TCDD has been shown to disturb the activities of both estrogen and progesterone [36]. As a known antagonist of estrogen, TCDD was determined to alter expression of CYP1A1 and CYP1B1 in human endometrial cells [37]. Because endometriosis is estrogen dependent, the disruption of normal estrogen function has the potential to influence the disease [8]. Therefore, the toxicity of dioxins and DLCs largely depends on the body’s estrogen content. While estrogen-activation of ERs prevents AhR complex expression, failure of estrogen to ignite these receptors leaves them open for activation by the dioxin-activated AhR-ARNT complex [38] (Fig. 6.1).

Concentrations of estrogen and ERs decrease in response to dioxin exposure, and thus, dioxins are often believed to exhibit anti-estrogenic properties. On the contrary, an increase in the incidence and extent of endometriosis has been demonstrated in monkeys [2] and growth of ectopic lesions have been seen in mice and rats [39, 40] both in response to dioxin exposure. It can be clearly understood that TCDD disrupts the human reproductive system by acting as an estrogen antagonist and also causing imbalances in progesterone distribution [36]. Other etiologic pathways of endometriosis may depend on TCDD exposure, other than the estrogen and progesterone disruption [36].TCDD activates an inflammation-like pattern [41], which explains the development of endometriosis. Also, TCDD and dioxin-like PCBs affect gene expression by using AhR expressed in both endometrial and immune cells and disrupt endocrine signaling [36, 42].

In 2004, Kitajima M et al. conducted a study on mice after surgically inducing endometriosis. Four weeks of exposure to TCDD did not seem to enlarge lesion size but instead diminished the size of epithelial and stromal masses. Treatment with estrogen alone resulted in the enlargement of epithelial and stromal cells mass within the lesions, indicating that estrogen is an important factor for the growth of these lesions. When TCDD was administered short term, its anti-estrogenic effects reduced ectopic lesions and cell mass [43].

Increases in local estrogen production by heightened ER activity can promote estrogen-dependent diseases such as endometriosis. Elevated expression of mRNA of aromatase, an enzyme essential to estrogen synthesis, has been noted to increase estrogen levels and promote endometriosis. Heightened expression of aromatase may be propelled by environmental factors such dioxins and results in reduced levels of 17β HSD type II. This creates an environment of elevated local estrogen, making the local peritoneal environment a prime location for survival of ectopic endometrial stromal cells. Studies have reported that progesterone hinders endometrial growth and causes regression of endometriosis with treatment [12]. The endometrium of women with the disease, however, demonstrates a decreased response to progesterone. Because TCDD inhibits progesterone, it often exacerbates endometriosis, especially when combined with estrogen [44]. Endometrial dysfunction has been linked to progesterone resistance in endometriosis patients. Progesterone action through progesterone receptors (PR) is necessary for female reproductive functions in humans and other mammals [15]. During pregnancy, progesterone exposure has been shown to protect against endometriosis.

In endometriosis, the matrix metalloproteinases (MMP) are involved in degrading the extracellular matrix, a process important to the development and invasion of endometriotic lesions [44]. Suppression of MMP by progesterone is required to up-regulate TGF-β, resulting in diminished growth of ectopic endometrial tissue [45]. In their study on nude mice, Nayyar et al. 2007 demonstrated that significant decreases in progesterone-mediated expressions of TNF-β2 and PR-B in response to TCDD exposure resulted in a more severe presentation of endometriosis [15]. The group concluded that TCDD can decrease progesterone levels via expression of TGF-β2. This decrease in progesterone-propelled ectopic growth of surgically placed endometrial tissue leads to endometriosis. Exposure of mice to TCDD both in utero and during reproductive maturation decreased PR-A and PR-B, predisposing them to endometriosis [15].

Bruner-Tran et al. 2010 were unable to find a definite correlation between endometriosis and TCDD exposure in cynomolgus monkeys and rodents. However, since TCDD has both estrogenic and antiestrogenic properties, reduced lesion size and spontaneous abortion are plausible outcomes of exposure. As such, the group reported that rodents exhibited infertility and an inability to maintain pregnancy secondary to TCDD exposure in utero and pre-puberty [46].

Human exposure to environmental pollutants is often inevitable, however, strategies have been suggested in an effort to limit exposure, maximize elimination from the body, and implement lifestyle changes (Fig. 6.2). These strategies may prove useful to limit the toxic effects of environmental contaminants in human populations.

Persistent toxicants remain as residuals in human body long after the first exposure. This is probably the most important obstacle that can inhibit the progress of detoxification since many of the environmental toxicants have a long half-lives. Genis et al. [47] analyzed the sweat of 20 individuals and found some phthalates metabolites. Hence, induced perspiration may be a way to eliminate potentially toxic metabolites. Exercising may be another way to eliminate these toxins since it induces sweating. However, some studies emphasize that excretion rates do not change depending on how perspiration occurs (e.g., infrared sauna, dry or wet regular saunas or exercise) [48].

There is also an effort to limit the exposure by restricting the use of these chemicals. Some nations, including the United States, have banned the use of some environmental toxicants like organochlorine pesticides, mostly DDT. Moreover, lifestyles changes like diet modification can be helpful. This include vitamin and mineral supplementation to replenish depleted body induces, increased fiber intake to limit body absorption of toxic compounds and promote elimination; and avoidance of certain types of foods known to have high accumulations of environmental toxins [49].

Conventional and novel treatment options for endometriosis are discussed elsewhere; this section will focus on disease prevention strategies and management options for endometriosis as they relate to human contamination with environmental toxins. Currently, no cure exists for the disease. As such, goals of management are mainly to provide relief from pain and restrict progression of the disease. When appropriate, efforts are also made to preserve or restore fertility through medical or surgical therapy. In general, combination oral contraceptives (COCPs), gonadotropin-releasing hormone (GnRH) agonists, progestational agents, danazol and aromatase inhibitors are commonly used in the medical treatment of endometriosis for patients who wish to conserve fertility.

As mentioned before, dioxins have been shown to up-regulate expression of P-450 aromatase, leading to increased estrogen synthesis within endometriotic tissue [50]. This is the rationale for the use of aromatase inhibitors to manage endometriosis. After administration, endometriotic lesions have been noted to regress, thus, signifying the need for aromatase in patients with persistent endometriotic lesions [51].

The role of dioxins in the development of endometriosis remains controversial. Thus far, research has produced varying results, contributing to this uncertainty. Over time, experiments on animals have culminated in the development of correlations between environmental toxins and of endometriosis in mammals. These studies, including those on primates, have propelled current exploration of a possible similar association in humans.

Similarities between dioxin characteristics and risk factors for endometriosis have been noted. For example, dioxins are lipophilic with long half-lives and accumulate in high fat tissues. Obese females have large amounts of adipose tissue; thus, the more fatty tissue present in the body, the longer it will take dioxins to be eliminated from the body. Given that obesity is a risk factor for endometriosis, a potential link exists between lipophilic compounds such as dioxins and endometriosis. Due to their accumulation in lipids, dioxins can be largely excreted in breast milk and eliminated from the body through lactation, which is believed to be a protective factor against the onset of endometriosis.

Epidemiological studies on endometriosis in association with environmental pollutants have been quite inconsistent in both animal and human studies. Although copious studies investigating the involvement of environmental toxins in endometriosis have produced promising results, no study has demonstrated a direct link nor confirmed a causal relationship between the two. Case-control studies can prove valuable under certain conditions. In addition to a large sample size, controls should be laparoscopically confirmed to be free of endometriosis. Since endometriosis tends to run in families, clinicians should aim to identify family members confirmed or suspected to have endometriosis when taking a family history.