CHIEF EDITOR’S NOTE: This article is part of a series of continuing education activities in this Journal through which a total
of 36 AMA/PRA category 1 creditsTMcan be earned in 2006. Instructions for how CME credits can be earned appear on the
last page of the Table of Contents.
A Conceptual Model for the
Pathophysiology of Vulvar Vestibulitis
Denniz Zolnoun, MD, MPH,* Katherine Hartmann, MD, PhD,†
Georgine Lamvu, MD, MPH,* Suzie As-Sanie, MD, MPH,‡
William Maixner, DDS, PhD,§ and John Steege, MD?
*Assistant Professor, Division of Advanced Laparoscopy and Pelvic Pain, Department of Obstetrics and
Gynecology, and Center for Women’s Health Research, University of North Carolina, Chapel Hill, North
Carolina; †Associate Professor, Departments of Obstetrics & Gynecology and Epidemiology, and Director
of Center for Women’s Health Research, University of North Carolina, Chapel Hill, North Carolina;
‡Lecturer, Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan;
§Professor, Department of Endodontics, and Director of the Center for Neurosensory Disorders, School
of Dentistry, University of North Carolina, Chapel Hill, North Carolina; and ?Professor and Director,
Division of Advanced Laparoscopy and Pelvic Pain, University of North Carolina, Chapel Hill,
Vulvar vestibulitis syndrome (vestibulitis), the most common type of chronic vulvovaginal
pain, impairs the psychologic, physical, and reproductive health of approximately 10% of
women at some point in their lives. Research on the pathophysiology of vestibulitis suggests
abnormalities in 3 interdependent systems: vestibular mucosa, pelvic floor muscles, and cen-
tral nervous system pain regulatory pathways. To date, causes and relative contributions of
these abnormalities to the development and maintenance of vestibulitis remain poorly under-
stood. Research consistently supports the conceptualization of vestibulitis as a chronic pain
disorder—akin to fibromyalgia, irritable bowel disorder, and temporomandibular disorder
(TMD)—that is far more complex than vestibular hypersensitivity alone. Nevertheless, the
clinical diagnosis of vestibulitis continues to rely on subjective report of pain during intercourse
and vestibular sensitivity on clinical examination after exclusion of other gynecologic disorders.
We propose that current diagnostic criteria, which are based on highly subjective patient and
clinician measures, are not sufficient to describe and properly classify the heterogeneous
clinical presentations of this disorder. To inform clinical care or research, we must be able to
objectively characterize women with vestibulitis. This narrative review critically appraises
current conceptualization of vestibulitis and presents a context for studying vestibulitis as a
chronic pain disorder, emphasizing the need for objective assessment of clinical features.
Target Audience: Obstetricians & Gynecologists, Family Physicians
Learning Objectives: After completion of this article, the reader should be able to state that vulvar
vestibulitis is common; recall that the disorder has three major pathophysiological pathways and that
understanding of these pathways is important in selecting treatment options, and explain that the clinician
must attempt to properly classify the clinical presentations of the disorder.
Volume 61, Number 6
OBSTETRICAL AND GYNECOLOGICAL SURVEY
Copyright © 2006
by Lippincott Williams & Wilkins
Although many women suffer in silence without
seeking care and many go undiagnosed after seeking
care, an estimated 200,000 women who receive a
diagnosis of vestibulitis seek care each year in spe-
cialty clinics in the United States (1,2). Little is
known about the etiology of vestibulitis, although it
is thought to result from an exaggerated inflamma-
tory response of the vulvar mucosa (vestibule) to
injury. Clinical diagnosis remains one of exclusion.
Before treatment for vestibulitis, patients have seen
an average of 3 physicians (3) and had 5 years of pain
(4,5). Vestibulitis is clinically defined by 3 subjective
signs and symptoms: 1) entry dyspareunia; 2) tender-
ness to light touch (eg, cotton swab palpation) on the
vestibule; and 3) presence of erythema (6–8). Treat-
ment options continue to be empiric and of variable
efficacy, with biofeedback and surgical resection be-
ing the 2 most commonly used modalities (9).
Vestibulitis, a functional versus organic disorder, is
controversial. Proponents of vestibulitis as predomi-
nantly an organic disorder cite well-documented ge-
netic differences in proinflammatory tendencies of
the vestibular mucosa (10–19). In this model, com-
monly mentioned psychologic abnormalities and pel-
vic muscle dysfunction (spasm and difficulty with
relaxation) are thought to result from a chronically
inflamed and painful vestibular mucosa that causes
reflexive guarding (20–25). On the other hand, others
suggest that vestibulitis is a functional disorder. In
this alternative model, psychosexual dysfunction is
the antecedent to the development of vestibulitis. In
support of this theory is the well-documented success
of treatment with biofeedback or cognitive behav-
ioral therapy (26–28). Neither theory sufficiently ex-
plains what we observe in clinical practice: a range of
vestibulitis patients, those in whom central nervous
system (CNS) dysfunction is more predominant and
others in whom mucosal sensitivity is primary. That
is, some women report improvement in pain only
after interventions specific to pelvic floor muscles
and psychosexual function, others report improve-
ment only after interventions directed at decreasing
sensitivity of the vestibular mucosa, whereas the
majority respond to combination therapy (29–32).
We speculate that the proinflammatory tendencies of
the mucosa may, in fact, be a “risk marker” for the
development of vestibulitis, that is, a necessary compo-
nent of the clinical syndrome that leads to symptoms
only in the context of a greater dysfunction (eg, pelvic
floor dyssynergia secondary to central dysregulation).
Our theory is that vestibulitis is a group of conditions
characterized by varying degrees of pain and dysfunc-
tion in the mucosa, underlying musculature, and asso-
ciated dysfunction in pain-regulatory systems (Fig. 1).
The clinical manifestations of vestibulitis may result
mechanisms, including a predisposition of the mucosa
toward heightened inflammatory response, pelvic mus-
cle dysfunction, previous trauma (eg, childbirth, puden-
and modulation by psychologic traits.
This review appraises current literature in the
pathophysiology of vestibulitis as it relates to periph-
eral (vestibular mucosa and pelvic floor muscles),
central, and psychosocial factors in the manifestation
of vestibulitis. The impetus behind this work is based
on 2 fundamental principles: 1) conditions yielding
persistent state of pain are too complex to be ade-
quately diagnosed using a single axis (eg, anatomic
location), and 2) concomitant assessment of biologic
(peripheral and CNS) and psychologic (CNS) factors
is necessary to identify subgroups with important
pathophysiological differences (33,34). At the con-
clusion, we review the clinical implications of these
observations and future directions for investigation
of vestibulitis as a multidimensional pain disorder.
Is Vestibulitis a Disease of the Vestibular Mucosa?
Mucosal inflammation plays a central role in the
clinical manifestations of vestibulitis (35–39). Histo-
logic and biomolecular analyses of vestibular mucosa
among women with vestibulitis demonstrate distinct
alterations in biochemical and neuronal composition
(15–19,40–42). In comparison to women without
pain, women with vestibulitis tend to express genetic
variants that result in more potent proinflammatory
substances (eg, IL-1?, TNF-?) (18) and less potent
sistent inflammation is the natural consequence of
this imbalance between the proinflammatory and an-
tiinflammatory arms of the immune system (12).
The authors have disclosed that they have no financial relation-
ships with or interests in any commercial companies pertaining to
this educational activity.
Dr. Zolnoun is a recipient of Grant/Research funding from
Celgene Corporation. All other authors have disclosed that they
have no financial relationships with or interests in any commercial
companies pertaining to this educational activity.
This work was in part supported by the NIH Building Interdisci-
plinary Research Career in Women’s Health (BIRCWH).
Reprint requests to: Denniz Zolnoun, MD, MPH, Department of
Obstetrics and Gynecology, CB 7570, MacNider Building, Uni-
versity of North Carolina, Chapel Hill, NC 27599-7570. E-mail:
396 Obstetrical and Gynecological Survey
Chronic inflammation results in proliferation of no-
ciceptive nerve fibers (c-fibers) with altered receptor
expression (41). Sustained inflammatory response in
the vulvar mucosa promotes both neuronal proliferation
and persistent elevation of proinflammatory substances
(43–46). This, in turn, lowers the sensory threshold of
vestibular mucosa. In this setting, a normally impercep-
tible and painless stimulus is felt as painful among
women with vestibulitis (allodynia) (38,44). Conse-
quently, even light touch can result in exaggerated
release of proinflammatory substances by the sensitized
nerve fibers. These proinflammatory substances, in
turn, activate inflammatory cells (eg, neuroendocrine
cells and mast cells) to release more proinflammatory
substances. This self-perpetuating process of inflamma-
tion (neurogenic inflammation) is thought to play a key
role in maintenance of the local inflammation in ves-
Inability to break this self-perpetuating cycle of
inflammation can lead to changes in the CNS such
that patients experience sensory and motor abnormal-
ities at regions (eg, arm, deltoid) remote from the
original site of inflammation. This phenomenon is
known as “central sensitization” (47–49). Compared
with women with no genital pain, women with ves-
tibulitis have higher sensitivity to experimental pain
stimuli at the nongenital regions. Central sensitiza-
tion as described here is offered as the explanatory
model. However, heightened sensitivity to nonpain-
ful stimuli may occur independently and precede the
development of chronic pain conditions such as ves-
tibulitis (50). For example, harboring a less potent
genetic variant of catecholamine-O-methyltransferase
(COMT), an enzyme involved in catecholamine me-
tabolism, is shown to be a risk factor for developing
chronic myofascial pain disorder (eg, temporoman-
dibular dysfunction); higher pain sensitivity to exper-
imental pain is also observed among carriers of this
less potent variant of COMT (50).
Is Vestibulitis a Disease of the Pelvic Floor Muscle?
Pelvic floor muscle dysfunction of varying severity
is commonly observed in women with vestibulitis.
Treatments targeting physical (ie, biofeedback) and
volitional control (ie, cognitive behavior therapy) of
pelvic muscle contraction are common modalities in
management of vestibulitis (9,51). One of the few
randomized treatment trials for vestibulitis assessed
the efficacy of 3 commonly used approaches for the
treatment of vestibulitis: biofeedback, cognitive–
behavioral therapy, and vestibulectomy on a sample
of 78 women. Across the 3 arms, the baseline pain
was 5.45 to 6.34 on a Likert scale of zero (no pain)
to 10 (worse imaginable pain), which decreased to
1.9 to 4.42 at 6-month follow up (P ? .01) (9) with
no meaningful difference across groups.
The importance of pelvic floor muscle dysfunction
in women with vestibulitis is widely acknowledged
(21). Most theories assume muscle dysfunction is
secondary to chronic inflammation of the mucosa and,
thus, reactive in nature (20–22,52). Some experts have
Fig. 1. Unifying conceptual model. This model displays the likely biologic and psychologic determinants that contribute to the odds
of developing vestibulitis. These factors are influenced by genetic factors and environmental events that determine an individual’s
psychologic profile and pain amplification status.
Pathophysiology of Vulvar Vestibulitis Syndrome Y CME Review Article397
postulated that skin disturbance in vestibulitis desta-
bilizes the pelvic floor muscles, resulting in high
resting tone and poor voluntary control (29–32). Oth-
ers have viewed it as a reflexive phenomenon sec-
ondary to ongoing pain with attempted intercourse,
similar to involuntary muscle “splinting” seen in the
setting of acute musculoskeletal pain (21,22). Neither
theory fully explains the observed clinical efficacy of
biofeedback in vestibulitis, which requires an explan-
atory model with pelvic floor muscle dysfunction as
a primary pathologic process. It is plausible that in
some women with vestibulitis, pelvic floor muscle
dysfunction may act as an initiator of sensory changes
in susceptible mucosa; whereas in others, muscle dys-
function may occur in response to mucosal inflam-
mation. Well-established constructs in neurosensory
research support this concept of muscle contraction
as either an initiator or a consequence of skin in-
flammation or an ongoing component of sustained
Temporomandibular disorder (TMD) offers a model
for muscle dysregulation as a primary process. Indi-
viduals with TMD have dysfunction in contraction
and relaxation of the facial muscles that is associated
with chronic orofacial pain (54). TMD muscle dys-
function has been traced to an imbalance between
central inhibitory and excitatory pathways. The net
result is loss of adequate inhibition from the CNS to
the involved muscles. This disinhibition of motor
signal is thought to cause some of the clinical man-
ifestations (clenching, difficulty with voluntary jaw
opening) in women with TMD. In this case, primary
abnormalities in muscle function are intimately as-
sociated with the development of pain. Such dys-
function in inhibitory pathways is also seen in
association with another syndromatic pain disorder
(eg, fibromyalgia). Not surprisingly, there is a known
comorbidity between fibromyalgia and TMD (55,56). In
fact, our own data support a similarly high comor-
bidity between TMD and vestibulitis. Seventy-eight
percent of women with vestibulitis recently studied
in our clinic were found to have concomitant diag-
nosis of TMD: clinical (40%) and subclinical (38%)
(submitted for publication).
Alternatively, pelvic muscle dysfunction may be
the consequence of chronic inflammation in the over-
lying vestibular mucosa. An inflammatory insult of
the mucosa may initiate hypersensitivity (hyperalge-
sia) in the underlying musculature (57). In animal
models, as well as in human models, pain fibers
(C-fibers and A-? fibers) that are sensitized by mu-
cosal inflammation initiate, through polysynaptic
spinal processes, hypersensitivity and contraction of
the underlying musculature. Further sensitization of
the muscle pain receptors may in turn, through a
process of central sensitization, reduce sensory pain
thresholds, resulting in a “vicious cycle” of inflam-
mation and additional muscle contraction (53,58).
In summary, the pelvic floor muscle dysfunction
commonly documented in women with vestibulitis,
although clinically similar, could, in fact, be driven
by distinctly different pathophysiological processes.
Does a State of Pain Amplification (Hypersensi-
tivity in Nongenital Sites) Precede or Follow the
Development of Vestibulitis?
Women with vestibulitis have measurable differ-
ences in sensory pain thresholds, a centrally regu-
lated trait. A substantial proportion of women with
vestibulitis shows hypersensitivity to several categories
of pain (tactile, thermal, and pressure) at nongenital
sites (25,48,59–61). The thermal pain threshold for
women with vestibulitis (42.2 ? 2.5°C) is sig-
nificantly lower than pain-free comparison groups
(43.6 ? 1.9°C) (P ? .006) (59). Similarly, high sen-
sitivity to pressure pain in the upper thighs (P ?
.004) and deltoids (P ? .05) is reported in this
population (25). Collectively, these observations point
to an abnormal state of pain amplification among
women with vestibulitis. However, the relative con-
tribution of a state of pain amplification in initiation
and maintenance of vestibulitis is poorly understood.
Some investigators attribute this pain sensitivity to
chronicity of pain in vestibulitis (central sensitiza-
tion) (25,62), whereas others view it as a reflection of
inherent dysfunction in pain-regulatory mechanisms
(61,63). Over the past 3 years, a growing body of
literature suggests that an inherent biologic abnor-
mality in pain processing (a state of pain amplifica-
tion) may be present in some women with vestibulitis
Subgroups of women with vestibulitis differ along
the continuum of extragenital pain sensitivity (60).
Women with vestibulitis are clinically divided into 2
subgroups: primary (women who have never had
comfortable intercourse) and secondary (women who
had no history of pain or dyspareunia until later into
adult life). Women with primary onset of vestibulitis
have greater pain sensitivity to thermal pain (P ?
.019) despite reports of intercourse-related pain that
are similar to women with secondary onset of ves-
tibulitis (60). These central regulatory differences
suggest differences in underlying pathophysiological
mechanisms (60). Women with secondary vestibuli-
tis may experience a local disease (ie, peripheral
398 Obstetrical and Gynecological Survey
process), whereas those with primary onset may have
dysfunction in pain-regulatory mechanisms in addi-
tion to the local vestibular and muscle pain. A one-
dimensional clinical classification schema based on
the history of the onset of pain (primary vs second-
ary) is unlikely to explain the varying contributions
of central and peripheral factors. Nevertheless, the
ability to see such differences using this crude clas-
sification emphasizes the magnitude of heterogeneity
in this population. The involvement of central pain-
regulatory mechanisms may help explain observed
differences in clinical severity and treatment out-
comes in subgroups of women with this condition
(60). Poor treatment outcomes among women with
extragenital pain sensitivity (marker for central dys-
regulation) (61) emphasize the need for a compre-
hensive multidimensional assessment of vestibulitis
as a pain disorder.
Is Vestibulitis a Psychologic Disorder?
Specific psychologic traits may precede or be mod-
ified by chronic pain disorders. Little empiric atten-
tion has been given to the role of psychologic distress
in vestibulitis with competing conceptualizations of
the condition as either functional or organic (65).
Surprisingly, evidence does not suggest that histories
of abuse or assault are more prevalent in patients
with vestibulitis (66–70). In fact, our own research
team found that patients with vestibulitis tend to
report less trauma and abuse than other populations
of women in our chronic pelvic pain clinic (Leser-
man, American Journal of Obstetrics and Gynecol-
ogy, in press). Nonetheless, anxiety, depression
(65,71–76), and somatization (tendency to report a
higher frequency of bodily complaints) are com-
monly observed psychologic features among women
with vestibulitis (25,70,75,77). Granot and Lavee
found more trait anxiety (standard difference [d] ?
0.65, P ? .01) and somatization (d ? 0.84, P ? .01)
among women with vestibulitis compared with a
vestibulitis-free comparison group (63).
Some investigators view vestibulitis as primarily a
psychologic disorder (73,78), whereas others view
psychologic dysfunction as a consequence of pro-
longed pain (74) and sexual dysfunction (69). Al-
though research supports both constructs (79,80), the
direction of these relationships remains unclear, and
both pathways may be operative in vestibulitis.
Differences in severity of anxiety and somatization
are also observed among subgroups of women with
vestibulitis (60,81). Women conventionally consid-
ered to have primary vestibulitis experience higher
levels of anxiety and somatization and are more
refractory to treatment compared with women with
secondary vestibulitis (60,81). Longer duration and
more severe pain are commonly postulated reasons
for the observed psychologic differences in cross-
sectional or retrospective studies between primary
and secondary vestibulitis.
Alternatively, some women with vestibulitis may
have psychologic profiles that favor anxiety and so-
matization as risk factors for the development of the
disorder and do not result from having the condition
(although the traits may be amplified by symptoms).
As outlined here, these individuals may have dys-
function in central pain-regulatory systems that pro-
mote psychologic traits that contribute to developing
vestibulitis symptoms. This combination of psycho-
logic abnormalities and pain sensitivity has been
shown prospectively to be a risk factor for develop-
ment of TMD among individuals who were asymp-
tomatic at baseline (50).
Our current clinical diagnostic criteria and classifica-
tion of vestibulitis are inadequate for understanding the
differences in underlying pathophysiological processes.
Consider the challenges presented by patient scenarios
as divergent as 1) a 28 year old with pain since tampon
use and an unconsummated marriage; 2) a 35 year old
with no history of painful intercourse until childbirth;
and, 3) a 28 year old with a lifelong history of occa-
sional pain with intercourse, which spontaneously re-
solved but became chronic after a severe candidal in-
fection. As clinicians, we are acutely aware of the
different challenges each of these patients present. Fur-
thermore, based on our experience, we often empiri-
cally use different first-line therapies. However, using
our current classification schema, these women, despite
distinct clinical differences, are classified together as
having the same disorder. We purpose a multidimen-
sional assessment akin to our daily clinical practice,
which includes detailed exploration of the patient’s
history and clinical examination findings before diag-
nosis and treatment.
In essence, the current state of diagnoses and treat-
ment of vestibulitis may be comparable to diagnosing
severe headache without a context and a conceptual
model to elicit pertinent historical and physical ex-
amination, critical for differentiating sinus, migraine,
cluster, or tension-type headaches. In the absence of
such knowledge, a diverse range of interventions (eg,
antibiotic treatment, analgesics, surgery, and acu-
puncture) are likely to be found effective when the
“symptom” is viewed as a “disorder.” Only when a
symptom is examined in the context of other associ-
Pathophysiology of Vulvar Vestibulitis Syndrome Y CME Review Article399
ated signs and symptoms can we begin to decipher
the differences in underlying pathophysiology.
Development of rational treatment interventions
informed by the underlying pathophysiology is crit-
ically impaired in vestibulitis as a result of the lack of
a conceptual model that examines the interplay be-
tween clinical variables. Reliable, reproducible, and
comprehensive evaluation will be required to further
advance study of vestibulitis pathophysiology, natu-
ral history, treatment efficacy, and long-term out-
comes. To that end, we must: 1) objectively measure
the clinical manifestation of vestibulitis as it relates
to mucosal, pelvic floor muscle, psychologic, and
central pain-processing mechanisms; 2) investigate
the potential for distinctive subtypes; and 3) develop
a conceptual framework informed by these measures
to guide effective therapeutic interventions.
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Pathophysiology of Vulvar Vestibulitis Syndrome Y CME Review Article401