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Diagnosis & Management of : Pathophysiology to Practice Educational Series on Women’s Health Issues Series on Women’s Educational APGO

1 APGO Educational Series on Women’s Health Issues Diagnosis & Management of Endometriosis: Pathophysiology to Practice

INFORMATION

Diagnosis & Management of Endometriosis: Pathophysiology to Practice, a module fully funded by an unrestricted educational grant from Abbott Laboratories, reviews the current evidence and practical clinical experience for the evaluation and treatment of endometriosis. The module also looks at recent data that may one day lead to improved outcomes for patients who currently suffer from pain, , and other symptoms often associated with endometriosis.

The complete module includes three components:

1. Online monograph for (a) medical school faculty to use to supplement training of residents and students and (b) practicing healthcare providers to use to enhance their knowledge of endometriosis-related care. The evidence-based yet practice-oriented text into a primer on the full spectrum of endometriosis management focused on key teaching points and principles for clinical practice. The monograph is downloadable as a PDF 2. Set of PowerPoint teaching slides on endometriosis-related care derived from the monograph for use as a teaching tool in medical schools, residency and fellowship programs, and continuing education presentations. The slides include speaker notes for use by educators. 3. Series of four interactive case studies. The self-directed interactive case studies use a combination of illustrations and 2D or 3D models, each focusing on a different aspect of endometriosis-related care. Each case study demonstrates concepts and principles across the scope of the monograph and slide set, and each includes interactive questions for the learner to answer at various points throughout the case narrative.

TARGET AUDIENCE

of life among reproductive-age females. Timely diagnosis and effective management of the disease represent a effectively manage the wide-ranging symptoms commonly associated with endometriosis, including , infertility, and reduced quality of life. This educational activity is intended for obstetricians/gynecologists and other healthcare professionals involved in the diagnosis and treatment of endometriosis, with emphasis on the fundamental skills essential for timely intervention and adequate treatment(s). By applying key concepts and employing fundamental techniques, healthcare professionals will be able to effectually diagnose, reduce morbidity, and optimize outcome in their affected patients.

PURPOSE & CONTENT

Understand the history and pathophysiology of endometriosis. Understand the critical need for timely diagnosis and effective intervention. Understand the considerable effects of chronic disease and employ best-practice techniques to mitigate them.

2 Educational Objectives At the conclusion of this activity, the participant should be able to: Understand the pathophysiology, varied presentation, and symptoms of endometriosis. Identify factors that can inform a timely and accurate diagnosis. Demonstrate an ability to recommend appropriate medical and surgical management.

Discussion of Off-Label Use Because this course is meant to educate physicians with what is currently in use as well as what may be available in the future, there may be “off-label” use discussed in the presentation. The audience will be informed if and when off-label use is being discussed.

Acknowledgment The Association of Professors of Gynecology and (APGO) and the APGO Medical Education Foundation gratefully acknowledge Abbott Laboratories for the unrestricted educational grant that has made this publication possible.

3 FACULTY

Chair Col. John R. Fischer, MD, USAF, MC, FS Associate Professor Uniformed Services University of the Health Sciences Department of Obstetrics & Gynecology 4301 Jones Bridge Road, C1065 Bethesda, Maryland 20814

Reviewers Linda C. Giudice, MD, PhD, MSc The Robert B. Jaffe MD Endowed Professor and Chair University of California San Francisco Department of Obstetrics, Gynecology and Reproductive Sciences 505 Parnassus Ave. M1496, Box 0132 San Francisco, CA 94143 [email protected]

Magdy Milad, MD, MS Northwestern Prentice Women’s Hospital Chicago, IL 60611 [email protected]

Cindy Mosbrucker, MD, FACOG Franciscan Women’s Health at Gig Harbor 11511 Canterwood Blvd. NW, Suite 145 Gig Harbor, WA 98332 [email protected]

Ken R. Sinervo, MD, MSc, FRCSC Medical Director Center for Endometriosis Care 1140 Hammond Drive, F-6220 Atlanta, GA 30328 [email protected]

4 CONTENTS

Introduction 6 6 Symptomology 8 Historical Background 8 Pathogenesis 9 Epidemiology & Pathophysiology 10 Economic Impact 11

Comorbidities 12 Adhesions 12 Infertility 13 Risk of Adverse Outcome & Preterm Birth 14 Dyspareunia 14 The “Evil Triplets” of : Interstitial Cystitis, Pudendal/Levator Neuralgia & Endometriosis 15 & Autoimmune Connection 15

Diagnosis 16 Barriers to Diagnosis 16 Clinical Diagnosis: & Pain Mapping 16 Imaging Studies 17 Surgical Diagnosis & Staging 18

Treatments 18 Surgical Intervention 18 18 //Salpingo-oophorectomy 21

Nonsurgical Therapies 22 Medical Therapies 22 Alternative Therapies 24

Conclusion 24

References 25

5 INTRODUCTION reliable noninvasive detection methods may likely contribute to lengthy delays in diagnosis. Practitioners from all disciplines, particularly obstetricians and gynecologists, must understand not only the medical disease that often results in substantial morbidity, pelvic aspects of this disease but the tremendous psychosocial pain, multiple , and infertility. Characterized and cost burdens as well. by the existence of endometrial glands and stroma outside the , the disease represents a of endometrial-like tissue found outside the , life among reproductive-age females. aberrant process leads to microscopic internal , Early symptoms may be underappreciated by caregivers, healthcare consumers, and clinicians (Figure 1). There may also be marked distortion of alike, and timely diagnosis combined with effective pelvic anatomy.1 Symptoms are wide-ranging and often management cannot be undervalued. The lack of start early in life, but they may go unrecognized by both

Figure 1. Burst

2012 © Jespersen & Associates, LLC.

6 the medical and lay communities. Indeed, symptoms lungs, where it can induce catamenial pneumothorax; may present even as early as 8 years of age, and high and very rarely, areas as far outside the abdominopelvic rates of disease and symptoms indicative of possible region as the brain (Figure 2). The are among future endometriosis have been noted in adolescents the most frequent of sites, with gastrointestinal and the and young women based on prevalence data.2 urinary tracts, soft tissues, and diaphragm following. Depending on location, the disease may present with Classic signs include severe , deep varied symptoms ranging from bowel obstruction, dyspareunia, chronic pelvic pain, Middleschmertz, melena, hematuria, dysuria, dyspnea, and swelling of associated cyclical or perimenstrual symptoms soft tissues, respectively.5 (eg, of bowel or bladder) with or without abnormal bleeding, infertility, and chronic fatigue.1 Women Endometriosis is an enigmatic disease that can present with endometriosis may also suffer from autoimmune as a diagnostic and therapeutic challenge; ectopic 3 As pregnancy, pelvic infection, and may well, endometriosis shares similarities with several mimic the symptoms and should be ruled out in the autoimmune disorders, including elevated levels of emergent setting. cytokines, decreased apoptosis, and cell-mediated abnormalities.4 Severely compromised quality of life and sexual health are common. cause or causes of endometriosis remain under debate, though demonstrated association with a number of Endometriosis typically develops on pelvic structures hereditary, environmental, epigenetic, and menstrual including the rectovaginal septum, bladder, bowels, intestines, ovaries, and fallopian tubes, but it may also reaction, infertility, and pelvic pain associated with be found in distant regions including the diaphragm; the endometriosis may also correspond to a variety of

Figure 2. Pelvic Structures Where Endometriosis Typically Develops

Ovary

Uterus

Endometrium Rectovaginal septum

Uterovesical fold

Bladder

Rectum

Perineum 2012 © Jespersen & Associates, LLC.

7 co-morbid conditions, ranging from autoimmune disease to food and environmental allergies and intolerances. The disorder remains a leading cause of gynecologic hospitalization and hysterectomy, Women with endometriosis are more likely to report approach to improve the wide-ranging sequela ranging their pain as “throbbing” and experience dyschezia from dyspareunia and chronic pain to infertility and when compared to women with an apparently normal subjective well-being. reported to occur more frequently in women with Symptomology the disease versus a control group. Endometriosis is Symptoms vary considerably, often mimicking those more commonly found on the left side, with at least one study indicating 56% of women having left-sided disease versus 50% having right-sided disease.8 Few laboratory tests are valuable in the diagnosis of endometriosis; for example, CA-125, CCR1mRNA, Women may also report hematochezia in association and MCP1 have low accuracy. A CBC with differential with menses when endometriosis involves the may help to eliminate other causes of pain, such as hematuria may be present if the bladder or ureters absence of the disease. Likewise, urinalysis and urine are involved. Sexually active women may report culture can rule out infection, and cervical Gram stain dyspareunia, which may be due to scarring of the uterosacral , nodularity of the rectovaginal diseases, which may lend to pelvic pain and infertility. septum, cul-de-sac obliteration, and/or uterine Beta HCG can rule out complications of possible retroversion, all of which may also lead to chronic pregnancy. Subsequently, anything other than surgical backache. These symptoms are often exaggerated uterosacral ligaments may have the most severe While laparoscopic intervention is the primary means impairment of sexual function.9 pain have completely normal pelvic anatomy at Acute exacerbations may be caused by chemical the time of surgical evaluation. To some extent, the peritonitis due to leakage of old blood from an . With conscious laparoscopic pain mapping, painful lesions were found to involve peripheral spinal nerves rather than autonomic nerves.7 implants. In these cases, the extent of the disease Partial or complete bowel obstruction may occur due to cannot be determined by visual inspection.6 However, formation or a circumferential endometriosis minimally invasive laparoscopic remains the lesion. Ureteral obstruction and hydronephrosis can gold standard for diagnosis and treatment. result from endometrial implants on the ureter or mass effect from an endometrioma.10 The degree or stage at which endometriosis is present has no correlation with pain or symptomatic Early symptom recognition, particularly in adolescence, impairment.7 Symptoms are variable but typically will lead to timely intervention, accuracy of diagnosis, effective treatment, and adequate referral as needed, which will ultimately assist in reducing the associated morbidity of endometriosis. Historical Background Although characteristics of endometriosis have been described as far back as 1600 BCE in the Egyptian Ebers Papyrus,11 Benagiano and Brosens12 note that constipation over the years a number of investigators have attempted

8 to reconstruct the pathway leading to the discovery of the eutopic and ectopic of women with what we call today and endometriosis. the disease. These factors contribute to pathogenesis and related symptomatology; today, endometriosis has Medical historian Vincent Knapp, PhD, contends that become a major clinical issue.12 endometriosis was described well over three centuries ago, attributing credit to German physician Daniel Pathogenesis Schrön. In his dissertations, Schrön described a “female disorder in which ulcers appear[ed] in the abdominal, in 1921, extensive research on pathogenesis has been the bladder, intestines and outside the uterus and cervix, carried out. Despite progress, however, no single causing adhesions.”13 Critics of Knapp’s assertions, however, believe that Schrön’s lectures referred instead satisfactorily; current concepts hold that multifactorial to infections rather than endometriosis. immune, hormonal, genetic, environmental, and anatomic factors may be responsible. The most notable Noted Montpelier physician Jean Astruc may have theories are described herein. been referencing endometriosis in his 1740 medical tome, wherein he wrote, “All in general know, that it It is proposed that there are, in fact, three distinct is as natural as happy for women to have their menses entities, each with different pathogenesis: peritoneal, without any preternatural Accidents. On the contrary, vicious……denotes some Permanent Deep endometriosis, together with cystic ovarian wherein Women commonly suffer before or at the endometriosis, represents the most severe form of Time of their Evacuation, and painful Colicks, sensible disease.18 Pains of the Matrix (uterus)…are the most constant accidents; though vomiting, diarrhœa, constipation, Researchers agree endometriosis is likely to be and the like are also rarely wanting.”14 polygenic and multifactorial, but the exact pathogenic mechanisms are still unclear. Each theory singularly In years following, other physicians would begin fails to account for all forms of endometriosis, thereby describing ectopic endometrial tissue in various cases, indicating multifactorial mechanisms. Rokitansky in 1860.12,15 Researcher Thomas Cullen later suggested that , or as he called adhesion, invasion, recruiting, angiogenesis, and them, adenomyomas, strongly resembled the mucous proliferation. Genetics, biomolecular aberrations in the membrane of the uterus.16 eutopic endometrium, dysfunctional immune response, It is Albany, New York, physician John Sampson, peritoneal environment may all ultimately MD, however, who is generally considered forefather be involved.19 of the disease, with his work on peritoneal and The oldest concept assumes that endometriosis arises in pathogenesis—though his postulation on retrograde situ menses and endometriosis is not without critique.17 metaplasia of peritoneal or ovarian tissue. Proposed as Emil Novak and other pioneering researchers in years early as 1870 by anatomist Heinrich von Waldeyer19 as germinal of the ovary, this theory continues on the sequela and pathogenesis of the enigmatic to be popular today and has the support of pathologists, disease known today as endometriosis. who often refer to it as the metaplastic theory.

Three basic concepts have evolved during the late Endometriosis found in the cul-de-sac, on the uterosacral and broad ligaments, beneath the ovarian supported by elevated cytokines and growth factor surface, on the peritoneum, on the omentum, and within the retroperitoneal lymph nodes is often (2) angiogenesis is favored in the establishment of referred to as mullerianosis. Disease diagnosed in implants, and (3) there exist biochemical differences in adolescents either prior to or shortly after

9 supports the notion of embryonic mullerian also display cell cycle checkpoint pathways required rest pathogenesis.19 to survive DNA-damaging events.22

Often seen as an extension of the coelemic metaplasia More recent research also links a K-RAS variant theory, which holds that germinal epithelium of the allele (found in 31% of women with endometriosis as peritoneal serosa and ovary can be transformed by opposed to 5% of a large diverse control population) metaplasia, the induction theory proposes that one or to the development of the disease. In a murine several endogenous, biochemical, or immunological model, endometrial xenografts containing the K-RAS factors could induce endometrial differentiation in variant demonstrated increased proliferation and undifferentiated cells.19 This asserts that substances released by the endometrium are transported by blood suggest that an inherited polymorphism of a let-7 and lymph systems to induce endometriosis in various miRNA binding site in K-RAS leads to abnormal areas of the body. Transplantation further utilizes the endometrial growth and endometriosis. The LCS6 theory that these substances can induce endometriosis through iatrogenic, lymphogenic, and hematogenic endometriosis risk.23 spread, which would account for the uncommon, extrapelvic sites of endometriosis invasion. Promising research on stem cells in the possible etiology “Sampson’s theory,” dating back to 1921, is perhaps the endometrium, with evidence to suggest a role of Dr. Sampson assumed that lesions are the result of stem/progenitor cells in development of the disease.24 “seedlings” from the ovaries.19 Later, in 1927, he Human endometrium undergoes cycles of growth and regression with each cycle; adult progenitor stem cells menstruation, wherein endometrium is showered are likely responsible for the regenerative capacity. backwards onto the peritoneum and ovaries, thus These same cells may have an enhanced capacity to taking hold and implanting. However, as retrograde generate endometriosis if shed in retrograde fashion as menstruation is a very common phenomenon among well. Mesenchymal stem cells are also involved in the women of reproductive age, there are undoubtedly pathogenesis of endometriosis and may be the principal other factors that contribute to the pathophysiology and source of endometriosis outside of the peritoneal cavity pathogenesis of the disease.20 Sampson’s theory fails when they differentiate into endometriosis in ectopic also to explain why progression occurs in some women locations. Finally, in addition to progenitor stem cells, only. Essentially, this theory considers endometriosis as normal endometrial cells that behave abnormally cells in the endometrium.25 because of abnormal peritoneal milieu; however, this is not supported or borne out universally.17 With many studies now providing credible evidence The key event in the process is implantation or future research will transform further understanding of metaplasia, which thus has been the subject of many pathogenesis and pathophysiology, as well as provide investigations, and the early subtle lesions become novel targets for noninvasive diagnostics and drug very important.21 The roles of molecular alteration, that therapies to treat this unrelenting disease.19 is, genomic instability, and cell survival are emerging debates in disease pathogenesis. Iron-induced oxidative Epidemiology & Pathophysiology stress has been purported to play a fundamental Prevalence corresponds to, and increases with, awareness and training of the surgeon, but menstruation with recent studies demonstrating endometriosis is estimated to affect nearly 176 million women globally; 775,000 in Canada and 8.5 increases the survival of endometriotic cells under iron- million in North America overall.26 Mistakenly once induced oxidative stress conditions possibly through believed to be a disease of older women, nearly 70% the activation of forkhead box (FOX) transcription of teens with pelvic pain are later diagnosed with endometriosis.27 Early intervention and increased awareness is requisite to reduce morbidity, infertility,

10 and progressive symptomatology in patients - of all ages. metriosis prevalence and chronic immunosuppression, for example, in transplant patients, nor with smoking Parity and infertility have long been associated with affecting NK activity, nor with caffeine or alcohol, nor endometriosis, with infertility among the chief clinical with any lifestyle variable.21 Studies have found that higher body mass index decreases risk of both deep as well as ovarian and pelvic endometriosis, as does par- response characterized by neovascularization and ity,37 though pregnancy is not a cure. abnormal complement deposition, and altered Frequency of endometriosis in women of higher social interleukin-6 are among clinical consequences.10 class has been reported, but this is likely the result of Endometriosis is also clearly associated with bias. The same diagnostic bias may explain the higher dysmenorrhea, but it is unknown whether this is a frequency in white women versus women of color, cause or a consequence.21 and in fact, data on prevalence in different races often do not consider the reason for admission for surgical There is no known disease prevention. Related to a procedure, which may be selectively associated with number of hereditary, environmental, epigenetic, and a higher or lower likelihood of an endometriosis menstrual characteristics and alterations, some sharing diagnosis. Few studies have evaluated comparable certain common processes with cancer,28 endometriosis population and socioeconomic conditions; those that remains the third leading cause of gynecologic did revealed no substantial differences among women hospitalization in United States29 and is considered of different races.19 Less understood are the factors, a leading cause of female primary and secondary if any, of nutrition and exercise, lifestyle, personality infertility, prevalent in 0.5% to 5.0% in fertile and traits, and other variables, with little evidence regarding 25% to 40% of infertile women.30 The disease is also these as more than simply modulating roles. a leading cause of hysterectomy in the United States, 31 disease are also sparse. However, in a recent provocative Though no particular demographic, personality study by Vercellini and colleagues38 determined that women with the most severe form of endometriosis characteristics have been associated with diagnosis, appeared more attractive to external observers than including decreased risk with late age at menarche32 those with peritoneal and/or ovarian endometriosis, and shorter menstrual cycles with longer duration as well as those without endometriosis. Women with 33 severe rectovaginal disease were judged to have a leaner silhouette, larger , and a history of earlier Likewise, family history cannot be undervalued, with coitarche. Whilst phenotyping may have future use in conjunction with genetic and environmental data to elucidate the pathogenesis of endometriosis, the have endometriosis.34 Further genetic analyses will authors did caution that further studies are warranted to clarify the role of family in disease risk. “exclude a spurious relationship between attractiveness and rectovaginal endometriosis and to rule out the Dioxin pollution has been suggested to be causally potentially confounding effect of deep dyspareunia on related to endometriosis based on the observation of some aspects of sexual behavior.” increased incidence and severity of disease in primates treated previously with dioxins.35 Related data suggest Economic Impact The literature concerning economic evaluations on and dosage may precipitate endometriosis through endometriosis is likewise spare, with few studies interaction with receptors or suppression of receptors.19 Conversely, at least one more existing data refer to generalized costs associated recent study concluded that dioxin may not contribute with pelvic pain and infertility, with few targeting to the etiology of endometriosis at all.36 studies quantify the economic impact among

11 adolescents. Nonetheless, while the true burden may be underestimated, the economic burden from both a the existing data should drive policy to improve the sufferer’s and societal perspective is profound. standard of care on a sustained basis, thus reducing the associated intangible and societal cost burden. One database analysis found that direct endometriosis- related costs were considerable and appeared driven COMORBIDITIES by hospitalizations; as endometriosis-related hospital length of stay steadily declined from 1993 to 2002, Adhesions per-patient cost increased 61%; approximately 50% Adhesions are a common co-morbidity among of >600,000 endometriosis-related ambulatory patient endometriosis patients.45,46 In addition to pain, visits involved specialist care; and females 23 years old anatomic distortions, and surgical complications, or younger constituted >20% of endometriosis-related adhesions may also play a role in the development of outpatient visits.39 ovarian endometriomas and deeply invasive nodules. Thus, prevention, whether de novo or by re-formation, An actuarial analysis revealed that women with of adhesions is one of the most important—yet endometriosis incur total medical costs that are, on neglected—aspects of treatment in endometriosis.46 average, 63% higher than medical costs for the average woman in a commercially insured group.40 Likewise, intangible effects of endometriosis cannot be dismissed. opposing serosal and/or nonserosal surfaces of the Fourquet et al41 previously assessed the burden of internal organs and the abdominal wall, at sites where endometriosis through Patient Reported Outcome there should be no connection. This connection can data, revealing that 72% reported having eight or more endometriosis-related or coexisting symptoms, being transparent or dense/opaque, or it could be a cohesive dysmenorrhea, incapacitating pain, and dyspareunia, connection of surfaces without an intervening with nonmenstrual pain that interfered with their adhesion band.”47 of respondents noted a decrease in quality of their In one study of patients diagnosed with adhesions, work and almost 20% reported being unable to work researchers found that 43% had had previous surgery, due to pain, while 69% reported that they continued work despite feeling pain. Forty percent of patients 2% had endometriosis; 47% of those who had adhesions surveyed perceived that as a direct consequence of at the time of laparoscopy did not demonstrate any endometriosis, their career growth was negatively recognized risk factor.48 affected due to high rates of absenteeism and/or low performance, not being promoted, not receiving merit/ Without question, intrapelvic adhesions lead to excellence bonuses, missing professional seminars, and loss of clients. Others reported being “totally hospitalizations resulted from surgeries that were incapacitated” and even dismissed from or left their performed primarily for adhesiolysis due to adhesions jobs due to symptoms. of the digestive and female reproductive systems, resulting in 846,415 days of inpatient care at a cost Most recent data indicate that the total annual burden of $1.3 billion. The high incidence of adhesion of endometriosis-associated symptoms in the United formation after surgery for endometriosis underscores States has reached a staggering $119 billion.42 the importance of optimizing surgical techniques to potentially reduce adhesion formation.49 loss of productivity: 11 hours per woman per week; 38% more than for women with similar symptoms The disruption of the peritoneal surface during surgical without endometriosis.43 Endometriosis is among the leading gynecologic adhesions. Minimal and gentle tissue handling, use diagnoses in women with recurrent and progressive of barrier agents, precise microsurgical treatment chronic pelvic pain.44 While studies aimed at calculating with minimal blood loss, prevention of glove powder healthcare costs and health-related quality of life in exposure, and copious pelvic irrigation can minimize

12 adhesion formation. In addition to optimized surgical factors are outside the scope of this module; the focus techniques, which diminish risk of tissue injury, tissue in infertility. Though the association is clear, with use of barriers, murine models have demonstrated mechanisms linking the two are uncertain. In general, biologic mechanisms connecting endometriosis and associated adhesion development and secondary infertility include: reducing not only experimental endometriosis- Distorted pelvic anatomy, including adhesions related postsurgical adhesion development but also resulting from endometriosis, which can impair 50 oocyte release or inhibit ovum pickup and transport,54 as well as damaged or obstructed Kruschinski and colleagues51 investigated the feasibility fallopian tubes or acquired or congenital and outcome of adhesiolysis in patients with severe and uterine defects.19 recurrent adhesions using gasless (lift) laparoscopy and a SprayGel® adhesion barrier with promising results (a Altered peritoneal function, including increases reduction in adhesion score at second-look laparoscopy was overall 89.8%; 90.1% reduction in extent, 89.3% microphages; ; IL-1, IL-6, TNF- reduction in severity, and 89.9% reduction in grade). alpha, IgG, and IgA antibodies; lymphocytes; SprayGel, however, is not available in the United an ovum capture inhibitor preventing cumulus- States. Other barrier membranes and gels are routinely 54 RANTES; angiogenic used in the United States, such as absorbable cellulose activity; IGFBP protease; and related mesh (Interceed®), combination hyaluronic acid 55 and carboxymethylcellulose (SepraFilm®), and 4% icodextrin (Adept®), to name a few. Endocrine and anovulatory disorders, including luteinized unruptured follicle syndrome (LUF), Despite the lack of data correlating adhesions to clear defect, abnormal follicular growth, and premature as well as multiple luteinized relationship and the value of adhesiolysis, as shown surges. It has been hypothesized that LUF by Diamond et al.52 Similarly, Steege and Stout53 may not be a consequence of endometriosis, but, in previously studied pain relief after adhesiolysis in fact, may be a cause or cofactor in the development patients with pain during their daily activity or with of the disease.55 dyspareunia. Of the patients with pain during daily activity, 56% had either resolution of pain or at least Impaired implantation, with evidence suggesting a reduction in their pain of greater than 50%. In the that endometriosis may be responsible for reduced patients diagnosed with dyspareunia, 70% had either resolution of pain or a reduction of at least 50% in during the time of implantation.54 pain.48,53 Progesterone resistance. The endometrial Despite adherence to techniques for prevention and dysfunction in women with endometriosis may promising product development, adhesions remain likely be attributed to a diminished response to a continued potential contributor to pain, even after progesterone. Changes in gene expression patterns endometriosis has been completely resected.49 It is noted in the eutopic endometrium of women with expected that growing awareness will lead to the development of new products, improved surgical 19 leading to techniques, research data, and additional technologies hyperproliferative and anti-apoptotic changes. to expand indications and favorable clinical outcome. to establish, maintain, and recur. Progesterone Infertility receptor may also indirectly induce intracrine, It is estimated that up to 50% of women with autocrine, juxtacrine, or paracrine factors, endometriosis may suffer from infertility.54 Assisted including MIG-6. reproductive technology, male factors, and other

13 By contrast, women with endometriosis have decreased in women with the disease; observational data have levels of cellular immunity, including of NK cell found that younger women ages 20 to 29 may suffer functions and BAX-positive peritoneal macrophages, from dyspareunia twice as often as older women which may hold importance for the survival and ages 50 to 60.58 proliferation of the aberrant, ectopic tissue.55 the quality of life and relationships of women with endometriosis. For many, it may be severe and result While controversy surrounds the relationship between in reduced sexual activity and enjoyment as well as endometriosis and infertility, growing data strongly reduced communication with the intimate partner. indicate alterations in the eutopic endometrium of those women with the disease, which favor invasion and maintenance of the lesions. location of pain: shallow, when pain is located in the vestibule of the vagina; deep, which is highly common Risks of Adverse Pregnancy Outcome & in endometriosis, wherein pain presents in the vaginal Preterm Birth vault; and general, when pain is present throughout Previous uncontrolled studies demonstrated an the entire vagina. The dysfunction may manifest increased incidence of spontaneous abortion in early, appearing at the beginning of intercourse and women with the disease. Subsequent data, however, subsiding soon after, or late, presenting at the end or have yielded contradictory results.56 after intercourse and lasting as many as several hours postcoitus. More recently, endometriosis has been linked to a spectrum of pregnancy complications, originating either in the implants or in the uterus. Disorders of intercourse; secondary dyspareunia arises later. More pregnancy associated with endometriosis include than half of women with endometriosis have suffered spontaneous hemoperitoneum in pregnancy (SHiP), primary deep dyspareunia during their entire sex lives, bleeding, and preterm birth. A recent cohort study severely impairing their quality of sexual life.9 also provided further evidence that subfertile women who conceive spontaneously are at increased risk Often depicted as psychogenic in nature, the true of pregnancy complications, including antepartum etiopathogenesis may well be the result of organic, hemorrhage, cesarean delivery, pregnancy-induced multidisciplinary causes. In women with endometriosis, hypertension, preeclampsia, and very preterm birth.56 dyspareunia is often among cardinal symptoms along with pelvic pain and dysmenorrhea; among disorders The disease extends beyond the mere presence of connected with dyspareunia, endometriosis brings ectopic endometrial glands and stroma, profoundly 58 affecting the different cellular compartments in the uterus, including the junctional zone . Deep dyspareunia is a frequent component of While the majority of clinical focus on the endometriosis-associated pain, affecting 60% to 80% consequences of uterine dysfunction associated with of patients undergoing surgery and between 50% and endometriosis has been on implantation defects and 90% of those using medical therapies. In women with infertility, it is known that these ectopic lesions are a the disease, deep dyspareunia is often most severe before menstruation; is usually positional, decreasing SHiP, obstetric bleeding, and preterm birth.56 Infertile with changing coital positions; and has been associated patients with endometriosis may require additional with the presence of deep lesions of the uterosacral monitoring with increased attention when they ligaments. Women with this type of lesion have a become pregnant.57 higher intensity of dyspareunia than those with lesions in other locations. The disorder may also be caused Dyspareunia by traction of scarred inelastic uterosacral ligaments Dyspareunia, a prominent sequela of endometriosis, during intercourse or by pressure on nodules imbedded is characterized as sexual dysfunction manifesting as pain in the reproductive organs before, during, or organs during sex may contribute to pathogenesis.9 soon after . It is highly common

14 interstitial cystitis; moreover, 80% of CPP patients a number of other organic pelvic disorders that 60 may cause or contribute to dyspareunia as well, including but not limited to interstitial cystitis, pelvic According to the International Pelvic Pain Society, in congestion syndrome, levator ani muscle myalgia, patients with pudendal neuralgia, adenomyosis, leiomyoma, , restrictions (subcutaneous panniculosis) are present. Upon examination, the tissue presents with tenderness mechanical trauma. and trophic changes, including abnormal skin texture Dyspareunia should be routinely investigated during thickening of subcutaneous tissue, and underlying endometriosis consultations even in absence of patient muscle . Functionally, ischemic tissues are complaint. Asking if there is pain present during or hypersensitive to touch and may cause pain upon after intercourse may address emotional and physical compression (peritoneal pain elevated by sitting, concerns the patient herself has left unspoken. reduced by standing). Increased sympathetic activity from painful stimuli, for example, the pudendal nerve, Medical treatment, surgical intervention, and combination therapy may improve deep dyspareunia in women with the disease. GnRH-A may temporarily agents with resultant tenderness and restriction. The decrease the state of the disease thus reducing pain with intercourse, while continuous oral contraceptive locations distant to the involved organ or nerve; for therapy or the -releasing intrauterine device may also reduce intensity of deep dyspareunia panniculosis in lower extremities.61 with limited side effects. Aromatase inhibitors, more recent to the realm of endometriosis treatment, were shown in combination with acetate to (88.5%) in chronic pelvic pain studies suggests that disease entity should be added to the differential though pain recurred after cessation of treatment.59 diagnosis for chronic pelvic pain syndrome, updating 62 In particular, laparoscopic excision of deep endometriotic lesions has been demonstrated to Cancer & Autoimmune Connection Endometriosis, more than simply “killer cramps” as it also the quality of sex life.9 is so often trivialized, may be related to a number of hereditary, environmental, epigenetic, and menstrual The “Evil Triplets” of Chronic Pelvic Pain: characteristics, some sharing certain common Interstitial Cystitis, Levator Neuralgia, & processes with cancer.28 Indeed, it is important to Endometriosis note that endometriosis is not cancer. The disease Interstitial cystitis, which has emerged as a more does, however, correspond to a variety of co-morbid common disorder than previously recognized, is conditions, ranging from autoimmune disease to food estimated to affect upwards of 2.5 million women in and environmental allergies to malignant concerns. the United States. Characterized by urinary urgency Multiple prior studies have indicated an association and frequency, pelvic pain, and dyspareunia without between endometriosis and a number of autoimmune presence of infection, interstitial cystitis is a progressive disorder that worsens if left untreated. Studies have long bowel disease, food intolerances, allergies, and demonstrated the high prevalence of and association chronic fatigue.3,63,64 between interstitial cystitis and endometriosis, termed the “evil twins” of chronic pelvic pain syndrome.60 Less clear is the potential link between endometriosis and certain . Much debate continues to surround Interstitial cystitis has long been ignored as a major the cancer-endometriosis link, with researchers calling contributor to chronic pelvic pain. Studies have shown the “histogenesis of endometriosis and endometriosis- associated ovarian cancer [one of the] most mysterious that over 90% of chronic pelvic pain patients have aspects of pathology.”65

15 DIAGNOSIS association represents causality or the sharing of similar risk factors and/or antecedent mechanisms.66 Barriers to Diagnosis Nonetheless, it has been well established that the Due to lack of awareness, endometriosis is an often disease is indeed associated with an increased risk for underappreciated diagnosis. Women and girls with non-Hodgkin lymphoma and certain malignant tumors, the disease suffer a delay in diagnosis, on average, notably ovarian, with 15% to 40% of endometrioid of 7 to 12 years68 ovarian carcinoma cases being associated with physicians before their pain is addressed. Moreover, endometriosis. Based on this frequent association, the disease may be mistakenly dismissed as routine many reports implicate endometriosis as a precursor menstrual pain, particularly in younger women. It is lesion to ovarian cancer. not possible to triage women with chronic pelvic pain The risk of ovarian cancer among those patients with from referral to a specialist center for careful clinical endometriosis is higher than those without the disease assessment and investigation; the gold standard by 30% to 40%. One analysis of benign ovarian remaining laparoscopic pelvic examination and, where endometrioid tumors found frequent coexistence appropriate, peritoneal biopsy.8 of endometriosis and endometrioid neoplasms, supporting a genetic link between the two. In an estimated 60% of endometriosis-associated ovarian knowledge about endometriosis is limited, with cancers, the cancer is adjacent to or directly arising possible direct consequences on the delay of diagnosis. from the endometriotic tissue, lending credence to the fact that malignant transformation can indicated they felt ill at ease in the diagnosis and and does occur.19 follow-up of patients with endometriosis. One-half could not cite three main symptoms of the disease out Animal studies suggest that common molecular of dysmenorrhea, dyspareunia, chronic pelvic pain, and infertility. Only 38% of general practitioners indicated PTEN/PI13, are involved in the pathogenesis of both that they perform a clinical gynecologic examination endometriosis and endometrioid ovarian carcinoma. for suspected endometriosis, and 28% recommended 69 multiple genes within the RAS/RAF/MAPK and P13K pathways in endometriosis patients, as compared In that endometriosis requires a surgical diagnosis, to controls. Of note, PTEN and K-RAS mutations use of biomarkers has recently been described as the were found to play a role in the development of low- highest priority in research due to the continued lack grade ovarian endometrioid carcinomas; synchronous of noninvasive diagnostic means. Lack of nonsurgical diagnosis and timely intervention,19 though proteomics endometriosis. Moreover, loss of the PTEN tumor and genomics are establishing the basis for future study suppressor gene has been implicated in progression related to biomarker development. from endometriosis to endometrioid ovarian cancer.19 Clinical Diagnosis: Pelvic Examination & Endometriosis does present serious risk factors that Pain Mapping can accelerate the development of ovarian cancer Though physical examination has poor sensitivity, by 5.5 years.19 association between endometriosis and cancer remain of imaging prior to surgery.70 Indeed, the poor 67 negative predictive value of the pelvic exam Nonetheless, providers from all disciplines should was demonstrated in one study of 91 patients, in for early detection. endometriosis and chronic pelvic pain had normal bimanual examinations.71

16 The most common areas involved with endometriosis suppressed sequences for all imaging examinations, include the cul-de-sac and uterosacral ligaments, because such sequences facilitate the detection of usually very accessible on pelvic exam. When probed, small endometriomas and aid in their differentiation the patient may exhibit pain. A thorough combination from mature cystic teratomas. It must also be of history, physical examination, and laboratory remembered that benign endometriomas, like many and additional diagnostic studies as indicated can pelvic malignancies, may exhibit restricted diffusion. determine the cause of pelvic pain and rule out other nonendometriosis concerns. The physical exam should Although women with endometriosis are at risk for include pain mapping, a helpful procedure used to developing clear cell and endometrioid epithelial identify location of the pain with various diagnostic modalities. While some studies have proposed that uterosacral nodularity is better palpated during of malignancy is offered. The presence of a dilated menses, no studies have conclusively demonstrated fallopian tube, particularly one containing hemorrhagic contents, is often associated with pelvic endometriosis. nodular masses along thickened uterosacral ligaments, posterior uterus, or the posterior rectovaginal septum pelvic ligaments, anterior rectosigmoid colon, bladder, may be present.70 Obliteration of the cul-de-sac in uterus, and cul-de-sac, as well as surgical ; the imply extensive disease. subcentimeter foci with T2 hyperintensity representing Rupture of an ovarian endometrioma may present as an acute abdomen. Extensive involvement of the rectum 72 and other areas of the gastrointestinal tract may cause adhesions and obstruction.10 endometriomas, which are characterized by high Imaging Studies signal intensity on T1-weighted images and low As effects of the disease may be devastating, signal intensity on T2-weighted images. Correlation radiologists should be familiar with the various imaging of the radiologic imaging features of endometriotic manifestations of endometriosis, particularly those that lesions with their laparoscopic appearances may allow its differentiation from other pelvic lesions.72 Still, whilst diagnostic imaging may be helpful in the diagnosis of endometriosis.76 endometriosis diagnosis, it is not without drawbacks and limitations. Transvaginal or endorectal ultrasonography may also reveal ultrasonographic features of endometriomas, In terms of best imaging modality, MRI enables very varying from simple cysts to complex cysts with small lesions to be detected and can distinguish the internal echoes to solid masses, usually devoid of hemorrhagic signal of endometriotic lesions due vascularity.77 Computed tomography scanning may to its very high spatial resolution. Indeed, in certain reveal endometriomas appearing as cystic masses; views, it is no longer acceptable to operate on severe endometriosis without exploring the uterus by MRI modalities should not be relied upon for diagnosis. to exclude the presence of uterine adenomyosis.73 Moreover, it performs better than the CT scan in As technologies improve, clinical symptomatology detecting the limits between muscles and abdominal combined with characteristic imaging features subcutaneous tissues.74 MRI has been shown to in appropriate patient populations may facilitate accurately detect rectovaginal disease and obliteration minimally invasive and noninvasive diagnoses. Current in more than 90% of cases when ultrasonographic gel areas of research include predictive biomarkers for was inserted in the vagina and rectum.75 early diagnosis utilizing a metabonomics approach,78 79 Siegelman and Oliver72 offer expert pearls concerning dynamic contrast-enhanced imaging studies,80 use of MRI for detection and characterization of pelvic for early diagnosis,81 and more.

17 Surgical Diagnosis & Staging Advanced disease with anatomic impairment Laparoscopic intervention remains the standard (distortion of pelvic organs, endometriomas, bowel or bladder dysfunction) endometrial glands and stroma in biopsy specimens Failure of expectant/medical management is typically required to make the diagnosis, Endometriosis-related emergencies, that is, rupture or torsion of endometrioma, bowel obstruction, or obstructive uropathy a presumptive diagnosis.82 The goals of conservative surgery include removal of Due to the subtle appearance of some implants, disease, lysis of adhesions, symptom reduction and accuracy of diagnosis depends on the ability of the relief, reduced risk of recurrence, and restoration of surgeon to adequately identify the disease. A thorough organs to normal anatomic and physiologic condition.84 and systematic examination of the pelvis and abdomen This may be achieved through a variety of instruments is essential in all patients to identify and document and techniques. If endometriosis is histologically all lesions, with care taken not to overlook peritoneal pockets and ovarian fossae.82 recommended management is to refer the patient to an endometriosis center.85 The American Society for Reproductive Medicine’s Laparoscopy is the most widely used and accepted staging system. When endometriosis is diagnosed at the time of surgery, surgical destruction is recommended,86 on size and number of lesions and bilaterality, as well with the objective to remove endometriotic lesions, as associated adhesion formation noted at the time preserve uterus and ovarian tissue, and restore of surgery, is a fairly accurate method of recording normal anatomy. This may be achieved through standard or robotic-assisted laparoscopy. Rarely is does not correspond well to pain and dyspareunia, and laparotomy indicated. fecundity rates cannot be predicted accurately.10 Laparoscopy remains a generally safe procedure, As a result, attempts to develop a staging system well-tolerated and associated with reduced hospital that meets the need to establish a common language stays, complications, and postoperative morbidity. Complications are becoming ever-increasingly of diagnosis, standardize comparisons, and facilitate less common; approximately 3.2 per 1000 cases.87 research have been undertaken. Adamson and Pasta83 However, traumatic complications may uncommonly have subsequently developed a validated, clinically occur (eg, bowel, bladder, or gastric perforation; large vessel or ureteral injury).88 When complications do endometriosis attempting non-IVF conception arise, they are primarily related to three categories: (Figure 3). Further efforts are required to develop complications of access, physiologic complications similar staging systems that will help predict outcomes of the pneumoperitoneum, and complications of for patients with endometriosis and pelvic pain for operative procedure.89 both surgical and nonsurgical treatment. A multidisciplinary team approach (eg, gynecologic TREATMENTS endoscopist, colorectal surgeon, urologist) can reduce risk and facilitate effective treatment.19 Surgical Intervention Likewise, advanced surgical skills and anatomical Indications for the surgical management of endome- knowledge are required for deep resection and should triosis include: be performed primarily in tertiary referral centers. Careful preoperative planning, informed consent, and Diagnosis of unresolved pelvic pain meticulous adherence to “best practice” technique is requisite to reduce morbidity and ensure effective functional impairment and reduced quality of life management of potential complications.90

18 Figure 3. Staging: American Society for Reproductive Medicine Revised Classification of Endometriosis

STAGE I (MINIMAL) STAGE II (MILD) STAGE III (MODERATE)

PERITONEUM PERITONEUM PERITONEUM Superficial Endo — 1–3cm -2 Deep Endo — >3cm -6 Deep Endo — >3cm -6 L. OVARY L. OVARY CULDESAC Superficial Endo — <1cm -1 Superficial Endo — <1cm -1 Partial Obliteration -4 Filmy Adhesions — <1/3 -1 Filmy Adhesions — <1/3 -1 L. OVARY TOTAL POINTS 4 R. OVARY Deep Endo — 1–3cm -16 Superficial Endo — <1cm -1 TOTAL POINTS 26 TOTAL POINTS 9

STAGE III (MODERATE) STAGE IV (SEVERE) STAGE IV (SEVERE)

PERITONEUM PERITONEUM PERITONEUM Superficial Endo — >3cm -3 Superficial Endo — >3cm -3 Deep Endo — >3cm -6 L. TUBE L. OVARY CULDESAC Dense Adhesions — <1/3 -16* Deep Endo — 1–3cm -32** Complete Obliteration -40 L. OVARY Dense Adhesions — <1/3 -8** R. OVARY Deep Endo — <1cm -4 L. TUBE Deep Endo — 1–3cm -16 Dense Adhesions — <1/3 -4 Dense Adhesions — <1/3 -8** Dense Adhesions — >1/3cm -4 R. TUBE TOTAL POINTS 51 L. TUBE Filmy Adhesions — <1/3 -1 Dense Adhesions — >2/3cm -16 R. OVARY *Point assignment changed to 16 L. OVARY Filmy Adhesions — <1/3 -1 **Point assignment doubled Deep Endo — 1–3cm -16 TOTAL POINTS 29 Dense Adhesions — >2/3cm -16 TOTAL POINTS 114

Images 2012 © Jespersen & Associates, LLC.

19 Figure 4. Endometriosis Fertility Index (EFI) Surgery Form

LEAST FUNCTION (LF) SCORE AT CONCLUSION OF SURGERY

Score Description Left Right 4 = Normal Fallopian Tube 3 = Mild Dysfunction 2 = Moderate Dysfunction Fimbria 1 = Severe Dysfunction 0 = Absent or Nonfunctional Ovary

To calculate the LF score, add together the lowest score for the left side and the lowest score for the right side. If an ovary is absent on one side, the LF Lowest Score + = score is obtained by doubling the lowest score on the side with the ovary. Left Right LF Score

ENDOMETRIOSIS FERTILITY INDEX (EFI) Historical factors Surgical factors

Factor Description Points Factor Description Points Age LF Score If age is < 35 year 2 If LF Score = 7 to 8 (high score) 3 If age is 36 to 39 years 1 If LF Score = 4 to 6 (moderate score) 2 If age is 40 years 0 If LF Score = 1 to 3 (low score) 0

Years Infertile AFS Endometriosis Score If years infertile is 3 2 If AFS Endometiosis Lesion Score is < 16 1 If years infertile is > 3 0 If AFS Endometiosis Lesion Score is 16 0 Prior Pregnancy AFS Total Score If there is a history of a prior pregnancy 2 If AFS total score is < 71 1 If there is no history of prior pregnancy 0 If AFS total score is 71 0

Total Historical Factors Total Surgical Factors

EFI = Total Historical Factors + TOTAL SURGICAL FACTORS: + = Historical Surgical EFI Score

ESTIMATED PERCENT PREGNANT BY EFI SCORE 100% EFI Score 80% 9–10 7–8 60% 6 40% 5 4 20% 0–3 0% 0 6 12 18 24 30 36 Months

Source: Fertility and Sterility 2010; 94:1609-1615 (DOI:10.1016/j.fertnstert.2009.09.035 ). Copyright © 2010 American Society for Reproductive Medicine.

20 Although excisional biopsy and resection offers a Complete excision of endometriosis, including higher success rate in treating the disease, surgical excision also requires a higher level of surgical in sexual functioning, quality of life, and pelvic pain, skill. As a result, many patients receive incomplete including in those symptomatic patients with deeply treatment, which in turn may lead to persistent symptoms and recurrent disease. It should be noted that fornix of the vagina.94 As well, the technique offers many women who have undergone repeated surgeries good results in terms of reduced bladder morbidity and had a hysterectomy still suffer.86 The need to and bowel symptoms.95,96,97 However, in that this kind improve surgical approach and/or engage in timely of surgery requires advanced skills and anatomical referrals is unquestionable. knowledge, again, it should be performed only in selected reference centers.95 Surgery to debulk and excise endometriosis may be 91 Complete removal Randomized controlled trials also demonstrate that excision is associated with a higher and appearance and visibility. True surgical resection and lower rate of recurrence, though it may cause injury to treatment poses formidable challenges, even the hands the ovarian reserve. Improvements to this aspect may of experienced clinicians. In particular, deep disease be represented by a combined excisional-vaporization technique or by replacing coagulation with surgical ovarian suture.98 and uterine artery.18 Potential adenomyosis should also be included in the preoperative workup, as it can improves general health and psycho-emotional status and symptoms associated with endometriosis.92 at 6 months from surgery without differences between patients submitted to intestinal segmental resection Lesions may present as “powder burn” implants, or intestinal nodule shaving.99 Pain, sexual function, foci of inactive disease containing glands embedded and quality of life were demonstrated to improve in hemosiderin deposits and stroma; nonpigmented lesions appearing as clear vesicles; and as pink, were associated with a good fertility rate and a low white, red, brown, yellow, and blue implants. complication and recurrence rate after a CO2 laser laparoscopic radical excision of endometriosis with normal-appearing peritoneum by light and electron colorectal wall invasion combined with laparoscopic microscopy.47 “Blood painting” or use of staining segmental bowel resection and reanastomosis.100 agents such as indigo carmine or methylene blue may also improve detection.93 Cellular activity is believed Hysterectomy/Oophorectomy/ Salpingo-oophorectomy intermediate lesions.87 Nearly 600,000 are performed annually in the United States, with endometriosis as the second Upon visual diagnosis, laparoscopy is usually extended 101 Though not curative, to an operative procedure, beginning with adhesiolysis hysterectomy with or without bilateral oophorectomy between bowels and pelvic organs in order to expose and adhesiolysis may be appropriate for those patients the pelvic cavity. Ovaries may then be dissected in whom the disease is uncontrolled through surgery from the cul-de-sac or pelvic sidewall, tubes freed or medical suppression. However, probability of pain from adhesions, and implants resected or otherwise persistence after hysterectomy is 15% and risk of pain destroyed. Bowel and genitourinary lesions should worsening 3% to 5%, with a six-time higher risk of be removed. If appropriate, presacral neurectomy or further surgery in patients with ovarian preservation as laparoscopic uterosacral nerve ablation may also be compared to ovarian removal.102 performed to treat central pelvic pain. Removal of endometriomas on the ovaries may also be performed. Excision of endometriosis with uterine preservation is Peritoneal implants should be destroyed using the almost always possible. However, hysterectomy may most effective, least traumatic manner to minimize and be considered for those patients in whom severe pelvic reduce risk of postoperative adhesion formation.47 pain affects the quality of their life and who do not

21 desire . The goal at hysterectomy adherent to, or invades into, the bladder and one is the same as in any endometriosis surgery, that is, to or both ureters.91 remove all disease. As with any procedure, patients should be counseled Common approaches include: outcomes of the hysterectomy option. Removal of uterus and cervix: removing only the uterus with hysterectomy has the same risk Nonsurgical Therapies for recurrence as conservative surgery. Subtotal hysterectomy involves removing the uterus but Medical Therapies keeping the cervix intact. Endometriosis relapse is a matter of debate, since Bilateral oophorectomy or bilateral salpingo- The high rate of recurrence suggests that a combination oophorectomy: for endometriosis treatment, of surgical and medical management might provide removal of ovaries is often performed in maximized outcomes, and any of the agents can combination with hysterectomy.91 be used before, after, or both before and after either conservative or radical surgery. There is no evidence Hysterectomy may be performed abdominally, that medical treatment of endometriosis improves vaginally, or through laparoscopic-assisted vaginal fertility; moreover, fertility is essentially eliminated hysterectomy. Recovery times for vaginal and LAVH during treatment because all medical treatments are shorter than for abdominal hysterectomy. However, inhibit .103 Selection of medical therapy hospital stays may be longer with LAVH than standard for the patient depends on therapeutic effectiveness, vaginal hysterectomy.91 tolerability, drug cost, physician experience, and expected patient compliance. rectum from the posterior vagina to the rectovaginal The rationale for medical therapy is to induce and create a hypoestrogenic environment that will theoretically inhibit endometrial growths and from the uterosacral ligaments, posterior cervix, promote regression of disease. Symptoms recur once posterior vagina, and rectum. Hysterectomy with therapy is discontinued. excision usually results in relief of the patient’s pain, and oophorectomy is not usually necessary. The most The primary goal of medical suppression is to impede severely affected ovary may be removed, however, the growth and activity of endometriotic lesions. especially if on the left, as this ovary frequently Gonadotropin-releasing hormone agonists (GnRH), becomes adherent to the bowel. Bilateral oophorectomy oral contraceptives, , aromatase inhibitors, is rarely indicated in women under age 40 undergoing and progestins are the mainstays in endometriosis hysterectomy for endometriosis.91 treatment, all with the potential to reduce pain and estrogen production.104 All have similar clinical Hysterectomy should not be done for extensive endometriosis with extensive cul-de-sac involvement, and duration of relief.10 unless the surgeon has the skill and time to resect Endometriotic implants express aromatase and vagina, uterosacral ligaments, and anterior rectum. consequently can generate their own estrogen, which In these patients, excision of the uterus using an can maintain their own viability and growth. In contrast to medical suppressives that target ovarian endometriosis behind to cause future problems. estrogen production, aromatase inhibitors inhibit local estrogen production in endometriotic implants themselves as well as in the ovary, brain, and adipose between the anterior rectum and the bladder. After tissue.105 A systematic review showed that aromatase hysterectomy, the endometriosis left in the anterior rectum and vaginal cuff frequently becomes densely associated pain when compared with GnRH

22 agonists alone.106 reduce endometriosis-associated pain. When inserted at the time of laparoscopic surgery, it has been found Aromatase inhibitors are administered in varying to reduce the recurrence of dysmenorrhea by 35%.10 doses, including 2.5 mg daily for letrozole and 1 mg daily for Anastrazole®. Aromatase inhibitors given The Mirena intrauterine device may also be considered to reproductive-age women will cause increased an alternative to hysterectomy in patients with follicle-stimulating hormone levels and subsequent adenomyosis. Anecdotal use in the adenomyosis superovulation. Other concerns about prolonged community has shown promise among those suffering therapy are associated bone loss and multifollicular from related dysmenorrhea, dyspareunia, pelvic pain, ovarian cyst development due to the initial FSH rise. pelvic tenderness, and pelvic indurations. In one study, For this reason, aromatase inhibitors are combined with an FSH suppression agent, such as COCs, improvement in hemoglobin levels to hysterectomy progestins, or GnRH agonists.103 They are well in treating adenomyosis-associated menorrhagia tolerated by patients and may represent a promising therapy for endometriosis.107 to improvements in health-related quality of life, LNG-IUS had superior effects on psychological and Oral contraceptive pills have been used empirically social life, thus making it a promising alternative to alleviate dysmenorrhea for many years. They are therapy to hysterectomy.111 generally well tolerated and confer fewer metabolic and hormonal side effects than Danazol or GnRH therapy. Open clinical trials have shown that oral contraceptives been studied extensively in randomized controlled trials relieve dysmenorrhea, through ovarian suppression for the treatment of primary dysmenorrhea and are of and continuous progestin administration. A study by 112 Although studies that focus solely Guzick et al108 examined a head-to-head comparison on use of NSAIDs for endometriosis are lacking, these of Lupron and continuous oral contraceptives for the agents are widely used because of their acceptable side treatment of endometriotic pelvic pain; both were effects, reasonable cost, and ready availability.104 found to be equally effective. Treatment with GnRH analogues is limited to only 6 to 12 months because Danazol acts by inhibiting the midcycle follicle- these agents induce a hypoestrogenic state that stimulating hormone and surges substantially decreases bone mineral density, whereas and preventing steroidogenesis in the . oral contraceptives may be a simple and effective way Though dated, Danazol has been shown to be as effective to manage the disease through avoidance or delay of as any of the newer agents, but with a much higher menses for upwards of 2 years.109 incidence of adverse effects including androgenic manifestations such as oily skin, acne, weight gain, Progestins inhibit the growth of endometriotic lesions deepening of the voice, and hirsutism. Hypoestrogenic by inducing followed by atrophy features due to Danazol include emotional lability, hot of uterine-type tissue. When compared to GnRH therapy, both treatment modalities show comparable The recommended dose is 600 to 800 mg/day though effectiveness in the treatment of endometriosis-related smaller doses have been used with success.104 chronic pelvic pain.110 GnRH agonists work by producing a hypogonado- trophic-hypogonadic state by downregulation of the in pain suppression in both the oral and injectable depot preparations. Oral doses of 10 to 20 mg/ medical therapy for endometriosis-associated pain day can be administered continuously. The time to in moderate to severe disease in recent decades. resumption of ovulation is longer and variable with Therapy may be administered via intramuscular, depot preparations. Adverse effects include weight to pain suppression, however, with no improvement bleeding. has been used in doses of on fertility rates.10 40 mg with similarly good results. The levonorgestrel concerning the various medical therapies used for ® intrauterine system (Mirena ) has been shown to endometriosis.113

23 With “add-back” therapy, GnRH agonists have a better therapeutic agents for treatment including growth factor inhibitors, angiogenesis inhibitors, cyclo- many series have demonstrated that add-back therapy oxygenase-2 inhibitors, phytochemical compounds, does not interfere with the GnRH agonist’s ability to immunomodulators, dopamine agonists, peroxisome relieve pelvic pain. Disadvantages of long-term use proliferator-activated receptor agonists, and other include the high cost of medication, bone mineral compounds that hold great promise for the future density loss, and hypoestrogenic side effects.104 It treatment of endometriosis. has also been recently suggested that combining progressive muscular relaxation with GnRH-A therapy CONCLUSION may improve anxiety, depression, and health-related quality of life in women with the disease.114 Despite receiving very little mention in historical compendiums of disease, endometriosis has impacted Preoperative GnRH therapy may reduce pelvic lives of women for centuries. It is without question the vascularity and size of endometriotic lesions, reducing disease remains, even now, a chronic, costly illness intraoperative blood loss and decreasing the amount requiring long-term, multidisciplinary treatments. of surgical resection needed. Postoperative therapy Endometriosis, a complex disorder that may go has been advocated as a means of eradicating residual undiagnosed for years, with no absolute cure and a endometriotic implants in patients with extensive disease in whom resection of all implants is impossible reproductive health concern with highly negative and or otherwise inadvisable.103 far-reaching effects.

Alternative Therapies The role of alternative therapies has not been impaired quality of life of the affected contribute to the validated; hence an in-depth discussion is outside urgent need for continued research and improvement the scope of this presentation. Yet, anecdotal in diagnostic and treatment modalities. Focus on better experience and early evidence suggest that herbal clarifying pathogenesis and pain mechanisms as well as medicine, physical therapy, certain diet and nutrition links to certain morbidities, for example, malignancies and autoimmune disease, is necessary. supplements, Traditional Chinese Medicine, and other complementary approaches may indeed result in some Though prevention remains elusive, increasingly reduction of pain and contribute to the treatment of sophisticated research efforts will lead to more timely endometriosis. In general, however, weak evidence intervention and appropriate, multifactorial treatments to restore quality of life, preserve or improve fertility, on impact of health-related quality of life in women and lead to long-term effective management of this with the disease.115 enigmatic disease.

Still, promising research continues to emerge in this area, including one recent study that reviewed the potential use of resveratrol and epigallocatechin-3- gallate (EGCG) as natural treatments. In this animal reduce the mean number and volume of established lesions, consistently diminish cell proliferation, and increase apoptosis within the lesions, as well as induce reduction in human endometrial epithelial cell and will assist in the future development of novel alternative treatments for the disease.116

Likewise, it is expected that the increasing number of related studies will lead to development of additional

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