Introduction
Endometriosis is a chronic incurable gynecological condition with cyclical pelvic pain, heavy bleeding, infertility, and reduced quality of life as its main manifestations. Almost half of women with it experience infertility. [1] No symptoms are specifically pathognomonic or characteristic of endometriosis. Often referred to as a ‘silent disease’ because of how often the diagnosis is missed, delayed, or dismissed, the rapid upward incidence of endometriosis since the 1980s has also led to the use of the term “silent epidemic”. [2] Approximately 10 percent of reproductive age women, or 190 million globally are impacted by it, which is no small number. [3]
Borrowing from Churchill’s famous phrase about Russia, endometriosis has been described as “a riddle wrapped in a mystery inside an enigma”. [4] First formally identified and named in 1921, the word “endometriosis” derives from the Greek terms, endo “inside,” metra “uterus” and osis “disease”. It is characterized by the implantation of womb-like tissue outside the uterus mainly on pelvic organs and tissues. A widespread theory, which is at best incomplete, attributes endometriosis to retrograde menstruation (RM) or the backward flow of menstrual blood with subsequent seeding of endometrial tissue outside the uterus.
The gold standard for definitive diagnosis of endometriosis is laparoscopic surgery with direct biopsy and histological confirmation. However, because surgery is costly, disruptive, and invasive, recent guidelines advocate for the use of ultrasound and magnetic resonance imaging (MRI) in place of or prior to diagnostic laparoscopy. The average delay of diagnosis is 6-11 years in part because of how vague and nonspecific its symptoms and signs are, and because these symptoms and signs frequently mimic other overlapping pelvic pain conditions like irritable bowel syndrome, pelvic inflammatory disease (PID), and interstitial cystitis. [5] Current treatment options, which include surgical removal of endometriosis tissue with or without hysterectomy, non-steroidal anti-inflammatory drugs (NSAIDs) and other analgesics, or hormonal manipulation, aim to control the symptoms. However, none are curative, and none are free from clinically relevant side effects; these include hot flashes, weight gain, and bone loss from hormone therapy, stomach upset/gastric ulcers from NSAIDs, and infections and adhesion formation from surgery. The cause or etiology of endometriosis is unclear, and no consensus has been reached on how to best describe or classify it.
Increasingly, however, endometriosis is recognized as an inflammatory disease that involves a specific type of innate immune cell called the macrophage. This article touches on the evidence for macrophages as the main perpetrators of endometriosis and discusses potential treatment options to rehabilitatively reprogram them.
Ms. Pac Man Macrophages
Much more than big eaters, as their name— “macro” meaning big and “phage” meaning eater—implies, macrophages are uniquely located at the intersection between immune suppression and immune aggression. Incredibly malleable and multifunctional cells, macrophages exist on a spectrum, straddling between two different states, M1 and M2, depending on the context. Like Pac Man (or Ms. Pac Man in this case), M1 macrophages engulf cellular debris, whereas M2 macrophages, like the Pac Man Ghosts, oppose the actions of M1 macrophages and contribute to the development of endometriosis, as shown in the Figure below. The M2 macrophages that accumulate in endometriosis tissue are referred to as endometriosis-associated macrophages (EAM); they have been linked not only to the growth and vascularization of endometriosis, but also to the recruitment and activation of pain nerve fibers, which is central to the symptomatology of the disease. [6]
‘Power Pellet’ Treatment Strategies
Like the Red, Pink, Cyan, and Orange Ghosts that become vulnerable Blue Ghosts when Ms. Pac Man engulfs a power pellet, M2 macrophages are potentially targetable with therapies that reprogram them to an M1 state.
Several minimally toxic, non-hormonal therapies have the potential to shift the macrophages from M2 to M1. These include phytochemicals or plant-based compounds, inhibitors of vascular endothelial growth factor (VEGF) like the anticancer agent, Avastin, the use of M1 macrophages themselves, [7] and other M2 macrophage-reprogramming therapies in preclinical and clinical development.[8]
Clinical trials are underway that will definitively put these therapies to the test in endometriosis and address their risk to benefit profiles.
Conclusion
Endometriosis is an age-old disease and an unmet medical need. A new paradigm is needed. The most widespread theory since 1920 has been that retrograde menstruation (RM) alone causes endometriosis. However, true or not, and, somewhat incredibly, the jury is still out on that, RM fails to account for several other factors such as genetics, and the presence and infiltration of macrophages in endometrial deposits.
Questions of validity and completeness aside, the real problem with RM is that it puts the emphasis on menstruation, which often, out of modesty, requires euphemisms, or perhaps euphemistic dysphemisms like “The Curse”, “Riding the Crimson Wave”, “Aunt Flo”, “on the rag”, and “the Red Coats are Coming” to talk about it. By extension, then, RM stigmatizes endometriosis as a “taboo” and not-to-be-publicly-discussed condition.
Despite the outspokenness of several celebrities like Spice Girl, Emma “Baby Spice” Bunton, model Olivia Culpo, and conservationist Bindi Irwin, who have publicly described their experiences with endometriosis, the stigma persists. Unlike other burdensome chronic diseases such as diabetes and asthma that are appropriately treated as top public health priorities, requiring immediate action, endometriosis continues to be marginalized, which is a major cause of untimely diagnosis, delayed treatment, lack of funding, and psychological and physical harm.
However, with the ongoing paradigm shift to EAMs (endometriosis-associated M2 macrophages) as the major underlying cause of endometriosis it is possible to recast and recontextualize the disease not as a problem of abnormal, retrograde menstruation but as one of immune dysfunction or even autoimmunity. Like cancer, which is associated with immune dysfunction and M2 tumor-associated macrophage (TAM) infiltration, endometriosis may benefit from therapies that have the potential to target EAMs at the sites of disease.
Perhaps most importantly, the anticipated success of this paradigm promises to usher in a new era, one which replaces stigma with support, and voicelessness with voice, hopefully making endometriosis a silent epidemic no more.
References
- Miller JE et al. Implications of immune dysfunction on endometriosis associated infertility. Oncotarget. 2017 Jan 24;8(4):7138-7147. doi: 10.18632/oncotarget.12577.
- Cottingham MD. The makings of a modern epidemic: Endometriosis, gender, and politics. Glob Public Health. 2015 Feb 7;10(2):273–4. doi: 10.1080/17441692.2014.986159. Epub 2014 Dec 12.
- Llarena NC et al. Fertility Preservation in Women With Endometriosis. Clin Med Insights Reprod Health. 2019 Sep 3;13:1179558119873386. doi: 10.1177/1179558119873386.
- Acién P et al. Endometriosis: a disease that remains enigmatic. ISRN Obstet Gynecol. 2013 Jul 17;2013:242149. doi: 10.1155/2013/242149.
- Husby GK et al (2003). Diagnostic delay in women with pain and endometriosis. Acta Obstetricia et Gynecologica Scandinavica, 82(7), 649-653. https://doi.org/10.1034/j.1600-0412.2003.00168.x
- Hogg C, Horne AW, Greaves E. Endometriosis-Associated Macrophages: Origin, Phenotype, and Function. Front Endocrinol (Lausanne). 2020 Jan 23;11:7. doi: 10.3389/fendo.2020.00007.
- Artemova D et al. M1 macrophages as promising agents for cell therapy of endometriosis. Heliyon. 2024 Aug 14;10(16):e36340. doi: 10.1016/j.heliyon.2024.e36340.
- Iona McIntyre I et al. Preclinical testing of RRx-001 in mouse models of experimental endometriosis reveals promising therapeutic impacts. bioRxiv 2024.08.12.607591; doi: https://doi.org/10.1101/2024.08.12.60759
Dr. Bryan Oronsky is the Chief Development Officer of EpicentRx. He directs development of the EpicentRx lead small molecule, RRx-001 (nibrozetone), a macrophage-reprogramming therapy, a radioprotector, and an NLRP3 inhibitor, which will start a Phase 2 clinical trial in endometriosis at the University of Edinburgh, Scotland.
Filed Under: Immunology, Obstetrics & gynecology