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. While 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 post-menopausal 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, PGP9.5, the sympathetic marker tyrosine hydroxylase, the parasympathetic marker vasoactive intestinal polypeptide, and the sensory nociceptor marker calcitonin gene-related peptide. Innervation density was measured as apparent percentage of 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 patients 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 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 as compared to systemic HT.

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

“…Affected populations include TH-ir sympathetic, VIP-ir presumptive parasympathetic axons, and non-adrenergic, non-cholinergic (NANC) fibers that presumably represent both peptidergic (i.e., CGRP-ir) and non-peptidergic afferent fibers. Interestingly, topical HRT is significantly more effective than systemic HRT in reducing vaginal innervation (Griebling et al, 2012), which is consistent with the idea that estrogen's effects are due to direct actions on the target tissue rather than being secondary to effects. It should be noted that some indices of vaginal innervation do change as a function of cyclic changes in reproductive hormone levels including nociceptive threshold (Cason et al, 2003) and neuropeptide receptor transcripts (Dangoor et al, 2005).…”

Sexuality of the ageing female – the underlying physiology

“…Griebling, Liao, and Smith (2012) found that postmenopausal women not receiving any HT had relatively high levels of innervation, the majority of axons expressing tyrosine hydroxylase (indicating nor-adrenergic sympathetic fibres associated mainly with smooth muscle of the vasculature and muscles) or VIP (vasoactive intestinal peptide expressed by cholinergic parasympathetic innervation associated predominantly with vascular and non-vascular smooth muscle). Some 20% of axons were non-cholinergic, non-adrenergic (NANC) presumed to be the unmyelinated sensory innervation which also showed decreases with the hormonal treatments but their small number did not allow quantitative analysis.…”

Vulvodynia in Menopause

“…Estrogen receptors present in the central and peripheral nervous systems are known to infl uence all aspects of neural activity from membrane permeability to gene regulation. The transition into menopause, with the accompanying change in systemic estrogen concentration, may therefore affect chronic pain [ 22 ].…”