Menopause: The Journal of The North American Menopause Society Vol. 22, No. 7, pp. 741/749 DOI: 10.1097/gme.0000000000000380 * 2014 by The North American Menopause Society
Effects of a soy-based dietary supplement compared with low-dose hormone therapy on the urogenital system: a randomized, double-blind, controlled clinical trial Lucio O. Carmignani, MD,1 Adriana Orcesi Pedro, MD, PhD,1 Eliana B. Montemor, MSc,1 Victor A. Arias, MD, PhD,2 Lucia H. Costa-Paiva, MD, PhD,1 and Aara˜o M. Pinto-Neto, MD, PhD1 Abstract Objective: This study aims to compare the effects of a soy-based dietary supplement, low-dose hormone therapy (HT), and placebo on the urogenital system in postmenopausal women. Methods: In this double-blind, randomized, placebo-controlled trial, 60 healthy postmenopausal women aged 40 to 60 years (mean time since menopause, 4.1 y) were randomized into three groups: a soy dietary supplement group (90 mg of isoflavone), a low-dose HT group (1 mg of estradiol plus 0.5 mg of norethisterone), and a placebo group. Urinary, vaginal, and sexual complaints were evaluated using the urogenital subscale of the Menopause Rating Scale. Vaginal maturation value was calculated. Transvaginal sonography was performed to evaluate endometrial thickness. Genital bleeding pattern was assessed. Statistical analysis was performed using W2 test, Fisher’s exact test, paired Student’s t test, Kruskal-Wallis test, Kruskal-Wallis nonparametric test, and analysis of variance. For intergroup comparisons, Kruskal-Wallis nonparametric test (followed by Mann-Whitney U test) was used. Results: Vaginal dryness improved significantly in the soy and HT groups (P = 0.04). Urinary and sexual symptoms did not change with treatment in the three groups. After 16 weeks of treatment, there was a significant increase in maturation value only in the HT group (P G 0.01). Vaginal pH decreased only in this group (P G 0.01). There were no statistically significant differences in endometrial thickness between the three groups, and the adverse effects evaluated were similar. Conclusions: This study shows that a soy-based dietary supplement used for 16 weeks fails to exert estrogenic action on the urogenital tract but improves vaginal dryness. Key Words: Menopause Y Soy Y Phytoestrogens Y Urogenital atrophy Y Hormone therapy Y Menopause Rating Scale.
T
he study of genitourinary health is of great interest because symptoms caused by vulvovaginal atrophy may affect 20% to 45% of midlife and older women. In contrast to vasomotor symptoms, which usually diminish across time, vulvovaginal atrophy can be progressive and difficult to resolve without treatment.1,2 It also has a negative effect on quality of life and sexual health in women.3, in vitro. The distribution of estrogen receptors on the urogenital
TABLE 4. Percentage variation in follicle-stimulating hormone and estradiol levels, by treatment group (N = 60) Variable
Hormone therapy (n = 20)
Follicle-stimulating hormone j46.2 (j62.3 to j30) Estradiol 513.7 (208.2 to 819.3) Data are presented as mean (95% CI). a Analysis of variance (followed by Tukey test). b Kruskal-Wallis nonparametric test (followed by Mann-Whitney U test).
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Soy (n = 20)
Placebo (n = 20)
P
9.0 (j7.7 to 25.7) 52.31 (19.3 to 123.9)
3.3 (j24.8 to 31.4) 22.0 (j9.3 to 55.2)
G0.001a G0.001b
* 2014 The North American Menopause Society
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EFFECT OF ISOFLAVONE ON THE UROGENITAL SYSTEM TABLE 5. Changes in endometrial thickness (mm) at baseline and after 16 weeks of treatment, by treatment group (N = 60) Hormone therapy (n = 20) Baseline 3.2 (1.3) After treatment 3.8 (1.6) Data are presented as mean (SD). a Kruskal-Wallis test.
Soy (n = 20)
Placebo (n = 20)
Pa
4.2 (2.3) 4.1 (2.0)
3.9 (2.2) 3.5 (2.6)
0.11 0.16
tract of postmenopausal women may have influenced the apparently divergent results of the studies. This topic requires further research.1,48 Improvement in urogenital symptoms without cytological improvement in genital trophism in the soy group could be explained by a certain trophic activity of phytoestrogen in the vaginal mucosa epithelium. However, phytoestrogen failed to alter MV, but its action was enough to improve symptoms of vaginal dryness. The trophic action of phytoestrogen on the vaginal mucosa has been well-demonstrated in animal studies, such as those cited previously.25,43,44 Current studies, showing significant improvement in genital symptoms in postmenopausal women, have proposed the use of phytoestrogen by the vaginal route. Some studies also obtained increased MVs.49,50 In this trial, the action of isoflavone on the vaginal epithelium was also compared with the action of placebo, and this reinforces the hypothesis of a probable beneficial action of phytoestrogen on the vaginal mucosa. Clinical improvement is clearly observed, although there is no cytological effect. There was no significant change in endometrial thickness in the study groups during the treatment period. These data suggest that isoflavone treatment is not sufficient to produce a proliferative effect on endometrial tissue. This finding is in line
with other investigations.28,29,51 The longest study of phytoestrogen soy treatment lasted 5 years, detecting no malignancy during endometrial biopsies and observing only a significant increase in simple endometrial hyperplasia.52 Despite a lack of statistical significance, genital bleeding rate was higher in the HT group than in the soy and placebo groups, reinforcing the hypothesis of a minimal proliferative action of isoflavones on the endometrium. Genistein has been well-demonstrated to have a higher binding affinity for ER-A than for ER-> in vitro.47 However, genistein has been shown to stimulate the transcriptional activity of both estrogen receptor subtypes.53,54 Other studies showed that isoflavones can modify the three-dimensional structures of ER-> and ER-A in different ways based on their particular molecular structure,55,56 assuming an agonist, partial agonist, or antagonist character depending on the estrogen receptor subtype considered.57 The adverse effects measured in this trial were nonsignificant, in agreement with much of the literature reviewed. All treatment modalities were well-accepted, which may have contributed to the absence of dropouts in this study. In the Cochrane Review of 2013, most trials revealed no significant difference between randomized groups.58 However, conclusions are limited owing to the heterogeneity of soy products and their different formulations used in the different studies.58,59 This study chose to use the MRS, which is a self-administered health-related quality-of-life scale that seeks to diminish errors made by health professionals when applying questionnaires.33,60 Moreover, the MRS is widely used and provides a quantitative evaluation of menopausal symptoms, allowing assessment of symptoms, success of various treatments, and comparison of symptoms evaluated across time.61 The MRS has been
TABLE 6. Percentage distribution of adverse effects during the treatment period, by study group (N = 60) Adverse effects Mastalgia Presenting symptom Other conditions Bleeding Presenting symptom Other conditions Skin problem: allergy Presenting symptom Other conditions Headache Presenting symptom Other conditions Nausea Presenting symptom Other conditions Weight gain Presenting symptom Other conditions Water retention Presenting symptom Other conditions Intestinal complaints Presenting symptom Other conditions Data are presented as n (%). a Fisher’s exact test.
Hormone therapy (n = 20)
Soy (n = 20)
Placebo (n = 20)
3 (15.0) 17 (85.0)
2 (10.0) 18 (90.0)
0 (0.0) 20 (100.0)
4 (20.0) 16 (80.0)
1 (5.0) 19 (95.0)
1 (5.0) 19 (95.0)
1 (5.0) 19 (95.0)
0 (0.0) 20 (100.0)
0 (0.0) 20 (100.0)
2 (10.0) 18 (90.0)
1 (5.0) 19 (95.0)
0 (0.0) 20 (100.0)
4 (20.0) 16 (80.0)
0 (0.0) 20 (100.0)
3 (15.0) 17 (85.0)
4 (20.0) 16 (80.0)
3 (15.0) 17 (85.0)
5 (25.0) 15 (75.0)
3 (15.0) 17 (85.0)
3 (15.0) 17 (85.0)
1 (5.0) 19 (95.0)
2 (10.0) 18 (90.0)
1 (5.0) 19 (95.0)
1 (5.0) 19 (95.0)
Pa 0.35 0.44 0.33 0.76 0.14 0.92 0.68 1.00
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validated for use in many cultures and different social classes.61 The Portuguese-language version was developed in Brazil following international methodological recommendations for the linguistic and cultural adaptation of health-related qualityof-life instruments.61 Some critics may point out that the length of soy isoflavone use is too short to elicit a satisfactory clinical response. Studies that have demonstrated an increase in vaginal MV lasted 12 to 24 weeks.18 and A expression in the vaginal walls and uterosacral ligaments of premenopausal and postmenopausal women. Fertil Steril 1999;71: 1099-1102. 47. Kuiper GG, Carlsson B, Grandien K, et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors > and A. Endocrinology 1997;138:863-870. 48. Reed SD, Newton KM, LaCroix AZ, Grothaus LC, Grieco VS, Erlich K. Vaginal, endometrial, and reproductive hormone findings: randomized placebo-controlled trial of black cohosh, multibotanical herbs, and dietary soy for vasomotor symptoms: the Herbal Alternatives for Menopause (HALT) Study. Menopause 2008;15:51-58.
49. Le Donne M, Caruso C, Mancuso A, et al. The effect of vaginally administered genistein in comparison with hyaluronic acid on atrophic epithelium in postmenopause. Arch Gynecol Obstet 2011;283:1319-1323. 50. Lima SMR, Yamada SS, Reis BF, Postigo S, Silva MAL, Aoki T. Effective treatment of vaginal atrophy with isoflavone vaginal gel. Maturitas 2013;74:252-258. 51. D’Anna R, Cannata ML, Marini H, et al. Effects of the phytoestrogen genistein on hot flushes, endometrium, and vaginal epithelium in postmenopausal women: a 2-year randomized, double-blind, placebocontrolled study. Menopause 2009;16:301-306. 52. Unfer V, Casini ML, Costabile L, Mignosa M, Gerli S, Di Renzo GC. Endometrial effects of long-term treatment with phytoestrogens: a randomized double-blind, placebo-controlled study. Fertil Steril 2004;82: 145-148. 53. Morito K, Aomori T, Hirose T, et al. Interaction of phytoestrogens with estrogen receptors > and A (II). Biol Pharm Bull 2002;25:48-52. 54. Mueller SO, Simon S, Chae K, Metzler M, Korach KS. Phytoestrogens and their human metabolites show distinct agonistic and antagonistic properties on estrogen receptor > (ER>) and ERA in human cells. Toxicol Sci 2004;80:14-25. 55. Morito K, Hirose T, Kinjo J, et al. Interaction of phytoestrogens with estrogen receptors > and A. Biol Pharm Bull 2001;24:351-356. 56. Pike AC, Brzozowski AM, Hubbard RE, et al. Structure of the ligandbinding domain of oestrogen receptor A in the presence of a partial agonist and a full antagonist. EMBO J 1991;18:4608-4618. 57. Lecce G, Meduri G, Ancelin M, Bergeron C, Perrot-Applanat M. Presence of estrogen receptor A in the human endometrium through the cycle: expression in glandular, stromal, and vascular cells. J Clin Endocrinol Metab 2001;86:1379-1386. 58. Lethaby A, Marjoribanks J, Kronenberg F, Roberts H, Eden J, Brown J. Phytoestrogens for menopausal vasomotor symptoms. Cochrane Database Syst Rev 2013;12:CD001395. doi: 10.1002/14651858. 59. Knight DC, Howes JB, Eden JA, Howes LG. Effects on menopausal symptoms and acceptability of isoflavone-containing soy powder dietary supplementation. Climacteric 2001;4:13-18. 60. Schneider HP, Heinemann LA, Rosemeier HP, Potthoff P, Behre HM. The Menopause Rating Scale (MRS): comparison with Kupperman index and quality-of-life scale SF-36. Climacteric 2000;3:50-58. 61. Heinemann LA, DoMinh T, Strelow F, Gerbsch S, Schnitker J, Schneider HP. The Menopause Rating Scale (MRS) as outcome measure for hormone treatment? A validation study. Health Qual Life Outcomes 2004;22:2-67.
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