15-year-old, female, rhesus macaque (Macaca mulatta)This single-housed animal had a long-standing history of seizures induced by ketamine sedation. One day, care staff noted blood in the cage, but no external injuries were noted. Clinical staff suspected epistaxis. However, closer observation revealed she was not eating or drinking. A physical examination at that point revealed traumatic amputation of the rostral third of the tongue. The veterinary staff and primary investigator elected for euthanasia.
Examined was a 5.5 kg, intact, female rhesus macaque.Â The serosa covering 2 cm of the proximal colon was irregularly thickened and rough with prominent blood vessels and was covered by several bright red, multifocal to coalescing, raised lesions admixed with dark red fibrillar material (fibrin and hemorrhage).Â The corresponding mucosa was also rough and thickened in this area.Â An 8 mm x 6 mm x 5 mm, oval, grey-brown nodule was present adjacent to the left ovary.Â The left oviduct is tortuous and thickened, and numerous small, coalescing, white to tan plaques cover the diaphragm and abdominal wall.Â The head of the pancreas was replaced by a 2.5 cm x 1.5 cm x 1.5 cm firm, yellow-brown mass with prominent, tortuous vessels and was attached to the stomach, duodenum and body wall by fibrous adhesions.Â Multiple brown-red foci ranging in size from 1mm to 5 mm diameter were present in the peripancreatic and mesenteric adipose.Â The urinary bladder was adhered to the uterus, also by a fibrous adhesion.
A section of mesenteric adipose is infiltrated by dissecting and intersecting streams of eosinophilic fibrillar material and elongated cells with scant deeply eosinophilic cytoplasm, indistinct cell borders and elongated, deeply basophilic nuclei with tapered ends (fibroblasts and fibrous connective tissue).Â These streams frequently contain groups of oval to polyhedral cells with pale eosinophilic cytoplasm and central, deeply basophilic nuclei often with perinuclear clearing (endometrial stromal cells).Â Abundant well-differentiated glands are present among the stromal cells which are lined by pseudo-stratified, ciliated, columnar epithelium punctuated by occasional clear cells.Â The glands contain dense amorphous to mildly granular eosinophilic or pale wispy eosinophilic material.Â Lymphocytes are scattered throughout the stoma along with fewer macrophages and neutrophils and rare eosinophils.Â Occasionally, lymphocytes and macrophages form aggregates within the stromal cells, and rarely small hemorrhages surrounded by macrophages containing greenish-brown pigment (hemosiderin) are noted in the stroma.
Ovary, oviduct, diaphragm, intestinal serosa, and mesenteric adipose tissue: Endometriosis, multifocal, subacute to chronic, moderate to marked with marked fibroplasia.
Blood work revealed BUN 39 mg/dl (21-31), creatinine 1.3 mg/dl (0.8-1.0), creatine kinase 3914 U/L (1-2692) and AST 120 U/L (28-58).Â The elevated BUN and creatinine levels are consistent with mild dehydration resulting from the reduced oral intake of food and fluids.Â The traumatic tongue injury explains the rise in serum creatine kinase and AST as both of these enzymes have a muscle isozyme that is released when muscle is injured.
Developed in 1950 by Te Linde and Scott, the rhesus macaque was first animal model for endometriosis.Â Presently the baboon model is utilized more frequently due to the ability to non-invasively monitor their menstrual cycle, continuous breeding in captivity, adequate volumes of spontaneous peritoneal fluid production and ease of vaginal transcervical uterine access.(4,6)
Endometriosis is an estrogen-dependent, chronic disease that occurs in menstruating species; which include human and non-human primates, the elephant shrew (Elephantulus myuras jamesoni) and one species of bat (Glossophaga soricina).Â Spontaneous endometriosis has only been reported in women and female non-human primates and the pathogenesis is not completely understood.Â It may be induced in other species through intra-peritoneal injection of viable endometrial tissue.Â Rodent models of the disease have been created in this manner.Â By definition, it is the presence of viable, ectopic, extra-uterine, functional endometrial glands with stroma in various sites throughout the pelvis and peritoneal cavity.(5,7)
The most widely accepted explanation of the pathogenesis is Sampsons three-fold transplantation: retrograde menstruation occurs, viable endometrial cells must be present, and adherence and implantation into structures in the peritoneum must successfully occur.Â Retrograde menstruation alone is not enough for the condition to occur.Â In some baboon studies, retrograde menstruation has been reported in over 83% of animals.Â Endometrial cells have been reported in the peritoneal fluid of 59-79% of women during menses.Â However, endometriosis is not clinically present at these rates and is estimated to affect only 15-20% of women during their reproductive lives.Â Other theories include vascular and lymphatic dissemination, in-situ development from Wolffian or M+ï¿½-+llerian duct remnants, and the development of metaplastic ovarian or peritoneal tissue.Â An alternate theory suggests induction and differentiation of mesenchymal cells that are affected by substances released by degenerating endometrial tissue following reflux into the peritoneal cavity.Â While the retrograde menstruation and transplantation theory is the most widely accepted, the cellular and molecular mechanisms that lead to the development of the disease are controversial.Â (2,4,7)
Angiogenesis, immune suppression (cytotoxic T-cells, NK cells), mesothelial lining injury and pro-inflammatory cytokines, matrix metalloproteinases, adhesion molecules, toxin (dioxin) exposure and genetic polymorphisms are all among the multitude of candidate factors in the creation of the proper peritoneal environment that must exist for successful survival, adhesion and implantation to occur.Â In women, an autoimmune component has also been proposed due to the demonstration of auto-antibodies and an association with other autoimmune diseases and immune mediated abortion.Â In humans, there is a 6-9 fold increase in prevalence among first-degree relatives.Â (2,4,7)
Briefly, an abnormal or permissive peritoneal environment in the face of endometrial reflux is thought to be central cause for this chronic inflammatory condition.Â Conditions that favor tubal reflux (e.g., cervical stenosis) in addition to increased sloughing and retrograde flow may increase tubal reflux and overwhelm peritoneal macrophages ability to eliminate the sloughed endometrial material.Â However, it should be noted that conditions such as cervical stenosis are not present in all cases(5,7).
Chronic inflammation and the release of certain cytokines in this inflammatory stage (TNF-alpha, IL-1, IL-6 and IL-8) may alter innate immunity and permit the viable cells to persist through decreased peritoneal macrophage, natural killer cell and cytotoxic T-cell activity.Â However, the decreased NK cell activity has also been described as constitutive rather than a result of cytokine or hormone induced immune suppression and secretory ICAM (sICAM) expression by endometrial tissue may bind LFA-1 and help prevent NK-cell recognition of endometrial implants.Â (2, 5, 7)
Endometrial cells from women with endometriosis have decreased rates of apoptosis, insensitivity to macrophage cytolysis, and enhanced gene expression of the anti-apoptotic gene Bcl-2, secretory ICAM (intercellular adhesion molecule), vascular endothelial growth factor (VEGF), and various matrix metalloproteinases which suggests increased intra-peritoneal viability, and ability to adhere and invade peritoneal membranes and tissues.Â (2, 5, 7)
The contributor provided an excellent review on endometriosis, which is the extrauterine growth and proliferation of endometrial glandular and stromal cells in menstruating animals, most commonly in Old World primates.Â Three histologic features of endometriosis are the presence of endometrial glands, endometrial stroma, and hemosiderophages; at least two of these features are required for a diagnosis of endometriosis.Â Endometriosis presents grossly as blood-filled chocolate cysts which progress to fibrotic scar tissue in chronic cases.Â While implantation generally occurs in the pelvic and extrapelvic abdominal cavity, endometriosis has also been reported in the thoracic cavity, lungs, and brain.Â There are also rare reports of endometriosis in men undergoing estrogen therapy for prostate cancer and in premenstrual girls.Â As the first tenet of Sampsons threefold transplantation theory (retrograde menstruation) is clearly lacking in these cases, it is possible that another of the proposed pathogeneses for endometriosis (in-situ development from Wolffian or M+ï¿½-+llerian duct remnants or development of metaplastic ovarian or peritoneal tissue) may still be reasonable theories in some individuals(1).
Conference participants also discussed various risk factors in non-human primates which predispose them to endometriosis.Â These include low numbers of pregnancies, with increased numbers of menstruations throughout life, resulting in increased endometrial turnover compared to multiparous primates.Â Non-laproscopic abdominal surgical procedures, including hysterectomy and estradiol therapy are also implicated, as well as genetic predisposition and age.Â Aged non-human primates are more likely to develop endometriosis than older women because unlike human females, menstruation continues indefinitely due to lack of menopause(3).
1.Â Assaf BT, Miller AD.Â Pleural Endometriosis in an Aged Rhesus Macaque (Macaca mulatta): A Histopathologic and Immunohistochemical Study.Â Vet Pathol. 2011 Apr 26.Â (Epub ahead of print).
2.Â DHooghe, TMD, Kyama CM, Chai D, Fassbender A, Vodolaskaia, A Bokor, A and Mwenda JM: Nonhuman primate models for translational research in endometriosis.Â Reproductive Sciences 16 (2): 152-161, 2009
3.Â Fazleabas AT, Brudney A, Gurates B, Chai D, Bulun S.Â A modified baboon model for endometriosis.Â Ann N Y Acad Sci. 2002 Mar;955:308-17; discussion 340-2, 396-406.
4.Â Hadfield RM, Yudkin PL, Coe CL, Scheffer J, Uno H, Barlow DH, Kemnitz JW and Kennedy SH: Risk factors for endometriosis is the rhesus monkey (Macaca mulatta): a case-control study.Â Human Reproduction Update 3(2): 190-115, 1997.
5.Â Matarese G, De Placido G, Nikas Y and Alviggi C: Pathogenesis of endometriosis: natural immunity dysfunction or autoimmune disease? Trends in Molecular Medicine 9 (5): 223-228, 2003.
6.Â Mwenda JM, Kyama CM, Chai DC, Debrock S and DHooghe TMD: The baboon as an appropriate model for the study of multifactorial aspects of human endometriosis.Â The Laboratory Primate, 1st ed., Chapter 33, Academic Press, 2005.
7.Â Van der Linden PJQ: Theories on the pathogenesis of endometriosis.Â Human Reproduction 11(3): 53-65, 1996.