Systemic and topical hormone therapies reduce vaginal innervation density in postmenopausal women

Abstract

Objective: Menopause is often accompanied by vaginal discomfort including burning, itching, dryness, and spontaneous or provoked pain. Although the direct effects of estrogen withdrawal on vaginal cells are implicated, surgical menopause in rodents causes autonomic and sensory nerves to proliferate, suggesting that indirect effects mediated by changes in vaginal innervation may contribute. We assessed whether postmenopausal women display hormone-dependent changes in vaginal innervation.

Methods: Vaginal biopsies from 20 postmenopausal women undergoing surgery for stress urinary incontinence and pelvic organ prolapse were fixed and immunostained for the pan-neuronal marker protein gene product 9.5, sympathetic marker tyrosine hydroxylase, parasympathetic marker vasoactive intestinal polypeptide, and sensory nociceptor marker calcitonin gene-related peptide. Innervation density was measured as an apparent percentage of the section area occupied by immunofluorescent axons. Specimens were grouped according to whether participants received systemic hormone therapy (HT), topical (vaginal) HT, or no HT.

Results: Women not receiving HT showed relatively high levels of total innervation, with most axons expressing tyrosine hydroxylase or vasoactive intestinal polypeptide immunoreactivity. In women receiving systemic HT, overall innervation was reduced, as were presumptive parasympathetic, sympathetic, and sensory axon populations. Topical HT elicited more dramatic reductions in innervation than in systemic HT.

Conclusions: Hormone therapy reduces autonomic and sensory vaginal innervation density, which may, in part, contribute to relief from vaginal discomfort. Moreover, topical therapy is more effective than systemic therapy, which may help explain the greater improvement reported with topical compared with systemic HT.

Figures

Fig. 1

Immunofluorescence photomicrographs of sections taken from specimens from the posterior vaginal wall of postmenopausal patients. Sections were obtained from patients receiving no hormone replacement therapy (no HT, a, d, g, j), systemic HT (b, e, h, k) and topical HT(c, f, I, l). Sections were immunostained for the pan-neuronal marker, PGP9.5 (a–c), for tyrosine hydroxylase (TH, d–f), vasoactive intestinal polypeptide (VIP, g–i), and calcitonin gene-related peptides (CGRP, j–l). Scale bar in l =50 μm for all panels.

Fig. 2

Quantitative analysis of nerve density in the vagina from postmenopausal patients. n=9 for no HT, n=6 for systemic HT, n=5 for topical HT. * P<0.05 vs. no HT, ** P<0.01 vs. no HT by one way anova with post-hoc testing using Student-Newman-Keuls method.