Manual of Endometriosis Kanthi Bansal
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Endometriosis: EvolutionCHAPTER 1

Asha Baxi,
Manila Jain Kaushal
 
INTRODUCTION
Endometriosis is a chronic inflammatory disease, characterized by implantation and growth of endometrial tissue outside the uterine cavity. This disabling condition is considered one of the most frequent diseases in gynecology, affecting 15–20% of women in their reproductive life.
The first histological description of a lesion consistent with endometriosis was given by Carl Von Rokitansky, an Austrian pathologist in 1860.1 By 1896, Cullen had suggested that endometriomas, or adenomyomas as he called these lesions, resembled the mucous membrane of the uterus.2 Over the following 50 years adenomyoma and endometriosis were considered pathologies separate from the so-called ‘hemorrhagic ovarian cysts’, and it was not until 1921 that this condition was recognized to be of endometriotic origin. The year 2010 marked the sesquicentennial of the discovery and description of adenomyosis and endometriosis by Carl Rokitansky of Vienna.3 The intervening 150 years have seen intense basic scientific and clinical research, and the diagnosis and treatment of millions of women worldwide. Yet there has been no scholarly history, and little mention of endometriosis and adenomyosis in historical compendiums of disease.
Sampson first described the disease formally in 1921.4 Then he proposed the hypothesis that the origin of peritoneal endometrial implants was tissue delivered by the retrograde menstruation.5 Retrograde menstruation is a nearly universal phenomenon among cycling women5,6 but it is not clear why endometrial tissue will implant and grow in the peritoneal cavity of only a subgroup of women. These endometrial cells can respond to ovarian hormones and, therefore undergo cyclic menstrual changes with periodic bleedings. Several key steps are required to establish an endometriotic implant: presence of ectopic endometrial glands and stroma, attachment of endometrial cells to the peritoneum, invasion into the mesothelium, and survival and growth of the ectopic tissue.7
The history of endometriosis is reviewed in the light of today's clinical and pathological knowledge of this disease. Prior to Sampson's report in 1921, attention was focused on the enclosed type of endometriosis, sited deep in the pelvis and called adenomyosis externa. Sampson's first hypothesis, that rupture 2of an ovarian endometrioma caused superficial peritoneal endometriosis, was probably changed after this observation that the free, superficial peritoneal implants reacted like eutopic endometrium. These implants were recognized as implants from menstrual blood regurgitated into the pelvic cavity. Adenomyosis externa, ovarian endometrioma and peritoneal endometriosis then came to be regarded as the same disease. In the light of today's knowledge, it may be important to remember this progressive understanding in the nosology of what is now universally called pelvic endometriosis.
 
Evolution in Pathogenesis of Endometriosis
The pathogenesis of endometriosis is still subject to debate, although the condition has been known since 1860. Researchers have abundant theories about the causes of endometriosis, but have yet to prove any of them. These include retrograde menstruation/transplantation theory, coelomic metaplasia theory, anatomic abnormalities, genetic basis, environmental cause and altered cellular immunity. Among the theories concerning the pathogenesis of endometriosis three main concepts can be discerned (Table 1.1).
The oldest concept is that endometriosis develops from the remnants of the Wolffian or Mullerian ducts, or alternatively, from metaplasia of the peritoneal or ovarian tissue.8,9.
In 1955, Levander and Normann introduced the induction theory.7 This theory is based the assumption that specific substances which are released by the degenerating endometrium induce endometriosis from omnipotent blastoma, present in connective tissues. It is based on the assumption that endometriosis results from differentiation of mesenchymal cells, activated by substances released by degenerating endometrium that arrives in the abdominal cavity (the induction theory).10,11
A third concept is based on the transplantation and subsequent implanta–tion of endometrial tissue.5 This would imply transport of viable endometrial cells during menstruation through the Fallopian tubes into the abdominal cavity, implantation of these cells onto the peritoneum and the development of these cells into endometriosis (the transplantation or implantation theory). The implantation theory was originally neglected for a long time, because menstrual effluent was considered to contain only non-viable endometrial tissue and retrograde menstruation was thought to be a rare phenomenon.
Table 1.1   Pathogenesis of endometriosis—three main concepts
•
In situ development
•
Transplantation
•
Combination of in situ development and endometrial transplantation and implantation
3
The implantation theory explains the pathogenesis by deposition and subsequent growth of retrogradely shed viable endometrial cells. Transforma–tion of mesothelium to endometrium-like tissue under the influence of products of regurgitated endometrium (induction) is a plausible alternative. In both models, cell adhesion molecules may play an important functional role.
Adequate animal models for endometriosis are not there. Rodents do not have spontaneous endometriosis which is not surprising since they do not have a menstrual cycle with a long luteal phase and menstruation. Also, primates are not an adequate model for endometriosis. The rhesus monkey only occasionally develops cystic ovarian endometriosis, possibly more after dioxin administration.12 Also, in the baboon, there was failure to induce the more severe cystic or deep endometriosis.
It is likely that endometriosis is a common multifactorial disease, caused by an interaction between multiple gene loci and environment. Causes of immune or inflammatory deficiency may be related to the effects of stress on immune functioning, or may be genetically determined. The immune system, genetics and metaplasia are implicated in the pathogenesis of endometriosis. Women with endometriosis exhibit abnormally high humoral immune responsiveness and macrophage activation while showing diminished cell-mediated immunity with decreased T-cell and natural killer cell responsiveness. However, this may result from the presence of endometriosis rather than the cause.13,14
Chronic immunosuppression in combination with hormonal regulation may have facilitated the aberrant growth of endometrial tissue within the peritoneum. It seems that the genetical, environmental, immunological and hormonal factors interfere with each other and, implicating that a circle occurred could be responsible for the development and progression of endometriosis. However, the mechanism appears to require endometrium and retrograde menstruation in most cases of disease.
Pelvic endometriosis, the most common form of the disease, is associated with increased secretion of proinflammatory cytokines, neoangiogenesis, intrinsic anomalies of the refluxed endometrium and impaired function of cell-mediated natural immunity.15 Recently, endometriosis has also been considered to be an autoimmune disease, owing to the presence of autoantibodies, the association with other autoimmune diseases and recurrent immune-mediated abortion. These findings are in apparent contradiction with the reduced cell-mediated natural immunity observed during the disease. Basic research on this field may lead to a better understanding of disease etiology. It is believed that some women's immune systems are unable to remove the fragments of endometrial tissue transported into the pelvic area, which can lead to endometriosis. Metaplasia, or changing from one normal type to another normal type of tissue to adapt to its environment, underlies another theory.16 The endometrium and the peritoneum are derivatives of the same coelomic 4wall epithelium. Peritoneal mesothelium has been postulated to retain its embryologic ability to transform into reproductive tissue. Such transformation may occur spontaneously, or it may be facilitated by exposure to chronic irritation by retrograde menstrual fluid.
 
Evolution in Clinical Presentations and Diagnosis
Endometriosis is a late-comer in medical knowledge about diseases. Since endometriosis is an internal disease, it is not surprising that historically the symptoms were poorly understood. It was not until 1690 that an astute German physician, Daniel Schoen, published Disputatio Inauguralis Medica de Ulceribus Ulceri, in which he clearly described what we now know as endometriosis. In 1774, a Scottish physician wrote, “in its worst stages, this disease affects the well-being of the female patient totally and adversely, her whole spirit is broken, and yet she lives in fear of still more symptoms such as further pain, the loss of consciousness and convulsions.” Indeed, that sounds like endometriosis!
Throughout the 18th century women were often considered to have “hysteria” rather than a gynecologic condition that caused pain. As for infertility, that was always blamed on the woman, but not specifically attributed to endometriosis. Recognition by the medical profession of endometriosis as a disease improved after it was clearly described by Dr Carl von Rokitansky in 1860. Since 1925, it has been known as “endometriosis,” which combines “endometrium” (the lining of the uterus) with “-osis” (meaning abnormal). In this case, the endometrial tissue was found in an abnormal place.
In 1932, Hill reported the presence of aberrant endometrium at microscopy in a series of 135 patients who were operated-upon for some pelvic pathology. Amongst these cases, 20 had adenomyomas of the uterus and 115 had peritoneal endometriosis.17 Pelvic pain related to menstruation was the principal reason for seeking relief through surgery and this usually happened some ten-years after the onset of disease.
Three different types of endometriosis were subsequently distinguished.
 
Peritoneal Endometriosis
In the 1980s, it became evident that peritoneal endometriosis has multiple appearances. These lesions may represent replacement of mesothelium by an endometrial epithelium or endometrial polyp formation.18-20 The anatomic distribution of ectopic endometrium supported the hypothesis of retrograde menstruation as the primary model of development of endometriosis.21 The clinical importance of even very small lesions was suggested when, in a prospective study of artificial insemination in women with minimal endometriosis, Jansen found reduced fecundability.22 Awareness of the existence of subtle peritoneal endometriosis produced an increase in the diagnosis of endometriosis, although clinical significance of early lesions remained controversial.23,245
From all published evidence Evers, et al25 concluded that peritoneal endometriosis appears to be a dynamic disease, especially in the early phase, when subtle, atypical lesions may emerge and vanish again. The final answer to the question whether and in which cases endometriosis is a progressive disease will have to come from long-term prospective investigations studying spontaneous evolution of peritoneal lesions without therapeutic interference.
 
Rectovaginal Endometriosis
As in the case of infertility, investigators found poor correlation between lesion characteristics or stage of disease and pelvic pain. A strong correlation between pelvic pain and the depth of invasion was described in the presence of implants more than 10 mm deep. In contrast with superficial peritoneal endometriosis, these lesions have a structure closely resembling the adenomyomas described by Cullen.2 In the late 1990s, rectal endoscopic ultrasonography was proposed to diagnose the presence of deep bowel infiltration and select patients for surgery.26
 
Ovarian Endometriosis
Ovarian endometriosis can present itself as very early lesions, plaques with free-floating adhesions, deep non-cystic lesions and typical chocolate cysts with adhesions. In a detailed study of 29 ovary specimens with chocolate cysts, Hughesdon23 found that in 90 percent of them the ovarian endometrioma was formed by a pseudocyst. The surface of the ovary is adherent, usually to the posterior side of the parametrium and part of the ovarian cortex is invaginated. Endometriotic tissue is found at the site of adhesion and a thin layer of superficial endometrium-like tissue extends to cover partially or fully the invaginated cortex. Hughesdon concluded that ectopic endometrium does not simply erode its way into the ovary: the ovary is actively invaginated, thus providing a pseudocyst mimicking a uterus.27
The prominent symptoms of the disease are chronic pelvic pain and infertility. However, some of the patients do not have clinical symptoms. Patients who have minimal disease would complain of severe pain, conversely patients who have severe lesions may not complain at all of pain.
The cause for the associated infertility and/or pain is poorly understood. Except for adhesions, the mechanisms of the associated infertility are not defined. Also for pain, there is lack of understanding that why so many of the typical, cystic, and deep lesions do not cause pain.
 
Evolution in Treatment
 
Medical Treatment
In 1953, Meigs28 recommended early and frequent childbearing as prophylaxis of endometriosis. He wrote: “It is the author's belief that avoidance of endometriosis through early marriage and frequent childbearing is the most 6important method of prophylaxis”. The availability, in the late forties, of a non-steroidal, synthetic estrogen, diethylstilbestrol (DES), prompted another line of experimental treatment for severe endometriosis. Karnaky29 in 1945, reported apparently good results, achieving amenorrhea with increasing daily doses of up 100 mg/day of diethylstilbestrol (DES). In his series, five patients became pregnant after stilbestrol was discontinued. Two researchers Kistner30 and Andrews31 brought new concept of “pseudopregnancy”, the artificial creation of a hormonal situation mimicking that occurring naturally during pregnancy” as a treatment for endometriosis. This was achieved by the first oral contraceptive ever marketed, Enovid (norethinodrel plus mestranol). Further new generation oral contraceptive pills were used. During the second part of the 20th century, a number of additional hormonal regimens have been proposed, the first being an antigonadotropic steroid, danazol.32 Until the late 1980s, this agent was the standard medical treatment for endometriosis. The chief drawback with danazol is its androgenic properties. Interesting results have been obtained with the introduction of gestrinone, a steroid with androgenic, antiprogestinic and antioestrogenic activities. Given the results obtained with a mild antiprogestin like gestrinone, it was logical to expect even better results with the first “real antiprogestrogen”, mifepristone. Ever since its introduction, Gonadotropin-releasing hormone agonists (GnRHa) have emerged as a primary medical therapy for patients with symptomatic disease, although secondary hypoestrogenic side effects may limit compliance. Add-back therapy is a means of surmounting this problem. Recent studies have demonstrated that the use of add-back enhances compliance and duration of therapy.33 Leuprolide acetate, goserelin acetate and nafarelin acetate are all effective agents.
Oral contraceptives, androgenic agents, estrogens, progestins, antigona–dotropic agents, antiprogestins and GnRHa have all been used successfully, although at the present time, the latter preparations are the most popular medical therapy for endometriosis. Recently levonorgestrel-releasing intrauterine system with a depot formulation of a GnRHa is used in the control of endometriosis-related chronic pelvic pain in patients with severe endometriosis.34 Among the additional advantages of the LNG-IUS is the fact that it does not provoke hypoestrogenism and requires only one medical intervention (for its introduction) every 5 years. Thus, it is the treatment of choice for chronic pelvic pain associated endometriosis in women who do not wish to conceive.
Ovarian suppression by hormonal treatment appears not effective and should not be offered for infertile patients with endometriosis. This recommendation is based on a metaanalysis by Huges et al.34 In addition, hormone suppression before or after surgical treatment of endometriosis is contraindicated since there is no evidence of increased effectiveness over that of surgery alone, and the treatment prolongs or delays the opportunity for conception to occur.7
 
Surgical Treatment
Surgical treatment of severe endometriosis started in the early 1900's, when anesthesia had advanced enough that surgery was relatively safe. The surgical exploration and endoscopic access constitute major progress in the surgical management of endometriosis.
Technical improvements in laparoscopy quickly produced new information on endometriosis and expanded gynecological applications of endoscopic surgery, to the extent that in the early 1970s leading gynecologists in Europe and US concluded that laparoscopy is the preferred tool for diagnosis and surgery of endometriosis.35
During the last 35 years, gynecologic laparoscopy has evolved from a limited surgical procedure used only for diagnosis. Surgical therapy is appropriate, especially for advanced stages of the disease.
The laparoscopic approach offers a number of advantages over more conventional approaches. It causes precise destruction of lesions and adhesions, minimal bleeding and minimal damage to adjacent structures thus minimizing neoadhesions formation and nondrying of structures as occurs at laparotomy.
Open microsurgery therapy for endometriosis consists of a series of minioperations performed under magnification using operating loupes. It emphasizes on limiting peritoneal damage and handling meticulous hemostasis and closure of raw areas without tension using finest non-absorbable suture.
Laparoscopy is an effective surgical approach with the goal of excising visible endometriosis in a hemostatic fashion. The goal of the surgery is to remove as much lesions as possible. The more aggressive approach to removal of implants and adhesions, increase the likehood of conception, particularly in patients with moderate and severe endometriosis with anatomical distortion.36
The treatment of infertility caused by endometriosis is surgical removal of endometriotic tissue or assisted reproductive technology. Peritoneal implants are resected or vaporized by means of an electric current or laser. Ovarian endometrioma and rectovaginal endometriotic nodules, however, can be removed effectively only with the use of full dissection. Surgical excision of the endometriomas carries a risk of reducing the oocyte pool of the patient which may add to her infertility problems. Ovarian reserve can be monitored by antimullerian hormone (AMH) levels in the serum in early follicular phase and could be of help to decide as of endometrioma should be removed before IVF or not. It is worthwhile to mention that surgery before IVF is suggested by ESHRE and the RCOG when ovarian endometrioma of > 4 cm in diameter is present37 or there is suspicion of malignancy.
Endometriosis is often treated surgically upon diagnosis but with a higher rate of recurrence, suggesting that a combination of surgical and medical management might provide better outcomes. It is unfortunate that 8understanding of the disease has not progressed very far. This area may be of paramount importance in the near future in order to develop a therapy that could prevent or eradicate endometriosis rather than merely relieving the symptoms.
 
CONCLUSION
Endometriosis remains an enigma despite having been extensively studied. Although the exact etiology of endometriosis is unknown, several hypotheses about its origin exist. Multiple in vitro and in vivo models have been developed to study endometriosis. Over the last decade, great interest has been shown for the reconstruction of the path that led to the identification of endometriosis. Peritoneal endometriosis became the signature of endometriosis and the introduction of laparoscopy in the sixties provided a golden tool for the visual diagnosis and surgical therapy. While endometriosis remains an enigmatic disease, the introduction of new pharmacologic agents, such as GnRHa and newer endoscopic methods of surgical treatment, have facilitated and improved the overall management of this disease. Although now there are many medical and surgical treatments for endometriosis, the knowledge about the disease is still in its infancy. We know what it looks like, but we do not know why it is there. We know that in some women it is inherited, but we are just beginning to know what genes are involved.
REFERENCES
  1. Von Rokitansky C. Ueber Uterusdrusen-Neubildung in Uterus- und Ovarial— Sarcomen. Ztschr KK Gesellsch der Aerzte zu Wien. 1860; 37:577–81.
  1. Cullen TS. Adenomyoma uteri diffusum benignum. Johns Hopkins Hosp Bull. 1896; 6:133–7.
  1. Benagiano G, Brosens I. Who identified endometriosis? Fertil Steril 2011;95:13–6.
  1. Sampson JA. Perforating hemorrhagic (chocolate) cysts of the ovary. Arch Surg 1921;3:245–323.
  1. Sampson JA. Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol. 1927;14:422–69.
  1. Sampson JA. The development of the implantation theory for the origin of peritoneal endometriosis. Am J Obstet Gynecol. 1940;40:549–57.
  1. Batt RE. Emergence of endometriosis in North America: a study in the history of ideas. Ph.D. dissertation. University of Buffalo, State University of New York.  Buffalo (SA):  2008:109–13.
  1. Ridley JH. The histogenesis of endometriosis. A review of facts and fancies. Obstet. Gynecol. Survey, 1968;23:1–23.
  1. Lauchlan SC. The secondary Mullerian system. Obstet. Gynecoi. Survey, 1972;27: 133–46.
  1. Levander G, Normann P. The pathogenesis of endometriosis. An experimental study. Acta Obstet. Gynecoi. Scand. 1955;34:366–98.
  1. Merrill JA. Endometrial induction of endometriosis across Millipore filters. Am. J. Obstet. Gynecoi, 1966;94:780–90.
  1. MacKenzie WF, Casey HW. Animal model of human disease. Endometriosis. Animal model: endometriosis in rhesus monkeys. Am J Pathol. 1975;80:341–4.
  1. 9 Gaetjii R, Lotzian S, Hermann G, et al. Invasiveness of the endometriotic cells in vitro. Lancet 1995;346:1463–4.
  1. Dmowski WP, Braun D, Gebel. The immune system in endometriosis. In: Rock J., ed. Modern approaches to endometriosis. Kluver Academic Publishers.  New York:  1991:97.
  1. Badawy SZA, Cuenca V, Marshall L, et al. Cellular components in peritoneal fluid in infertile patients with and without endometriosis. FertiL. Steril., 1984;42:704–7.
  1. Jones RK, Bulmer JN, Searle RF. Immunohistochemical characterization of proliferation, oestrogen receptor and progesterone receptor expression in endometriosis: a comparison of eutopic and ectopic endometrium in normal cycling endometrium. Hum. Reprod. 1995;10:3272–9.
  1. Hill LL Jr. Aberrant endometrium. Am J Surg. 1932;18:303–21.
  1. Vasquez G, Cornillie F, Brosens IA. Peritoneal endometriosis: scanning electron microscopy and histology of minimal pelvic endometriotic lesions. Fertil Steril 1984;42:696–703.
  1. Murphy AA, Green WR, Bobbie D, dela Cruz ZC, Rock JA. Unsuspected endometriosis documented by scanning electron microscopy in visually normal peritoneum. Fertil Steril 1986;46:522–4.
  1. Wiegerinck MA, Van Dop PA, Brosens IA. The staging of peritoneal endometriosis by the type of active lesion in addition to the revised American Fertility Society classification. Fertil Steril 1993;60:461–4.
  1. Jenkins S, Olive L, Haney AF. Endometriosis: pathogenetic implications of the anatomic distribution. Obstet Gynecol 1986;67:335–8.
  1. Jansen RP. Minimal endometriosis and reduced fecundability: prospective evidence from an artificial insemination by donor program. Fertil Steril 1986;46:141–3.
  1. Jansen RPS, Russell P. Nonpigmented endometriosis: clinical, laparoscopic, and pathologic definition. Am J Obstet Gynecol. 1986;155:1154–9.
  1. Stripling MC, Martin DC, Chatman DL, Vander Zwaag R, Poston WM. Subtle appearance of pelvic endometriosis. Fertil Steril 1988;49:427–31.
  1. Evers JL, Land JA, Dunselman GA, van den Linden PJ, Hamiltion JC. ‘The flemish giant’, reflections on the defense against endometriosis, inspired by Professor Emeritus Ivo A. Brosens. Eur J Obstet Gynecol Reprod Biol 1998;81:253–8.
  1. Hughesdon PE. The structure of endometrial cysts of the ovary. J Obstet Gynaecol Br Emp. 1957;64:481–7.
  1. Meigs JV. Endometriosis; etiologic role of marriage age and parity: conservative treatment. Obstet Gynecol 1953;2:46–53.
  1. Karnaky KJ. The use of’ stilbestrol for endometriosis; preliminary report. Southern Med J 1948;41:1109–11.
  1. Kistner RW. The use of newer progestins in the treatment of endometriosis. Am J Obstet Gynecol 1958;75:264–78.
  1. Andrews MC, Andrews WC, Strauss AF. Effects of progestin-induced pseudopregnancy on endometriosis: clinical and microscopic studies. Am J Obstet Gynecol 1959;78:776–85.
  1. Greenblatt RB, Dmowski WP, Mahesh VB, Scholer HF. Clinical studies with an antigonadotropin-Danazol. Fertil Steril 1971;22:102–12.
  1. Surrey ES. Gonadotropin-releasing hormone agonist and add-back therapy: what do the data show? Curr Opin Obstet Gynecol. 2010;22:283–8.
  1. Petta CA, Ferriani RA, Abrao MS, Hassan D, Rosa E, Silva JC, et al. Randomized clinical trial of a levonorgestrel-releasing intrauterine system and a depot GnRH analogue for the treatment of chronic pelvic pain in women with endometriosis. Hum Reprod 2005;20:1993–8.
  1. 10 Huges E, Brown J, Collins JJ, Farquhar C, Fedorkow DM, Vandekeckhove P. Ovulation suppression for endometriosis. Cochrane Database Syst Rev 2007;18;(3): CD000155.
  1. Nezhat C, Crowgey SR, Garrison CP. Surgical treatment of endometriosis via laser laparoscopy. Fertil Steril 1986;45:778–83.
  1. Cohen MR. Surgical laparoscopy in infertility. J Reprod Med 1975;15:51–3.
  1. Verecellini P, Somigliana E, Vigano P, et al. Surgery for endometriosis associated infertility: a pragmatic approach. Human Reproduction 2009;24(2):254–69.