Nonhuman Primate Models for Translational Research in Endometriosis.

Abstract

Endometriosis is a painful disorder for millions of women worldwide. It is identified by endometrium-like tissue outside the uterine cavity, and results in chronic pelvic pain and subfertility. Spontaneous endometriosis only occurs in women and menstruating non-human primates. Endometriosis remains an enigmatic disease. The longest standing theory, the Sampson hypothesis, proposes that retrograde menstruation through the fallopian tubes results in invasion and attachment of endometrial fragments into the peritoneum. There are principally three types of preclinical endometriosis models; those that replicate the pathogenesis of the human disease by inoculation/surgical placement of human, non-human primate, or rodent endometrial tissue in a rodent system, those evaluating spontaneous disease in the non-human primate, and those that induce disease in a non-human primate. Although each strategy has limitations, these models provide an invaluable tool for the study of the pathophysiology of the disease. Immunodeficient mice can be surgically implanted with human endometrial and endometriotic tissues, which grow in the mice, and the resulting lesions undergo menstruation-like bleeding similar to endometriosis in women. While the study of endometriosis in rodents is a cost-effective model, the ectopic lesions are very small and are not physiologically identical to those found in advanced endometriosis in women. Spontaneous endometriosis in non-human primates is advantageous because it provides a physiologically similar animal model to the human. However, non-surgical diagnosis of spontaneous endometriosis in non-human primates is very difficult and usually occurs at very advanced stages of the disease, thus reducing the utility of the model for testing therapeutic agents. Inducing endometriosis by inoculating endometrial currettings to the abdominal cavity of the baboon is currently the prototypic primate model. The resulting lesions are physiologically and histologically similar to endometriotic lesions in women. Since macaques are the preferred non-human primate in many research institutes and the pharmaceutical industry, anti-endometriotic therapies evaluated in the macaque could be well-positioned for translation to clinical trials. We recently developed methods to reliably create endometriosis in rhesus macaques by inoculation of the peritoneal cavity with menstrual endometrium. To do this we used a minimally invasive laparoscopic method to transfer menstrual debris to the peritoneum. Menstrual seedings were timed to the 2nd day of mense and were repeated monthly for 3 cycles. Thereafter, the abdomen was inspected laparoscopically and animals were graded for stage of the disease, similar to grading done in women. Utilizing this technique, macroscopic and microscopic endometriosis was induced in 5/5 animals. The induced, early stage lesions were histologically similar to the disease in women and immunohistochemistry of the lesions revealed endometrium-like glands and stroma, with abundant proliferating cells and strong staining for estrogen receptor-1 and progesterone receptor. In sum, induced endometriosis in non-human primates, including the macaque and baboon, provides an excellent model to study the pathogenesis of the disease. The presence of induced, newly formed, ectopic peritoneal lesions also provides a model system for preclinical testing of novel therapeutic strategies. Support: P51OD011092.