Liao Zhaohui, Smith Peter G
Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas.
Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas Institute for Neurological Discoveries, University of Kansas Medical Center, Kansas City, Kansas Kansas Intellectual and Developmental Disabilities Research Center, University of Kansas Medical Center, Kansas City, Kansas
Biol Reprod. 2014 Dec;91(6):144. doi: 10.1095/biolreprod.114.121103. Epub 2014 Oct 30.
Provoked vestibulodynia, a female pelvic pain syndrome affecting substantial numbers of women, is characterized by genital hypersensitivity and sensory hyperinnervation. Previous studies have shown that the risk of developing provoked vestibulodynia is markedly elevated following adolescent use of oral contraceptives with high progesterone content. We hypothesized that progesterone, a steroid hormone with known neurotropic properties, may alter genital innervation through direct or indirect actions. Female Sprague Dawley rats received progesterone (20 mg/kg subcutaneously) from Days 20-27; tissue was removed for analysis in some rats on Day 28, while others were ovariectomized on Day 43 and infused for 7 days with vehicle or 17beta estradiol. Progesterone resulted in overall increases in vaginal innervation at both Day 28 and 50 due to proliferation of peptidergic sensory and sympathetic (but not parasympathetic) axons. Estradiol reduced innervation in progesterone-treated and untreated groups. To assess the mechanisms of sensory hyperinnervation, we cultured dissociated dorsal root ganglion neurons and found that progesterone increases neurite outgrowth by small unmyelinated (but not myelinated) sensory neurons, it was receptor mediated, and it was nonadditive with NGF. Pretreatment of ganglion with progesterone also increased neurite outgrowth in response to vaginal target explants. However, pretreatment of vaginal target with progesterone did not improve outgrowth. We conclude that adolescent progesterone exposure may contribute to provoked vestibulodynia by eliciting persistent genital hyperinnervation via a direct effect on unmyelinated sensory nociceptor neurons and that estradiol, a well-documented therapeutic, may alleviate symptoms in part by reducing progesterone-induced sensory hyperinnervation.
激发性前庭疼痛是一种影响大量女性的女性盆腔疼痛综合征，其特征为生殖器超敏反应和感觉神经纤维过度分布。先前的研究表明，青春期使用高孕酮含量的口服避孕药后，发生激发性前庭疼痛的风险会显著升高。我们推测，孕酮作为一种具有已知神经趋向性的甾体激素，可能通过直接或间接作用改变生殖器神经分布。雌性斯普拉格 - 道利大鼠在第20至27天接受皮下注射孕酮（20毫克/千克）；部分大鼠在第28天取出组织进行分析，而其他大鼠在第43天进行卵巢切除，并在接下来的7天内注入赋形剂或17β-雌二醇。孕酮导致第28天和第50天阴道神经分布总体增加，这是由于肽能感觉和交感（而非副交感）轴突的增殖。雌二醇减少了孕酮处理组和未处理组的神经分布。为了评估感觉神经纤维过度分布的机制，我们培养了分离的背根神经节神经元，发现孕酮可增加小的无髓鞘（而非有髓鞘）感觉神经元的神经突生长，这是受体介导的，且与神经生长因子无相加作用。用孕酮预处理神经节也可增加对阴道靶外植体反应的神经突生长。然而，用孕酮预处理阴道靶并不能改善神经突生长。我们得出结论，青春期暴露于孕酮可能通过直接作用于无髓鞘感觉伤害性神经元引发持续性生殖器神经纤维过度分布，从而导致激发性前庭疼痛，而有充分文献记载的治疗药物雌二醇可能部分通过减少孕酮诱导的感觉神经纤维过度分布来缓解症状。
