Endometriosis: Theories of Pathogenesis

Often referred to as an "invisible illness," endometriosis remains poorly understood

Endometriosis is a condition characterized by ectopic endometrial tissue growth, resulting in inflammation, infertility, and severe, chronic pain. Symptoms include dysmenorrhea, pain with intercourse, pain with bowel movements or urination, excessive bleeding or intermenstrual bleeding, and infertility.

It is estimated that endometriosis affects approximately 1 in 10 women of reproductive age, with a mean latency of 6.7 years from the onset of symptoms to diagnosis. It is also considered an invisible illness contributing to an increased risk of depression.

Pathogenesis theories

Endometriosis remains poorly understood, and several theories for its pathogenesis have been proposed.

Retrograde menstruation is an early theory, proposing that endometriosis is the result of retrograde flow of cells and debris into the pelvic cavity via fallopian tubes during menstruation. Shed cells attach to the peritoneum, proliferate, differentiate, and invade the underlying tissue.  

Coelomic metaplasia theory postulates endometriosis results from extrauterine cells in the mesothelial lining of the visceral and abdominal peritoneum that abnormally differentiate into endometrial cells. Hormonal and immunological factors are thought to stimulate differentiation.

Embryonic rest theory proposes that specific stimuli to cells present in the peritoneal cavity, originating from the müllerian duct system, may induce them to form endometrial tissue. This theory may account for the presence of rectovaginal endometriosis.

Lymphatic and vascular metastasis theories propose that endometrial cell spread to ectopic sites may be the result of lymphatic and hematogenous spread. This theory is supported by the presence of endometriosis at various sites within the body, including the brain, lung, lymph nodes, and abdominal wall.

Stem cell theory has emerged more recently. The endometrium is composed of an inner basalis layer consisting of stroma, leukocytes, and vasculature, and an outer functionalis layer consisting of dense glandular tissue and a loose connective stroma. During each menstrual cycle, the functionalis and a small part of the basalis are shed, and evidence supports the existence of an adult stem cell population within the endometrium serving as a source of regenerative endometrial cells. These undifferentiated cells may spread outside the endometrium via retrograde menstruation, or hematogenous or lymphatic dissemination and initiate the formation of lesions. Evidence suggests bone marrow-derived stem cells may also contribute to the pathogenesis of endometriosis. 

Diagnosis

Superficial peritoneal lesions are usually located on pelvic organs or the pelvic peritoneum. Classic lesions are bluish or blue-black and resemble the endometrium, whereas non-classic lesions include clear, red, and white lesions. Ovarian endometriomas consist of a dense, brown fluid, and deep infiltrating endometriosis (DIE) is a blend of fibromuscular tissue and adenomyosis, primarily found in the uterosacral ligaments or cul-de-sac. 

Visual inspection by laparoscopy is the gold standard for the diagnosis of endometriosis, combined with histological confirmation. Two or more of the following histologic features must be present for diagnosis: endometrial epithelium, endometrial glands, endometrial stroma, or hemosiderin-laden macrophages.

Non-invasive techniques include ultrasound and MRI. Transvaginal ultrasound may be useful to diagnose endometriomas, bladder lesions, and deep nodules. MRI may be used to guide surgical approaches for deep infiltrating endometriosis. 

Diagnosis also relies on symptom evaluation, patient history review, and physical examination to identify nodules, retroverted uterus, masses, or external endometriomas. 

Emerging Treatments and Clinical Trials

There is no single, effective treatment strategy for endometriosis, and several clinical trials will begin to examine the effects of novel treatment strategies. Dichloroacetate (DCA), for example, has been shown to stop the growth and survival of endometriosis cells and reduce lactate production in a laboratory setting and its effects on endometriosis-associated pain will be examined in a single-arm open label exploratory clinical trial. Low-dose Naltrexone combined with hormonal suppression (standard of care) will also be evaluated for its effects on endometriosis pain.

Endometriosis is also associated with poor reproductive outcomes in the context of in vitro fertilization, and embryo transfer. Elagolix (Orilissa) is a new generation orally active GnRHR antagonist FDA approved for the treatment of endometriosis and pelvic pain. In a randomized controlled trial, the medicine will be compared to oral contraceptives for suppression of endometriosis prior to embryo transfer.  

Other studies will examine hormonal suppression in combination with novel treatments. Interleukin-1 (IL-1) receptor antagonist Anakinra, is a subcutaneous injectable drug FDA approved for rheumatoid arthritis, and its effects in combination with hormonal suppression will be examined for pelvic pain. Similarly, a study will examine the effects of GnRHa combined with autologous natural killer (NK) cell therapy.


Michelle Dotzert, PhD

Michelle obtained her PhD in Kinesiology from the University of Western Ontario. Her research examined the effects of exercise training on skeletal muscle lipid metabolism and insulin resistance in the context of Type 1 Diabetes.