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North American Chapter of The International Society for The Study of Vulvovaginal Disease

VulvodyniaCauses and Diagnosis

Hope K. Haefner, MD

No conflicts of interest


Additional Information

https://medicine.umich.edu/dept/obgyn/patient‐care‐services/womens‐health‐library/center‐vulvar‐diseases/resources‐providers

or search Google for

Resources for Providers University of Michigan

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Learning ObjectivesAt the end of this presentation, the participant

will:

• Understand the current classification system for vulvar pain (2015 Consensus Terminology and Classification of Persistent Vulvar Pain)

• Explore the various causes of vulvodynia

• Be familiar with the diagnosis of vulvodynia


Additional Information

https://medicine.umich.edu/dept/obgyn/patient‐care‐services/womens‐health‐library/center‐vulvar‐diseases/resources‐providers

or search Google for

Resources for Providers University of Michigan

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Resources for Providers - Michigan Medicine -University of Michigan

Resources for Providers. Vulvar Diseasesr. Patient Education Booklet: This booklet describes various vulvar conditions as outlined below: Diseases of the Vulva; Some suggested vulvar pain and itching measures; Vulvar Self Exam; Yeast Infections; Lichen Sclerosus; Lichen Planus; Vulvodynia; Squamous Cell Hyperplasia ..


Tijuana, Mexico ‐ August, 2017Vaginal and Vulvar Colposcopy (PPT PDF)Vulvar Diagnosis and Treatment (PPT PDF)Vulvodynia Approach, Diagnosis, and Treatment (PPT PDF)Chicago, Advocate Lutheran Grand Rounds ‐ February 2018Management of Complex Vulvovaginal Conditions (PPT PDF)Your Diagnosis Is (PDF)Severe Itch Scratch Cycle Tips (PDF)

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Definition of Vulvodynia

Chronic discomfort

Burning

Stinging

Irritation

Rawness

International Society for the Study of Vulvovaginal Disease

(ISSVD)

Question 1

I see patients with vulvodynia

Yes

No

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Question 2

I like to see patients with vulvodynia

Yes

No

8.3% of women have vulvodynia

Reed BD, Harlow SD, Sen A, Legocki LJ, Edwards RM, Arato N, Haefner HK. Prevalence and demographic characteristics of vulvodynia in a population-based sample. Am J Obstet Gynecol 2011.

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By age 40 years, 7-8% in Boston and Minneapolis/St. Paul reported vulvar pain consistent with vulvodynia.

Harlow BL, Kunitz CG, Nguyen RHN, Rydell SA, Turner RM, Maclehose RF. Prevalence of symptoms consistent with a diagnosis of vulvodynia: Population-based estimates from 2 geographic regions. Am J Obstet Gynecol. 2014;210:40.e1-40.e8.

Diagnosis of Vulvodynia

Define diseaseCotton swab test

Vulvoscopy?

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Not tender; no area of vulva described as area of burning

Alternative diagnosis

Diagnosis of Vulvodynia

Define diseaseCotton swab test

Vulvoscopy ×

Thorough history

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Does Degree of Vulvar Sensitivity Predict VulvodyniaCharacteristics and Prognosis?

Reed BD, Plegue MA, Harlow SD, Haefner HK, Sen A. Journal of Pain 2016 Volume 18, Issue 2, Pages 113–123.

Various Terms Utilized for Vulvar Pain Prior to 2003

• Essential vulvodynia

• Dysesthetic vulvodynia

• Vulvar vestibulitis syndrome

• Vulvar dysesthesia (generalized or localized)

• Provoked vulvar dysesthesia

• Spontaneous vulvar dysesthesia

CONTROVERSY!

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Generalized

Generalized1

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Localized1

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Localized1

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April 2015

Support from the National Vulvodynia Association

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2015 Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia

A. Vulvar pain caused by a specific disorder*• Infectious (eg, recurrent candidiasis, herpes)• Inflammatory (eg, lichen sclerosus, lichen planus, immunobullous disorders)• Neoplastic (eg, Paget disease, squamous cell carcinoma)• Neurologic (eg, postherpetic neuralgia, nerve compression or injury, neuroma)• Trauma (eg, female genital cutting, obstetric)• Iatrogenic (eg, postoperative, chemotherapy, radiation)• Hormonal deficiencies (eg, genitourinary syndrome of menopause [vulvovaginal atrophy], lactational amenorrhea)B. Vulvodynia—Vulvar pain of at least 3 months’ duration, without clear identifiable cause, which may havepotential associated factors

The following are the descriptors:• Localized (eg, vestibulodynia, clitorodynia) or Generalized or Mixed (Localized and Generalized)• Provoked (eg, insertional, contact) or Spontaneous or Mixed (Provoked and Spontaneous)• Onset (primary or secondary)• Temporal pattern (intermittent, persistent, constant, immediate, delayed)

* Women may have both


Appendix:Potential Factors Associated with Vulvodyniaa

• Comorbidities and other pain syndromes (e.g., painful bladder syndrome, fibromyalgia, irritable bowel syndrome, temporomandibular disorder; level of evidence 2)• Genetics (level of evidence 2)• Hormonal factors (e.g., pharmacologically induced; level of evidence 2)• Inflammation (level of evidence 2)• Musculoskeletal (e.g., pelvic muscle overactivity, myofascial, biomechanical; level of evidence 2)• Neurologic mechanisms

• Central (spine, brain; level of evidence 2)• Peripheral: neuroproliferation (level of evidence 2)

• Psychosocial factors (e.g., mood, interpersonal, coping, role, sexual function; level of evidence 2)• Structural defects (e.g., perineal descent; level of evidence 3)

a The factors are ranked by alphabetical order.

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Etiologies







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Painful Bladder SyndromeEmbryologic Derivation

Urogenital sinus

Urogenital sinus

Similarities Between Interstitial Cystitis/Bladder Pain Syndrome and Vulvodynia:

Implications for Patient Management

• Intertwined from the perspectives of embryology, pathology and epidemiology

• Similar responses to therapies

Fariello and Moldwin 2015

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Oxalates and Vestibulodynia

Oxalates and Vestibulodynia

Greenstein A, Militscher I, Chen J, Matzkin H, Lessing JB, Abramov L. Hyperoxaluria in women with vulvar vestibulitis syndrome. J Reprod Med. 2006 Jun;51(6):500-2

Harlow BL, Abenhaim HA, Vitonis AF, Harnack L. Influence of dietary oxalates on the risk of adult-onset vulvodynia. Journal of Reproductive Medicine 2008;53(3):171-178

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For the life of me, I don’t know how I got that yeast infection. I was in and out of that bakery in less than a minute.

Recurrent Yeast Infections and Vulvodynia: Can We Believe Associations Based on Self-Reported Data?

Harlow BL, Caron RE, Parker SE, Chatterjea D, Fox MP, Nguyen RHN.JOURNAL OF WOMEN’S HEALTHVolume 26, Number 10, October 1, 2017 1069-76.Mary Ann Liebert, Inc.

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Recurrent Yeast Infections and Vulvodynia: Can We Believe Associations Based on Self-Reported Data?

Positive relationship between yeast infections preceding and following the diagnosis of vulvodynia

-Varies from strong to nonexistent depending on the relative accuracy of the recalled diagnosis of yeast infections among cases and controls







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Genetics• Inflammatory response

Candida

– Mannose binding lectin

– NALP3 expressed in macrophages

• Neurotransmitters

- Guanosine triphosphate

cyclohydrolase (GCH1)

• G protein coupled-receptors

- Melanocortin-1 receptor

• Neuroinflammatory (cytokines)

- Interleukins (IL)

• MicroRNA

• New thoughts

- Dectin 1

- Familiality


Candida









- Interleukins (IL)

• MicroRNA

• New thoughts

- Dectin 1

- Familiality

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Candida









- Interleukins (IL)

• MicroRNA

• New thoughts

- Dectin 1

- Familiality

Familiality Analysis of Provoked Vestibulodynia Treated by Vestibulectomy Supports Genetic

Predisposition

• 183 potential vestibulectomy probands were identified using CPT codes

• Relative risk of vestibulectomy was elevated in first-degree (20 [6.6-47], P < .00001), second-degree (4.5 [0.5-16], P = .07), and third-degree female relatives (3.4 [1.2-8.8], P = .03)

• Suggests that vestibulodynia treated by vestibulectomy has a genetic predisposition

Morgan et al. 2016

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Catechol-O-methyltransferase gene polymorphism and vulvar pain in women with vulvodynia.

Patanwala IY, Lamvu G, Ledger WJ, Witzeman K, Marvel R, Rapkin A, Bongiovanni AM, Feranec J, Witkin SS.

American Journal of Obstetrics & Gynecology 2017;216(4):395.e1-395.e6

Enzyme that metabolizes catecholamines-Neuromodulator that is involved with perception and sensitivity to pain







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Hormonal Changes Controversy!

Eva LJ, MacLean AB, Reid WM, Rolfe KJ, Perrett CW. American Journal of Obstetrics & Gynecology. 2003;189:458-61.

Johannesson U, Sahlin L, Masironi B, et al. Steroid receptor expression and morphology in provoked vestibulodynia. Am J Obstet Gynecol. 2008;198(3):311 e1–6.

Estrogen Receptor Expression

• Study group showed a significant decrease in estrogen receptor expression, and 50% of the samples did not exhibit any receptor expression

Eva LJ, MacLean AB, Reid WM, Rolfe KJ, Perrett CW. American Journal of Obstetrics & Gynecology. 2003;189:458-61.

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Steroid receptor expression and morphology in provoked vestibulodynia

Ulrika Johannesson Karolinska Institutet,

Danderyd Hospital, SwedenCo-authors;Lena Sahlin, Britt Masironi, Bo Blomgren,

Marita Hilliges, Eva Rylander, Nina Bohm-Starke

Boxplot by Group

Variable: ERa tot bv v v s

Median

25%-75% Min-Max

1 2

Group

0

10

20

30

40

50

60

70

ER

a to

t b

v vv

s

Boxplot by Group

Variable: ERa tot v v s

Median

25%-75% Min-Max

1 2

Group

0

20

40

60

80

100

120

ER

a to

t v

vs

ERα stroma

ERα epithelium

Patients

Patients

Controls

Controls

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Conclusion

• Increased expression of ERα in the vulvar vestibular

mucosa in patients with provoked vestibulodynia in the

absence of an altered epithelial morphology

For women aged <50 years of age, OC use did not increase the risk of subsequent vulvodynia.

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Polymorphisms of the Androgen Receptor Gene and Hormonal Contraceptive Induced Provoked

VestibulodyniaGoldstein et al. 2014• .

•Risk of developing combined hormonal contraceptive (CHC)-induced vestibulodynia may be due to lowered free testosterone combined with an inefficient androgen receptor that predisposes women to vestibular pain







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Mast Cells

• Bornstein et al. (2004) found significant increase in inflammatory infiltrate, number of mast cells and degranulated mast cells in vestibulitis patients (N=40) compared to normal controls (N=7, ages 18-48)

• Regauer et al. (2015) evaluated 35 patients with vulvodynia

-Median age was 24 years (ranged from 18 to 70 years).

-Control tissues obtained from autopsies (? number)

-Only 20/35 vulvodynia specimens showed a T-lymphocyte dominant inflammatory infiltrate on HE-stained sections, but all showed mast cells. 4/35 biopsies showed <10 mast cells/mm2, 15/35 specimens 40–60 mast cells/mm2 and 16/35 specimens >60 mast cells/mm2 (average 80/mm2). Control tissue contained typically <10 mast cells.

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Vestibular Mast Cell Density in Vulvodynia: A Case-Controlled Study

• No difference in mast cell density in biopsies of the vestibule found between white cases and racially matched controls

• Black control women have a lower mast cell density compared with white control women

Papoutsis D, Haefner HK, Crum CP, Opipari AW, Reed BD. J Lower Genit Tract Dis 2016;20: 275-9

Toll-Like Receptor Signaling Contributes to Proinflammatory Mediator Production in Localized Provoked Vulvodynia

Human vulvar fibroblasts express a broad spectrum of TLRs

A significantly higher TLR-mediated proinflammatoryresponse was observed in LPV case vestibular fibroblasts

Falsetta ML, Foster DC, Woeller CF, et al. Journal of Lower Genital Tract Disease. 22(1):52-57, January 2018.

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Heightened Pelvic Floor Muscle Tone and Altered Contractility in Women With Provoked Vestibulodynia

Morin M, Binik YM, Bourbonnais D, Khalife S, Ouellet S, Bergeron S. J Sex Med

2017 Apr;14(4):592-600.

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Heightened Pelvic Floor Muscle Tone and Altered Contractility in Women With Provoked Vestibulodynia

Evaluated the passive component of the PFM tone in women with PVD

Findings show that women with PVD sustaining quiescent muscle activity during stretching still presented greater passive forces, stiffness, and hysteresis than asymptomatic controls

Women with PVD showed muscle over-activation as well as persistent alterations in muscle viscoelastic properties







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Vulvodynia as Neuropathic Pain

PeripheralCentral

Vulvodyniaand the Brain

Augmented Central Pain Processing in

Vulvodynia. J Hampson, BD Reed, DJ Clauw, R Bhavsar, RH Gracely, HK Haefner, RE Harris. Journal of Pain June, 2013;14:579-89.

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Vulvodyniaand the Brain

• On MRI, 24 vestibulodynia patients displayed greater levels of activation during thumb stimulation within the insula, dorsal mid-cingulate, posterior cingulate and thalamus compared to controls (P<0.005 corrected)

• The augmented brain activation in VVD patients in response to a stimulus remote from the vulva suggests central neural pathology in this disorder

Mechanisms of Pain

Stimulus Spinal cord

Brain

from Robert Bennett, MD

A-delta – 1st sharp

C fiber – 2nd

burning, throbbing

Willis 1985

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Mechanisms of Pain

StimulusSpinal cord

Brain

from Robert Bennett, MD

Acute pain

Peripheral nociceptive input from thermal, chemical or mechanical nociceptors

Chronic pain

Central factors typically predominate

Question 3

The nerve which supplies the major portion of the vulva is the

1. Ilioinguinal nerve

2. Genitofemoral nerve

3. Perineal nerve

4. Pudendal nerve

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Pudendal Nerve

Originates from S2, S3, and S4 foramina

Journal of Lower Genital Tract Disease: January 2017;21:78-84.

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JLGTD April 2018 Volume 22:139-146

NGF increased in response to Candida Antigen stimulation in vulvodynia patients-NGF produces pain via direct effect on nerves, and indirect effect on mast cells neutrophils, and efferent neurons.

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Proposed neuroimmunological mechanism of the allodynia/hyperpathia of vulvodynia

Potentially inciting factors: Infections Irritants Toxins Medications Other

Distal nerve sprouting

Allodynia and

hyperpathia

IL-12 andIL-18

Substance P CGRP

IL-4

Increased proinflammatory cytokines: IL-1, IL-6, IL-8 IFN- TNF-

Nerve growth factor

increased

Allodynia and

hyperpathia

Mast cell accumulation

= stimulatory = inhibitory Legend:

IL-1ra

A review of the available clinical therapies for vulvodynia management and new data implicating pro-inflammatory mediators in pain elicitation

Fibroblasts isolated from the vestibule of LPV patients are sensitive to pro-inflammatory stimuli and copiously produce pain-associated pro-inflammatory mediators (IL‐6 and PGE2)

Falsetta ML, Foster DC, Bonham AD, Phipps RP. BJOG 2017 Jan;124(2):210-218

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A Prospective 2-Year Examination of Cognitive and Behavioral Correlates of Provoked

Vestibulodynia Outcomes

• Changes in both cognitive and behavioral variables were significantly associated with improved pain and sexual satisfaction outcomes

Davis SN, Bergeron S, Bois K, Sadikaj G, Binik YM, Steben M.Clinical Journal of Pain 2015;31(4):333-41.

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New Concepts on Functional Chronic Pelvic and Perineal Pain: Pathophysiology and

Multidisciplinary Management

• Dysregulation of nociceptive messages derived from the pelvis and perineum

Ploteau S, Labat JJ, Riant T, Levesque A, Robert R, Nizard J. Discovery Medicine 2015;19(104):185-92.

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Not One Disease

F1000Research 2016,5.

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The Human Dimension

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