Antigonadotropin (danazol) in the treatment of endometriosis

GYNECOLOGY

Antigonadotropin (danazol) in· the treatment of endometriosis Evaluation of posttreatment fertility and three-year follow-up data

W. PAUL DMOWSKI, M.D., PH.D. MELVIN R. COHEN, M.D. Chimgo, Illinois Nin&ty-nine women who completed danazol treatment for endometriosis proved by operation were re-evaluated clinically an average of 37 months later. The recurrence of symptoms was reported by 39 per cent and pelvic findings suggestive of endometriosis were noted in 33 per cent. An average time interval between the end of treatment and the recurrence was 15 months for the entire group. However, 31 women who conceived subsequent to treatment had a much lower recurrence rate of the disease (15 per cent) and a much longer average time until the recurrence (31 months). Of 84 infertile women who desired pregnancy after treatment, 39 conceived, for a pregnancy rate of 46.4 per cent. However, when patients with absolute sterility due to other causes were excluded, the within the first six months after discontinuation of danazol and a total of 30 occurred within the first year. Four second- and third-trimester intrauterine fetal deaths were observed among women who conceived within the first three cycles after discontinuation of the drug.

(AM. J. 0BSTET. GYNECOL. 130:41, 1978.)

a synthetic steroid derivative capable of suppressing follicle-stimulating hormone (FSH) and luteinizing hormone (LH), has been applied in the treatment of endometriosis since 1967. 1 Initially, the drug was used exclusively in clinical research projects and it became generally available only recently. Several reports indicate significant improvement. in symptoms and findings of endometriosis after a course of danazol therapy. 1 - 3 In our earlier studies, wc 4 performed laparoscopic and histologic evaluation of the extent of endometriosis before and after danazol administration DANAZOL,*

From the Department of Obstetrics and Gynecology, Michael Reese Hospital and Medical Center, University of Chicago, Pritzlu!r School of Medicine, and the Department of Obstetrics and Gynecology, Northwestern University Medical School, The Prentice Women's Hospital and Maternity Center and The Fertility Institute. Presented at the meeting of the Chicago Gynecological Society, May 20, 1977. Received for publication June 9, 1977. Revised July 20, 1977. Accepted July 21, /977. Reprint requests: Dr. W. Paul Dmowski, Department of Obstetrics and Gynecology, Michael Reese Hospital and Medical Centn, 29th and Ellis, Chicago, Illinois 60616.

*Danocrine, Winthrop Labs., New York, New York.

41

42 Omowski and Cohen

Table I. Treatment of endometriosis with danazol: Follow-up data No. of patients with proved endometri- 103 osis who received a full course of treatment No. of patients re-evaluated 99 (96%) Mean duration of treatment (mo.) 6 (range 3-18) Mean interval between the end of treat- 37 (range 27-52) ment and re-evaluation (mo.)

and objectively showed the beneficial effects of this drug with the use of laparoscopic photographs. The mechanism of the salutary effect of danazol on endometriosis has not been elucidated. Some investigators suggest that danazol may have a direct suppressive effect on the ectopic endometrium by acting peripherally on the end organ. 5 In our opinion all evidence indicates that the beneficial effect of danazol is exerted through its central action on the hypothalamic-pituitary-ovarian axis. 6 It has been shown that danazol inhibits ovarian steroidogenesis through suppression of pituitary FSH and LH. 6 • 7 With completely suppressed ovarian estrogen secretion, peripheral changes, similar in effect to those of castration, are observed. Thus, atrophy of the vaginal mucosa and of the uterine endometrium occurs simultaneously with atrophic changes in the ectopic endometrium of endometriosis. This in turn allows healing processes to take over. Suppressed endogenous estrogen levels may be associated with "hot flashes," "sweats," or other vasomotor disturbances, characteristic of the menopausal state, in some patients. The effect of danazol is temporary, limited to the period of therapy. Menstrual periods return with discontinuation of the drug and the beneficial effect of "pseudomenopause" on endometriosis is no longer present. It is, therefore, logical to expect recurrence of endometriosis some time after the course of therapy is over, just as the recurrence of this disease has been reported after conservative surgery or after treatment with pseudopregnancy. The purpose of this study was to evaluate clinical response to danazol therapy and to determine the recurrence rate of endometriosis among 99 women with proved disease who were treated with danazol and were available for a subsequent follow-up investigation. Some of the questions that we attempted to answer included the following: How soon does endometriosis recur after discontinuation of danazol and what is the recurrence rate three years after termination of treatment? What are the chances for pregnancy if infertility was caused by endometriosis? How does pregnancy subsequent to treatment affect recurrence of the dis-

January I, 1978 Am. J. Obstet. Gynecol.

ease? What is the outcome of pregnancies occurring after danazol treatment?

Material and methods One hundred and three private patients with endometriosis diagnosed by laparoscopy or laparotomy completed a full course of danazol treatment (Table I). Danazol was administered in a dose of 200 mg. four times daily for a period of three to 18 months (average, six months), depending upon the extent of endometriosis and the type of clinical response. The extent of endometriosis was determined at the time of diagnostic visualization of the pelvic structures prior to treatment. It was classified as severe, moderate, or mild. Endometriosis was considered as severe when both ovaries were enlarged by endometriomas. Involvement of other pelvic organs and bowel was usually present. Moderate endometriosis was diagnosed when only one ovary was enlarged by an endometrioma. Small foci of endometriosis were generally present on the contralateral ovary and on other pelvic structures. Endometriosis was considered mild when small foci of endometriosis were recognised on one or more of the following structures: ovaries, uterosacral ligaments, vesicouterine peritoneum, or elsewhere in the pelvic peritoneum. Of 103 women, 99 were available for clinical reevaluation an average of 37 months after completion of therapy. All information that follows will, therefore, apply only to these 99 patients. All women were of reproductive age. :-.Jormal menstrual function was present in 97, while two had prior hysterectomy. Of these 99, 90 had infertility along with endometriosis. Symptoms of endometriosis were reported by 80 and clinical findings were present in 71. Endometriosis was mild in 44 women, moderate in 42, and severe in 13. Laparoscopic evaluation of endometriosis before and at the end of treatment was performed in 37. A de· tailed report on the findings has been published previously.4 At the time of follow-up visits, all patients were ques· tioned regarding the presence, time of recurrence, and severity of symptoms that were present prior to danazol therapy and were related to endometriosis. Any new symptoms reported by patients were also noted. If a pregnancy (pregnancies) followed discontinuation of treatment, appropriate data on the course of pregnancy and delivery were obtained. Careful pelvic examination was performed at the same time to evaluate the extent (if any) of the recurrence.

Results Symptoms and findings related to endometriosU. During the course of danazol treatment, 66 per cent of

Danazol in treatment of endometriosis 43

lolume 130
20%

20

OVERALL RECURRENCE RATE WITHIN AN AVERGE OF 37 MONTHS

39%

5

<6

7·12

13·24

25·36

37·48

MONTHS

Fig.l. Time interval between end of treatment and recurrence of symptoms among 99 patients who were followed up.

patients developed amenorrhea, 28 per cent had occasional vaginal spotting, and 3 per cent had irregular bleeding and spotting throughout the course of treatment (two patients had prior hysterectomy). Menstrual periods returned within eight weeks after discontinua .. tion of danazol in 94 women. Three conceived about t\'vo \veeks after discontinuation of therapy, without having a complete menstrual cycle. Of the 99 women, 80 reported symptoms such as dysmenorrhea or pelvic pain prior to therapy. All 80 noticed marked improvement during treatment (Table II). Of 71 patients with mild to severe dysmenorrhea prior to treatment, 70 had no symptoms and one had only mild pains during therapy and for several cycles thereafter. It is interesting to note that even those patients who were spotting or bleeding irregularly while receiving danazol had no dysmenorrhea. Of 56 women with mild to severe pelvic pain prior to treatment, 54 reported a gradual decrease in frequency and severity of this symptom during treatment so that by the end of therapy they were essentially asymptomatic. Two patients reported only mild pains at the end of therapy as opposed to moderate to severe symptoms at the begmmng.

Of the 99 patients, 71 had clinical findings such as tender adnexal or pelvic masses or tender cul-de-sac nodularities prior to treatment (Table II). During the course of treatment, gradual improvement in the ex-

Table II. Symptoms and findings related to endometriosis prior to treatment, immediately thereafter, and an average of 37 months later, at the time of re-evaluation Time Pri.or to treatment

Patients Patients symptomatic Patients with clinical findings Immediate results Patients symptomatically improved Patients clinically improved Re-evaluation Patients symptomatic Patients asymptomatic Patients with clinical findings Patients without clinical findings

Total No.

99

80 71

% 100 81

72

80

100 85

39 60 33

39 61 33 67

60

tent and tenderness of pelvic findings was observed in 60 of 71 women (85 per cent). Clinical improvement was observed in 88 per cent of patients with mild and moderate endometriosis and in 69 per cent of patients with severe endometriosis. A group of 37 women had laparoscopic evaluation before and at the end of treatment. 4 In this group, a second laparoscopy demonstrated a general decrease in the extent of endometriosis and much less congestion of pelvic organs. Endometrial cysts were either absent or significantly smaller and there were no active foci of the disease.

44

Dmowski and Cohen

January I, 19' Am . J. Obstet. Gynecc

25

23'

r:::::t] NUMBER OF CONCEPTIONS ITOTALOF 391

20

NUMBER OF TERM DE LIVE RES !TOTAL OF 3 3 )

5

4 4

I

13·18 MONTHS

<6MONTHS

4 4

I

>24

'THREE 3RD TRIMESTER IUFD.OHE ABORTION • •ONE 2ND TRIMESTER ABORTION

Fig. 2. Occurrence of first conception after termination of treatment. Table III. Infertility before and after treatmenr

ITotal No. Patients infertile prior to treatment Patients desiring pregnancy after treatment Patients with absolute sterility of other causes (tubal factor, male factor) Patients with good fertility potential Conceptions after treatment Pregnancy rate Corrected pregnancy rate

90 84 30 54 39 46.4%

72.2%

At the time of re-evaluation, an average of 37 months after discontinuation of danazol, 3Y patients reported recurrence of symptoms (Table II). Endometriosis had been previously diagnosed as mild in II of these, as moderate in 20, and as severe in eight. Mild to severe dysmenorrhea was reported by 31, and pelvic pain of varying intensity was experienced by 20. Pelvic findings suggestive of endometriosis, such as tender cul-de-sac nodules or pelvic (adnexal) masses, were detected in 33 of 39. The time interval between the end of treatment and the recurrence of symptoms was variable (Fig. I). In the majority of patients (23), the symptoms recurred within the first year after discontinuation of danazol. Of the total of 39 patients with recurrence , 24 required additional treatment. Since danazol at that time was no longer available for clinical investigation, 13 patients

were treated with pseudopregnancy and II were operated upon. The recurrence rate of symptoms and findings oft~ disease among women who conceived subsequent to treatment was 15 per cent, and the average time at recurrence was 31 months. This contrasts with the 39 per cent recurrence and the average time of 15 months for the entire group of 99 patients. A beneficial effect of posttreatment pregnancy on recurrence of endometriosis may be further illustrated by the case of a 31· year-old nulligravid woman with symptomatic but mild endometriosis and infertility of two years' duration. The patient conceived during the first cycle after dis~ continuation of danazol and was delivered of a normal, healthy infant at term . After a year of contraception she again conceived and had another term delivery. A yea r later (47 months after discontinuation of danazol) laparoscopic tubal cautery was performed. There wa:t no evidence of endometriosis at that time. Infertility before and after treatment. Prior tQ treatment, infertility was the major complaint in 90 of 99 patients (Table Ill). Endometriosis was diagnosed only during infertility investigation. After completion of treatment, six patients changed their minds about their desire for conception and for various reasoniJ (adoption, divorce, other marital problems) decided t() use contraception. Subsequent to discontinuation of treatment, 39 women conceived (pregnancy rate of

Volume 130 Number l

Danazol in treatment of endometriosis 45

Table IV. Results of first conceptions after danazol treatment Menstrual cycles between the end of treatment and conception

I

None Term deliveries, normal infant Premature deliveries Stillbirth, third trimester Stillbirth, second trimester Spontaneous abortions, first trimester

0 It (36wk.) 1 (26wk.) 0

Total pregnancies

3

1-3

9 0

1

U (33 wk.)

1 (21 wk.) I (9 wk.)

12

I

>3 21

2*

0 0 1§(6wk.)

24

Total

"I

2 2 2 2

39

*Both infants survived. tSet of twins, placental insufficiency cause of IUFD (?). tCord torsion cause of IUFD (?). §Habitual abortion in first and second trimester prior to danazoL

46.4 per cent) and 12 of these had two or more pregnancies. The pregnancy rates were 52.6 per cent for patients with mild endometriosis, 45.7 per cent for those with moderate disease, and 27.3 per cent for those with severe disease. In addition to endometriosis, other causes. of infertility that could not be corrected, such as a male factor or tubal occlusion, were present in 30 cases. Sterility in these patients was considered absolute. Thus, if only patients with good fertility potential (total of 54) are considered, the 39 intrauterine pregnancies account for a corrected over-all pregnancy rate of 72.2 per cent. Among women with mild endometriosis, the corrected pregnancy rate is 83.3 per cent. Corresponding figures for those with moderate and severe endometriosis are 72.7 and 37.5 per cent, respectively. In calculating corrected pregnancy rate, we did not exclude patients with other minor causes of infertility such as a luteal phase defect or anovulation. The majority of first conceptions (23) occurred within the first six months after discontinuation of danazol (Fig. 2), and a total of 30 occurred within the first year. During subsequent years, an average of three conceptions per year was observed. The average number of months between the end of treatment and conception was 9.5, with a range of 0.5 to 36 months. Among 39 patients who conceived, the duration of infertility prior to danazol treatment varied between 18 and I 14 months. with an average of 52 months. In 30 of 39, conception occurred without further treatment. Seven, in whom an inadequate luteal phase was diagnosed, received lll.Jections of human chorionic gonadotropin (hCG) in the immediate postovulatory phase of the conception cycle, while two were treated with ovulation-inducing agents. The results of the first conceptions that followed danazol treatment are shown in Table IV. There were 31 normal term deliveries, two premature deliveries

(both infants survived), three stillborn infants in the third trimester (one set of twins), two stillborn infants in the second trimester, and two first-trimester abortions.

Comment Of all currently available treatment methods for endometriosis, only extirpative surgery offers a reasonable chance for a permanent cure. The procedure requires resection of endometriosis as well as surgical castration. All other methods of treatment, including conservative surgery and hormonal therapy, provide only temporary remission until the disease recurs. The length of the remission period, the rate of recurrence, and the intensity of subsequent progression of the dis· ease are individually variable. Some patients may never need another treatment. Others receive only tempo· rary relief from the disease or a greater chance to attempt pregnancy before definitive surgery is performed. There are no conclusive data in th(~ literature on the exact recurrence rate of endometriosis after conservative surgery. Most series are rather '>mall with a -relatively short follow-up period. It has been stated, however, that repeated surgery may be required in about one of three women who undergo conservative operations for endometriosis. 8 Similarly, information on the exact recurrence rate of endometriosis after treatment with pseudopregnancy is lacking. Reports on large series of patients usually contain short observation periods, while those with an adequate length of follow-up are generally limited to a small number of patients. Riva and associates9 reported 17.8 per cent and Kistner10 reported 16.6 per cent recurrence after a period ofless than one year of observation. A follow-up period of about nine years in a small group of patients disclosed a 50 per cent recurrence rate of symptoms.~

46 Dmowski and Cohen

To our knowledge follow-up studies on patients after danazol treatment have not been published and the recurrence rate after such treatment is not known. The data presented here indicate a recurrence rate of 39 per cent three years after discontinuation of danazol. Of these patients, 24 per cent required subsequent additional therapy. This recurrence rate appears to be similar to that reported after conservative surgery or pseudopregnancy. This similarity may indicate that regardless of the treatment method the rate of recurrence of endometriosis remains the same and depends more upon the pathophysiology of the disease and its spread than upon the choice of treatment used. In 20 per cent of the patients, recurrence of symptoms took place in the second half of the first year after discontinuation of danazol. Only a few patients (3 per cent) reported the recurrence of symptoms within the first six months. After the first year, the annual recurrence rate averaged 5 per cent. Recurring dysmenorrhea and pelvic pain were typically mild at the beginning and gradually increased in severity. As expected, conception in the immediate posttreatment period had additional beneficial effects on endometriosis. In the group of 39 patients who conceived, the recurrence rate of the disease was less than half of that obse.rved for all 99 women. Furthermore, the average time until recurrence was twice as long among 39 women who conceived as compared to the entire study group (31 versus 15 months). Of a total of 84 women who desired pregnancy after treatment, 39 conceived, accounting for a pregnancy rate of 46.4 per cent. However, if patients with absolute sterility due to occluded tubes or a male factor are excluded, the corrected pregnancy rate is 72.2 per cent. We did not exclude patients with minor and presumably correctable causes of infertility, such as a luteal phase defect or anovulation. Instead, appropriate therapy was instituted after discontinuation of danazol. Thus, of 39 conceptions, 30 occurred without further treatment and in nine patients specific treatment was used. The variability in the posttreatment pregnancy rate between groups of patients with different severities of endometriosis was expected. However, three pregnancies among 11 patients with severe disease, many of whom had extensive alterations in the pelvic anatomy even after treatment, were a pleasant surprise. The posttreatment pregnancy rate reported here compares favorably with that observed after conservative surgery or pseudopregnancy. After conservative surgery, about 30 per cent of women conceive if no other cause for infertility exists. 11 In selected series of

January l, 1978 Am. J. Obstet. Gynecol.

patients, pregnancy rates varying between 4 7 and 63 per cent have been reported. 12 • Ja Several reports have been published on pregnancy rates after treatment of endometriosis with pseudopregnapcy. Probably the largest series were reported by Kistner, 10 • 14 who observed a posttreatment pregnancy rate of 55 per cent. 15 Andrews and Larsen 8 reported a somewhat lower posttreatment pregnancy rate of 42.8 per cent. In our experience with danazol, most pregnancies (23) occurred within the first six months after therapy. Seven additional pregnancies occurred during the second half of the first year. Thus, 30 of 39 conceptions occurred during the first year after treatment, and only nine occurred during the following three years. The highest chances for conception apparently are immediately after completion of treatment. Once the disease begins to reappear, chances for conception decrease. In reviewing our results, we noted that four of 39 pregnancies ended in midtrimester or third-trimester intrauterine fetal death (IUFD) (Table IV). This ac~ counts for a stillbirth rate of about 12 per cent. A corresponding fetal mortality rate (gestation of 20 weeks or more) quoted in the literature is significantly lower, in the neighborhood of 14 to 26 per I ,000, depending on race. 16 As demonstrated in Table IV, all four IUFD's occurred in women who conceived within the first three cycles after discontinuation of danazol. Three conceptions occurred about two weeks after discontinuation of danazol without a full menstrual cyc)e. Of these, only one was carried to term. The other two resulted in second~ and third-trimester IUFD's. No apparent cause was reported for the second-trimester IUFD, while the IUFD of twins in the third trimester was allegedly due to placental insufficiency. Of the 12 women who con~ ceived between the first and fourth menstrual cycles after treatment, nine carried the fetus to term; two had second- or third-trimester IUFD; and one had a firsttrimester abortion. There were 24 conceptions that occurred more than three full cycles after discontinuation of danazol. Two of these resulted in premature deliveries; 21 were normal term deliveries, and one was an early abortion in a woman who was a habitual aborter. It has been demonstrated previously that danazol significantly suppresses proliferation of the endometrium, which may become extremely thin. 1 It is possible that this endometrial thinning may result in abnormal placentation and subsequent increased risk of IUFD. It should be kept in mind, however, that the numbers

Volume 180 Number 1

presented here are very small and, although they are suggestive, they are by no means conclusive. Additional data on the outcome of pregnancies after danazol treatment should be obtained from other investigators who worked with this drug before any conclusions can be drawn. If this observation is confirmed by others, it may be prudent to advise patients planning pregnancy after· danazol treatment to attempt conception only

RSFEIUNCES

Danazol in treatment of endometriosis

47

after a menstrual period that is normal in amount of flow and duration has occurred and when full regeneration of the endometrium can be rea-;onablv anticipated. Danazol capsules for treatment of endometriosis were provided by the Sterling-Winthrop Research Institute, Rennsselaer, New York.

5. Wentz, A. C., Jones, G. S., Sapp, K. C., and King, T. M.: Progestational activity of Danazol in the human female subject, AM. j. Ossn:T. GYNEcoL. 126: 378, 1976. 6. Dmowski, W.P., and Scommegna, A.: The rationale for treatment of endometriosis with danazol, in Greenblatt, R. B., editor: Recent Advances in Endometriosis, ~.~~;~~da~,} 9~, Exc';~P~~. ~edica .F_o_u?da.tio~.' I?.· 8?,." 7 . .C.iUHUM:e,j~ L., VInOWSKl, VV. r., anO Manesn, V. ti.: 1:,1fects of castration of immature rats on serum FSH and LH and of various steroid treatments after castration, Bioi. Reprod. 10: 438. 1974.

8. A.ndrev·;s, W. C., and Larsen. G. D .. Endon1etriosis: treatment with hormonal pseudopregnancy and/or operation, AM. J. 0BSTET. GYNECOL. 118: 643, 1974. 9. Riva, H. L., Wilson, J. H., and Kawasaki. D. M.: Etfect of norethynodrel on endometriosis, AM. J. OIISTFT. GYNECOL. 82: 109, 1961. 10. Kistner, R. W.: Infertility with endometriosis. A plan of therapy. Fertil. Steril. 13:237, 1962. 11. Kistner, R. W.: Endometriosis and infertility, in Behrman, S. J., and Kistner, R. W., editors: Progress in Infertility. Boston, 1975, Little, Brown & Company. p. 345. 12. McCoy, J. B., and Bradford, W. Z.: Surgical treatment of endometriosis with conservation of reproductive potential, AM. j. 0BSTET. GYNECOL. 87: 394. 1963. 13. Petersohn, L.: Fertility in patients with ovarian endometriosis before and aftt>r treatment, Act:\ Obstet. GynecoL Scand. 49: 331, 1970. 14. Kistner, R. W.: The effects of new synthetic progestogens on endometriosis in the human femalt", Fcrtil. Steril. 16: 61, 1965. 15. Kourides, I. A., and Kistner, R. W.: Three new synthetic progestins in the treatment of endometriosis, 'Obstet. Gynecol. 31: 821, 1968. 16. Chase, H. C.: Perinatal mortality. Overview and mrrent trends, Clin. Perinatal. I: 3. !9'74.

Dtecuesion DR. MELVIN GERBIE, Chicago, Illinois. Although controversy exists on the etiology and pathophysiology of endometriosis, as well as its mechanism in causing infertility, there is no doubt that there is a relationship. A s~nificant number of patients with normal clinical findings are found to have endometriosis when subjec;ted to direct vision. This paper represents an excellent follow-up of the authors' initial report of 39 patients who underwent laparoscopy before and after danazol treatment. The ' ... results of this longer-term study are quite similar to ,.~ose of others in which conservative surgery or . esttb',.~Cl>progestin therapy was used, namely, approximately 70 per cent had corrected fertility and 40 to 50 per cent i1.:ld recurrence of symptoms and findings. These figur<::s lead one to conclude that none of the ~ethods is betk!' than another and that none is actually :turative. Selection ~Jf ~:~atients for treatment is essential. With danazol, a new medical treatment is available. 'the question will arise <.s to who should be treated with

hormone combinations, with danazol. or by conservative operation. Patients with large endometriomas, extensive tuboovarian adhesions, or significant lesions of other organs are probably best treated surgically. Some of these patients will be aided by postc•perative medical therapy. An additional reason for surgical therapy is the need for prolonged medical therapy, an average of six months plus another three months after completing either danazol or hormone therapy. Presently the cost of Danazol is $4.00 per clay for HOO mg., the recommended daily dose for three to II months. Although cost should not be a factor if there were a distinct advantage, hormone therapy can be used for most patients who are candidates for danazol. A history of thromboembolic complications, large niyomas, rnigraine htadaches, and other side effects or the lack of response to pseudopregnancy would suggest a change to danazol. The authors did not discuss side effects in this paper although they reviewed them in their first report. I

1. Greenblatt, R. B., Dmowski, W. P., Mahesh, V. B., and Scholer, H. F. L.: Clinical studies with an antigonadotropill-Danazol, Fertil. Steril. 22: 102, 1971. 2. Friedlander, R. L.: The treatment of endometriosis with Danazol,J. Reprod. Med. 10: 197, 1973. 3. Greenblatt, R. B., and Gutierrez, M.: Summation of the role of danazol in therapy of endometriosis, in Greenblatt, R. B., editor: Recent Advances in Endometriosis, Amsterdam, 1976, Excerpta Medica Foundation, p. 116. 4. Dmowski, VI. P., and Cohen, ~~f. R.: Treatment of endo· metriosis with an antigonadotropin, Danazol. A laparoscopic and histologic evaluation, Obstet. Gynecol. 46: 14 7,

1975.

48 Omowski and Cohen

wonder if they have changed their thoughts regarding the side effects being few and minor. Anecdotally, I have heard from a few practitioners and have noted myself the rather severe weight gain and fluid retention some patients develop. The authors reported on I 03 patients who completed a full course of danazol therapy. I do not believe the term "full course" is correct since the time varied from three to 18 months and was dependent on response. Were any patients dropped from the study because of disease progression or severe side effects? A corrected 72 per cent fertility rate was given with exclusion of those with occluded tubes or a male factor. Of the 39 patients who conceived, however, nine required ovulation induction. To me this would indicate a rate of 55 per cent. Finally the authors noted the high incidence of intrauterine deaths and suggested an atrophic endometrium as the cause. I would suspect that there may be a genetic etiology for some of the early fetal deaths, similar to that in those patients who become pregnant in the first or second cycle after discontinuing oral contraceptives. DR. DMOWSKI (Closing). It has long been observed that fertility improves after treatment of endometriosis with conservative surgery or estrogen-progestogen preparations. However, it has also been observed that the disease has a tendency to recur after discontinuation of treatment. Our results following danazol therapy indicate the same trend. This may relate rpore to the nature of the disease than to the treatment used. The pregnancy rate after treatment and the rate of recurrence are variable and dependent to a great extent upon patient selection and completeness of treatment. Our results compare favorably with previously published data after conservative surgery or estrogenprogestogen treatment. In our series 85 per cent of patients who underwent repeated laparoscopy upon completion of treatment had no laparoscopic or histologic evidence of active endometriosis. I do not agree with Dr. Gerbie's conclusion that no method of treatment for endometriosis is better than another. Each offers special advantages. Conservative surgery, for instance, may be an adequate and prefer-

January I, 197! Am.]. Obstet. Gynecol

able treatment method if a large endometrioma i~ present and no other endometriotic implants can be found. However, this is a rather rare occurrence. Multiple endometriotic implants, especially those involving viscera, cannot be adequately treated by operation or with fulguration. Of the two hormonal treatments currently available, I consider danazol a far superior drug that should not be reserved for use only when the estrogen-progestogen combination fails. It is much better tolerated than the oral contraceptives used for this purpose and its side effects are much less serious. The type and incidence of side effects noted in this study do not differ from those reported previously by us. Furthermore, the suppressive effect of danazol on endometriosis takes place from the very first month of treatment without the initial delay caused by hypertrophy and edema of the endometrium observed with estrogen-progestogen preparations. Different durations of treatment in our study were dicated by the variability in the extent of endometriosis, which in all patients was evaluated laparoscopically prior to treatment. The term "full course" was used to indicate that at the completion of treatment there was no symptomatic, clinical, or laparoscopic evidence of active endometriosis. Three patients dropped out of the study without a "full course" of treatment. One stopped danazol on her own after 31 days because of irregular vaginal bleeding; in another, the drug was discontinued after one week because of a generalized allergic rash. The third patient had chronic pelvic inflammatory disease along with endometriosis; she did not improve symptomatically during I 0 days of treatment and the drug was discontinued. We included in the corrected pregnancy rate patients who, in addition to endometriosis, had other relative causes of infertility. Thus, only those with absolute sterility were excluded and those with anovulation or a luteal phase defect underwent appropriate treatment. There were only two anovulatory women; one conceived after clomiphene and the other conceived after FSH. The remaining seven received hCG to stimulate corpus luteum function, as stated. All nine patients had long-standing infertility and had been treated with similar hormonal preparations prior to danazol.