~ 0889-8545/97 $0.00 ENDOMETNOSIS + .20 PATHOPHYSIOLOGY The Biologic Principles of Disease Tony G. Zreik, MD, and David L. Olive, MD Endometriosi...

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PATHOPHYSIOLOGY The Biologic Principles of Disease Tony G. Zreik, MD, and David L. Olive, MD

Endometriosis, although associated with a variety of symptoms, primarily produces pain and infertility. The strong correlation with these conditions coupled with questions as basic as why does endometriosis develop and when does it achieve the status of a disease is as yet poorly understood. Appearance, location, depth of invasion, and other factors all may influence symptoms as well as many other confounding variables. PATHOPHYSIOLOGY OF PAIN

Many investigators have attempted to explain the pathophysiology of endometriosis-associated pain. The heterogeneity of the disease process, however, suggests that a range of pathophysiologic processes are involved. Mechanisms theorized to be responsible for pain include inflammation, pressure, adhesions, neuronal involvement, increased prostaglandin production, and psychological factors. Different types of lesions may cause pain by means of different routes. Atypical papular lesions may produce more prostaglandins than do older lesions, and these may be responsible for functional pain symptoms such as dy~menorrhea.~~ Classic lesions are thought to be older or burnt-out examples of endometri~sis.~~ These might be more likely to provoke organic pain from mechanical pressure of cystic nod-

From the Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut





ules and from stimulation of pain fibers by scars and stretching of areas of fibrotic infiltration (as could occur during intercourse on deep penetration).63 Recently, the depth of infiltration of endometriosis has been recognized to correlate with pelvic pain.%,37 Because depth cannot be easily assessed by inspection alone, surgical excision is required to make an accurate evaluation. Very deep implants appear to be more active and may be found exclusively in patients with pain. Cornillie and co-workers found that nearly all women with lesions deeper than 1 cm suffer from severe pain.'l In this study, women with superficial (<1 mm), intermediate ( 2 4 mm), or deep (5-10 mm) infiltration had pain in 17%, 53%, and 37% of cases. Total lesion volume, however, has not been found to be directly related to patient symptoms.", 34 Peritoneal fluid (PF) inflammatory cells, especially macrophages, are increased in number in patients with endometriosis as is the case in other inflammatory condition^?^, 43 This accumulation of white blood cells may release lysosomal enzymes and induce tissue damage and pain. Tissue damage caused by acute and chronic inflammation may leave a marked degree of fibrosis and adhesions. Adhesion formation is common in patients with endometriosis and may be related to the degree of pain. Adhesions may cause pain by direct nerve damage, from tissue destruction and scar formation, or by devitalization and ischemia of parts of the internal pelvic organs, secondary to damage to the blood supply. Organs such as bowel or adnexa may become adherent in abnormal areas, so that physiologic movement may place traction on their nerve supply and cause pain. Over time, scarring of the posterior uterine surface may become extensive enough to produce a fixed retroflexion, possibly resulting in sacral pain because of direct pressure. Pain may be referred to the back, lower abdomen, rectum, and thighs because of the proximity of lumbar and sacral nerves. Sturgis and Call have suggested that endometriotic lesions surrounded by a fibrotic capsule are likely to cause pain.58In support of this theory, Ripps and co-workers found 96% of lesions associated with focal tenderness to be fibrotic.49Menstrual pain may be related to a buildup of pressure within the fibrotic lesion before or during menstruation. This pressure may be enough to stimulate pain fibers in the capsular tissue. Alternatively, the cyclic menstrual pain may be related to sequential swelling, with extravasation of blood and menstrual debris from endometrial glands into surrounding tissue.18Similarly, adhesions and fibrosis may result in painful traction on tissues during coitus. Perineural involvement with endometriosis or with its subsequent adhesion formation may also play a role in pain syndromes. The presence of perineural inflammatory reaction, particularly in deep endometriosis, has been demonstrated.'l An association between pain syndromes and uterosacral ligament involvement also has been described.4O Additional evidence of endometriosis directly irritating nerve fibers stems from reports of painful syndromes involving the obturator nerve in the obturator fossa or the femoral nerve in the inguinal



Several investigators have examined the relationship between endometriosis and prostaglandin production in an attempt to elaborate the role of these compounds in the pathogenesis of pelvic pain.3,13, 27, PF inflammatory cells, such as macrophages, are known to produce pro~taglandins.4~ The peritoneum itself, ovary, and retrograde menstrual debris all may contribute to the peritoneal pool of pro~tag1andins.I~ Several prostanoids have been postulated as mediating the painful effects in endometriosis. Eicosanoid products of the cyclo-oxygenase pathway such as prostacyclin (PGI,) and prostaglandin E2 (PGE,) have been shown to sensitize pain receptors to chemical mediators and mechanical stirnuli.,l Leukotriene B4 (LTB4)>a product of the lipoxygenase pathway, is a known chemotactic agent, and may initiate an influx of leukocytes, which potentially can release lysosomal enzymes, leading to tissue destruction and adhesion formation. Other prostaglandins possibly involved include prostaglandin F2a (PGF2a), thromboxanes A, and B, (TxA,, TxBJ, and 6-ketoprostaglandin Fla (6-KF).17,l3 Numerous experimental animal models for endometriosis have been evaluated.66Autotransplantation of uterine squares to the peritoneal cavity in rats shows that viable endometrial implants produce PGF2a at concentrations similar to those measured in uterine tissue.65In rabbits with artificially induced peritoneal endometriosis, PF PGFa levels are significantly elevated over controls.53 Several investigators have attempted to determine peritoneal prostaglandin levels in women with endometriosis. Badawy found that women with endometriosis, regardless of pelvic pain, show significantly elevated levels of PGF2a in PF.3 Drake’s team reported an elevated concentration of TxB, and 6-KF in women between days 8 and 12 of their menstrual cycle.50 Dawood and others investigated patients with chronic pelvic pain and found that, except for an increase in 6-KF, the PF prostaglandin levels measured in patients with endometriosis did not differ from normal women, women with chronic pelvic inflammatory disease (PID), and other women with chronic pelvic pain.13 Rapkin and Bhattacherjee also examined the relationship between PF eicosanoids and chronic pelvic pain and found no correlation between the symptoms, underlying diagnosis, and concentration of eicosanoids PGE,, PGI,, and LTB,.45 Although these studies present conflicting data, it appears that at least a subgroup of patients with pelvic pain may suffer from increased prostaglandin exposure.17,68 It is unclear whether this is primarily a result of the activity of the lesions or the degree of inflammatory response.” The wide variation in lesion activity, inflammatory response, the relative insensitivity of pain quantification methods, and the transient nature of prostaglandin action further complicate investigation into this association. Psychological factors also may play a role in the pathogenesis and persistence of chronic pelvic pain. Patients with chronic pelvic pain frequently have abnormal psychological profiles, including a history of



depression or dysfunctional family backgrounds, findings that seem unrelated to the presence or absence of underlying pelvic p a t h o l ~ g y . ~ ~ Sexual and physical abuse may promote the chronicity of pelvic paink6 Such findings support the importance of obtaining a history of physical abuse when evaluating these patients. The implementation of a multidisciplinary pain management approach often seems indicated.47 The involvement of a psychologist may be successful in ameliorating feelings of helplessness that promote passive "illness" behavior and depression.

PATHOPHYSIOLOGY OF INFERTILITY Clearly, there is no single unifying explanation for infertility in the many women also found to have endometriosis. Several mechanisms have been proposed: some logical and well proven, others hypothetical, and some highly unlikely. There is general agreement that women with endometriosis and mechanical distortion of the normal pelvic anatomy have a clear cause for decreased fertility. Advanced disease results in adhesions, distal tubal obstruction, fimbrial agglutination, and proximal tubal obstruction, all known causes of infertility. The current debate over the relationship between endometriosis and infertility centers on early-stage disease.

DOES EARLY-STAGE ENDOMETRIOSIS CAUSE INFERTILITY? Attempts to determine the relationship between early-stage endometriosis (implants alone) and infertility have used both animal models and human studies. In both the rabbiF3 and monkey5*models, transplanted endometrium has been shown to decrease fertility; however, in both experiments this was apparently caused by pelvic adhesion formation; in the absence of such anatomic distortion, there was no change in fertility.I2,2o Clinical investigators also have addressed this issue. Jansen prospectively analyzed 91 women undergoing artificial insemination with donor sperm who had no other apparent infertility factor.32All had husbands with azoospermia or severe oligospermia. Of the 91 women, 7 had endometriosis on screening laparoscopy. Subsequent fertility was significantly lower in the women with endometriosis. Several problems exist with this study, however. First, the number of endometriosis patients was small, allowing for small errors in diagnostic accuracy to have a potentially substantial effect. Along these lines, multiple referring physicians performed the laparoscopies; thus, it is unlikely that uniform criteria for the diagnosis of endometriosis were applied. Finally, the monthly rate of conception among women with endometriosis in this donor program was fewer than 4%, a figure far lower than that seen in



most endometriosis-associated infer ti lit^.^^ This study therefore must be considered suggestive at best. Conflicting evidence is presented by Rodriguez-Escudero and colleagues?' In a population of 21 donor sperm recipients with endometriosis, they were able to demonstrate a monthly probability of pregnancy in excess of 20%. A study by Chauhan and associates9also investigated women undergoing donor insemination. In regrouping these women to include those with both oligospermic and azoospermic husbands, recalculation of their monthly probability of pregnancy revealed a 9.3% rate among women with treated endometriosis versus a 9.9% rate among those without identifiable female infertility factors. Finally, a comprehensive multivariate investigation into potential pathogenic factors affecting fertility in 731 infertile women determined that endometriosis without adhesions did not alter the cumulative conception rate.19 These studies, taken together, seriously question the concept that implants alone can be a primary cause of infertility. HYPOTHESES FOR ENDOMETRIOSIS MECHANISMS OF INFERTILITY Mechanical Pelvic Factors Pelvic endometriosis can produce massive, dense adhesions among reproductive structures. The adhesions distort anatomic relationships and may directly interfere with oocyte release and tubal pickup. Fimbrial distortion or destruction and occasionally distal occlusion can result. In the mouse, distal tubal endometriosis even in the absence of tubal occlusion interferes with fimbrial function and ovum capture.'jO The disease can also produce proximal obstruction, with implants found to be the cause in as many as 14% of such cases.22,36 Similarly, midtubal occlusion also may result from endometriosis.62Ovarian endometriosis produces inaccessibility of the ovary to the fallopian tube. In extreme cases, destruction of ovarian stroma can occur. Peritoneal Fluid Abnormalities The fallopian tubes and ovaries are constantly bathed in PF; it was thus logical to propose a constituent of this fluid as a possible perpetrator of infertility. Several such factors have been suggested. A large number of studies have suggested that a gamete or embryotoxic factor exists in the PF as a result of endometriosis. This has been demonstrated to affect sperm in terms of motility* and zona binding.'O Unfortunately, such a factor has yet to be isolated and identified, a necessary step to demonstrate causal linkage to endometriotic implants. Furthermore, reduced fertilization of 00cytes~~ and gamete have been noted



by some investigators, as well as the presence of PF from patients with endometriosis, although results have been inconsistent.2,l4 Abnormal prostaglandin levels also have been proposed as a mechanism to decrease fecundity. The theory is attractive in that prostaglandins can alter many reproductive processes in animal models; however, such effects are seen inconsistently in humans. Furthermore, abnormal levels of prostaglandins in PF are not universal with endometriosisassociated infertility; indeed, when time of the menstrual cycle is controlled, elevations of prostaglandin levels in endometriosis patients are unusual.4,5. 7, 24. 56 Macrophages are the major leukocyte constituents of PF. Several studies have demonstrated increased number of macrophages, a higher concentration, and increased activation in the PF of infertile women with endometriosis compared with fertile controls or tuba1 factor infertility patients.25,26, 28 When compared with women having unexplained infertility (the appropriate control group because they are identical except for endometriotic implants), however, no differences in macrophage parameters are noted.42 Ovulatory Dysfunction Several investigators have suggested anovulation resulting from endometriosis as a cause of infertility, with rates of 17% to 27%.', 69 This rate does not differ from the rate seen among infertile patients as a whole, however.57Thus, anovulation may well be a concurrent problem unrelated to endometriosis, except perhaps in those with ovarian adhesions. Other researchers have claimed altered follicular dynamics2l an increased rate of luteal phase defect,16and luteinized unruptured follicle syndrome.61The last has been suspected based on the lack of sonographic disappearance of the follicle at midcycle and the inability to visualize an ovulatory stigma during laparoscopy early in the luteal phase.15,61 Nevertheless, these abnormalities do not appear to play a major causal role in the infertility among endometriosis patients. Immunologic Abnormalities Many investigators are currently in search of immunologic abnormalities in women with endometriosis. Defects uncovered include both humoral and cellular errors in immune function and competency. Although most such abnormalities have been linked to pathogenic issues, an attempt has been made to relate aberrant immune structure or function to infertility. A thorough listing of these derangements is given here: Increased total leukocytes, macrophages, and T-helper lymphocytes Increased macrophage activation and differentiation Increased ratio of T-helper to T-suppressor cells



Decreased natural killer cell activity Increased levels of IL-1, IL-6, IL-8, TNF-a, and MCP-1

To date, no direct link to fertility status has been demonstrable with the presence of these disorders. Other Theories

Widely disparate hypotheses such as fallopian tube dysfun~tion,’~ ~ ~ been ~ ~ proposed ~ , hyperprolactinemia,6and early pregnancy ~ o s s55 have as mechanisms for reduced fertility, as well as the following: Distortion of normal anatomic relationships Interference with oocyte release and tuba1 pick up Fallopian tube dysfunction Anovulation Luteinized unruptured follicle syndrome Gamete or embryotoxicity Reduced fertilization Immunologic abnormalities Hyperprolactinemia Luteal phase defect Implantation failure Early pregnancy loss All either await confirmation or have failed to provide a sufficient linkage to establish a cause-and-effect relationship with endometriosis, however. A promising new theory has suggested that avp3 integrin, a component of the embryo implantation cascade in the uterus, is deficient in some women with infertility.35Recently, such a deficiency has been noted in some women with early-stage endometriosis and appears to be correctable with treatment of the disease. The significance of this finding awaits further study. CONCLUSION

Endometriosis is a complex disorder that clearly has been linked epidemiologically to both pain and infertility. In neither case, however, do we truly understand the mechanism by which these symptoms result from the disease. It is clear that to make effective progress in the treatment of pain and infertility related to endometriosis, a more thorough understanding of the relationship between disease and symptoms must be acquired. References 1. Acosta AA, Buttram VC, Besch PK, et al: A proposed classification of pelvic endometriosis. Obstet Gynecol 42:19, 1973



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Address reprint requests to Tony G. Zreik, MD Yale University School of Medicine Department of Obstetrics and Gynecology P.O. Box 208063 333 Cedar Street New Haven, CT 06520-8063