Deciphering the pathogenesis, pain, and infertility enigmas of endometriosis

Pathogenesis

Article 1 of 3: Deciphering the pathogenesis, pain, and infertility enigmas of endometriosis

Deciphering the pathogenesis, pain, and infertility enigmas of endometriosis

Enhanced understanding of disease pathology is aiding in the refinement of existing endometriosis management strategies and informing the development of emerging therapies

BY KATHLEEN KRAFTON

Endometriosis is a common yet enigmatic disease with a reported prevalence of 10% of reproductive-aged women, 50% of infertile women, and more than 60% of patients with chronic pelvic pain. While the majority of women present with an array of symptoms, chronic pelvic pain, dysmenorrhea, deep dyspareunia, dyschezia, and subfertility form the hallmark of symptoms associated with the disease.1

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Perspectives on Endometriosis Management


The symptoms of endometriosis can profoundly affect a woman's health-related quality of life, and efforts to elucidate its pathophysiology and molecular mechanisms largely have been driven by the desire to enhance treatment outcomes, beginning with timely diagnosis and extending to sustained management and potentially disease prevention.

In recent years, great strides have been made in understanding this complex gynecologic disorder. The role of genetics and the immune system in the development of endometriosis has been extensively studied, with some surprising discoveries.

While there is still much to learn, gains in understanding of the pathophysiology of endometriosis undoubtedly portend progress for enhancing clinical outcomes.

Pathophysiology

Copyright © 2011 by the American College of Obstetricians and Gynecologists.
Published by Wolters Kluwer Health, Inc. All Rights Reserved. Used With Permission.

Copyright © 2011 by the American College of Obstetricians and Gynecologists.
Published by Wolters Kluwer Health, Inc. All Rights Reserved.
Used With Permission.

Endometriosis is believed to result from various anatomical or biochemical aberrations of uterine function.1,2 The three subtypes of endometriosis—endometriomas (ovarian cysts), peritoneal endometriosis, and deeply infiltrating endometriosis (multifocal disease in the pelvis, including the retrocervical area and rectovaginal nodules)—may be variants of the same pathologic process or may be caused by different mechanisms.3,4

Common histologic features across subtypes include the presence of endometrial stromal and/or epithelial cells, chronic bleeding, and signs of inflammation. These lesions may occur singly or in combination.5,6

Presently, a composite model of retrograde menstruation with implantation of endometrial tissue in conjunction with peritoneal factors to stimulate cell growth is the most widely accepted explanation for the development of endometriosis.7 However, this theory does not account for why only certain women with retrograde menstruation develop endometriosis.

According to Linda C. Giudice, MD, PhD, Distinguished Professor of Obstetrics, Gynecology, and Reproductive Sciences at the University of California, San Francisco, “A little bit of retrograde reflux of endometrial tissue at the time of the menses happens in over 90% of women, but only in about 10% to 15% of women does the tissue actually adhere to the various components and organs in the pelvis. When it does, it starts to invade, it makes its own blood supply."

"It also causes an inflammatory reaction and nerves start to grow into these lesions, causing pain.”

Dr. Guidice

Hugh S. Taylor, MD, Chair of Obstetrics, Gynecology, and Reproductive Sciences at Yale School of Medicine and Chief of Obstetrics and Gynecology at Yale-New Haven Hospital in New Haven, Connecticut, believes retrograde menstruation is only part of the story.

“We know that most endometriosis comes from retrograde menstruation,” he said. “But we also know there are probably other etiologies. What my group identified and continues to work on is the contribution of stem cells to endometriosis—how the cells from bone marrow and probably some other sources can actually contribute to and feed endometriosis. We think these circulating stem cells probably account for endometriosis that we occasionally find in areas outside of the uterus, for instance, in the lung and the brain.”

The question of why most women have retrograde menses, but only some develop endometriosis, may be answered by an inherent immune dysfunction in women who develop the disease. This dysfunction impairs normal clearance while simultaneously promoting disease progression through factors that promote adherence or invasion, angiogenesis, and sensory, sympathetic, or parasympathetic innervations.1

Tommaso Falcone, MD, Professor and Chair of Obstetrics and Gynecology at the Cleveland Clinic in Cleveland, Ohio, pointed to work published by Serdur Bulun, MD, in the New England Journal of Medicine that described the molecular mechanisms involved in the pathogenesis of endometriosis.2 Bulun linked increased cell survival, inflammation, and deficient differentiation in endometriosis to a stromal-cell defect involving the overexpression of estrogen and prostaglandin, as well as progesterone resistance. These were shown to originate from two distinct epigenetic changes that affect the transcription factors SF1 and estrogen receptor β.2

“These genes, because of defective methylation, give rise to overproduction of estrogen locally, at the level of the endometriosis, and prostaglandin,” said Dr. Falcone, “and they suppress progesterone receptors, which is what leads to progesterone resistance. So if you have a progesterone-receptor deficiency, if you have a progesterone resistance, you have a molecular abnormality in the endometrium.”

The endometrium expresses certain genes that allow the retrograde menstruation to implant, Dr. Falcone said. “And this collective molecular abnormality gives rise to an enhanced survival, so the endometrium survives longer in the belly of women who are genetically predisposed to endometriosis because of molecular events...

…and it leads to inflammation, the most important biological marker of endometriosis.”

Studies targeting the excessive production of estrogen and prostaglandin and the development of progesterone resistance are clinically significant because the therapeutic targeting of aromatase in the estrogen biosynthetic pathway, cyclooxygenase-2 (COX-2) in the prostaglandin pathway, or the progesterone receptor have been shown to reduce pelvic pain or laparoscopically visible endometriosis or both.2

Additionally, recent research by Dr. Taylor and his colleagues showed that endometriosis can secrete inflammatory molecules and microRNAs into the circulation. “Some of the widespread manifestations of this disease may very well be from these things that are secreted into the circulation,” he said. “Inflammatory molecules that create generalized inflammation and microRNAs that may have influences on cells and other tissues in the body.”

In an experiment conducted by Dr. Taylor and his research group, endometriosis was inserted “in an area far away from the uterus—between the shoulder blades” of mice.

“We showed that, even with endometriosis far away from the uterus, not touching the uterus, not inflaming the area around the uterus, it still changed the uterus in a way to make it less fertile.”

In other experiments, Dr. Taylor also has shown that endometriosis created in mice altered different genes in the liver that affect metabolism. “We’ve known that endometriosis patients tend to be thin, and the thought was that to be thin or not eating right was perhaps a risk factor for endometriosis, but we’ve proven that it’s just the opposite…the disease caused the thinness and poor eating.”

Such findings are helping clinicians to recognize endometriosis not as “a little local disease in the pelvis, but as a systemic disease,” said Dr. Taylor. “I think that is a major change in philosophy that our group has been responsible for describing. We can clearly show that, in the animal models, the disease causes these dysfunctions that go way beyond just affecting the uterus and the surrounding tissues.”

Mechanisms of pain

Clinical evidence points to the presence of increased proinflammatory cytokines and growth factors in endometriosis (ie, nerve growth factor, prostaglandin, and estradiol), which are closely related to pain sensation.8

Altered cytokine production by both cells of the immune system and the endometrial tissue is believed to contribute to these elevated cytokine levels, and altered progesterone responsiveness has been implicated as a key driver for the increased production of proinflammatory cytokines.9

Dr. Falcone believes these findings may help to explain why many women with minimal endometriosis still experience significant pain.1 “There’s a lot more of these growth factors in minimal disease,” he said. “Inflammation is what causes the problems we see—the pain and infertility.”

Endometriosis has been described as a hyperalgesic state. Researchers believe this is the result of amplified pain processing, a response to how the spinal cord and the brain process pain from lesions and other sensory information. Peripheral nerve fibers that supply endometriosis lesions could sensitize spinal segment neurons, and this in turn could ultimately lead to central nervous system sensitization, resulting in an exaggerated central nervous system response, despite ablation of lesions.1,10–12

Anatomy also plays an important if obvious role. “If the endometriosis is in an area that is either particularly sensitive or deeply invasive—if it gets in a particularly sensitive area filled with nerve endings—either of those can be a problem,” said Dr. Taylor.

Clinically, the deeply infiltrating disease subtype is strongly associated with pelvic pain, such as dysmenorrhea, deep dyspareunia, chronic pelvic pain, and dyschezia.13 Symptom intensity has been shown to correlate with the depth of infiltration, the location, and the tendency of some endometrial lesions to invade neuronal structures.14–16

“Simultaneously with a lot of adhesions, deep endometriosis invades nerves and produces these inflammatory cytokines, such as TNF [tumor necrosis factor]-alpha, and that causes pain, even in mild disease,” said Dr. Falcone. Significant scarring, such as that seen in advanced disease, also can result in significant pain.

Mechanisms of subfertility

The same mechanisms that have been implicated in endometriosis pain have been identified as mechanisms of subfertility in women with endometriosis.

“About 10% to 15% of women who have unexplained infertility are thought to have endometriosis,” said Dr. Giudice. This is called endometriosis-related infertility, she says. Her research has pointed to the pro-inflammatory milieu in the endometrium, which is thought to be adverse to implantation, and abnormalities in the lining of the uterus in women with endometriosis.

“The inflammatory milieu in the pelvis is thought to have an adverse effect on egg quality, sperm quality, fertilization, and embryo development. We and others have shown that the lining of the uterus doesn’t respond to progesterone as well as one would hope it would, or as in normal women.” And this response is critical for implantation, she said.

Additionally, in cases involving advanced adhesive disease, the reduction in tubo-ovarian motility has been shown to diminish pick-up function.1 “When you have a lot of disease, a lot of adhesions and scarring, it’s very difficult,” said Dr. Falcone. “Infertility is a mechanical problem. There’s no movement of the tubes, no movement of the ovaries, the ovary itself maybe has a decreased ovarian reserve, a decreased fertility intrinsically because it developed a cyst.”

Adhesions also can block and distort the anatomy, said Dr. Taylor.

“I think one of the biggest ways that endometriosis interferes [with fertility] is its effect on the uterus in which it decreases the implantation rate—the embryos can’t attach as well.”

Dr. Taylor

Management strategies

Management of pain and subfertility associated with endometriosis involves either a medical or surgical approach.

“Most people start off with medical therapy for the symptoms of pain,” said Dr. Giudice. “That would be NSAIDs like ibuprofen and some kind of contraceptive—either continuous birth control pills or progestins, either an IUD or an implant or Depo-Provera [medroxyprogesterone acetate]. If that doesn’t work, one usually goes to third-line therapy, which is a GnRH agonist.”17

While birth control pills are characteristically prescribed as first-line agents for endometriosis, approximately one-third of women will fail birth control pill therapy, said Dr. Taylor. “Those patients will need to move on to something more aggressive. These days, that’s typically Lupron [leuprolide] in the US, although there are a lot of other drugs being developed to battle endometriosis. There are some really nice new drugs on the horizon.”

Surgery is an effective means of quickly relieving pain associated with endometriosis, but recurrence is a major drawback. “There is usually a latency after the surgery when the pain returns,” said Dr. Giudice. “That can be anywhere from 1 to 5 years, and the data show about 50% of women have a return of symptoms by 5 years, requiring repeat surgery.”

“You really need to think about medical management for long-term suppression,” said Dr. Taylor.

If a patient wishes to conceive, an alternate treatment approach is required as the medical therapies that are available for endometriosis are contraceptives. “Ovulation enhancement with aromatase inhibitors or clomiphene are very good treatments for women who have endometriosis and infertility,” said Dr. Giudice. “IVF [in vitro fertilization] also is a very good treatment for subfertility associated with endometriosis.”

While promising new therapies are on the horizon, Dr. Taylor pointed to a more immediate method for improving outcomes in women with endometriosis: early diagnosis.

“Taking advantage of our new knowledge of the pathophysiology, using biomarkers like circulating microRNAs that may allow us to soon have a blood test for endometriosis, maybe we can get people diagnosed earlier. We can start treating it earlier, before it progresses to the point where it does damage that is no longer fixable by medical therapy.”

Dr. Taylor

Until such time that a blood test or other noninvasive diagnostic modality becomes available, Dr. Taylor suggests clinicians make a presumptive diagnosis and begin treatment when classic symptoms of endometriosis are present.

“The treatments are very harmless,” he said. “Something such as a birth control pill is used for so many other reasons—there’s little downside to giving it a try.”

References


1. Falcone T, Lebovic DI. Clinical management of endometriosis. Obstet Gynecol. 2011;118(3):691–705.
2. Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268–279.
3. Garry R. The endometriosis syndromes: a clinical classification in the presence of aetiological confusion and therapeutic anarchy. Hum Reprod. 2004;19(4):760–768.
4. Brosens I. Endometriosis rediscovered? Hum Reprod. 2004;19(7):1679–1680.
5. Guzick DS, Silliman NP, Adamson GD, et al. Prediction of pregnancy in infertile women based on the American Society for Reproductive Medicine's revised classification of endometriosis. Fertil Steril. 1997;67(5):822–829.
6. Stovall DW, Bowser LM, Archer DF, Guzick DS. Endometriosis-associated pelvic pain: evidence for an association between the stage of disease and a history of chronic pelvic pain [published correction appears in: Fertil Steril. 1998;69(5):979.]. Fertil Steril. 1997;68(1):13–18.
7. Gazvani R, Templeton A. Peritoneal environment, cytokines and angiogenesis in the pathophysiology of endometriosis. Reproduction. 2002;123(2):217–226.
8. Lebovic DI, Mueller MD, Taylor RN. Immunobiology of endometriosis. Fertil Steril. 2001;75(1):1–10.
9. Nothnick W, Alali Z. Recent advances in the understanding of endometriosis: the role of inflammatory mediators in disease pathogenesis and treatment. F1000Res. 2016;5.
10. Bajaj P, Bajaj P, Madsen H, Arendt-Nielsen L. Endometriosis is associated with central sensitization: a psychophysical controlled study. J Pain. 2003;4(7):372–380.
11. Asante A, Taylor RN. Endometriosis: the role of neuroangiogenesis. Annu Rev Physiol. 2011;73:163–182.
12. Stratton P, Berkley KJ. Chronic pelvic pain and endometriosis: translational evidence of the relationship and implications. Hum Reprod Update. 2011;17(3):327–346.
13. Chapron C, Santulli P, de Ziegler. Ovarian endometrioma: severe pelvic pain is associated with deeply infiltrating endometriosis. Hum Reprod. 2012;27(3):702–711.
14. Koninckx PR, Meuleman C, Demeyere S, Lesaffre E, Cornillie FJ. Suggestive evidence that pelvic endometriosis is a progressive disease, whereas deeply infiltrating endometriosis is associated with pelvic pain. Fertil Steril. 1991;55(4):759–765.
15. Anaf V, Simon P, El Nakadi I, et al. Relationship between endometriotic foci and nerves in rectovaginal endometriotic nodules. Hum Reprod. 2000;15(8):1744–1750.
16. Anaf V, Simon P, El Nakadi I, et al. Hyperalgesia, nerve infiltration and nerve growth factor expression in deep adenomyotic nodules, peritoneal and ovarian endometriosis. Hum Reprod. 2002;17(7):1895–1900.
17. Giudice LC. Clinical practice. Endometriosis. N Engl J Med. 2010;362(25):2389−2398.

Drs. Guidice, Taylor, and Falcone report no financial relationships relevant to this article.
Kathleen Krafton is a contributing writer for OBG MANAGEMENT.

 
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