Hot flashes in postmenopausal women ameliorated by danazol*

r Vol. 43, No.3, March 1985 Printed in U,SA.

FERTILITY AND STERILITY Copyright e 1985 The American Fertility Society

Hot flashes in postmenopausal women ameliorated by danazol*

Giraud V. Foster, M.D., Ph.D.t Howard A. Zacur, M.D., Ph.D. John A. Rock, M.D. Department of Gynecology and Obstetrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland

Six postmerwpausal women with hot flashes were studed for two 8 -week periods during which they received low-dose danazol (100 mg/24 hours) for one time interval and placebo for the other in a randomized double-blind manner. The patients recorded the number and severity of their hot flashes daily. On the last day of each period the patients were admitted to the research center overnight for an 8-hour monitoring of forehead skin temperatures and for continuous withdrawal of blood to determine 20-minute integrated levels of luteinizing hormone. Three of the six patients responded to danazol with a mean reduction of 88% in the number of hot flashes and a 53% decrease in the severity of hot flashes. Responders differed from nonresponders in that on treatment the frequency of nocturnal pulses of luteiniZing hormone was reduced more (36.1% versus 14.4%), the increase in amplitude of the pulses was greater ( + 30. 7% versus -11.8%), and the fall in the mean level of luteinizing hormone was more marked (19.0% versus 10.5%). The findings suggest that danazol may be a reasonable alternative to estrogen in the treatment of postmenopausal women with severe vasomotor symptoms. Fertil Steril43:401, 1985

The etiology of hot flashes is unknown. The preponderance of evidence indicates that they are consequent to estrogen withdrawal, since following bilateral oophorectomy they frequently develop within days. Gonadotropin levels are elevated in postmenopausal patients, and vasomotor symptoms are temporally associated with pulsatile release of luteinizing hormone (LH).1-4 The symptoms themselves are not due, however, to gonadotropins themselves, since they are not induced by exogenous hormone, LH-releasing hor-

Received November 21,1983; revised and accepted November 23, 1984. *Supported in part by a grant from Winthrop-Breon Labora- . tories, New York, New York. tReprint requests: Giraud V. Foster, M.D., Ph.D., Division of Reproductive Endocrinology, Department of Gynecology and Obstetrics, The Johns Hopkins Hospital, Baltimore, Maryland 21205. Vol. 43, No.3, March 1985

mone (LH-RH), or LH-RH agonists. 5 The view that gonadotropins do not playa causative role is further supported by the observation that they are provoked by hypophysectomy.6 It has been proposed that an estrogen-sensitive intermediary exerts control at the level of the central nervous system and that this intermediary control is linked to regulation of the pulsatile release of LH-RH.7 Danazol, an isoxazol derivative of 17a-ethinyltestosterone, lowers levels ofLH and follicle-stimulating hormone in both man and animals. 8 - 10 The present investigations were undertaken in postmenopausal women to determine whether or not danazol could ameliorate hot flashes or reduce their frequency. Since danazol in daily doses of 400 to 800 mg, as given for treatment of endometriosis or chronic cystic mastitis,l1 lowers estrogen levels in some patients 12 , 13 and even induces hot flashes, 14, 15 a low dose was chosen. Foster et al. Hot flashes and danazol

401

MATERIALS AND MEmODS

Eight consenting healthy postmenopausal pa- . tients on no medication were entered into a randomized double-blind study. Criteria for inclusion included (1) five or more hot flashes a day, (2) no menstrual period for 12 or more months, (3) elevated LH levels, and (4) symptoms severe enough to interfere with sleep. All patients kept a daily log of the number of hot flashes they observed each day and rated the effect that their symptoms had on their daily life on a scale of 0 to 10 with 0 being no hot flashes; 1 to 4, mild hot flashes; 5 to 9, hot flashes severe enough to interfere with sleep; and 10, hot flashes so severe as to prevent sleep altogether. Patients also recorded their compliance on both pill taking and counting hot flashes and commented on any intervening illnesses. After a 4- to 10-week introductory period of record keeping to assess compliance and an overnight stay in the research center to become familiar with blood-collecting methods and temperature monitoring, the patients were started on two consecutive 8-week periods of treatment assigned in a double-blind manner. During one period they received 100 mg danazol daily and during the other a placebo. 16 On the final day of each period the patients were studied overnight, during which time forehead skin temperature was recorded with an Autogen 1000b Feedback Thermometer and Autogen 5800 Data Acquisition Center (Autogenic Systems, Berkeley, CA), and blood was continuously drawn to collect 20-minute samples for subsequent radioimmunoassay of LH. During observation, the patients were asked to report the duration of each hot flash and score its severity on a scale of 1 to 10, with 10 being the most severe. During the 4-month period, two patients were excluded from the study: one for spontaneously ovulating and the other for developing severe myalgia, later found to have occurred while taking the placebo. At the conclusion of each period pill checks were made and recording was reviewed to assure that compliance was > 95%. Intrasubject data obtained for the placebo and danazol were assessed by Student's t-test.

the placebo (Fig. 1). These changes were reflected by a concomitant amelioration in the effect of the hot flashes on their daily life, the same patients reporting 98.5%, 68.7%, and 14.0% lower subjective ratings (P < 0.001). The onset of response to danazol was variable, with improvement beginning 1 day to 1 month after commencement of the drug. The response was suffi.ciently dramatic that all patients who responded requested to stay on treatment. No similar change was observed in Danazal

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Of the six patients studied, three responded to danazol with 98.5%, 80.0%, and 34.7% fewer hot flashes (P < 0.001) than during treatment with 402

Foster et a1. Hot flashes and danazol

Figure 1 Number of hot flashes ( - - ) and patients' subjective assessment of hot flashes (0---0) in three responding patients taking danazol and taking the placebo. Each point indicates the mean of values for 1 week (± standard error of the mean).

Fertility and Sterility

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Table 1. Differences in Number of Hot Flashes and Their Severity in Responders and Nonresponders as Determined by Subjective Assessment No. of hot flashes! 24 hours Danazol Placebo Responders 11.8 E. J. 6.8 L.T. 9.1 M.V. N onresponders 4.2 A.P. 9.4 E. T. 8.4 G.M.

260 240

Patients' daily rating of hot flashe)l Danazol Placebo

•

Placebo I Peak IHr. 0.3 Hal Fla.he.1 Hr.

220 200 180

± 0.2 ± 0.1 ± 0.2

7.7 ± 0.3 0.1 ± 0.1 1.8 ± 0.2

8.5 ± 0.1 6.6 ± 0.1 6.7 ± 0.1

7.3 ± 0.2 0.1 ± 0.1 2.1 ± 0.2

± 0.2 ± 0.1 ± 0.2

5.0 ± 0.2 9.9 ± 0.2 9.9 ± 0.2

5.1 ± 0.3 6.4 ± 0.1 5.6 ± 0.1

5.5 ± 0.2 5.4 ± 0.1 5.5 ± 0.1

160 140 120 100

•

9PM

Values are means ± standard error of the mean.

Danazol 0.8 peaka/Hr. O. I Ha I F I . . h I Hr . !:lAM

,'--'--'--L...-JL-.J'I....-L-.JL........I' , lAM

Figure 2 LH levels in a representative patient taking danazol and the placebo. The upper arrows indicate hot flashes occurring while taking the placebo, whereas the lower arrow indicates hot flashes while taking danazol.

any of the six subjects either during their introductory period or while taking the placebo (Table 1). The return of symptoms after treatment was variable. In one patient, symptoms returned to their initial frequency and severity within 1 week. In another, symptoms returned within 2 to 3 weeks to a frequency that was ~ 25% less than that originally observed. The third patient has remained almost symptom-free for 5 months, with only two or three hot flashes per month. The three patients who did not respond to danazol reported no appreciable change in the number and severity of their symptoms. The improvement in symptoms correlated well with observations during in-house monitoring of temperature. Although there was no appreciable change in either the duration of the hot flashes or the amplitude of their recorded temperature curves, there was a mean reduction of 51.0% in the frequency of hot flashes and a 52.6% improvement in subjective assessment (Table 2). Responders did not differ appreciably from nonresponders in number of hot flashes, severity of hot flashes, or the seasonal time that they were studied. As observed during in-house clinical

monitoring, initial mean LH levels did not differ significantly (157.4 ng/ml versus 175.8 ng/ml), the frequency of peaks was the same (0. 9!hour) , and average peak heights were almost identical (43.4 and 40.2 ng/ml). However, the change in secretory pattern in those patients whose vasomotor symptoms improved with danazol clearly differed from that in nonresponders (Table 3). Compared with patients receiving the placebo, danazol produced in responders a greater fall in the mean level of gonadotropin (19.0% versus 10.5%), a greater decrease in frequency of nocturnal pulses of LH (36.1% versus 14.4%), and an increase in pulse amplitude (+ 30.7% versus -11.8%) (Fig. 2). The changes were identical to those observed in normal cycling women receiving danazol 17 and in men given testosterone. lB , 19 DISCUSSION

In the present studies it was demonstrated that (1) danazol effectively reduced the frequency of

Table 2. Vasomotor Differences Between Responders and Nonresponders During Observation in the Laboratory %

Responders E.J. L.T. M.V. Average N onresponders A. P. E.T. G.M. Average

Vol. 43, No.3, March 1985

Mean subjective rating of hot flashes while taking placebo

Mean subjective rating of hot flashes while taking danazol

90.0 42.9 20.0

7.6 ± 0.8 30.0 ± 0.0 6.0 ± 0.0

7.0 ± 0.0 0.0 ± 0.0 3.0 ± 0.0

-7.9 -100.0 -50.0

51.0

5.5

3.3

-52.6

0 30.8 11.1

7.0 ± 1.2 3.8 ± 1.0 3.0 ± 0.7

7.7 ± 0.7 2.0 ± 0.0 4.3 ± 0.6

+10.0 -47.4 +43.3

14.0

4.6

4.7

+2.0

Decrease in frequency of hot flashes while taking danazol

%

Change in subjective rating while taking danazol

Foster et al. Hot flashes and danazol

403

Table 3. LH Levels During Placebo Period and Changes in LH Secretory Pattern During Treatment with Danazol LH during placebo period Mean

Responders E. J. L.T. M.V. Average N onresponders A.P. E. T. G.M. Average

Peak

LH during treatment period

Avera,e peak height

% Difference in amplitude of peaks

perhr

ng/ml

100.9 162.9 208.4

1.1 0.7 0.8

16.2 76.8 37.3

31.0 3.9 22.0

45.5 42.0 20.0

0.0 +32.0 +59.8

157.4

0.9

43.4

19.0

36.1

+30.7

210.3 168.7 148.3

0.4 1.3 0.9

68.8 22.7 29.1

18.0 14.4 9.0

0.0 30.8 12.5

-20.3 -4.8 -10.3

175.8

0.9

40.2

10.5

14.4

-11.8

REFERENCES 1. Meldrum DR, Tataryn IV, Frumar AM, Erlik Y, Lu KH, Judd HL: Gonadotropins, estrogens, and adrenal steroids during the menopausal hot flash. J Clin Endocrinol Metab 50:685, 1980 2. Tataryn IV, Meldrum DR, Lu KH, Frumar AM, Judd HL: LH, FSH and skin temperature during the menopausal hot flash. J Clin Endocrinol Metab 49:152, 1979 3. Casper RF, Yen SSC, Wilkes MM: Menopausal flushes: a neuroendocrine link with pulsatile luteinizing hormone secretion. Science 205:823, 1979 4. Tataryn IV, Meldrum DR, Frumar AM, Erlik Y, Lu KH, Judd HL: The hormonal and thermal regulatory changes in postmenopausal hot flushes. In Thermoregulatory Mechanisms and Their Therapeutic Implications, Edited by B Cox, AS Milton, P Lomax. Basel, S. Karger, 1979, p 202 5. DeFazio J, Meldrum DR, Lauffer L, Vale W, Rivier J, Lu KH, Judd HL: Induction of hot flashes in premenopausal Foster et at.

ginning of peaks

ng/ml

hot flashes in three of six patients with severe enough vasomotor symptoms that all initially had complained ofloss of sleep, (2) amelioration of symptoms occurred between 1 and 28 days of treatment, and (3) discontinuance of treatment was not always associated with a return of hot flashes to their previous level of severity. These events are unlikely to have been spuriously reported by the patients for two reasons. First, the patients noted no significant improvement while taking the placebo. Second, improvement in responders was associated with a unique change in the profile of gonadotropin secretion, with frequency of LH oscillations decreasing and their amplitude increasing more than in nonresponders. The data of this preliminary study suggest that danazol in low doses may effectively reduce the number and severity of hot flashes in at least some postmenopausal women.

404

% Decrease in be-

mean level

% Decrease in

Hot {lashes and danazol

6. 7.

8. 9.

10.

11. 12.

13.

14.

15.

16.

17.

18.

19.

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