title: Persistent genital hyperinnervation following progesterone administration to adolescent female rats.
abstract: 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.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Liao
authors.affiliation: 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 psmith@kumc.edu.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Smith
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology; D002478:Cells, Cultured; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005836:Genitalia, Female / Q000187:drug effects* / Q000294:innervation*; D059225:Nociception / Q000187:drug effects; D011374:Progesterone / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000473:pathology; D012741:Sexual Maturation / Q000187:drug effects; D014621:Vagina / Q000187:drug effects / Q000294:innervation / Q000473:pathology; D056650:Vulvodynia / Q000139:chemically induced / Q000473:pathology
chemical_list: D011374:Progesterone; D004958:Estradiol
keywords: axons; cell culture; oral contraceptives; parasympathetic; progesterone; rat model; sensory nociceptor; sympathetic; tissue explant culture; vagina; vulvodynia