Immunoresponsiveness in endometriosis: implications of estrogenic toxicants

Endometriosis is a reproductive disease characterized by the growth of endometrial cells at sites outside the uterus. This disease is a serious disorder associated with chronic pain and infertility, which may be present in 6 million women in this country. Traditional medical therapy has consisted of hormonal regimens that limit the action of endogenous estrogen. The etiology of endometriosis is unknown, but studies suggest that soluble factors known as cytokines play a role in disease pathogenesis. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD or dioxin) is an environmental toxicant that alters the action of estrogen in reproductive organs and adversely affects immunocompetence. The incidence of endometriosis was determined in rhesus monkeys that were chronically exposed to dioxin for a period of approximately 4 years. Ten years after termination of dioxin treatment, the presence and severity of endometriosis was assessed by surgical laparoscopy. The incidence of endometriosis correlated with dioxin exposure and disease severity was dependent upon the dose administered. Moderate to severe endometriosis was not found in control animals but was documented in three of seven animals exposed to 5 ppt dioxin (43%) and in five of seven animals exposed to 25 ppt dioxin (71%). The frequency of spontaneous disease in the control group was 33%, similar to an overall prevalence of 30% in 304 rhesus monkeys with no history of dioxin exposure. This study indicates that endometriosis may be associated with dioxin exposure in the rhesus. In view of overwhelming evidence that cytokines participate in the mediation of reproductive-endocrine phenomena and regulation of endometrial growth, future assessment of the effects of environmental toxicants on reproductive health may depend upon our understanding of the bidirectional cytokine network between the immune and endocrine systems.