The Use of Leuprolide Acetate in the Diagnosis and Treatment of Menstrual Migraine: The Role of Artificially Induced Menopause

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

 

Reprinted from
Headache Quarterly, Current Treatment and Research

Edward M. Lichten, M.D., F.A.C.O.G., F.A.C.S., Jason B. Lichten, B.A.,
Albert J. Whitty, Ph.D., and David Pieper, Ph.D.
Headache Quarterly, Current Treatment and Research. 1995;6:4:313-317

 

Abstract:br> Objective: To access the effect of leuprolide acetate and oophorectomy on menstrual migraine in reproductive age female subjects.
Study Design: Twenty-nine women with recurrent, medically unresponsive, menstrually related migraine were treated for 2 months, first with placebo, then depo-leuprolide acetae 3.75 mg. Those who became migraine free on leupolide acetate continued this therapy for 12 months, added transdermal estradiol, and when appropriate, were offered hysterectomy and bilateral oophorectomy.
Results: Of 29 women, 17 remained migraine free at 2 months. Fourteen remained relatively migraine free at one years. Of these 14 women, 13 elected surgical castration within 2 years and 12 remained relatively migraine free an additional year.
Conclusions: In the diagnosis of hormonally related migraine, leuprolide acetate therapy was helpful in determining which patients might benefit from surgically induced menopause. Although neither leuprolide acetate therapy nor bilateral oophorectomy should be routine in the treatment of hormonally related migraine, their effectiveness in these selected patients supported the concept that hormonal migraine is a distinct clinical entity.

Background Information:
Headache is one of the most common complaints of patients in a doctor’s practice. Although more than 80 percent of the intense, periodic headaches or migraines 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 nonsteroidal anti-inflammatory agent (NSAID) and a prophylactic agent, typically a beta-blocking or calcium-channel blocking agent; then, add an antidepressant such as imipramine for its central nervous system effects. Should this fail, the secondary treatment focus is on interrupting or aborting the migraine attack, using medications that act as vasoconstrictive agents such as caffeine, ergotamine, isometheptene mucate, or methysergide maleate. However, even with multiple drug therapies, migraine at or near menstruation remains extremely difficult to treat effectively.

Previous demographic studies here and in China (Zhao et al, 1988), document: 1) 5:1 ratio of female to male headache sufferers; 2) the peak incidence of first occurrence at age 15 to 19 (puberty); 3) the rarity of headaches before age 10 or after age 60; and, 4) the correlation of severe migraine attacks to menstruation. Although 70 percent of the most severe migraines experienced by women are premenstrual, less than 7 percent of these women report migraine exclusively at the onset of menstruation. In a recent publication (Lichten et al, 1991), we confirmed that the use of danazol, an ethinyl-testosterone derivative, was effective in preventing the most severe premenstrual and menstrual migraine in more than 62 percent of the 131 women studied. We proposed the mechanism of action was by preventing the luteal phase rise and then fall in estrogen.

However, danazol has multiple modes of action including its androgenic effect and its ability to bind to various intracellular androgen, progesterone, glucocorticoid, and estrogen receptors. Therefore, the direct action of danazol on estrogen levels may or may not be the proposed true mode of action on these women's migraines.

This study was undertaken to record what effect the GnRH-agonist leuprolide acetate, which directly suppresses the pituitary-ovarian axis without androgenic or progestational actions, might have on women with complaints of intractable, periodic, menstrual migraine attacks. The plan called for using the GNRHagonists in injectable form, initially for 2 months, and subsequently for up to one year in those who remained relatively migraine-free.

MATERIALS AND METHODS
Definition of Terms
Menstrual migraine refers specifically to those attacks that occur within the first 2 days of 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 intermittent not constant; 3) association with photophobia, and phonophobia; and, 4) the systemic symptoms of nausea, facial pallor, and the interruption of the person's normal activates. Migraine, by definition, cannot be associated with any physical or organic lesion.

Patient Selection
A group of women between the ages of 26 and 47 years of age with a primary diagnosis of migraine, as defined by the Headache Classification Committee of the International Headache Society (1988), was asked to participate in the study. These patients were selected based on their failure to respond to all previous medication trials. Each woman had experienced more than one day of severe and incapacitating migraines per month at the onset of menstruation over the preceding 5 years and had been seen in emergency departments at least four times in the previous 12 months. Each patient had previously been diagnosed by an internist and/or neurologist as experiencing migraine without aura. Each reported no improvement or side effects with medical treatments (propranolol, ergot amine with caffeine, amitriptyline, NSAIDS, danazol, butalbital combination analgesics, and physical therapy). Each patient had been evaluated for both temporal mandibular and cervicogenic headaches by a licensed physical therapist (Ph.D.). Each volunteer for the study underwent an anesthetic blockade of the major occipital nerve per the criteria of Sjaastad et al (1990), and recorded no relief from headache pain.

The human subject Institutional Review Broad of Providence Hospital, Southfield, Michigan, approved the study design and method. Each participant completed a written informed consent form prior to her enrollment. Each subject was required to complete a daily diary to verify headache occurrence, frequency, and intensity, any use of medication, and any resultant headache relief throughout the course of treatment.

Headaches were to be logged daily on a five-point rating system: 0 = no pain; 1 = mild pain requiring no medication; 2 = moderate pain responding to mild analgesics; 3 = severe pain requiring class 11 pain relievers, such as a butalbarbital combination analgesic; and, 4 = incapacitating pain unresponsive to amine/ caffeine and codeine. All patients reported pain at level 4, usually lasting for several days each month. They documented that their most intense headaches occurred immediately preceding menstruation and into the second day of menstrual flow.

All patients underwent a complete physical examination including basic blood profiles and an electroencephalogram, visual evoked potential, and brain auditory response. All had either a CT scan or an MRI after the failure of the previous treatment modalities. Subjects with abnormal test results were excluded, as were those with a history of major psychiatric disorders, drug abuse, and underlying medical conditions. Serum hormonal assays excluded those with hypothyroidism, hyperthyroidism, hyperprolactinemia, and menopause.

The study plan consisted of three phases. After confirming the failure of previous drug therapies, the first phase consisted of 2 months of injection of 1 cc of normal saline as placebo, followed by 2 months of the active agent, depo-leuprolide acetate 3.75mg. The second phase consisted of continuous leuprolide acetate therapy for up to 12 months. During this second phase, the transdermal estradiol 0.05mg "add-back" was used to minimize the osteoporotic changes and vasomotor instability associated with leuprolide acetate's hypoestrogenic state. Phase three was limited to those who discontinue leuprolide acetate therapy after more than one year in lieu of surgical castration and hysterectomy (while continuing transdermal estradiol therapy).

Treatment success was defined as a greater than 50 percent reduction in the headache index, calculated as the monthly summation of daily headache indices graded on the 1 to 4 severity scale. For statistical purposes, the maximum headache index per month was limited to 50. Patients were also asked to record the amount of medication used and the number of trips to the emergency room and office for injectable opioids. Any complications were to be reported immediately during any phase of this study.

Statistical Analysis
Data was collected over the course of the study on the study forms and then entered into a computerized data base. The principal statistical data analysis used the student t-test comparing the effect of GNRH agonist to the other factors at each phase of these study Statistical analysis was performed using the BMDP statistical package.

RESULTS
Twenty-nine patients entered the 2-year study. Fourteen reported a greater than 50 percent decrease in the headache index after the first 2 months and continued the medication for at least one years; three reported a 50 percent decrease in headache index but discontinued the study prior to one year (cost, side-effects); five expressed some improvement but less than 50 percent by headache index; and seven had severe side-effects for which they had to discontinue the medication after the first month and seek treatment for complications of GnRH therapy (six: status migraine, one: joint pain).

The demographics of the 29 participants and the statistical evaluation of thier demographics are noted in Table 1. The calculated mean age of the study participants was 37.85 - 1.53 years; the average age of first menses was 12.9 years; and the average age of first migraine was 21 - 1.7 years with a range from 9 to 36 years. The severity of migraine measured by the headache index was equally distributed between those women over and those under 40 years of age.

There were no overwhelming demographic or statistical differences between those who: 1) reported a >50 percent improvement on leuprolide (17 volunteers); 2) those with less than 50 percent improvement on leuprolide (5 volunteers); and, 3) those with worse symptoms on leuprolide (7 volunteers). Approximately two-thirds of the study participants reported migraine beginning prior to age 24 and being present for more than 10 years.

LEUPROLIDE ACETATE-MENSTRUAL MIGRAINE STUDY

Leuprolide acetate for greater than 4 months and surgical castration (oophorectomy and TAH)
	on entry                  menarche headache index
name         age        G/P            /1 st HA     before/lupron#l/lupron2/after2yrs TAH/BSO endo/dysmenorrhea
PB	42  G2P2	16/17	50	38	26	11  yes	no   no
JK	37   G2P2	11/33	45	26	12	6    yes	yes  yes
PPB	40   G2Pl	13/18	34	24	13	8    yes	no    yes
BG	45   GOPO	14/24	23	6	4	1    yes	no    yes
LB	40   G2Pl	14/31	21	8	5	6    yes	yes   no
LD	36   GlPl	14/12	20	5	3	2    no	no     no
JS	36   G5P2	15/28	50	10	19	12  yes	no     no
MA	31   G4P3	13/20	39	19	6	18  yes	no     no
AA	36   GOPO	16/3	42	18	14	6    yes	yes   yes
EG	43   G3P3	13/27	44	26	14	8    yes	no     no
LG	40   GlPl	9/11	39	12	10	7    yes	no     no
LR	35   G2Pl	14/22	50	30	22	16  yes	yes    yes
JS	42   G3P2	11/36	50	26	16	5    yes	no      no

Leuprolide acetate for 2 months - minor side effects
KP	27   GOPO	13/12	18	6	7	3    no	n/a     yes
KC	32   G3P3	13/29	31	12	15	8    no	yes     yes
SH	45   Gl Pl	13/36	36	1	6	1    no	n/a      yes
LC	37   G5P2	12/13	50	10	19	12   no	yes     no
RD	32   G3P2	10/23	44	2	1	-     no	no       no
TM	25   GOPO	11/23	24	4	4	-     no	n/a      no
LH	46   G3P2	11/11	22	18	8	-     no	n/a      no
JD	45   G2P2	10/17	31	21	18	-     no	no       no

Discontinued study after 1 month - Severe side effects
GD	39   G2P2	13/12	50	50	-	-     no	no       no
LG	35   G2P2	12/9	32	50	-	-     no	yes     yes
JJ	46   GOPO	15/23	46	50	-	-     no	n/a      no
SK	32   G3P3	15/26	36	50	-	-     no	no       no
LF	35   Gl Pl	13/19	30	50	-	-     no	yes     yes
TS	26   G3Pl	14/24	24	35	-	-     no	yes     yes
AL	29   GOPO	14/19	36	50	-	-     no	no       no

Average age participant	37.85 - 1.53 years
Average age first menses	12.9 
Average age first migraine 21 - 1.7 years

At the end of the 2 month study period, the probability of leuprolide being effective for the
reduction of the headache index was p < .01. Those who experienced control of their severe
migraines and who were followed for more than 2 years, were noted to also use significantly
less pain medication (based on the Headache Index) than when they entered the study;
p < .001 (figure 1). Transdermal estradiol "add-back" was not associated with any
subsequent increase in the headache index. Similarly, one year after surgical castration,
only one patient recorded significant headache activity, albeit at 50 percent of pre-treatment level.

Figure 1: Leuprolide acetate effect on migraine.

The study population was also noted to have the following gynecologic complaints: dysmenorrhea (11 of 29 volunteers), and endometriosis (10 of 23 with previous pelvic surgery). These symptoms and findings were present equally in those whose migraines responded to leuprolide and those who did not respond. Expectedly, 5 of 7 patients with endometriosis had a complaint of dysmenorrhea.

The finding of a severe drug reaction in 7 of 29 volunteers given leuprolide acetate was completely unexpected. Although a worsening of migraine might occur, the severity and "status migrainosus" in five patients for up to 4 weeks was a difficult complication to treat.

DISCUSSION

Although much has been written about the interplay of women's hormones, specifically estrogen with migraine attacks, few researchers have been able to establish a scientific basis to this phenomenon. Somerville (1972), using estradiol injections to interrupt menstrual migraine attacks, first documented the temporary delay; secondly, the higher estrogen levels; and lastly, the worsened migraine attack when the estrogen level fell below a relative "estrogen threshold." Although Somerville clearly presented the concept that the menstrual migraine attack was precipitated by the fall in estrogen levels at menstruation, attempts to prevent migraine by maintaining elevated estrogen levels failed. Dennerstein et al (1988), Greenblatt (1 975), and Lichten (in press) reported control of various migraines in women using respectively, the percutaneous estradiol patch (in menstruating women), estradiol pellets (in both), and depo-estradiol injections (in menopausal women). These studies confirmed a definite role for additional studies of both estrogenic and anti-estrogenic hormonal therapies in migraine.

Although the present study selected for "lupron successes," the fact that these patients had documented severe migraine headaches for years and failed to respond to all standard modalities, physical therapy, and anesthetic blockade makes their response to "artificial menopause" significant. For leuprolide acetates success and that of bilateral oophorectomy, reconfirm the finding that a stable, low level of estrogen, may also be effective in controlling hormonal migraine, just as danazol therapy established in a previous publication (Lichten et al, 1991).

The unusual finding of 10 confirmed cases of endometriosis in 23 of the study patients' operative reports may be explained by the patient population referred to this facility. Further studies in a large population are planned to discover if a significant correlation could exist between the clinical finding of endometriosis and the complaint of severe migraine.

The development of severe daily migraine in four patients given leuprolide acetate was troublesome. The worsening of migraine with the use of GNRH agonists must be recognized as a complication of such therapy. The initial use of a daily GNRH agonist might allow for the rapid reversal of these symptoms should they occur.

CONCLUSIONS

Many migraines in women appear to be hormonally related events, based on both demographic and large cohort studies. This study supports the concept that the fluctuation and fall of estrogen levels premenstrually can trigger some women's migraine attacks. Leuprolide acetate, by suppressing estrogen levels, prevented the most severe migraine attacks in 52 percent of female study participants unresponsive to all previous medical and physical therapies. As reported previously, hormonal suppression therapy seems to work best for those with migraine in the week before and first few days of menstruation. Of the 14 women in whom the leuprolide acetate and transdermal estradiol therapy was successful in preventing migraine occurrence, 13 elected surgical castration (oophorectomy and prophylactic hysterectomy) in an attempt to prevent migraine reoccurrence after discontinuing leuprolide acetate. Transdermal estradiol "add-back" during prolonged leuprolide acetate therapy and post-oophorectomy was an effective means of relieving menopausal symptoms without precipitating recurrence of migraines.

This study confirms that both leuprolide acetate and oophorectomy, by inducing a hypoestrogenic state, could be instrumental in controlling the worst premenstrual and menstrual migraine attacks in some women. Oophorectomy should not be offered unless leuprolide acetate and transdermal estradiol "add-back" are successful in relieving migraines for at least 6 months. Recognization must be made of the unexpected and serious side-effect of status migraine. This complication aside, the study established that there is a place for further hormonal and medication headache research to understand their unique roles in the diagnosis and treatment of hormonal migraine, a distinct and significant clinical entity.

CITED MEDICATIONS
LEUPROLIDE ACETATE (lupron) TAP Pharmaceutical
ESTRADIOL  (estraderm)               (Estrace CIBA Pharmaceutical                          Bristol-Myer-Squibb
NSAIDs  
Propanolol  (Inderal-LA) Wyeth-Ayerst
Calcium Channel Blockers  
Amitriptyline  (Elavil) Stuart
Ergotamine with caffeine Organon
ISOMETHEPTENE MUCATE (midrin) Carnrick Laboratroies
METHYSERGIDE MALEATE (Sansert) Sandoz
DANAZOL Winthrop
BUTALBITAL Sandoz
Opioids  

REFERENCES

  1. Dennerstein L, Morce C, Burrows G, Oats G, Brown J, Smith M. Menstrual migraine: A double-blind trial of percutaneous estradiol. Gynecol Endocrinol. 1988; 2:113-120.

  2. Greenblatt RW. Menopausal Syndrome. New York: Medcom Press; 1974; 102-110.

  3. International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuraigias and facial pain. Cephalalgia. 1988; 8(suppl 7):10-73.

  4. Lichten EM, Bennett RS, Whifty AJ, Daoud Y. Efficacy of danazol in the control of hormonal migraine. JReproducMed. 1991; 36:419-424.

  5. __________, Lichten JB, Whitty AJ. The Confirmation of a Biochemical Marker for Women's Hormonal Migraine: The Depo-Estradiol Challenge Test. Headache. 1996;36(6):367-70.

  6. Sjaastad 0, Fredriksen TA, Pfaffenrath V. Cervicogenic headache: Diagnostic criteria. Headache. 1990; 20:725;726.

  7. Somerville BW. The influence of progesterone and estradiol upon migraine. Headache. 1972; 12:93-102.

  8. Zhao F, Tsay JY, Cheng X, Wong W, Li S, Yao S, et al. Epidemiology of migraine. A survey in 21 provinces of the People's Republic of China, 1985. Headache. 1988; 28:558-565.


Acknowledgement

This study for supported by a TAP-Abbott Laboratories Grant.

 

Lichten's Pearls

Luprolide Acetate is a very potent blocker of FSH and LH.  Lowering not only estrogens but also testosterone and progesterone creates a menopause. Its use in this study was to prove the pathophysiology of menstrual migraine. Its side-effects are much worse than danazol and is not recommended for long-term use. The use of hysterectomy in these severe cases was predilected by a secondary gynecologic pathology.