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Objective To assess whether primary and secondary vestibulodynia represent different pathologic pathways. Methods This was an analysis of archived vestibulectomy specimens from 88 premenopausal women with vestibulodynia (2002–2008). Patient records were reviewed to classify the type of vestibulodynia, duration of symptoms, and hormone status. Histologic sections were stained for hematoxylin and eosin to grade inflammation, S100 to highlight nerves, CD117 for mast cells, estrogen receptor α, and progesterone receptor. Differences between primary and secondary vestibulodynia were tested by t-tests, chi-square analysis, linear and logistic regression. Results Primary vestibulodynia showed significant neural hypertrophy and hyperplasia (p=0.02, adjusted odds ratio 3.01 [1.2–7.6]) and increased progesterone receptor nuclear immunostaining (p=0.004, adjusted odds ratio 3.94 [1.6–9.9]) compared with secondary vestibulodynia. estrogen receptor α expression was also greater in primary vestibulodynia when symptom diagnosis was less than 5 years (p=0.004, adjusted odds ratio 5.53 [1.71–17.91]). Conclusions Primary and secondary vestibulodynia have significantly different histologic features, suggesting that they may have separate mechanistic pathways. Clinically, this may mean the discovery of distinct conditions.

Vestibulodynia is a form of provoked vulvodynia characterized by profound tenderness, hyperinnervation, and frequently inflammation within well-defined areas of the human vestibule. Prior experiments in animal models show that inflammatory hypersensitivity and hyperinnervation occur in concert with establishment of a local renin-angiotensin system (RAS). Moreover, mechanical hypersensitivity and sensory axon sprouting are prevented by blocking effects of angiotensin II on AT2 receptors. This case-control study assessed whether a RAS contributes to hyperinnervation observed in human vestibulodynia. Vestibular biopsies from asymptomatic controls or patients’ nontender areas showed moderate innervation and small numbers of inflammatory cells. In women with vestibulodynia, tender areas contained increased numbers of mechanoreceptive nociceptor axons, T-cells, macrophages and B-cells, while mast cells were unchanged. RAS proteins were increased due to greater numbers of T-cells and B-cells expressing angiotensinogen, and increased renin-expressing T-cells and macrophages. Chymase, which converts angiotensin I to angiotensin II, was present in constant numbers of mast cells. To determine if tender vestibular tissue generates angiotensin II that promotes axon sprouting, we conditioned culture medium with vestibular tissue. Rat sensory neurons cultured in control-conditioned medium showed normal axon outgrowth, while those in tender tissue-conditioned medium showed enhanced sprouting that was prevented by adding an AT2 antagonist or angiotensin II neutralizing antibody. Hypersensitivity in provoked vestibulodynia is therefore characterized by abnormal mechano-nociceptor axon proliferation, which is attributable to inflammatory cell-derived angiotensin II (or a closely related peptide) acting on neuronal AT2 receptors. Accordingly, reducing inflammation or blocking AT2 represent rational strategies to mitigate this common pain syndrome. Perspective: This study provides evidence that local inflammation leads to angiotensin II formation which acts on the angiotensin II receptor type 2 to induce nociceptor axon sprouting in vulvodynia. Preventing inflammation and blocking AT2 therefore present potential pharmacological strategies for reducing vestibular pain.

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