MANAGEMENT OF ENDOMETRIOSIS IN THE INFERTILE PATIENT ROBERT W. KISTNER, M.D.

Transcription

1 FERTILITY AND STERILITY Copyright" 1975 The American Fertility Society Modern Trends Vol. 26, No. 12, December 1975 Printed in U.SA. MANAGEMENT OF ENDOMETRIOSIS IN THE INFERTILE PATIENT ROBERT W. KISTNER, M.D. Department of Obstetrics and Gynecology, Harvard Medical School and The Boston Hospital for Women, Parkway.Division, Brookline, Massachusetts A definite correlation exists between infertility and endometriosis. Rubin 1 stated that the expectation of pregnancy when this disease is present is about onehalf that in the general population. Thus, compared with the usual incidence of infertility approximating 15%, the incidence of infertility approximates 30 to 40% in patients with endometriosis. However, if no other cause for infertility exists, conservative surgical procedures result in subsequent pregnancy in 40 to 90% of patients. Acosta and co-workers 2 reported a pregnancy rate of 45.7% and Spangler and co-workers 3 cited a 52% rate following conservative surgery. Kelly and Rock 4 reported endometriosis to be the causative factor of tubo-ovarian adhesions in 24% of 143 women who had undergone culdoscopy because of infertility, and Garcia5 stated that endometriosis is found in onethird of "infertility laparotomies." If studies of an infertile patient show ovulation to be occurring regularly, the oviducts to be patent, the endometrium to be normal, and the postcoital test to be adequate, endometriosis should be considered and diagnostic procedures instituted. There are several factors that influence the pregnancy rate: 1. Extent of the disease. Acosta et al. 2 reported a 75% pregnancy rate in mild cases, 50% in moderate cases, and only 33% in severe cases (see Table 1). Received July 30, Age of the patient. Over 20% become pregnant within the next 2 years. The precise factors responsible for this prolonged delay are unknown. However, we have noted luteal phase insufficiency in almost 25% of patients immediately following conservative surgery for endometriosis. 6 If this remains untreated, it could be a factor in the delay of conception. The exact cause of infertility in patients with endometriosis is unknown. The oviducts are usually patent, but perisalpingeal and perioophoritic adhesions are frequently found with an adherent, retroverted uterus. The endometrium is usually normal and biopsy specimens show secretory endometrium with progestational maturity. If other pathologic conditions such as submucous myomas and endometrial polyps are excluded, we believe

2 1152 KISTNER December 1975 TABLE 1. A Proposed Classiftcation of Pelvic Endorru!triosis" Mild Scattered, fresh lesions (i.e., implants not associated with scarring or retraction of the peritoneum) in the anterior or posterior cul-de-sac or pelvic peritoneum Rare surface implant on ovary, with no endometrioma, without surface scarring and retraction, and without periovarian adhesions No peri tubal adhesions Moderate Endometriosis involving one or both ovaries with several surface lesions, with scarring and retraction or small endometriomas Minimal periovarian adhesions associated with the ovarian lesions Superficial implants in the anterior or posterior cul-de-sac, or both, with scarring and retraction. Some adhesions, but no sigmoid invasion Severe Endometriosis involving one or both ovaries with endometriomas larger than 2 x 2 em One or both ovaries bound down by adhesions associated with endometriosis, with or without tubal adhesions to ovaries One or both tubes bound down or obstructed by endometriosis, with associated adhesions or lesions Obliteration of the cul-de-sac by adhesions or lesions associated with endometriosis Thickening of the uterosacral ligaments and culde-sac lesions from invasive endometriosis, with obliteration of the cul-de-sac Significant bowel or urinary tract involvement "From Acosta et al? that the most important factor responsible for infertility is an inadequacy of tubo-ovarian motility secondary to fibrosis and scarring. This results in imperfect ovum acceptance by the fimbriae. DIAGNOSIS The diagnosis may be suggested by the history, corroborated by the pelvic examination, and verified by culdoscopy, biopsy, and laparoscopy. On pelvic examination the finding of tender, nodular, uterosacral ligaments in conjunction with a fixed uterine retroversion is almost pathognomonic. Biopsy of suspect lesions in the vagina, perineum, umbilicus, or cervix will prove the presence of endometriosis in those areas. Investigation of the cul-de-sac may be performed by culdoscopy or posterior colpotomy if the rectum is not too adherent. Laparoscopy is recommended if the cul-de-sac is obliterated. It should be recalled that small areas of endometriotic tissue removed at laparotomy may show only endometrial stroma with hemorrhage and hemosiderin-laden macrophages. This should be sufficient for diagnosis in most cases, but in order to aid the pathologist, tiny blue spots or "powder burns" should be tagged with a suture for easy identification. The nodularity of the cul-de-sac, so common in endometriosis, may be produced in rare instances by metastatic ovarian carcinoma, bowel cancer, or calcified mesotheliomas. A gastric carcinoma with ovarian metastases may occasionally produce nodularity in the cul-de-sac. Rarely, cul-de-sac irregularity may be produced by infestation with Enterobius vermicularis. Calcified particles of splenic tissue have been reported in the cul-de-sac subsequent to rupture of the spleen and should be included in the differential diagnosis of cul-de-sac nodules. Bidigital rectovaginal and bimanual abdominopelvic examination must be performed in order to palpate adequately the uterosacral ligaments, the posterior surface of the uterus, and the ovaries. The ovaries are often fixed in or lateral to the cul-de-sac, so that they can be palpated rectally. The pelvic examination should be repeated during the first 24 hours of the next menstrual period or during the 2nd or 3rd day of flow. To facilitate the thoroughness of the examination, the bladder must be empty and the rectum emptied by enemas. Laboratory studies are not of particular diagnostic value, but occasionally moderate leukocytosis and an elevated erythrocyte sedimentation rate are found. Gross or microscopic blood in the urine or feces at the time of menstruation is highly suggestive of perforating endometriosis of the bladder mucosa or rectosig-

3 Vol. 26, No. 12 MANAGEMENT OF ENDOMETRIOSIS IN THE INFERTILE PATIENT 1153 moid. Cystoscopic and sigmoidoscopic examination may aid in establishing the diagnosis, and biopsy of bladder or sigmoid lesions is occasionally necessary. In specific instances, x-ray study of the colon may be of value in detecting lesions above the reach of the sigmoidoscope. The differential diagnosis includes such diverse lesions as adenomyosis, pelvic inflammatory disease, nonspecific adhesions, and ovarian carcinoma. Adenomyosis may produce similar symptomatology but usually occurs in older, multiparous patients. The adenomyotic uterus may be symmetrically enlarged, nodular, and tender, but the cul-de-sac is usually normal. In pelvic inflammatory disease, the pelvic examination frequently reveals bilateral, tender, broad~ligament masses which are characteristically doughy or fluctuant. Laboratory findings indicate the presence of an inflammatory process, and objective and subjective improvement follows proper antibiotic and conservative therapy. Nonspecific adhesions frequently occur after previous surgical intervention, especially appendectomy or incomplete surgery for pelvic infection. Ovarian carcinoma may be detected by laparoscopy or laparotomy, with biopsy or aspiration of ascitic fluid. The presence of a persistent pelvic mass, especially if solid, in the adnexal area is an absolute indication for abdominal exploration. TREATMENT The crippling characteristics of this malady, which occurs during the reproductive period of life, prevent the fulfillment of marital potential and too often terminate in hysterectomy or castration. An optimal method of treatment will secure relief from pain, allow adequate coitus, prevent abnormal bleeding, and preserve or increase the possibility of motherhood. Therapy is discussed under four headings: (1) prophylaxis, (2) observation and analgesia, (3) suppression of ovulation, and ( 4) surgical treatment. Prophylaxis If endometriosis develops as a result of the distribution by various routes of fragments of fully differentiated Mullerian tissue primarily from the mucosa lining the uterus or tubes, or if it can be produced in situ by the activation of the same tissue by trauma, it is evident that great care should be exercised in certain diagnostic and operative procedures. The following observations are noteworthy: 1. During pelvic examination at or about the time of menstruation, forceful manipulation should be discouraged because of the danger of squeezing endometrial blood and detritus into the tubes. 2. The Rubin test or uterosalpingography should not be performed too near the end of menstruation or immediately following curettage, because of the danger of forcing bits of viable endometrium through the tube. Experimentally, peritoneal implantation can be produced in rabbits and guinea pigs by uterine insufflation. 3. Although it has been suggested that posterior displacements of the uterus should be corrected to ensure better drainage of menstrual blood, there is no conclusive evidence that women with simple third-degree retroversion of the uterus have an increased incidence of endometriosis. 4. Cervical obstruction should be corrected not only because of the possibility of increasing the tendency to retrograde tubal menstruation, but also to correct abnormalities of the endocervical epithelium and aid in sperm penetration. 5. If the patient is married, early pregnancy is suggested, and the patient is advised to have subsequent pregnancies as quickly as is economically sound. Meigs 7 suggested pregnancy as the optimal prophylactic and therapeutic treatment for

4 1154 KISTNER December 1975 endometriosis, since the symptoms and signs regress during the period of gestation and for various periods of time thereafter. 6. There is suggestive evidence that women who have been taking oral contraceptives for prolonged periods of time, especially those with a potent progestin and minimal amounts of estrogen, may have a diminished chance of developing endometriosis. This is based on observations that these agents produce endometrial atrophy and lessen menstrual flow, thus preventing tubal reflux of menstrual detritus into the peritoneal cavity. In patients subjected to hysterectomy and bilateral salpingo-oophorectomy at the time of withdrawal flow from oral contraceptives, step sections of the oviduct have not shown the usual intraluminal menstrual elements. Observation and Analgesia Observation as a form of treatment is often rewarding, since many patients either "outgrow" the endometriosis or become pregnant and remain asymptomatic indefinitely. Expectant treatment is worthwhile for the patients who have only minimal symptoms and pelvic findings, such as slight tenderness and nodularity of the cul-desac. Reassurance and mild analgesics are adequate for these patients. Some authors have suggested that the only treatment for endometriosis is surgical and that observation cannot be regarded as treatment. In this regard, the observations of Dr. Sampson, 8 made almost 40 years ago, are still pertinent: "I would hesitate very much to suspend a retro-displaced uterus which was symptomless in order to prevent the possible incidence of endometriosis. I wouldn't operate on any patient with endometriosis in the absence of subjective symptoms." These admonitions are just as acceptable today if infertility is included as a subjective symptom. Pregnancy is suggested as the optimal prophylactic therapy for endometriosis. Should increased or irregular bleeding occur, a careful examination with anesthesia and thorough curettage are performed. Regular pelvic examinations should be scheduled at least every 6 months if endometriosis is suggested, since, although the incidence of malignancy in endometriosis is low, rapid growth and the development of large endometriotic cysts may occur in a short time. At the time of pelvic examination, the ovaries should be carefully palpated and changes in their size and mobility noted. Progression of disease, as suggested by the obliteration of the cul-de-sac or the development ofrectovaginal masses, necessitates specific therapy. If the patient is infertile, an adequate study of the husband should be made, and an endometrial biopsy, tubal insufflation, and postcoital tests should be performed. If pregnancy does not occur after 1 year of study (including culdoscopy or laparoscopy), observation, and planned coitus, the methods of treatment outlined in the succeeding paragraphs are indicated. The optimal treatment of the infertile patient is determined by the extent of the endometriosis. Therefore, if anatomical factors such as tubo-ovarian adhesions or large endometriomas have been found by endoscopic examination, treatment is surgical. Hormonal therapy is effective for amelioration of pain and to interrupt the progress of the disease but, with the exception of minimal ovarian involvement, we have not found it of value for improvement of infertility. We do, however, advocate a combination of estrogen-progestin (pseudopregnancy) following a conservative surgical procedure in certain patients (see below). Suppression of Ovulation Pregnancy has often been suggested as the optimal prophylactic and therapeutic

5 Vol. 26, No. 12 MANAGEMENT OF ENDOMETRIOSIS IN THE INFERTILE PATIENT 1155 treatment for endometriosis, since the symptoms and signs regress during the period of gestation and for varying periods thereafter. This regression is probably due to a combination of anovulation and amenorrhea brought about by adenohypophyseal suppression. The author has suggested that the improvement may also be due in part to a transformation of functioning endometriotic tissue into decidua by increased levels of chorionic estrogen and progesterone. If pregnancy is not contemplated or is not desired, it is possible to secure anovulation by the administration of estrogens, androgens, progestins, or a combination thereof. Estrogens. Almost 30 years ago, Karnaky9 9 a suggested the use of constant estrogen administration in increasing amounts to suppress ovulation and to produce softening in areas of endometriosis. We utilized his regimen and that suggested by Haskins and Woolf1 during the late 1940s and early 1950s and, although symptomatic improvement was observed, we were unable to demonstrate necrobiosis and absorption of endometriotic tissue by sequential biopsy of vaginal lesions. In addition, serious side effects such as edema, mastodynia, nausea, and breakthrough bleeding made this regimen unacceptable to many patients. Subsequently, we used the nonsteroidal estrogen, chlorotrianisene (TACE; Merrell-National Laboratories, Cincinnati, 0.) to suppress ovulation in patients with symptomatic endometriosis.11 Although subjective improvement was noted during the period of anovulation, breakthrough bleeding was common, necessitating curettage in numerous patients. The endometrium obtained in these cases showed varying degrees of cystic and adenomatous hyperplasia and in five patients a diagnosis of dysplastic endometrium was obtained. Because of these side effects and in an effort to simulate the decidual effect observed in biopsies of endometriotic tissue from several patients at the time of cesarean section, we began to use the estrogen-progestin combinations which first became available for clinical research in The results with the first 12 patients treated with norethynodrel plus mestranol or hydroxyprogesterone caproate plus diethylstilbestrol were reported in Beecham 13 has stated that "the physiological amenorrhea of pregnancy or the pregnancy equivalent induced by stilbesterol has produced regressive changes so remarkable that operative treatment once endorsed by all gynecologists is declining in popularity and usage." The author is in firm agreement with this statement. Some observers insist that the salutary effect of estrogen-progestin pseudopregnancy is due to the estrogen alone-that the progestin is converted to estrogen and has no specific progestational effect. This concept, however, completely ignores the extensive decidual effect in the stroma, which is similar to that seen during pregnancy, with subsequent necrobiosis and replacement by fibrous connective tissue. This conversion of stroma to decidua is not seen with estrogen alone. Androgens. The salutary effects of androgens are presumed to be due to direct action on areas of endometriosis. High doses will inhibit ovulation as well as cause involution and suppression of follicular growth, but amounts exceeding 300 mg/month frequently cause masculinization. Testosterone and methyltestosterone have been widely used and reported to be effective in relieving the symptoms of endometriosis. 14 Methyltestosterone Linguets, 10 mg daily, are usually recommended. This dose may subsequently be reduced to 5 mg daily. The medication is continued for 6 to 12 weeks and, if effective, repeated after 1 to 2 months' rest. The 5-mg dose may be given continuously. Relief of symptoms is reported to occur in 80% of patients and subsequent

6 1156 KISTNER December 1975 pregnancy in 60% of those complaining of infertility. 14 However, there are no statistically significant series of androgen-treated patients to support this contention. Jones and Pourmand 15 reported 9 pregnancies in a group of 28 patients in whom methyltestosterone (5 mg daily for 6 months) was given. However, the authors stated that only three pregnancies probably occurred as a result of the androgen therapy, two were questionably related, and four were "most certainly not related." Thus a pregnancy rate of only 10% can be attributed to the androgenic therapy. Side effects, especially in sensitive individuals, include acne, hoarseness, edema, hirsutism, enlargement of the clitoris, and, occasionally, hepatocellular jaundice. There is no doubt about the effectiveness of androgens in relieving symptoms due to endometriosis. An antiestrogenic effect of the androgen on endometriotic tissue may negate the usual action of estrogen and may thus prevent bleeding in foci of aberrant endometrium. Estrogen plus Progestin. In 1956, the author began to treat patients with endometriosis by means of inducing a pseudopregnancy with the administration of combinations of estrogens and newer synthetic progestins for 6 to 9 months. This concept of therapy was predicated on the fact that pregnancy usually brings about both objective and subjective improvements in patients with extensive pelvic endometriosis. Thus, a state similar to pregnancy would seem of particular value when the patient is infertile, does not desire pregnancy, or is unmarried. It was further suggested that the changes brought about in endometriosis by pregnancy were due to a combination of (1) anovulation and amenorrhea, (2) decidual transformation of functioning endometriotic tissue, and (3) decidual necrosis and absorption. A morphologically similar decidual reaction can be brought about both in the endometrium and in areas of endometriosis by the prolonged administration of estrogens and progestins. It is suggested that the decidual cells undergo a gradual process of necrosis that is followed by liquefaction and absorption. The decidual reaction in areas of endometriosis produced by newer agents in lower dosage is just as extensive as that noted in previous studies utilizing extremely large doses of Enovid. The optimal treatment for endometriosis is prolonged cessation of menstruation. If pregnancy can be obtained, this is recommended as primary therapy. If culdoscopy or laparoscopy reveals ovarian endometriosis without anatomical deformity of the ovary or tube, pseudopregnancy for 6 months, induced by norgestrel plus ethinyl estradiol (Ovral) or norethynodrel plus mestranol (Enovid-E) is suggested. Endoscopy repeated at the end of6 months usually reveals no evidence of endometriosis. If no other cause for infertility exists, pregnancy may be expected to occur in approximately 50% of these patients within 1 year of cessation of therapy. Prolonged hormonal therapy is applicable in the following patients: 1. Unmarried patients with maximal symptoms and minimal palpable findings. Extension of the disease may be prevented and subsequent fertility preserved. 2. Patients with recurrent disease after a previous conservative operation. Pregnancies have been noted subsequent to hormonal treatment in patients to whom hysterectomy had been suggested. Short-term hormonal therapy is indicated in the following situations: 1. Prior to conservative surgey. Areas of endometriosis will enlarge and appear hemorrhagic, making identification and excision simpler and more complete. Six to eight weeks of therapy are adequate. 2. Subsequent to conservative therapy (in order to inhibit ovulation and prevent

7 Vol. 26, No. 12 MANAGEMENT OF ENDOMETRIOSIS IN THE INFERTILE PATIENT 1157 reactivation of remaining areas of endometriosis). Twelve to twenty-four weeks of therapy are adequate. Postoperative pseudopregnancy is utilized only when the disease is extensive and if all areas of endometriosis cannot be excised. In patients who demonstrate unusual or excessive side effects to the estrogenic component of Ovral of Enovid-E, we have utilized Depo-Provera (depo-medroxyprogesterone acetate). However, this preparation should not be used if pregnancy is immediately desirable, since its long action may prevent ovulation for 6 to 12 months subsequent to cessation of therapy. This anovulatory situation may usually be corrected by the administration of clomiphene-human chorionic gonadotropin. The regimen we have used is as follows: 100 mg of Depo-Provera every 2 weeks for four doses, then 200 mg monthly for 4 additional months. Breakthrough bleeding occurs frequently because of the antiestrogenic activity of Depo-Provera but this may be alleviated by the administration of ethinyl estradiol, 0.02 mg daily, for 21 days of each month. The corrected conception rates following the use of estrogen-progestin pseudopregnancy for endometriosis are shown in Table 2. In assessing the clinical efficacy of these hormones, the clinician is handicapped by the existence of a variety of drugs, with lack of consistent information. Unfortunately, the various clinical studies to date lack uniformity and, consequently, correlative data on the biologic effect of the drug are difficult to interpret. Riva's experience 16 is particularly pertinent in identifying that approximately 11.8% of the patients treated hormonally had clinical recurrence and required either secondary hormonal treatment or surgery. The beneficial effect of pregnancy on endometriosis was first suggested by Meigs17 in The microscopic examination of implants of endometriosis removed incidentally at the time of cesarean section in 1956 first suggested to me the possibility that the hormones of pregnancy might have a profound effect upon the disease. Thus, when the potent progestational agents became available, the experimental application of these hormones to produce a pseudopregnant state was initiated. Subsequent publications verified the fact that necrobiosis of areas of endometriosis, similar to that seen during pregnancy, could indeed be produced by these agents However, McArthur and Ulfelder 20 analyzed the behavior of endometriosis in 24 patients culled from the world literature and concluded that: "the impression that pregnancy exerts a consistent curative effect upon endometriosis is not supported by critical analysis of the reported cases and appears to be ill-founded." Despite this conclusion, Ulfelder 21 stated 1 year later that: "At present it appears that hormone therapy for endometriosis will be the most widely applicable form of management in the future." The statement of McArthur and Ulfelder that proponents of pregnancy (Meigs, Kistner) suggest that pregnancy exerts a "curative effect" on endometriosis is as ill-founded as their negative conclusion. Neither Meigs nor Kistner suggested pregnancy as a curative method. They did suggest that it might have an ameliorating effect in certain patients and that pregnancy should be accomplished as soon as possible since later extension of the disease might produce relative infertility. Ranney 22 noted that his experience with progestin pseudopregnancy has been disappointing-no patients becoming pregnant subsequent to therapy. Furthermore, he stated that in his experience only four patients had become pregnant during or after hormonal therapy-all treated with testosterone. Ranney reserves hormonal therapy for the occasional patient with moderate endometriosis and severe dysmenorrhea who desires postponement of surgery for several months.

8 1158 KISTNER December 1975 TABLE 2. Corrected Conception Rates following Use of Estrogen-Progestin for Endometriosis" Author Drugli Dosage and schedule' Andrews et al a-hydroxyproges- 250 mg D, IM q. 7 terone caproate (D), or 10 days + 5 conjugated estrogen mg PR q.d., or (PR), or stilbestrol 2 mg S q.d. (S) Chambers 38 Gunning and Moyer Kistner''" Kourides and Kistner" 4 Riva et al.' 6 Snaith 40 Timonen and Johansson 41 Williams 42 Norethynodrel and mestranol (E) N orethisterone acetate-ethinyl estradiol (A) Norethynodrel and mestranol (E) or norethindrone and ethinyl estradiol (N) Medroxyprogesterone acetate (DP) and conjugated estrogen (PR) or Estinyl or Depoestradiol 17a-Hydroxyprogesterone caproate and estradiol valerate (DL2x) Medroxyprogesterone acetate with ethinyl estradiol (P) Norethindrone acetate and ethinyl estradiol (N) Lynestrenol and mestranol Norgestrel and ethinyl estradiol (NG) Norethynodrel and mestranol (E) N orethisterone acetate or allylestrinol or norethynodrel and mestranol (A or E) Lynestrenol (0) Norethynodrel and mestranol (E) 30 mg q.d. for wks 2 tablets/day for 4-9 mo 100 mg DP IM q. 2 wks 2 mg q.d. for mo, mg q.d. for mo 250 mg (1 ml) q. wk IM for mo 20 mg q.d. for mo 1-3 tablets/day for 3 mo-l yr 1-2 tablets/day for 3-6 mo 1-2 tablets/day for 3-6 mo mg q.d. for 1-12 mo 1 tablet/day for 2-7 mo mg q.d. for l'h-29 mo 20 mg q.d. for days Total no. of patients Symptomatic response 46.6% well, 46.6% improved (of 15 patients) 75% Corrected conception rate NRd 26.5% (12 patients) 78.5% (follow-up, 28.5% (2 patients) 4-7 mo) 83o/o (follow-up, 6-52 mo) 72.7% 87.3% 87.3% 72% (follow-up, 6 mo) 78.7% 60% 93% (follow-up, 3 mo) 47% 63% (7 patients) 45% (5 patients) 30o/o (6 patients) 72% (8 patients) 25% (1 patient) 5% (1 patient) 72% (11 patients) "Modified from Wilkinson EJ, Mattingly RF: Medical versus surgical treatment of endometriosis. In Controversy in Obstetrics and Gynecology, Second Edition, Edited by DE Reid, CD Christian. Philadelphia, W B Saunders Co, 1974, p 653. Used with permission of the authors and publisher. b A, Anovlar; D, Delalutin; DL2x, Deluteval 2x; DP, Depo-Provera; E, Enovid; NG, norgestrel; N, Norlestrin; 0, Organon; P, Provest; PR, Premarin; S, stilbestrol. "1M, Intramuscularly. "NR, Not reported.

9 Vol. 26, No. 12 MANAGEMENT OF ENDOMETRIOSIS IN THE INFERTILE PATIENT 1159 Ranney 22 also noted that 3.7% of patients operated on by him during a 20- year period required emergency operations for hemoperitoneum resulting from spontaneous avulsions of endometriosis. All of these had occurred during progestational phases of the cycle, some (number not stated) caused by exogenous progestins. Because of these experiences, Ranney deduced that there is an inherent danger during the progestational phase of the cycle, or during progestin-pseudopregnancy therapy, among women who have moderate to severe pelvic endometriosis. During the 20 years that I have used pseudopregnancy for endometriosis, I have seen only one patient who sustained a perforated endometrioma during therapy. This patient would not have been treated hormonally under usual circumstances because of the excessive size of the ovarian lesions. However, operation was delayed at the request of the patient. The most plausible explanation for the disappointing results of some clinical investigators in the treatment of endometriosis for infertility seems to be in the selection of patients for hormonal therapy. As previously mentioned, if anatomical factors such as tubo-ovarian adhesions or large endometriomas have been found by endoscopic examination, the optimal treatment is surgical. Obviously, large endometriomas may rupture if softening of the usually thick capsule is produced by exogenous hormones, and patients demonstrating such pathology should be operated on without delay. Similarly, if an endoscopic procedure has not been performed, pseudopregnancy will not be followed by pregnancy if tubo-ovarian adhesions prevent ovum pickup. Thus, it is not a fair evaluation to state that a hormonal regimen has failed to improve the infertility status. In such patients, the physician has usually failed to assess the factors producing infertility adequately and has attributed failure to the therapeutic regimen.. We advocate pseudopregnancy only for those patients who are infertile and in whom moderate degrees of surface ovarian endometriosis are demonstrated at endoscopy. Short periods of pseudopregnancy are also advocated after conservative surgery if all areas of endometriosis cannot be excised. In my 1966 report 23 ofpseudopregnancy in 110 patients, 47% of those desiring pregnancy conceived within 1 year of cessation of therapy. However, it should be noted that many of these patients had combination therapy-surgery plus pseudopregnancy. In our report 34 in 1968 of three new progestational agents, 17 of 43 patients ( 40%) became pregnant subsequent to treatment. These patients were carefully selected for hormonal therapy in lieu of surgical intervention by endoscopic examination. If it is possible to secure pregnancy in 40% of patients by a nonsurgical method, it should be obvious that such an approach is desirable, particularly to most patients. If pregnancy is not forthcoming after a hormonal regimen, surgery can be performed subsequently. Analysis of our results during the last 20 years indicates that a pregnancy rate of approximately 50% may be expected following pseudopregnancy alone in patients whose only abnormality, as determined by endoscopy, is surface ovarian endometriosis without endometriomas or tubo-ovarian adhesions (50.8% in 186 patients). The pregnancy rate subsequent to surgical treatment of ovarian endometriomas, with or without peritoneal endometriosis involving the bladder, uterus, cul-de-sac, or lateral pelvic wall, was 76% in 232 patients. It should be noted, however, that postoperative pseudopregnancy was used in these patients only if all areas of endometriosis could not be excised at the time of surgery. Furthermore, 96% of these patients were under 32 years of age and no other factors contributing to infertility were present. The incidence of

10 1160 KISTNER December 1975 pregnancy following surgical therapy in 106 patients who were found to have ovarian and peritoneal endometriosis complicated by tubo-ovarian, utero-ovarian, or sigmoido-ovarian adhesions, however, was only 38%. Since 1966 we have administered dexamethasone-promethazine preoperatively, intraperitoneally, and postoperatively in all patients undergoing surgery for infertility. Postoperative pseudopregnancy was also utilized in this group of patients with adhesions only if all areas of endometriosis could not be excised. The pregnancy rate for those patients who received postoperative hormonal treatment was essentially the same as for those who did not. However, it is obvious that pseudopregnancy was invariably utilized in patients with more extensive disease. Estrogen-progestin pseudopregnancy is contraindicated under the following conditions: 1. Unproved endometriosis or merely a suspicion of the disease by history, with minimal palpable findings. 2. Obscure diagnosis of pelvic lesions, particularly when ovarian enlargement is of such degree that a neoplastic growth cannot be excluded. 3. Uterine leiomyomas of such size that the stimulation of growth by estrogenic substances could initiate complications. Danazol. An interesting new compound, Danazol, a synthetic (2,3-isoxozol) derivative of17a-ethinyl testosterone, was made available for animal and clinical investigation in In experimental animals it suppressed gonadotropin release, had some progestational-like effect on estrogen-pretreated rats, and exhibited mild androgenicity at high dose levels In the human female, at oral doses of 200 to 800 mg/day, Danazol markedly diminished serum follicle-stimulating hormone and luteinizing hormone levels in postmenopausal women and prevented the luteinizing hormone surge of the normal ovulatory cycle. It induced marked atrophy of the endometrium and amenorrhea, especially at higher doses. Mild anabolic and androgenic activity were occasionally encountered. The basal body temperature during the administration of Danazol was monophasic and endometrial biopsies were usually nonsecretory. The cervical mucus was scanty, thick, and without ferning, and the vaginal smears were mildly hypoestrogenic. All of these attributes seemed to indicate that this steroidal substance would be of advantage in the treatment of patients with pelvic discomfort, dysmenorrhea, dyspareunia, and mastodynia due to fibrocystic disease. Greenblatt and associates 27 subsequently reported that Danazol, in a dose of 100 mg daily, ameliorated pelvic pain, dysmenorrhea, dyspareunia, and breast tenderness. In addition, this compound proved effective in preventing pregnancy in potentially fertile women without disrupting for any length of time the subsequent resumption of ovarian function. Side effects were mild weight gain, minor changes in the menstrual cycle, and a 20% incidence of amenorrhea while the drug was taken. Greenblatt and associates 28 treated 21 infertile patients with pelvic endometriosis, 11 of whom had the diagnosis established by previous hist~pathologic study. The remainder were treated because of a history and pelvic examination suggestive of the disease. Of the 11 patients with proven endometriosis, 6 conceived following Danazol therapy. Three of the ten patients with suspected endometriosis conceived. The dosage used for these patients ranged between 400 and 800 mg daily. Conception occurred 1 to 4 months after cessation of therapy. Ovulatory suppression appeared to result in most instances from the 200-mg dosage and no patient conceived while taking the drug. After cessation of the medication, resumption of normal ovulatory menses occurred

11 Vol. 26, No. 12 MANAGEMENT OF ENDOMETRIOSIS IN THE INFERTILE PATIENT 1161 within 30 to 45 days. This prompt resumption of ovulation is of advantage in patients with primary or recurrent endometriosis after surgery in whom estrogenprogestin combinations are contraindicated because of previous thromboembolic disease or limited because of excessive estrogen-induced side effects. In the past we have utilized Depo-Provera in such patients but the sustained action is a serious problem resulting in prolonged anovulation after this steroid. The over-all pregnancy rate in this group of patients was 42.8%, but in those in whom the diagnosis of endometriosis had been proven histopathologically, as well as in the clinically suspected group, the pregnancy rates were 54.5 and 30%, respectively. Although the clinical use of Danazol has not as yet been approved by the Federal Food and Drug Administration, it appears that it will be an effective hormonal agent in the treatment of endometriosis. Surgical Treatment In contemplating surgical treatment of endometriosis, one should remember that functioning ovarian tissue is necessary for the continued activity of the disease. Therefore, successful treatment of endometriosis depends on a knowledge of when it is reasonably safe or desirable to maintain ovarian function and when it is necessary to destroy it. It is obvious that ovarian function should be preserved in treating the very early, and perhaps symptomless, lesions, and hysterectomy should be performed only when the ovaries are destroyed by endometriosis. Unfortunately, the majority of cases fall between these two extremes and may present problems in surgical judgment seldom encountered in any other pelvic disease. As our knowledge of the life history of endometriosis has increased, there has been a definite tendency to become more conservative, particularly in the treatment of the infertile patient. In general, it is believed that one should err on the side of conservatism; this belief is based on the facts that endometriosis (1) usually progresses slowly over a period of years, (2) is not, and rarely becomes, malignant, and (3) regresses at the menopause. Early implantations on the surface of the peritoneum should be excised. Electrocoagulation is not recommended because of the possibility of subsequent adhesions to the small intestine or the adnexal structures. Small endometrial cysts on the ovary may be excised or a major portion of one or both ovaries may be resected. Small endometrial implants on the intestines should be excised. To aid in the prevention of recurrence, conservative operations should be accompanied by correction of uterine displacements, relief of cervical obstruction, and removal of any other concomitant pelvic pathologic changes. Endometriosis coexisting with uterine myomas, ovarian cysts, or other pelvic abnormalities may be insignificant; on the other hand, the extent or location of these may make conservative surgery hazardous. Decisions cannot always be made prior to laparotomy, and the patient should be so informed. Conservative Surgery (Ovarian Resection). If childbearing function is to be preserved, operative procedures should be as conservative as possible. All surgical procedures should be preceded by a thorough curettage, and every patient should have had a cytologic examination to exclude possible malignancy of the cervix. The approach should usually be through a transverse suprapubic incision. However, if the ovarian masses are large, a midline incision may be necessary. Thorough exploration of the pelvic and abdominal organs should be performed routinely, and the decision reached as to

12 1162 KISTNER December 1975 whether conservative or radical surgery is preferable. Because of recurrent bleeding and fibrosis associated with the process of endometriosis, the ovaries are frequently adherent to the posterior leaf of the broad ligament and must be carefully displaced from this site before resection is possible. When the disease is extensive, the uterus is usually fixed in third-degree retroversion, with both ovaries adherent to the uterus or the posterior leaf of the broad ligament and to the rectosigmoid. When this situation exists, it is frequently safer to displace the ovaries by gentle fingerdissection rather than by sharp dissection with a knife or scissors. In extensive endometriosis, the ureter is frequently displaced medially and may be immediately adjacent or adherent to the fixed ovary. Knife or scissors dissection might inadvertently injure or divide the ureter. If the ovarian masses are large, as with bilateral endometriomas, it is advisable to finger-dissect both ovarian masses first and then elevate the uterus from its fixed position. In order to free the uterus, it is frequently necessary to place upward traction on the rectosigmoid so that its attachment to the back of the uterus and cervix may be identified. Occasionally the ovary is intimately attached to the lateral peritoneum immediately over the course of the ureter. In this case the posterior peritoneum is opened at the level of the promontory of the sacrum in the same way as for a presacral neurectomy. We usually perform the presacral neurectomy first, so that the posterior peritoneum may be left open until all steps of the operation have been concluded. This prevents ureteral damage during mobilization of the fixed ovaries. Allis clamps are then placed on the edge of the peritoneum and the right ureter is identified on the lateral flap. The left ureter lies below the superior hemorrhoidal vessels and is somewhat more difficult to locate. A right-angle clamp is then used to tease the ureter free from the peritoneum in the area where the ovary is attached. After this has been accomplished, the ovary may be mobilized by sharp dissection. Since the contents of endometriomas are irritating to the peritoneum and bowel serosa, several packs are placed above the pelvis to protect these structures. Small areas of endometriosis are frequently found deep in the substance of the ovary and these are excised. Occasionally the major portion of the ovarian substance has been completely destroyed or replaced by endometriosis, and at the conclusion of the resection only a small fragment of ovarian cortex at the hilus remains. This should not be an absolute indication for oophorectomy, since we have observed pregnancies in women who have had a unilateral salpingo-oophorectomy and three-quarters of the remaining ovary removed. In the ovarian reconstruction, the operator should attempt to reapproximate the cortical surface as closely as possible in order to prevent adhesions of omentum or small intestine to the ovary. Areas of endometriosis on the posterior surface of the uterus and cervix or on the anterior surface of the rectosigmoid should be excised as completely as possible. This frequently results in large areas of denudation ofthe peritoneum and raw, oozing surfaces in the cul-de-sac. While it is possible to cover these areas by reflecting the redundant sigmoid inferiorly and suturing it to the posterior aspect of the uterus, this results in obliteration of the cul-de-sac. In order to preserve the anatomical configuration of the cul-desac, we believe that it is advantageous to cover the raw surface with omental or peritoneal grafts. We have had the opportunity to observe these grafts at second operations and have found them to be intact and free of adhesions to the adnexal structures or intestines.

13 Vol. 26, No. 12 MANAGEMENT OF ENDOMETRIOSIS IN THE INFERTILE PATIENT 1163 Although many gynecologic surgeons have favored fulguration of areas of endometriosis both on the ovaries and in the cul-de-sac, we have not been in favor of this procedure. Endoscopy performed at varying periods of time after laparotomy for endometriosis have shown adhesions of intestine and omentum to previously fulgurated areas in the pelvis. At the conclusion of the ovarian resection the entire oviduct should be carefully inspected, and adhesions of the fimbriated portion of the distal oviduct to the ovary should be freed. Ligation of small blood vessels on the oviduct is accomplished with 5-0 chromic catgut or Dexon. If the bowel lumen is entered, closure of the submucosal and seromuscular layers is done in the usual two-layer manner. After all areas of endometriosis have been excised, the edges of available peritoneum are closed with fine catgut. All denuded areas should be covered with peritoneal or omental grafts. In conservative operations for endometriosis, a uterine suspension and presacral neurectomy are usually performed. We believe that it is important, from the viewpoint of subsequent fertility, to ensure the anatomical normality of the cul-de-sac, and this is best accomplished by anterior uterine suspension. Plication ofthe uterosacral ligaments is an adjunctive procedure to uterine suspension and improves the posterior deflection of the cervix, thus aiding anterior positioning of the uterus. In many cases the denuded area over the rectosigmoid is adequately peritonealized by plication of the uterosacral ligaments. This is accomplished with three interrupted sutures of 1-0 chromic catgut, the first suture being placed just at the insertion of the uterosacral ligaments and two sutures just below the first. After this has been completed, the sigmoid colon fits nicely into the arc of the uterosacral ligaments. When plicating the uterosacral ligaments, care must be taken not to place the sutures too far laterally, because of the possibility of kinking or obstructing the ureter. Since we advise doing the presacral neurectomy before the ovarian and cul-de-sac resections, it is frequently advantageous to leave the posterior peritoneum open until this has been concluded. The ureters will then be easily visualized during these dissections and reconstructions. If subsequent pregnancy is not a prime factor or if there is evidence of extensive involvement of other pelvic structures, such as the bowel or ureter, a hysterectomy and bilateral salpingo-oophorectomy may be indicated. Since leiomyomas of the uterus are found in approximately 15% of the patients with endometriosis, single or multiple myomectomy should be carried out as part of the conservative approach. It has been our practice to do a presacral neurectomy whenever the uterus is not removed. Even if the patient has not had dysmenorrhea or pelvic pain preceding surgery, these symptoms may develop subsequently, due to recurrent disease. The presacral procedure should be extensive, with excision of all nerve tissue between the right ureter and the superior hemorrhoidal vessels. In addition, we frequently remove a part of the uterosacral ligaments at their insertion into the uterus, thus accomplishing more complete pelvic denervation. An appendectomy is performed at the time of surgery because functioning endometriosis of the appendiceal serosa has been noted in many patients. Endometriosis of the terminal ileum is seen only rarely and may be treated by superficial excision. If the muscularis and mucosa are involved, resection and end-to-end anastomosis should be performed. Pseudopregnancy is induced for a minimum of 3 months after operation if all areas of endometriosis cannot be excised, and then concerted efforts toward conception are made. Approximately 50%

14 1164 KISTNER December 1975 of women so treated will become pregnant if no other cause for infertility exists. One author29 has reported the incidence of pregnancy to be as high as 94% following conservative surgery, but this seems to be an exceptionally high success rate and may depend on patient selection. It has been our policy to perform a careful peritoneal toilet and irrigate the pelvis with warm isotonic saline at the conclusion of the surgical procedure. Since it is almost impossible to remove an endometrioma intact, without spillage, removal of the cellular debris and thick fluid contents is advised. In an effort to reduce the incidence of postoperative adhesions we have, since 1966, utilized dexamethasone and promethazine preoperatively, intraperitoneally before closure, and postoperatively (20 mg of dexamethasone and 25 mg of promethazine 2 hours prior to surgery and then every 4 hours for 12 doses postoperatively; the same amount is placed in the cul-desac through a small catheter). The incidence of pregnancy following conservative surgery varies widely and is dependent on such factors as extent of the disease, age of the patient and her husband, frequency of coitus, previous parity, and the presence of other pelvic pathology (leiomyomata, tubal disease, or adhesions) at the time of surgery. Williams30 suggested that the pregnancy rate was improved if uterine suspension and presacral neurectomy were performed. He speculated that these adjunctive procedures could diminish dyspareunia and effect more satisfactory and more frequent coitus. Spangler et al.3 reported a pregnancy rate of 51% in 85 patients treated surgically for endometriosis (62% with presacral neurectomy, 44% without) Rogers and Jacobs31 had a pregnancy incidence of 63% in 120 patients, all of whom had had presacral neurectomy. Green32 reported 41% fertility after conservative surgery but was able to perform such surgery in only 21% of his patients; most of the remainder had had a hysterectomy and bilateral salpingo-oophorectomy. Sheets and associates, 33 from the Mayo Clinic, had a fertility rate of 36%, and Andrews and Larson34 reported a rate of 19%. Grant,35 of Sydney, Australia, reported a 40% pregnancy rate. The highest reported rates of pregnancy subsequent to conservative surgery are those of Norwood, %, and Ranney, %. Acosta and associates2 reported that the highest pregnancy rates were achieved by surgery in patients who presented with 1 to 3 years of infertility (57%), whereas the lowest rates (25%) occurred in patients with 4 to 5 years of infertility. They studied 107 patients and their pregnancy rate was 45.7%. Thirty-two per cent of the operated patients became pregnant during the first 12 postoperative months and an additional twelve per cent conceived during the 2nd year. There was a definite correlation with the extent of the disease. The pregnancy rate in patients classified as having "mild" endometriosis was 75%; in those with "moderate" degrees, the rate was 50%; whereas in patients having "severe" disease, the preg- nancy rate was only 33%. Peterson36 reported a series of 125 infertile patients in whom a diagnosis of endometriosis was made by laparoscopy. Of 111 patients who had been trying to become pregnant for more than 1 year, 47% did so after conservative surgery. If the surgery was performed for endometrial cysts only, the conception rate was 79%. However if tubo-ovarian adhesions were also corrected, the rate was only 40%. It seems reasonable to expect that approximately 40 to 50% of patients who are desirous of childbearing and who have conservative surgical treatment for endometriosis will become pregnant. Such pregnancy usually occurs within the first 24 months, although, in a few patients,

15 Vol. 26, No. 12 MANAGEMENT OF ENDOMETRIOSIS IN THE INFERTILE PATIENT 1165 the delay may last 3 to 4 years. The cause for such prolonged infertility is unknown, although I have been impressed by the increased frequency ofluteal phase insufficiency following extensive ovarian resection. Appropriate therapy for this disorder frequently is responsible for hastening the occurrence of pregnancy. In general, results are better in younger patients, undoubtedly in relation to their desire and sexual practices. Similarly, uterine suspension and presacral neurectomy seem to be advantageous. Meticulous attention to the minutiae of surgical technique and complete hemostasis are necessary for optimal results. Postoperative pseudopregnancy for 8 to 12 weeks may improve the fertility rate in patients in whom complete excision of all areas of endometriosis is impossible. Finally, the incidence of troublesome postoperative tubo-ovarian adhesions may be diminished by the use of dexamethasone and promethazine. REFERENCES 1. Rubin IC: Sterility. Obstet Gynecol 3:161, Acosta AA, Buttram VC Jr, Besch PK, Malinak RL, Franklin RR, Vanderheyden JD: A proposed classification of endometriosis. Obstet Gynecol 42:19, Spangler DB, Jones GS, Jones JW: Infertility due to endometriosis: conservative surgical therapy. Am J Obstet Gynecol 109:850, Kelly JV, Rock J: Culdoscopy for diagnosis in infertility. Am J Obstet Gynecol 72:523, Garcia C-R: In Symposium on Long-Term Safety of Progestin-Estrogen Combinations, Absecon N J, May 3, Kistner RW: Endometriosis and infertility. In Progress in Infertility, Second Edition, Edited by SJ Behrman, RW Kistner. Boston, Little, Brown, 1975, p Meigs JV: The medical treatment of endometriosis and the significance of endometriosis. Surg Gynecol Obstet 89:317, Sampson JA: Heterotopic or misplaced endometrial tissue. Am J Obstet Gynecol 10:649, Kamaky KJ: Endometriosis. In Current Therapy, Edited by HF Conn. Philadelphia, W B Saunders Co, 1957, p 606 9a. Karnaky KJ: The use of stilbestrol for endometriosis. South Med J 41:1109, Haskins AL, Woolf RB: Stilbestrol-induced hyperhormonal amenorrhea for the treatment of pelvic endometriosis. Obstet Gynecol 5:113, Kistner RW, Duncan CJ, Mansell H: Suppression of ovulation by tri-p-anisyl chloroethylene (TACE). Obstet Gynecol 8:399, Kistner RW: The use of newer progestins in the treatment of endometriosis. Am J Obstet Gynecol 75:264, Beecham CT: Letter to the editor. JAMA 163: 678, MerrillJA: Benign lesions of the cervix, corpus, tubes, and ovaries. In Textbook of Obstetrics and Gynecology, Second Edition, Edited by DN Danforth. New York, Harper and Row, 1966, p Jones GS, Pourmand K: An evaluation of etiologic factors and therapy in 555 private patients with primary infertility. Fertil Steril 13:398, Riva HL, Kawasaki DM, Messinger AJ: Further experience with norethynodrel in treatment of endometriosis. Obstet Gynecol19:111, Meigs JV: Endometriosis. Etiologic role of marriage, age and parity: conservative treatment. Obstet Gynecol 2:46, Kistner RW: The treatment of endometriosis by inducing pseudopregnancy with ovarian hormones: a report of 58 cases. Fertil Steril 10:539, Kistner RW: Observations on the effects of new synthetic progestogens on endometriosis in the human female. Fertil Steril 16:61, McArthur JW, Ulfelder H: The effect of pregnancy upon endometriosis. Obstet Gynecol Survey 20:709, Ulfelder H: The treatment of endometriosis. Med Sci 8:503, Ranney B: The management of endometriosis. In Controversy in Obstetrics and Gynecology, Second Edition, Edited by DE Reid, CD Christian. Philadelphia, W B Saunders Co, 1974, p Kistner RW: Current status of the hormonal treatment of endometriosis. Clin Obstet Gynecol 9:271, Kourides IA, Kistner RW: Three synthetic progestins in the treatment of endometriosis. Obstet Gynecol 31:821, Potts GO, Beyler AL, Burnham DF: Data from the files of Sterling-Winthrop Research Institute, Rensselaer NY, Dmowski WP, Scholer HFL, Mahesh VB, Greenblatt RB: Danazol-a synthetic steroid derivative with interesting physiologic properties. Fertil Steril 22:9, 1971