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Coital pain in the elderly: could a low dose estriol gel thrill the vulvar vestibule?
European Journal of Obstetrics & Gynecology and Reproductive Biology 207 (2016) 121–124
Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Coital pain in the elderly: could a low dose estriol gel thrill the vulvar vestibule? Filippo Murinaa,* , Alessandra Graziottinb , Raffaele Felicea , Stefania Di Francescoa a b
Lower Genital Tract Disease Unit, V. Buzzi Hospital–University of Milan, Milan, Italy Gynaecology Unit, San Raffaele Resnati Hospital, Milan, Italy
A R T I C L E I N F O
A B S T R A C T
Article history: Received 7 June 2016 Received in revised form 25 September 2016 Accepted 18 October 2016
Objective: The aim of this study was to evaluate the effectiveness of the application of 0.005% estriol gel to the vulvar vestibule in the management of postmenopausal dyspareunia. Study design: Postmenopausal women with dyspareunia were enrolled in this study. Patients were instructed to use a fingertip to apply 0.25 g of vaginal gel containing 25 mg of estriol to the vulvar vestibule daily for three weeks and then twice weekly for up to 12 weeks. Results: Assessment of symptoms (dyspareunia and cotton swab test) and signs of vestibular atrophy were performed, and changes between baseline and weeks 3 and 12 were assessed. Adverse events were recorded. A total of 63 women were included. Of the 63, 59 (93.6%) completed the 12-week treatment period, and four dropped out for vestibular burning. Dyspareunia improved or was cured (score 1) by week 12 in 81.4% of patients. The patients also showed a statistically significant reduction in vestibular atrophy and cotton swab test at the end of treatment. Conclusions: Application of 0.005% estriol gel to the vulvar vestibule is effective in correcting menopausal coital pain. This suggests that reduction in sensory vestibular innervation sensitivity is likely to play a pivotal role in the relief of dyspareunia. One limitation of this study is the limited follow-up, but the therapy may be continued for as long as the patients are distressed by their symptoms without estrogen intervention. ã 2016 Elsevier Ireland Ltd. All rights reserved.
Keywords: Dyspareunia Estriol Postmenopausal Vestibulodynia Vulvodynia Gel
Introduction It is estimated that 10%–40% of postmenopausal women experience discomfort due to vulvovaginal atrophy that requires treatment, and approximately 40% of women with vaginal atrophy report dyspareunia [1]. Difficulty during sexual intercourse is very relevant; in fact, it was estimated that 52% of women 50–79 years of age have been sexually active with a partner in the past year [2]. Furthermore, a review of published literature revealed that 22% of married women 70 to 79 years of age report that they still have sexual intercourse [3]. Vulvovaginal atrophy refers to the appearance of the vulva and vagina in post menopause, but it does not describe the symptoms. Actually, it is suggested that the term, genitourinary syndrome of menopause (GSM), be used to better describe the condition [4]. It is described as a syndrome because of the array of signs and symptoms with genital and urinary elements.
* Corresponding author. E-mail address: fi[email protected] (F. Murina). http://dx.doi.org/10.1016/j.ejogrb.2016.10.016 0301-2115/ã 2016 Elsevier Ireland Ltd. All rights reserved.
GSM may include genital symptoms of dryness and burning and sexual symptoms of lack of lubrication, discomfort or pain and impaired function. We can also observe urinary symptoms of urgency, dysuria and recurrent UTIs. Women may present with some or all the signs and symptoms. The primary goals in GSM management are to alleviate symptoms and reverse atrophic changes. The North American Menopause Society’s (NAMS) position on the role of local vaginal estrogen is that non-hormonal lubricants and moisturizers in combination with regular sexual activity should be considered first-line therapies [1], but women often find these products inadequate. Estrogen therapy, administered either vaginally or systemically, is considered the therapeutic standard for moderate to severe vulvovaginal symptoms. Current recommendations advise that treatment choices should be customized to the needs of each woman, and symptoms of vulvovaginal atrophy such as dyspareunia, should be treated with the lowest effective dose of estrogen therapy for the shortest amount of time to achieve and maintain satisfactory results [1]. The classic explanation as to why estrogen is effective in reversing vaginal menopausal symptoms is that it acts directly on vaginal tissue estrogen receptors to restore normal function.
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However, many data have suggested that although these factors are important, they are incomplete as explicative mechanisms. Autonomic and sensory neurons express estrogen receptors and are responsive to estradiol in culture, supporting the idea that estrogens can act directly on neurons [5]. It was demonstrated that vaginal innervation was reduced in women receiving estrogen replacement; moreover, topical therapy is more effective than systemic therapy [6]. In addition, very few studies on postmenopausal dyspareunia have focused on location and quality of the pain. It was reported that 95% of menopausal women with dyspareunia also had localized provoked pain in the vestibule, despite the use of hormone supplements in 31% of them [7]. This is principally related to differences in nerve density between vagina and vulvar vestibule. A rich nerve plexus within the vaginal submucosa was identified, but it is composed only of sympathetic and parasympathetic axons with smaller contributions by sensory fibers; in the vulvar vestibule, the sensory nerve endings are dense and shallow, making this region physiologically more sensitive [8]. The aim of this study was to evaluate the effectiveness of the application of a new 0.005% estriol vaginal gel delivering 25 mg of estriol to the vulvar vestibule in the management of postmenopausal dyspareunia. Materials and methods Participants Women included in the study were postmenopausal with at least one year of amenorrhea. They presented with dyspareunia and signs of vestibular and vaginal atrophy including a thinned, dry, fragile or pale mucosa. Women were excluded if they had a history of malignant lesions of the breasts or endometrium. Also excluded were women who had received any type of hormone therapy within three months before the start of the study, were allergic to the test drug or its constituents, or had any serious disease or chronic condition. All patients included in the study have used lubricants during sexual intercourse with little or no benefit. Institutional Review Board approval for the study was obtained and all participating individuals gave written informed consent. Gynecological examination At the initial consultation, a careful examination of the vulva and vagina was conducted to exclude any other cause for entry dyspareunia. The grading of dyspareunia was recorded according to the 3 grade classification of Marinoff and Turner [9]. Grade 1 is characterized by intercourse that is always painful but only occasionally prevents penetration, grade 2 is characterized by intercourse that is always painful and often prevents penetration, and grade 3 is characterized by complete apareunia. Women found suitable for the study underwent a cotton swab test for scoring the sensitivity in seven foci around the vestibule. The cotton swab test is used to test for pain locations on the vulva. Testing starts at the thighs and moves medially to the vestibule as the face of a clock. The vestibule is tested at the 2:00, 4:00, 6:00, 8:00 and 10:00 positions. Each time the vestibule is touched, the patient is asked to quantify the pain as none (score 0), mild (score 1), moderate (score 2) or severe (score 3). Vulvar vestibule was assessed objectively by examining epithelial integrity, surface thickness and superficial color. Grading of vestibular health was quantified using a four-point scoring system (no atrophy = 0,
mild = 1, moderate = 2 and severe = 3). The gynecological examination was performed by two experienced examiners (FM, RF). Treatment protocol Patients were instructed to apply, with the fingertip, 0.25 g of vaginal gel containing 25 mg of estriol to the vulvar vestibule, administered daily for three weeks and then twice weekly for up to 12 weeks. An applicator was used to dose an adequate amount of drug, and patients were advised to administer the treatment preferably at night. Women were asked to stop sexual activity until at least 15 days after starting therapy using an aqueous lubricant. Data analysis The primary efficacy end point was the change in dyspareunia score from baseline to week 12. The appearance of vulvar vestibule and the swab test sensitivity after 12 week of therapy were considered secondary outcomes. All the results were reported as the mean standard error of absolute values. Baseline values were compared by Student’s t-test. To determine the changes in dyspareunia, appearance of vulvar vestibule and the swab test sensitivity scores at the end of treatment in comparison with baseline, Mann–Whitney U-test was performed. Treatment differences were expressed as least-squares means (standard error) and 95% confidence intervals (CIs), and the statistical significance was defined as P < 0.05. Statistical analysis was performed with SPSS 17.0 for Windows (IBM SPSS, Armonk, NY). Results Of the 63 women enrolled in the study, 59 (93.6%) completed the 12-week treatment. The baseline characteristics of the enrolled subjects are reported in Table 1. After 12 weeks of therapy with 25 mg of estriol applied to the vulvar vestibule, there was a statistically significant decrease from baseline in the mean score of the dyspareunia (baseline score 2.85, last observation after therapy 1.23—Table 2). This symptom improved or was cured (dyspareunia score 1) by week 12 in 81.4% of women. At baseline the mean score for vestibular health was 2.91. After 12 weeks of 25 mg of estriol treatment, the mean vestibular health score had decreased to 1.98, and this difference was statistically significant (P = 0.001) compared with baseline (Fig. 1). The patients also showed a statistically significant reduction in cotton swab test scores at the end of treatment (on a 0–3 range, 2.81 compared with 1.25 at baseline, P = 0.02). Looking at the various subgroups, age did not affect the outcome of estriol treatment as we found no significant differences
Table 1 Patients demographics and baseline characteristics. Patients (n = 63) Age (y) Range
56.4 (5.6) 49–69
Time since last menses (y) Range Less than 2 2 to less than 5 5 or more
8.2 (5.3) 1–23 10 (16%) 25 (39.6%) 28 (44.4%)
Duration of dyspareuniaa (mo)
18.7 (14.7)
Data are presented as the mean values standard deviation. a Scored from 0 to 3 (0 = absent, 1 = mild, 2 = strong, 3 = severe).
F. Murina et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 207 (2016) 121–124 Table 2 Results of symptoms and signs before and after therapy. Symptoms and signs
Baseline
After therapy (12 weeks)
p value
Dyspareunia* Vestibular health score Cotton swab test*
2.85 (0.36) 2.91 (0.30) 2.81 (0.44)
1.23 (0.78) 1.98 (0.60) 1.25 (0.78)
0.002 0.001 0.002
Data are presented as the mean values standard deviation. Score from 0 to 3: *0 = absent, 1 = mild, 2 = strong, 3 = severe); no atrophy = 0, mild = 1, moderate = 2 and severe = 3. p < 0.05 is considered statistically significant, refers to Students T test results.
Fig. 1. Dyspareunia and vestibular health score at baseline and week 12. Score from 0 to 3. Dysparuenia: 0 = absent, 1 = mild, 2 = strong, 3 = severe; vestibular health: no atrophy = 0, mild = 1, moderate = 2 and severe = 3.
in dyspareunia improvement before and after the treatment of different ages (P = 0.18, ANOVA with Bonferroni test). When dividing patients about the time since last menses (less than 2 years, 2 to less than 5 years and 5 or more years),we also did not find any statistical differences regarding the symptoms and signs between the three groups. Neither age at onset of dyspareunia (P = 0.146, t test), nor duration of the disease before entering the study (P = 0.35, Mann– Whitney U-test), were found to significantly relate to a lack of response to treatment in our study patients. Thus, in these subgroups, the response rates were similar to the overall study group. Discontinuations occurred in four of the 63 (6.3%) patients treated—all for local irritation and burning, after a mean of 4, 5 day of gel application. No adverse effects related to the breast (mastalgia) or endometrium (vaginal bleeding) were observed. Discussion This study illustrates the efficacy and safety of a new ultra-low dose estriol formulation providing 25 mg of estriol per application in a highly hydrating gel base for the local treatment of postmenopausal dyspareunia. In fact, coital pain improved in the vast majority of women (81.4%). A primary issue raised by the study is the location and nature of coital pain complaints in menopausal women. To our knowledge, this is the first report of estrogen therapy successfully targeting the vestibule rather than the vagina in correcting postmenopausal dyspareunia. The association of low estrogen levels and nerve proliferation in vaginas of rats has already been reported; at baseline estrogen levels in estrus cycles, nerves proliferate, and then these nerves retreat when estrogen is highest [10]. This is consistent with observations that postpartum women can exhibit entry dyspareunia in approximately 50% of attempts at intercourse, and resolution is associated with the return of menstruation after lactation [11].
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It is our experience that many menopausal women with complaints of dyspareunia have vestibular tenderness with more pronounced atrophic changes in this region rather than the vagina. Furthermore, it is likely, as Kao et al. suggest, that vulvovaginal atrophy alone does not adequately explain the findings of vestibular pain [12]. In 95% of her postmenopausal cohort with vestibular pain and dyspareunia, women used a variety of estrogen supplements, and atrophy varied but vestibular pain persisted. Topical estrogen therapy is effective in reducing the density of vaginal autonomic and sensory nerves [5]. Estrogen is known to affect inflammatory neuropeptides involved in chronic pain, in which the lack of estrogen is associated with an increased density of sympathetic, parasympathetic and sensory nerve fibers in the vulva; acute or chronic estrogen administration may decrease the total and sympathetic fiber numbers [13]. We can conclude that between the level of estrogen and vaginal innervation there is an inverse proportionality relationship. The vulvar vestibule, a thin band of tissue demarcating the entrance to the vagina, exhibits a high concentration of sensory free ends with a dense and shallow ramification. Falling estrogen levels may trigger the development of a subtype of menopausal vestibulodynia, which can explain a large number of cases of postmenopausal coital pain. Vestibulodynia, the most common localized provoked vulvodynia that affects 10%–16% of premenopausal women, is characterized by sharp, burning pain localized to the vulvar vestibule in response to light pressure (i.e., mechanical allodynia) and is accompanied by enhanced vulvar pain perception (i.e., mechanical hyperalgesia) [14]. The mechanisms underlying vestibulodynia are mainly characterized by vestibular neurogenic inflammation, altered peptidergic vestibular innervation and genetic susceptibilities that contribute to abnormal inflammatory cascades [15]. This is consistent with the elegant work presented by Leclair et al. in which women with postmenopausal vestibulodynia were compared with premenopausal patients [16]. The authors demonstrated that postmenopausal vestibular tissue showed more severe chronic inflammation than either premenopausal group and less neural hyperplasia than their premenopausal primary vestibulodynia counterparts. We hypothesize that the vestibule is more sensitive to withdrawal of estrogen during menopause and develops the features of vestibulodynia alongside visual changes of atrophy. The vagina can also develop marked atrophy but does not become tender to the same degree as the vestibule because it has different innervation (neurovegetative versus sensitive). Despite the common description of estrogen topical supplementation, our results suggest that estrogen replacement should target the vestibule to reduce its sensitivity. This may explain how coital pain cannot reverse with estrogen inserted in vagina; it is insufficient to correct severe vestibular allodynia. Another strong point in our study was the use of 0.005% estriol vaginal gel. This formulation allows the clinical use of a 10-fold reduction in the dose of the current estrogen on the market for GSM treatment. Moreover, the low potency of estriol implies an additional minimization of the estrogenic exposure more potent estrogens such as estradiol, recognized to be 80 times more potent than estriol [17]. Why does the application of very low concentration estriol gel reduce postmenopausal dyspareunia? In our opinion, the vulvar vestibule as the site of estriol application and the gel as the vehicle of the drug are crucial elements. Two polymers, polycarbophil and carbopol, were used to form this gel with an excellent mucoadhesive capacity. The main advantage of mucoadhesive systems is the possibility of increasing
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the time of residence in situ of estriol, enhancing bioavailability [18]. Therefore, not only is topical low concentration estriol gel associated with potentially lower health risk, but it also represents a more efficacious treatment modality because of its more profound effects on vestibular innervation. As mentioned above, the change in dyspareunia score after 12 weeks of treatment was considered the primary endpoint of this study, but we noted the singular finding that there was no correspondence between dyspareunia reduction and vestibular health score improvement (Fig. 1). This suggests that reduction in sensory vestibular innervation sensitivity play a pivotal role in the relief from dyspareunia, regardless of atrophic changes experienced by many postmenopausal women. Estrogen can, therefore, both lower the pain threshold and be a potent mediator of peripheral nerve remodeling as further confirmed by the hypersensitivity decrease to the cotton swab test. Local adverse effects led to a discontinuation rate of 6.3% in our study population. Reasons for discontinuation were related to vestibular burning after application of the estriol gel. The very low rate of discontinuation shows high tolerability of the drug. In fact, vestibular mucosa is very reactive and therefore more vulnerable to the effects of externally applied agents. In this study, the highly hydrating properties of the gel were possibly adequate for preventing vestibular discomfort. Although some systemic absorption of estradiol occurs with all vaginal estrogens products, systemic absorption of estradiol from low-dose vaginal estrogen products was shown to be low in previous comparative studies [19]. In our trial, the absence of systemic adverse effects related to the breast (mastalgia) or endometrium (vaginal bleeding) is consistent with findings of Cano et al. [20], in which 0.005% estriol vaginal gel proved to be an efficacious therapy for the treatment of postmenopausal vaginal atrophy. There are no data about absorption of estrogen from the vestibule, but we can conclude that the absorption would be very low because the surface area of the introitus is smaller than that of the vagina. Our study had no control population using 0.005% estriol gel inserted in vagina. A previous placebo-controlled study evaluated the efficacy of 1 g of vaginal gel containing 50 mg of estriol gel compared with a placebo gel [20]. The authors reported the superiority of estriol gel in improving vaginal symptoms related to atrophy (pruritus, vaginal burning, dryness and dysuria). Dyspareunia improved or was cured by week 12 in 86.5% of women in the estriol group and 75% of women on the placebo, without a statistically significant difference between the two groups. We reported similar results with half-dose estriol in our patients who have previously used hormone-free gel lubricant without significant results. Moreover, an applicator inserted deep inside the vagina can reduce women’s compliance with therapy. One limitation of this study is the limited follow-up, but the therapy may be continued for as long as the patients are distressed by their symptoms without estrogen intervention. However, the results are encouraging and should stimulate the research regarding this innovative pathophysiological neural mechanism of postmenopausal dyspareunia. In conclusion, these results confirm the efficacy of vestibular use of 0.005% estriol for the treatment of postmenopausal
dyspareunia. The 10-fold reduction in dose of estrogen currently administered was effective in significantly normalizing vestibular innervation sensitivity, and its formulation as a highly mucoadhesive hydrating gel provides a reservoir effect for lengthy maintenance of active estriol on the vestibular surface. Funding This research was not funded. Declaration of financial/other relationships The authors have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article. References [1] Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society. Menopause 2013;20(9):888–902. [2] McCall-Hosenfeld JS, Jaramillo SA, Legault C, et al. Correlates of sexual satisfaction among sexually active postmenopausal women in the Women’s Health Initiative Observational Study. J Gen Intern Med 2008;23(12):2000–9. [3] Schneidewind-Skibbe A, Hayes RD, Koochaki PE, Meyer J, Dennerstein L. The frequency of sexual intercourse reported by women: a review of communitybased studies and factors limiting their conclusions. J Sex Med 2008;5(2):301– 35. [4] Portman DJ, Gass MLS. Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women’s Sexual Health and The North American Menopause Society. Maturitas 2014;79(3):349–54. [5] Ting AY, Blacklock AD, Smith PG. Estrogen regulates vaginal sensory and autonomic nerve density in the rat. Biol Reprod 2004;71(4):1397–404. [6] Griebling TL, Liao Z, Smith PG. Systemic and topical hormone therapies reduce vaginal innervation density in postmenopausal women. Menopause 2012;19 (6):630–5. [7] Kao A, Binik YM, Amsel R, Funaro D, Deroux N, Khalife S. Biopsychosocial predictors of postmenopausal dyspareunia: the role of steroid hormones, vulvovaginal atrophy, cognitive-emotional factors, and dyadic adjustment. J Sex Med 2012;9:2066–76. [8] Goldstein I, Meston C, Davis S, Traish A. Women’s sexual function and dysfunction: study diagnosis and treatment. CRC Press; 2005. [9] Marinoff SC, Turner ML. Vulvar vestibulitis syndrome: an overview. Am J Obstet Gynecol 1991;165:1228–33. [10] Zoubina E, Smith P. Sympathetic hyperinnervation of the uterus in the estrogen receptor alpha knock-out mouse. Neuroscience 2001;103:237–44. [11] Goetsch M. Postpartum dyspareunia—an unexplored problem. J Reprod Med 1999;44:963–8. [12] Kao A, Binik YM, Amsel R, Funaro D, Leroux N, Khalife S. Challenging atrophied perspectives on postmenopausal dyspareunia: a systematic description and synthesis of pain characteristics. J Sex Marital Ther 2012;38:128–50. [13] Straub R. The complex role of estrogens in inflammation. Endocr Rev 2007;28 (5):521–74. [14] Moyal-Barracco M, Lynch PJ. 2003 ISSVD terminology and classification of vulvodynia: a historical perspective. J Reprod Med 2004;49:772–7. [15] Graziottin A, Murina F. Vulvodynia tips and tricks. Springer; 2011. [16] Leclair CM, Goetsch M, Li H, Morgan TK. Histopathologic characteristics of menopausal vestibulodynia. Obstet Gynecol 2013;122:787–93. [17] Minkin MJ, Maamari R, Reiter S. Postmenopausal vaginal atrophy: evaluation of treatment with local estrogen therapy. Int J Womens Health 2013;6:281–8. [18] Yu T, Malcolm K, Woolfson D, Jones DS, Andrews GP. Vaginal gel drug delivery systems: understanding rheological characteristics and performance. Expert Opin Drug Deliv 2011;8(10):1309–22. [19] Suckling J, Lethaby A, Kennedy R. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst Rev 2006;18(4):CD001500. [20] Cano A, Estévez J, Usandizaga R, et al. The therapeutic effect of a new ultra low concentration estriol gel formulation (0.005% estriol vaginal gel) on symptoms and signs of postmenopausal vaginal atrophy: results from a pivotal phase III study. Menopause 2012;19(10):1130–9.
Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Coital pain in the elderly: could a low dose estriol gel thrill the vulvar vestibule? Filippo Murinaa,* , Alessandra Graziottinb , Raffaele Felicea , Stefania Di Francescoa a b
Lower Genital Tract Disease Unit, V. Buzzi Hospital–University of Milan, Milan, Italy Gynaecology Unit, San Raffaele Resnati Hospital, Milan, Italy
A R T I C L E I N F O
A B S T R A C T
Article history: Received 7 June 2016 Received in revised form 25 September 2016 Accepted 18 October 2016
Objective: The aim of this study was to evaluate the effectiveness of the application of 0.005% estriol gel to the vulvar vestibule in the management of postmenopausal dyspareunia. Study design: Postmenopausal women with dyspareunia were enrolled in this study. Patients were instructed to use a fingertip to apply 0.25 g of vaginal gel containing 25 mg of estriol to the vulvar vestibule daily for three weeks and then twice weekly for up to 12 weeks. Results: Assessment of symptoms (dyspareunia and cotton swab test) and signs of vestibular atrophy were performed, and changes between baseline and weeks 3 and 12 were assessed. Adverse events were recorded. A total of 63 women were included. Of the 63, 59 (93.6%) completed the 12-week treatment period, and four dropped out for vestibular burning. Dyspareunia improved or was cured (score 1) by week 12 in 81.4% of patients. The patients also showed a statistically significant reduction in vestibular atrophy and cotton swab test at the end of treatment. Conclusions: Application of 0.005% estriol gel to the vulvar vestibule is effective in correcting menopausal coital pain. This suggests that reduction in sensory vestibular innervation sensitivity is likely to play a pivotal role in the relief of dyspareunia. One limitation of this study is the limited follow-up, but the therapy may be continued for as long as the patients are distressed by their symptoms without estrogen intervention. ã 2016 Elsevier Ireland Ltd. All rights reserved.
Keywords: Dyspareunia Estriol Postmenopausal Vestibulodynia Vulvodynia Gel
Introduction It is estimated that 10%–40% of postmenopausal women experience discomfort due to vulvovaginal atrophy that requires treatment, and approximately 40% of women with vaginal atrophy report dyspareunia [1]. Difficulty during sexual intercourse is very relevant; in fact, it was estimated that 52% of women 50–79 years of age have been sexually active with a partner in the past year [2]. Furthermore, a review of published literature revealed that 22% of married women 70 to 79 years of age report that they still have sexual intercourse [3]. Vulvovaginal atrophy refers to the appearance of the vulva and vagina in post menopause, but it does not describe the symptoms. Actually, it is suggested that the term, genitourinary syndrome of menopause (GSM), be used to better describe the condition [4]. It is described as a syndrome because of the array of signs and symptoms with genital and urinary elements.
* Corresponding author. E-mail address: fi[email protected] (F. Murina). http://dx.doi.org/10.1016/j.ejogrb.2016.10.016 0301-2115/ã 2016 Elsevier Ireland Ltd. All rights reserved.
GSM may include genital symptoms of dryness and burning and sexual symptoms of lack of lubrication, discomfort or pain and impaired function. We can also observe urinary symptoms of urgency, dysuria and recurrent UTIs. Women may present with some or all the signs and symptoms. The primary goals in GSM management are to alleviate symptoms and reverse atrophic changes. The North American Menopause Society’s (NAMS) position on the role of local vaginal estrogen is that non-hormonal lubricants and moisturizers in combination with regular sexual activity should be considered first-line therapies [1], but women often find these products inadequate. Estrogen therapy, administered either vaginally or systemically, is considered the therapeutic standard for moderate to severe vulvovaginal symptoms. Current recommendations advise that treatment choices should be customized to the needs of each woman, and symptoms of vulvovaginal atrophy such as dyspareunia, should be treated with the lowest effective dose of estrogen therapy for the shortest amount of time to achieve and maintain satisfactory results [1]. The classic explanation as to why estrogen is effective in reversing vaginal menopausal symptoms is that it acts directly on vaginal tissue estrogen receptors to restore normal function.
122
F. Murina et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 207 (2016) 121–124
However, many data have suggested that although these factors are important, they are incomplete as explicative mechanisms. Autonomic and sensory neurons express estrogen receptors and are responsive to estradiol in culture, supporting the idea that estrogens can act directly on neurons [5]. It was demonstrated that vaginal innervation was reduced in women receiving estrogen replacement; moreover, topical therapy is more effective than systemic therapy [6]. In addition, very few studies on postmenopausal dyspareunia have focused on location and quality of the pain. It was reported that 95% of menopausal women with dyspareunia also had localized provoked pain in the vestibule, despite the use of hormone supplements in 31% of them [7]. This is principally related to differences in nerve density between vagina and vulvar vestibule. A rich nerve plexus within the vaginal submucosa was identified, but it is composed only of sympathetic and parasympathetic axons with smaller contributions by sensory fibers; in the vulvar vestibule, the sensory nerve endings are dense and shallow, making this region physiologically more sensitive [8]. The aim of this study was to evaluate the effectiveness of the application of a new 0.005% estriol vaginal gel delivering 25 mg of estriol to the vulvar vestibule in the management of postmenopausal dyspareunia. Materials and methods Participants Women included in the study were postmenopausal with at least one year of amenorrhea. They presented with dyspareunia and signs of vestibular and vaginal atrophy including a thinned, dry, fragile or pale mucosa. Women were excluded if they had a history of malignant lesions of the breasts or endometrium. Also excluded were women who had received any type of hormone therapy within three months before the start of the study, were allergic to the test drug or its constituents, or had any serious disease or chronic condition. All patients included in the study have used lubricants during sexual intercourse with little or no benefit. Institutional Review Board approval for the study was obtained and all participating individuals gave written informed consent. Gynecological examination At the initial consultation, a careful examination of the vulva and vagina was conducted to exclude any other cause for entry dyspareunia. The grading of dyspareunia was recorded according to the 3 grade classification of Marinoff and Turner [9]. Grade 1 is characterized by intercourse that is always painful but only occasionally prevents penetration, grade 2 is characterized by intercourse that is always painful and often prevents penetration, and grade 3 is characterized by complete apareunia. Women found suitable for the study underwent a cotton swab test for scoring the sensitivity in seven foci around the vestibule. The cotton swab test is used to test for pain locations on the vulva. Testing starts at the thighs and moves medially to the vestibule as the face of a clock. The vestibule is tested at the 2:00, 4:00, 6:00, 8:00 and 10:00 positions. Each time the vestibule is touched, the patient is asked to quantify the pain as none (score 0), mild (score 1), moderate (score 2) or severe (score 3). Vulvar vestibule was assessed objectively by examining epithelial integrity, surface thickness and superficial color. Grading of vestibular health was quantified using a four-point scoring system (no atrophy = 0,
mild = 1, moderate = 2 and severe = 3). The gynecological examination was performed by two experienced examiners (FM, RF). Treatment protocol Patients were instructed to apply, with the fingertip, 0.25 g of vaginal gel containing 25 mg of estriol to the vulvar vestibule, administered daily for three weeks and then twice weekly for up to 12 weeks. An applicator was used to dose an adequate amount of drug, and patients were advised to administer the treatment preferably at night. Women were asked to stop sexual activity until at least 15 days after starting therapy using an aqueous lubricant. Data analysis The primary efficacy end point was the change in dyspareunia score from baseline to week 12. The appearance of vulvar vestibule and the swab test sensitivity after 12 week of therapy were considered secondary outcomes. All the results were reported as the mean standard error of absolute values. Baseline values were compared by Student’s t-test. To determine the changes in dyspareunia, appearance of vulvar vestibule and the swab test sensitivity scores at the end of treatment in comparison with baseline, Mann–Whitney U-test was performed. Treatment differences were expressed as least-squares means (standard error) and 95% confidence intervals (CIs), and the statistical significance was defined as P < 0.05. Statistical analysis was performed with SPSS 17.0 for Windows (IBM SPSS, Armonk, NY). Results Of the 63 women enrolled in the study, 59 (93.6%) completed the 12-week treatment. The baseline characteristics of the enrolled subjects are reported in Table 1. After 12 weeks of therapy with 25 mg of estriol applied to the vulvar vestibule, there was a statistically significant decrease from baseline in the mean score of the dyspareunia (baseline score 2.85, last observation after therapy 1.23—Table 2). This symptom improved or was cured (dyspareunia score 1) by week 12 in 81.4% of women. At baseline the mean score for vestibular health was 2.91. After 12 weeks of 25 mg of estriol treatment, the mean vestibular health score had decreased to 1.98, and this difference was statistically significant (P = 0.001) compared with baseline (Fig. 1). The patients also showed a statistically significant reduction in cotton swab test scores at the end of treatment (on a 0–3 range, 2.81 compared with 1.25 at baseline, P = 0.02). Looking at the various subgroups, age did not affect the outcome of estriol treatment as we found no significant differences
Table 1 Patients demographics and baseline characteristics. Patients (n = 63) Age (y) Range
56.4 (5.6) 49–69
Time since last menses (y) Range Less than 2 2 to less than 5 5 or more
8.2 (5.3) 1–23 10 (16%) 25 (39.6%) 28 (44.4%)
Duration of dyspareuniaa (mo)
18.7 (14.7)
Data are presented as the mean values standard deviation. a Scored from 0 to 3 (0 = absent, 1 = mild, 2 = strong, 3 = severe).
F. Murina et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 207 (2016) 121–124 Table 2 Results of symptoms and signs before and after therapy. Symptoms and signs
Baseline
After therapy (12 weeks)
p value
Dyspareunia* Vestibular health score Cotton swab test*
2.85 (0.36) 2.91 (0.30) 2.81 (0.44)
1.23 (0.78) 1.98 (0.60) 1.25 (0.78)
0.002 0.001 0.002
Data are presented as the mean values standard deviation. Score from 0 to 3: *0 = absent, 1 = mild, 2 = strong, 3 = severe); no atrophy = 0, mild = 1, moderate = 2 and severe = 3. p < 0.05 is considered statistically significant, refers to Students T test results.
Fig. 1. Dyspareunia and vestibular health score at baseline and week 12. Score from 0 to 3. Dysparuenia: 0 = absent, 1 = mild, 2 = strong, 3 = severe; vestibular health: no atrophy = 0, mild = 1, moderate = 2 and severe = 3.
in dyspareunia improvement before and after the treatment of different ages (P = 0.18, ANOVA with Bonferroni test). When dividing patients about the time since last menses (less than 2 years, 2 to less than 5 years and 5 or more years),we also did not find any statistical differences regarding the symptoms and signs between the three groups. Neither age at onset of dyspareunia (P = 0.146, t test), nor duration of the disease before entering the study (P = 0.35, Mann– Whitney U-test), were found to significantly relate to a lack of response to treatment in our study patients. Thus, in these subgroups, the response rates were similar to the overall study group. Discontinuations occurred in four of the 63 (6.3%) patients treated—all for local irritation and burning, after a mean of 4, 5 day of gel application. No adverse effects related to the breast (mastalgia) or endometrium (vaginal bleeding) were observed. Discussion This study illustrates the efficacy and safety of a new ultra-low dose estriol formulation providing 25 mg of estriol per application in a highly hydrating gel base for the local treatment of postmenopausal dyspareunia. In fact, coital pain improved in the vast majority of women (81.4%). A primary issue raised by the study is the location and nature of coital pain complaints in menopausal women. To our knowledge, this is the first report of estrogen therapy successfully targeting the vestibule rather than the vagina in correcting postmenopausal dyspareunia. The association of low estrogen levels and nerve proliferation in vaginas of rats has already been reported; at baseline estrogen levels in estrus cycles, nerves proliferate, and then these nerves retreat when estrogen is highest [10]. This is consistent with observations that postpartum women can exhibit entry dyspareunia in approximately 50% of attempts at intercourse, and resolution is associated with the return of menstruation after lactation [11].
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It is our experience that many menopausal women with complaints of dyspareunia have vestibular tenderness with more pronounced atrophic changes in this region rather than the vagina. Furthermore, it is likely, as Kao et al. suggest, that vulvovaginal atrophy alone does not adequately explain the findings of vestibular pain [12]. In 95% of her postmenopausal cohort with vestibular pain and dyspareunia, women used a variety of estrogen supplements, and atrophy varied but vestibular pain persisted. Topical estrogen therapy is effective in reducing the density of vaginal autonomic and sensory nerves [5]. Estrogen is known to affect inflammatory neuropeptides involved in chronic pain, in which the lack of estrogen is associated with an increased density of sympathetic, parasympathetic and sensory nerve fibers in the vulva; acute or chronic estrogen administration may decrease the total and sympathetic fiber numbers [13]. We can conclude that between the level of estrogen and vaginal innervation there is an inverse proportionality relationship. The vulvar vestibule, a thin band of tissue demarcating the entrance to the vagina, exhibits a high concentration of sensory free ends with a dense and shallow ramification. Falling estrogen levels may trigger the development of a subtype of menopausal vestibulodynia, which can explain a large number of cases of postmenopausal coital pain. Vestibulodynia, the most common localized provoked vulvodynia that affects 10%–16% of premenopausal women, is characterized by sharp, burning pain localized to the vulvar vestibule in response to light pressure (i.e., mechanical allodynia) and is accompanied by enhanced vulvar pain perception (i.e., mechanical hyperalgesia) [14]. The mechanisms underlying vestibulodynia are mainly characterized by vestibular neurogenic inflammation, altered peptidergic vestibular innervation and genetic susceptibilities that contribute to abnormal inflammatory cascades [15]. This is consistent with the elegant work presented by Leclair et al. in which women with postmenopausal vestibulodynia were compared with premenopausal patients [16]. The authors demonstrated that postmenopausal vestibular tissue showed more severe chronic inflammation than either premenopausal group and less neural hyperplasia than their premenopausal primary vestibulodynia counterparts. We hypothesize that the vestibule is more sensitive to withdrawal of estrogen during menopause and develops the features of vestibulodynia alongside visual changes of atrophy. The vagina can also develop marked atrophy but does not become tender to the same degree as the vestibule because it has different innervation (neurovegetative versus sensitive). Despite the common description of estrogen topical supplementation, our results suggest that estrogen replacement should target the vestibule to reduce its sensitivity. This may explain how coital pain cannot reverse with estrogen inserted in vagina; it is insufficient to correct severe vestibular allodynia. Another strong point in our study was the use of 0.005% estriol vaginal gel. This formulation allows the clinical use of a 10-fold reduction in the dose of the current estrogen on the market for GSM treatment. Moreover, the low potency of estriol implies an additional minimization of the estrogenic exposure more potent estrogens such as estradiol, recognized to be 80 times more potent than estriol [17]. Why does the application of very low concentration estriol gel reduce postmenopausal dyspareunia? In our opinion, the vulvar vestibule as the site of estriol application and the gel as the vehicle of the drug are crucial elements. Two polymers, polycarbophil and carbopol, were used to form this gel with an excellent mucoadhesive capacity. The main advantage of mucoadhesive systems is the possibility of increasing
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the time of residence in situ of estriol, enhancing bioavailability [18]. Therefore, not only is topical low concentration estriol gel associated with potentially lower health risk, but it also represents a more efficacious treatment modality because of its more profound effects on vestibular innervation. As mentioned above, the change in dyspareunia score after 12 weeks of treatment was considered the primary endpoint of this study, but we noted the singular finding that there was no correspondence between dyspareunia reduction and vestibular health score improvement (Fig. 1). This suggests that reduction in sensory vestibular innervation sensitivity play a pivotal role in the relief from dyspareunia, regardless of atrophic changes experienced by many postmenopausal women. Estrogen can, therefore, both lower the pain threshold and be a potent mediator of peripheral nerve remodeling as further confirmed by the hypersensitivity decrease to the cotton swab test. Local adverse effects led to a discontinuation rate of 6.3% in our study population. Reasons for discontinuation were related to vestibular burning after application of the estriol gel. The very low rate of discontinuation shows high tolerability of the drug. In fact, vestibular mucosa is very reactive and therefore more vulnerable to the effects of externally applied agents. In this study, the highly hydrating properties of the gel were possibly adequate for preventing vestibular discomfort. Although some systemic absorption of estradiol occurs with all vaginal estrogens products, systemic absorption of estradiol from low-dose vaginal estrogen products was shown to be low in previous comparative studies [19]. In our trial, the absence of systemic adverse effects related to the breast (mastalgia) or endometrium (vaginal bleeding) is consistent with findings of Cano et al. [20], in which 0.005% estriol vaginal gel proved to be an efficacious therapy for the treatment of postmenopausal vaginal atrophy. There are no data about absorption of estrogen from the vestibule, but we can conclude that the absorption would be very low because the surface area of the introitus is smaller than that of the vagina. Our study had no control population using 0.005% estriol gel inserted in vagina. A previous placebo-controlled study evaluated the efficacy of 1 g of vaginal gel containing 50 mg of estriol gel compared with a placebo gel [20]. The authors reported the superiority of estriol gel in improving vaginal symptoms related to atrophy (pruritus, vaginal burning, dryness and dysuria). Dyspareunia improved or was cured by week 12 in 86.5% of women in the estriol group and 75% of women on the placebo, without a statistically significant difference between the two groups. We reported similar results with half-dose estriol in our patients who have previously used hormone-free gel lubricant without significant results. Moreover, an applicator inserted deep inside the vagina can reduce women’s compliance with therapy. One limitation of this study is the limited follow-up, but the therapy may be continued for as long as the patients are distressed by their symptoms without estrogen intervention. However, the results are encouraging and should stimulate the research regarding this innovative pathophysiological neural mechanism of postmenopausal dyspareunia. In conclusion, these results confirm the efficacy of vestibular use of 0.005% estriol for the treatment of postmenopausal
dyspareunia. The 10-fold reduction in dose of estrogen currently administered was effective in significantly normalizing vestibular innervation sensitivity, and its formulation as a highly mucoadhesive hydrating gel provides a reservoir effect for lengthy maintenance of active estriol on the vestibular surface. Funding This research was not funded. Declaration of financial/other relationships The authors have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article. References [1] Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society. Menopause 2013;20(9):888–902. [2] McCall-Hosenfeld JS, Jaramillo SA, Legault C, et al. Correlates of sexual satisfaction among sexually active postmenopausal women in the Women’s Health Initiative Observational Study. J Gen Intern Med 2008;23(12):2000–9. [3] Schneidewind-Skibbe A, Hayes RD, Koochaki PE, Meyer J, Dennerstein L. The frequency of sexual intercourse reported by women: a review of communitybased studies and factors limiting their conclusions. J Sex Med 2008;5(2):301– 35. [4] Portman DJ, Gass MLS. Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women’s Sexual Health and The North American Menopause Society. Maturitas 2014;79(3):349–54. [5] Ting AY, Blacklock AD, Smith PG. Estrogen regulates vaginal sensory and autonomic nerve density in the rat. Biol Reprod 2004;71(4):1397–404. [6] Griebling TL, Liao Z, Smith PG. Systemic and topical hormone therapies reduce vaginal innervation density in postmenopausal women. Menopause 2012;19 (6):630–5. [7] Kao A, Binik YM, Amsel R, Funaro D, Deroux N, Khalife S. Biopsychosocial predictors of postmenopausal dyspareunia: the role of steroid hormones, vulvovaginal atrophy, cognitive-emotional factors, and dyadic adjustment. J Sex Med 2012;9:2066–76. [8] Goldstein I, Meston C, Davis S, Traish A. Women’s sexual function and dysfunction: study diagnosis and treatment. CRC Press; 2005. [9] Marinoff SC, Turner ML. Vulvar vestibulitis syndrome: an overview. Am J Obstet Gynecol 1991;165:1228–33. [10] Zoubina E, Smith P. Sympathetic hyperinnervation of the uterus in the estrogen receptor alpha knock-out mouse. Neuroscience 2001;103:237–44. [11] Goetsch M. Postpartum dyspareunia—an unexplored problem. J Reprod Med 1999;44:963–8. [12] Kao A, Binik YM, Amsel R, Funaro D, Leroux N, Khalife S. Challenging atrophied perspectives on postmenopausal dyspareunia: a systematic description and synthesis of pain characteristics. J Sex Marital Ther 2012;38:128–50. [13] Straub R. The complex role of estrogens in inflammation. Endocr Rev 2007;28 (5):521–74. [14] Moyal-Barracco M, Lynch PJ. 2003 ISSVD terminology and classification of vulvodynia: a historical perspective. J Reprod Med 2004;49:772–7. [15] Graziottin A, Murina F. Vulvodynia tips and tricks. Springer; 2011. [16] Leclair CM, Goetsch M, Li H, Morgan TK. Histopathologic characteristics of menopausal vestibulodynia. Obstet Gynecol 2013;122:787–93. [17] Minkin MJ, Maamari R, Reiter S. Postmenopausal vaginal atrophy: evaluation of treatment with local estrogen therapy. Int J Womens Health 2013;6:281–8. [18] Yu T, Malcolm K, Woolfson D, Jones DS, Andrews GP. Vaginal gel drug delivery systems: understanding rheological characteristics and performance. Expert Opin Drug Deliv 2011;8(10):1309–22. [19] Suckling J, Lethaby A, Kennedy R. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst Rev 2006;18(4):CD001500. [20] Cano A, Estévez J, Usandizaga R, et al. The therapeutic effect of a new ultra low concentration estriol gel formulation (0.005% estriol vaginal gel) on symptoms and signs of postmenopausal vaginal atrophy: results from a pivotal phase III study. Menopause 2012;19(10):1130–9.