Decades of research efforts have tried to characterize the role of inflammation in endometriosis, but scientists still don’t know which immune factors contribute to the disease’s inflammatory components, or how they can be targeted to develop new treatment options. A University of Kansas Medical Center review explored both previous research failures and current advancements in the field, like the shift in focus to the estrogen receptor and its role in inflammation.
Since endometriosis is an estrogen-dependent disease, treatment approaches still rely on mechanisms to suppress estrogen action. But this approach has the considerable disadvantage of affecting fertility and producing menopausal-like side effects.
In endometriosis, increased inflammation and the release of inflammatory cytokines partly result from altered progesterone production. The hormone has anti-inflammatory properties, and drugs mimicking progesterone action have been used to treat the condition. The treatment’s efficiency, however, is not universal, and many women do not experience pain relief from it.
Scientists believe that an altered sensitivity to the hormone might be a result of a reduced expression of progesterone receptors, and have turned their gaze to specific inflammatory mediators.
TNF-α was one of the first inflammatory factors investigated, and while preclinical research looked promising, clinical trials delivered disappointing results. The use of different endpoints in animal and human trials play a large part in these failures.
Researchers in early studies investigating anti-TNFα therapy in animals focused solely on reducing disease burden and lesion size, and did not explore pain outcomes. In humans, in contrast, anti-TNFα trials were designed to primarily evaluate pain, which was not reduced by treatment.
Considering the lack of non-surgical biomarkers of disease burden, scientists do not actually know whether the treatment given people lowered their disease burden. And in animal models, they did not assess if pain was present or diminished with the decrease in disease burden.
Nevertheless, the focus of today’s investigations has moved to other mediators of inflammation.
Macrophage migration inhibitory factor (MIF) is a factor that, like TNFα, is elevated in women with endometriosis. Extensive research shows that MIF stimulates the release of a host of other pro-inflammatory molecules, among them TNF-α. Many of the factors induced by MIF are associated with the expansion of cells and blood vessels, making their involvement in endometriosis development plausible.
Animal experiments using the MIF blocker ISO-1 have produced promising results, reducing lesion size without affecting estrogen action. To further confirm the utility of MIF as a therapeutic target, studies investigating if MIF blockers can relieve pain in both animals and humans are necessary.
Another factor influenced by MIF is prostaglandin E2 (PGE2), which is elevated in endometriosis and has, in fact, been proposed to be a master regulator of endometriosis. Blocking PGE2 receptors reduces growth and survival of endometriotic lesions, and slows the ingrowth of new blood vessels and nerves to the lesion.
A clinical trial of rofecoxib — a blocker of the PGE2 precursor COX2 — reduced pain in women with endometriosis. Since both TNFα and MIF stimulate PGE2 production, it is possible that the effects on lesion burden when blocking these factors might be mediated by PDE2.
Yet other studies point to the possibility that development of endometriosis is driven by an imbalance between the two estrogen receptors: ER-α and ER-β. The later is highly expressed in endometriotic tissue and its activation leads to a downregulation of ER-α. Recent research using two drugs — chloroindazole and oxabicycloheptene sulfonate (OBHS) targeting ER-β and ER-α, respectively — showed that the treatment reduced lesions and blocked inflammation.
Most importantly, the combination of drugs had beneficial effects without disrupting reproductive cycles or fertility. More studies are needed to explore if targeting the ER-α/β pathway also reduces pain.
Recent progress in endometriosis research has, in other words, shown that the role of estrogen in the disease can be divided into inflammatory pathways promoting lesion growth, and pathways that regulate fertility. By recognizing this distinction, scientists now realize that the most effective target for endometriosis treatment might be the estrogen receptor, after all.