madman
Super Moderator
Treating where it hurts—a randomized comparative trial of vestibule estradiol for postmenopausal dyspareunia (2023)
Martha F. Goetsch, MD, MPH, Bharti Garg, MBBS, MPH, Jen Lillemon, MD, and Amanda L. Clark, MD, MCR, NCMP
Abstract
Objective: To compare the efficacies of two strengths of estradiol cream applied to the vulvar vestibule and the 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, and 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 a 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 pre-coital silicone lubricant, is a promising alternative to vaginal therapy for dyspareunia.
The prevalence of dyspareunia associated with genitourinary syndrome of menopause (GSM) is as high as 78%.1 Genitourinary syndrome of menopause is known to progress with time after menopause2-4 and to reduce the quality of life (QoL) for both women and their partners.5-9 Intravaginal application of estradiol therapy (ET) is the standard for treating GSM. In addition to the often-expressed concerns about estrogen exposure, many women find it to be inadequate for relief.10-12
In a study of dyspareunia in hypoestrogenic breast cancer survivors, the vulvar vestibule, not the vagina, was found to be the primary site of pain associated with dyspareunia.13 Further, dyspareunia in these breast cancer survivors was largely prevented by topical lidocaine applied to the vestibule, along with the use of silicone lubricant during intercourse, without treating underlying atrophy.14 These findings suggest that the vestibule might be the optimal target for dyspareunia therapies. Further support comes from an observational study using vestibular estradiol cream to successfully treat severe vulvar pain in postmenopausal women who had failed prior therapies.15 Pain slowly resolved after weeks of nightly therapy, suggesting that more intensive and prolonged therapy may be required for severe cases.
The primary objective of this pilot randomized trial was to compare the efficacies of two strengths of estradiol cream applied to the vestibule, along with the use of a silicone lubricant, to reduce intercourse pain scores. The primary and most severe site of pain elicited during the baseline physical examination was the vulvar vestibule in this cohort.16 In addition, we assessed secondary outcomes of QoL, physical examination findings, and parameters of safety to study this route of ET.
Clinical and research implications
When dyspareunia is the presenting symptom in postmenopausal women, a comprehensive pelvic examination is essential to ascertain all sites of tenderness as a guide to directed therapy. Pelvic floor muscle tenderness and vaginal stenosis will need specific additional therapy. When the vestibule is the primary site of tenderness, we can be reassured that introital applications of estradiol cream, with lubricated intercourse, are a reasonable alternative to intravaginal estrogen applications for dyspareunia, but the complete resolution should not be expected for all affected women by 12 weeks. The estradiol regimen required to induce full pain relief and the regimen required to maintain relief is unknown. Because GSM is a chronic condition requiring ongoing therapy, clinical follow-up is essential to optimize therapeutic benefits and balance this with potential safety concerns for each woman. Effective therapy for mild cases might be important to avoid progression to severities that require longer courses of daily therapy. Precoital, introital application of lidocaine 4% topical solution can be offered as an adjunct therapy during prolonged ET. Future research should include a better definition of severity, validated pain scales, and the objective physical correlates of dyspareunia used in our study. The relevance of measures of introital size, vaginal length, elasticity, and lubrication could be explored.
Strengths and limitations
Strengths of our study include using metered doses of estradiol cream and lubricant and instruments and physical examination outcome measures with strong psychometric properties from the domain of vulvar pain research.17,20-25,27,28 This study is generalizable only to urban, heterosexually active, White women with similarly defined moderate/severe dyspareunia. The absence of a placebo control precludes measurement of the magnitude of a treatment benefit. The use of the more sensitive liquid or gas chromatography/mass spectroscopy would have provided more exact measurements of systemic estradiol levels.
CONCLUSION
When a comprehensive genital examination reveals the vestibule to be the site of greatest tenderness, estradiol cream targeted to the vulvar vestibule is a reasonable alternative to intravaginal applications for the treatment of GSM dyspareunia. With similar efficacies, the 50-μg dose is preferable to the 100-μg dose regarding concerns about absorption, but the need for prolonged nightly dosing to achieve meaningful correction deserves more detailed research. The use of outcome measures from vulvar pain research provides a more expansive description of dyspareunia associated with GSM and may help to refine our therapies.
Martha F. Goetsch, MD, MPH, Bharti Garg, MBBS, MPH, Jen Lillemon, MD, and Amanda L. Clark, MD, MCR, NCMP
Abstract
Objective: To compare the efficacies of two strengths of estradiol cream applied to the vulvar vestibule and the 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, and 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 a 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 pre-coital silicone lubricant, is a promising alternative to vaginal therapy for dyspareunia.
The prevalence of dyspareunia associated with genitourinary syndrome of menopause (GSM) is as high as 78%.1 Genitourinary syndrome of menopause is known to progress with time after menopause2-4 and to reduce the quality of life (QoL) for both women and their partners.5-9 Intravaginal application of estradiol therapy (ET) is the standard for treating GSM. In addition to the often-expressed concerns about estrogen exposure, many women find it to be inadequate for relief.10-12
In a study of dyspareunia in hypoestrogenic breast cancer survivors, the vulvar vestibule, not the vagina, was found to be the primary site of pain associated with dyspareunia.13 Further, dyspareunia in these breast cancer survivors was largely prevented by topical lidocaine applied to the vestibule, along with the use of silicone lubricant during intercourse, without treating underlying atrophy.14 These findings suggest that the vestibule might be the optimal target for dyspareunia therapies. Further support comes from an observational study using vestibular estradiol cream to successfully treat severe vulvar pain in postmenopausal women who had failed prior therapies.15 Pain slowly resolved after weeks of nightly therapy, suggesting that more intensive and prolonged therapy may be required for severe cases.
The primary objective of this pilot randomized trial was to compare the efficacies of two strengths of estradiol cream applied to the vestibule, along with the use of a silicone lubricant, to reduce intercourse pain scores. The primary and most severe site of pain elicited during the baseline physical examination was the vulvar vestibule in this cohort.16 In addition, we assessed secondary outcomes of QoL, physical examination findings, and parameters of safety to study this route of ET.
Clinical and research implications
When dyspareunia is the presenting symptom in postmenopausal women, a comprehensive pelvic examination is essential to ascertain all sites of tenderness as a guide to directed therapy. Pelvic floor muscle tenderness and vaginal stenosis will need specific additional therapy. When the vestibule is the primary site of tenderness, we can be reassured that introital applications of estradiol cream, with lubricated intercourse, are a reasonable alternative to intravaginal estrogen applications for dyspareunia, but the complete resolution should not be expected for all affected women by 12 weeks. The estradiol regimen required to induce full pain relief and the regimen required to maintain relief is unknown. Because GSM is a chronic condition requiring ongoing therapy, clinical follow-up is essential to optimize therapeutic benefits and balance this with potential safety concerns for each woman. Effective therapy for mild cases might be important to avoid progression to severities that require longer courses of daily therapy. Precoital, introital application of lidocaine 4% topical solution can be offered as an adjunct therapy during prolonged ET. Future research should include a better definition of severity, validated pain scales, and the objective physical correlates of dyspareunia used in our study. The relevance of measures of introital size, vaginal length, elasticity, and lubrication could be explored.
Strengths and limitations
Strengths of our study include using metered doses of estradiol cream and lubricant and instruments and physical examination outcome measures with strong psychometric properties from the domain of vulvar pain research.17,20-25,27,28 This study is generalizable only to urban, heterosexually active, White women with similarly defined moderate/severe dyspareunia. The absence of a placebo control precludes measurement of the magnitude of a treatment benefit. The use of the more sensitive liquid or gas chromatography/mass spectroscopy would have provided more exact measurements of systemic estradiol levels.
CONCLUSION
When a comprehensive genital examination reveals the vestibule to be the site of greatest tenderness, estradiol cream targeted to the vulvar vestibule is a reasonable alternative to intravaginal applications for the treatment of GSM dyspareunia. With similar efficacies, the 50-μg dose is preferable to the 100-μg dose regarding concerns about absorption, but the need for prolonged nightly dosing to achieve meaningful correction deserves more detailed research. The use of outcome measures from vulvar pain research provides a more expansive description of dyspareunia associated with GSM and may help to refine our therapies.
