2-Methoxyestradiol in the Pathophysiology of Endometriosis: Focus on Angiogenesis and Therapeutic Potential

Abstract

Endometriosis is a common condition among women of childbearing potential in which ectopic endometrial tissue is found outside the uterine cavity. Neoangiogenesis plays a major role in the development of endometriotic implants. Some evidence suggests that a disorder in the balance of proangiogenic and antiangiogenic factors that favors the former is induced by local hypoxia and is mediated by the hypoxia-inducible factor-vascular endothelium growth factor pathway could partially explain the development of this condition in some women. 2-methoxyestradiol is a biologically active metabolite of estradiol having antiangiogenic action. Changes in estradiol homeostasis have been locally observed in endometriosis. In this review, we summarize current knowledge of endometriosis pathophysiology, in particular, the balance between local 2-methoxyestradiol production and angiogenesis, which could promote the development of endometriotic lesions. 2-Methoxyestradiol emerges as a promising new candidate for the treatment of endometriosis.

Pathogenesis of deep endometriosis

“…For many other factors it remains unclear whether they are the cause or the consequence of endometriosis. Pelvic endometriosis is associated with a low-grade inflammation of the peritoneal cavity with higher concentrations of activated macrophages and thus with higher concentrations of the many different cytokines (68-72) and angiogenic factors (73)(74)(75)(76)(77)(78)(79)(80)(81)(82)(83)(84)(85)(86)(87)(88)(89)(90)(91). The many immunologic disturbances were recently reviewed (92)(93)(94)(95)(96)(97)(98)(99).…”

Interplay between Misplaced Müllerian-Derived Stem Cells and Peritoneal Immune Dysregulation in the Pathogenesis of Endometriosis

“…Changes in estradiol homeostasis have been locally observed in endometriosis. A balance was observed between local 2-methoxyestradiol production and angiogenesis, which could promote the development of endometriotic lesions [147]. …”

Thermal, X-ray Structural, and Dissolution Characteristics of Solid Forms Derived from the Anticancer Agents 2-Methoxyestradiol and 2-Methoxyestradiol-3,17-O,O-Bis-Sulfamate

“…1a), the endogenous metabolite of 17$-estradiol, have been documented extensively during the last two decades. As noted in reviews and research articles referring to the status of 2ME as a drug candidate, [1][2][3][4] it has been administered orally in Phase I/II clinical trials for a range of diseases (e.g., ovarian, brain, breast, and prostate cancers) and found to display relatively low toxicity. However, the low aqueous solubility of 2ME and its extensive metabolism (via glucuronidation in particular) have been shown to result in low bioavailability (ß1.5%), which has limited its development, 3,5 and consequently prompted efforts to create active analogs and derivatives by chemical elaboration of the 2ME scaffold (see below).…”

“…For example, in a recent study using mouse models, it was shown that 2ME shows acute anti-inflammatory activity that cannot be attributed to its known antiproliferative/antiangiogenic activities. 6 2ME has also been identified as a promising new candidate for the treatment of endometriosis 4 and its possible future role in the context of more general disorders of female reproductive tissues has been reviewed very recently. 7 Combined use of 2ME and conventional chemotherapeutic agents (e.g., gemcitabine and cisplatin) has been shown to result in enhanced growth inhibition of human pancreatic cancer cells, 8 prompting the suggestion that clinical trials of such combinations are warranted.…”