 pg/ml with a standard deviation of 5.6 pg/ml. The day of migraine occurrence was between days 13 and 21. The average day of migraine was 18.5 + 2.8. The mean serum level of estrone was 178 + 77.9 pg/ml and the total estrogen 220 + 124 pg/ml, on the blood drawn closest to the most severe migraine. Additionally at this time the study participants described the migraine as more severe than any other they had experienced in recent years.

Table l.-Results of Serum Estradiol Levels (pg/mL) in 16 Women with History of Migraine

Level Recorded on Day

Patient	0	4	7	14	21	28  Headache on Day
1 59 57 236 83 35 29.2 22 2 31.3 92 111.5 61.4 87 9.9 23 3 88 92.5 129.5 50.4 42.4 39.2 16 4 88.5 116 84.3 79 24.1 34.4 18 5 39 170 243 59.7 38 18 6 222.2 95 49.2 71.3 42 11.1 23 7 24 150.4 173 59.1 30.3 21.2 15 8 277 248 108 96 41.1 46.4 20 9 31 105 77 31.5 109.7 194 18 10 13 125.3 162 38.2 28.5 23 19 11 152 46 65.2 36 22 14.3 14 12 429 300 126 28.7 18.1 21 13 116 158 91.8 39.7 16.5 21 14 36 43.3 55 46 14 15 332 249.5 147 71.2 37.5 13.5 18 16 19.3 143.2 101 41.7 25.3 12.1 17 -----------------------------------------------------------------------------------------------------
Table 2.-Results of Serum Estradiol Levels (pg/ml) in the Control group in the Control Group

Level Recorded on Day
Patient 0 4 7 14 21 28

1		97.4	80.3	18	38.7
2	77.3	177	105	95	65.8	77
3	110	173.7	45.5	81.4	30	14.7
4	46	147.6	230.4	120	74.3	13.8
5	123.3	127.1	121	120	19.6	22
6	32.6	62	65.1	30	26.8	44
7	14.5	58	216	180.5	14.2	24
8	224	125	286	207	49
9	54.8	211	189	81	103
10	71	165	97	32	47.2	26
11	123.3	127.1	121	120	19.6
12	7.1	103	88.6	54.2	10	2.3

Table 3.-Results of Mean Serum Estradiol Levels (pg/mL) in the Combined Group

Level Recorded on Day 0	   4	      7	    14	   21      28

Migraine group	106102	12963	13159	6221	4325	3725
Control group	8862	11549	13775	9559	428	2813
Total patients	9587	12356	13466	7745	5926	3440
Table 4.-Demographic Characteristics

						Headaches By

	Group  Age,years   Height, in     Weight, lb   No Ovaries   Fam Hx Migraine Hx

Migraine (n=16)	42  5    63.6  2.8	150.5  28.8    60     50% yes  100% yes
Control (n=12)	48 + 7    64.8  1.5	164.5  31.6   72%	none   none
Control-2(n=10)* 	45  5    64.8  1.5	155.3  19.3   75%	none   none

*Excluding two oldest controls.

The average age of the headache group was 5 years less than the control group 42 + 5 versus

47.9 7 (Table 4). If the two oldest patients were removed from the study, the control group's age drops to 45 4.6. The control group was on average 1 inch taller and weighed 4 pounds more than the headache group. However, recalculation of all variables, even after exclusion of the two oldest control subjects, did not affect the statistical significance of any of the relative parameters.


Previous literature on the subject of menopausal migraine has been confusing, based on the absence of serum estrogen levels and adequate exclusion criteria to focus exclusively on hormonal aspects of migraine. The incompatibility of estradiol levels between institutions has already been noted."' Nevertheless, Kudrow, Stryker, Dennerstein et al, and Greenblatt concluded that there was a positive effect on migraine when estrogen was given continuously.
This present study focused exclusively on menopausal women who received a 5 mg depo-estradiol injection instead of their oral or transdermal estradiol replacement. The findings confirmed that for the 16 volunteers with a history of cyclic, menstrually related migraine, migraine did recur after the depo-estradiol injection. These migraines occurred within a narrow window of time, day 14 to 23. Only retrospectively was it identified that 100% of the women experiencing migraine after the depo-estradiol injection had a previous history of migraine. There was statistical significance when comparing the serum estradiol levels on the days closest to migraine versus other days (Figure 2). Finally, the "estradiol threshold" of 46.4 5.6 pg/mL at the time of the migraine in this population is almost identical to the 50 pg/mL (5 ng/lOOml) noted by Somerville.[8] Recognizing that migraine is definitely multifactorial by nature, family history of migraine was a significant factor in predicting menopausal migraine. But its occurrence in 50% of those who did experience migraine during the study remained less significant than the previous history of migraine during the reproductive years, as 100% of these study patients with migraine reported their occurrence after the hormonal injection.


Since not all women experience migraine, there must exist some genetic predisposition for this disorder. This can be explained by the increased occurrence of migraine within certain families. But of equal importance is the factor of estrogen withdrawal. Since migraine is mediated through changes in carotid vascularity, any drug which affects the vascular wall may have an effect on migraine occurrence. It is postulated that estrogen's mode of action may be through its effect on peripheral vein walls, as noted in recent receptor studies which documented that "estrogen receptors were found in all peripheral vein samples from fertile women but not in all samples from postmenopausal women and men."[19] Therefore, a better model of migraine in women is that of a genetic trait predisposing to migraine and a biochemical trigger of estrogen withdrawal. In those women without the genetic trait, migraine does not occur even with estrogen withdrawal. However, for those with the genetic predisposition, estrogen withdrawal either during menstruation in the reproductive years or with the depo-estradiol injections in the menopausal years will precipitate severe migraines. It is interesting that the serum levels of estradiol at the time of migraine for menstruating women in Somerville's study closely approximates that seen in menopausal women in this study.
The work of Studd and Whitehead[20] may explain why menopausal patients not on estrogen replacement still suffer with migraine. In serial estradiol draws on an hourly basis, they identified a variation of serum levels in one patient from 1 0 to 40 pg/mL. Their data showed that the menopausal ovary still may respond to the elevated serum FSH and LH levels of menopause with irregular pulsatile release of estrogen. This 'instability" may explain why some menopausal migraine patients fail ,to find headache relief without or with oral estrogen supplements.
Since the genetic makeup of the individual cannot be altered, the control of these hormonally influenced migraines necessitates a better understanding of the use of the female hormone, estrogen. The use of continuous estrogen replacement including estrogen injections in these menopausal migraine patients should, then, not be avoided because of an unfounded fear of exacerbating migraine. Rather, further studies are necessary to determine if the use of estradiol injections or other forms of continuously released estradiol can be used to prevent the occurrence of menopausal migraine by establishing a 'stable estrogen milieu."
Acknowledgment. This study was supported by a grant from Providence Hospital Research and Educational Fund 1993-643, Department of Obstetrics and Gynecology, 16001 West Nine Mile, Southfield, MI 48075.


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Lichten's Pearls

This article is the most critically important in the field of hormones and migraine. It establishes that there are two distinct groups of women, one of whom is genetically predisposed to migraine. The triggering factor for that genetic group is the drop in estradiol prior to menstruation.

Therefore, both genetic and environmental factors are important for this medical condition.

Stabilizing the estradiol level low with danazol or higher with the estradiol patch are options that are very often successful.