Efficacy of Danazol in the
Edward Lichten, M.D.,PC
Edward M. Lichten, M.D. Ronald S. Bennett, M.D. Albert J. Whitty, Ph.D. Yahya Daoud, M.A.
From the Departments of Obstetrics and Gynecology and of Neurology, Sinai Hospital of Detroit, Detroit, Michigan. Address reprint requests to: Edward M. Lichten, M.D. 180 East Brown Street, Birmingham, MI 48009. [phone 248.593.9999 Email: firstname.lastname@example.org]
Abstract: Of 131 women with hormonally related migraines unresponsive to standard medication, 67 (51.1%) noted profound relief after a 12-month, phased study using danazol for migraine prevention. The first three phases consisted of two-month cycles: dietary control and acetazolamide, the addition of danazol and danazol discontinuation. Eighty-three women (63.36%) reported control of their hormonal migraines while using danazol. In phase IV, 81 women whose headaches were controlled by danazol restarted danazol for an additional six months. Sixty-seven (82.7%) reported continued success with this medication. Danazol proved highly successful in the control of women's cyclic migraine. Its effectiveness remained consistent throughout the treatment course. In the prophylactic treatment of women's hormonal migraine, 400 mg of danazol administered daily for 25 days each month can prove effective when standard medical therapy fails. Furthermore, the response to danazol supported the concept that hormonal migraine should be treated as a distinct clinical entity.
Migraine in women most likely is a hormonal event. Women of reproductive age experience more than three times as many migraine headaches as do men of similar age; that is a striking difference from the equal incidence noted before puberty and after menopause. Statistically, 20-30% of all women of reproductive age describe "an attack of vascular headache of migraine type in the previous year." Klee and Nattero documented separately that 6070% of such women report that the majority of their headaches occur just prior to menstruation. As summarized by the National Chinese Headache Study, (1) there is a 5:1 ratio of female to male headache sufferers, (2) the peak incidence of first occurrence is at age 15-19 (puberty), (3) such headaches are rare before 10 and after 60 years of age, and (4) many women relate their headaches to menstruation. Thus, it appears that the hormonal fluctuation that governs reproduction significantly influences the incidence of migraine.
Danazol, an ethinyltestosterone derivative, prevents the rise in both estrogen and progesterone levels in the luteal phase of the menstrual cycle. Used to maintain steady, low levels of estrogen in the treatment of endometriosis and fibrocystic breast disease, danazol, we thought, might prove efficacious in preventing hormonal migraine. Calton and Burnett in fact, documented one such application. However, using danazol for only three days at midcycle defeats the agent's long-term potential.
The purpose of the study described below was to follow the standard protocol for the use of danazol daily for 25 days with an interruption for three days to allow for menstruation and to analyze its effect on hormonal migraine.
Definition of Terms
Such terms as menstrual migraine, premenstrual migraine, midmenstrual migraine, ovulatory migraine and
Materials and Methods A group of women between the ages of 20 and 51 years with a primary diagnosis of migraine, as defined by the Ad Hoc Committee on Classification of Headache were asked to participate in our 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, which included propranolol, cafergot, fiorinal, amitriptyline and nonsteroidal antiinflammatory drugs.
The human subject institutional review board of Sinai Hospital of Detroit, an affiliate of Wayne State University School of Medicine, approved the study design and method. Each participant completed a written informed consent form prior to her enrollment. Each 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 Fiorinal; and 4 = incapacitating pain unresponsive to cafergot and codeine. All patients reported pain at levels 3 and 4, usually lasting for several days each month. The overwhelming majority documented that their most intense headaches occurred in the week preceding menstruation and the first two days of menstrual flow.
All the patients underwent a complete physical examination, including basic blood profiles and an electroencephalogram, visual evoked potential and brain auditory evoked response. Subjects with abnormal test results were excluded, as were those with a history of psychiatric disorders, drug abuse and underlying medical conditions. Serum hormonal assays assisted in excluding hypothyroidism, hyperthyroidism, hyperprolactinemia and menopause.
The study plan consisted of four phases. The first three lasted two months each; the last continued the therapy for an additional six months: phase I-dietary restriction with the addition of acetazolamide, 125 mg daily, after the first month; phase II- addition of danazol, 400 mg, for 25 days per month; phase III discontinuation of danazol therapy; and phase IV- restart of danazol, 400 mg, for 25 days each month.
Phase I Within a month-long interval, patients were to chart symptoms in regard to the frequency and intensity of their migraines while adhering to a strict hypoglycemic diet with the elimination of known headache food triggers. Such foods as caffeine, cheese/ dairy products, alcohol and products containing salt, nitrites and monosodium glutamate were prohibited. Six patients (5%) noted a significant improvement and were excluded from the study.
While adhering to dietary restrictions, patients in the second month added a mild diuretic, 125 mg of acetazolamide, daily. An additional eight patients (6%) reported > 50% relief of their migraines and were eliminated from the study.
Phase IV At the conclusion of the initial six-month study, those patients who reported relief from migraine while on danazol and the return of migraine while off danazol were encouraged to continue the drug for an additional six-month period. After the second six-month trial, patients were interviewed by phone to determine the success of the treatment. This information was formatted for a computer analysis of the data.
Treatment success was defined as a > 75% reduction in the headache index, with the monthly sum of daily headaches graded on a 1-4 scale of severity. For example, a 75% reduction in the headache index could be determined by a 50% reduction in the frequency of headaches and a 50% reduction in the severity of headaches. Patients were asked to report any complications at all phases of the study.
Statistical Analysis Data were collected over the course of the study on the study forms and then entered into a computerized data base. The data integrity was double checked for quality and validity. The principal statistical data analysis used the X2 test comparing the effect of danazol to the other factors at each phase of the study Statistical analysis was performed using the BMDP statistical package running on an IBM PS/2, model 80.
Results One hundred thirty-one patients completed the first six months of the study. Eighty-three (63.35%) initially reported a 75% decrease in the headache index, 27 (20.61%) had no improvement, and 21 (16.03%) had side effects that caused them to discontinue the medication. There was a significant association between age and the effect of danazol on hormonal migraine (X2=12.120, degrees of freedom=4, P=.0165). Of women > 40 years old, 75% confirmed headache relief, whereas 31.8% of women < 30 noted an improvement. Therefore, it appeared that danazol's success was age related: the older the patient, the more likely that she would experience migraine suppression. The age at the initial onset of migraine and the number of years of headache complaints did not reach statistical significance (Table 1), yet 46 of the women reporting headache relief with danazol had suffered for > 10 years. Also illustrated was the lack of association between the drug's effectiveness and the onset of migraine with a hormonal event-menarche, oral contraceptive use, pregnancy and tubal ligation.
The vast majority of the study participants noted that their migraines occurred within the week before menstruation. Danazol's effects were most significant in this group (Figure 1) and those whose migraine occurred with menstruation. At ovulation or after the cessation of menses, danazol therapy was statistically ineffective. If a woman listed her migraines as occurring only premenstrually, her chance of relief with danazol was excellent. If her migraines occurred during three or more phases of the menstrual cycle, danazol was totally ineffective (Figure 2).
Of the 83 patients who found relief while using danazol, all reported the return of migraines in the months after drug discontinuation (phase III). Sixty-seven (82.6%) documented the successful prevention of migraine in the six-month continuation of danazol therapy (Table 11). Fourteen (17%) experienced side effects. Two did not enter phase IV for other reasons. Two had severe side effects, joint pain and acne. Twelve reported mild side effects. No significant association was observed in phase IV between danazol and age at first headache, years since first migraine or onset of migraine with a specific hormonal event.
Table I : Effects of Danazol on Hormonal Migraine, Study Phase II
*Side effects were significant; patients discontinued the study protocol. #Statistically significant, P<.05.
Table II: Effects of Danazol on Hormonal Migraine, Study Phase IV
*Two patients had severe side effects (joint pain, acne); the other 12 had mild side effects. #Statistically significant, P <.05.
Although serum estradiol levels dropped markedly with danazol therapy, the decrease was similar in all three study groups and was not statistically significant.
Of the 83 patients reporting successful control of migraines, 35 (42.2%) experienced amenorrhea, 11 (13.2%) noted some breakthrough bleeding, and 33 (39.8%) had regular, albeit light, menses. Four patients who had had hysterectomies represented the last 4.8% in the study.
Many factors support the strong correlation of migraines with hormonal events. Women report having more headaches while on oral contraceptives and estrogen replacement in menopause. Typically, these headaches occur during the medication-free part of the cycle, when the serum level of hormones drops. Some women report a lessening of headaches after discontinuing oral contraceptives and estrogen supplements, which elevate estrogen levels. Migraine headaches usually disappear in pregnancy 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 estrogen levels decline, migraine attacks occur.
Few researchers have attempted to control migraines in women by using hormonal preparations. Even less research has focused on the role of estrogen levels in migraine. Sommerville, in using estradiol injections to abort premenstrual and menstrual migraine attacks, proved that the effect was only temporary. Several days later, when the estrogen level fell, the migraine occurred in a more severe form than before the injection. The lack of success 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."[14
Thus, attempts at preventing migraine with elevated estrogen levels have failed. Furthermore, as Sommerville described, when short-acting estradiol is utilized, there is no change in, migraine occurrence. That may explain why ovulatory or midcycle 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." Since the elevation of estrogen levels seems to provoke a worsening of migraine, headaches may be controlled by maintaining a suppressed. low level of serum estrogen.
Singh attempted to prevent migraines with synthetic progestins. Although such medication is thought to prevent the luteal rise in estrogen production, the results have been inconsistent. Dalessio, in Wolff's Headache, stated, "Manipulation of blood progesterone level does not affect menstrual migraine."
Effect of danazol in the control of headache, by number of occurrences.
Since progestins seem to be ineffective in the control of hormonal migraine and estrogens seem to aggravate such attacks, another hormone influencing these headaches may be testosterone and its derivatives.
Danazol is an isoxazole derivative of the synthetic steroid 17a-ethinyltestosterone. Current laboratory findings suggest that danazol interacts with only two major classes of human proteins, steroid hormone receptors and enzymes of steroidogenesis. Barbieri reported that danazol binds to intracellular androgen, progesterone, and estrogen receptors. However, the androgen effect of danazol is the main pharmacological action. Women taking danazol have a doubling of circulating testosterone bioavailability. Steingold confirmed that danazol blocks the normal estrogen rise and recorded a 50% decrease in serum estradiol levels by a direct action on follicular steroidogenesis. Danazol prevents the ovulatory and midluteal rise in estrogen levels, maintaining a constant estrogen state.
Because of side effects there has been a relatively high danazol discontinuation rate at the standard, 800-mg dosage. Most significant are weight gain, fluid retention, acne, hot flashes, hair loss, decreased breast size and, infrequently, worsening headache. However, drug tolerance is extended to approximately 85% when the recommended dosage is cut in half (400 mg daily). Furthermore, whereas standard therapy, with 800 mg of danazol daily, usually lasts 69 months, many researchers have continued lower dose therapy for > 18 months without significant side effects.
No drug interaction with beta blockade, pain medication or cafergot has been reported. No evidence of changes can be found when phenytoin sodium or valproic acid is used in conjunction with danazol. Lichten documented an interaction with carbamazepine. Doubling of the serum carbamazepine level must be recognized in patients with combined therapy Extreme caution should be used when prescribing danazol with carbamazepine, warfarin and erythromycin.
Pseudotumor cerebri has been noted in nine cases of danazol use over the past 18 years. The findings of papilledema and intracranial hypertension improved after cessation of drug use. If the headaches worsened, discontinuation of danazol was indicated. Acetazolamide was the recommended treatment. No long-term sequelae have been noted.
Migraine in women most likely is a hormonal event. Demographic data demonstrate a strong correlation with reproductive age, hormonal therapy and fluctuating estrogen serum levels. Our study substantiated that the hormonal fluctuation can be a trigger of some women's migraine attacks. Danazol, by inhibiting estrogen fluctuation, prevented migraines in 51% of women study participants unresponsive to standard medical therapy. Those most helped by hormonal therapy seem to be women whose migraines occurred predominantly premenstrually. Since statistically many women migraine sufferers report having migraines only at that time in the menstrual cycle, danazol's action in preventing these hormonal changes is a natural deterrent. Although danazol might have certain undesirable side effects in larger doses, our study demonstrated that it is the first practical approach to preventing women's previously untreatable hormonal headaches. When used at a low dosage (400 mg) and combined with a mild diuretic, acetazolamide, the medication is well tolerated. When danazol's success was noted in the first month of therapy, the drug remained effective throughout the study for the vast majority of the participants. Further studies are indicated since they might assist in establishing the underlying pathophysiology of hormonal migraine.
The material does not dictate an exclusive course of treatment or procedure to be followed and should not be construed as excluding other acceptable methods of practice.