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Infertility with Endometriosis
Infertility with Endolnetriosis A Plan of Therapy ROBERT W. KISTNER, M.D.
is a disabling disease affecting young and middle-aged women and is the result of proliferation, growth, and functioning of endometrial tissues in areas other than the uterus. The sites most commonly involved are the ovaries, the posterior cul-de-sac, and the peritoneal surfaces of the uterosacral ligaments, rectosigmoid, and bladder. Both the cause of the disease and that of associated infertility are not clearly understood but the symptoms, if present, are undoubtedly associated with local irritation and subsequent fibrosis in multiple areas of miniature menstruation in endometriotic foci. The infertility state may be the result of inadequate tuboovarian motility that is secondary to fibrosis and scarring, with imperfect ovum acceptance by the fimbria. Certain peculiar facets of this disease merit discussion. Endometriosis has been noted with increasing frequency during the past 2 decades; several reports have indicated that it is found in 5-15 per cent of pelvic operations. It is not frequent in the Negro and seems to be found most often among women of the higher socia-economic groups. The median age is about 37 years but about 15 per cent of patients are under 30. It has been suggested that a specific body-type and psychiC demeanor are frequently found: mesomorphic but underweight, overanxious, intelligent, egocentric, and perfectionist. These characteristics represent a personality pattern in which marriage and childbearing are likely to be deferred and, therefore, predispose the woman to prolonged periods of uninterrupted ovulation. At the Free Hospital for Women during the interval 1950-1960, endometriosis has been noted by microscope in specimens from about 18 per cent of all laparotomies performed for gynecologic disease. The importance of the disease depends upon its high incidence, the incapacitating symptoms which it produces, and its association with infertility. ENDOMETRIOSIS
From the Department of Obstetrics and Gynecology, Harvard Medical School, Boston, Mass. and the Free Hospital for Women, Brookline, Mass. Presented at the meeting of the Pacific Coast Fertility Society, Las Vegas, Nevada, Nov. 10, 1960.
237
238
KISTNER
FERTILITY
& STERILITY
Although endometriosis is commonly associated with infertility, it is not known whether endometriosis occurs because pregnancy is deferred or whether infertility is the eventual result of extensive endometriosis. Rubin commented on this relationship stating that when the disease is present, the expectation of pregnancy is about half that of the general population. Thus, with a natural incidence of infertility approximating 15 per cent, it is valid to say that in the presence of endometriosis the sterility incidence approximat~s 30-40 per cent. However, when surgery is performed (specifically for endometriosis or during an "infertility laparotomy"), from 30-50 per cent of patients will subsequently conceive. If conservative procedures are carried out and if there is no other cause of sterility, the rate of conception may approach 85-90 per cent. Kelly and Rock have reported endometriosis to be the causative factor of tubo-ovarian adhesions in about one fourth of their patients submitting to culdoscopy. The disease process was found in about one third of all patients who have surgery for infertility at the Free Hospital for Women. THERAPY
The crippling characteristics of this disease, occurring during the reproductive period of the woman's life, prevent the fulfillment of marital potential and too often terminate in castration. An optimum method of treatment will secure pain relief, allow coitus, prevent abnormal bleeding, and preserve, or increase the possibility of, motherhood. Conservative surgery will accomplish this in most patients, but pregnancy has been suggested as the optimum prophylaxis and therapeusis since the symptoms and signs of endometriosis regress during the period of gestation and for varying periods of time thereafter. This is probably the result of a combination of anovulation and amenorrhea brought about by adenophypophyseal suppression. As I suggested in 1956,3 this improvement may be due, in part, to a transformation of functioning endometriotic tissue into decidua by the rising levels of chorionic estrogen and progesterone. Where the patient does not contemplate or desire pregnancy, or if the patient is infertile, I have suggestedS that a combination of estrogen and progestogenic substance could be given continuously and in increasing dosage to induce a so-called pseudopregnancy. Since 1956 over 200 patients with proven endometriosis have been treated with such a regimen. Patients were accepted for therapy only if endometriosis had been diagnosed previously by laparotomy, by biopsy of vaginal lesions, or by culdoscopy. As of Jan. 1, 1961, 110 patients who had adequate follow-up study for a minimum of 6 months following termination of therapy were available for analysis.
VOL,13,No.3,1962
INFERTILITY WITH ENDOMETRIOSIS
239
At present I use the following regimens of therapy: Enovid: o 2.5 mg. daily for 1 week 5.0 mg. daily for 1 week 10 mg. daily for 2 weeks 15 mg. daily for 2 weeks 20 mg. daily indefinitely Norlutinf 5 mg. daily for 2 weeks. Increase by 5 mg. every 2 weeks until maintenance dose of 15-20 mg. is reached. Add estrogen for "breakthrough bleeding." Deluteval 2X t 1 cc (250 mg. Delalutin and 5 mg. estradiol valerate) I.M. weekly. Increase by 0.5 cc. every 6 weeks or whenever ''breakthrough bleeding" occurs. Depo-Provera: § 2 cc. (100 mg.) I.M. every 2 weeks X 4 doses; then 2 CC. every 4 weeks. Add oral estrogen for "breakthrough bleeding."
The majority of the patients reported in this paper received Enovid in much larger dosage. Subsequently it was found that the lower dose schedule is just as effective. RESULTS
Table 1 outlines the results in 53 patients (Group 1) who had primary hormone therapy, that is, no previous surgery for endometriosis. The diagnosis was substantiated in most patients by culdoscopy or posterior colpotomy. The treatment period varied from 3-12 months depending upon the extent of the disease. A satisfactory result during therapy was obtained in 42 of 53 patients, and 18 (of 38 patients trying to conceive) subsequently became pregnant. Remissions lasted as long as 40 months and recurrences were noted in 7 patients. All of the latter have been treated again hormonally. The average time of onset of the first menstrual period after cessation of therapy was 46 days and, in patients who became pregnant, conception frequently occurred at the time of the second or third spontaneous ovulation following pseudopregnancy. As noted in Table 1,16 patients were treated continuously for 7-12 months. The usual dosage regimen was: 10 mg. Enovid daily for 2 weeks with a 10 mg. daily increase every 2 weeks until a maintenance dose of 40 mg. daily was reached. A few patients received 60-70 mg. daily because of persistent breakthrough bleeding. Bleeding did not occur, however, from visible areas of *G. D. Searle & Co., Chicago 80, Ill. tParke, Davis & Company, Detroit 32, Mich. :l:E. R. Squibb & Sons, New York 22, N. Y. §The Upjohn Co., Kalamazoo 99, Mich.
240
FERTILITY
KISTNER
& STERILITY
TABLE 1. Results of Treatment in 53 Patients with No Previous Surgery for Endometriosis (Group 1) No. treated
Treatment duration (mo.)
10
3
Satisfactory result
7
Longest remission (mo.)
Subsequent surgery
40
3 (2 adenomyos~s; 1 p.i.d. & endo-
27
4-6
21
37
16
7-12
14
24
TOTAL:
53
42
metriosis) 5 (3 adenomyosis; 2 p.i.d. & endometriosis) 1 (fibrotic endometriosis,) 9
Subsequent pregnancy
Recurrence*
0
4
11
2
7
1
18t
7
* All re-treated. tOf 38 trying to conceive.
endometriosis, e.g., vagina, even when breakthrough bleeding was noted from the endometrium. Certain symptoms typical of normal pregnancy were noted during the treatment period: nausea (which usually disappeared spontaneously after 3-4 days, breast tenderness, increased appetite, occasional euphoria, insomnia, edema and, in a few patients, a vague "tired feeling" or depreSSion. Physical findings included softening of the vagina and cervix, increased vaginal discharge, temporary uterine enlargement and breast engorgement with increased nipple pigmentation. A slight increase in fine facial hair was noted in a few patients, as was increased pigmentation of the linea alba. However, ths was not more than is seen in normal pregnancy. True hirsutism did not occur even in patients receiving 5~O mg. daily for 9 months. Serial determinations of serum cholesterol were not significantly changed in 9 patients. Similarly, the level of protein-bound iodine did not seem to vary appreciably although minor elevations were frequent. The results of the determinations of 17-keto-steroids and 17-hydroxycorticoids were normal. Microscopic examination of the ovaries in the patients subjected to surgery during or following pseudopregnancy showed no morphologic change except for a decidual reaction in areas of endometriosis with follicular arrest and atresia of varying degrees. Table 2 outlines the results in 35 patients (Group 2) treated because of recurrent endometriosis. Six were treated for only 3 months and one of these subsequently developed another recurrence necessitating hysterectomy and bilateral salpingo-oophorectomy. (The author suggests that every patient with recurrent disease should be treated for at least 10-12 months.) The re-
VOL.
13, No.3, 1962
241
INFERTILITY WITH ENDOMETRIOSIS
TABLE 2. Results of Treatment in 35 Patients with Recurrent Endometriosis (Group 2) No. treated
Treatment duration (mo.)
Satisfactory result
Longest remission (mo.)
6
3
6
24
19
4-6
17
27
7-12
9 32
29
10 TOTAL:
35
Subsequent surgery
Subsequent pregnancy
Second recurrenee
1 ( endometriosis) 3 (adenomyosis: 1; endometriosis: 1; p.i.d.: 1
2
1
5
1
0
2 9°
0
4
2
*Of 28 trying to conceive.
maining 29 patients were treated for 4-12 months with a satisfactory result during therapy for 26. The longest remission was 29 months from the termination of hormonal therapy. Nine of 28 of these patients attempting pregnancy have conceived. Four patients in the total group required subsequent surgery, 2 for recurrent endometriosis, 1 for adenomyosis and 1 for pelvic inflammatory disease. Satisfactory improvement was noted in 32 of 35 patients during the period of therapy. This particular group of patients presents a serious challenge to the gynecologist or surgeon since all have had previous surgery for endometriosis. In several patients, recurrent disease was discovered less than 6 months following laparotomy. Repeat surgery is not looked upon favorably by most of these patients; pseudopregnancy seems to be a particularly valuable therapeutic adjunct in such a group. Table 3 summarizes the results in 22 patients (Group 3) who were treated "prophylactically" immediately follOwing surgery. Pseudopregnancy was started on the fifth postoperative day and was continued for 3-6 months depending upon the extent of the endometriosis. However, if the disease involved the colon or bladder, treatment was continued for as long as 12 months. TABLE 3. Results of Postoperative Therapy in 22 Patients (Group 3) It
No. treated
Treatment duration (mo.)
16 3 3
3 4-6 7-12
TOTAL:
22
Satisfactory result
16 3 3 22
Longest remission (mo.)
32 29 36
*No subsequent surgery was necessary in these treatment groups. tOf 15 trying to conceive.
Subsequent pregnancy
5 1 1 7t
242
KISTNER
FERTILITY
& STERILITY
Satisfactory results during hormonal therapy have been accomplished in all patients, but the introduction of two variables-surgery and hormonesrender statements on the effectiveness of one meaningless. However, in 2 patients with extensive involvement of the rectosigmoid, abnormal roentgenograms returned to normal after 4 months of pseudopregnancy. The longest remission has been 36 months, in a patient who had a laparotomy in 1957 and was thought to have bilateral ovarian carcinoma. No definitive operative procedure was done because of the extensiveness of the disease but the ovarian biopsies subsequently showed only endometriosis. Enovid pseudopregnancy was administered from January until October 1957 and the patient has remained asymptomatic since that time and recurrent disease has not been detected by pelvic examination. Seven of 15 patients desirous of pregnancy have conceived subsequent to postoperative hormonal therapy. Five of these were treated for only 3 months. Conception occurred in all patients less than 9 months after cessation of therapy. No untoward effects have been noted in any of the infants born of the women treated. DISCUSSION
Several questions have arisen in regard to the prolonged use of progestational agents. The major items of concern involve the functional potential of the endometrium, the effects of follicular atresia, and the possible interference with hypothalamic-pituitary relationships after 9-12 months of inactivity. A patient on continuous pre-operative Enovid therapy (40--60 mg. daily) for 1 year showed no symptoms or signs of androgenicity or adrenal dysfunction during therapy. Examination of the tissue removed from the rectosigmoid reveals an atypical decidual reaction, with necrosis, vacuolization of the cytoplasm, and nuclear disintegration with pyknOSis (Fig. 1). The reaction resembles that seen in normal and tumor cells following radiation therapy. Spontaneous ovulation occurred 8 weeks after cessation of pseudopregnancy. In another patient who had had 1 year of continuous Enovid therapy, the morphology seen in an endometrial curetting was disturbing in that there has been a partial replacement of normal stroma by cells resembling fibroblasts and the glandular elements were practically absent (Fig. 2). However, the patient had a spontaneous menstrual period 7 weeks follOWing cessation of pseudopregnancy. Her menstrual cycles subsequently have been normal and regular and endometrial biopsies show normal secretory effect. It should be remembered that the endometrium is a unique tissue particularly adapted for cyclic destruction and regeneration. As such, it possesses an unusual growth
VOL.
13, No.3, 1962
INFERTILITY WITH ENDOMETRIOSIS
243
potential, providing that adequate hormonal stimuli are present. As long as the glands of the basalis are present and their vascular support has not been seriously compromised, regrowth and restoration of function is not only possible but probable. This is evidenced by the short interval between pseudo-
Fig. 1. Endometriotic tissue removed from serosa of sigmoid colon after continuous Enovidinduced pseudopregnancy of 1 year. Note the atypical decidual cells with necrosis, cytoplasmic vacuolization, and nuclear disintegration. ( X 400)
pregnancy and conception in the patients previously described. There is no evidence that the endometriurri -has been functionally compromised since there has not been an increased incidence of spontaneous abortion, placenta previa, or placenta accreta. Histochemical studies on tissue obtained by endometrial biopsy, following prolonged therapy show no particular abnormality in regard to glycogen secretion or the amounts of ribonucleoprotein and alkaline phosphatase. The morphologic effects on the ovary following the prolonged cyclic use of Enovid for contraception have been previously noted by Rock et al. Our own observations confirm these findings. Decidual reactions in areas of ovarian endometriosis and arrest of follicular maturation have been constant findings. The prompt ovulatory response following cessation of therapy is, however, indicative of continued end-organ receptivity. The possibility of prolonging menopause to an undesirable age has been suggested as a possible undesirable side effect of prolonged anovulation. It
244
KISTNER
FERTILITY & STERILITY
has been theorized that sparing of primordial follicles and ova by this therapeutic regimen would merely hold them in reserve for later use. However, a similar process occurs in the grand multipara who has a succession of pregnancies and ovulates only 15-20 times during her life time as a result of pitui-
Fig. 2. Endometrial curetting obtained after continuous Enovid-induced pseudopregnancy of 1 year. Note the decidual cells at the top center and replacement of the normal stroma by inHammatory cells and fibroblasts. No glands are evident. A normal, spontaneous menstrual period oCCUI'!'ed 7 weeks after cessation of therapy. (X 200 )
tary suppression by chorionic hormones. Delayed menopause is not a usual finding in such patients. The natural process of aging with associated degenerative changes is probably of more importance than the mere presence of unused ova. Studies of pituitary gonadotrophic activity subsequent to the prolonged administration of progestogens have not been published although the much needed investigation of this problem is now in progress. On the basis of clinical experience, however, resumption of normal gonadotrophic function may be assumed to have occurred in most patients. In a few women, in the older age group on the threshold of menopause, prolonged suppression of pituitary function has resulted in delays of spontaneous ovulation and menstruation for as long as 6 months. In the presence of endometriosis, however, this is a desirable side-effect whereas in the younger, infertile patient, this time waste would be considered undesirable. Whenever such persistent anovulation
VOL. 13, No.3, 1962
245
INFERTILITY WITH ENDOMETRIOSIS
occurs, the physician should secure studies of gonadotrophic function (FSH determinations), X-rays of the sella turcica, a vaginal smear for estrogen effect (fern test or Harris-Shorr test for pyknotic index), endometrial biOpsy, and urinary levels of 17-hydroxycorticoids and 17-ketosteroids. If the only abnormalities are a low FSH and a low estrogen level, cyclic progestin therapy may be administered as a temporary expedient or the. physician may simply await the subsequent reactivation of pituitary ovarian function. SUMMARY
Prolonged use of various steroids (Enovid, Norlutin, Deluteval, DepoProvera) for endometriosis indicates that: (1) they are effective inhibitors of ovulation and produce a decidual reaction in areas of endometriosis; (2) about 85 per cent of the patients are improved during the period of therapy and for varying periods of time thereafter; (:3) no abnormalities of endometrial, ovarian, or pituitary function have been noted during the posttreatment period and subsequent pregnancies have occurred without complications in a high percentage of cases. Dr. Howard Ulfelder,li in a discussion of the various therapeutic schemes presently available, stated "At present it appears that hormone therapy for endometriosis will be the most widely applicable form of management in the future." 82 Cumberland Ave. Brookline 46, Mass.
REFERENCES 1. RUBIN,1. C. Diagnosis of the etiological factors in female sterility. BuU. New York Acad. Med. 18:537, 1942.
.
2. KELLY, J. V., and ROCK, J. Culdoscopy for diagnosis in infertility. Am. J. Obm. & Gynee. 72:523, 1956.
3. KISTNER, R. W. Use of newer progestins in the treabnent of endometriosis. Am. J. Obm. & Gynee. 75:264, 1958.
J., PINCUS, G., and GARCIA, C. R. Use of some progestational 19 nor-steroids in gynecology. Am. J. Obm. & Gynee. 79:758, 1960. 5. ULFELDER, H. Endometriosis. Medical Science 8:503, 1960. 4. ROCK,
is a disabling disease affecting young and middle-aged women and is the result of proliferation, growth, and functioning of endometrial tissues in areas other than the uterus. The sites most commonly involved are the ovaries, the posterior cul-de-sac, and the peritoneal surfaces of the uterosacral ligaments, rectosigmoid, and bladder. Both the cause of the disease and that of associated infertility are not clearly understood but the symptoms, if present, are undoubtedly associated with local irritation and subsequent fibrosis in multiple areas of miniature menstruation in endometriotic foci. The infertility state may be the result of inadequate tuboovarian motility that is secondary to fibrosis and scarring, with imperfect ovum acceptance by the fimbria. Certain peculiar facets of this disease merit discussion. Endometriosis has been noted with increasing frequency during the past 2 decades; several reports have indicated that it is found in 5-15 per cent of pelvic operations. It is not frequent in the Negro and seems to be found most often among women of the higher socia-economic groups. The median age is about 37 years but about 15 per cent of patients are under 30. It has been suggested that a specific body-type and psychiC demeanor are frequently found: mesomorphic but underweight, overanxious, intelligent, egocentric, and perfectionist. These characteristics represent a personality pattern in which marriage and childbearing are likely to be deferred and, therefore, predispose the woman to prolonged periods of uninterrupted ovulation. At the Free Hospital for Women during the interval 1950-1960, endometriosis has been noted by microscope in specimens from about 18 per cent of all laparotomies performed for gynecologic disease. The importance of the disease depends upon its high incidence, the incapacitating symptoms which it produces, and its association with infertility. ENDOMETRIOSIS
From the Department of Obstetrics and Gynecology, Harvard Medical School, Boston, Mass. and the Free Hospital for Women, Brookline, Mass. Presented at the meeting of the Pacific Coast Fertility Society, Las Vegas, Nevada, Nov. 10, 1960.
237
238
KISTNER
FERTILITY
& STERILITY
Although endometriosis is commonly associated with infertility, it is not known whether endometriosis occurs because pregnancy is deferred or whether infertility is the eventual result of extensive endometriosis. Rubin commented on this relationship stating that when the disease is present, the expectation of pregnancy is about half that of the general population. Thus, with a natural incidence of infertility approximating 15 per cent, it is valid to say that in the presence of endometriosis the sterility incidence approximat~s 30-40 per cent. However, when surgery is performed (specifically for endometriosis or during an "infertility laparotomy"), from 30-50 per cent of patients will subsequently conceive. If conservative procedures are carried out and if there is no other cause of sterility, the rate of conception may approach 85-90 per cent. Kelly and Rock have reported endometriosis to be the causative factor of tubo-ovarian adhesions in about one fourth of their patients submitting to culdoscopy. The disease process was found in about one third of all patients who have surgery for infertility at the Free Hospital for Women. THERAPY
The crippling characteristics of this disease, occurring during the reproductive period of the woman's life, prevent the fulfillment of marital potential and too often terminate in castration. An optimum method of treatment will secure pain relief, allow coitus, prevent abnormal bleeding, and preserve, or increase the possibility of, motherhood. Conservative surgery will accomplish this in most patients, but pregnancy has been suggested as the optimum prophylaxis and therapeusis since the symptoms and signs of endometriosis regress during the period of gestation and for varying periods of time thereafter. This is probably the result of a combination of anovulation and amenorrhea brought about by adenophypophyseal suppression. As I suggested in 1956,3 this improvement may be due, in part, to a transformation of functioning endometriotic tissue into decidua by the rising levels of chorionic estrogen and progesterone. Where the patient does not contemplate or desire pregnancy, or if the patient is infertile, I have suggestedS that a combination of estrogen and progestogenic substance could be given continuously and in increasing dosage to induce a so-called pseudopregnancy. Since 1956 over 200 patients with proven endometriosis have been treated with such a regimen. Patients were accepted for therapy only if endometriosis had been diagnosed previously by laparotomy, by biopsy of vaginal lesions, or by culdoscopy. As of Jan. 1, 1961, 110 patients who had adequate follow-up study for a minimum of 6 months following termination of therapy were available for analysis.
VOL,13,No.3,1962
INFERTILITY WITH ENDOMETRIOSIS
239
At present I use the following regimens of therapy: Enovid: o 2.5 mg. daily for 1 week 5.0 mg. daily for 1 week 10 mg. daily for 2 weeks 15 mg. daily for 2 weeks 20 mg. daily indefinitely Norlutinf 5 mg. daily for 2 weeks. Increase by 5 mg. every 2 weeks until maintenance dose of 15-20 mg. is reached. Add estrogen for "breakthrough bleeding." Deluteval 2X t 1 cc (250 mg. Delalutin and 5 mg. estradiol valerate) I.M. weekly. Increase by 0.5 cc. every 6 weeks or whenever ''breakthrough bleeding" occurs. Depo-Provera: § 2 cc. (100 mg.) I.M. every 2 weeks X 4 doses; then 2 CC. every 4 weeks. Add oral estrogen for "breakthrough bleeding."
The majority of the patients reported in this paper received Enovid in much larger dosage. Subsequently it was found that the lower dose schedule is just as effective. RESULTS
Table 1 outlines the results in 53 patients (Group 1) who had primary hormone therapy, that is, no previous surgery for endometriosis. The diagnosis was substantiated in most patients by culdoscopy or posterior colpotomy. The treatment period varied from 3-12 months depending upon the extent of the disease. A satisfactory result during therapy was obtained in 42 of 53 patients, and 18 (of 38 patients trying to conceive) subsequently became pregnant. Remissions lasted as long as 40 months and recurrences were noted in 7 patients. All of the latter have been treated again hormonally. The average time of onset of the first menstrual period after cessation of therapy was 46 days and, in patients who became pregnant, conception frequently occurred at the time of the second or third spontaneous ovulation following pseudopregnancy. As noted in Table 1,16 patients were treated continuously for 7-12 months. The usual dosage regimen was: 10 mg. Enovid daily for 2 weeks with a 10 mg. daily increase every 2 weeks until a maintenance dose of 40 mg. daily was reached. A few patients received 60-70 mg. daily because of persistent breakthrough bleeding. Bleeding did not occur, however, from visible areas of *G. D. Searle & Co., Chicago 80, Ill. tParke, Davis & Company, Detroit 32, Mich. :l:E. R. Squibb & Sons, New York 22, N. Y. §The Upjohn Co., Kalamazoo 99, Mich.
240
FERTILITY
KISTNER
& STERILITY
TABLE 1. Results of Treatment in 53 Patients with No Previous Surgery for Endometriosis (Group 1) No. treated
Treatment duration (mo.)
10
3
Satisfactory result
7
Longest remission (mo.)
Subsequent surgery
40
3 (2 adenomyos~s; 1 p.i.d. & endo-
27
4-6
21
37
16
7-12
14
24
TOTAL:
53
42
metriosis) 5 (3 adenomyosis; 2 p.i.d. & endometriosis) 1 (fibrotic endometriosis,) 9
Subsequent pregnancy
Recurrence*
0
4
11
2
7
1
18t
7
* All re-treated. tOf 38 trying to conceive.
endometriosis, e.g., vagina, even when breakthrough bleeding was noted from the endometrium. Certain symptoms typical of normal pregnancy were noted during the treatment period: nausea (which usually disappeared spontaneously after 3-4 days, breast tenderness, increased appetite, occasional euphoria, insomnia, edema and, in a few patients, a vague "tired feeling" or depreSSion. Physical findings included softening of the vagina and cervix, increased vaginal discharge, temporary uterine enlargement and breast engorgement with increased nipple pigmentation. A slight increase in fine facial hair was noted in a few patients, as was increased pigmentation of the linea alba. However, ths was not more than is seen in normal pregnancy. True hirsutism did not occur even in patients receiving 5~O mg. daily for 9 months. Serial determinations of serum cholesterol were not significantly changed in 9 patients. Similarly, the level of protein-bound iodine did not seem to vary appreciably although minor elevations were frequent. The results of the determinations of 17-keto-steroids and 17-hydroxycorticoids were normal. Microscopic examination of the ovaries in the patients subjected to surgery during or following pseudopregnancy showed no morphologic change except for a decidual reaction in areas of endometriosis with follicular arrest and atresia of varying degrees. Table 2 outlines the results in 35 patients (Group 2) treated because of recurrent endometriosis. Six were treated for only 3 months and one of these subsequently developed another recurrence necessitating hysterectomy and bilateral salpingo-oophorectomy. (The author suggests that every patient with recurrent disease should be treated for at least 10-12 months.) The re-
VOL.
13, No.3, 1962
241
INFERTILITY WITH ENDOMETRIOSIS
TABLE 2. Results of Treatment in 35 Patients with Recurrent Endometriosis (Group 2) No. treated
Treatment duration (mo.)
Satisfactory result
Longest remission (mo.)
6
3
6
24
19
4-6
17
27
7-12
9 32
29
10 TOTAL:
35
Subsequent surgery
Subsequent pregnancy
Second recurrenee
1 ( endometriosis) 3 (adenomyosis: 1; endometriosis: 1; p.i.d.: 1
2
1
5
1
0
2 9°
0
4
2
*Of 28 trying to conceive.
maining 29 patients were treated for 4-12 months with a satisfactory result during therapy for 26. The longest remission was 29 months from the termination of hormonal therapy. Nine of 28 of these patients attempting pregnancy have conceived. Four patients in the total group required subsequent surgery, 2 for recurrent endometriosis, 1 for adenomyosis and 1 for pelvic inflammatory disease. Satisfactory improvement was noted in 32 of 35 patients during the period of therapy. This particular group of patients presents a serious challenge to the gynecologist or surgeon since all have had previous surgery for endometriosis. In several patients, recurrent disease was discovered less than 6 months following laparotomy. Repeat surgery is not looked upon favorably by most of these patients; pseudopregnancy seems to be a particularly valuable therapeutic adjunct in such a group. Table 3 summarizes the results in 22 patients (Group 3) who were treated "prophylactically" immediately follOwing surgery. Pseudopregnancy was started on the fifth postoperative day and was continued for 3-6 months depending upon the extent of the endometriosis. However, if the disease involved the colon or bladder, treatment was continued for as long as 12 months. TABLE 3. Results of Postoperative Therapy in 22 Patients (Group 3) It
No. treated
Treatment duration (mo.)
16 3 3
3 4-6 7-12
TOTAL:
22
Satisfactory result
16 3 3 22
Longest remission (mo.)
32 29 36
*No subsequent surgery was necessary in these treatment groups. tOf 15 trying to conceive.
Subsequent pregnancy
5 1 1 7t
242
KISTNER
FERTILITY
& STERILITY
Satisfactory results during hormonal therapy have been accomplished in all patients, but the introduction of two variables-surgery and hormonesrender statements on the effectiveness of one meaningless. However, in 2 patients with extensive involvement of the rectosigmoid, abnormal roentgenograms returned to normal after 4 months of pseudopregnancy. The longest remission has been 36 months, in a patient who had a laparotomy in 1957 and was thought to have bilateral ovarian carcinoma. No definitive operative procedure was done because of the extensiveness of the disease but the ovarian biopsies subsequently showed only endometriosis. Enovid pseudopregnancy was administered from January until October 1957 and the patient has remained asymptomatic since that time and recurrent disease has not been detected by pelvic examination. Seven of 15 patients desirous of pregnancy have conceived subsequent to postoperative hormonal therapy. Five of these were treated for only 3 months. Conception occurred in all patients less than 9 months after cessation of therapy. No untoward effects have been noted in any of the infants born of the women treated. DISCUSSION
Several questions have arisen in regard to the prolonged use of progestational agents. The major items of concern involve the functional potential of the endometrium, the effects of follicular atresia, and the possible interference with hypothalamic-pituitary relationships after 9-12 months of inactivity. A patient on continuous pre-operative Enovid therapy (40--60 mg. daily) for 1 year showed no symptoms or signs of androgenicity or adrenal dysfunction during therapy. Examination of the tissue removed from the rectosigmoid reveals an atypical decidual reaction, with necrosis, vacuolization of the cytoplasm, and nuclear disintegration with pyknOSis (Fig. 1). The reaction resembles that seen in normal and tumor cells following radiation therapy. Spontaneous ovulation occurred 8 weeks after cessation of pseudopregnancy. In another patient who had had 1 year of continuous Enovid therapy, the morphology seen in an endometrial curetting was disturbing in that there has been a partial replacement of normal stroma by cells resembling fibroblasts and the glandular elements were practically absent (Fig. 2). However, the patient had a spontaneous menstrual period 7 weeks follOWing cessation of pseudopregnancy. Her menstrual cycles subsequently have been normal and regular and endometrial biopsies show normal secretory effect. It should be remembered that the endometrium is a unique tissue particularly adapted for cyclic destruction and regeneration. As such, it possesses an unusual growth
VOL.
13, No.3, 1962
INFERTILITY WITH ENDOMETRIOSIS
243
potential, providing that adequate hormonal stimuli are present. As long as the glands of the basalis are present and their vascular support has not been seriously compromised, regrowth and restoration of function is not only possible but probable. This is evidenced by the short interval between pseudo-
Fig. 1. Endometriotic tissue removed from serosa of sigmoid colon after continuous Enovidinduced pseudopregnancy of 1 year. Note the atypical decidual cells with necrosis, cytoplasmic vacuolization, and nuclear disintegration. ( X 400)
pregnancy and conception in the patients previously described. There is no evidence that the endometriurri -has been functionally compromised since there has not been an increased incidence of spontaneous abortion, placenta previa, or placenta accreta. Histochemical studies on tissue obtained by endometrial biopsy, following prolonged therapy show no particular abnormality in regard to glycogen secretion or the amounts of ribonucleoprotein and alkaline phosphatase. The morphologic effects on the ovary following the prolonged cyclic use of Enovid for contraception have been previously noted by Rock et al. Our own observations confirm these findings. Decidual reactions in areas of ovarian endometriosis and arrest of follicular maturation have been constant findings. The prompt ovulatory response following cessation of therapy is, however, indicative of continued end-organ receptivity. The possibility of prolonging menopause to an undesirable age has been suggested as a possible undesirable side effect of prolonged anovulation. It
244
KISTNER
FERTILITY & STERILITY
has been theorized that sparing of primordial follicles and ova by this therapeutic regimen would merely hold them in reserve for later use. However, a similar process occurs in the grand multipara who has a succession of pregnancies and ovulates only 15-20 times during her life time as a result of pitui-
Fig. 2. Endometrial curetting obtained after continuous Enovid-induced pseudopregnancy of 1 year. Note the decidual cells at the top center and replacement of the normal stroma by inHammatory cells and fibroblasts. No glands are evident. A normal, spontaneous menstrual period oCCUI'!'ed 7 weeks after cessation of therapy. (X 200 )
tary suppression by chorionic hormones. Delayed menopause is not a usual finding in such patients. The natural process of aging with associated degenerative changes is probably of more importance than the mere presence of unused ova. Studies of pituitary gonadotrophic activity subsequent to the prolonged administration of progestogens have not been published although the much needed investigation of this problem is now in progress. On the basis of clinical experience, however, resumption of normal gonadotrophic function may be assumed to have occurred in most patients. In a few women, in the older age group on the threshold of menopause, prolonged suppression of pituitary function has resulted in delays of spontaneous ovulation and menstruation for as long as 6 months. In the presence of endometriosis, however, this is a desirable side-effect whereas in the younger, infertile patient, this time waste would be considered undesirable. Whenever such persistent anovulation
VOL. 13, No.3, 1962
245
INFERTILITY WITH ENDOMETRIOSIS
occurs, the physician should secure studies of gonadotrophic function (FSH determinations), X-rays of the sella turcica, a vaginal smear for estrogen effect (fern test or Harris-Shorr test for pyknotic index), endometrial biOpsy, and urinary levels of 17-hydroxycorticoids and 17-ketosteroids. If the only abnormalities are a low FSH and a low estrogen level, cyclic progestin therapy may be administered as a temporary expedient or the. physician may simply await the subsequent reactivation of pituitary ovarian function. SUMMARY
Prolonged use of various steroids (Enovid, Norlutin, Deluteval, DepoProvera) for endometriosis indicates that: (1) they are effective inhibitors of ovulation and produce a decidual reaction in areas of endometriosis; (2) about 85 per cent of the patients are improved during the period of therapy and for varying periods of time thereafter; (:3) no abnormalities of endometrial, ovarian, or pituitary function have been noted during the posttreatment period and subsequent pregnancies have occurred without complications in a high percentage of cases. Dr. Howard Ulfelder,li in a discussion of the various therapeutic schemes presently available, stated "At present it appears that hormone therapy for endometriosis will be the most widely applicable form of management in the future." 82 Cumberland Ave. Brookline 46, Mass.
REFERENCES 1. RUBIN,1. C. Diagnosis of the etiological factors in female sterility. BuU. New York Acad. Med. 18:537, 1942.
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2. KELLY, J. V., and ROCK, J. Culdoscopy for diagnosis in infertility. Am. J. Obm. & Gynee. 72:523, 1956.
3. KISTNER, R. W. Use of newer progestins in the treabnent of endometriosis. Am. J. Obm. & Gynee. 75:264, 1958.
J., PINCUS, G., and GARCIA, C. R. Use of some progestational 19 nor-steroids in gynecology. Am. J. Obm. & Gynee. 79:758, 1960. 5. ULFELDER, H. Endometriosis. Medical Science 8:503, 1960. 4. ROCK,