study, monkeys exposed over 12 months to low-dose dioxin (0.71 ng/kg/day) had endometriosis implants with smaller maximal and minimal diameters and similar survival rate when compared with endometriotic lesions in unexposed controls, suggesting no effect of dioxin on endometriosis (127). After 12 months of exposure to high-dose dioxin (17.86 ng/kg/day), larger diameters and a higher survival rate of endometriosis implants were observed in exposed Rhesus monkeys compared with unexposed controls. The second randomized study performed in 80 Rhesus monkeys compared those with no treatment with those treated with 0, 5, 20, 40, and 80 μgof Aroclor (1,254 kg per day) for 6 years. Endometriosis occurred in 37% of controls and in 25% of treated monkeys as determined by laparoscopy and necropsy data (128). No association was observed between endometriosis severity and PCB exposure. These data question the importance of dioxin exposure, except at high doses, in the development of endometriosis in primates.
Rodents Continuous exposure to 2,3,7,8-tetrachlorodibenzo-P-dioxin inhibited the growth of surgically induced endometriosis in ovariectomized mice treated with high-dose estradiol. No correlation was observed between the dose of dioxin and survival of endometrial implants, adhesions, and serum E2 levels (129). In ovariectomized mice induced with endometriosis, similar stimulating effects of estrone and 4-chlorodiphenyl ether (4-CDE) were observed on survival rates of endometriotic mice, suggesting an estrogen-like effect of 4-CDE (130). Potential mechanisms mediating dioxin action to promote endometriosis in rodents are complex and probably different in rats and mice, and furthermore in women. The mouse appears to be a better model to elucidate these mechanisms, but both models have important limitations (131,132).
Stem Cells Endometrial stem cells are identified, are bone marrow derived, can differentiate into neurogenic or pancreatic-β cells, may contribute to the development of endometriosis in a murine model, and their potential role in the pathogenesis of endometriosis needs to be investigated (133–136).
Future Research The study of endometriosis is compounded by the need to determine the presence or absence of pathology. The pathogenesis of endometriosis, the pathophysiology of related infertility, and the spontaneous evolution of endometriosis are being studied. At the time of diagnosis, most patients with endometriosis had the disease for an unknown period, making it difficult to initiate clinical experiments that would determine the etiology or progression of the disease (31). Because endometriosis occurs naturally only in women and nonhuman primates, and invasive experiments cannot be performed easily, it is difficult to undertake properly controlled studies. There is a need for the development of a good animal model with spontaneous endometriosis. The main advantage of the rat and rabbit models used to study endometriosis is their low cost relative to primates, but the disadvantages are numerous (137–140). In both models, the type of lesion appears to be quite different from the variety of pigmented and nonpigmented lesions observed in women (137–139). Primates are phylogenetically close to humans, have a comparable menstrual cycle, are afﬂicted with spontaneous endometriosis, and when induced with endometriosis, develop macroscopic lesions that are similar to those found in human disease (41,141–145). Spontaneous endometriosis in the baboon is minimal and disseminated, similar to the different stages of endometriosis in women (141,146–148).