Effects of estrogen on vaginal innervation: denervation or remodeling?

V ulvar and vaginal symptoms, including discomfort, dryness, itching, burning, and pain, are common among postmenopausal women. Although aging plays an etiological role, the association of symptoms with declining estrogenic activity and the reported improvement of symptoms with estrogen treatment have established estrogen deficiency as the main etiological factor for those symptoms. Until recently, most clinical research in the field of postmenopausal vulvar and vaginal health focused on estrogen modulation of epithelial structure. The study by Griebling et al, published in the current issue of Menopause, presents novel data in postmenopausal women in vivo about the effects of hormone treatment (with emphasis on estrogen) on vaginal submucosal innervation. Expression of neurons was assayed using immunological techniques and described in terms of reactivity to the pan-neuronal antibody (PGP9.5) and to antibodies that react predominantly with sympathetic (TH) or parasympathetic (VIP) neurons. The authors report diffuse immunoreactivity to the antibodies in submucosal regions of the vaginal tissue, suggesting rich innervation. The type-specific immunoreactivities suggest the presence of plexi, composed mainly of sympathetic and parasympathetic axons, and confirm earlier anatomical and histological reports that the bulk of human vaginal submucosal innervation is composed of sympathetic and parasympathetic neurons. The authors also assessed the effect of hormone treatment on PGP9.5, TH, and VIP immunoreactivities and found reduced immunoreactivities in vaginal submucosal tissues of treated versus nontreated women. These novel data in human vaginal submucosa are consistent with previous studies in animal models. In addition, the researchers found greater reductions in the immunoreactivities in tissues of women treated topically with estrogen than in women receiving systemic hormone treatment. The authors suggest that the reduced immunoreactivities in response to hormone treatment reflect decreased autonomic innervation and advance the hypothesis that estrogen treatment relieves vaginal discomfort by inducing autonomic and sensory denervation. This speculation apparently contradicts the known direct trophic effect of estrogen, which tends to promote axon outgrowth and regeneration of sensory and sympathetic neurons. To overcome this impediment, the researchers proposed that the loss of innervation is secondary to estrogen effect on nonneuronal submucosal cells, leading to the production of prodegenerative mediators. The local prodegenerative conditions dominate over the direct effects of estrogen and result in denervation. DO THE NOVEL DATA HAVE BIOLOGICAL SIGNIFICANCE? The neuronal autonomic system in the vaginal submucosa controls and regulates blood flow, sensation, and blood vessels and nonvascular smooth muscle tone. These estrogendependent functions play an important role in sexual function and reproduction. Decreased estrogenic activity after menopause is associated with abrogation of these functions and may lead to decreased blood flow, hyposensitivity, and decreased vaginal tone. Interestingly, the Griebling et al hypothesis stipulates the opposite, namely that estrogen leads to the denervation of autonomic neurons and that vaginal denervation promotes clinical well-being. This intriguing hypothesis stands in sharp contrast with the current dogma that estrogen promotes tissue buildup, growth, and remodeling. The major weakness of the Griebling hypothesis is the lack of mechanistic understanding that could integrate the new scientific findings with known clinical data. The authors speculate about possible signal mechanisms and mediators that could mediate estrogen-dependent denervation, but they did not present experimental data and failed to suggest an adequate explanation of how vaginal denervation could improve woman’s well-being and alleviate vaginal symptoms.