Genitourinary Syndrome of Menopause: Pathophysiology, Clinical Presentation, and Differential Diagnosis.

Scientific information is incomplete regarding the genitourinary syndrome of menopause. Both the lower genital and urinary tracts are rich in receptors for reproductive hormones and are highly susceptible to waning ovarian hormones at menopause. Symptoms of dryness and pain emerge in late perimenopause, but they can also result earlier from cancer therapies or bilateral oophorectomy. Lower urinary tract symptoms rise in prevalence at midlife and increase further with advancing age. Because ovarian senescence is typically followed by years of aging, some postmenopausal complaints may be attributable to increasing longevity.

Comparing Vestibule Examination Techniques: Light Touch, Serial Forces, and the Lidocaine Test.

OBJECTIVE: The purpose of this study was to compare techniques and pain scales that assess tenderness in the vulvar vestibule in provoked vestibulodynia, using the cotton swab test and a vulvalgesiometer, and assess topical lidocaine solution with each. MATERIALS AND METHODS: This randomized study at a specialty vulvar clinic evaluated tender vestibules of reproductive-aged women with vestibulodynia using light rolling cotton swab touch at 6 sites and evaluated the vulvalgesiometer at 2 sites, randomizing the order of the initial tool. Participants reported pain using the Numerical Rating Scale 0-10 and the Verbal Pain Scale 0-3. With the vulvalgesiometer, the pain tolerance threshold was measured using forces of 10, 25, 50, 100, 200, and 300 g. After both initial tests, lidocaine 4% topical solution was applied for 3 minutes, and the swab test and vulvalgesiometer were repeated in the order initially performed, constituting the lidocaine test. Data analysis used t tests, Fisher exact tests, Wilcoxon signed rank tests, and Spearman rank correlation. RESULTS: Sixteen patients completed the study, 8 starting with each instrument. Light swab touch evoked significant pain, and lidocaine reduced pain to zero or mild levels. The pain threshold was 25 g, and only 38% could tolerate testing past 100 g without lidocaine. The Verbal Pain Scale correlated well with the Numerical Rating Scale. CONCLUSIONS: Light rolling cotton swab touch using the 4-item verbal scale can map vestibulodynia tenderness that can be extinguished by lidocaine, consistent with distinguishing a mucosal condition. Forces by vulvalgesiometer of greater than 100-200 g may evoke pain other than mucosal allodynia.

Severe Postmenopausal Genital Pain Treated Successfully With Prolonged Estrogen Therapy: A Case Series and Narrative Review.

OBJECTIVE: The aim of the study was to describe a debilitating postmenopausal condition of continuous burning genital pain that remitted with prolonged estrogen focused on the vulvar vestibule. MATERIALS AND METHODS: Postmenopausal patients with constant genital pain seen by the author in a specialty vulvar health clinic comprised an institutional review board-approved descriptive case series. Examinations to localize pain used 4% lidocaine topical solution. Each patient received estradiol nightly as vestibule crème or constantly by transdermal route and was followed by serial examinations and follow-up telephone contact. Statistical tests included Student t test, Fisher exact test, and Pearson correlation coefficient. RESULTS: Between 2008 and 2016, 16 women presented with constant genital pain that was partly or fully extinguishable with topical vestibular lidocaine, and their pain slowly responded to prolonged vestibule-directed estradiol therapy. The mean age was 66.8 years (± 11.2). The mean pain score was 5 (range = 2-10 on a 0-10 scale). Seven (44%) characterized their pain as debilitating, and 13 (81%) had accompanying urinary symptoms. In 9 patients (56%), ovaries had been removed before natural menopause at ages 27-50 years (mean = 39), followed by minimal or no estrogen therapy. Prolonged estrogen therapy eliminated constant pain in 69% and mitigated it in 31%. CONCLUSIONS: Information about this severe but remediable condition that is associated with lack of estrogen may guide specialists who are treating complex vulvar pain. The patients' clinical histories and therapeutic courses invite a review of estrogen receptor physiology related to urogenital pain conditions.

CD4-positive T-cell recruitment in primary-provoked localized vulvodynia: potential insights into disease triggers.

OBJECTIVE: To better understand the potential disease triggers of neurogenic inflammation in provoked localized vulvodynia (PLV), our objective was to determine whether the types of infiltrating lymphocytes were different in vestibular biopsies from women with primary PLV, secondary PLV, and unaffected controls. METHODS: Secondary retrospective analysis of archived vestibular biopsies from a series of adult premenopausal women with primary PLV (n = 10), secondary PLV (n = 10), and unaffected controls (n = 4) was performed. All study patients had severe entry dyspareunia for more than 1 year. Subjects were excluded if pregnant, or they had a known infection, or history of generalized vulvodynia. Biopsies were performed during the midfollicular phase. Lymphocyte subtypes were highlighted in histologic sections using antibodies against CD3, CD4, and CD8 and scored as the mean number of T-cell subtypes per high-power field. Flow cytometry was also used to test fresh biopsies from a de novo prospective series of primary PLV (n = 4) and unaffected controls (n = 2). RESULTS: Unaffected control biopsies showed more CD8-positive than CD4-positive T cells, similar to previous reports of the gynecologic tract. In contrast, biopsies from women with primary PLV showed significantly more CD4-positive T cells than those from women with secondary PLV and unaffected controls (p = .003). This observation was further supported by flow cytometry. CONCLUSIONS: CD4-positive T cells are more numerous in vestibular biopsies from premenopausal women with primary PLV. This may be important because subtypes of CD4-positive T cells are specifically recruited by infectious, allergic, or autoimmune triggers. Future studies distinguishing these subtypes may lead to new insights into this common disease.

Treating where it hurts-a randomized comparative trial of vestibule estradiol for postmenopausal dyspareunia.

OBJECTIVE: To compare efficacies of two strengths of estradiol cream applied to the vulvar vestibule and use of silicone lubricant to reduce intercourse pain scores in postmenopausal women with moderate/severe dyspareunia. METHODS: This pilot randomized comparative trial assigned 50 women to nightly applications of estradiol cream, 50 or 100 µg, for 12 weeks. We asked women to have lubricated penetration twice weekly, with intercourse or performing a tampon test. Pain, recorded in dairies, was rated using the 0-10 Numerical Rating Scale. We assessed biopsychosocial outcomes, urinary symptoms, and measured serum estradiol levels and endometrial stripe thicknesses. We performed physical examinations to determine tenderness levels of the vestibule, vagina, pelvic floor muscles, bladder, uterus, and adnexa. Comparisons were made using two-sample t test, Wilcoxon rank-sum test, or χ2 /Fisher's exact test. RESULTS: Forty-seven women (94%), with a mean age of 59.7 years, completed the trial. The baseline median intercourse pain score was 8/10 (interquartile range, 6, 8). After 12 weeks, we measured no statistically significant difference between groups in the primary outcome, intercourse pain score, or any secondary outcome measure. For both groups together, the median intercourse pain score diminished by 50% after 4 weeks and 75% after 12 weeks ( P < 0.001). The most tender anatomic area, the vulvar vestibule, improved by 82% to 100% ( P < 0.001) with therapy. We did not measure a statistically significant difference in serum estradiol levels or endometrial stripe thickness between groups. CONCLUSION: Estradiol cream applied to the vulvar vestibule, paired with precoital silicone lubricant, is a promising alternative to vaginal therapy for dyspareunia.

Unprovoked vestibular burning in late estrogen-deprived menopause: a case series.

OBJECTIVE: This study aimed to document cases of severe menopausal vulvar burning localized to the vestibule. MATERIALS AND METHODS: Seven postmenopausal women presented to a vulvar clinic between 2007 and 2011 complaining of debilitating constant vulvar burning pain. They were treated according to the vulvar findings. Statistical tools were descriptive. RESULTS: The women's ages ranged from 56 to 79 years (mean age = 67 years). Pain had begun 1 to 4 years before presentation (mean = 1.8 years) and was vestibular. Five had contraindications to estrogen supplements. Only 1 patient was using estrogen; the mean number of years from menopause to onset of burning was 16 years (range = 4-27 years). Three patients developed pain during or after aromatase inhibitor therapy for breast cancer. Pelvic floor myalgia was present in 3 patients. Of the patients, 3 improved on systemic estrogen, 3 improved using topical vestibular estrogen therapy, and 1 was managed with reassurance alone. Vestibulodynia regressed in those using estrogen supplementation. One patient noted resolution after localized removal of vestibular mucosa. CONCLUSIONS: Severe unprovoked vestibulodynia can present as unprovoked generalized pain in late menopause, and topical lidocaine can aid the diagnosis. Constant pain can arise after years of only provoked pain or in association with further lowering of estrogen from antiestrogen therapy for breast cancer. Therapy to the vestibule can provide relief. Lidocaine and local application of estrogen cream to the vestibule are effective therapies, and physical therapy can be important. With encouragement to avoid estrogen during menopause and with the increasing use of aromatase inhibitors for breast cancer, menopausal unprovoked vestibulodynia may be increasing and can be challenging to diagnose and treat.

Where does postmenopausal dyspareunia hurt? A cross-sectional report.

OBJECTIVE: A common symptom of genitourinary syndrome of menopause (GSM) is dyspareunia, attributed to vulvovaginal atrophy. Our objective was to systematically describe the pain characteristics and anatomic locations of tenderness in a cohort with moderate/severe dyspareunia likely due to GSM. METHODS: This cross-sectional study reports the baseline data of postmenopausal women with dyspareunia screened for an intervention trial of topical estrogen. Postmenopausal women not using hormone therapy who had moderate or severe dyspareunia were eligible if estrogen was not contraindicated. Biopsychosocial assessments were performed using the Vulvar Pain Assessment Questionnaire, and participants underwent a systematic vulvovaginal examination that included a visual assessment and cotton swab testing for tenderness rated using the Numerical Rating Scale (0-10). Vaginal pH and mucosal sensitivity were assessed; pelvic floor muscles and pelvic viscera were palpated for tenderness. RESULTS: Fifty-five eligible women were examined between July 2017 and August 2019. Mean age was 59.5 ±â€Š6.8 years, and duration of dyspareunia was 6.2 ±â€Š4.3 years. The mean intercourse pain score was 7.3 ±â€Š1.8, most often described as "burning" and "raw." Ninety-eight percent had physical findings of vulvovaginal atrophy. Median pain scores from swab touch at the vulvar vestibule (just outside the hymen) were 4 to 5/10, and topical lidocaine extinguished pain. Median vaginal mucosal pain was zero. CONCLUSIONS: Participants described their pain as "burning" and "dry." Tenderness was most severe and most consistently located at the vulvar vestibule. Correlating the symptom of dyspareunia with genital examination findings may further our understanding of treatment outcomes for GSM.

Video Summary:http://links.lww.com/MENO/A916 .

Histologic and receptor analysis of primary and secondary vestibulodynia and controls: a prospective study.

OBJECTIVE: The objective of the study was to assess the association between hormone receptor densities, pain nerves, and inflammation in vestibulodynia patients. STUDY DESIGN: In a prospective study, tender and nontender biopsies from 10 primary and 10 secondary vestibulodynia patients were compared with biopsies in 4 nontender controls. Hormone receptors were evaluated using immunohistochemistry for estrogen receptor-alpha and -beta, androgen, and progesterone receptors. Inflammation, nerves, and mast cells were assessed histologically. Statistical analysis was by Fisher's exact test, analysis of variance, paired Student t test, and Wilcoxon rank test. RESULTS: Tender sites from primary vestibulodynia had increased nerve density compared with secondary and control biopsies (P = .01). Tender sites in secondary vestibulodynia had more lymphocytes than tender primary sites and control biopsies (P < .0001). Mast cells were increased in tender sites compared with nontender and controls. There were no differences in hormone receptor expression. CONCLUSION: Markers of inflammation differed between primary and secondary vestibulodynia and controls.

Group B streptococcus: prevalence in a non-obstetric population.

OBJECTIVE: To establish and compare the prevalence of group B streptococcus (GBS) colonization in the vaginas of nonobstetric women with and without vaginitis. MATERIALS AND METHODS: Cross-sectional analysis GBS vaginal culture status of nonpregnant, estrogen-replete women 18 years or older presenting for annual gynecological examinations or vaginal infection. Subjects were classified into 3 groups: no vaginitis if symptoms were absent and examination results was normal; common vaginitis (CV) if microscopic examination revealed yeast, bacterial vaginosis, or trichomonads; or inflammatory vaginitis (IV) if examination revealed inflammation and immature squamous cells but no pathogens. RESULTS: Of the 215 women recruited, 147 (68.4%) showed no evidence of vaginitis, 41 (19.1%) had CV, and 27 (12.6%) showed evidence of IV. The overall prevalence rate of GBS was 22.8%. Vaginitis was associated with a significantly increased risk of GBS colonization (adjusted odds ratio: CV = 2.7, 95% CI = 1.1-6.2; IV = 2.9, 95% CI = 1.1-8.0). Logistic regression revealed pH higher than 4.5, presence of abnormal discharge on examination, and a women's complaint of current symptoms as significant predicators of the presence of GBS. CONCLUSIONS: Group B streptococcus colonization occurs more commonly in women with vaginitis. This suggests that disruption of the normal vaginal bacterial environment is an important predictor for GBS colonization.

Incidence of Bartholin's duct occlusion after superficial localized vestibulectomy.

OBJECTIVE: The objective of the study was to analyze the incidence of occlusion of Bartholin's ducts after the procedure of superficial localized vestibulectomy for severe vulvar vestibulitis. STUDY DESIGN: One hundred fifty-five women underwent modified superficial vestibulectomy for severe primary or secondary vestibulitis between 1989 and 2007. Charts were reviewed and data were calculated regarding occlusion of Bartholin's ducts. Database software was FileMaker Pro 5 (FileMaker, Inc, Santa Clara, CA). SPSS 16.0 (SPSS, Inc, Chicago, IL) calculated means. RESULTS: Fourteen of 155 women (9%) had small blisters noted at a Bartholin's duct site after healing. Of these, 6 (43%) noted local symptoms related to sexual arousal. Surgical unroofing was attempted in 8 (62%) and corrected symptoms in all but 1. The subject with remaining symptoms notes deep pain with arousal suggestive of Bartholin's adenitis. CONCLUSION: The incidence of duct ostium occlusion after superficial modified vestibulectomy was 9%, and only half had symptoms. Methods of surgical treatment of the occlusion are compared.

Patients' assessments of a superficial modified vestibulectomy for vestibulodynia.

OBJECTIVE: To assess long-term outcomes of surgical treatment of vestibulodynia by reporting patients' tabulated questionnaire responses. STUDY DESIGN: Between 1988 and 2006, 133 subjects underwent modified superficial vestibulectomies. At 4 time intervals, portions of the expanding cohort were queried with a mailed questionnaire. Results were compared to the clinical findings. Questionnaires had closed questions, ranked and non-ranked, as well as open questions and visual analogue scales. Percentages were calculated by SPSS statistical software. RESULTS: A total of 119 women (89%) returned questionnaires, allowing a mean follow-up interval of 2.8 years; 68% reported that dyspareunia was cured completely, and for 24% it was lessened. Twenty-two percent said they perceived a different pain after surgery, many identifying it as muscular. Eighty-seven percent said they would have the procedure again. Qualitative responses revealed the importance of physical therapy, the complexities of pain issues, the toll on emotions and relationships and suggestions for more education of health practitioners and women generally about this entity. CONCLUSION: A large majority of women who underwent superficial vestibule surgery for vestibulodynia found it quite acceptable and instrumental in treating dyspareunia. Many wished they had had it sooner. Individualized, superficial surgery is very effective and should not be withheld if short-term medical and physical therapy have proven to be incomplete therapies.

Surgery combined with muscle therapy for dyspareunia from vulvar vestibulitis: an observational study.

OBJECTIVE: To explore the dual importance of treating vestibule allodynia and pelvic floor myalgia in correcting dyspareunia associated with severe vulvar vestibulitis. STUDY DESIGN: In this observational study, 111 women were treated by modified superficial vestibulectomy and were evaluated for referral to physical therapists for pelvic floor myalgia. They were followed with interval repeat examinations. Later cohort assessment was by patient questionnaire surveys. Data from pelvic floor muscle examinations and physical therapy referrals were added by retrospective chart review. Primary outcomes were swab touch sensitivity and dyspareunia. RESULTS: Eighty-five percent of subjects ultimately had nontender vestibule examinations postoperatively. Fewer, numbering 64%, reported resolution of dyspareunia, 24% had less dyspareunia, 9% were no better, and 3% reported they were worse. Fifty percent of those with continued dyspareunia had no remaining vestibulitis, but had tight or tender pelvic muscles. Failure of surgery and physical therapy to correct dyspareunia related significantly to length of symptoms before therapy (p = 0.02). Follow-up averaged 3.7 years, with a range of 0.25-14. CONCLUSION: Superficial surgery can correct vulvar vestibulitis, but without treatment for pelvic floor myalgia, women may continue to have dyspareunia. Physical therapy is an important adjunct to achieve comfort.

KTP-nd:YAG laser therapy for the treatment of vestibulodynia: a follow-up study.

OBJECTIVE: To evaluate the results of KTP-Nd:YAG laser therapy for the treatment of vestibulodynia. STUDY DESIGN: Retrospective review and follow-up mail survey of women with vestibulodynia who underwent laser treatment. Demographics, number of laser treatments and symptom severity prior to laser treatment (100-mm visual analog scale) were obtained from the medical record. The survey included questions regarding current sexual pain, sexual quality of life and satisfaction with treatment. RESULTS: Of41 treated women, 37 women were located and agreed to participate. The mean number of laser sessions was 2.81 (range, 1-8). The mean age was 32.9 years and mean follow-up, 2.8. Following laser treatment, most (24 of 37, 68%) subjects reported less pain with sexual intercourse. One subject reported more pain, while 29% (11 of 37) reported no change. Sixty percent (21 of 37) reported their sex lives to be more satisfying/pleasurable following laser treatment. Thirteen women (13 of 37, 35%) underwent vestibulectomy following laser therapy, and 2 subjects were treated with a laser after failed vestibulectomy. CONCLUSION: Most women with vestibulodynia treated with a KTP-Nd:YAG laser achieve a reduction in sexual pain and improved sexual satisfaction without excisional therapy.

Cervical preparation using laminaria with adjunctive buccal misoprostol before second-trimester dilation and evacuation procedures: a randomized clinical trial.

OBJECTIVE: This study was undertaken to determine whether buccal misoprostol improves cervical preparation achieved with laminaria before second-trimester dilation and evacuation procedures. STUDY DESIGN: A randomized, double blind, placebo-controlled trial of preoperative cervical preparation with overnight laminaria and either buccal placebo or 400 microg buccal misoprostol approximately 90 minutes before second-trimester surgical abortion. Block randomization was used to provide balanced enrollment into 2 separate gestational age study groups: early (13-15(6/7)) and mid (16-20(6/7)) second trimester. Surgeons tested maximal cervical dilation by inserting the largest dilator that could be passed through the cervical os without force. Subject demographics and preprocedure symptoms were tracked. RESULTS: Groups were similar in regard to age, gravity, parity, delivery type, and gestational age. Data were analyzed from 125 women in the 13 to 15(6/7) (30 misoprostol, 32 placebo) and 16 to 20(6/7) (31 misoprostol, 32 placebo) gestational age groups. Overall, misoprostol treatment did not improve the initial mean dilation achieved with laminaria alone in either the 13 to 15(6/7) (46.0 fr +/- 5.0; placebo 45.0 fr +/- 6.2, P = .68) or 16 to 20(6/7) (50.9 fr +/- 5.6, placebo 48.9 fr +/- 5.2, P = .16) groups. However, a subanalysis of gestations 19 weeks or more demonstrated significantly greater dilation in the misoprostol group (53.6 fr fr +/- 5.3, placebo 48.5 fr +/- 5.0, P = .01). Subjects receiving misoprostol reported significantly more cramping than those receiving placebo (13-15(6/7) weeks misoprostol 25/30, 83%; placebo 17/32, 53%, P = .02; 16-20(6/7) week misoprostol 25/31, 81%, placebo 16/32, 50%, P = .02). CONCLUSION: Cervical dilation with laminaria is augmented by 400 microg buccal misoprostol in gestations 19 weeks or more, but not in earlier gestations. Misoprostol causes more abdominal cramping.

A Practical Solution for Dyspareunia in Breast Cancer Survivors: A Randomized Controlled Trial.

PURPOSE: Dyspareunia is common in breast cancer survivors because of low estrogen. This study explored whether dyspareunia is introital pain, preventable with analgesic liquid. PATIENTS AND METHODS: In a randomized, controlled, double-blind trial, estrogen-deficient breast cancer survivors with severe penetrative dyspareunia applied either saline or 4% aqueous lidocaine to the vulvar vestibule for 3 minutes before vaginal penetration. After a 1-month blinded trial of patient-assessed twice-per-week tampon insertion or intercourse, all patients received lidocaine for 2 months in an open-label trial. The primary outcome was patient-related assessment of penetration pain on a scale of zero to 10. Secondary outcomes were sexual distress (Female Sexual Distress Scale), sexual function (Sexual Function Questionnaire), and resumption of intercourse. Comparisons were made with the Mann-Whitney U and Wilcoxon signed rank test with significance set at P < .05. RESULTS: In all, 46 patients, screened to exclude those with pelvic muscle and organ pain, uniformly had clinical evidence of severe vulvovaginal atrophy, dyspareunia (median pain score, 8 of 10; interquartile range [IQR], 7 to 9), increased sexual distress scores (median, 30.5; IQR, 23 to 37; abnormal, > 11), and abnormal sexual function. Users of lidocaine reported less pain during intercourse in the blinded phase (median score of 1.0 compared with saline score of 5.3; P = .007). After open-label lidocaine use, 37 (90%) of 41 reported comfortable penetration. Sexual distress decreased (median score, 14; IQR, 3 to 20; P < .001), and sexual function improved in all but one domain. Of 20 prior abstainers from intercourse who completed the study, 17 (85%) had resumed comfortable penetrative intimacy. No partners reported penile numbness. CONCLUSION: Breast cancer survivors with menopausal dyspareunia can have comfortable intercourse after applying liquid lidocaine compresses to the vulvar vestibule before penetration.

Locating pain in breast cancer survivors experiencing dyspareunia: a randomized controlled trial.

OBJECTIVE: To locate sites of genital tenderness in breast cancer survivors not using estrogen who experience dyspareunia and to test the hypothesis that tenderness is limited to the vulvar vestibule rather than the vagina and is reversed by topical anesthetic. METHODS: Postmenopausal survivors of breast cancer with moderate and severe dyspareunia were recruited for an examination including randomization to a double-blind intervention using topical aqueous 4% lidocaine or normal saline for 3 minutes to the areas found to be tender. Comparisons of changes in patients' reported numerical rating scale values were made with the Wilcoxon rank-sum test with significance set at P<.05. RESULTS: Forty-nine patients aged 37-69 years (mean 55.6±8.6 years) had a median coital pain score of 8 (interquartile range 7-9, scale 0-10). On examination, all women had tenderness in the vulvar vestibule (worst site 4 o'clock median 6, 4-7). In addition, one had significant vaginal mucosal tenderness and two had pelvic floor myalgia. All had vulvovaginal atrophy with 86% having no intravaginal discharge. Aqueous lidocaine 4% reduced the vestibular tenderness of all painful sites. For example, pain at the worst site changed from a median of 5 (4-7) to 0 (0-1) as compared with saline placebo, which changed the worst site score from 6 (4-7) to 4 (3-6) (P<.001). After lidocaine application, speculum placement was nontender in the 47 without either myalgia or vaginal mucosal tenderness. CONCLUSION: In breast cancer survivors with dyspareunia, exquisite sensitivity was vestibular and reversible with aqueous lidocaine. Vaginal tenderness was rare despite severe atrophy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01539317. LEVEL OF EVIDENCE: I.

Histopathologic characteristics of menopausal vestibulodynia.

OBJECTIVE: To assess whether premenopausal and postmenopausal vestibulodynia have different histologic features. METHODS: We conducted a retrospective analysis of vestibulectomy specimens from 21 women with postmenopausal vestibulodynia and compared them with 88 premenopausal patients (42 primary, 46 secondary). Women with primary vestibulodynia experienced pain at first introital touch and women with secondary vestibulodynia experienced pain after an interval of painless intercourse. Clinical records established the type of vestibulodynia, duration of symptoms, and hormone status. Tissues were stained for inflammation, nerves, mast cells, estrogen receptor α, and progesterone receptor. Histologic findings in the postmenopausal patients were compared with primary and secondary premenopausal patients using proportional odds logistic regression and analysis of variance. RESULTS: Seventy-one percent (15/21) of postmenopausal women reported vestibular dyspareunia related to a drop in estrogen either with menopause (13/21) or previously, postpartum (2/21). Eighty-six percent (18/21) of postmenopausal patients were using local or systemic estrogen but pain persisted. Compared with premenopausal primary and secondary vestibular biopsies, postmenopausal tissues had more lymphocytes (unadjusted odds ratio [OR] 9.0, 95% confidence interval [CI] 2.8-33.3; adjusted OR for parity and duration of symptoms 9.1, 95% CI 2.6-31.9; unadjusted OR 6.2, 95% CI 1.9-20.0; adjusted OR 6.6, 95% CI 2.0-21.9, respectively) and mast cells (mean 36 compared with 28 and 36 compared with 26, respectively). There was significantly less neural hyperplasia and progesterone receptor expression in postmenopausal biopsies compared with primary cases but less progesterone receptor and similar neural hyperplasia compared with premenopausal secondary cases. Estrogen receptor α did not vary among groups. CONCLUSION: Premenopausal and postmenopausal vestibulodynia share histologic features of neurogenic inflammation but differ strikingly in degree. When estrogen supplement does not alleviate symptoms of postmenopausal dyspareunia, vestibulodynia should be considered. LEVEL OF EVIDENCE: : II.