(197) Hormone Receptor Distribution and Innervation in Neuroproliferative Vestibulodynia: Immunohistochemical Evidence
Authors: Yee A , Dury A , Ouellet J , Komisaruk B , Goldstein S , Goldstein I 
Published: May 2023

Abstract

Introduction
There are limited hormonal and neurological studies of the vestibule despite its importance to sexual health and its pathophysiologic role in entrance dyspareunia. It is widely accepted that the vulva and vagina have estrogen receptors, but little is known regarding the types and density of various hormone receptors in the vestibule. Tactile and pressure sensations of the vestibule during sexual activity are likely transmitted via pudendal (somatic) and pelvic (visceral) nerve branches. The vestibule also releases mucinous lubrication from minor and major vestibular glands, likely induced by efferent pelvic (parasympathetic) nerve activation and terminated by efferent hypogastric (sympathetic) nerve activation. Immunohistochemical (IHC) studies of nerve structures and of androgen, estrogen, progesterone receptors in human vestibular tissue would aid in better understanding of relevant physiologic functions of the vestibule.

Objective
To better understand vestibular hormonal and neurological physiology through IHC studies of vestibulectomy tissue and to help improve clinical management of vestibulodynia.

Methods
IHC was performed on 7 vestibular specimens with confirmation of NPV diagnosis by positive CD117 and PGP9.5 staining, consistent with excess mast cells and nerve endings, respectively. Specimens were also studied with primary antibodies (Anti-ERα, Ab 32063; Anti-AR, MI 06680; Anti-PR, Dako PGR636; Anti-Synapsin, Cell Signaling 5297T). Finally, sections were lightly counterstained with Gill-modified hematoxylin.

Results
Androgen and estrogen alpha receptors were richly expressed in tissue samples of all 7 patients. Dense labeling of both receptor types was noted in the germinal layer of the epithelium (Fig. 1a,b) and mucinous vestibular glands (Fig. 2a,b), with comparatively sparse expression in the subepithelial stroma. While labeling of progesterone receptors was highly variable (Fig. 3a,b), all samples showed evidence of moderate progesterone receptor labeling in the subepithelial stroma. Variability may be due to menstrual cycle phase in which samples were obtained. Synapsin labeling showed thin filamentous arrangement in the rete pegs, thicker filamentous arrangement in the subepithelial stroma, and dense labeling in blood vessel endothelium and epithelium of mucinous vestibular glands (Fig, 4a, b).

Conclusions
This preliminary study provides evidence of dense androgen and estrogen receptor expression in the vestibule, consistent with the observation that in patients with hormonal deficiency, entrance dyspareunia may be more successfully treated at the vestibule with combined testosterone and estradiol cream than with topical estradiol alone. Also consistent with these findings is that treatment with intravaginal DHEA, converted to testosterone and estradiol intracrinologically and subsequently diffusing to the vestibule, successfully resolves entrance dyspareunia. While the significance of variable vestibular progesterone receptor expression is unclear, the addition of topical progesterone in these patients may be considered. Synapsin staining in rete pegs, stroma, surrounding blood vessels, and mucinous vestibular glands supports functional sensory innervation and autonomic regulation of vestibular lubrication that occurs during sexual activity.

Disclosure
Any of the authors act as a consultant, employee or shareholder of an industry for: Endoceutics.