LAUSR

Uterine fibroids (UFs), also known as leiomyomas, are benign pelvic tumors that occur in nearly 70% of all reproductiveaged women (1, 2). Some of these women will develop severe symptoms associated with the presence of these tumors. Annually, UFs account for over 200,000 hysterectomies in the U.S. This is due to the lack of long-term effective medical therapies (3). Tumor growth is characterized by slow proliferation with increased deposition of extracellular matrix (proteoglycans and collagens), which participates in the fibrotic phenotype of UFs (3). This process is usually in a steroidhormone dependent manner (2). Besides steroid hormones, growth and maintenance of UFs are strongly related to growth factors, stem cells, and genetic and epigenetic abnormalities and other risk factors (1, 2). The myometrial smooth muscles are supplied by nerves (sympathetic, parasympathetic, sensory), which run in neurovascular bundles between myometrial cells (2). Distortion of the nerves by masses of UFs leads to pelvic pain and dysmenorrhea symptoms (2). Axonal degeneration could be pathological or physiological. The latter occurs in adults as a part of autonomic (sympathetic, parasympathetic) axon remodeling in the reproductive tract. Previous innervation remodeling animal studies in female reproductive tract provided insight into mechanisms underlying neuroplasticity associated with hormonal changes driven by changes in reproductive status. Sympathetic nerves are found to be the most susceptible uterine nerves to the cyclical variations in ovarian sex hormones; estrogen-induced uterine sympathetic axon degeneration (axon pruning), which regenerate rapidly during the low estrogen stages. The process is similar to what occurs during pregnancy, where uterine sympathetic innervation undergoes widespread degeneration, followed by reinnervation after delivery. Explanation of these findings is that estrogen acts directly on the myometrium to render it inhospitable to sympathetic axons, thus preventing the normally robust outgrowth induced by this target (2, 4). Brain-derived neurotrophic factor is a neurotrophin that elicits uterine sympathetic denervation. However, neutralization of this growth factor failed to fully reverse estrogen's effects. This led investigators to explore novel target-derived, estrogen-regulated factors that could/may play a role in regulating such steroid-dependent innervations in human. Neurotrimin (NTM), a glycophatidylinositol) that is an anchored neuronal cell adhesion molecule belonging to the Ig-like cell adhesion molecule protein family. NTM presents in the uterus and is regulated by estrogen. NTM is known to regulate development/outgrowth of neuronal projections (neurites). In human, NTM gene is situated on chromosome 11q25 and encodes a 39-kDa protein. Interestingly, a mouse model revealed NTM to have opposing effects on different types of nerves; sensory and sympathetic neurons. NTM promotes neurite outgrowth