Danazol in the treatment of endometriosis: analysis of 100 cases with a 4-year follow-up

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1 FERTILITY AND STERILITY Copyright c 1982 The American Fertility Society Vol. 37, No.6, June 1982 Printed in U.S A. Danazol in the treatment of endometriosis: analysis of 100 cases with a 4-year follow-up Robert L. Barbieri, M.D.* Stephen Evans, M.D. Robert W. Kistner, M.D. Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts A prospective study to evaluate the efficacy of danazol in the treatment of endometriosis was initiated in One hundred patients with endometriosis, as demonstrated by laparoscopy, were entered into the study. The mean length of patient follow-up was 49 months. All patients were treated with 800 mg of danazol per day. The mean duration of danazol therapy was 17.3 weeks. Eighty-nine percent of the patients reported symptomatic improvement, and 94% were improved, as demonstrated by repeat laparoscopy or laparotomy. After completing a course of danazol therapy, 57% of the patients underwent conservative laparotomy for fertility enhancement, pain control, or ovarian masses. Two patients underwent total abdominal hysterectomy-bilateral salpingo-oophorectomy for advanced disease poorly responsive to danazol therapy. In those patients desiring fertility (56), there were 38 pregnancies in 26 women, for an overall fertility rate of 46%. The overall recurrence rate was 33%, as determined by symptoms and physical findings. Significant side effects from danazol were reported by 85% of the patients. The major side effects were weight gain, edema, decrease in breast size, oily skin, hirsutism, and deepening of the voice. Only one patient discontinued danazol therapy due to side effects. Clinical issues concerning the use of danazol with or without surgery and the miscarriage rate following danazol therapy are discussed. Fertil Steril37:737, 1982 The medical management of endometriosis has undergone a significant evolution during the past three decades. High dose diethylstilbestrol (DES) therapy 1 and methyltestosterone therapy 2 both achieved moderate degrees of success in providing relief from the symptoms of endometriosis. However, the high percentage of disturbing side effects produced by these two hormonal regimens precluded their widespread application. In the Received November 20, 1981; revised and accepted February 16, *Reprint requests: Robert L. Barbieri, M.D., Laboratory of Human Reproduction, Harvard Medical School, 45 Shattuck Street, Boston, Massachusetts late 1950s the introduction of ''progestin-only" and pseudopregnancy regimens 3 resulted in a marked improvement in the medical management of endometriosis. The pseudopregnancy regimen provides symptomatic relief in 50% to 80% of patients with endometriosis and is associated with a smaller percentage of disturbing side effects than DES or methyltestosterone therapy. The pseudopregnancy regimen remains the standard against which all new regimens are judged. The introduction of the synthetic steroid danazol creates another option in the medical management of endometriosis. In this paper the longterm results of treating 100 cases of endometriosis with danazol are analyzed. Vol. 37, No. 6, June 1982 Barbieri et al. Danazol therapy for endometriosis 737

2 MATERIALS AND METHODS In 1976 a prospective study to evaluate the efficacy of danazol in the treatment of endometriosis was initiated. All clinical management decisions were made by one physician (R. W. K.). In all cases the diagnosis of endometriosis was confirmed by laparoscopy. At the time of laparoscopy all patients were clinically staged on the basis of the classification system of Kistner et al. 4 No operative therapeutic procedures were performed at the time of laparoscopy. Biopsies for pathologic diagnosis were not obtained during laparoscopy. The laparoscopic diagnosis of endometriosis was based on the characteristic visual presentation of the disease. After the diagnosis of endometriosis was made, all patients received 800 mg of danazol per day (400 mg twice daily). The Sterling-Winthrop Research Institute (New York, NY) kindly supplied danazol to all patients without charge. All patients were seen at 6- to 8-week intervals while on danazol. During each visit all patients were interviewed concerning pelvic pain, dysmenorrhea, dyspareunia, and menorrhagia. Examinations were performed to evaluate cul-de-sac nodularity, ovarian enlargement, and uterosacral ligament involvement. Patients were treated with danazol for varying time periods on the basis of clinical evaluation of response and need for surgical intervention. All patients had repeat laparoscopy or laparotomy at the completion of their course of danazol therapy to evaluate the response of the disease. Fifty-seven percent ofthe patients underwent conservative laparotomy at the completion of their course of danazol therapy. At conservative laparotomy the following procedures were performed when indicated: excision and fulguration of accessible areas of endometriosis, lysis of adhesions, ovarian reconstruction, tubal reconstruction, appendectomy, and uterine suspension. A few patients were given danazol postoperatively in an attempt to suppress nonresectable areas of endometriosis. All patients completing a course of danazol and desiring pregnancy were instructed to avoid conception until one menses of normal length and flow had occurred. After completing danazol therapy patients were followed at 6-month intervals. A complete infertility workup was obtained when clinically indicated. One hundred nine consecutive patients with newly diagnosed endometriosis or endometriosis poorly responsive to other medical regimens were asked to participate in the study. One hundred 738 Barbieri et al. Danazol therapy for endometriosis patients entered the study and completed at least a 4-week course of danazol therapy. Of the remaining nine patients seven declined to participate, and two patients agreed to participate but never started the drug. Most patients who did not participate cited fears of the side effects of the drug as the major reason for not joining the study. RESULTS A brief summary of patient characteristics is presented in Table 1. Of the 100 patients who entered the study, 56% were infertile. The mean age of these patients at entry into the study was 27.2 years. For those patients not desiring pregnancy the mean age at entrance into the study was 26.4 years. For all patients the average mean and median follow-up was 49 and 46 months, respectively. Of the 100 patients who entered the study, 41 had stage I disease; 32, stage II disease; 15, stage III disease; and 12, stage IV disease (Table 2). All patients were treated with 800 mg of danazol per day. The overall mean danazol treatment period was 17.3 weeks. The length of therapy ranged from 4 to 31 weeks. After completing danazol therapy most patients had their first menses within 6 weeks. In Table 3 the major symptoms experienced by the patients before and after danazol therapy are tabulated. Before danazol therapy the major symptoms included dysmenorrhea (79%), pelvic pain (69%), dyspareunia (42%), and menorrhagia (27%). During danazol therapy there was a marked decrease in the number and severity of symptoms. Immediately after completing danazol therapy and prior to the "second look" laparoscopy or laparotomy, the symptom pattern was dysmenorrhea (19%), pelvic pain (18%), dyspareunia (16%), and irregular bleeding (25%). In general, those patients with continued symptoms Table 1. Patient Characteristics Number of patients Number of patients desiring pregnancy Mean age of patients desiring pregnancy Number of patients becoming pregnant Number of patients not desiring pregnancy Mean age of patients not desiring pregnancy Average follow-up of all patients Median Mean yrs 26 (46%) yrs 46 mos 49 nios Fertility and Sterility

3 Table 2. Danazol Dosage, Length of Treatment, and Weeks to Resumption of Menses Weeks of danazol therapy Weeks to resumption Stage" No. of patients Daily danazol dose of first menses Mean Range (mean) mg I II m IV "Results are stratified according to clinical staging of endometriosis as described by Kistner et al. 4 while on danazol reported them to be much milder while on danazol therapy. Eleven patients reported no symptomatic improvement while on danazol therapy. Only one patient complained of increasingly severe symptoms while on danazol therapy. When symptomatic improvement was stratified by stage of disease, it was observed that 95% of patients with stage II, III, and IV disease reported improvement in symptoms (Table 4). This observation is in contrast to stage I patients, 20% of whom reported no improvement in symptoms while on danazol therapy. ' Abnormal physical findings noted on pelvic examination prior to institution of danazol therapy tended to resolve during therapy (Table 3). Prior to institution of danazol therapy, 80% of the patients had cul~de-sac nodularity, 25% had ovarian enlargement, and 85% had uterosacral ligament involvement. After danazol therapy, and prior to "second look" laparotomy or 1aparoscopy, 9% of the patients had cul-de-sac involvement, 7% had ovarian enlargement, and 12% had uterosacral ligament involvement. At the completion of their course of danazol therapy, all patients had repeat laparoscopy or laparotomy performed for evaluation of the status of their endometriosis. Ninety-four percent of the patients had objective evidence of improvement. When the data for laparoscopic or laparotomy evidence of improvement was stratified by stage of disease, the following improvement rates were noted: stage I, 95%; stage II, 97%; stage III, 87%; and stage IV, 92% (Table 4). Fifty-seven percent of the patients in the study underwent conservative laparotomy for fertility enhancement, pain control, or ovarian masses. Two patients with stage IV disease had total abdominal hysterectomy with bilateral salpingo-oo- Table 3. Symptoms and Findings on Pelvic Examination Before and After Danazol Therapy None Mild Moderate Severe Total no. of patients with symptoms Symptoms Dysmenorrhea Before After Pelvic paina Before After Dyspareunia Before After Menorrhagia Before After Physical findings Cul-de-sac involvement Before After Ovarian enlargement Before After Uterosacral ligament involvement Before After Pelvic pain.refers to pain not related to menses or sexual intercourse. Vol. 37, No. 6, June 1982 Barbieri et al. Danazol therapy for endometriosis 739

4 r Table 4. Summary of Symptomatic and Laparoscopic Improvement Following Danazol Therapy and Tabulation of Conceptions, Recurrence of Disease, and Number of Patients Undergoing Conservative Laparotomy No. of patients Improvement by treated with Stage No. of Symptomatic laparoscopy/ danazoland Conceptions in Recurrences by patients improvement laparotomy conservative those desir- physical exam laparotomy ing fertility or symptoms I (80%) 39 (95%) 12 (29%) 11/22 (50%) 9 (22%) II (94%) 31 (97%) 22 (69%) 6/16 (38%) 13(41%) III (93%) 13 (87%) 14 (93%) 5/11 (45%) 5 (33%) IV (100%) 11 (92%) ll(92%)a 417 (57%) 6 (50%) Total (89%) 94 (94%) 59 (59%) 26/56 (46%) 33 (33%) "Two patients with stage IV disease underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. phorectomy for advanced disease poorly respon" sive to danazol or pseudopregnancy management. When stratified according to the stage of disease, the following percentage of patients in each stage underwent surgery: stage I, 29%; stage II, 69%; stage III, 93%; and stage IV, 92%. Over the 5-year follow-up period 33% of the patients complained of recurrent symptoms or were noted to have recurrent physical findings suggestive of endometriosis. When stratified by stage of disease, the following recurrence rates were noted: stage I, 22%; stage II, 41 %; stage Ill, 33%, and stage IV, 50%. A minority of patients underwent a "third look" laparoscopy or laparotomy for objective documentation of the recurrence. Of the ten patients who underwent a "third look" procedure, nine had objective evidence of recurrent endometriosis. At a "third look" laparoscopy these nine patients all had minimal disease: 56% stage II and 44% stage I. Nine patients with recurrence of symptoms and signs of endometriosis were treated with a second course of danazol. All of these patients showed symptomatic and objective evidence of improvement. The time courses of the recurrences were as follows: 0 to 6 months, 7%; 6 to 12 months, 9%; 12 to 24 months, 6%; 24 to 36 months, 8%; and more than 36 months, 3% (total 33%). Interestingly, there was only a 15% overall recurrence rate in those patients who carried a term pregnancy after completing danazol therapy. Of those patients desiring fertility (56), 26 patients became pregnant for an overall fertility rate of 46%. A total of 38 pregnancies occurred in these 26 women. There were five spontaneous first-trimester abortions. There were no secondor third-trimester losses. Interestingly, of those pregnancies occurring immediately after the completion of a course of danazol, 17 resulted in male and 7 resulted in female children. Eleven patients with infertility and stage I, II, or III disease became pregnant after danazol ther- apy alone (Table 5). There were 12 conceptions in these patients. Ten were full-term deliveries. One patient requested a therapeutic abortion, and one patient had a spontaneous abortion at 8 weeks. Fifteen patients who received danazol therapy followed by conservative laparotomy became pregnant (Table 6). There was a total of 26 conceptions in these 15 patients. There were 19 fullterm deliveries. Three pregnancies are presently in the second or third trimester. There were four spontaneous abortions at 8 to 10 weeks by menstrual dates. One patient in this group required clomiphene induction of ovulation for oligomen" orrhea. Table 7 tabulates the time of occurrence of the first conception after termination of danazol therapy. Fifty-four percent of the first conceptions occurred within 6 months of termination of danazol therapy. Only two first conceptions resulted in spontaneous abortions. Both of these conceptions occurred more than 15 months after the completion of danazol therapy. Table 8 tabulates the side effects reported by patients while on danazol therapy. Eighty-five percent of the patients reported side effects. The most common side effects, in decreasing order of frequency, were weight gain, edema, decreased breast size, acne, hirsutism, oily skin, and deepening of the voice. Uncommon side effects included menorrhagia, headache, vaginitis, decreased libido, muscle cramps, and hot flashes. Only one patient discontinued therapy due to side effects. DISCUSSION The medical management of endometriosis has been significantly advanced by the introduction of the synthetic steroid danazol. Danazol has at least four pharmacologic properties that could account for its therapeutic efficacy in the treatment of endometriosis~ (1) suppression of gonadotropin- 740 Barbieri et al. Danazol therapy for endometriosis Fertility and Sterility

5 Table 5. Pregnancies After Danazol Therapy Alone Interval from Patient infertility" triosis therapy to conception Total period of Stage.of endome- Weeks of danazol end of danazol therapy Outcome Sex Mass mo mo pounds/ounces 3 30 II 17 4 Full-term F 6/ I 20 9 Therapeutic abortion I 14 3 Full-term M 7/ I 17% 4 Full-term F 7/ I Full-term M 7/ I Full-term F 8/ I 26 2 Full-term M 8/ I 17 4 Full-term M 6/3 52 Full-term M 6/ I Spontaneous abortion at 8 weeks I 13 2 Full-term M 7/ 'III 12 4 Full-term M 7/13 "Total period of infertility refers to number of months of infertility prior to entering danazol study. releasing hormone 5 and/or gonadotropin secretion6; (2) direct interaction with endometrial androgen and progesterone receptors 7 8 ; (3) direct inhibition of ovarian steroidogenesis 9 10 ; and ( 4) increased metabolic clearance of estradiol and progesterone. 10 These properties of danazol produce an endocrine environment that inhibits the growth of endometrial tissue. By a direct androgenic and antiprogestational action on the endometrial implants of endometriosis, danazol produces atrophy of this tissue. In addition, danazol blocks ovarian follicular growth by direct actions on the hypothalamic-pituitary axis and the ovary. The lack of ovarian follicular activity results in a hypoestrogenic-hypoprogestational environment that also inhibits endometrial growth. Finally, by producing amenorrhea, danazol prevents the peritoneal "reseeding" of endometrial tissue that could occur during the menses. Given these pharmacologic properties of danazol, it is not surprising that danazol therapy results in a significant degree of symptomatic and objective improvement in patients with endometriosis. Many of the results reported in this study confirm the original findings of Dmowski and Cohen.11 Prior to comparing these two studies one important difference in methodology needs to be emphasized: danazol therapy was combined with follow-up conservative laparotomy in a greater number of patients in our study than in the Dmowski and Cohen report. In this respect the studies are not directly comparable. However, the findings of both studies are similar in the following respects: (1) danazol alone produced sympto- Vol. 37, No. 6, June 1982 matic and objective improvement in more than 85% of patients with endometriosis; (2) the overall recurrence rate of endometriosis after completing a course of danazol (with or without conservative surgery) was 15% to 20% in the first year and 5% each year thereafter; (3) in those women who carried a full-term pregnancy after completing. a course of danazol (with or without conservative surgery) the recurrence rate was approximately 15% over a 3-year follow-up period; (4) after discontinuing danazol therapy (with or without conservative surgery) approximately one-half the pregnancies occurred within 6 months of stopping the drug; and (5) the overall fertility rate was 46% in both studies. Our findings differ from those of Dmowski and Cohen in the following respects: (1) in our study the majority of patients (85%) complained of side effects while on drug therapy; and (2) in our experience no increased incidence of spontaneous abortions, ectopic pregnancies, or stillbirths were noted in pregnancies occurring after the completion of danazol therapy. The reason for these discrepancies is unclear. The observation by Dmowski and Cohen that there was an increased incidence of second and third trimester intrauterine fetal deaths in those conceptions occurring within three cycles of discontinuing danazol therapy has yet to be confirmed. Dmowski and Cohen have postulated that their observed relationship between early conception after completion of dana-. zol therapy and an increased stillbirth rate is due to abnormal placentation in an atrophic endometrium. In the late 1950s, Kistner 12 observed that Barbieri et al. Danazol therapy for endometriosis 741

6 Table 6. Pregnancies After Danazol Therapy and Tnfertility Laparotomy Total Stage of Weeks of Patient period of endome danazol infertility trio sis therapy Interval from end of dan azol therapy to conception Outcome Sex Mass mo 2 60 I IV 19% IV IV lli I lli II lli lli I IV II II II 8% mo pounds/ounces 18 Full-term M 7/12 4 Full-term F 6/15 Full-term M. 7/8 Pregnant at 20 weeks 12 Full-term F 8/2 Spontaneous abortion at 8 weeks Pregnant at 30 weeks 6 Full-term M 8/2 Full-term F 7/0 8 Ful}-term M 8/3 Ful -term M 9/4 14 Full-term M 8/6 Full-term M 7/6 4 Full,term F 5/10 '1 week Full-term M 6/2 12 Full-term M 7/10 6 Full-term M 7/2 4 Full-term M 6/9 Spontaneous abortion at 10weeks Pregnant at 33 weeks 19 Spontaneous abortion at 8 weeks 10 Full-term F 7/3 Spontaneous abortion at 10 weeks 8 Full-term M 7/10 13 Full-term M 7/10 2 Full-term M 7/13 "progestin-only" and pseudopregnancy therapy for endometriosis resulted in a pseudo-decidualization of the endometrium. Aware of the possibility of abnormal implantation in the decidualized endometrium, he cautioned that patients desiring a conception after completing a course of pseudopregnancy therapy should wait one menstrual period of normal flow and duration before attempting to conceive. Consequently, all patients in this study who were attempting to become pregnant after a course of danazol therapy were cautioned to avoid conception until one menses of normal length and flow had occurred. It is possible that this advice led to the low inci~ence of spontaneous abortions and stillbirths in our study. However, data recently reported by Daniell and Christianson13 are in marked disagreement with the findings ofdmowski and Cohen.11 Daniell and Christianson reported 36 pregnancies occurring in Barbieri et al. Danazol therapy for endometriosis women after the completion of a course of danazol therapy. They advised their infertility patients to begin to attempt conception immediately after discontinuing danazol therapy. Overall, there were only two spontaneous abortions and one ectopic pregnancy. There were no stillbirths. Five patients stopped danazol and became pregnant without an intervening menstrual period. All five had a normal full-term delivery. Daniell and Christianson conclude that since most conceptions following a course of danazol therapy occur within the first 6 months of completion of therapy, there is no advantage to waiting for one normal menstrual cycle before conceiving. In their opinion, the delay does not decrease the risk of spontaneous abortion or stillbirth but does prevent the patient from attempting conception during a very fertile time period. The. observation that endometriosis itself is associated with an in- Fertility and Sterility

7 Table 7. Time of Occurrence of First Conception After Termination of Danazol Treatment Interval from end of danazol ther No. of Spontaneous apy to con- pregnancies abortions ception mo > creased spontaneous abortion rate 14 further complicates the interpretation of the relationship between danazol and spontaneous abortions. It is of interest that all five spontaneous abortions that occurred in our study occurred more than 15 months after completing a course of danazol (with or without conservative surgery). It is possible that recurrent endometriosis was in part responsible for these spontaneous abortions. Further investigations will be needed to resolve this area of controversy. Guidelines concerning the use of danazol continue to evolve. Controversies remain concerning many aspects of the application of danazol in the treatment of endometriosis. However, one area of almost universal agreement is that a patient should have the diagnosis of endometriosis documented by laparoscopy prior to starting danazol therapy. Another point of general consensus is that the patient should not be pregnant while taking danazol. Danazol and related isoxazole compounds cross the placenta and can induce significant urogenital abnormalities in human and laboratory animal offspring exposed in utero The safest way to initiate danazol is to start therapy immediately after 5 days of normal menstrual flow. Alternatively, in the oligomenorrheic patient, pregnancy testing with sensitive blood ~-human chorionic gonadotropin measurements in conjunction with an. appropriate period of abstinence from sexual exposure can be used to exclude an early pregnancy. Interestingly, we have observed one patient who initiated a "low-dose" danazol regimen (400 mg/day) after a normal menstrual period and became pregnant some time within the first 2 weelts of therapy. We are not aware of a similar occurrence in patients taking 800 mg of danazol per day. This has prompted us to caution all patients on low-dose danazol to use an alternative method of contraception or to practice abstinence during the first 2 weeks of Vol. 37, No. 6, June 1982 therapy. In patients on low doses of danazol, who have a history of poor medication compliance, vigilance should be maintained to exclude an unsuspected interval pregnancy. Many areas of controversy still remain concerning the therapeutic application of danazol. A major area where consensus is lacking concerns the appropriate dose of danazol. The major early studies investigating the efficacy of danazol in the therapy of endometriosis employed a dose of 800 mg/day " 19 More recently; experienced clinicians have suggested that a dose of 400 mg/day of danazol results in symptomatic improvement, amenorrhea, and objective regression of disease in most patients They have suggested that all patients be started on 400 mg/day of danazol and that the dosage be modified on the basis of symptom response and physical examination. If necessary, the dose can be increased to 600 to 800 mg/day of danazol. In the study reported here, all patients were treated with 800 mg/day of danazol. Since 1978 we have treated most patients with 400 mg/day of danazol. Experience with this dose of danazol in approximately 200 patients has been uniformly excellent. A major benefit of this reduction of dose is the important reduction in total cost of a course of danazol therapy. Another benefit is that severity of side effects appear to be somewhat dose-related. Recently, some clinicians have suggested starting all patients on 200 mg of danazol daily. Although this dose uniformly produces a decrease in symptoms, we have been reluctant to use this dose for two reasons: (1) most women on this dose continue to have uterine bleeding, and (2) a small percentage of women will ovulate on this dose of danazol. As noted above, significant side effects were reported by 85% of the patients. The major side effects (in decreasing order of frequency) were weight gain, edema, decrease in breast size, acne, hirsutism, oily skin, and deepening of the voice. The acne, oily skin, hirsutism, and deepening of Table 8. Side Effects of Danazol (Number of Patients) Mild Moderate Severe Total Weight gain Edema or bloat ing (water retention) Decrease in breast size Acne Hirsutism Oily skin Deepening of voice Barbieri et al. Danazol therapy for endometriosis 743

8 the voice are probably due to the androgenic properties of danazol. The decrease in breast size probably reflects both a hypoestrogenic environment and the androgenic properties of danazol. The mechanisms by which danazol produces weight gain and edema are unclear. Although some of the weight gain might be due to "anabolic" properties of danazol, mineralocorticoid and glucocorticoid effects of danazol might be responsible for the observed weight gain and edema. 7 Although the majority of patients on danazol experience significant drug-related side effects, in general these side effects are not severe enough to require discontinuation of the drug. In our study only one patient discontinued danazol therapy due to side effects (acne, oily skin), and this occurred after 12 weeks of therapy. Since most women taking danazol will experience side effects, it is reasonable to review these effects with the patient prior to instituting therapy. In the nonpregnant, nonlactating woman, very few absolute contraindications to danazol therapy exist. Because danazol is metabolized by the liver and can produce modest elevations in serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPI'), its use in patients with liver disease is relatively contraindicated. In addition, the dramatic gain in weight and the fluid retention seen in some patients on danazol make this drug relatively contraindicated in patients with cardiac or renal disease. Many aspects of the application of danazol to the treatment of endometriosis should be tailored to the needs of the individual patient. In this regard the length of treatment with danazol is an important variable. Courses of therapy as short as 3 months to as long as 24 months can be justified in certain clinical situations. For example, in the patient with advanced endometriosis and infertility who is scheduled for a conservative laparotomy, a 12- to 14-week preoperative course of danazol might be appropriate. For the patient with painful endometriosis not desiring fertility who is adamantly opposed to surgery, an 18- to 24-month course of danazol is not unreasonable if side effects are carefully monitored. An important finding of this study is that in the infertile patient with stage I and stage II endometriosis, a course of danazol alone resulted in a 50% uncorrected fertility rate. This observation confirms the findings of Van Zyl et al. 22 who studied 20 infertile patients with mild to moderate endometriosis (staging system of Acosta et al. 23 ). 744 Barbieri et al. Danazol therapy for endometriosis Eight conceptions were obtained after a course of danazol without surgical intervention. Although the mechanisms by which danazol enhances fertility in patients with mild to moderate endometriosis are unclear, it is possible that danazol decreases the production of prostaglandins (PG) by endometriotic tissue. PG and related metabolites have been implicated as hormonal mediators of the infertility of endometriosis. 24 In patients with infertility and advanced stages of endometriosis, surgery is usually necessary to remove implants of endometriosis and to repair anatomic abnormalities. Few experimental data are available concerning the value of danazol in the pre- or postoperative management of endometriosis. In our experience danazol is of significant value in the preoperative management of endometriosis because it decreases the number and size of endometriotic areas and thus reduces the extent of surgery. A reduction in the extent of surgery probably results in fewer postoperative adhesions and complications. In addition, the preoperative use of danazol eliminates the chance of traumatizing a corpus luteum. In general, we have limited the use of danazol in the postoperative management of the infertile patient. Most conceptions following surgical therapy occur within the first 6 months after surgery. 25 Therefore, by treating the surgical patient with danazol for a prolonged period postoperatively, one will lose part of the time interval with the greatest fertility potential. For the patient not interested in conception, postoperative danazol can prove helpful in reducing endometriosis in areas that could not be surgically resected and delaying recurrent disease. A controversial subject is the effect of danazol on endometriomas. No systematic study assessing the effect of danazol on endometriomas has been reported. Observations in this and other studies suggest that danazol can often reduce the size of endometriomas, but that it is unusual for danazol to cause complete regression of an endometrioma. Therefore, in most infertility patients with endometriomas surgical intervention will be required. Nevertheless, the use of danazol preoperatively will decrease the overall extent of the endometriosis and thereby probably reduce the extent of the surgery. One cautionary observation must be made concerning the use of danazol in the preoperative management of the patient with an endometrioma: it is possible for the endometrioma to rupture preoperatively. If this should occur, chances for fertility are probably reduced. Fertility and Sterility

9 A major problem in the treatment of endometriosis is that the disease tends to recur unless definitive surgical therapy is performed. In our study there was a 16% recurrence rate in the 1st year. Thereafter, there was a 3% to 8% recurrence rate per year, for an overall recurrence rate of 33% during the 4-year follow-up period. For those patients who carried a term pregnancy after completing danazol (with or without conservative laparotomy) the overall recurrence rate was only 15%. These observations are similar to the findings of Dmowski and Cohen. 11 Nine patients who had recurrent endometriosis after completing danazol therapy were treated with a second course of danazol therapy (400 mg/day). All nine patients responded with improvement in symptoms and physical findings. None of these patients experienced any unusual side effects from their second course of therapy. These observations suggest that recurrent endometriosis can be treated effectively with a second course of danazol therapy. Theoretically, the endometriotic implants could become "resistant" to multiple courses of danazol therapy. We have yet to observe this phenomenon. One major controversy concerning the use of danazol in the treatment of endometriosis is the efficacy of danazol versus a pseudopregnancy regimen. Very little experimental data are available that directly address the issue of danazol versus pseudopregnancy in the treatment of endometriosis. The results of one small prospective randomized trial of danazol versus mestranol/norethynodrel has been reported by Noble and Letchworth.26 They studied 42 patients with endometriosis documented by laparoscopy or laparotomy. Patients were randomly assigned to groups receiving danazol or mestranol/norethynodrel. Patients were started on low doses of danazol (200 mg/day), and the dose was increased until amenorrhea occurred. Patients in the pseudopregnancy group were started on mestranol 150 ~Jog/day and norethynodrello mg/day. The validity of the results of the study is difficult to evaluate because of numerous methodologic problems: (1) questionable comparability of treatment groups; (2) unbalanced treatment groups-danazol, n = 25, pseudopregnancy, n = 17; and (3) unclear length of follow-up. However, since this is the only randomized prospective study that examines this important question, the results are of interest. Eighty-six percent of the patients treated with danazol reported improvement in their symptoms. Only 30% of the pseudo- Vol. 37, No. 6, June 1982 pregnancy group reported symptomatic improvement. Eighty-four percent of the patients treated with danazol had improvement in their objective findings, compared with only 18% of patients on the pseudopregnancy regimen. Eighteen percent of the pseudopregnancy group required hysterectomy, and only 4% of the danazol-treated group required hysterectomy. Side effects were a major problem for patients receiving both therapeutic regimens. Four percent of the danazol -group and 41% of the pseudopregnancy group discontinued therapy due to side effects. The findings of Noble and Letchworth26 suggest that danazol is more effective than pseudopregnancy in reducing the symptoms and objective findings of endometriosis. These findings are consistent with our clinical impression that danazol is more effective than pseudopregnancy in the treatment of endometriosis. For example, it has been our experience that patients with stage lib endometriosis often have significant residual disease after a course ofpseu dopregnancy therapy. In contrast, most patients with stage lib endometriosis have little or no endometriosis after a course of danazol. Danazol provides a further advantage for the infertile patient because ovulation resumes promptly after completing therapy. Resumption of ovulation is often delayed in patients completing a course of pseudopregnancy. A major disadvantage of danazol therapy is its cost. The management of each case of endometriosis presents its own diagnostic and therapeutic challenges to the clinician. The synthetic steroid danazol represents a significant advance in the medical management of endometriosis. Further studies will be required to arrive at a full understanding of danazol's mechanism of action and its appropriate clinical application. Acknowledgments. We would like to thank Diane Staples and Stavroula Diozzi for their valuable assistance in the preparation of the manuscript. REFERENCES 1. Karnaky KJ: The use of stilbestrol for endometriosis. South Med J 41:1109, Creadick RN: Nonsurgical treatment of endometriosis: a preliminary report on the use of methyltestosterone. NC Med J 11:675, Kistner RW: The use of progestins in the treatment of endometriosis. Am J Obstet Gynecol 75:264, Kistner RW, Siegler AM, Behrman SJ: Suggested classification of endometriosis: relationship to infertility. Fertil Steril 28:1008, 1977 Barbieri et al. Danazol therapy for endometriosis 7 45

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