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Nafarelin versus danazol in the treatment of endometriosis
N afarelin versus danazol in the treatment of endometriosis Rune Rolland, MD, PhD, and P. F. M. van der Heijden, MD Nijmegen, The Netherlands A double-blind, double-dummy, 6-month multicenter study comparing the effects of nafarelin and danazol in the treatment of endometriosis was completed recently by investigators from 13 institutions in seven European countries. The 194 patients (aged 18 to 45 years) selected for the study were divided into two groups. One group received nafarelin, 200 ILg twice daily, and placebo capsules identical to danazol, twice daily. The other group received danazol capsules, 200 mg twice daily, and a placebo nasal spray identical to nafarelin, twice daily. A comparison of decreases in both groups of American Fertility Society endometriosis scores and in severity scores developed by the investigators indicates that nafarelin and danazol are equally effective in the treatment of endometriosis. (AM J OBSTET GVNECOL 1990;162:586-8.)
Key words: Danazol, endometriosis, nafarelin This study was conducted to assess the efficacy of nafarelin, a substitute decapeptide and gonadotropinreleasing hormone agonist, in the treatment of endometriosis and to compare the effects of nafarelin with those of danazol, a substitute steroid hormone used in established medical therapy for endometriosis. 1,2 The following parameters were evaluated: (1) arrest of the spread or reduction of the size and number of endometriotic foci as seen on laparoscopy, (2) decrease in clinical symptoms associated with endometriosis (i.e., pelvic pain, dyspareunia, and dysmenorrhea) and reduction of pelvic induration and tenderness found on gynecologic examination, (3) induction of hypoestrogenism and amenorrhea, and (4) overall assessment by the physicians and patients of the results of therapy.
Material and methods Investigators studied 194 patients with endometriosis from 13 medical centers in seven European countries* in a 6-month study that was conducted according to a parallel, randomized, double-blind, double-placebo design, with danazol used as an active control. The criteria for patient selection were age between 18 and 45 years; body weight between 45 and 110 kg; menstrual cycles of 24 to 36 days (for 4 months before From the Department of Obstetrics and Gynecology, Unwerslty Hospital. Reprint requests: Rune Rolland, MD, Department of Obstetncs and Gynecology, University Hospital, Nijmegen, PO 9101,6500 HB Nijmegen, The Netherlands. *The principal investigators in the European multicenter study were D. Barlow, England (33 patients); C. Bergquist, Sweden (16 patIents); A. Caballero Gordo, Spain (8 patients); P. DeVroey, Belgzum (4 patients); M. Elstein, England (12 patients); A. Kauppila and L. Ronnberg, Finland (9 patIents); G. Lefebvre, France (10 patIents); E. Recasens, Spain (4 patients); R. Rolland, The Netherlands (39 patients); R. Shaw, England (32 patients); K. Thomas, Belgium (6 patients); M. Vltse, France (12 patients); and O. Yhkorkala, Finland (9 patients). 610117311
586
the study); pelvic pain, dyspareunia, dysmenorrhea, or infertility; endometriosis confirmed by laparoscopy or laparotomy; agreement to use barrier contraception during the study; negative pregnancy test result; negative Papanicolaou smear; and informed consent. Exclusion criteria included the presence of amenorrhea, interfering concurrent diseases, surgical treatment for endometriosis at baseline laparoscopy or within 6 months before the study, gonadal hormone or danazol use within 3 months before the study, or simultaneous participation in another clinical trial. Patients selected for the study were scored for the severity of endometriosis according to the American Fertility Society classification system' and by means of a severity score profile developed by the investigators. With this profile, each patient was given a score of from o to 3 points for each of five symptoms: dysmenorrhea, dyspareunia, pelvic pain, uterine immobility, and pelvic tenderness. On the basis of the total of these scores, each case of endometriosis was rated mild (1 to 2 points), moderate (3 to 5 points), severe (6 to 10 points), or very severe (11 to 15 points). These scores provided a basis for dividing the patients into two groups: those with minimal or mild endometriosis and those with moderate and severe disease. Patients were then randomized for drug therapy. Of the 194 women who were initially enrolled in the study, two thirds (127 patients) received nafarelin 2.0 mg/ml nasal spray, 200 I-Lg twice daily, and placebo capsules identical to danazol, twice daily. The remaining one third of the patients (67 patients) received danazol capsules, 200 mg twice daily, and a placebo nasal spray apparently identical to nafarelin, twice daily. Patients were seen in the outpatient departments of the participating clinics at 2-week intervals for 1 month and on a monthly basis thereafter until the completion of treatment. Patients also kept a diary, recording the
Nafarelin versus danazol in endometriosis
Volume 162 Kumber 2
date and duration of any vaginal bleeding, the occurrence of hot Hashes, and the date of any missed doses. These diary records were discussed with investigating physicians at each follow-up session, during which the effects of the drug taken by the patient were evaluated. Evaluation methods included medical history and physical examination, pelvic examination, Papanicolaou smear, clinical laboratory tests, serum estradiol, pregnancy test, laparoscopy, patient diary records, symptom severity profile, assessment of menstrual bleeding pattern, overall assessment by the investigating physician of disease regression, and overall assessment by the patient of the acceptability of treatment. Treatment was stopped prematurely by 20 (15.8%) patients in the nafarelin group and 4 (6%) in the danazol group. Of these, investigators attributed the termination of treatment to adverse events in seven women taking nafarelin and in two taking danazol. Intercurrent illness led to discontinuance by one woman in the nafarelin group and two in the danazol group. The other patients who withdrew from the study prematurely were from the nafarelin group: three patients withdrew from the study for personal reasons, three were lost to follow-up, one withdrew because of lack of drug efficacy, and five withdrew for other reasons. A total of 107 patients in the nafarelin group and 63 patients in the danazol group continued treatment for the duration of the study.
60 50 en C
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40
a..
'0 30
Cii .c
§
z
20 10
The American Fertility Society scores and endometriosis severity scores of patients in both the nafarelin and danazol groups showed a considerable decrease as a result of treatment. For the nafarelin group a total American Fertility Society score of approximately 14.5 before treatment dropped to approximately 7 at the end of 6 months. The pretreatment American Fertility Society score of 17 for patients taking danazol fell to about 8.5 after treatment. The decrease is highly significant for both groups, but there is no meaningful difference between the two groups. For the investigators' endometriosis severity score, the mean decrease was more than 60% for both groups. Again, the difference between the two groups was not significant (Fig. 1). Similarly, the distribution of American Fertility Society staging before and after treatment revealed that a significant percentage of women with moderate or severe endometriosis before treatment had mild or no signs after treatment with either nafarelin or danazol. In fact, 24% of patients in the nafarelin group and 22% in the danazol group had no signs of endometriosis after treatment. The investigators' symptom severity scores also dropped after 6 months for both the nafarelin and
Nafarelin
r1 At admission ~ At 6 months
~:~:~: .:.:.: :::::: :~:~:~ :.:.:.
p <.0001
.:.:.: :.:.:. .:.:.: :::::: :.:.:. .:.:.:
~~~~~~ ......
:::::: :.:.:. .:.:.: :.:.:.
::::::
O~~~~~~~~~~~--~~---
None
o
en
30
C Q)
Moderate Severe
Danazol
Very Severe 11-15
r2I At admission E3 At 6 months p <.0001
.:.:.: :.:.:.
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~
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'020
...
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Mild
1-2 3-5 6-10 Symptom Severity Score
40
Q)
Results
..:.:.: ..... ::=:::
587
10
":::::
t~
:.:.: ':':". :.:.:. ......
:::::: ::::::
:::::: ...... :::::: Ol~~~~~~~~~~~~~~--None
o
Mild
1-2
Moderate Severe 3-5
6-10
Very Severe 11-15
Symptom Severity Score Fig. 1. Distribution of patients by endometnosis symptom severity scores before and after treatment with nafarelin or danazol.
danazol groups. There were no symptoms in 57% of the patients in the nafarelin group or 48% of patients in the danazol group. Adverse effects probably related to treatment by nafarelin or danazol (Table I) included hot Hashes, vaginal dryness, decreased libido, insomnia, headache, acne, myalgia, and nervousness, with patients taking danazol having these symptoms to a lesser degree. Only the patients in the danazol group had asthenia, gastrointestinal pain, or rash. As a result of the 6-month regimen, both the nafar-
588
Rolland and van der Heijden
February 1990 Am J Obstet Gyneco1
Table I. Adverse effects probably related to treatment with either nafarelin or danazol Nafarelin Side effect
Hot flashes Vaginal dryness Decreased libido Insomnia Headache Acne Myalgia Nervousness Asthenia Gastrointestinal pain Rash
I
n
106 20 18 14 13 7 4 3 0 0
Danazol
%
n
90 16 14 11 10 6 3 2
p
%
Value
45 6 2 4 7 4 9 6 5 4
70 9 3 6 10 6 9 9 7 6
0.001 0.268 0.013 0.306 1.000 1.000 0.097 0.066 0.004 0.013
4
6
0.013
0
elin and danazol groups had a sharp decrease from baseline values of serum estradiol concentration, to approximately 55% of the initial value determined in the early follicular phase of the menstrual cycle. Also, there was no difference between the two groups with respect to the number of women with amenorrhea or the length of time until amenorrhea developed. Among patients taking danazol, there was a small but significant increase of 4.9 mm Hg in systolic blood pressure (p < 0.05); for patients in the nafarelin group a 0.6 mm Hg decrease was observed. Diastolic blood pressure also tended to increase in the danazol group and decrease in the nafarelin group, and these differences between the two groups were significant. In addition, a mean weight gain of 2.7 kg in the danazol group contrasted with virtually no change in the nafarelin group. Because several laboratories were involved in this study, changes in laboratory values can best be summarized as mean changes from baseline values. An increase in total cholesterol levels was seen in both groups: specifically, danazol increased low-density lipoprotein cholesterol levels and decreased high-density lipoprotein cholesterol levels, whereas nafarelin increased high-density lipoprotein cholesterol and had little or no effect on low-density lipoprotein cholesterol levels. The increase in aspartate aminotransferase was twice as much for the danazol group as for the nafarelin group. Alkaline phosphatase increased significantly (by 20.5%) in the nafarelin group compared with a decrease of 6.9% in the danazol group. This highly significant difference probably is the result of the increase in bone metabolism typically seen in women receiving gonadotropin-releasing hormone agonist therapy.'
I
Comment Based on decreases in symptoms and laparoscopic scores, nafarelin and danazol, in the dosages used in this study, are equally effective in the treatment of endometriosis. These results are in agreement with the study by Henzl et al. 5 The adverse effects of nafarelin treatment (amenorrhea, hot flashes, vaginal dryness, and decreased libido) are related to the hypoestrogenemic state. Patients treated with danazol have the same symptoms to a lesser degree and have more complaints of myalgia, nervousness, asthenia, and gastrointestinal pain. Danazol treatment also results in a significant increase in body weight. Therefore nafarelin, along with other gonadotropinreleasing hormone agonists,6 is a welcome addition to the available medical treatment regimens for women suffering from endometriosis.
REFERENCES 1. Friedlander RL. The treatment of endometriosis with danazo!' J Reprod Med 1973;10:197. 2. Greenblatt RB, Dmowski WP, Mahesh VB, et a!. Clinical studies with an antigonadotropin danazo!. Fertil Steril 1971 ;22: 102. 3. The American Fertility Society. Classification of endometriosis. Ferti! Steril 1979;32:633. 4. Devolgelaer JP, Nagant de Deuxchaisnes C, Donnez J, et a!. LHRH analogues and bone loss. Lancet 1987;1: 1498. 5. Henzl MR, Corsar SL, Moghissi K, et a!. Administration of nasal nafarelin as compared with oral danazol for endometriosis. N Engl J Med 1988;318:485. 6. Franssen AMHW, Kauer FM, Chadha DR, et a!. Endometriosis: treatment with gonadotropin-releasing hormone agonist buserelin. Fertil Steril 1989;51 :401.
Key words: Danazol, endometriosis, nafarelin This study was conducted to assess the efficacy of nafarelin, a substitute decapeptide and gonadotropinreleasing hormone agonist, in the treatment of endometriosis and to compare the effects of nafarelin with those of danazol, a substitute steroid hormone used in established medical therapy for endometriosis. 1,2 The following parameters were evaluated: (1) arrest of the spread or reduction of the size and number of endometriotic foci as seen on laparoscopy, (2) decrease in clinical symptoms associated with endometriosis (i.e., pelvic pain, dyspareunia, and dysmenorrhea) and reduction of pelvic induration and tenderness found on gynecologic examination, (3) induction of hypoestrogenism and amenorrhea, and (4) overall assessment by the physicians and patients of the results of therapy.
Material and methods Investigators studied 194 patients with endometriosis from 13 medical centers in seven European countries* in a 6-month study that was conducted according to a parallel, randomized, double-blind, double-placebo design, with danazol used as an active control. The criteria for patient selection were age between 18 and 45 years; body weight between 45 and 110 kg; menstrual cycles of 24 to 36 days (for 4 months before From the Department of Obstetrics and Gynecology, Unwerslty Hospital. Reprint requests: Rune Rolland, MD, Department of Obstetncs and Gynecology, University Hospital, Nijmegen, PO 9101,6500 HB Nijmegen, The Netherlands. *The principal investigators in the European multicenter study were D. Barlow, England (33 patients); C. Bergquist, Sweden (16 patIents); A. Caballero Gordo, Spain (8 patients); P. DeVroey, Belgzum (4 patients); M. Elstein, England (12 patients); A. Kauppila and L. Ronnberg, Finland (9 patIents); G. Lefebvre, France (10 patIents); E. Recasens, Spain (4 patients); R. Rolland, The Netherlands (39 patients); R. Shaw, England (32 patients); K. Thomas, Belgium (6 patients); M. Vltse, France (12 patients); and O. Yhkorkala, Finland (9 patients). 610117311
586
the study); pelvic pain, dyspareunia, dysmenorrhea, or infertility; endometriosis confirmed by laparoscopy or laparotomy; agreement to use barrier contraception during the study; negative pregnancy test result; negative Papanicolaou smear; and informed consent. Exclusion criteria included the presence of amenorrhea, interfering concurrent diseases, surgical treatment for endometriosis at baseline laparoscopy or within 6 months before the study, gonadal hormone or danazol use within 3 months before the study, or simultaneous participation in another clinical trial. Patients selected for the study were scored for the severity of endometriosis according to the American Fertility Society classification system' and by means of a severity score profile developed by the investigators. With this profile, each patient was given a score of from o to 3 points for each of five symptoms: dysmenorrhea, dyspareunia, pelvic pain, uterine immobility, and pelvic tenderness. On the basis of the total of these scores, each case of endometriosis was rated mild (1 to 2 points), moderate (3 to 5 points), severe (6 to 10 points), or very severe (11 to 15 points). These scores provided a basis for dividing the patients into two groups: those with minimal or mild endometriosis and those with moderate and severe disease. Patients were then randomized for drug therapy. Of the 194 women who were initially enrolled in the study, two thirds (127 patients) received nafarelin 2.0 mg/ml nasal spray, 200 I-Lg twice daily, and placebo capsules identical to danazol, twice daily. The remaining one third of the patients (67 patients) received danazol capsules, 200 mg twice daily, and a placebo nasal spray apparently identical to nafarelin, twice daily. Patients were seen in the outpatient departments of the participating clinics at 2-week intervals for 1 month and on a monthly basis thereafter until the completion of treatment. Patients also kept a diary, recording the
Nafarelin versus danazol in endometriosis
Volume 162 Kumber 2
date and duration of any vaginal bleeding, the occurrence of hot Hashes, and the date of any missed doses. These diary records were discussed with investigating physicians at each follow-up session, during which the effects of the drug taken by the patient were evaluated. Evaluation methods included medical history and physical examination, pelvic examination, Papanicolaou smear, clinical laboratory tests, serum estradiol, pregnancy test, laparoscopy, patient diary records, symptom severity profile, assessment of menstrual bleeding pattern, overall assessment by the investigating physician of disease regression, and overall assessment by the patient of the acceptability of treatment. Treatment was stopped prematurely by 20 (15.8%) patients in the nafarelin group and 4 (6%) in the danazol group. Of these, investigators attributed the termination of treatment to adverse events in seven women taking nafarelin and in two taking danazol. Intercurrent illness led to discontinuance by one woman in the nafarelin group and two in the danazol group. The other patients who withdrew from the study prematurely were from the nafarelin group: three patients withdrew from the study for personal reasons, three were lost to follow-up, one withdrew because of lack of drug efficacy, and five withdrew for other reasons. A total of 107 patients in the nafarelin group and 63 patients in the danazol group continued treatment for the duration of the study.
60 50 en C
Q) .~
40
a..
'0 30
Cii .c
§
z
20 10
The American Fertility Society scores and endometriosis severity scores of patients in both the nafarelin and danazol groups showed a considerable decrease as a result of treatment. For the nafarelin group a total American Fertility Society score of approximately 14.5 before treatment dropped to approximately 7 at the end of 6 months. The pretreatment American Fertility Society score of 17 for patients taking danazol fell to about 8.5 after treatment. The decrease is highly significant for both groups, but there is no meaningful difference between the two groups. For the investigators' endometriosis severity score, the mean decrease was more than 60% for both groups. Again, the difference between the two groups was not significant (Fig. 1). Similarly, the distribution of American Fertility Society staging before and after treatment revealed that a significant percentage of women with moderate or severe endometriosis before treatment had mild or no signs after treatment with either nafarelin or danazol. In fact, 24% of patients in the nafarelin group and 22% in the danazol group had no signs of endometriosis after treatment. The investigators' symptom severity scores also dropped after 6 months for both the nafarelin and
Nafarelin
r1 At admission ~ At 6 months
~:~:~: .:.:.: :::::: :~:~:~ :.:.:.
p <.0001
.:.:.: :.:.:. .:.:.: :::::: :.:.:. .:.:.:
~~~~~~ ......
:::::: :.:.:. .:.:.: :.:.:.
::::::
O~~~~~~~~~~~--~~---
None
o
en
30
C Q)
Moderate Severe
Danazol
Very Severe 11-15
r2I At admission E3 At 6 months p <.0001
.:.:.: :.:.:.
:~:~:~
:.:.:. .:.:.:
~
a..
'020
...
.c E :J
Z
Mild
1-2 3-5 6-10 Symptom Severity Score
40
Q)
Results
..:.:.: ..... ::=:::
587
10
":::::
t~
:.:.: ':':". :.:.:. ......
:::::: ::::::
:::::: ...... :::::: Ol~~~~~~~~~~~~~~--None
o
Mild
1-2
Moderate Severe 3-5
6-10
Very Severe 11-15
Symptom Severity Score Fig. 1. Distribution of patients by endometnosis symptom severity scores before and after treatment with nafarelin or danazol.
danazol groups. There were no symptoms in 57% of the patients in the nafarelin group or 48% of patients in the danazol group. Adverse effects probably related to treatment by nafarelin or danazol (Table I) included hot Hashes, vaginal dryness, decreased libido, insomnia, headache, acne, myalgia, and nervousness, with patients taking danazol having these symptoms to a lesser degree. Only the patients in the danazol group had asthenia, gastrointestinal pain, or rash. As a result of the 6-month regimen, both the nafar-
588
Rolland and van der Heijden
February 1990 Am J Obstet Gyneco1
Table I. Adverse effects probably related to treatment with either nafarelin or danazol Nafarelin Side effect
Hot flashes Vaginal dryness Decreased libido Insomnia Headache Acne Myalgia Nervousness Asthenia Gastrointestinal pain Rash
I
n
106 20 18 14 13 7 4 3 0 0
Danazol
%
n
90 16 14 11 10 6 3 2
p
%
Value
45 6 2 4 7 4 9 6 5 4
70 9 3 6 10 6 9 9 7 6
0.001 0.268 0.013 0.306 1.000 1.000 0.097 0.066 0.004 0.013
4
6
0.013
0
elin and danazol groups had a sharp decrease from baseline values of serum estradiol concentration, to approximately 55% of the initial value determined in the early follicular phase of the menstrual cycle. Also, there was no difference between the two groups with respect to the number of women with amenorrhea or the length of time until amenorrhea developed. Among patients taking danazol, there was a small but significant increase of 4.9 mm Hg in systolic blood pressure (p < 0.05); for patients in the nafarelin group a 0.6 mm Hg decrease was observed. Diastolic blood pressure also tended to increase in the danazol group and decrease in the nafarelin group, and these differences between the two groups were significant. In addition, a mean weight gain of 2.7 kg in the danazol group contrasted with virtually no change in the nafarelin group. Because several laboratories were involved in this study, changes in laboratory values can best be summarized as mean changes from baseline values. An increase in total cholesterol levels was seen in both groups: specifically, danazol increased low-density lipoprotein cholesterol levels and decreased high-density lipoprotein cholesterol levels, whereas nafarelin increased high-density lipoprotein cholesterol and had little or no effect on low-density lipoprotein cholesterol levels. The increase in aspartate aminotransferase was twice as much for the danazol group as for the nafarelin group. Alkaline phosphatase increased significantly (by 20.5%) in the nafarelin group compared with a decrease of 6.9% in the danazol group. This highly significant difference probably is the result of the increase in bone metabolism typically seen in women receiving gonadotropin-releasing hormone agonist therapy.'
I
Comment Based on decreases in symptoms and laparoscopic scores, nafarelin and danazol, in the dosages used in this study, are equally effective in the treatment of endometriosis. These results are in agreement with the study by Henzl et al. 5 The adverse effects of nafarelin treatment (amenorrhea, hot flashes, vaginal dryness, and decreased libido) are related to the hypoestrogenemic state. Patients treated with danazol have the same symptoms to a lesser degree and have more complaints of myalgia, nervousness, asthenia, and gastrointestinal pain. Danazol treatment also results in a significant increase in body weight. Therefore nafarelin, along with other gonadotropinreleasing hormone agonists,6 is a welcome addition to the available medical treatment regimens for women suffering from endometriosis.
REFERENCES 1. Friedlander RL. The treatment of endometriosis with danazo!' J Reprod Med 1973;10:197. 2. Greenblatt RB, Dmowski WP, Mahesh VB, et a!. Clinical studies with an antigonadotropin danazo!. Fertil Steril 1971 ;22: 102. 3. The American Fertility Society. Classification of endometriosis. Ferti! Steril 1979;32:633. 4. Devolgelaer JP, Nagant de Deuxchaisnes C, Donnez J, et a!. LHRH analogues and bone loss. Lancet 1987;1: 1498. 5. Henzl MR, Corsar SL, Moghissi K, et a!. Administration of nasal nafarelin as compared with oral danazol for endometriosis. N Engl J Med 1988;318:485. 6. Franssen AMHW, Kauer FM, Chadha DR, et a!. Endometriosis: treatment with gonadotropin-releasing hormone agonist buserelin. Fertil Steril 1989;51 :401.