ORIGINAL ARTICLE |
https://doi.org/10.5005/jp-journals-10006-2237
|
A Prospective Study to Investigate the 12-week Efficacy of Soy Isoflavone Vaginal Gel (0.5%) in Postmenopausal Women with Symptoms of Vulvovaginal Atrophy
1,3Department of Obstetrics and Gynaecology, SMS Medical College, Jaipur, Rajasthan, India
2Department of Obstetrics and Gynaecology, IKDRC, Ahmedabad, Gujarat, India
4Department of Psychiatry, SMS Medical College, Jaipur, Rajasthan, India
Corresponding Author: Deepa Chaudhary, Department of Obstetrics and Gynaecology, SMS Medical College, Jaipur, Rajasthan, India, Phone: +91 9413843022/+91 98290621111, e-mail: deepagaurav35@gmail.com
How to cite this article: Chaudhary D, Mishra V, Chaudhary S, et al. A Prospective Study to Investigate the 12-week Efficacy of Soy Isoflavone Vaginal Gel (0.5%) in Postmenopausal Women with Symptoms of Vulvovaginal Atrophy. J South Asian Feder Obst Gynae 2023;15(3):308–312.
Source of support: Nil
Conflict of interest: None
Received on: 17 April 2022; Accepted on: 01 October 2022; Published on: 31 July 2023
ABSTRACT
Purpose: To assess the feasibility and efficacy of a nonhormonal soy isoflavone vaginal gel in improving vulvovaginal estrogen-deprivation symptoms in postmenopausal women.
Materials and Methods: It was a single-center, prospective study. We identified postmenopausal women having at least one of the following self-assessed moderate to severe symptoms of vulvovaginal atrophy (VVA). Participants used soy isoflavone gel (0.5%) twice weekly for 12 weeks. Vulvovaginal symptoms and pH were assessed at three time points [baseline (T1), 4 weeks (T2) and 12 weeks (T3) with clinical evaluation, the Vaginal Health Index, Vaginal Assessment Scale, and the Vulvar Assessment Scale]. Efficacy and tolerability were assessed using the Patient Global Impression of Improvement (PGI-I) Scale and adverse effects were also recorded. In the results of 95 patients, the mean age was 55 years (range, 31–78), 68% (n = 69) were partnered, and 60% (n = 61) were sexually active. Vaginal Assessment Scale/Vulvar Assessment Scale scores significantly improved at all assessment points (all p = 6.5) and decreased from 26% at T1 to 19% at T3 (p = 0.18).
Conclusion: Soy isoflavone vaginal gel (0.5%) use on a daily basis for 12 weeks leads to significant improvements in the symptoms of VVA in postmenopausal women. Topical isoflavones are a good treatment option for VVA, especially in women who either do not wish to use hormonal therapy or have contraindications to its use.
Keywords: Patient satisfaction, Pelvic ultrasonography, Postmenopausal women, Pruritus vulva, Year since menopause.
INTRODUCTION
Postmenopausal estrogen deficiency leads to a variety of physiological changes in the body of a female and affects almost all organ systems.1 A few systems like cardiovascular, musculoskeletal, and urogenital systems are much more vulnerable to the effects of estrogen deficiency, due to their high concentrations of estrogen receptors. One of the most common and clinically significant conditions that appears 4–5 years after menopause is vulvovaginal atrophy (VVA).2 A declining estrogen level after menopause is responsible for various changes in the vaginal tissue such as reduced blood flow, decreased collagen content, decreased mucosal thickness, and increased pH. Symptoms of VVA include vaginal dryness, itching, dyspareunia, and recurrent infections. These changes have profound effects on the sexual health of women and also negatively impact their quality of life and well-being.
Despite the effectiveness of estrogen, both oral as well as topical preparations, in treating the symptoms of VVA, concerns over its side effects and safety have limited its widespread use by postmenopausal women, especially in low- and middle-income countries. Recently, phytoestrogen supplements have gained significance as safer alternatives to estrogen therapy, with many clinical trials proving their safety and efficacy. Isoflavones are the most studied phytoestrogens, some trials involving their oral form for treating climacteric symptomatology have shown that, though effectual for vasomotor symptoms, they have little impact on vaginal epithelium or endometrium in oral forms. Topical preparations of isoflavones have been used for the prevention and deferment of skin maturation in postmenopausal women and have shown satisfactory outcomes.3
There are only a few studies available investigating the efficacy of vaginal administration of isoflavones on VVA symptoms in postmenopausal women as an alternative therapy to hormonal treatment. The current investigation aimed to analyze the efficacy of soy isoflavone vaginal gel (ISOVG) and evaluate its tolerability and efficacy in postmenopausal women with VVA. The primary objective was to evaluate the efficacy and tolerability of topical application of vaginal gel (ISOVG) as a treatment option for VVA in postmenopausal women. Secondary objectives were to assess the efficacy of ISOVG in improving the symptoms of VVA (time frame: 28 days), and in reducing the vaginal pH (28 days), and to assess the overall treatment efficacy of vaginal gel (ISVOG) in improving the women’s quality of life (time frame: 84 days).
MATERIALS AND METHODS
Study Settings
The present study was a single-center, longitudinal prospective study conducted at the Institute of Kidney Disease and Research Center, Ahmedabad, India. Patients were enrolled over a period of 9 months (April 2019 to October 2019). The study protocol and consent form were approved by the Ethical Committee of the Institute. The study was conducted according to ‘Schedule-Y’ (Drugs and Cosmetics Rules, Government of India), the International Conference on Harmonization Guidelines for Good Clinical Practice (ICH-GCP E6 Guidelines), and the Declaration of Helsinki [World Medical Association (WMA) Ethical Principles for Medical Research Involving Human Subjects-Seventh Revision; 64th WMA General Assembly, Fortaleza, Brazil, October 2013].
Subject Inclusion Criteria
Participants aged >18 years to <65 years, with at least one of the following self-assessed moderate to severe symptoms of VVA from the following list that is identified by them as being the most bothersome to her:
− Dryness
− Soreness or burning
− Irritation
− Dyspareunia
Serum Estradiol (E2) levels less than 20 pg/mL, follicular stimulating hormone (FSH) levels more than 40 mIU/mL, endometrial thickness less than or equal to 4 mm, and mammography report normal within the last one year
Vaginal pH > 5.0 at screening
Willing to provide written informed consent to participate in the study.
Subject Exclusion Criteria
The following participants were not included:
On hormone replacement therapy currently or within the last 3 months.
Consuming a high-soy diet or any foods or other compounds that are sold as remedies for postmenopausal symptoms over the last 3 months.
History of endometrial hyperplasia or uterine/endometrial, breast, or ovarian cancer.
Any ongoing urogenital infection during the screening visit.
Hypersensitivity to soy isoflavones.
Participation in another clinical trial within the past 30 days.
Screening and Enrollment
Informed consent was obtained from women before conducting any physical or laboratory examinations to ascertain their eligibility for the study. After consent, they underwent a medical examination (interview and gynecologic examination) to determine patient eligibility. Only those patients who fulfilled the inclusion/exclusion criteria and were considered eligible for participating in the study were enrolled. Transvaginal scans for endometrial thickness and serum FSH and E2 levels were also done.
Medical history and physical examination of the patient were conducted, as well as vital signs were recorded at the time of enrollment. Vulvovaginal atrophy symptoms were assessed using the Vaginal Assessment Scale (VAS)4 and Vulval Assessment Scale (VuAS)5 score and baseline Vaginal Health Index (VHI)6 was recorded. Tolerability of the treatment was assessed on the basis of the patient’s response as compared to the pretreatment phase [Patient Global Impression of Improvement (PGI-I) Scale] on day 84. Adverse events were monitored on both follow-up visits.
Concomitant Medications
Use of any exogenous sex hormones or corticosteroids was avoided for all patients during the entire course of the study. Concomitant use of benzodiazepines, diazepam, rifampin, pentobarbital, and codeine was also avoided since isoflavones affect cytochrome activity and coadministration of cytochrome-substrate drugs with isoflavones can cause unanticipated adverse reactions or therapeutic failures.
Sample Size
Without information on the vaginal effect of the isoflavone gel, a sample size of 100 patients was required. Considering a dropout rate of 20%, it was planned to enroll 120 patients in the present study.
Study Intervention
Soy ISOVG – 5 gm (soy isoflavones). The enrolled postmenopausal women were prescribed one 5 gm of vaginal gel, to be used intravaginally biweekly at bedtime for 84 days (entire 12 weeks).
Efficacy End Points
Improvement in Primary Efficacy End Point
Changes in subjective vaginal and vulvar symptoms were monitored closely for the study duration using validated scales (baseline to 12 weeks). The VAS and Vulvar Assessment Scale (VuAS) are each four-item measures, administered to the patient by a trained health care provider to quantify and rate (none, mild, moderate, or severe) their perception of dryness, soreness, irritation, and pain (dyspareunia or painfulness to touch with external stimulation) for both the vaginal and vulvar areas.5 Each item in the VAS and VuAS is scored from 0 (none) to 3 (severe). The VAS composite and VuAS composite scores (both with a range of 0–3) are calculated by taking the mean of the items when at least two of four items are not missing. Lower scores indicate better function. The VAS/VuAS measure patient perceptions of their vulvovaginal tissue quality and shown to be sensitive to change as a self-report measure. The validated VAS and VuAS measures12 were our primary efficacy outcome measures, and changes in VAS and VuAS scores from baseline to T3 (12 weeks) were our primary efficacy endpoints.
Secondary efficacy endpoint: Changes in vaginal pH, VHI, both were assessed using clinical examination at 0, 4, and 12 weeks. Vaginal pH was measured using litmus paper and coded into clinically meaningful categories (<5, 5–6.5, and >6.5). Normal vaginal pH is less than 5. Higher vaginal pH indicates greater vaginal atrophy. Modified VHI-6 additional indicators of vaginal health were assessed (moisture, rugosity, elasticity, epithelial integrity, vaginal length (cm), and vascularity) and rated on a four-point scale (0, 1, 2, and 3). Each parameter is graded from 1 to 3, and total score ranges from 7 to 21. The lower score has greater vaginal atrophy and vice versa.
Feasibility End Point
At 12 weeks on study, participants’ satisfaction with acceptability (tolerability) of the treatment with isoflavone gel was assessed using Patient Global Rating-1 Scale (PGI-1 Scale) and any adverse event was also noted.
Global rating of overall efficacy (GRE) by health care workers was used to assess the overall improvement.
Statistical Analysis
Without information on the vaginal effect of the isoflavone gel, a sample size of 100 patients was required, considering a dropout rate of 20%. Around 120 patients were enrolled in the study. All collected data are entered into the SPSS V20. Continuous data are expressed as mean ± SD form. Continuous data follow nonparametric distribution. Mann–Whitney’s test has been used for carrying out significant p-value. Noncontinuous data are countable and are expressed as in frequency and in percentages. Chi-square test has been used for carrying out significant p-value. (*represents statistically significant difference. p-value < 0.05 is considered to be statistically significant difference between groups.)
RESULTS
Of the 120 participants who were enrolled over a period of 9 months. After considering the inclusion and exclusion criteria in detail, we were left with 103 participants. Therefore, 103 women received 5 gm of ISOVG 4% biweekly for 12 weeks. Three women discontinued the treatment due to a lack of improvement and five subjects were lost to follow-up. Baseline characteristics of participants finally enrolled in the study (n = 95), i.e., age, duration of menopause, weight, and BMI are shown in Table 1.
Sl. no. | Characteristics | Value |
---|---|---|
1 | Mean age (years) | 49 ± 4.8 |
2 | Mean duration of menopause (years) | 4.4 ± 3.2 |
3 | Weight (kg) | 64.7 ± 11.7 |
4 | BMI | 24.7 ± 5.2 |
The use of Isoflavone gel was associated with a statistically significant improvement (p-value < 0.01) in vaginal health indicators. The mean VHI at baseline was 15.91 ± 1.52 and at 3 months increased to 21.62 ± 1.31. The vaginal pH also improved significantly as shown in Figure 1. The mean pH at the start of the study was 6.61 ± 0.49 and at 3 months posttreatment was 4.71 ± 0.58 (p-value < 0.01) (Fig. 1).
Fig. 1: The improvement in VHI, vaginal pH, and VAS score before (baseline) and after the treatment (12 weeks)
The PGI-I Scale used to grade the tolerability and efficacy of isoflavone gel for symptoms of VVA also showed very favorable outcomes. More than 65% of patients reported a score of 1 or 2 on PGI-I, suggestive of marked improvement in symptoms by the drug. The drug also showed a very favorable response in regards to efficacy on the GRE, as assessed by the physician (p < 0.01; Table 2). The use of vaginal gel (soy isoflavones 0.5%) was not associated with any significant change in FSH, estradiol, and endometrial thickness at 12 weeks, as compared to their baseline values (Table 3). There was no case of postmenopausal bleeding or endometrial hyperplasia.
Improvement | 1(very much better) | 2 (much better) | 3(little better) | 4(no change) | 5(little worse) | 6/7(much/very much worse) | p-value |
---|---|---|---|---|---|---|---|
PGI | 27 (28.42%) | 35 (36.84%) | 24 (25.26%) | 8 (8.42%) | 1 (1.05%) | 0 (0%) | <0.01* |
Efficacy | 0 (no efficacy) | 1 (moderate) | 2 (fairly good) | 3 (good) | 4 (very good) | ||
GRE | 6 (6.32%) | 28 (29.47%) | 25 (26.32%) | 21 (22.11%) | 15 (15.79%) | <0.01* |
Baseline | At 12 weeks of therapy Median (maximum–minimum) | |
---|---|---|
FSH (mIU/mL) | 62.5 (45–90) | 56.3 (42–85) |
Serum estradiol (pg/mL) | 18 (15–20) | 17.6 (14–20) |
Endometrial thickness (mm) on transvaginal ultrasound | 4 (2–4) | 3.6 (2.5–4) |
The vaginal dryness complaints at baseline vaginal atrophy score were severe in 71.58%, and moderate in 28.4%, of cases. After 1 month of treatment, 4% of patients said that they were completely relieved of their symptoms while 18.94% had only mild symptoms. The results at 3 months were even more favorable, with more than 85% of patients having either mild symptoms or being completely relieved. Only 4.2% of patients complained that they did not have any improvement even after 12 weeks of therapy.
The effect on vulval atrophy was more modest if compared to vaginal symptoms. All patients enrolled in the study had vulval atrophy scores in the moderate to severe category at the time of initial recruitment. Around 14.7% reported complete relief at 1 month while 15.7% at 3 months of treatment. But the number of patients with severe symptoms had shown a significant decline from 60 to 6.32% of the total (p-value < 0.01). The mean VAS score at baseline was 2.72 ± 0.45, at 1 month 1.94 ± 0.60, and the end of 3 months was 1.31 ± 0.59. The mean VuAS score at baseline was 2.6 ± 0.49, at 1 month 1.91 ± 0.57 and at 3 months was 1.28 ± 0.57. A 12-week treatment with isoflavone gel led to significant improvements in both the scores as shown in Figure 2.
Fig. 2: Changes in Vulval and Vaginal Assessment score (VUS and VAS) during treatment
DISCUSSION
Vulvovaginal health is an important aspect of the sexual and overall health and well-being of a female. Decreased estrogen levels of menopause have adverse effects on it, manifesting in the form VVA presenting as dryness, decreased lubrication, and elasticity, leading to dyspareunia and also discomfort and irritation in the vulvovaginal region.7
This is one of the most common and bothersome symptoms of menopause. The vagina, vestibule, and bladder trigone contain high levels of estrogen receptors. With declining serum estrogen levels, there is thinning of the vaginal epithelium, thinning, and retraction of the labia minora, and reduction in lubrication. Decreased vaginal elasticity and increased friability also contribute to dyspareunia.8
The North American Menopause Society8 recommends nonhormonal vaginal therapies as first-line treatment for genitourinary syndrome, while recommendations in Europe support vaginal estrogen therapy.10 While estrogens have a well-established role in the management of postmenopausal VVA, a few recent studies including a recent randomized controlled trial found neither prescribed vaginal estradiol tablet nor over-the-counter vaginal moisturizer provides additional benefit over placebo vaginal tablet and gel in reducing postmenopausal vulvovaginal symptoms.11
Women in low- and middle-income countries like India are often hesitant to visit a physician or gynecologist for complaints like VVA. Although many over the counter medications like lubricants are available, women are either unfamiliar, uninformed or more often shy to talk about them. Although topical estrogen therapy is beneficial and gold standard treatment for symptoms of VVA, some women are hesitant to use these preparations, despite repeated counseling regarding their safety. Another concern in using vaginal estrogen therapy is its systemic absorption. Many clinical trials have examined serum levels of estradiol in response to the use of vaginal estrogens in postmenopausal women.8 A small incremental increase in circulating estradiol levels was found in women who used vaginal estrogen products. Although the effects are usually insignificant, they can be bothersome in patients with breast cancer or thromboembolic diseases.7
A few previous studies also support the fact that topical isoflavones are effective in the treatment of postmenopausal dyspareunia. Vaginal dryness significantly improves the genital score (score used in previous studies to assess the vaginal symptoms).9 The improvement in vulval and vaginal symptoms of menopause is due to a significant increase in the number of blood vessels or vaginal neovascularization that has been demonstrated in animal studies and further confirmed in human studies as well. It also leads to an increase in superficial cells on microscopy, and also increase in collagen and hyaluronic acid concentration of the vaginal epithelium. The epithelium also demonstrates an increase in estrogen receptor expression and also improved epithelial thickness.10 Majority of patients in our study reported a significant improvement in VHI and vaginal pH. Our results were similar to the results obtained by Lima et al., who in their randomized controlled trial found that the results were comparable to topical estrogen therapy.12
Although reliable and reproducible clinical tools to assess vulvovaginal health are scarce, VAS4 and VuAS5 are simple and feasible tools that have been used in a few previous studies.5 Our study is probably the first study that comprehensively assessed both the vaginal as well as vulval symptoms and quantified them on the basis of patient perceived scores. We found that a 12-week treatment with isoflavone gel led to significant improvements in both the vaginal and vulval atrophy scores. The mean VAS score at baseline was 2.72 ± 0.45, at 1 month 1.94 ± 0.60 and at the end of 3 months was 1.31 ± 0.59. The mean VuAS score at baseline was 2.6 ± 0.49, at 1 month 1.91 ± 0.57 and at 3 months was 1.28 ± 0.57. Almost all patients reported a very favorable outcome with improvement in vaginal health indicators. Similar improvement in symptoms of VVA has been reported by a few studies done in the past also. A similar study from Brazil reported that isoflavone topical gel significantly improved the genital scores and increased the median maturation value after 12 weeks of use. The effects reported were comparable to conjugated equine estrogen vaginal cream.12
LIMITATION
The present study had certain limitations. First, the sample size was not very large, so generalization of the results to general population should be done with a word of caution. Second, the follow-up period was only 12 weeks. So, the authors are not certain that the beneficial effects of topical isoflavone gel would be short acting only, or will stay for a longer duration. Therefore, further studies with larger sample sizes and prolonged follow-up are recommended.
CONCLUSION
Soy isoflavone vaginal gel (0.5%) use on daily basis for 12 weeks leads to significant improvements in the symptoms of VVA in postmenopausal women. Topical isoflavones are a good treatment option for VVA, especially in women who either do not wish to use hormonal therapy or have contraindications for its use.
REFERENCES
1. Nappi RE, Kokot-Kierepa M. Women’s voices in the menopause: Results from an international survey on vaginal atrophy. Maturitas 2010;67(3):233–238. DOI: 10.1016/j.maturitas.2010.08.001.
2. Archer DF. Efficacy and tolerability of local estrogen therapy for urogenital atrophy. Menopause 2010;17(1):194–203. DOI: 10.1097/gme.0b013e3181a95581.
3. Pastore LM, Carter LA, Hulka BS, et al. Self-reported urogenital symptoms in postmenopausal women: Women’s Health Initiative. Maturitas 2004;49(4):292–303. DOI: 10.1016/j.maturitas.2004.06.019.
4. Sturdee DW, Panay N, on behalf of the International Menopause Society Writing Group. Recommendations for the management of postmenopausal vaginal atrophy. Climacteric 2010;13(6):509–522. DOI: 10.3109/13697137.2010.522875.
5. Eaton AA, Baser RE, Seidel B, et al. Validation of clinical tools for vaginal and vulvar symptom assessment in cancer patients and survivors. J Sex Med 2017;14(1):144–151. DOI: 10.1016/j.jsxm.2016.11.317.
6. Sokol ER, Karram MM. An assessment of the safety and efficacy of a fractional CO2 laser system for the treatment of vulvovaginal atrophy. Menopause 2016;23(10):1102–1107. DOI: 10.1097/GME.0000000000000700.
7. Lynch CM. Vaginal estrogen therapy for the treatment of atrophic vaginitis. J Women Health 2009;18(10):1595–1606. DOI: 10.1089/jwh.2008.1281.
8. North American Menopause Society. Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society. Menopause 2013;20(9):888–902. DOI: 10.1097/GME.0b013e3182a122c2.
9. Tedeschi C, Benvenuti C, Research Group EG. Comparison of vaginal gel isoflavones versus no topical treatment in vaginal dystrophy: Results of a preliminary prospective study. Gynecol Endocrinol 2012;28(8):652–654. DOI: 10.3109/09513590.2011.650764.
10. Rees M, Angioli R, Coleman RL, et al. European Menopause and Andropause Society (EMAS) and International Gynecologic Cancer Society (IGCS) position statement on managing the menopause after gynecological cancer: Focus on menopausal symptoms and osteoporosis. Maturitas 2020;134(6):56–61. DOI: 10.1016/j.maturitas.2020.01.005.
11. Lima SM, Bernardo BF, Yamada SS, et al. Effects of Glycine max (L.) Merr. soy isoflavone vaginal gel on epithelium morphology and estrogen receptor expression in postmenopausal women: A 12-week, randomized, double-blind, placebo-controlled trial. Maturitas 2014;78(3):205–211. DOI: 10.1016/j.maturitas.2014.04.007.
12. Lima SM, Yamada SS, Reis BF, et al. Effective treatment of vaginal atrophy with isoflavone vaginal gel. Maturitas 2013;74(3):252–258. DOI: 10.1016/j.maturitas.2012.11.012.
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