Molecular Targets for Nonhormonal Treatment Based on a Multistep Process of Adenomyosis Development

Adenomyosis is an estrogen-dependent gynecologic disease characterized by the presence of endometrial tissue within the myometrium. Adenomyosis presents with abnormal uterine bleeding, pelvic pains, and infertility. This review aimed to investigate the major estrogen downstream effectors involved in the process of adenomyosis development and their potential use for nonhormonal treatment. A literature search was performed for preclinical and clinical studies published between January 2010 and November 2021 in the PubMed and Google Scholar databases using a combination of specific terms. Adenomyosis presents with a wide spectrum of clinical manifestations from asymptomatic to severe through a complex process involving a series of molecular changes associated with inflammation, invasion, angiogenesis, and fibrosis. Adenomyosis may develop through a multistep process, including the acquisition of (epi)genetic mutations, tissue injury caused at the endometrial-myometrial interface, inside-to-outside invasion (from the endometrial side into the uterine wall), or outside-to-inside invasion (from the serosal side into the uterine wall), and epithelial-mesenchymal transition, tissue repair or remodeling in the myometrium. These processes can be regulated by increased estrogen biosynthesis and progesterone resistance. The expression of estrogen downstream effectors associated with persistent inflammation, fragile and more permeable vessel formation, and tissue injury and remodeling may be correlated with dysmenorrhea, heavy menstrual bleeding, and infertility, respectively. Key estrogen downstream targets (e.g., WNT/β-catenin, transforming growth factor-β, and nuclear factor-κB) may serve as hub genes. We reviewed the molecular mechanisms underlying the development of adenomyosis and summarized potential nonhormonal therapies.