Spotlight On: Endometriosis

This month we cast a spotlight on articles, SurgeryU videos, and Journal of Minimally Invasive Gynecology (JMIG) article recommendations from the AAGL Endometriosis Special Interest Group (SIG) led by Chair, Shanti Mohling, MD. 

Access to SurgeryU and JMIG are two of the many benefits included in AAGL membership. The SurgeryU library features high-definition surgical videos by experts from around the world. JMIG presents cutting-edge, peer-reviewed research, clinical opinions, and case report articles by the brightest minds in gynecologic surgery.

SurgeryU video recommendations by our SIGs are available for public access for a limited time. The links to JMIG article recommendations are accessible by AAGL members only. For full access to SurgeryU, JMIG, CME programming, and member-only discounts on meetings, join AAGL today! 

NEW to SurgeryU:
Resection of Deep Infiltration Endometriosis of Psoas, Genitofemoral N, Femoral N                 
by Nicholas Fogelson, MD, and Keri Swanson, RN-FA 

This video demonstrates an unusual case of endometriosis involving a deep infiltrating lesion involving the psoas muscle, genitofemoral nerve, and femoral nerve. This patient experienced cyclic right anterior leg pain, groin pain, as well as motor dysfunction in the right leg. While initially appearing superficial, the lesion proved to extend deeply into the psoas muscle, surrounding fascia, inguinal ligament, and ultimately abutting the femoral nerve posterior and lateral to the psoas muscle. Robotic surgery was used to identify all relevant anatomy and resect this complex lesion.

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SIG Recommended Video #2:
Pelvic Sidewall Excision of Endometriosis
by Robyn Power, MD

This video is recommended because it offers a very straightforward and accessible approach to excision of endometriosis for the minimally invasive gynecologic surgeon. 

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SIG Recommended Video #3: 
Systematic Approach to Robotic Assisted Endometrioma Cystectomy
by Jordann-Mishael Duncan, MD

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The Endometriosis SIG recommends the following two articles from March 2024, Volume 31, Issue 3 of JMIG. These were chosen because they are unique and relevant as well as timely in the current edition.

JMIG Article Recommendation #1:

Serum Levels of Interleukins in Endometriosis Patients:  A Systematic Review

JMIG Article Recommendation #2: 

A Call for New Theories on the Pathogenesis and Pathophysiology of Endometriosis

An Update on Immunologic Aspects of Endometriosis

Endometriosis is thought to be an estrogen-driven disease involving endometrium-like tissue outside the uterus in a setting of chronic inflammation, leading to a number of sequelae including chronic pain, adhesive disease, infertility, disability, and even ovarian cancer. In a recent review, entitled “Immunologic Aspects of Endometriosis” published in Current Obstetrics and Gynecology Reports, we summarize foundational studies and highlight recent scientific developments.

The endometrial cavity is an especially dynamic microenvironment, which has a unique milieu of immune cells and microbiota cyclically in flux under the influence of steroidogenic hormones remodeling the architecture of the endometrial lining. Overall, T lymphocytes dominate the proliferative phase of the menstrual cycle in the endometrial cavity, while NK cells dominate the secretory. Alterations to these and other cells in endometriosis may increase inflammation, play a role in fertility state, and reduce clearance of desquamated endometrial lining, leading to increased retrograde flow. In the peritoneal lining, macrophages predominate. Specifically, the anti-inflammatory M2 subtype is increased in endometriosis patients, reducing the phagocytic capability of these cells and further reducing clearance of the products of retrograde menstruation, including iron-rich blood products that can lead to oxidative stress. Recent studies have been aimed at mitigating this proinflammatory effect by targeting cytokines, such as TNF-α, IL-8, and IL-2. Cytokines have been shown to play a role in the hypersensitization of sensory nerves, which can in turn influence the immune system through neuropeptides.

Endometriosis patients also display a greater diversity of bacteria, including pathogenic bacteria, in the endometrial cavity and even on ectopic endometriosis implants. More recent studies have also implicated the gut microbiome in endometriosis, pointing to dietary changes and even fecal transplant possibly playing a role in the management of the disease in the future.

Fascinatingly, endometriosis lesions have found ways to alter intracellular signaling pathways to their own advantage, particularly with estrogen and progesterone signaling. Though the peritoneal fluid that bathes endometriosis lesions already has 100 to 1000-fold increased concentration of steroidogenic hormones than serum, lesional cells upregulate enzymes that further increase the local availability of estrogen. Intracellular estrogen signaling is increased as the ERβ receptor is overexpressed by greater than 100-fold over the normal endometrial cells, increasing proliferation and adhesion, activating the inflammasome, and decreasing apoptosis. Furthermore, up to a third of endometriosis patient’s lesional cells have deregulated PR-B, leading to resistance to progesterone. These mechanisms are vitally important to understand as first-line treatments for this disease often include progesterone alone or in combination with estrogen. Recent studies support the use of cyclooxygenase inhibitors (which play a role in estrogen signaling through PGE₂), aromatase inhibitors, and even potentially selective ER ligands.

Though much is yet to be elucidated regarding the etiology and progression of this disease, increasing evidence strongly features the immune microenvironment of the endometrial and peritoneal cavities, its microbiome and resident immune cells, the complex interplay of steroidogenic hormones, and the involvement of the nervous system.

About the Authors:
Alexandria N. Young, MD, PhD
Louise P. King, MD, JD
     

Dr. Young is an OBGYN Resident at General Brigham/Harvard Medical School in Boston, Massachusetts. 

Dr. King is a member of the AAGL Endometriosis SIG, Assistant Professor at Brigham and Women’s Hospital, Director of Research, Minimally Invasive Gynecologic Surgery, Associate Program Director, Fellowship in Minimally Invasive Gynecologic Surgery, Director of Reproductive Bioethics, Center for Bioethics, Co-Director, Ethics, Essentials of the Profession Harvard Medical School, and Affiliated Faculty Petrie Flom Center Harvard Law School, Division of Minimally Invasive Gynecologic Surgery, Department of Obstetrics and Gynecology, at Brigham and Women’s Hospital, Harvard Medical School, in Boston, Massachusetts. 

Pelvic Hemorrhagic Ascites: A Rare Presentation of Endometriosis

Hemorrhagic ascites is a rare manifestation of endometriosis. The differential for pelvic ascites includes ovarian hyperstimulation, Meigs syndrome, hepatic cirrhosis from portal hypertension, ovarian or peritoneal cancer, and nephrotic syndrome among other more obscure etiologies. Typical symptoms of ascites: abdominal tenderness and distention and a feeling of fullness. In the setting of endometriosis, the typical pain of advanced endometriosis is magnified by the bloating and discomfort of ascites.

Hemorrhagic ascites is defined as the detection of more than 10,000 red blood cells per μL of ascitic fluid. The diagnosis can also be made based on radiographic findings and macroscopic appearance of the bloody/dark red color of the fluid drained (1). The literature suggests a predominance of these patients will be of African descent, however specific statistics are not definitive. In one Nigerian study, they found that 1/3 of their patients with endometriosis also had ascites (2). In a review from 2010, approximately 63.0% of the recruited women for whom ethnicity was specified were of African origin (29 out of 46 patients). Of the 50 subjects with known obstetric history, 41 (82.0%) were nulliparous (3).

Case Report:

A 32-year-old nulligravida patient of Nigerian descent was referred for surgical treatment. She had known endometriosis and recurring ascites over the past 4 years and had recently undergone paracentesis drainage of several liters of fluid that quickly re-accumulated. She moved to the US for work after graduate school in Environmental management studies. She was first diagnosed with endometriosis by laparoscopy 2018 in Nigeria after having debilitating periods beginning when she was a teenager. The ascites seems to have begun a year prior to diagnosis. She had a repeat laparoscopy with fulguration and biopsy in the US in 2021, at which time she was told she had stage IV endometriosis. She was treated for a year with Lupron and Aegestin but discontinued these medications due to side effects of bone pain and dizziness. She was then placed on Depo-provera, which helped with pain and menstrual suppression, but ascites persisted. She desired surgical excision with a fertility sparing procedure. 

Preoperative exam revealed re-accumulation of ascites, a fixed pelvis and 10-week sized myomatous uterus. No evidence of bowel invasion was detected on exam or imaging.

Surgical findings demonstrated total pelvic and abdominal adhesions and dark ascites, widespread peritoneal disease, and an enlarged uterus. She was managed conservatively in a lengthy surgery due to the highly friable tissue, massive adhesions and widespread disease including diaphragm and pelvis. Postoperatively, she progressed well and wished to be maintained on Depo-provera until she pursues pregnancy. 

Surgical tips:

1. Due to the inflammatory nature of ascites associated with endometriosis, the tissues may be very friable and bleed with even light surgical manipulation. Excision of inflamed peritoneum steadily helps to control bleeding.
2. Endometriosis associated with ascites may also involve tissue necrosis and adhesions, however, the retroperitoneum may remain accessible for surgical exploration and treatment, thus allowing for further control of bleeding and disease.
3. Conservative management is possible with appropriate peritonectomy and excision of inflamed and endometriotic tissue.

References

1. Pandraklakis A, Prodromidou A, Haidopoulos D, Paspala A, Oikonomou MD, Machairiotis N, Rodolakis A, Thomakos N. Clinicopathological Characteristics and Outcomes of Patients With Endometriosis-Related Hemorrhagic Ascites: An Updated Systematic Review of the Literature. Cureus. 2022 Jun 22;14(6):e26222. doi: 10.7759/cureus.26222. PMID: 35911338; PMCID: PMC9313015.
2. Babah OA, Ojewunmi OO, Osuntoki AA, Simon MA, Afolabi BB. Genetic polymorphisms of Vascular Endothelial Growth Factor (VEGF) associated with endometriosis in Nigerian women. Hum Genomics. 2021 Oct 30;15(1):64. doi: 10.1186/s40246-021-00364-x. PMID: 34717756; PMCID: PMC8556990.
3. Gungor, T., Kanat-Pektas, M., Ozat, M. et al. A systematic review: endometriosis presenting with ascites. Arch Gynecol Obstet 283, 513–518 (2011). https://doi.org/10.1007/s00404-010-1664-1
4. Gonzalez A, Artazcoz S, Elorriaga F, Timmons D, Carugno J. Endometriosis Presenting as Recurrent Haemorrhagic Ascites: A Case Report and Literature Review. Int J Fertil Steril. 2020 Apr;14(1):72-75. doi: 10.22074/ijfs.2020.5895. Epub 2020 Feb 25. PMID: 32112640; PMCID: PMC7139225.
5. Bahall V, De Barry L, Harry SS, Bobb M. Gross Ascites Secondary to Endometriosis: A Rare Presentation in Pre-Menopausal Women. Cureus. 2021 Aug 10;13(8):e17048. doi: 10.7759/cureus.17048. PMID: 34522526; PMCID: PMC8427934.

About the Author: 
Shanti I. Mohling, MD, FACOG
    

Dr. Mohling is Chair of AAGL’s Endometriosis Special Interest Group and a minimally invasive gynecologic surgeon at Northwest Endometriosis and Pelvic Surgery in Portland, Oregon.