Henzl and Kwei
copy and evaluation of symptoms. The pregnancy rates were comparable to those achieved after danazol treatment. Nafarelin induced a more profound hypoestrogenemic state than did danazol and, consequently, more nafarelin users achieved amenorrhea more quickly. Clinical symptoms of endometriosis abated rapidly, and in most patients this relief of symptoms was maintained for 6 months after treatment. Adverse effects of nafarelin were limited largely to those of hypoestrogenemia, whereas danazol, with its androgenic activity, was associated with adverse effects on liver enzymes and lipid profiles, as well as masculinizing effects. Hypoestrogenemia in adults may be associated with loss of bone mineral content, and the results have shown some loss of vertebral bone mineral content, which was predictable and largely reversible. There was no effect on the density of compact bone.
February 1990 Am J Obstet Gynecol
In summary, the results of these two large-scale clinical trials demonstrated that the gonadotropinreleasing hormone agonist nafarelin was as effective as danazol for the management of endometriosis and had a more favorable safety profile, mainly as a result of the predictable effects of hypoestrogenemia, with a lack of effect on lipid and liver metabolism. REFERENCES I. Henzl MR, Corson SL, Moghissi K, et al. Administration
of nasal nafarelin as compared with oral danazol for endometriosis: a multicenter double-blind comparative clinical trial. N Engl] Med 1988;318:485-9. 2. Burry KA, Patton PE, Illingworth RD. Metabolic changes during medical treatment of endometriosis: nafarelin acetate versus Danocrine. AM ] OBSTET GYNECOL 1989; 160: 1454-61.
Nafarelin in the treatment of pelvic pain caused by endometriosis Robert W. Shaw, MD London, United Kingdom As part of a large, multicenter trial, 82 patients with endometriosis were randomized to 6 months of treatment with either nafarelin or danazol. Among 73 patients who had subjective symptoms (dysmenorrhea, dyspareunia, or pelvic pain) at baseline, 94% of patients treated with nafarelin and 91% of those treated with danazol had improvement. Resolution of physical findings also was observed in similar percentages of patients in each treatment group. Long-term studies are needed to determine whether these two agents are associated with different cure rates or times to recurrence of disease. (AM J OBSTET GVNECOL 1990;162:574-6.)
Key words: Danazol, endometriosis, gonadotropin-releasing hormone agonists, nafarelin Patients with endometriosis may have a variety of symptoms. Some symptoms are related to the site of endometriotic deposits, but the extent of disease does not correlate with the degree of symptoms. Furthermore, many patients with endometriosis have no symptoms whatsoever. Recently, nafarelin, a gonadotropin-releasing hor-
From the Academic Department of Obstetrics and Gynecology, Royal Free Hospital School of Medicine. Reprint requests: Robert W. Shaw, MD, AcademiC Department of Obstetrics and Gynecology, Royal Free Hospital School of Medlczne. Pond St., London NW3 2QG, Umted Ktngdom.
610116864
574
mone agonist, has shown promise in relieving the symptoms of endometriosis. In an effort to shed more light on the efficacy of this agent, a double-blind, randomized, multicenter study was conducted in both Europe and the United States. In the United Kingdom, 82 patients were assessed at two sites. This article summarizes findings in the latter group of patients.
Material and methods The patients in this study were randomized to receive 6 months of therapy with either danazol, 200 mg three times daily (the recommended dosage in most parts of Europe), or nafarelin, 200 JLg twice daily, intranasally. To maintain the blind nature of the study, patients
Nafarelin for pelvic pain caused by endometriosis
Volume 162 Number 2
575
Table I. Effects on subjective symptoms in 73 patients randomized to 6 months of therapy with nafarelin or danazol Treatment Nafarelzn
Symptom status
Total No. patients
11
Improved Complete relief Unchanged
67 43 6
I
Danazol
I
%
n
47/50 29/ 50
94 58
20/ 23 14/23
87 61
3/50
6
3/ 23
13
assigned to danazol also received placebo nasal spray, and those assigned to nafarelin also received placebo capsules. A subjective scoring system was used to evaluate three major symptoms of endometriosis: dysmenorrhea, dyspareunia, and pelvic pain. Each symptom was scored on a four-point scale, with 0 indicating the absence of such a finding. Scores of 1 through 3 were used to describe mild, moderate, and severe symptoms, respectively. Mild symptoms were defined as those resulting in some loss of work efficiency. Symptoms that caused the patient to remain in bed part of the day were described as moderate, and those resulting in the patient being bedridden or incapacitated for 1 or more days were defined as severe. Results
Of the 82 patients enrolled at the two centers in the United Kingdom, 8 did not complete the study. Among the group that received nafarelin, three patients withdrew from the study because of side effects thought to be drug related, and one could not be followed up because she left the country. The complaints reported by the three patients who had side effects were, respectively, depression, muscle aches, and mastalgia; giddiness. nausea, and vague paresthesia; and a maculopapular rash. Among the group that received danazol, two patients withdrew from the study because of side effects: one developed a viral illness and the other a maculopapular rash. In addition, two patients (one in each study group) were not analyzed because of their poor compliance. Consequently, 74 patients completed the study and were included in the data analysis. These patients also underwent second-look laparoscopy. Subjective symptoms. The data analysis showed that all but I of the 74 patients had subjective symptoms on entry into the study. When the individual scores were pooled at the conclusion of 6 months of therapy, 67 of these 73 patients (or 92%) showed improvement: 47 (94%) of 50 who received nafarelin and 20 (87%) of 23 who received danazol (Table I). Furthermore, 43 pa-
%
Table II. Percentages of patients (n = 50) with subjective symptoms at baseline and after 1,3, and 6 months of nafarelin therapy Months of nafarehn therapy ('lo)
Symptom
Pretreatment (%)
Dysmenorrhea Dyspareunia Pelvic pain No symptoms
100 74 86 0
I 46 36 64 30
3
4 34 42 48
I
6
2 22 18 58
tients (58% and 61% of the nafarelin and danazol groups, respectively) indicated that their symptoms had been completely relieved . Symptoms remained unchanged in six patients : three (6%) in the nafarelin group and three (13%) in the danazol group. Table II shows the percentages of patients who had specific symptoms before therapy, as well as after 1,3, or 6 months of treatment with nafarelin. All patients complained of dysmenorrhea at baseline, but within 1 month of the initiation of treatment more than half of these patients had complete relief ofthis symptom. This finding was not surprising because nafarelin had induced amenorrhea in most patients by this point. By the end of the sixth month of therapy, only one patient continued to report symptoms classified as dysmenorrhea. Dyspareunia took slightly longer to resolve than did dysmenorrhea, and complete follow-up data are not yet available. The analysis conducted to date shows that 11 of the 50 patients continued to have some degree of dyspareunia after 6 months of nafarelin therapy, although the severity of this symptom may have decreased . Notably, the number of patients who gained complete relief increased with the duration of treatment. A similar trend was evident with regard to pelvic pain. Physical findings. Of the overall group of 74 subjects, 53 had positive physical findings (pelvic tenderness or induration) at the time of entry into the study.
Shaw
Pelvic examinations performed at the conclusion of the trial revealed that these findings had resolved in similar percentages of patients in each treatment group. Likewise, comparable percentages of patients in each group had either improvement, no change, or worsening of the physical findings. Amenorrhea and hormonal changes. The percentages of patients with amenorrhea during any given cycle of the 6-month study were similar in the nafarelin and danazol groups. Assessment of hormonal changes revealed that both therapies suppressed estradiol, resulting in levels of approximately 100 pmol! L after 3 to 4 months of treatment. Notably, however, more patients in the nafarelin group had significant hypoestrogene mia, to levels less than 100 pmol! L, reflecting the
February 1990 Am J Obstet Gynecol
greater ability of this drug to Su ppress ovarian steroidogenesis.
Comment In this comparative study, nafarelin and danazol were found to have similar side-effect profiles in patients with endometriosis. Furthermore, the two agents offered approximately equivalent efficacy with regard to the relief of symptoms, provided that amenorrhea was induced. An unanswered question relates to whether these drugs are associated with different cure rates or times to recurrence of disease. Long-term studies will be needed to shed more light on these issues.
Nafarelin in the treatment of infertility caused by endometriosis David H. Barlow. MD Oxford, United Kingdom Patients with infertility caused by endometriosis may be managed by expectant strategies, surgery, or pharmacologiC intervention. The relative benefits conferred by each of these approaches remain to be confirmed. Data gathered thus far suggest, however, that nafarelin, a gonadotropin-releasing hormone agonist, may be associated with fecundity rates as low as those seen after surgical intervention. (AM J OBSTET GVNECOL 1990;162:576-9.)
Key words: Infertility, nafarelin The mechanisms that may form the basis for an association between endometriosis and infertility remain controversial. In addition to the anatomic damage that may occur with severe endometriosis, other suggested mechanisms in women with endometriosis include an increased frequency of anovulation, I increased occurrence of hyperprolactinemia,2 and effects within the peritoneal environment (Fig. 1). Several groups have reported increased prostaglandin levels in the peritoneal fluid in endometriosis,3.• with possible effects on the occurrence of luteinized unruptured follicles,' corpus luteum activity, luteolysis, or abortion. There may also be midcycle gonadotropin surges.
From the Nuffield Department of Obstetrics and Gynecology, Umversity of Oxford. Reprint requests: David H. Barlow, Department of Obstetncs and Gynecology, John Radcliffe Hospital, Oxford, United Kmgdom. 6/0/16868
576
Peritoneal fluid in endometriosis has been reported by some groups to contain higher macrophage concentrations,6 and these macrophages are thought to be more activated,' thus affecting the rate of sperm phagocytosis8 and producing factors that might make the peritoneal fluid less hospitable to oocytes and sperm." Studies in in vitro fertilization have shown that reduced fertilization rates occur in women with endometriosis (particularly those who have ovarian cysts). 10 The epidemiologic work of Vessey et al. II has revealed that, by 1 year, approximately 82% of a normal female population will conceive; this translates into a monthly fecundity figure of approximately 12% among women who are not known to be infertile. This figure should be kept in mind when treating women with infertility caused by endometriosis. Depending on the needs of the individual patient, the management of infertility may be based on either
copy and evaluation of symptoms. The pregnancy rates were comparable to those achieved after danazol treatment. Nafarelin induced a more profound hypoestrogenemic state than did danazol and, consequently, more nafarelin users achieved amenorrhea more quickly. Clinical symptoms of endometriosis abated rapidly, and in most patients this relief of symptoms was maintained for 6 months after treatment. Adverse effects of nafarelin were limited largely to those of hypoestrogenemia, whereas danazol, with its androgenic activity, was associated with adverse effects on liver enzymes and lipid profiles, as well as masculinizing effects. Hypoestrogenemia in adults may be associated with loss of bone mineral content, and the results have shown some loss of vertebral bone mineral content, which was predictable and largely reversible. There was no effect on the density of compact bone.
February 1990 Am J Obstet Gynecol
In summary, the results of these two large-scale clinical trials demonstrated that the gonadotropinreleasing hormone agonist nafarelin was as effective as danazol for the management of endometriosis and had a more favorable safety profile, mainly as a result of the predictable effects of hypoestrogenemia, with a lack of effect on lipid and liver metabolism. REFERENCES I. Henzl MR, Corson SL, Moghissi K, et al. Administration
of nasal nafarelin as compared with oral danazol for endometriosis: a multicenter double-blind comparative clinical trial. N Engl] Med 1988;318:485-9. 2. Burry KA, Patton PE, Illingworth RD. Metabolic changes during medical treatment of endometriosis: nafarelin acetate versus Danocrine. AM ] OBSTET GYNECOL 1989; 160: 1454-61.
Nafarelin in the treatment of pelvic pain caused by endometriosis Robert W. Shaw, MD London, United Kingdom As part of a large, multicenter trial, 82 patients with endometriosis were randomized to 6 months of treatment with either nafarelin or danazol. Among 73 patients who had subjective symptoms (dysmenorrhea, dyspareunia, or pelvic pain) at baseline, 94% of patients treated with nafarelin and 91% of those treated with danazol had improvement. Resolution of physical findings also was observed in similar percentages of patients in each treatment group. Long-term studies are needed to determine whether these two agents are associated with different cure rates or times to recurrence of disease. (AM J OBSTET GVNECOL 1990;162:574-6.)
Key words: Danazol, endometriosis, gonadotropin-releasing hormone agonists, nafarelin Patients with endometriosis may have a variety of symptoms. Some symptoms are related to the site of endometriotic deposits, but the extent of disease does not correlate with the degree of symptoms. Furthermore, many patients with endometriosis have no symptoms whatsoever. Recently, nafarelin, a gonadotropin-releasing hor-
From the Academic Department of Obstetrics and Gynecology, Royal Free Hospital School of Medicine. Reprint requests: Robert W. Shaw, MD, AcademiC Department of Obstetrics and Gynecology, Royal Free Hospital School of Medlczne. Pond St., London NW3 2QG, Umted Ktngdom.
610116864
574
mone agonist, has shown promise in relieving the symptoms of endometriosis. In an effort to shed more light on the efficacy of this agent, a double-blind, randomized, multicenter study was conducted in both Europe and the United States. In the United Kingdom, 82 patients were assessed at two sites. This article summarizes findings in the latter group of patients.
Material and methods The patients in this study were randomized to receive 6 months of therapy with either danazol, 200 mg three times daily (the recommended dosage in most parts of Europe), or nafarelin, 200 JLg twice daily, intranasally. To maintain the blind nature of the study, patients
Nafarelin for pelvic pain caused by endometriosis
Volume 162 Number 2
575
Table I. Effects on subjective symptoms in 73 patients randomized to 6 months of therapy with nafarelin or danazol Treatment Nafarelzn
Symptom status
Total No. patients
11
Improved Complete relief Unchanged
67 43 6
I
Danazol
I
%
n
47/50 29/ 50
94 58
20/ 23 14/23
87 61
3/50
6
3/ 23
13
assigned to danazol also received placebo nasal spray, and those assigned to nafarelin also received placebo capsules. A subjective scoring system was used to evaluate three major symptoms of endometriosis: dysmenorrhea, dyspareunia, and pelvic pain. Each symptom was scored on a four-point scale, with 0 indicating the absence of such a finding. Scores of 1 through 3 were used to describe mild, moderate, and severe symptoms, respectively. Mild symptoms were defined as those resulting in some loss of work efficiency. Symptoms that caused the patient to remain in bed part of the day were described as moderate, and those resulting in the patient being bedridden or incapacitated for 1 or more days were defined as severe. Results
Of the 82 patients enrolled at the two centers in the United Kingdom, 8 did not complete the study. Among the group that received nafarelin, three patients withdrew from the study because of side effects thought to be drug related, and one could not be followed up because she left the country. The complaints reported by the three patients who had side effects were, respectively, depression, muscle aches, and mastalgia; giddiness. nausea, and vague paresthesia; and a maculopapular rash. Among the group that received danazol, two patients withdrew from the study because of side effects: one developed a viral illness and the other a maculopapular rash. In addition, two patients (one in each study group) were not analyzed because of their poor compliance. Consequently, 74 patients completed the study and were included in the data analysis. These patients also underwent second-look laparoscopy. Subjective symptoms. The data analysis showed that all but I of the 74 patients had subjective symptoms on entry into the study. When the individual scores were pooled at the conclusion of 6 months of therapy, 67 of these 73 patients (or 92%) showed improvement: 47 (94%) of 50 who received nafarelin and 20 (87%) of 23 who received danazol (Table I). Furthermore, 43 pa-
%
Table II. Percentages of patients (n = 50) with subjective symptoms at baseline and after 1,3, and 6 months of nafarelin therapy Months of nafarehn therapy ('lo)
Symptom
Pretreatment (%)
Dysmenorrhea Dyspareunia Pelvic pain No symptoms
100 74 86 0
I 46 36 64 30
3
4 34 42 48
I
6
2 22 18 58
tients (58% and 61% of the nafarelin and danazol groups, respectively) indicated that their symptoms had been completely relieved . Symptoms remained unchanged in six patients : three (6%) in the nafarelin group and three (13%) in the danazol group. Table II shows the percentages of patients who had specific symptoms before therapy, as well as after 1,3, or 6 months of treatment with nafarelin. All patients complained of dysmenorrhea at baseline, but within 1 month of the initiation of treatment more than half of these patients had complete relief ofthis symptom. This finding was not surprising because nafarelin had induced amenorrhea in most patients by this point. By the end of the sixth month of therapy, only one patient continued to report symptoms classified as dysmenorrhea. Dyspareunia took slightly longer to resolve than did dysmenorrhea, and complete follow-up data are not yet available. The analysis conducted to date shows that 11 of the 50 patients continued to have some degree of dyspareunia after 6 months of nafarelin therapy, although the severity of this symptom may have decreased . Notably, the number of patients who gained complete relief increased with the duration of treatment. A similar trend was evident with regard to pelvic pain. Physical findings. Of the overall group of 74 subjects, 53 had positive physical findings (pelvic tenderness or induration) at the time of entry into the study.
Shaw
Pelvic examinations performed at the conclusion of the trial revealed that these findings had resolved in similar percentages of patients in each treatment group. Likewise, comparable percentages of patients in each group had either improvement, no change, or worsening of the physical findings. Amenorrhea and hormonal changes. The percentages of patients with amenorrhea during any given cycle of the 6-month study were similar in the nafarelin and danazol groups. Assessment of hormonal changes revealed that both therapies suppressed estradiol, resulting in levels of approximately 100 pmol! L after 3 to 4 months of treatment. Notably, however, more patients in the nafarelin group had significant hypoestrogene mia, to levels less than 100 pmol! L, reflecting the
February 1990 Am J Obstet Gynecol
greater ability of this drug to Su ppress ovarian steroidogenesis.
Comment In this comparative study, nafarelin and danazol were found to have similar side-effect profiles in patients with endometriosis. Furthermore, the two agents offered approximately equivalent efficacy with regard to the relief of symptoms, provided that amenorrhea was induced. An unanswered question relates to whether these drugs are associated with different cure rates or times to recurrence of disease. Long-term studies will be needed to shed more light on these issues.
Nafarelin in the treatment of infertility caused by endometriosis David H. Barlow. MD Oxford, United Kingdom Patients with infertility caused by endometriosis may be managed by expectant strategies, surgery, or pharmacologiC intervention. The relative benefits conferred by each of these approaches remain to be confirmed. Data gathered thus far suggest, however, that nafarelin, a gonadotropin-releasing hormone agonist, may be associated with fecundity rates as low as those seen after surgical intervention. (AM J OBSTET GVNECOL 1990;162:576-9.)
Key words: Infertility, nafarelin The mechanisms that may form the basis for an association between endometriosis and infertility remain controversial. In addition to the anatomic damage that may occur with severe endometriosis, other suggested mechanisms in women with endometriosis include an increased frequency of anovulation, I increased occurrence of hyperprolactinemia,2 and effects within the peritoneal environment (Fig. 1). Several groups have reported increased prostaglandin levels in the peritoneal fluid in endometriosis,3.• with possible effects on the occurrence of luteinized unruptured follicles,' corpus luteum activity, luteolysis, or abortion. There may also be midcycle gonadotropin surges.
From the Nuffield Department of Obstetrics and Gynecology, Umversity of Oxford. Reprint requests: David H. Barlow, Department of Obstetncs and Gynecology, John Radcliffe Hospital, Oxford, United Kmgdom. 6/0/16868
576
Peritoneal fluid in endometriosis has been reported by some groups to contain higher macrophage concentrations,6 and these macrophages are thought to be more activated,' thus affecting the rate of sperm phagocytosis8 and producing factors that might make the peritoneal fluid less hospitable to oocytes and sperm." Studies in in vitro fertilization have shown that reduced fertilization rates occur in women with endometriosis (particularly those who have ovarian cysts). 10 The epidemiologic work of Vessey et al. II has revealed that, by 1 year, approximately 82% of a normal female population will conceive; this translates into a monthly fecundity figure of approximately 12% among women who are not known to be infertile. This figure should be kept in mind when treating women with infertility caused by endometriosis. Depending on the needs of the individual patient, the management of infertility may be based on either
