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Endometriosis and anovulation: A coexisting problem in the infertile female
Endometriosis and anovulation: A coexisting problem in the infertile female MICHAEL L.
R.
RUSSELL
ROBERT ALLEN Houston,
SOULES, MALINAK.
BURY.
M.D. M.D..
F.A.(:.O.G
D.V,M
POINDEXTER.
M.D.
Texu,\
Over un 8 year period. 350 casts oj endonwtriosis (77 per rent conjirmed histologically) Jrom the Department of Obstetrics aad Gynecology, Baylor College of kiedicine, were reviewed. Of these case.r, 58 (17 per wn$ exhibited signijicant anovulation as meawred &v a scoring system. Endometriosis and anovulation can coexist contra?) to classic concepts of these diseases. Both infertility factors required treatment to achieve pregnancy. A 43 per cent pregnancy rate reflerts the duul infertility problem.
AXIOMS in medicine are like sacred institutions-they persevere and go unchallenged. Persistent statements that endometriosis is solely a condition arising in regularly ovulatory women is such an axiom. This enigmatic disease is an unstable area, at best, in which to be so dogmatic. Nevertheless, the belief that regular cyclic ovarian function is mandatory for the development of pelvic endometriosis has persisted. Review of the literature discloses such statements as the following: “Endometriosis is linked to ovarian function and the production of its hormones”.’ Other writers have commented on the association between endometriosis and ovulation. The following statement appears in a current textbook of gynecology: “It (endometriosis) is rarely seen in women with anovulatory cycles, but it is common in those who have uninterrupted cyclic menstruation for periods exceeding five years.“* Ranney3 stated that “endometriosis tends to proliferate actively in the presence of cyclic ovarian function.” In discussing the etiology of endometriosis, Meigs” stated that the disease did not occur without years of uninterrupted cyclic menstruation. It is the purpose of this report to document the
coexistence of ovulatory problems and endometriosis in a significant number of patients and to emphasize the importance of recognizing this potential association in evaluation and treatment of the infertile female.
CERTAIN
From the Department College of Medicine.
of Obstetrics
and Gynecology,
Materials and methods Records from 350 cases of pelvic endometriosis from the Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston. Texas, from 1966 to 1974, were reviewed. The diagnosis of endometriosis was established in 270 cases (77 per cent) at laparotomy, by histologic examination of excised tissue, and by pelvic endoscopy in the remainder. The patient records were again reviewed in careful detail for ovulation history. In an attempt to objectif! the ovulatory status of each patient, a scoring system was created (Table I). A minimum anovulatory score of 3 was required for inclusion. This report concerns itself with those patients with endotnetriosis who were found to be anovulatory based on laboratory, operative, and historical data. A patient was considered symptomatic if she complained of moderate to severe dysmenorrhea or experienced any two of the following symptoms: deep dyspareunia, sacral backache, generalized pelvic pain, or significant gastrointestinal symptoms associated with menstrual periods. A pelvic examination raised a suspicion of endometriosis if uterosacral nodularity. excessive uterosacral tenderness, or immobile retroverted uterus was present.
Baylor
Presented at the Forty-third Annual Meetzng oj the Central Association of Obstetricians and Gynecologirts. Colorado Springs, Colorado, September 26-28, 1975. Reprint requests: Dr. L. Russell Malinak, Department Obstetrics and Gynecology, Baylor College of Medicine, 1200 Moursund Ave., Houston, Texas 77025.
qf
412
Endometriosis and anovulation
Volume Number
125
Table
I. Ovulatory
3
scoring
system*
Menstrual periods Endo-biopsy BBT’s Progestogen withdrawal Ovarian morphology Ovulatory agents *Minimum Table
score of 3 required
II. Menstrual Inteval
interval
0
I
Regular Secretory Biphasic None Normal Empirical
Irregular or > 33 days Proliferative Mixed Occasional
for diagnosis of anovulation-
(days)
Patients
1 30 5 22
III. Endometriosis
classification I Patients
I Pregnancy rate (5%)
Mild Moderate Severe Totals
23 34 1 58
39 59 2 loo
17 29 1 47
2 Amenorrhea Monophasic Regularly required Polycystic or poorly stimulated Required
patients (17 per cent) fulfilled the criteria.
Results
distribution
23-33 34-45 46-60 > 60
Table
413
8 12 0 FJ
47 41 0 43
Thirty-four patients recorded basal body temperature charts, 42 had hysterosalpingograms, and semen analysis was performed in 40 husbands prior to the diagnosis of endometriosis.* In each case, cervical dilatation with endometrial biopsy or curettage was performed at the time of pelvic endoscopy or laparotomy. The conservative operation for endometriosis entailed resection of endometrial implants, presacral neurectomy, plication of uterosacral ligaments, and uterine suspensiom6 The extent and location of lesions were classified according to the scheme of Acosta and associates5 Ovarian morphology was designated as: (1) normalsized convoluted ovaries; (2) poorly stimulated ovaries (less than normal size, smooth without surface convolutions, and no evidence of recent ovulation); (3) polycystic ovaries (bilaterally enlarged ovaries with a smooth, thickened capsule and multiple subcapsular follicles). A patient was considered lost to follow-up if her record ended less than 6 months postoperative, unless she became pregnant in this time period. *Minimal criteria for normal semen analysis-20 million sperm per milliliter, 40 per cent motility, 60 per cent normal forms, and 2 to 6 c.c.~
Fifty-eight (17 per cent) patients fulfilled the anovulatory criteria based on the above scoring system. The average “anovulation score” was 4.3. Characteristics of the anovulatory patients were: (1) the median age was 26 years, with a range of 17 to 31 years; (2) 42 patients had primary infertility and 16 had secondary infertility; (3) 32 patients had infertility evaluation, including 24 who had clomiphene ovulation therapy, prior to referral and diagnosis of endometriosis; (4) 48 patients had received prior oral contraceptive treatment, in many to treat dysmenorrhea or to “regulate” menses; (5) 33 patients had symptoms consistent with endometriosis, however, 25 patients were asymptomatic except for infertility; (6) pelvic examination was suspicious for endometriosis in 36 cases (62 per cent). The intermenstrual interval was abnormal and this was listed among the primary complaints on presentation in each anovulatory patient save one (Table II). In the 34 patients with BBT records, 44 per cent were monophasic and 56 per cent were mixed. No patient had consistent biphasic charts. Endometrial histology was proliferative in 48 cases (83 per cent) and secretory in the remainder. The extent of endometriosis is detailed in Table III; a majority of patients were in the moderate to severe groups. Ovarian morphology among the anovulatory patients is presented in Table IV-a large minority had poorly stimulated or polycystic ovaries. Operative management consisted of endoscopy alone in 13 patients, a group largely composed of mild endometriosis cases. Forty-five had the conservative operation for endometriosis; this group accounted for a majority of the moderate and severe cases. Of 47 patients with adequate follow-up, 20 became pregnant (43 per cent); all but three within the first year. The average time to conception was 8 months, with a range of 3 to 2 1 months. Of 38 patients who had conservative endometriosis surgery, 14 (37 per cent) became pregnant; 71 per cent had moderate or severe endometriosis. Two thirds of the group with endoscopy only conceived; 66 per cent of these patients had mild endometriosis. The pregnancy rates are outlined
414
Soules et al. Am. J.
Table
IV.
Ovarian
morphology
Pregnancy rate (%)
0 Normal Poorly stimulated Polycystic Totals
Table
V.
adequate
Pregnancy follow-up Assistance
Clomiphene Pergonal AIH AID Hydrotubation
35
28
9
14 9 58
IO 2 47
6 5
32 60 56 43
20
assistance in cases with
I
Patim& 32
1 8 I 1
for severity of endometriosis and ovarian morphology in Tables III and IV. It is of interest that 80 per cent of the successful (pregnant) patients received ovulatory assistance. A majority required postoperative fertility assistance as outlined in Table V. Eleven patients were lost to adequate follow-up. There was no correlation between symptoms of endometriosis and objective severity of the disease. Fifty-seven per cent of those with mild endometriosis had significant symptoms compared to 50 per cent with moderate to severe disease. It was observed that anovulatory patients who had received clomiphene prior to endometriosis diagnosis were found to have a higher incidence of moderate to severe endometriosis. Twenty-four patients received clomiphene preoperatively, 18 (75 per cent) of whom had moderate to severe disease. Of the 34 patients not receiving clomiphene only 50 per cent had extensive endometriosis. Clomiphene therapy had no effect on the presence of preoperative endometriosis symptoms.
Comment The presence of anovulation as determined by objective criteria in 17 per cent of cases with endometriosis is a significant association, particularly when enhancement of fertility is a consideration. Rare reports in the literature have alluded to this association.‘-” Of note. Rannev reported 350 cases of endometriosis, 17 of which were postmenopausal with active disease. Only two of these 17 had received exogenous estrogens, yet all were symptomatic enough to warrant hysterectomy.s The paper by Schifrin and
June 1, 1976 Obstet. Gynecol.
associates8 on teenage endometriosis described a group not expected to have regular ovulation. The 37 per cent pregnancy rate in these patients undergoing conservative infertility surgery for endometriosis reflects the associated ovulatory problem. Pregnancy rates of 60, 46, and 52 per cent33 ‘* lo with conservative surgery have been reported in three recent series. Presumably, in these series the majority of patients were regular ovulatory. This report concentrates exclusively on that particular minority M.ith proved dual infertility factors; a lower pregnancy rate would be expected. In fact, the pregnancy rate in this series is probably falsely elevated secondary to the number of mild endometriosis cases (39 per cent) and the degree of postoperative fertility assistance (77 per cent-ovulation induction in most cases) when compared to series with the majority of patients having conservative surgery for endometriosis alone. ‘The reports in the literature do not contain the degree of concentration of mild cases and fertility assistance found here. When a second infertility factor is present, a significantly lower pregnancy rate would be expected. Patients with surgically treated endometriosis in the presence of polycystic ovary syndrome and poorly stimulated ovaries had a singular degree of success in achieving pregnancy following ovulation induction. This cannot be related to the extent of endometriosis nor the degree of ovulatory assistance since 33 per cent had mild disease (39 per cent in the entire group) and 74 per cent were assisted (77 per cent in the entire group). It is postulated that these ovulatory problems are more straightforward to account for the pregnant) rate. When one is left with an ovulation problem and endometriosis with morphologically normal ovaries the therapeutic direction is less clear. Approximately half of the patients did not have significant symptoms of endometriosis; in contrast, the literature reports at least 65 per cent of patients symptomatic.” This observation supports the concept that the pain of endometriosis is secondary to cyclic ectopic menstrual function in a confined space. The endometriosis implants of these patients were not undergoing regular cyclic changes. Consistent with this idea, the pelvic examination was not as useful in leading to the diagnosis of endometriosis as in other reported series. It was suspected in 62 per cent of patients in this study: 80 per cent is commonly reported. 7 lo These findings are consistent with the substantial number of mild endometriosis cases in this series. In agreement with previous reports the symptoms of endometriosis did not correlate with the extent of the disease.
Volume Number
125 3
It is interesting to speculate whether clomiphene, by stimulation of the “ovarian-endometrial axis” exacerbates endometriosis. This study would suggest that contention since more moderate to severe endometriosis was associated with preoperative clomiphene therapy. The majority of these patients presented with irregular bleeding and infertility exceeding 2 years. Many had received a wide range of evaluations and treatments, including ovulation induction. Endometriosis had been suspected prior to referral in only one case, though the ovulatory problem was commonly recognized and treated. When endometriosis-oligoovulation coexist the pelvic examination is not as diagnostic:ally productive and symptoms are unreliable in endometriosis anyway. Obviously, these patients initially appeared to have an ovulation problem as the etiology of their infertility. Ovulatory difficulties surface early in an infertility evaluation, but their presence should not prevent a thorough work-up, including endoscop.r. Endometriosis does exist in classic anovulatory patients.
REFERENCES
Parsons, L.: Obstet. Gynecol. 32: 576, 1968. 2. Kistner, R. W.: Gynecology, Ed. 2, 1971, p. 435.
1.
3. Ranney, B.:AM. J. OBSTET. GYNECOL. 107: 743, 1971. 4. Meigs, J. V.: Obstet. Gynecol. 2: 46, 1953. 5. MacLeod, J.: Obstet. Gynecol. Surv. 26: 335, 1971. 6. Rogers, S., and Jacobs, W.: Fertil. Steril. 19: 529, 1968.
Discussion W. P. DEVERELJX, Dallas, Texas. The authors have effectively demonstrated the existence of endometrios’:: with anovulation and with grossly irregular menses. I would like to qualify this by adding “during the time patients were under their observation.” These data do not necessarily conflict with the alleged axiomatic statements that there is a marked association of endometriosis with ovulation; that it is rarely seen in women with anovulatory cycles, but common in those with uninterrupted cyclic menstruation. My own acceptance of this concept has been supported by many years’ observation of patients with endometriosis. In 1963 we reported an analysis of 105 patients with endometriosis then currently still being observed for from 5 to 20 years.’ Our data did not reveal any case in which ovulation was a problem. The report stated “catamenia was not remarkable, there being little variation from the 12/28/5 general pattern. Only two had menarche as late as 15.” Of the 105 patients 81 had a total of 163 pregnancies, conclusive evidence of ovulation. I suppose anovulation could have been a factor in a few of the 12 involuntarily infertile. DR.
Endometriosis and anovulation
415
It is logical to assume that the preponderance of mild endometriosis in this series is a reflection of inhibited progression of disease without regular ovulation. Yet even mild endometriosis retains the ability to cause infertility and requires diagnosis and treatment. Once endoscopic diagnosis of endometriosis is established the timing of operative intervention depends on the extent of disease. Moderate to severe endometriosis requires prompt operative therapy; reasonable delay is warranted in mild disease. The final pregnancy rate in this report reflects that both infertility factors need to be treated. Twenty-four of these patients had their ovulation problem treated, without conceiving, prior to endometriosis surgery, that later responded to the same drug. One should consider conservative operation even for mild endometriosis associated with oligo-ovulation after a reasonable trial of medical therapy. The associated ovulation problem should not delay operative intervention.
7. Acosta, A., Buttram, V., Besch, P., Malinak, R., Franklin, R., and Vanderheyden, J.: Obstet. Gynecol. 42: 19, 1973. 8. Schifrin, B. S., Selcuk, E., and Moore, J. G.: AM. J. OBSTET. GYNECOL. 116: 973, 1973. 9. Ranney, B.: AM. J. OBSTET. GYNECOL. 109: 1137, 1971. 10. Spangler, D. B., Jones, G. J., and Jones, H. W.: AM. J. OBSTET. GYNECOL. 109: 850, 1971. Why, then, does the authors’ material contain relatively so many with anovulation? I suggest these explanations: 1. The department from which this material comes is deservedly well known in Houston and the Southwest for its interest and expertise in the field of infertility. Could not its patient population have been heavily loaded with this type of problem! 2. This department has been diligently searching for this endometriosis-anovulation association for several years. 3. The material includes many patients who have or may have ovulated in the past, though perhaps not regularly: (a) Sixteen had secondary infertility, obviously having been ovulatory at one time. (b) Forty-eight had received prior oral contraceptives; maybe some had previously been ovulatory in varying degree, becoming anovulatory only after discontinuing the pill. Some reported as having received the pill for dysmenorrhea might have had ovulatory dysmenorrhea rather than the pain of endometriosis. (c) Fourteen had poorly stimulated ovaries, documented only during the time of observation. (d) There were only nine with polycys-
416
Soules
et al
,June I, 1976 Gynecol.
Am. J. Obstet.
tic ovaries, the most likely candidates fi)r total and chronic anovulation. Speculating further, might not some of these at some time had lutenization without actual ovulation, sort of a “near-miss” ovulation? Whether or not ovulation at some time is essential for development of endometriosis is still, I think. an unsettled issue, and can lead only to academic discussion unless it affords a clue to etiology. We might suggest to Dr. J. Merrill that for his next Millipore filter chanber endometrial implants he utilize ycmng, sheltered. virginal, anovulatory rabbits, if such exist, and see if the metaplasia he describes is induced Identification of the coexistence of endometriosis and anovulation, as stressed by the authors. is a situation which in clinical practice should not be overlooked in the infertile patient. However. 1 still believe, with few exceptions, that endometriosis will be found in women who ovulate and menstruate in more or less cyclic manner. REFERENCE
1. I>evereux, &‘. P.: Endometriosis; long-term observation. with particular reference to incidence of pregnant). O&et. Gvnecol. 22: 444, 1963. DR. HERMAN I. KANTOR, Dallas, Texas. In this interesting report, Dr. Soules and his co-authors record the occasional coexistence of endometriosis and oligo-ovulation. When infertility is a dominant problem, both must be treated. I would like to discuss these two areas of their report. To determine that ovulation is absent or unsatisfactory, the authors chose a scoring system using the six factors which they presented. In carrying out infertility studies, clinicians recognize that the endometrial biopsy, taken at or near menstruation, is a very reliable indicator of both ovulation and the adequacy of progesterone secretion. When analysis of hormone levels is not readily available, the biphasic basal temperature graph is a good indication that ovulation has occurred. However, a monophasic or mixed graph may infrequently be seen even though a mature secretory phase is reported from the endometrial biopsy. Of the 58 anovulatory patients in the authors’ report, 10 had a secretory endometrium. This paradox may require explanation. Was a correlated basal temperature graph taken? Was it biphasic? Even among women who ovulate regularly, an occasional anovulatory cycle, with bleeding from cstrogen withdrawal alone.’ may occur. The msured diagnosis of anovulation, or of a progestational phase defect, can be made after multiple, properly timed, endometrial biopsies. The authors’ use of “ovulation assistance” ma!’ have increased the number of pregnancies achieved after conservative surgery. Were any of these patients previously treated with the amenorrhea regimen
fi)llowed by sitnilar “ovulation assistance’? In 0uI practice, a number of women with endometriosis and ovulation deficiencies became pregnant after treatment with Clomid. This mav be specially true if their ovaries appear normal \\,hcn seen through the laparoscope. To understand the association of endometriosis and oligo-ovulatiorl, thr study of their etiologies may be significant. Several years ago I introduced the concept that the symptoms caused by endometriosis ma)- be related to the etiology. With tissue metaplasia of congenital rests. infertility is ,ro! a problem, and symptoms are usually related only to the involved areas. On the other, when retrograde endometrial implants cause the endometriosis, the full gamut of typical symptoms including infertility may he present. This concept may explain why some patients, even with wide-spread endometriosis. may have few symptoms, and m problem conceiving. The unexpected, asymptomatic endometriosis. occasionally a surprise finding during laparotomy, ma\ also he due to tissue metaplasia. Since the patients included in this report all had infertility. in accord with this concept their endometriosis was caused by retrograde implantation. Perhaps the Fallopian tuhr \vhich permits sucl~ retrograde menstruation nla! cause infertilit) by interfering with sperm ;II~ ovum transport. Can this be the cause of infertility in endometriosis? However. when endometriosis and ovulation deficiencies occur together, they do n/jt have a common etiology. Therefore. if pregnancy is desired treatment sho;lld logically be aimed at both conditions. I should like to ask if’, in rctrospcc’t, the authors still tee1 that Clomitl IWIT cause progression 01 the lesions of endomctriosis? There are onI!, two situations in which the endometrial biopsy as a measure of ovulation md progestational adequacv may be misleading. Fortunately both are rare: ( I) a refractorv endometrium, one M:hich does 11ot respond to adequate hormonal stimulation: (2) abnormal progesterone secretion from sources other than the postovulatory corpus lateum. DR. AKOOKS KASNEI’. Yankton, South Dakota. III 19.X. Dr. Leon S. hlcGoogan reported 011 SOIIIC’ instanctrs of ovarian infertility. Hc included groups ol‘ patients \vho had multicystic ovaries and endometriosis of the ovaric\. FHc cmphasi7cd the important? 01‘ considering (t/l taclors Jvhilc evaluating results of treatmenl for inl’crtilitv. Since the ess+t alluded IO 1’7 patients that 1 had rcportcd to have, had endometriosis present postv/~N~N~NIII~ at the time of operation, I should remind \ou that sc‘vt’n of those were considered to be incidental endometriosis. But 10 patients had signifitanl, s\mptoniati(endometriosis. six of whom had large et&metrial cysts and four of whom had dense pelvic, adhesions with active endometriosis involved.
Volume 125 Number3
Two of these women had been receiving exogenous estrogens and the other eight women had had recrudescence of their estrogen production from 6 months to 12 years after the menopause. DR. SOULES (Closing). Several of the patients had been on birth-control pills. As a matter of fact, 48 of them had at one time or another been on birth-control pills in their past history. In reviewing their charts and seeing these patients, the birth-control pills were usually administered more for treating the irregularity of their periods than for treating symptomatic pelvic pain which later might have become endometriosis. Dr. Devereux brought up the point that a significant minority of the patients on endometrial biopsy had had secretory endometrium, which perhaps would make the whole contention suspect. Maybe we should have written the title as “Anovulation and oligo-ovulation associated with endometriosis.” In reviewing the charts, the average anovulation score was 4.3, but some scores were 7 or 8. and were clearly anovulatory; others were
Endometriosis and anovulation
417
clearly more oligo-ovulatory by their basal body temperature record, and those were the few that showed up with secretory endometrium. Dr. Devereux mentioned treating the patients preoperatively for ovulation problems prior to diagnosis and treatment for the endometriosis. Many of these patients were treated for ovulation problems. Twenty-four had had Clomid therapy prior to referral to the group at Baylor. So, in this group of patients, rhey had been inadequately treated in that their dual infertility problem was not recognized. We speculated that Clomid might exacerbate endometriosis in that using the classification system that I mentioned earlier. Of the ones that had had Clomid, 75 per cent had moderate to severe endometriosis, whereas in the group of patients that had not been on Clomid, only 50 per cent had moderate to severe endometriosis. But we certainly have no proof of Clomid increasing endometriosis; it is purely speculation.
R.
RUSSELL
ROBERT ALLEN Houston,
SOULES, MALINAK.
BURY.
M.D. M.D..
F.A.(:.O.G
D.V,M
POINDEXTER.
M.D.
Texu,\
Over un 8 year period. 350 casts oj endonwtriosis (77 per rent conjirmed histologically) Jrom the Department of Obstetrics aad Gynecology, Baylor College of kiedicine, were reviewed. Of these case.r, 58 (17 per wn$ exhibited signijicant anovulation as meawred &v a scoring system. Endometriosis and anovulation can coexist contra?) to classic concepts of these diseases. Both infertility factors required treatment to achieve pregnancy. A 43 per cent pregnancy rate reflerts the duul infertility problem.
AXIOMS in medicine are like sacred institutions-they persevere and go unchallenged. Persistent statements that endometriosis is solely a condition arising in regularly ovulatory women is such an axiom. This enigmatic disease is an unstable area, at best, in which to be so dogmatic. Nevertheless, the belief that regular cyclic ovarian function is mandatory for the development of pelvic endometriosis has persisted. Review of the literature discloses such statements as the following: “Endometriosis is linked to ovarian function and the production of its hormones”.’ Other writers have commented on the association between endometriosis and ovulation. The following statement appears in a current textbook of gynecology: “It (endometriosis) is rarely seen in women with anovulatory cycles, but it is common in those who have uninterrupted cyclic menstruation for periods exceeding five years.“* Ranney3 stated that “endometriosis tends to proliferate actively in the presence of cyclic ovarian function.” In discussing the etiology of endometriosis, Meigs” stated that the disease did not occur without years of uninterrupted cyclic menstruation. It is the purpose of this report to document the
coexistence of ovulatory problems and endometriosis in a significant number of patients and to emphasize the importance of recognizing this potential association in evaluation and treatment of the infertile female.
CERTAIN
From the Department College of Medicine.
of Obstetrics
and Gynecology,
Materials and methods Records from 350 cases of pelvic endometriosis from the Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston. Texas, from 1966 to 1974, were reviewed. The diagnosis of endometriosis was established in 270 cases (77 per cent) at laparotomy, by histologic examination of excised tissue, and by pelvic endoscopy in the remainder. The patient records were again reviewed in careful detail for ovulation history. In an attempt to objectif! the ovulatory status of each patient, a scoring system was created (Table I). A minimum anovulatory score of 3 was required for inclusion. This report concerns itself with those patients with endotnetriosis who were found to be anovulatory based on laboratory, operative, and historical data. A patient was considered symptomatic if she complained of moderate to severe dysmenorrhea or experienced any two of the following symptoms: deep dyspareunia, sacral backache, generalized pelvic pain, or significant gastrointestinal symptoms associated with menstrual periods. A pelvic examination raised a suspicion of endometriosis if uterosacral nodularity. excessive uterosacral tenderness, or immobile retroverted uterus was present.
Baylor
Presented at the Forty-third Annual Meetzng oj the Central Association of Obstetricians and Gynecologirts. Colorado Springs, Colorado, September 26-28, 1975. Reprint requests: Dr. L. Russell Malinak, Department Obstetrics and Gynecology, Baylor College of Medicine, 1200 Moursund Ave., Houston, Texas 77025.
qf
412
Endometriosis and anovulation
Volume Number
125
Table
I. Ovulatory
3
scoring
system*
Menstrual periods Endo-biopsy BBT’s Progestogen withdrawal Ovarian morphology Ovulatory agents *Minimum Table
score of 3 required
II. Menstrual Inteval
interval
0
I
Regular Secretory Biphasic None Normal Empirical
Irregular or > 33 days Proliferative Mixed Occasional
for diagnosis of anovulation-
(days)
Patients
1 30 5 22
III. Endometriosis
classification I Patients
I Pregnancy rate (5%)
Mild Moderate Severe Totals
23 34 1 58
39 59 2 loo
17 29 1 47
2 Amenorrhea Monophasic Regularly required Polycystic or poorly stimulated Required
patients (17 per cent) fulfilled the criteria.
Results
distribution
23-33 34-45 46-60 > 60
Table
413
8 12 0 FJ
47 41 0 43
Thirty-four patients recorded basal body temperature charts, 42 had hysterosalpingograms, and semen analysis was performed in 40 husbands prior to the diagnosis of endometriosis.* In each case, cervical dilatation with endometrial biopsy or curettage was performed at the time of pelvic endoscopy or laparotomy. The conservative operation for endometriosis entailed resection of endometrial implants, presacral neurectomy, plication of uterosacral ligaments, and uterine suspensiom6 The extent and location of lesions were classified according to the scheme of Acosta and associates5 Ovarian morphology was designated as: (1) normalsized convoluted ovaries; (2) poorly stimulated ovaries (less than normal size, smooth without surface convolutions, and no evidence of recent ovulation); (3) polycystic ovaries (bilaterally enlarged ovaries with a smooth, thickened capsule and multiple subcapsular follicles). A patient was considered lost to follow-up if her record ended less than 6 months postoperative, unless she became pregnant in this time period. *Minimal criteria for normal semen analysis-20 million sperm per milliliter, 40 per cent motility, 60 per cent normal forms, and 2 to 6 c.c.~
Fifty-eight (17 per cent) patients fulfilled the anovulatory criteria based on the above scoring system. The average “anovulation score” was 4.3. Characteristics of the anovulatory patients were: (1) the median age was 26 years, with a range of 17 to 31 years; (2) 42 patients had primary infertility and 16 had secondary infertility; (3) 32 patients had infertility evaluation, including 24 who had clomiphene ovulation therapy, prior to referral and diagnosis of endometriosis; (4) 48 patients had received prior oral contraceptive treatment, in many to treat dysmenorrhea or to “regulate” menses; (5) 33 patients had symptoms consistent with endometriosis, however, 25 patients were asymptomatic except for infertility; (6) pelvic examination was suspicious for endometriosis in 36 cases (62 per cent). The intermenstrual interval was abnormal and this was listed among the primary complaints on presentation in each anovulatory patient save one (Table II). In the 34 patients with BBT records, 44 per cent were monophasic and 56 per cent were mixed. No patient had consistent biphasic charts. Endometrial histology was proliferative in 48 cases (83 per cent) and secretory in the remainder. The extent of endometriosis is detailed in Table III; a majority of patients were in the moderate to severe groups. Ovarian morphology among the anovulatory patients is presented in Table IV-a large minority had poorly stimulated or polycystic ovaries. Operative management consisted of endoscopy alone in 13 patients, a group largely composed of mild endometriosis cases. Forty-five had the conservative operation for endometriosis; this group accounted for a majority of the moderate and severe cases. Of 47 patients with adequate follow-up, 20 became pregnant (43 per cent); all but three within the first year. The average time to conception was 8 months, with a range of 3 to 2 1 months. Of 38 patients who had conservative endometriosis surgery, 14 (37 per cent) became pregnant; 71 per cent had moderate or severe endometriosis. Two thirds of the group with endoscopy only conceived; 66 per cent of these patients had mild endometriosis. The pregnancy rates are outlined
414
Soules et al. Am. J.
Table
IV.
Ovarian
morphology
Pregnancy rate (%)
0 Normal Poorly stimulated Polycystic Totals
Table
V.
adequate
Pregnancy follow-up Assistance
Clomiphene Pergonal AIH AID Hydrotubation
35
28
9
14 9 58
IO 2 47
6 5
32 60 56 43
20
assistance in cases with
I
Patim& 32
1 8 I 1
for severity of endometriosis and ovarian morphology in Tables III and IV. It is of interest that 80 per cent of the successful (pregnant) patients received ovulatory assistance. A majority required postoperative fertility assistance as outlined in Table V. Eleven patients were lost to adequate follow-up. There was no correlation between symptoms of endometriosis and objective severity of the disease. Fifty-seven per cent of those with mild endometriosis had significant symptoms compared to 50 per cent with moderate to severe disease. It was observed that anovulatory patients who had received clomiphene prior to endometriosis diagnosis were found to have a higher incidence of moderate to severe endometriosis. Twenty-four patients received clomiphene preoperatively, 18 (75 per cent) of whom had moderate to severe disease. Of the 34 patients not receiving clomiphene only 50 per cent had extensive endometriosis. Clomiphene therapy had no effect on the presence of preoperative endometriosis symptoms.
Comment The presence of anovulation as determined by objective criteria in 17 per cent of cases with endometriosis is a significant association, particularly when enhancement of fertility is a consideration. Rare reports in the literature have alluded to this association.‘-” Of note. Rannev reported 350 cases of endometriosis, 17 of which were postmenopausal with active disease. Only two of these 17 had received exogenous estrogens, yet all were symptomatic enough to warrant hysterectomy.s The paper by Schifrin and
June 1, 1976 Obstet. Gynecol.
associates8 on teenage endometriosis described a group not expected to have regular ovulation. The 37 per cent pregnancy rate in these patients undergoing conservative infertility surgery for endometriosis reflects the associated ovulatory problem. Pregnancy rates of 60, 46, and 52 per cent33 ‘* lo with conservative surgery have been reported in three recent series. Presumably, in these series the majority of patients were regular ovulatory. This report concentrates exclusively on that particular minority M.ith proved dual infertility factors; a lower pregnancy rate would be expected. In fact, the pregnancy rate in this series is probably falsely elevated secondary to the number of mild endometriosis cases (39 per cent) and the degree of postoperative fertility assistance (77 per cent-ovulation induction in most cases) when compared to series with the majority of patients having conservative surgery for endometriosis alone. ‘The reports in the literature do not contain the degree of concentration of mild cases and fertility assistance found here. When a second infertility factor is present, a significantly lower pregnancy rate would be expected. Patients with surgically treated endometriosis in the presence of polycystic ovary syndrome and poorly stimulated ovaries had a singular degree of success in achieving pregnancy following ovulation induction. This cannot be related to the extent of endometriosis nor the degree of ovulatory assistance since 33 per cent had mild disease (39 per cent in the entire group) and 74 per cent were assisted (77 per cent in the entire group). It is postulated that these ovulatory problems are more straightforward to account for the pregnant) rate. When one is left with an ovulation problem and endometriosis with morphologically normal ovaries the therapeutic direction is less clear. Approximately half of the patients did not have significant symptoms of endometriosis; in contrast, the literature reports at least 65 per cent of patients symptomatic.” This observation supports the concept that the pain of endometriosis is secondary to cyclic ectopic menstrual function in a confined space. The endometriosis implants of these patients were not undergoing regular cyclic changes. Consistent with this idea, the pelvic examination was not as useful in leading to the diagnosis of endometriosis as in other reported series. It was suspected in 62 per cent of patients in this study: 80 per cent is commonly reported. 7 lo These findings are consistent with the substantial number of mild endometriosis cases in this series. In agreement with previous reports the symptoms of endometriosis did not correlate with the extent of the disease.
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It is interesting to speculate whether clomiphene, by stimulation of the “ovarian-endometrial axis” exacerbates endometriosis. This study would suggest that contention since more moderate to severe endometriosis was associated with preoperative clomiphene therapy. The majority of these patients presented with irregular bleeding and infertility exceeding 2 years. Many had received a wide range of evaluations and treatments, including ovulation induction. Endometriosis had been suspected prior to referral in only one case, though the ovulatory problem was commonly recognized and treated. When endometriosis-oligoovulation coexist the pelvic examination is not as diagnostic:ally productive and symptoms are unreliable in endometriosis anyway. Obviously, these patients initially appeared to have an ovulation problem as the etiology of their infertility. Ovulatory difficulties surface early in an infertility evaluation, but their presence should not prevent a thorough work-up, including endoscop.r. Endometriosis does exist in classic anovulatory patients.
REFERENCES
Parsons, L.: Obstet. Gynecol. 32: 576, 1968. 2. Kistner, R. W.: Gynecology, Ed. 2, 1971, p. 435.
1.
3. Ranney, B.:AM. J. OBSTET. GYNECOL. 107: 743, 1971. 4. Meigs, J. V.: Obstet. Gynecol. 2: 46, 1953. 5. MacLeod, J.: Obstet. Gynecol. Surv. 26: 335, 1971. 6. Rogers, S., and Jacobs, W.: Fertil. Steril. 19: 529, 1968.
Discussion W. P. DEVERELJX, Dallas, Texas. The authors have effectively demonstrated the existence of endometrios’:: with anovulation and with grossly irregular menses. I would like to qualify this by adding “during the time patients were under their observation.” These data do not necessarily conflict with the alleged axiomatic statements that there is a marked association of endometriosis with ovulation; that it is rarely seen in women with anovulatory cycles, but common in those with uninterrupted cyclic menstruation. My own acceptance of this concept has been supported by many years’ observation of patients with endometriosis. In 1963 we reported an analysis of 105 patients with endometriosis then currently still being observed for from 5 to 20 years.’ Our data did not reveal any case in which ovulation was a problem. The report stated “catamenia was not remarkable, there being little variation from the 12/28/5 general pattern. Only two had menarche as late as 15.” Of the 105 patients 81 had a total of 163 pregnancies, conclusive evidence of ovulation. I suppose anovulation could have been a factor in a few of the 12 involuntarily infertile. DR.
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It is logical to assume that the preponderance of mild endometriosis in this series is a reflection of inhibited progression of disease without regular ovulation. Yet even mild endometriosis retains the ability to cause infertility and requires diagnosis and treatment. Once endoscopic diagnosis of endometriosis is established the timing of operative intervention depends on the extent of disease. Moderate to severe endometriosis requires prompt operative therapy; reasonable delay is warranted in mild disease. The final pregnancy rate in this report reflects that both infertility factors need to be treated. Twenty-four of these patients had their ovulation problem treated, without conceiving, prior to endometriosis surgery, that later responded to the same drug. One should consider conservative operation even for mild endometriosis associated with oligo-ovulation after a reasonable trial of medical therapy. The associated ovulation problem should not delay operative intervention.
7. Acosta, A., Buttram, V., Besch, P., Malinak, R., Franklin, R., and Vanderheyden, J.: Obstet. Gynecol. 42: 19, 1973. 8. Schifrin, B. S., Selcuk, E., and Moore, J. G.: AM. J. OBSTET. GYNECOL. 116: 973, 1973. 9. Ranney, B.: AM. J. OBSTET. GYNECOL. 109: 1137, 1971. 10. Spangler, D. B., Jones, G. J., and Jones, H. W.: AM. J. OBSTET. GYNECOL. 109: 850, 1971. Why, then, does the authors’ material contain relatively so many with anovulation? I suggest these explanations: 1. The department from which this material comes is deservedly well known in Houston and the Southwest for its interest and expertise in the field of infertility. Could not its patient population have been heavily loaded with this type of problem! 2. This department has been diligently searching for this endometriosis-anovulation association for several years. 3. The material includes many patients who have or may have ovulated in the past, though perhaps not regularly: (a) Sixteen had secondary infertility, obviously having been ovulatory at one time. (b) Forty-eight had received prior oral contraceptives; maybe some had previously been ovulatory in varying degree, becoming anovulatory only after discontinuing the pill. Some reported as having received the pill for dysmenorrhea might have had ovulatory dysmenorrhea rather than the pain of endometriosis. (c) Fourteen had poorly stimulated ovaries, documented only during the time of observation. (d) There were only nine with polycys-
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tic ovaries, the most likely candidates fi)r total and chronic anovulation. Speculating further, might not some of these at some time had lutenization without actual ovulation, sort of a “near-miss” ovulation? Whether or not ovulation at some time is essential for development of endometriosis is still, I think. an unsettled issue, and can lead only to academic discussion unless it affords a clue to etiology. We might suggest to Dr. J. Merrill that for his next Millipore filter chanber endometrial implants he utilize ycmng, sheltered. virginal, anovulatory rabbits, if such exist, and see if the metaplasia he describes is induced Identification of the coexistence of endometriosis and anovulation, as stressed by the authors. is a situation which in clinical practice should not be overlooked in the infertile patient. However. 1 still believe, with few exceptions, that endometriosis will be found in women who ovulate and menstruate in more or less cyclic manner. REFERENCE
1. I>evereux, &‘. P.: Endometriosis; long-term observation. with particular reference to incidence of pregnant). O&et. Gvnecol. 22: 444, 1963. DR. HERMAN I. KANTOR, Dallas, Texas. In this interesting report, Dr. Soules and his co-authors record the occasional coexistence of endometriosis and oligo-ovulation. When infertility is a dominant problem, both must be treated. I would like to discuss these two areas of their report. To determine that ovulation is absent or unsatisfactory, the authors chose a scoring system using the six factors which they presented. In carrying out infertility studies, clinicians recognize that the endometrial biopsy, taken at or near menstruation, is a very reliable indicator of both ovulation and the adequacy of progesterone secretion. When analysis of hormone levels is not readily available, the biphasic basal temperature graph is a good indication that ovulation has occurred. However, a monophasic or mixed graph may infrequently be seen even though a mature secretory phase is reported from the endometrial biopsy. Of the 58 anovulatory patients in the authors’ report, 10 had a secretory endometrium. This paradox may require explanation. Was a correlated basal temperature graph taken? Was it biphasic? Even among women who ovulate regularly, an occasional anovulatory cycle, with bleeding from cstrogen withdrawal alone.’ may occur. The msured diagnosis of anovulation, or of a progestational phase defect, can be made after multiple, properly timed, endometrial biopsies. The authors’ use of “ovulation assistance” ma!’ have increased the number of pregnancies achieved after conservative surgery. Were any of these patients previously treated with the amenorrhea regimen
fi)llowed by sitnilar “ovulation assistance’? In 0uI practice, a number of women with endometriosis and ovulation deficiencies became pregnant after treatment with Clomid. This mav be specially true if their ovaries appear normal \\,hcn seen through the laparoscope. To understand the association of endometriosis and oligo-ovulatiorl, thr study of their etiologies may be significant. Several years ago I introduced the concept that the symptoms caused by endometriosis ma)- be related to the etiology. With tissue metaplasia of congenital rests. infertility is ,ro! a problem, and symptoms are usually related only to the involved areas. On the other, when retrograde endometrial implants cause the endometriosis, the full gamut of typical symptoms including infertility may he present. This concept may explain why some patients, even with wide-spread endometriosis. may have few symptoms, and m problem conceiving. The unexpected, asymptomatic endometriosis. occasionally a surprise finding during laparotomy, ma\ also he due to tissue metaplasia. Since the patients included in this report all had infertility. in accord with this concept their endometriosis was caused by retrograde implantation. Perhaps the Fallopian tuhr \vhich permits sucl~ retrograde menstruation nla! cause infertilit) by interfering with sperm ;II~ ovum transport. Can this be the cause of infertility in endometriosis? However. when endometriosis and ovulation deficiencies occur together, they do n/jt have a common etiology. Therefore. if pregnancy is desired treatment sho;lld logically be aimed at both conditions. I should like to ask if’, in rctrospcc’t, the authors still tee1 that Clomitl IWIT cause progression 01 the lesions of endomctriosis? There are onI!, two situations in which the endometrial biopsy as a measure of ovulation md progestational adequacv may be misleading. Fortunately both are rare: ( I) a refractorv endometrium, one M:hich does 11ot respond to adequate hormonal stimulation: (2) abnormal progesterone secretion from sources other than the postovulatory corpus lateum. DR. AKOOKS KASNEI’. Yankton, South Dakota. III 19.X. Dr. Leon S. hlcGoogan reported 011 SOIIIC’ instanctrs of ovarian infertility. Hc included groups ol‘ patients \vho had multicystic ovaries and endometriosis of the ovaric\. FHc cmphasi7cd the important? 01‘ considering (t/l taclors Jvhilc evaluating results of treatmenl for inl’crtilitv. Since the ess+t alluded IO 1’7 patients that 1 had rcportcd to have, had endometriosis present postv/~N~N~NIII~ at the time of operation, I should remind \ou that sc‘vt’n of those were considered to be incidental endometriosis. But 10 patients had signifitanl, s\mptoniati(endometriosis. six of whom had large et&metrial cysts and four of whom had dense pelvic, adhesions with active endometriosis involved.
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Two of these women had been receiving exogenous estrogens and the other eight women had had recrudescence of their estrogen production from 6 months to 12 years after the menopause. DR. SOULES (Closing). Several of the patients had been on birth-control pills. As a matter of fact, 48 of them had at one time or another been on birth-control pills in their past history. In reviewing their charts and seeing these patients, the birth-control pills were usually administered more for treating the irregularity of their periods than for treating symptomatic pelvic pain which later might have become endometriosis. Dr. Devereux brought up the point that a significant minority of the patients on endometrial biopsy had had secretory endometrium, which perhaps would make the whole contention suspect. Maybe we should have written the title as “Anovulation and oligo-ovulation associated with endometriosis.” In reviewing the charts, the average anovulation score was 4.3, but some scores were 7 or 8. and were clearly anovulatory; others were
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clearly more oligo-ovulatory by their basal body temperature record, and those were the few that showed up with secretory endometrium. Dr. Devereux mentioned treating the patients preoperatively for ovulation problems prior to diagnosis and treatment for the endometriosis. Many of these patients were treated for ovulation problems. Twenty-four had had Clomid therapy prior to referral to the group at Baylor. So, in this group of patients, rhey had been inadequately treated in that their dual infertility problem was not recognized. We speculated that Clomid might exacerbate endometriosis in that using the classification system that I mentioned earlier. Of the ones that had had Clomid, 75 per cent had moderate to severe endometriosis, whereas in the group of patients that had not been on Clomid, only 50 per cent had moderate to severe endometriosis. But we certainly have no proof of Clomid increasing endometriosis; it is purely speculation.