Estrogen and female reproductive tract innervation: Cellular and molecular mechanisms of autonomic neuroplasticity

Abstract

The female reproductive tract undergoes remarkable functional and structural changes associated with cycling, conception and pregnancy, and it is likely advantageous to both individual and species to alter relationships between reproductive tissues and innervation. For several decades, it has been appreciated that the mammalian uterus undergoes massive sympathetic axon depletion in late pregnancy, possibly representing an adaptation to promote smooth muscle quiescence and sustained blood flow. Innervation to other structures such as cervix and vagina also undergo pregnancy-related changes in innervation that may facilitate parturition. These tissues provide highly tractable models for examining cellular and molecular mechanisms underlying peripheral nervous system plasticity. Studies show that estrogen elicits rapid degeneration of sympathetic terminal axons in myometrium, which regenerate under low-estrogen conditions. Degeneration is mediated by the target tissue: under estrogen's influence, the myometrium produces proteins repulsive to sympathetic axons including BDNF, neurotrimin, semaphorins, and pro-NGF, and extracellular matrix components are remodeled. Interestingly, nerve depletion does not involve diminished levels of classical sympathetic neurotrophins that promote axon growth. Estrogen also affects sympathetic neuron neurotrophin receptor expression in ways that appear to favor pro-degenerative effects of the target tissue. In contrast to the uterus, estrogen depletes vaginal autonomic and nociceptive axons, with the latter driven in part by estrogen-induced suppression BMP4 synthesis. These findings illustrate that hormonally mediated physiological plasticity is a highly complex phenomenon involving multiple, predominantly repulsive target-derived factors acting in concert to achieve rapid and selective reductions in innervation.

Dynamic Expression of Serotonin Receptor 5-HT3A in Developing Sensory Innervation of the Lower Urinary Tract

“…In our retrograde tracing studies we focused only on male mice to avoid estrous cycles as a confounding factor in gene expression (Mónica Brauer and Smith, 2015). Since neurogenic bladder and bladder pain syndromes occur more frequently and with greater severity in women than men, sex-specific variation in gene expression may be a contributing factor to these differences (Irwin et al, 2006; Chrysanthopoulou and Doumouchtsis, 2014; Mónica Brauer and Smith, 2015). It will be of interest in subsequent studies to investigate sex differences in Htr3a gene expression patterns throughout development or into adulthood.…”

“…Male mice were used exclusively to avoid confounding effects of estrous cycle on neuronal gene expression patterns (Mónica Brauer and Smith, 2015). Injection of retrograde tracing dye, Fast Blue, into the bladder dome was carried out under general anesthesia as previously described (Payne et al, 2015).…”

Recent advances in understanding provoked vestibulodynia

“…This may explain the coexistence of PVD and interstitial cystitis in some women 22 , as well as the significantly higher level of umbilical sensitivity in women with PVD1 23 . Acquired PVD has also been attributed to neural proliferation in response to an inflammatory process (see below) or endocrine factors 24, 25 .…”

Estrogen Replacement Regulates Vaginal Innervations in Ovariectomized Adult Virgin Rats: A Histological Study

“…In ovariectomized mice, estradiol treatment resulted in a greater than 5-fold increase in the uterine expression of mature brain-derived neurotrophic factor (BDNF), pro-BDNF, and nerve growth factor receptor (NGFR) [16]. A review of estrogen-induced remodeling of reproductive tract innervation by Mónica Brauer and Smith [2] showed that estrogen depletion results in the rapid degeneration of sympathetic terminal axons in the myometrium, as well as vaginal autonomic and nociceptive axons, but such axons could regenerate under low-estrogen conditions. Impaired hormonal-neural control may result in a malfunction of the genital response including loss of desire, loss of genital sensitivity, loss of vaginal lubrication, erectile dysfunction, ejaculation disorder, and orgasmic disorder [17].…”

“…Menopause, which is characterized by declining ovarian function and reduced circulatory estrogen levels, is associated with a variety of adverse symptoms including vaginal dryness, irritation, itching, burning, and dyspareunia, indicating that reproductive hormones, especially estrogen, are vital for the normal maintenance of the female reproductive tract. These vaginal symptoms not only result from loss of hormonal trophic support for vaginal tissues, but also are a result of changes in vaginal innervation stemming from decreased estrogen availability [2]. …”