Efficacy and safety of nafarelin in the treatment of endometriosis Milan R. Henzl, MD, PhD, and Long Kwei, PhD Palo Alto, California The efficacy and safety of the gonadotropin-releasing hormone agonist nafarelin for treatment of endometriosis were compared with those of danazol in two large-scale, double-blind trials. Assessments of severity of symptoms, laparoscopic scores before and after therapy, and pregnancy rates showed that nafarelin, 400 and 800 flog administered intranasally, was as efficacious as oral danazol, 600 and 800 mg. The adverse effects seen with nafarelin, mainly hot flashes, were related to its mode of action, namely hypoestrogenemia induced by reversible inhibition of ovarian hormone production. Hypoestrogenemia was associated with a decrease of bone density in the lumbar vertebrae, but these changes were partially or completely reversible after treatment was discontinued. No significant changes in bone mass occurred in the distal radius. Danazol was associated with androgenic and metabolic adverse effects, including weight gain, negative effects on the lipid profile, and elevated liver enzyme levels. Nafarelin was found to be as effective as danazol for the management of endometriosis, with a different and more favorable safety profile. (AM J OasTET GVNECOl 1990;162:570-4.)
Key words: Danazol, endometriosis, gonadotropin-releasing hormone agonists, nafarelin Nafarelin, a synthetic agonIstic analog of native gonadotropin-releasing hormone, is a promising new treatment for endometriosis. Like other gonadotropinreleasing hormone analogs, nafarelin stimulates the hypothalamic-pituitary-ovarian axis during short-term administration but inhibits its activity during long-term administration. Since the growth of ectopic endometriotic tissue is fueled by ovarian hormones, this paradoxical suppression of estradiol to near-menopausal levels, roughly 40 points = severe to extensive disease (stage IV). tThe reported Student paired t test results were confirmed by Wilcoxon's signed-rank test.
Table II. Changes in severity: relief of clinical symptoms of endometriosis Complete relzef Treatment
Study I NAF800 NAF400 DAN800 Study II NAF400 DAN600
No. of patzents
No.
I
P artzal reitef
%
No
I
No change
%
No.
1
Worsened
%
No.
2 4 4
70 73 70
38 34 34
54 47 49
27 33 29
39 45 41
3 2 3
4 3 4
104 63
59 30
57 48
40 29
38 46
4 3
4 5
I
% 3 5 6
NAFBOO, Nafarelin, 800 fLg/day (400 fLg twice a day); NAF400, nafarelin, 400 fLg/day (200 fLg twice a day); DANBOO, danazol, 800 mg/day (400 mg twice a day); DAN600, danazol, 600 mg/day (200 mg three times a day).
danazol, 600 mg/day, and 80 received danazol, 800 mg/day. Hormonal suppression. In both studies, estradiol levels were suppressed within 14 days after danazol therapy was started. With nafarelin, estradiol levels initially rose in response to the acute stimulus to ovarian steroidogenesis, but 2 weeks after treatment started these levels began a sharp decline. After 1 month, estradiol suppression with nafarelin was more profound than with danazol, and consequently more patients receiving nafarelin became amenorrheic. With both drugs, progesterone levels fell to < 1 ng / ml, indicating anovulation. After treatment with either drug was discontinued, estradiol and progesterone returned to pretreatment levels. Eftects on endometriotic lesions. In both studies there was a statistically significant decrease in mean American Fertility Society scores (p = 0.0001) in each treatment group. Table I shows that the results in both studies were nearly identical. Complete resolution of lesions was evident in 20% of women receiving nafarelin, 800 J.Lg/day, and 18% receiving 400 J.Lg/day, as well as in 16% of those receiving danazol, 800 mg/day,
and 22% receiving 600 mg/day. Irrespective of treatment, lesions partially resolved in an additional 60% to 70% of patients, were unchanged in about 10%, and worsened in 4% to 8%. The percentage of patients with mild to severe disease decreased from 69% at the start of the trial to 36% after treatment, with a corresponding increase in the percentage of patients with no or minimal endometriosis. Clinical symptoms. In both studies nafarelin, as well as danazol, rapidly and significantly relieved clinical symptoms of endometriosis. At the end of the first treatment month, less than 4% of the patients had severe or very severe symptoms and about 70% had no or only mild symptoms. Table II shows the improvement in clinical symptoms of endometriosis in the individual treatment groups. It is important to note that at the end of the treatment, more than 90% of patients using nafarelin, 400 J.Lg/day, obtained relief of clinical symptoms, and more than 50% of these patients were completely symptom free. Table III compares the severity of clinical symptoms of endometriosis at admission to the study and at the end of therapy for all the treatment groups. Of particular note is the reduction
572 Henzl and Kwei
Februarv 1990 Am J Obstet Gynecol
Headaches Hot flashes Emotional lability Acne Myalgia Reduced breast size Edema Seborrhea Weight gain Hirsutism Libido increased Weight loss
~~~i~~~~~~~~~~~~"'1'---•
~~~=======:J
Nafarelln (n = 203) Danazol (n = 80)
o
~~~=======:J
~~==========::::::J ~~~======::J
~~================::::J ~==::J
.p < .05 •• P ::::: .01 ••• p :::::. 001
~==:J
Libido decreased ~~~::~ Vaginitis ~ Rhinitis Insomnia Depression
o
20
10
40
50 60 Patients, %
30
70
90
80
100
Fig. 1. Adverse effects in patients treated with nafarelin, 400 f.l.g/day, or danazol, 800 mg/day.
Table III. Distribution of patients by symptom severity at admission and end of treatment Seven ty uf symptums Mdd
Nune Treatment
n
Study I NAF800
70
NAF400
73
DANSOO
70
Total Study II NAF400
213
DAN600
63
Total
104
167
I
'k
No.
5 38 5 34 S 34
7 54 7 47
14 21 14 26
49
0 59 I 30
0 57 2 48
V~Ht
No.
Admission 6 Mo Admission 6 Mo Admission 6 Mo Admission 6 Mo Admission 6 Mo
II
I
Muderate
%
No.
21 10 22 12 24 7
30 14 30 16 34 10
52 13 20 9
50 13 32 14
%
Nu.
28
20 30 19 36 16 40
21 32 17 24
20 31 27 38
II
I
Severe
I
Very severe
%
No.
24 I 24 I 24 I
34 I 33 I 34 I
6 0 8 0 3 0
30 0 24 0
29
I 0 I 0
38
I
% 9 II
4
2
NAF800, Nafarelin, 800 f.l.g/day (400 f.l.g twice a day); NAF400, nafarelin , 400 f.l.g/day (200 f.l.g twice a day); DAN800, danazol, 800 mg/day (400 mg twice a day); DAN600. danazol. 600 mg/day (200 mg three times a day).
at the end of treatment in the percentage of patients with severe or very severe symptoms. At the present, results of the 6-month posttreatment follow-up are available only from the first controlled clinical trial. Of the 213 enrolled patients, 156 (73%) underwent the 6-month posttreatment follow-up examination (12 months after start of treatment). Thirtytwo (15% of 213) patients did not undergo this examination because they had become pregnant. Fifteen patients (7%) did not undergo this examination because they had undergone surgical or medical therapy for endometriosis; twice the percentage of patients taking danazol required the same procedures as those taking
both nafarelin dosages . Only 3% of the patients were lost to follow-up, and in 1% of the patients the examinations were incomplete. Of the 156 patients evaluated for severity of symptoms 6 months after treatment ended, 77% who took nafarelin, 800 fLg/ day, 72% who took nafarelin, 400 fLg/day, and 78% who used danazol, 800 fLg/ day, remained symptom free, reported only mild clinical symptoms, or were pregnant. Thus in a substantial number of patients the beneficial effects of the treatment continued for at least 6 months after the study drugs were discontinued. Pregnancy rates. Of the 149 patients attempting pregnancy, 52% receiving nafarelin, 800 fLg, and 30%
Efficacy of nafarelin
Volume 162 !'I:ulIlbcr 2
573
8
-
.2 ns a::
..J
C
:I:
---
..J
C
..J
DANAZOL
7
6 5
4 NAFARELIN
3 2
0
2
4
6
Months Fig. 2. Mean low/high-densilY lipoprolein (LDLI HDL) ralios during 6-molllh lrealmelll wilh nafarelin or danazol.
recelvmg 400 fJ..g succeeded within 12 months after treatment, as did 36% receiving danazol. In each treatment group, more than a third of the women who became pregnant had moderate to severe disease on admission to the study. The data on pregnancy rates from the second study are not available at the present time. Safety. Fig. 1 compares the incidence of adverse effects among patients receiving either nafarelin (400 fJ..g/day) or danazol (800 mg/day). The more profound hypoestrogenemia induced by nafarelin led to hot flashes, as reported by 90% of the patients receiving this agent, compared with 68% of the danazol users (p ::s; 0.001), but few patients withdrew from the trial because of this effect. Vaginal dryness and decreased libido, also hypoestrogenemic effects. were more prevalent in the nafarelin users (p::s; 0.01 and
Key words: Danazol, endometriosis, gonadotropin-releasing hormone agonists, nafarelin Nafarelin, a synthetic agonIstic analog of native gonadotropin-releasing hormone, is a promising new treatment for endometriosis. Like other gonadotropinreleasing hormone analogs, nafarelin stimulates the hypothalamic-pituitary-ovarian axis during short-term administration but inhibits its activity during long-term administration. Since the growth of ectopic endometriotic tissue is fueled by ovarian hormones, this paradoxical suppression of estradiol to near-menopausal levels, roughly 40 points = severe to extensive disease (stage IV). tThe reported Student paired t test results were confirmed by Wilcoxon's signed-rank test.
Table II. Changes in severity: relief of clinical symptoms of endometriosis Complete relzef Treatment
Study I NAF800 NAF400 DAN800 Study II NAF400 DAN600
No. of patzents
No.
I
P artzal reitef
%
No
I
No change
%
No.
1
Worsened
%
No.
2 4 4
70 73 70
38 34 34
54 47 49
27 33 29
39 45 41
3 2 3
4 3 4
104 63
59 30
57 48
40 29
38 46
4 3
4 5
I
% 3 5 6
NAFBOO, Nafarelin, 800 fLg/day (400 fLg twice a day); NAF400, nafarelin, 400 fLg/day (200 fLg twice a day); DANBOO, danazol, 800 mg/day (400 mg twice a day); DAN600, danazol, 600 mg/day (200 mg three times a day).
danazol, 600 mg/day, and 80 received danazol, 800 mg/day. Hormonal suppression. In both studies, estradiol levels were suppressed within 14 days after danazol therapy was started. With nafarelin, estradiol levels initially rose in response to the acute stimulus to ovarian steroidogenesis, but 2 weeks after treatment started these levels began a sharp decline. After 1 month, estradiol suppression with nafarelin was more profound than with danazol, and consequently more patients receiving nafarelin became amenorrheic. With both drugs, progesterone levels fell to < 1 ng / ml, indicating anovulation. After treatment with either drug was discontinued, estradiol and progesterone returned to pretreatment levels. Eftects on endometriotic lesions. In both studies there was a statistically significant decrease in mean American Fertility Society scores (p = 0.0001) in each treatment group. Table I shows that the results in both studies were nearly identical. Complete resolution of lesions was evident in 20% of women receiving nafarelin, 800 J.Lg/day, and 18% receiving 400 J.Lg/day, as well as in 16% of those receiving danazol, 800 mg/day,
and 22% receiving 600 mg/day. Irrespective of treatment, lesions partially resolved in an additional 60% to 70% of patients, were unchanged in about 10%, and worsened in 4% to 8%. The percentage of patients with mild to severe disease decreased from 69% at the start of the trial to 36% after treatment, with a corresponding increase in the percentage of patients with no or minimal endometriosis. Clinical symptoms. In both studies nafarelin, as well as danazol, rapidly and significantly relieved clinical symptoms of endometriosis. At the end of the first treatment month, less than 4% of the patients had severe or very severe symptoms and about 70% had no or only mild symptoms. Table II shows the improvement in clinical symptoms of endometriosis in the individual treatment groups. It is important to note that at the end of the treatment, more than 90% of patients using nafarelin, 400 J.Lg/day, obtained relief of clinical symptoms, and more than 50% of these patients were completely symptom free. Table III compares the severity of clinical symptoms of endometriosis at admission to the study and at the end of therapy for all the treatment groups. Of particular note is the reduction
572 Henzl and Kwei
Februarv 1990 Am J Obstet Gynecol
Headaches Hot flashes Emotional lability Acne Myalgia Reduced breast size Edema Seborrhea Weight gain Hirsutism Libido increased Weight loss
~~~i~~~~~~~~~~~~"'1'---•
~~~=======:J
Nafarelln (n = 203) Danazol (n = 80)
o
~~~=======:J
~~==========::::::J ~~~======::J
~~================::::J ~==::J
.p < .05 •• P ::::: .01 ••• p :::::. 001
~==:J
Libido decreased ~~~::~ Vaginitis ~ Rhinitis Insomnia Depression
o
20
10
40
50 60 Patients, %
30
70
90
80
100
Fig. 1. Adverse effects in patients treated with nafarelin, 400 f.l.g/day, or danazol, 800 mg/day.
Table III. Distribution of patients by symptom severity at admission and end of treatment Seven ty uf symptums Mdd
Nune Treatment
n
Study I NAF800
70
NAF400
73
DANSOO
70
Total Study II NAF400
213
DAN600
63
Total
104
167
I
'k
No.
5 38 5 34 S 34
7 54 7 47
14 21 14 26
49
0 59 I 30
0 57 2 48
V~Ht
No.
Admission 6 Mo Admission 6 Mo Admission 6 Mo Admission 6 Mo Admission 6 Mo
II
I
Muderate
%
No.
21 10 22 12 24 7
30 14 30 16 34 10
52 13 20 9
50 13 32 14
%
Nu.
28
20 30 19 36 16 40
21 32 17 24
20 31 27 38
II
I
Severe
I
Very severe
%
No.
24 I 24 I 24 I
34 I 33 I 34 I
6 0 8 0 3 0
30 0 24 0
29
I 0 I 0
38
I
% 9 II
4
2
NAF800, Nafarelin, 800 f.l.g/day (400 f.l.g twice a day); NAF400, nafarelin , 400 f.l.g/day (200 f.l.g twice a day); DAN800, danazol, 800 mg/day (400 mg twice a day); DAN600. danazol. 600 mg/day (200 mg three times a day).
at the end of treatment in the percentage of patients with severe or very severe symptoms. At the present, results of the 6-month posttreatment follow-up are available only from the first controlled clinical trial. Of the 213 enrolled patients, 156 (73%) underwent the 6-month posttreatment follow-up examination (12 months after start of treatment). Thirtytwo (15% of 213) patients did not undergo this examination because they had become pregnant. Fifteen patients (7%) did not undergo this examination because they had undergone surgical or medical therapy for endometriosis; twice the percentage of patients taking danazol required the same procedures as those taking
both nafarelin dosages . Only 3% of the patients were lost to follow-up, and in 1% of the patients the examinations were incomplete. Of the 156 patients evaluated for severity of symptoms 6 months after treatment ended, 77% who took nafarelin, 800 fLg/ day, 72% who took nafarelin, 400 fLg/day, and 78% who used danazol, 800 fLg/ day, remained symptom free, reported only mild clinical symptoms, or were pregnant. Thus in a substantial number of patients the beneficial effects of the treatment continued for at least 6 months after the study drugs were discontinued. Pregnancy rates. Of the 149 patients attempting pregnancy, 52% receiving nafarelin, 800 fLg, and 30%
Efficacy of nafarelin
Volume 162 !'I:ulIlbcr 2
573
8
-
.2 ns a::
..J
C
:I:
---
..J
C
..J
DANAZOL
7
6 5
4 NAFARELIN
3 2
0
2
4
6
Months Fig. 2. Mean low/high-densilY lipoprolein (LDLI HDL) ralios during 6-molllh lrealmelll wilh nafarelin or danazol.
recelvmg 400 fJ..g succeeded within 12 months after treatment, as did 36% receiving danazol. In each treatment group, more than a third of the women who became pregnant had moderate to severe disease on admission to the study. The data on pregnancy rates from the second study are not available at the present time. Safety. Fig. 1 compares the incidence of adverse effects among patients receiving either nafarelin (400 fJ..g/day) or danazol (800 mg/day). The more profound hypoestrogenemia induced by nafarelin led to hot flashes, as reported by 90% of the patients receiving this agent, compared with 68% of the danazol users (p ::s; 0.001), but few patients withdrew from the trial because of this effect. Vaginal dryness and decreased libido, also hypoestrogenemic effects. were more prevalent in the nafarelin users (p::s; 0.01 and
