Danazol and medroxyprogesterone acetate inefficacious in the treatment of infertility in endometriosis*

Vol. 50, No.6, December 1988

FERTILITY AND STERILITY

Printed in U.S.A.

Copyright" 1988 The American Fertility Society

Danazol and medroxyprogesterone acetate inefficacious in the treatment of infertility in endometriosis*

Sakari Telimaa, M.D.t Department of Obstetrics and Gynecology, University of Oulu, Oulu, Finland

Danazol (200 mg three times a day) and medroxyprogesterone acetate (MPA, 100 mg a day) were compared with placebo in the treatment of infertility of patients with endometriosis. Twenty-seven patients had medical therapy alone for 6 months, and 22 patients received it after conservative surgery. The clinical characteristics of the patients in the danazol group (n = 18), the MPA group (n = 17), and the placebo group (n = 14) were comparable to each other. The follow-up time was 30 months. The cumulative pregnancy rates, 33% in the danazol group (n = 6),42% in the MPA group (n = 7), and 46% in the placebo group (n = 6), did not differ significantly from each other. The time to pregnancy after the start oftherapy was 17.7 ± 8.4 (standard deviation [SD]) months in the danazol group, 18.0 ± 9.0 months in the MPA group and 10.0 ± 5.8 months in the placebo group with no significant difference between the groups. The abortion rate was 26%, and there was no significant difference among the groups. Cox multivariant analysis did reveal ovarian endometriosis a prognostically significant negative indicator as regards fecundation in endometriosis (P < 0.05). In summary, correction of infertility alone does not appear to be an indication for the use of danazol or MP A in the treatment of endometriosis, and ovarian endometriotic lesions but not peritoneal ones do make a worse prognosis as regards fecundation in endometriosis. Fertil SteriI50:872, 1988

The value of postoperative medical therapy in the management of infertile patients with endometriosis is obscure. I - 2 Danazol has been reported to be effective,3-6 but conflicting results have also been reported. 7- 10 Results concerning the efficacy of progestin therapy with low to moderate doses have also been conflicting; positive findings 1,11 and negative findings 12 have been reported. The value of high -dose medroxyprogesterone acetate (MP A), widely used without tolerance problems in endometrial cancer/ 3 has never been tested in this respect. In our prospective, placebo-controlled studies with 119 patients, MPA and danazol were identical in resolving endometriotic lesions and alleviating endometriosis-associated symptoms. 14,15 Received April 14, 1988; revised and accepted August 5, 1988.

* Supported by grants from the Research and Science Foundation of Farmos Ltd., Turku, Finland, and the Cultural Foundation of Keski -Pohjanmaa, Finland. t Reprint requests: Sakari Telimaa, M.D., Department of Obstetrics and Gynecology, Mikkelin Keskussairaala, SF50100 Mikkeli, Finland.

872

Telimaa Infertility and endometriosis

Forty-nine of these patients (41%) suffered from infertility. We have now extended this study by evaluating the fertility of these patients during a follow-up period of 30 months. This paper gives the results concerning the pregnancy rates and time of fecundation in the three treatment categories.

MATERIALS AND METHODS

The study protocol, approved by the appropriate Medical Review Boards, included two treatment schemes; medical therapy alone 14 and medical treatment after conservative surgery.15 In both schemes, the patients were randomly allocated to receive danazol (600 mg a day), MPA (100 mg a day), or placebo for 6 months from the first day of the next menstrual bleeding after laparoscopy or laparotomy. Second-look laparoscopy was done in each patient 12 months after the beginning of the study, if the patient had not conceived. The total number of patients with infertility was 49: 18 belonging to the danazol group, 17 to the Fertility and Sterility

Table 1

Clinical Characteristics of the Patients in the Danazol, MP A, and Placebo Groups·

Variable Number of patients Age in years (mean ± SD) Duration of infertility in years (mean ± SD) Severity of endometriosis (AFS) Stages I and II Stages III and IV Type of operation (n) Laparoscopy Laparoscopy + electrocautery Excision of peritoneal implants Ovarian resection and excision of peritoneal implants Unilateral oophorectomy Quality of partner's semen Normal Subfertile

Danazol (6)

MPA (7)

Placebo (6)

18 (6)

17 (7)

14 (6)

27.8 ± 3.0

29.4 ± 3.8

29.4 ± 3.5

4.2 ± 2.4

4.1 ± 2.6

4.1 ± 1.6

16 (5) 2 (1)

14 (7) 3 (0)

11 (5) 3 (1)

(2) (2) (0) (2) (0)

6 (3) 3 (0) 3 (2) 5 (2) 0(0)

5 (2) 3 (2) 1 (1) 4 (1) 1 (0)

14 (5) 4 (1)

12 (6) 5 (1)

11 (5) 3 (1)

7 3 5 2 1

• The number of patients who conceived is in parentheses.

MPA group, and 14 to the placebo group (Table 1). None ofthe patients suffered from tubal occlusion. In the medical treatment scheme, 10 patients received danazol, 9 patients MPA, and 8 patients placebo. In the group having medical treatment after surgery, the respective figures were 8, 8, and 6 patients. In the medical treatment group, the severity of endometriosis, according to the American Fertility Society classification,16 was stage I in 19 patients and stage II in 8 patients; and in the medical treatment after surgery group, stage I in 7 patients, stage II in 7 patients, and stage III or IV in 8 patients (Table 1). In stage I or II ovarian endometrioma, tubal occlusion or adhesions causing infertility were indications for surgery. Other patients with stage I or II disease were treated with medical therapy alone. However, electrocoagulation of some peritoneal endometriosis lesions was performed in three patients in each of the three treatment groups. Twelve partners had sub fertile semen, but there was no exclusion of patients because of azoospermia in these men or pathologic serum prolactin concentrations in the patients. In the two treatment groups combined, there were no significant differences among the danazol, MPA, and placebo groups in age, duration of infertility, severity of disease, quality of partner's semen, or frequency and type of various operations (Table 1). One patient in the medical treatment group and one patient in the medical plus surgery treatment group, both receiving placebo, were reoperated on 12 months immediately after repeat laparoscopy, Vol. 50, No.6, December 1988

because of adhesions and endometrioma, and they postoperatively received danazol for 6 months. They have therefore been excluded from the evalu-. ation after the 12 months' operation. The patients were interviewed 30 months after the start of treatment. After the second-look laparoscopy, ovulation induction with clomiphene citrate was carried out in four patients in the danazol group, four patients in the MPA group, and three patients in the placebo group. All pregnancies were registered, and the interval to pregnancy was defined as the time between primary laparoscopy/laparotomy and the last menstrual bleeding before conception. Statistics

The data were analyzed by the use of life tables and survival functions (BMDP; BMDP Statistical Software Inc., University of California, Los Angeles, CA) for treatment regimens and stages, applying Breslow and Mantel-Cox methods for the estimation of significance levels. The characteristics of the patients in the three different treatment groups were compared by analysis of variance. In the evaluation of prognostic factors for fecundation, survival analysis with covariates (BMDP2L) was used. RESULTS

Six patients in the danazol group (33%), seven patients in the MPA group (42%), and six patients in the placebo group (46%) conceived (no signifiTelimaa Infertility and endometriosis

873

70 ~ 60 50 toZ 40

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U

II: W

A.

3 20 10

~ I 'r

o

j

1;]---

1 9-------+c;J--o-=-~-"-. _ _-'J '

I

14

18

--

-2

6

10

22

26

30

MONTHS TO CONCEPTION

Figure 1 The cumulative pregnancy rates in the danazol (.), MPA (0), and placebo (X) groups. The vertical lines indicate the mean intervals to fecundation (Breslow, P = 0.4134; Mantel-Cox, P = 0.5716).

cant difference between the groups; Fig. 1). Eleven patients with stage I disease (45%), six patients with stage II disease (40%), and two patients with stage III + IV disease (25%) became pregnant, there being no statistical differences between the clinical stages of endometriosis. Five patients had spontaneous abortion (26%): two in the danazol group, one in the MPA group and two in the placebo group. There was no difference in the abortion rate of patients treated by medical therapy alone (27%) or medical therapy after conservative surgery of endometriosis (25%). One patient each in the danazol, MP A, and placebo groups had received clomiphene citrate (CC) before fecundation. The mean (± standard deviation [SD]) interval to pregnancy was 17.7 ± 8.4 months in the danazol group, 18.0 ± 9.0 months in the MP A group, and 10.0 ± 5.8 months in the placebo group. They did not differ statistically from each other. Cox multivariant single factor or proportional hazards stepwise analysis was done to reveal some prognostic indicator as regards fecundation. According to that analysis, the prognosis was significantly worse in women having endometriotic lesions only in ovaries (P < 0.05) (Table 2). DISCUSSION

The present placebo-controlled trial evaluating the efficacy of hormone therapy in the treatment of infertility in endometriosis is a continuation of our previous clinical studies on danazol, MP A, and placebo in endometriosis. 14- 15,17 In randomization of the treatment groups, infertility was not taken into account. However, the number of patients with infertility and their clinical characteristics were identical in each treatment group. The infertility rate of 41 % in the group of 119 patients with endometriosis is of the same magnitude as reported by Kistner18 and Muse and Wil874

Telimaa Infertility and endometriosis

son. 19 In previous studies, danazol as a single therapy has been associated with pregnancy rates of 30.9% to 52.6% in mild endometriosis, 23.1% to 50% in moderate endometriosis, and 0% to 100% in severe endometriosis. 1 Wheeler and Malinak5 treated 139 patients with severe endometriosis only by surgery or with danazol after surgery. The pregnancy rate was 30% in the surgery group versus 79% in the postoperative danazol treatment group. They concluded that danazol in the immediate postlaparotomy period is beneficial in severe endometriosis. This study, however, was retrospective. On the other hand, Buttram et al. 20 observed that 30% of 24 patients treated postoperatively with danazol conceived, compared with 56% in their historical control group. Ronnberg and Jiirvinen6 observed a pregnancy rate of 32% after postoperative danazol treatment. These results agree well with the present cumulative pregnancy rate of 33% in the danazol group. Pseudopregnancy regimens with progestin have been reported to yield pregnancy rates 20% to 90%.1,11 Hull et aU2 observed that the cumulative pregnancy rate after MPA therapy at a daily. dose of 30 mg for 90 days after laparoscopic confirmation of stage I or II disease was 71 %, which did not differ from the pregnancy rate of 46% in danazoltreated women or 55% in women with expectation therapy. The present cumulative pregnancy rate of 42% in MPA-treated women is in line with the previous observations. In this study, the significance of danazol and Table 2 Cox Multivariant Hazards Analysis of Prognostic Factors for Pregnancy in 49 Patients with Endometriosis Single factor Stepwise analysis analysis (approximately) (approximately)

Age Duration of infertility Severity of endometriosis (AFS) Type of operation Drug treatment (danazol, MPA, placebo) Distribution of endometriotic implants (n) Only peritoneal implants (30) Only ovarian implants (5) Ovarian and peritoneal implants (14) a

chi 2

P value

chi2

P value

0.20 0.58

0.6559 0.9210

0.20 0.62

0.6569 0.4318

0.76 0.00

0.3842 0.9582

0.82 0.00

0.3556 0.9582

1.05

0.3056

1.03

0.3099

0.90

0.3433

0.90

0.3434

2.13

0.1440

4.68

0.0305 a

0.50

0.4783

0.55

0.4596

P< 0.05.

Fertility and Sterility

MP A in endometriosis-associated infertility was evaluated for the first time in a prospective trial employing placebo treatment as a reference. Interestingly, the present cumulative pregnancy rate of 46% in the placebo group did not differ from that in the MP A or the danazol group. On the contrary, the patients receiving placebo conceived about 8 months earlier than the patients in the hormone treatment groups. These results agree well with the observations of Seibel et aI. 7 and Hull et aI.,12 who, instead of placebo, had expectation as a reference therapy. The spontaneous abortion rate was reduced from 49% to 20% in the study of Rock et aI. 21 and from 46% to 8% in the trial of Naples et aI. 22 after conservative surgery for endometriosis. However, the identical abortion rates in the medical group of 27% and in the laparotomy group of 25% in the present study do not support the concept of a beneficial effect of surgical therapy on the clinical course of pregnancy in endometriosis. The statistical analyses on prognostic indicators for fecundation yielded positive results as regards ovarian endometriotic lesions. On the other hand there were only five such patients who had endometriosis only in ovaries and no pregnancy occurred in this group. Four of them had endometrioma and were surgically eliminated; and one patient had superficial endometriotic lesions in an ovary which were electrocoagulated during laparoscopy. This result may be at least partly due to the small number of patients evaluated. However, the reason for infertility in endometriosis is not merely mechanical; endocrinologic factors have an important role. Hence, surgical or medical elimination of the lesions does not guarantee any success in the treatment of infertility. In conclusion, it appears that if infertility is the main complaint associated with endometriosis, danazol or MP A has no therapeutic value. On the contrary, hormonal therapy with these drugs appears to lead to delayed fecundation. Acknowledgments. The drugs were donated by the Farmos Group Ltd., Turku, Finland.

REFERENCES 1. Schmidt CL: Endometriosis: a reappraisal of pathogenesis and treatment. Fertil SteriI44:157, 1985 2. Olive DL, Haney AF: Endometriosis-associated infertility: A critical review of therapeutic approaches. Obstet Gynecol Surv 41:538, 1986

VoL.50, No.6, December 1988

3. Dmowski WP, Cohen MR: Antigonadotropin (danazol) in the treatment of endometriosis: evaluation of posttreatment fertility and three-year follow-up data. Am J Obstet GynecoI130:41, 1978 4. Daniell JF, Christianson C: Combined laparoscopic surgery and danazol therapy for pelvic endometriosis. Fertil Steril 35:521, 1981 5. Wheeler JM, Malinak LR: Postoperative danazol therapy in infertility patients with severe endometriosis. Fertil Steril 36:460, 1981 6. Ronnberg L, Jarvinen PA: Pregnancy rates following various therapy modes for endometriosis in infertile patients. Acta Obstet Gynecol Scand 123:69, 1984 7. Seibel MM, Berger MJ, Weinstein FG, Taymor ML: The effectiveness of danazol on subsequent fertility in minimal endometriosis. Fertil Steril 38:534, 1982 8. Portuondo JA, Echanojauregui AD, Herran C, Alijarte I: Early conception in patients with untreated mild endometriosis. Fertil Steril 39:22, 1983 9. Butler L, Wilson E, Belisle S, Gibson M, Albrecht B, Schiff I, Stillman R: Collaborative study of pregnancy rates following danazol therapy of stage I endometriosis. Fertil SteriI41:373, 1984 10. Kable WT, Yussman MA: Fertility after conservative treatment of endometriosis. J Reprod Med 30:857, 1985 11. Moghissi KS, Boyce CR: Management of endometriosis with oral medroxyprogesterone acetate. Obstet Gynecol4 7: 265, 1976 12. Hull ME, Moghissi KS, Magyar DF, Hayes MF: Comparison of different treatment modalities of endometriosis in infertile women. Fertil Steril4 7:40, 1987 13. Kauppila A: Progestin therapy of endometrial, breast and ovarian carcinoma. Acta Obstet Gynecol Scand 63:441, 1984 14. Telimaa S, Puolakka J, Ronnberg L, Kauppila A: Placebocontrolled comparison of danazol and high-dose medroxyprogesterone acetate in the treatment of endometriosis. Gynecol Endocrinol1:13, 1987 15. Telimaa S, Ronnberg L, Kauppila A: Placebo-controlled comparison of danazol and high -dose medroxyprogesterone acetate in the treatment of endometriosis after conservative surgery. Gynecol Endocrinol1:363, 1987 16. The American Fertility Society: Classification of endometriosis. Fertil Steril32:633, 1979 17. Kauppila A, Telimaa S, Ronnberg L, Vuori J: Placebo-controlled study on serum concentrations of CA -125 before and after treatment of endometriosis with danazol or high-dose medroxyprogesterone acetate alone or after surgery. Fertil Steril49:37, 1988 18. Kistner RW: Endometriosis and infertility. Clin Obstet GynecoI22:101, 1979 19. Muse K, Wilson EA: How does mild endometriosis cause infertility? Fertil Steril38:145, 1982 20. Buttram VC Jr, Reiter RC, Ward S: Treatment of endometriosis with danazol: report of a 6-year prospective study. Fertil Steril43:353, 1985 21. Rock J, Guzick DS, Sengos C, Schweditsch M, Sapp KC, Jones HW Jr: The conservative surgical treatment of endometriosis: evaluation of pregnancy success with respect to the extent of disease as categorized using contemporary classification systems. Fertil Steril35:131, 1981 22. Napples J, Batt R, Sadigh H: Spontaneous abortion rate in patients with endometriosis. Obstet Gynecol 57:509, 1981

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