A baboon model for endometriosis: implications for fertility

Abstract

Endometriosis is one of the most common causes of chronic pelvic pain and infertility in women in the reproductive age group. Although the existence of this disease has been known for over 100 years our current knowledge of its pathogenesis and the pathophysiology of its related infertility remains unclear. Several reasons contribute to our lack of knowledge, the most critical being the difficulty in carrying out objective long-term studies in women. Thus, we and others have developed a model of this disease in the non-human primate, the baboon (Papio anubis). Intraperitoneal inoculation of autologous menstrual endometrium results in the development of endometriotic lesions with gross morphological characteristics similar to those seen in the human. Multiple factors have been implicated in endometriosis-associated infertility. We have described aberrant levels of factors involved in multiple pathways important in the establishment of pregnancy, in the endometrium of baboons induced with endometriosis. Specifically, we have observed dysregulation of proteins involved in invasion, angiogenesis, methylation, cell growth, immunomodulation, and steroid hormone action. These data suggest that, in an induced model of endometriosis in the baboon, an increased angiogenic capacity, decreased apoptotic potential, progesterone resistance, estrogen hyper-responsiveness, and an inability to respond appropriately to embryonic signals contribute to the reduced fecundity associated with this disease.

Figure 1

Laparoscopic Evaluation of Lesions in a Baboon Model of Experimental Endometriosis. Visualization of the peritoneal cavity by laparoscope demonstrated the presence of powder burns (identified by a single asterisk) and blue (identified by the arrow) and chocolate lesions (identified by the double asterisks) within three (A,B) and six (C,D) months of induction of disease.

Figure 2

Characterization of Lesions Visualized by Laparoscope in Baboons Experimentally Induced with Endometriosis. Laparoscopic evaluation of the peritoneal cavity of baboons a) one month following induction of disease revealed similar levels of red, blue, chocolate, white, and mixed lesions. The peritoneal cavity contained a significantly higher number of red lesions b) three months following induction of endometriosis; however, c) 6 months after inoculation with menstrual endometrium significantly higher numbers of blue lesions were present in the peritoneal cavity of baboons with induced disease. Similar numbers of each lesions type were visible by laparoscopy d) 15 months after induction of endometriosis. Columns represent the mean number of red, blue, chocolate, white, and mixed lesions visualized by laparoscope a) 1 month (n = 6), b) 3 months (n = 21), c) 6 months (n = 10), and d) 15 months (n = 5) after induction of disease. Error bars represent the standard error of the mean. (*, p < 0.05, Kruskal-Wallis ANOVA, with Dunn's Correction for multiple testing.)

Figure 3

Histological Evaluation of Endometriotic Lesions. Panel A is a section through a chocolate lesion harvested from the uterine surface at three months. Panels B and C are sections through blue lesions obtained at six months of disease from the uterine fundus (B) and 12 months of disease in peritoneal fat (C). Panel D is a section through a red lesion obtained at 16 months of disease from the peritoneal wall. The presence of endometriotic tissue is histologically confirmed by the presence of endometrial glands (indicated with arrows) and stroma (highlighted with asterisks): the stroma surrounding glands of endometriotic lesions ranges from only a few cells (as in B) to several cells in depth (as in C).

Figure 4

Coordinated Endometrial Changes Associated with Endometriosis. Eutopic endometrial changes induced by the presence of ectopic endometriotic lesions can be classified as early responses, with increased levels of c-fos and CYR61, a transitional period, when the Pgr becomes decreased, and late responses when maintained down-regulation of Pgr may mediate down-regulation of the progesterone-regulated gene, HOXA10. (↑, represents up-regulation, ↓, represents down-regulation, and ↔, represents no change in gene expression.)