Robert W. Kistner

Elevated serum concentrations of CA-125 in patients with advanced endometriosis

CA-125 is a high-molecular-weight glycoprotein that is expressed on the cell surface of some derivatives of embryonic coelomic epithelium. Based on results of an immunoradiometric assay developed to detect CA-125 in peripheral blood, 82% of patients with ovarian cancer and less than 1% of apparently healthy controls have elevated peripheral blood levels of CA-125. Because endometriotic lesions are likely to be derivatives of embryonic coelomic epithelium, the authors investigated serum CA-125 levels in patients with endometriosis. Preoperative serum CA-125 concentrations were measured in 147 patients undergoing diagnostic laparoscopy or laparotomy. Serum CA-125 concentrations were elevated in patients with stage III or IV endometriosis, compared with controls with negative diagnostic laparoscopies (66.5 +/- 14.5 versus 8.20 +/- 0.59 U/ml, mean +/- standard error of the mean; P less than 0.001). Fifty-four percent of patients with stage III or IV endometriosis and 0% of the controls had CA-125 levels greater than 35 U/ml. Occasional patients with stage II endometriosis (13%), leiomyomata uteri (14%), and chronic pelvic inflammatory disease (5%) also had serum CA-125 concentrations greater than 35 U/ml. Immunocytochemical techniques demonstrated the presence of CA-125 on the cell surface of endometriotic lesions.

The use of newer progestins in the treatment of endometriosis

The ability of the oral contraceptives Delalutin (17-alpha-hydroxyprogesterone caproate) and Enovid (17-alpha-ethynyl-17-hydroxy-5(10)-estren-3-one) combined with various estrogens to control endometriosis was examined. The pharmacological nature of the drugs their chemical structures and 4 treatment plans utilized in the study were presented. Case reports were given for patients with symptoms of endometriosis involving the posterior cul-de-sac uterosacral ligaments with fixation of the uterus or adnexal masses for each of the treatment schedules; and the progressive diminishment of symptoms with treatment was discussed. The occurrence of decidual transformation of endometrial tissue and decidual necrosis and absorption was reported. The use of culdoscopy was recommended as a diagnostic method. It was suggested that estrogens might be eliminated in treatment of endometriosis since a decidua may be produced with progestins.

Management of Endometriosis in the Infertile Patient

Infertility has a 30-40% incidence in women with endometriosis. However, conservative surgical procedures can result in pregnancy for 40-90% of these patients. The pregnancy rate is influenced by 5 factors: 1) extent of the disease, 2) age, 3) history of previous surgery for endometriosis, 4) duration of infertility before surgery, and 5) length of postsurgical follow-up. The factor responsible for infertility among women with endometriosis is believed to be an inadequacy of the tubo-ovarian motility secondary to fibrosis and scarring, which results in imperfect ovum acceptance by the fimbriae. Therapy encompasses 4 approaches: 1) prophylaxis, 2) observation and analgesia, 3) suppression of ovulation, and 4) surgical treatment. Pregnancy is suggested as the optimal prophylactic treatment for endometriosis since the symptoms and signs regress during gestation and for varying periods thereafter. This regression is probably due to a combination of anovulation and amenorrhea caused by adenohypophyseal suppression. It may also be due to a transformation of functioning endometriotic tissue into decidua by increasing levels of chorionic estrogen and progesterone. If pregnancy is not desired, anovulation can be secured by the administration of sex hormones. Pseudopregnancy for 6 months, induced by norgestrel plus ethinyl estradiol or norethynodrel plus mestranol, can lead to pregnancy in 50% of patients whose only abnormality is surface ovarian endometriosis within 1 year of cessation of therapy. Short periods of pseudopregnancy are also advocated after conservative surgery if all areas of endometriosis cannot be excised. 40-50% of these patients can expect to become pregnant within 24 months. The incidence of postoperative tubo-ovarian adhesions may be diminished by use of dexamethasone and promethazine.

Suggested Classification for Endometriosis: Relationship to Infertility*

Pregnancy rates following treatment for endometriosis have been reported from 30 to 95% depending on the extent of the disease. Over age 35 the pregnancy rate is 25% or less. Infertility for over 5 years reduces the pregnancy rate after surgery. Adhesions are a frequent cause of the infertility. Only rarely may the oviducts be blocked. Inadequate tuboovarian motility is thought to be the most important factor. A classification of the endometriosis process into 4 stages is submitted with appropriate drawings to illustrate each phase. The uterus becomes fixed in retroposition by the endometriosis and by the adherent rectosigmoid. Dissemination of endometriotic tissue via vascular or lymphatic channels is also possible but not related to infertility.

THE PREVENTION OF POSTOPERATIVE PELVIC ADHESIONS FOLLOWING CONSERVATIVE OPERATIVE TREATMENT FOR HUMAN INFERTILITY

A combination of Decadreon (dexamethasone) and Phenergan (promethazine) was tested in this collaborative study of 240 infertility patients as a means of preventing postoperative adhesion formation after simple pelvic surgery. 24 patients were lost to follow-up. The overall pregnancy rate among the 240 patients was 51.7% (124): 49% with primary infertility and 58% with secondary infertility conceived after surgery. 90 full-term deliveries were recorded, 27 spontaneous abortions occurred, and 7 ectopic gestations were conceived. In all, 31 cases were reinspected for various reasons after the drug treatment postsurgery; 42% showed no adhesions, 23% showed minimal adhesions, and 35% had significant adhesions. Complications coincident with use of the combined medication were seen in 2.2% (11 of 240) patients. Though this study lacked controls, the authors feel thta the use of corticosteroids postoperatively after pelvic intervention may control the numbers of adhesions which form postoperatively.

Histological effects of progestins on hyperplasia and carcinoma in situ of the endometrium—Further observations

Abstract Twenty-three patients with cystic and adenomatous hyperplasia and 8 patients with carcinoma in situ of the endometrium were treated with progestogens after excluding invasive carcinoma by thorough uterine curettage. All patients were in the menopausal or postmenopausal age group. In each case glandular atrophy and stromal decidua were produced and in one-third the patients there was evidence of residual hyperplasia with “drug effect” by the progestogenic agent. In no instance did subsequent invasive carcinoma occur.

The Effects of Progestational Agents on Hyperplasia and Carcinoma in Situ of the Endometrium

In predisposed individuals the unopposed action of estrogenic substances for a considerable period of time will result in adenomatous hyperplasia carcinoma in situ and carcinoma. The optimum therapeutic approach depends on the age of the individual and on the reversibility of the lesions. In the postmenopausal patient the obvious treatment is hysterectomy while in a young woman a conservative approach is desirable. In these patients the clinician should make every effort to secure regular ovulation and cyclic secretory differentiation of the endometrium followed by shedding; subsequent therapy with cortisone or clomiphene to encourage pregnancy should be carried out; if pregnancy is impossible exogenous progestin should be administered in cyclic fashion. A study conducted on several premenopausal patients having atypical hyperplasia or carcinoma in situ of the endometrium showed that treatment with progestational agents for periods from 3 weeks to 2 months reduced the carcinoma in situ to the basal layer of the endometrium. Although progestational agents are able to effect changes in the morphology of the endometrial glands they are in no way a substitute for the usual medical diagnostic procedures and appropriate therapy. Hysterectomy is indicated for any degree of endometrial hyperplasia only in the postmenopausal patient.

Infertility with Endometriosis

Endometriosis is the proliferative growth and functioning of endometrial tissues in areas other than the uterus. Adjacent tissues are most commonly involved. Symptoms are associated with local irritation and subsequent fibrosis. Areas of miniature menstruation occur in endometriotic foci. Infertility may result in 30-40% of patients. The median age is 37. Endometriosis has been found in about 18% of laparotomies performed for gynecologic disease and in about 1/3 of those done for infertility. Conservative surgery has been considered indicated for most patients. Since symptoms and signs regress during gestation the optimum treatment is pregnancy. A pseudopregnancy produced by a combination of estrogen and a progestogenic substance given continuously is recommended. Since 1956 more than 200 patients have been so treated. Although larger doses were used at first Enovid beginning at 2.5 mg daily and increased gradually to 20 mg daily was found adequate. Norlutin Deluteval and Depo-Provera have also been used. Estrogen was added for breakthrough bleeding. Treatment varied from 3 to 12 months. A satisfactory result was obtained in 42 of 53 patients who had no previous surgical treatment. Recurrences occurred in 7. Of 38 patients trying to conceive 18 became pregnant. Average time to onset of first menstration after cessation of therapy was 46 days. Cases of recurrent endometriosis after surgery or drug therapy should be treated 10-12 months. Of 35 patients with recurrences treated 4-12 months 32 had improvement and 26 had a satisfactory result. Of these 28 attempted pregnancy and 9 conceived. Subsequent surgery was required for 4. Of 22 patients treated immediately after surgery and continued 3-6 months. Pregnancy has occurred in 7 of 15 of this group who desired conception. Histologically areas of endometriosis in treated patients show an atypical decidual reaction with necrosis vacuolization of cytoplasm and nuclear disintegration. Endometrial ovarian and pituitary functions remain normal after treatment is discontinued.

Effects of clomiphene citrate† on endometrial hyperplasia in the premenopausal female

Clomiphene was administered continuously in a dose of 100 to 200 mg daily for 16 to 18 months to 6 patients (5 approaching menopause and one postmenopausal) having endometrial hyperplasia with a presenting complaint of irregular and profuse bleeding. After cessation of clomiphene therapy the results were atypical secretory endometrium—2 patients; normal menstrual cycles—3 patients; spontaneous menopause—one patient. The therapeutic effects of clomiphene are temporary. If the ovary maintains its potential for follicular maturation and ovulation, a secretory phase will be induced in the endometrium which lasts 6 to 8 weeks. Endometrial atrophy then will develop and remain unchanged as long as therapy is continued. The major side effects of clomiphene are hot flashes and ovarian cysts.

THE EFFECTS OF NEW SYNTHETIC PROGESTOGENS ON ENDOMETRIOSIS IN THE HUMAN FEMALE.

The synthetic progestogens employed to produce pseudopregnancy in 36 patients with endometriosis were ethynodiol diacetate with mestranol (Metrulen) chlormadinone with mestranol (Lormin) and megestrol acetate with ethinyl estradiol. The optimum maintenance dose was in the range of 4-6 mg of ethynodiol diacetate or chlormadinone plus .2 mg mestranol or 5-10 mg megestrol acetate plus .2 mg ethynyl estradiol daily. There was a marked variation in the amount required to suppress ovulation and yet prevent break-through bleeding. Side effects such as nausea vaginal discharge and breast tenderness were fewer than with previously used combinations. Excessive weight gain (5 pounds) was noted in almost 50% of the patients treated. Only slight changes if any were noted in 17-ketosteroids 17-ketogenic steroids protein-bound iodine and iodine-131 uptake. No change was noted in bromsulphalein excretion. Satisfactory objective and subjective remissions were obtained in 82% of the patients. Pregnancy had occurred subsequent to treatment in 11 of 22 patients who were infertile and desired pregnancy. It was concluded that these compounds are effective in the management of patients with endometriosis and are well tolerated. The cost is low and the precise dose and length of therapy depends on the individual patient.