Conservative treatment of endometriosis externa: the effects of danazol therapy*

Vol. 40 PP 164-169, August 1983 Printed in U.8A.

Conservative treatment of endometriosis externa: the effects of danazol therapy*

Joel G. Puleo, M.D. Charles B. Hammond, M.D.t Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina

This report presents the clinical responses of 39 women who underwent danazol treatment for conservative therapy of proven endometriosis. The patients were treated with 800 mg of danazol daily for a mean duration of 7.3 months and were clinically reevaluated at 16.9 months (mean) following the end of treatment. Complete subjective pain relief was noted in 38 patients (97%) within 6 weeks of the onset of danazol therapy. One patient noted only partial amelioration of pain. Recurrence of pain was noted in 38% of all patients at a mean of 6.9 months following therapy. More advanced disease was associated with an increased likelihood and rapidity of recurrence. Twenty-nine of the women were infertile. After. treatment, nine conceived (33%). However, when patients with infertility potentially due to other causes also present were excluded, the corrected pregnancy rate was 56%. The side effects of danazol therapy were minimal and cleared rapidly following termination of the drug. These results compare favorably with other study populations where recurrence of disease and corrected pregnancy rates werespeci{ically considered. Fertil Steril40:164, 1983

Endometriosis externa is a common gynecologic disease and is a frequent cause of infertility. Numerous treatment regimens have been derived for infertility thought to be secondary to endometriosis and have included a variety of hormonal and surgical types of therapy.1-3 Danazol, a synthetic steroid derivative of ethisterone, has been studied as an agent for treatment of endometriosis since 1967.4 However, to date, the literature

Received February 8, 1983; revised and accepted April 27, 1983. *Presented at the Annual Meeting of the District IV American College of Obstetricians and Gynecol6gists, October 29, 1981, Cerromar Beach, Puerto Rico. tReprint requests: Charles B. Hammond, M.D., Duke University Medical Center, P.O. Box 3853, Durham, North Carolina 27710.

44

still contains relatively few clinical trials reporting the usefulness of this drug. In.particular, few of the studies detail the specific other causes of infertility in such patients or document the sites and extent of the disease, or provide a significant length of follow-up to evaluate this treatment modality. The purpose of this report is to review the clinical responses of 39 women with proven endometriosis who were treated with danazol with respect to its impact on the likelihood, timing, and severity of recurrence after therapy and the resolution of infertility. MATERIALS AND METHODS

The present study is a retrospective analysis (January 1974 through April 1981) of39 patients

Table 1. Classification of Endometriosisa Extent of disease

Mild

Moderate

Severe

Findings

1. Scattered, superficial implants on stru~tures other than uterus, tubes, or ovarIes; no scarring 2. Rare, superficial implants on ovaries 3. No significant adhesions 1. Involvement of one or both ovaries with multiple implants or small endometriomas « 2 cm) 2. Minimal peri tubular or periovarian adhesions 3. Scattered, scarred implants on other structures 1. Large ovarian endometriomas (> 2 cm) 2. Significant tubal or ovarian adhesions 3. Tubal obstruction 4. Obliteration of cul-de-sac, major uterosacral involvement 5. Significant bowel or urinary tract disease

tients with severly compromised tubal patency documented by previous hysterosalpingography, and two patients with repeatedly poor results in postcoital tests. Six patients who presented with secondary infertility had a mean duration of infertility of 3.3 years (range, 1 to 5 years). In two cases, ovulatory defects as well as male factors were involved, and four patients were found to have compromised hysterosalpingograms. All of these secondary causes of infertility had been treated prior to danazol therapy. None had conceived. An interval of at least 6 months for resolution of infertility from the last prior therapy, with no change in status, was noted prior to the onset of danazol therapy. Once the danazol therapy was begun, all patients were followed closely.

aModified from Acosta et a1. 5

with histologic or laparoscopically proven endometriosis externa which was evaluated and treated with danazol. Classification was done by endoscopic visualization and was according to the extent and sites of disease (Table 1). 5 All patients received danazol, 800 mg daily, in four divided doses. Therapeutic courses were titrated to the staged extent of disease, with 6.0 months as the mean for mild disease, 6.6 months and 9.3 months being the means for moderate and severe disease states, respectively. All 39 patients were available for clinical reevaluation at an interval of 6 months or longer (range, 8 to 18 months) after therapy. All patients were of reproductive age, and all had normal cyclic menstrual function. Of the original study population of39 patients, 33 had primary infertility and 6 had secondary infertility. By the time therapy was completed, ten patients had elected not to pursue fertility at that time (because of divorce, etc.) and thus, in the consideration of resolution of infertility to follow, only 29 patients are considered (Table 2). All patients had associated symptoms, clinical findings, and laparoscopically proven endometriosis before treatment. Of the patients who reported primary infertility, the mean duration of infertility was noted to be 4.6 years (range, 2 to 10 years). In some of these patients, several other factors that had an effect upon fertility were also identified. These included four patients with luteal phase defects, five patients whose husbands had mild oligospermia and/or varicocele, five pa-

RESULTS Thirty-nine patients were available for reevaluation after an interval of 6 months or longer following the completion of danazol therapy. Of these 39 patients, 29 patients still actively desired and and pursued pregnancy upon completion of treatment. If the classification of Acosta et al. 5 is applied to the 29 patients who still actively pursued pregnancy, 10 patients had mild disease 13 patients had moderate disease, and 6 patient~ had severe disease. All 39 patients noted significant dysmenorrhea prior to danazol therapy. Complete subjective symptomatic relief was noted in all 39 patients after therapy, regardless of the stage of disease, except in 1 patient with severe disease. This patient noted some amelioration of pain but less than complete resolution. Such relief was generTable 2. Demography No. of patients with infertility

Primary, 33; secondary, 6

Period of infertility

Mean, 3.7 years; range, 1-10 years

Race

37 Caucasian; 2 other

Parity

Nulliparous, 33; 1 or more, 6

Age

Mean, 29.4 years; range, 18-41 years

Extent of disease

Mild: primary, 9; secondary, 3 Moderate: primary, 14; secondary, 2 Severe: primary, 10; secondary, 1

Total no.

39 patients with laparoscopic and histologically confirmed disease

45

Table 3. Fertility, Recurrence, and Subsequent Surgery: Survey Following Danazol Therapy" Mild

Severe

Moderate

11 16 12 Patients infertile prior to therapy 6 13 10 Patients pursuing pregnancy following therapy 2 3 4 Conceptions after therapy 33% 23% 40% Pregnancy rate 3 5 5' Patients with other causes of infertility 3 S 5 Patients with enhanced fertility potential 66% 3S% SO% Corrected pregnancy rate 45% (5/11) 37% (6/16) 33% (4/12) Recurrence of disease 6.7 months 6.S months 7.3 months Mean rate of recurrence after therapy 2 conservative 4 conservative 2 conservative No. of patients requiring 2 radical subsequent surgery aCombined pregnancy rate, 33%; combined corrected pregnancy rate, 56%; combined recurrence rate, 3S%.

ally noted to occur within the first months of danazol therapy. Recurrent dysmenorrhea after cessation of danazol therapy was noted in 4 of 12 patients (33%) within a 4- to 8-month range (mean, 7.3 months) in the mild disease group. Likewise, 6 of 16 patients (37%) noted recurrence of pain within a 5to 7-month range (mean, 6.8 months) of danazol therapy in the moderate category. In the severe group, 5 of 11 patients (45%) reported recurrent dysmenorrhea within a 3- to 9-month range (mean, 6.7 months). Thus, a combined recurrence rate of dysmenorrhea after danazol therapy of 38% (15 of 39 patients) was noted. The remaining 62% of the women (24 of 39 patients) were followed for 10 to 18 months without recurrent dysmenorrhea. Of the 39 patients surveyed, 10 patients had redeveloped persistent clinical symptoms and recurrent dysmenorrhea following danazol therapy of sufficient magnitude to warrant conservative surgical resection (8 of 10 patients). Full resection, total abdominal hysterectomy with bilateral salpingo-oophorectomy, was necessary in two patients. Pregnancy rates after danazol therapy for the 29 infertile patients who actively pursued pregnancy were as follows: mild disease, 40% (4/10); moderate disease, 23% (3/13); and severe disease, 33% (2/6). There was a combined pregnancy rate of 33% (9/29) for all stages. Upon closer survey of these 29 couples, other factors regarding fertility were identified in 13 couples. Thus only 16 couples with otherwise normal fertility potential remained. This resulted in a corrected pregnancy rate of 80% (4/5) for mild disease, 38% (3/8) for moderate disease, and 66% (2/3) for severe dis46

ease, with a combined corrected pregnancy rate of 56% (9/16).

Most pregnancies occurred within the first several months following discontinuation of danazol (mean, 3.9 months), with all nine conceptions occurring by 10 months. The remaining 20 patients pursuing pregnancy who did not conceive were followed for an average of 16.5 months following completion of danazol therapy without conception. All nine pregnancies progressed to term without anomaly noted. Six patients delivered spontaneously by the vagina; forceps rotation was necessary in two patients; and one term cesarean section was done for cephalopelvic disproportion. No other complications of pregnancy, labor, or delivery were noted (Tables 3 and 4). No fetal anomalies or other fetal problems were seen. DISCUSSION

Endometriosis externa is, by definition, the presence of functioning endometrial tissue outside its usual location within the endometrial cavity. These ectopic foci seem reponsive to cyclic hormonal stimulation in a fashion similar to that of normally positioned endometrium. Suppression of ovulatory function and conservative surgery have all been observed to alleviate symptoms in most patients. 1-3 The most recent agent to be investigated for endometriosis is danazol, a synthetic steroid derivative of 17a-ethinyltestosterone. In studies in castrate laboratory rodents, danazol was found to suppress high levels of serum follicle-stimulating hormone and luteinizing hormone (LH).6 Early primate data indicated that androgenic and ana-

Table 4. Conception and Pregnancy Data Following Danazol Therapy

Extent of disease

Duration of danazol therapy (800 mg/day)U

Time interval from end of treatment to conception b

mo

mo

6 6

10

Mild Mild Mild Mild Moderate Moderate Moderate Severe Severe

Pregnancy outcome

Term Term Term Term Term Term Term Term Term

4

5 2 9 6 4

10 4

the decrease in serum LH induced by danazol not to be associated with diminished pituitary responsiveness to gonadotropin-releasing hormone, thus supporting the hypothesis that danazollowers serum LH primarily by the inhibition of hypothalamic secretion of gonadotropin-releasing hormone. Other recent studies suggest that danazol may have a direct action on the gonads and thus alter steroidogenesis. 10, 11 Andrews and Wentz 12 found no change in the hypothalamic-adrenal axis in women with chronic danazol therapy. Subsequent publications by Barbieri et a1. l0 implicated danazol as inhibiting multiple enzymes of gonadal steroidogenesis and in vitro inhibition of the rat. However, neither the antigonadotropic effects nor the steroid enzyme inhibitory effects alone are sufficient to account for all of danazol's mechanisms of action. Stillman et a1. l3 confirmed that danazol did indeed actively bind to the substrate of cytochrome P-450 and effectively inhibited adrenal steroidogenesis. Several investigators 11, 14 have proposed that danazol actively competes with both endometrial and myometrial cytosol receptor sites for 17~­ estradiol and progesterone. This receptor effect could prevent estrogenic stimulatory effects at the target tissue proper, thus implying that danazol may possess an anti estrogenic quality.B Whatever the exact mechanism, the major physiologic effects of danazol appear due to the hypothalamic-pituitary-ovarian stimulatory and control axis. Pregnancy rates in the present study population treated with danazol compare favorably with the results of other therapies previously reported by this department in the treatment of infertility secondary to endometriosis. In these studies, the uncorrected conception rate after hormonal pseudopregnancy was 30%; with conservative surgery alone, 50%; and with conservative surgery followed by hormonal therapy, 31%. Methyltestosterone therapy alone was found to yield only an

1 1 4 4 5 5 1

aMean, 5.8 months. bMean, 3.9 months.

bolic properties of this compound were observed at a somewhat higher dosage, while no estrogenic, progestational, antiestrogenic, antiprogestational, or antiandrogenic activities were demonstrable. 7 More recent human data by DmowskiB indicate danazol as having strong antigonadotropic properties and mild androgenic effects. Danazol also displays an atypical progestational effect in humans, as well as antiprogestational and antiandrogenic properties in several bioassay systems. The drug is also capable of elevating the plasma level of a specific a-globulin C-1 inhibitor.B Danazol's mechanism of action upon endometriosis is not completely understood, but many investigators believe that it primarily involves suppression of the pituitary-ovarian axis. Thus, while ovarian steroidogenesis is suppressed, beneficial atrophic changes may occur in the various sites of ectopic tissue. Greenblatt et a1. 4 demonstrated estrogenic activity to be diminished and no evidence of ovulation, because the midcycle ovulatory surge of LH and follicle-stimulating hormone was inhibited. The effect of exogenously administered gonadotropins on the gonad was not altered, however. In addition, Shane et a1. 9 found Table 5. Pregnancy Rates of Patients Treated for Endometriosisa Therapy

Stilbestrol Pseudopregnancy (estrogen! progestin) Methyltestosterone Conservative surgery Danazol

Infertile patients

Patients conceiving

52 208

8 56

197 216 169

126 81

68

Uncorrected pregnancy rate

Corrected pregnancy rate

%

%

17 39

24 55 37

58 59

aComposite studies from the literature.

47

Table 6. Side Effects of Danazol Therapy in 39 Patients Side effects

Weight gain of 5 pounds Muscle cramps Acne Anabolic effect Hirsutism Vasomotor symptoms Pruritic rash Migraine headaches Diarrhea

No. of patients

10 10 6 4

3 3 2 2 1

11 % conception rate, whereas an 18% rate for methyltestosterone therapy following conservative surgery was noted. 15 The present study of the effect of danazol upon fertility rates revealed 40%, 23%, and 33% conception rates in mild, moderate, and severe categories, the overall rate being 33%. Corrected pregnancy rates were subsequently noted of 80%, 38%, and 66% in mild, moderate, and severe categories, the overall rate being 56%. Thirty-eight percent of the patient population experienced dysmenorrhea and/or pelvic changes within 6 to 7 months of danazol termination. These data suggest that more advanced disease is associated with more rapid recurrence and a greater likelihood of recurrence than that seen with less extensive disease. Likewise, this study population closely mirrors others demonstrating improved fertility and recurrence rates following danazol therapy, most notably the study by Dmowski and Cohen,16 where an average time interval between the end of treatment and the recurrence of disease was 15 months for an entire group. The same authors similarly reported an uncorrected pregnancy rate of 52.6% and a corrected pregnancy rate of 83.3% for mild disease; 45.7% and 72.7%, respectively, for moderate disease; and 27.3% and 37.5%, respectively, for severe disease 16 (Table 5). The most consistent side effect of danazol is weight gain, which occurred in 10 of the 39 patients in this study (Table 6). Muscle cramps, acne, anabolic effects, hirsutism, and vasomotor symptoms were also prevalent during danazol therapy but were mild and rapidly cleared with the termination of therapy. The long-term effects of danazol are presently unknown. With danazol, prompt relief of the symptoms of endometriosis is available. The literature indicates that the sites and the extent of the disease are the determining factors in the success of this treatment modality. We believe that patients who are infertile and who have large endometriomas,

48

tuboovarian adhesions, or more extensive disease are still best treated with surgical resection. Patients with mild endometriosis would seem to be the best candidates for medical therapy, including danazol. The drug may be used alone or in conjunction with a conservative approach to facilitate surgery and perhaps augment fertility response. Care should be used, however, in the sequence and duration of combined therapy. In the final analysis, no single modality or definitive treatment emerges as completely satisfactory. It appears that for selected patients with endometriosis, danazol offers some specific benefits as well as a reasonable opportunity for clinical improvement.

REFERENCES 1. Andrews WC: Hormone therapy of endometriosis: estrogens, androgens, progestin-estrogens. In Recent Advances in Endometriosis, Edited by RB Greenblatt. Amsterdam, Excerpta Medica, 1976, p 46 2. Hammond CB, Rock JA, Parker RT: Conservative treat· ment of endometriosis: the effects of limited surgery and hormonal pseudopregnancy. Fertil Steril 27:756, 1976 3. Hammond CB, Haney AF: Conservative treatment of endometriosis. Fertil Steril 30:497, 1978 4. Greenblatt RB, Dmowski WP, Mahesh VB, Scholer HFL: Clinical studies with an antigonadotropin-danazol. Fertil Steril 22:102, 1971 5. Acosta AA, Buttram VC, Besch PK, Malinak LR, Franklin RR, Vanderheyden JD: A proposed classification of pelvic endometriosis. Obstet Gynecol 42:19, 1973 6. Eldridge JC, Dmowski WP, Mahesh VB: Effects ofcastration of immature rats on serum FSH and LH and of various steroid treatments after castration. BioI Reprod 10:438, 1974 7. Dmowski WP, Scholer HFL, Mahesh VB, Greenblatt RB: Danazol-a synthetic steroid derivative with interesting physiologic properties. Fertil Steril 22:9, 1971 8. Dmowski WP: Endocrine properties and clinical application of danazol. Fertil Steril 31:237, 1979 .9. Shane JM, Kates R, Barbieri RL, Todd RB, Davies IJ: Pituitary gonadotropin responsiveness with danazol. Fertil Steril 29:637, 1978 10. Barbieri RL, Canick JA, Makris A, Todd RB, Davies IJ, Ryan KJ: Danazol inhibits steroidogenesis. Fertil Steril 28:809, 1977 11. Tsang BK, Henderson KM, Armstrong DT: Effects of danazol on estradiol-17-beta and progesterone secretion of porcine ovarian cells in vitro. Am J Obstet Gynecol 133: 256, 1979 12. Andrews WC, Wentz AC: The effects of danazol on gonadotropins and steroid blood levels in normal and anovulatory women. Am J Obstet GynecoI121:817, 1975 13. Stillman RJ, Fencl MDeM, Schiff I, Barbieri RL, Tulchinsky D: Inhibition of adrenal steroidogenesis by danazol in vivo. Fertil Steril 33:401, 1980

14. Jenkin G, Cookson I, Thorburn G, Robinson JS: Action of danazol on steroid receptors of the human endometrium. In Proceedings of the Endocrine Society of Australia, Vol 21, 1978. Abstract 54 15. Hammond MG, Hammond CB, Parker RT: .Conservative treatment of endometriosis externa: the effects of methyltestosterone therapy. Fertil Steril 29:651, 1978

16. Dmowski WP, Cohen MR: Antigonadotropin (danazol) in the treatment of endometriosis: evaluation of post-treatment: fertility and three-year follow-up data. Am J Obstet Gynecol 130:41, 1978

49