Endometriosis is a painful disorder for millions of women. Progress on new therapeutic approaches for endometriosis has been slow because there are limited physiologically relevant animal models for the disease. Nonhuman primates (NHPs) constitute the most suitable animals for in vivo studies, and creating endometriosis by inoculating endometrial currettings to the abdominal cavity of the baboon is the prototypic primate model. However, research in baboons is grossly limited by animal availability, cost, and housing constraints for large NHPs. In contrast, macaques are the preferred NHP in many research institutes and the pharmaceutical industry, and therapies evaluated in the macaque would be well-positioned for translation to clinical trials. Several studies have created ectopic endometrium in macaques, those studies failed to yield a reliable endometriosis model. Those failures appear technological and we propose that a reliable macaque endometriosis model can be created that will have a lasting impact on women's health.
In Specific Aim 1 we will refine and validate a protocol for creating endometriosis in naturally cycling macaques. Curettage, as used in baboons, cannot be carried out in macaques because of anatomical restrictions in the macaque cervix. To overcome this, we will collect menstrual endometrium debris by needle aspiration and transfer it to the abdominal cavity laparoscopically. Enthusiasm for Aim 1 emanates from pilot studies where we inoculated the peritoneum with menstrual endometrium in artificially-cycled monkeys.
In Specific Aim 2 we will document the growth of induced endometriotic lesions and assess the effects of lesion abundance and size on the presentation of pain in the animals. Based on our pilot data we designed a pain and discomfort scoring system, which will be combined with activity monitoring, to quantify discomfort in animals with induced disease and guide the prescription of pain relief for the animals. Objective data on pain, sleep, and activity will be used for scoring pain throughout the menstrual cycle in animals with induced endometriosis. Like women, NHPs with endometriosis are expected to display reduced fertility compared to endometriosis-free subjects.
In Specific Aim 3 we will assess the effect of the induced lesions on fertility. Fertility will be assessed by mating the animals with fertile mals. Pelvic ultrasound and contrast enhanced ultrasound imaging will be used to characterize the effects of induced endometriosis on uterine function and embryo implantation. This research will provide a definitive assessment of techniques required to create endometriosis in the macaque for future studies, and characterize the progression of the disease with specific emphasis on assessment of pain and infertility in this useful NHP model.
(Public Relevance Statement): Progress to develop new therapies for endometriosis is limited by the availability of suitable animal models. In this study we will develop a new protocol to create the disease on demand in macaques. This inducible model of endometriosis will provide additional animal resources for testing emergent therapies for the disease.