factors. This compromises any examination of the frequency of stigmata in relation to the varying severity of endometri- osis. A fourth theoreticalposition28 claims ...
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Current Concepts in Endometriosis CRAIG A. MOLGAARD, PhD, MPH; AMANDA L. GOLBECK, PhD, and LOUISE GRESHAM, MPH, San Diego
There are no conclusive data available on the incidence or prevalence of endometriosis, yet the notion persists that the frequency of cases has dramatically risen in western societies during the past 25 years. Race, familial predisposition, reproductive history, socioeconomic status, personality type and a historical drop in age at menarche have been posited as risk factors for the complex and as-yet-unclear epidemiology of this disorder. The epidemiology of endometriosis is constrained by the difficulty of the diagnosis. Several analytic concepts from epidemiology, however, could be profitably used to further our knowledge of endometriosis. Included are the case-control study, survival andlife-table analyses and correlations of psychologic traits with susceptibility to development of the disease. Though none of these techniques is original or without potential for bias, they may be underutilized in solving the conundrum ofendometriosis. (Molgaard CA, Golbeck AL, Gresham L: Current concepts in endometriosis. WestJ Med 1985 Jul; 143:42-46) Endometriosis is a crippling and enigmatic disorder that frequently coexists with severe pelvic pain and infertility. It is characterized by the presence of tissue resembling endometrium, the mucous membrane lining the uterus, in various abnormal locations including the uterine walls, ovaries or extragenital sites. Endometriosis was first brought to the attention of the medical community by Rokitansky in 1860. Between that time and Sampson's contributions to knowledge ofthis disease in the 1920s, fewer than 20 cases of endometriosis were reported in the literature.I Thereafter, reported cases have dramatically increased in western societies. The onset of endometriosis during the reproductive years may prevent childbearing and often necessitates a hysterectomy or castration. The exact cause of infertility in patients with this disease-twice the rate of that found in the normal population-is not known. The epidemiology of endometriosis is not well defined. The purpose of this review is to provide a summary of current concepts contributing to our population-level knowledge of this disease and to promote future analyses using epidemiologic tools in the study of endometriosis. Salient Clinical Features Etiology The pathogenesis of endometriosis is unclear. The most popular notion is that it is caused by implantation of endome-
trial cells, although why endometrial cells should be implanted at abnormal sites is a mystery. Marik2 has reviewed the numerous theories of etiology and made the point that no one theory explains the presence of endometriosis in all of the unusual locations where it has been found. He categorized the causative theories into three main groupings: transport, mutation and a combination of these. Transport could occur by spontaneous implantation, surgical or iatrogenic transplantation, metastasis via lymphatic channels or blood vessels or by direct extension to organs immediately adjacent to the uterus. Mutation could result from coelomic metaplasia, ovarian metaplasia, dedifferentiation or from activation of embryonic rests by the cyclic female hormonal stimuli to form aberrant endometrial tissue. A recent genetic study indicated multifactorial inheritance: 7 % of first-degree relatives of the index cases were affected compared with 1 % of a control group consisting of relatives of the patients' husbands.3 This control group was chosen because they were considered similar to the general population in terms of life-style, socioeconomic status, professional goals and age. A tendency for familial aggregation of cases has long been noted, though the inherited endocrinologic, enzymatic or chemical mechanisms are unknown. None of these causes is more powerful than the others in explaining the posited association with infertility.
From the Division of Epidemiology and Biostatistics, Graduate School of Public Health (Molgaard and Gresham), and the Department of Mathematical Sciences (Golbeck), San Diego State University. Submitted, revised, September 13, 1984. Reprint requests to Craig A. Molgaard, PhD, MPH, Division of Epidemiology and Biostatistics, Graduate School of Public Health, San Diego State University, San Diego, CA 92182.
42
THE WESTERN JOURNAL OF MEDICINE
CURRENT CONCEPTS IN ENDOMETRIOSIS
Symptoms Endometriosis may be acute or chronic and the site of the disorder often affects the type and degree of symptoms. Although endometriosis occurs most frequently in the pelvic region, on rare occasions it has been located in such distant sites as the gallbladder, kidneys, spleen, lungs and skin. The four cardinal features of the disease are infertility, dysmenorrhea and pelvic pain, dyspareunia and menstrual problems.' Differential diagnoses include adenomyosis, pelvic inflammatory disease, nonspecific adhesions and ovarian carcinoma.5 Patients with massive endometriosis may be devoid of symptoms, whereas a woman with only minor endometriotic involvement may be incapacitated with dysmenorrhea or pelvic pain. Pelvic pain may be due to direct action of endometriosis on local nerve endings or to impaired function of involved or adjacent organs. In either case, a definitive diagnosis of endometriosis cannot be made without direct visualization, either by laparotomy or laparoscopy.6 Determining the incidence and prevalence of endometriosis has been severely constrained in the past by the difficulty of the diagnosis.
Treatment Choice of treatment depends on the situation of an individual patient. The three major options are organ excision, conservative surgical treatment or medical treatment.7 Organ excision involves removing the interral pelvic reproductive organs, that is, the source of the endometriosis (the uterus) and the hormonal stimulus for its growth (the ovarian hormones), by a hysterectomy and bilateral salpingo-oophorectomy. Conservative surgical removal consists of excising tissues with endometriosis. Medical treatment attempts to end menstruation through the use of oral contraceptives, progestogens (to cause pseudopregnancy) or danazol (to cause pseudomenopause). A recent study by Shaw8 points to intranasal treatment with buserelin acetate, an analog of natural luteinizing hormone-releasing hormone, which blocks release of pituitary gonadotropins, in turn suppressing ovarian steroid production. Comparison of treatment alternatives is extremely difficult because of the lack of isomorphism between symptoms and degree of involvement; the tendency of endometriosis to regress, especially if pregnancy occurs, and the lack of a universally accepted classification system for endometriosis. The last affects not only the comparison of studies of treatment efficacy, but also the interpretation of frequency of occurrence estimates by different researchers. Recurrence of endometriosis is variable and depends on the type of intervention involved. It cannot be predicted by the severity ofthe endometriosis. 9
Epidemiologic Features Information concerning the prevalence of endometriosis is incomplete, though pelvic endometriosis has been reported in 5% to 15% of all women having pelvic operations.10 Corson11 has suggested that it occurs less in England and Australia than in the United States. However, the notion persists that the incidence is increasing,12 supported by increased case findings in recent decades. Concomitantly, a constellation of epidemiologic beliefs has evolved concerning endometriosis, the most general of which is that endometriosis is a product of JULY 1985 * 143 * 1
modern civilization. This theory is based on the supposed infrequency of endometriosis among blacks and Asians. 13-15 A second notion is that of an endometriosis personality type, Kistner"6 describing this as the interaction of body type and psychic demeanor. The main characteristics involve being mesomorphic but underweight, having above-average intelligence, a higher than normal anxiety level, egocentrism and a need for perfection. Age at diagnosis, in lieu of age at onset, is usually the third or fourth decade. Absence of the condition in girls before menarche is explained by the fact that endometriosis requires fluctuating levels of estrogen and progesterone for its initiation and spread. Endometriosis, however, may be symptomatic after menopause if there is a resurgence of endogenous hormonal stimulation or if the use of exogenous hormones stimulates the endometriosis. 17 In terms of reproductive history, the condition is believed to be more common in women who delay their first pregnancy and less common in the highly parous. 18 The lack of opportunity for retrograde menstruation among the latter group has been offered as a possible explanation. Related to reproductive history is the usually higher-thanaverage socioeconomic status of women with this condition. Women from high socioeconomic groups tend to have fewer and later pregnancies than those from lower socioeconomic groups.19 The position has been taken that the incidence is lower in blacks not because of race, but because of endemic poverty among a large proportion of the black population.20 Poverty could create an apparent differential in disease occurrence among racial groups because of differential access to specialized medical care and the existence of a prejudicial diagnostic posture based on what is "known" about racial susceptibility to endometriosis.
Association With Infertility: Spurious or Real? Support for the association between endometriosis and infertility is based on clinical data and has been well accepted. The argument has been based on the assumption that infertility characterizes 15 % of the general female population of reproductive age, and that this increases to 30% to 40% in the population of patients with endometriosis.5 Further support for the association involves surgical series, where subsequent pregnancy rates of40 % to 73 % occurred among patients with endometriosis (and no other cause for infertility) following conservative surgical treatment.21 It is possible, however, that the apparent relationship between infertility and endometriosis is an example of sampling bias related to the frequency with which a laparotomy or laparoscopic examination is used to evaluate cases of infertility. Few studies have reported if laparoscopy was done as a routine procedure in the evaluation of infertile patients when physical examination had shown no other positive findings, or what signs and symptoms are considered sufficient to warrant laparoscopy. Information supporting the association of endometriosis and infertility has been considered inconclusive.22 Given that the association exists, it has been held in the past that endometriosis does not cause infertility unless it is severe enough to alter tubo-ovarian function. Ifboth tubes and ovaries are involved in the process and peritubal adhesions are present, tubal dysfunction could impair ovum pickup. The increased use, however, of laparoscopy in infertility studies 43
CURRENT CONCEPTS IN ENDOMETRIOSIS
has revealed the coexistence of minimal endometriosis (peritoneal involvement only) and infertility. It is unclear how the mild form of endometriosis can alter the process of conception, and this fact has led to the suggestion that minimal endometriosis may be the effect rather than the cause of infertility.23 Yet evidence for the efficacy of conservative surgical treatment in cases of even mild endometriosis has continued to accumulate. Buttram2l evaluated the effect of conservative operations on 56 patients with mild endometriosis as the only known cause of infertility: 78% of these women had been trying to conceive for two or more years. Within 15 months after an operation, 73 % were pregnant. His cautious conclusion was that the surgical procedure somehow altered the pelvic environment (enzymatic, chemical, immunologic) so that the effect of the endometriosis on fertility was altered. In contrast, a subsequent study24 based on a life-table analysis of conceptions concluded that mild endometriosis does not necessarily interfere with fertility. One current theory explaiting the relationship between endometriosis and infertility is immunologic. It proposes that ectopic or abnormal endometrium is recognized differently by the immune system, which launches an antibody response to the condition that may affect the patient's fertility. An autoimmune response is triggered in some women when endometriotic tissue is phagocytized and absorbed by the host. This might cause rejection of an embryo or disrupt sperm transport.25 A second theory posits that the ovum may be attracted to any endometrium wherever it is located. Evidence for this position involves reports of abdominal pregnancies in areas of endometriosis. Given that the distance between the ovary and normal endometrium is greater than that between the ovary and the endometriosis, a patient's fertility could again be impaired. A third theory, which is the subject of controversy, is that of the "luteinized unruptured follicle" syndrome.26 In brief, this hypothesis posits a situation wherein the ovarian follicle fails to release the ovum despite proceeding through the other changes associated with ovulation. This assumes that retrograde menstruation is actually a common event, that endometrial cells do not implant as frequently as they might and that the failure to implant can be explained by steroid hormone concentrations in peritoneal fluid. Women with complete ovulatory cycles have very high steroid hormone (progesterone) concentrations after ovulation, which would prevent growth and development of endometrial cells by rendering them inactive, whereas women with unruptured luteinized follicle syndrome do not.25 The result would be infertility and endometriosis, but infertility would be the cause of endometriosis, as mediated through the unruptured luteinized follicle syndrome, and not the result. This hypothesis has been challenged as being very inaccurate.27 The most general criticism has been that identifying the stigma, or site of the ovum release, by laparoscopic examination of the surface of the luteal structure is fraught with potential for error. If the stigma is absent, luteinized unruptured follicle is presumed, but recognizing the stigma depends on the experience of the laparoscopist, the time in the cycle and other idiosyncratic factors. This compromises any examination of the frequency of stigmata in relation to the varying severity of endometriosis. A fourth theoretical position28 claims no causal relationship to date involving the role of prostanoids in the peritoneal 44
cavity and infertility among endometriosis patients. A fifth theory points to the high concentrations of peritoneal macrophages found in patients with this disease. Attracted perhaps by irritants in the oviduct, monocytes migrate to the peritoneal region and differentiate into macrophages, possibly resulting in sperm phagocytosis. Of the major epidemiologic research designs, a case-control design is perhaps the only appropriate choice for the study ofthe association between endometriosis and infertility. A case-control study was recently undertaken at the Mayo Clinic to compare the presence of endometriosis in infertile and fertile populations as visualized by laparoscopy.29 The medical records retrieval system of the Rochester Epidemiology Program Project was used to conduct the study.30 The records of 100 Mayo Clinic referral patients who had been evaluated for infertility by means of laparoscopy between 1970 and 1979 were retrieved. Operative reports were reviewed for each case and the extent of endometriosis or adhesions or both were classified according to a system proposed by the American Fertility Society.3" This classification system is a four-stage model (mild, moderate, severe and extensive) based on the site, size and type of endometrial involvement. Of the cases, 12% had a clinical diagnosis of endometriosis before the index date. From 1,905 patients who had laparoscopy for tubal ligation during the same time period, 200 fertile controls were chosen. Controls were matched to the cases by age ( ±2 years) at the time of laparoscopy and by clinic registration numbers so that the length of time of medical care in the Mayo system was similar. The approach of comparing fertile and infertile populations for endometriosis as documented by laparoscopy was considered to be superior to previous reports relating endometriosis and infertility based on data describing conception after treatment of endometriosis. However, several caveats must be inserted. Both cases and controls were taken from the clinic referral series, and a bias in the choice of patients certainly exists. A population-based case-control study was not deemed feasible given the relatively small population of Rochester, Minnesota. Second, by the nature of the design, the comparison is extreme. Of the infertile patients, 21/100 (21 %) were found to have endometriosis, including 11 mild, 8 moderate and 2 severe cases. Among the 200 fertile controls, only 4 (2%) had evidence of endometriosis, all staged as mild. Thus, endometriosis is significantly more common (Xi=31.52, P
