Objective. Evaluate in postmenopausal women the effect of red clover extract (RCE) isoflavones over subjective status of skin, appendages, and several mucosal sites. Method. Postmenopausal women ( ) were randomly assigned to receive either two daily capsules of the active compound (80？mg RCE, Group A) or placebo of equal appearance (Group B) for a 90-day period. After a washout period of 7 days, medication was crossed over and taken for 90 days more. Subjective improvement of skin, appendages, and several mucosal site status was assessed for each studied group at 90 and 187 days using a visual analogue scale (VAS). In addition, libido, tiredness, and urinary, sleep, and mood complaints were also evaluated. Results. Women after RCE intervention (both groups) reported better subjective improvement of scalp hair and skin status, libido, mood, sleep, and tiredness. Improvement of urinary complaints, nail, body hair, and mucosa (oral, nasal, and ocular) status did not differ between treatment phases (intra- and intergroup). Overall satisfaction with treatment was reported higher after RCE intervention (both groups) as compared to placebo. Conclusion. RCE supplementation exerted a subject improvement of scalp hair and skin status as well as libido, mood, sleep, and tiredness in postmenopausal women. 1. Introduction As a result of increased life expectancy, nowadays, women spend more than one third of their lives in a state of estrogen deprivation which in turn leads to a number of significant long-term changes [1]. Indeed, two out of three women in the menopausal transition present different complaints [2]. Increased osteoporosis and cardiovascular risk, vasomotor episodes, and sleep disturbances have been the main research topics and focus of treatment. Others aspects such as urinary complaints, loss of libido, and changes in hair, nail, skin, or mucosal status have often been disregarded (neglected) by researchers and health care providers but not by women themselves. Hormone therapy (HT), using different estrogenic compounds, has shown its effectiveness over a number of these complaints; nevertheless, current HT use has become controversial due to suspected increased risk of breast cancer and cardiovascular disease [3]. Furthermore, 10% of western women display conditions that contraindicate HT use: history of estrogen-dependent malignancy, liver disease, thromboembolic disorders, and severe migraine [4]. Under this scenario, the use of alternatives to HT such as botanical and dietary supplements (i.e., phytoestrogens) has increased for the management of
References
[1]
M. Imhof, A. Gocan, F. Reithmayr et al., “Effects of a red clover extract (MF11RCE) on endometrium and sex hormones in postmenopausal women,” Maturitas, vol. 55, no. 1, pp. 76–81, 2006.
[2]
S. Geller and L. Studee, “Soy and red clover for mid-life and aging,” Climacteric, vol. 9, no. 4, pp. 245–263, 2006.
[3]
E. Barrett-Connor, D. Grady, and M. L. Stefanick, “The rise and fall of menopausal hormone therapy,” Annual Review of Public Health, vol. 26, pp. 115–140, 2005.
[4]
North American Menopause Society, “Treatment of menopause associated vasomotor symptoms: position statement of the North American Menopause Society,” Menopause, vol. 11, no. 1, pp. 11–33, 2004.
[5]
V. Beck, U. Rohr, and A. Jungbauer, “Phytoestrogens derived from red clover: an alternative to estrogen replacement therapy?” Journal of Steroid Biochemistry and Molecular Biology, vol. 94, no. 5, pp. 499–518, 2005.
[6]
K. M. Jordan and C. Cooper, “Epidemiology of osteoporosis,” Best Practice and Research: Clinical Rheumatology, vol. 16, no. 5, pp. 795–806, 2002.
[7]
A. H. Roudsari, F. Tahbaz, A. Hossein-Nezhad, B. Arjmandi, B. Larijani, and S. M. Kimiagar, “Assessment of soy phytoestrogens' effects on bone turnover indicators in menopausal women with osteopenia in Iran: a before and after clinical trial,” Nutrition Journal, vol. 4, p. 30, 2005.
[8]
X. Zhang, X. O. Shu, H. Li et al., “Prospective cohort study of soy food consumption and risk of bone fracture among postmenopausal women,” Archives of Internal Medicine, vol. 165, no. 16, pp. 1890–1895, 2005.
[9]
M. T. Goodman, L. R. Wilkens, J. H. Hankin, L. C. Lyu, A. H. Wu, and L. N. Kolonel, “Association of soy and fiber consumption with the risk of endometrial cancer,” American Journal of Epidemiology, vol. 146, no. 4, pp. 294–306, 1997.
[10]
P. L. Horn-Ross, E. M. John, A. J. Canchola, S. L. Stewart, and M. M. Lee, “Phytoestrogen intake and endometrial cancer risk,” Journal of the National Cancer Institute, vol. 95, no. 15, pp. 1158–1164, 2003.
[11]
W. H. Xu, W. Zheng, Y. B. Xiang et al., “Soya food intake and risk of endometrial cancer among Chinese women in Shanghai: population based case-control study,” British Medical Journal, vol. 328, no. 7451, pp. 1285–1288, 2004.
[12]
S. M. Boyapati, X. O. Shu, X. R. Zhi et al., “Soyfood intake and breast cancer survival: a followup of the Shanghai Breast Cancer Study,” Breast Cancer Research and Treatment, vol. 92, no. 1, pp. 11–17, 2005.
[13]
B. N. Fink, S. E. Steck, M. S. Wolff et al., “Dietary flavonoid intake and breast cancer survival among women on long island,” Cancer Epidemiology Biomarkers and Prevention, vol. 16, no. 11, pp. 2285–2292, 2007.
[14]
C. B. Tempfer, E. K. Bentz, S. Leodolter et al., “Phytoestrogens in clinical practice: a review of the literature,” Fertility and Sterility, vol. 87, no. 6, pp. 1243–1249, 2007.
[15]
K. Morito, T. Aomori, T. Hirose et al., “Interaction of phytoestrogens with estrogen receptors alpha and beta (II),” Biological & Pharmaceutical Bulletin, vol. 25, no. 1, pp. 48–52, 2002.
[16]
N. L. Booth and C. E. Piersen, “Red Clover (Trifolium pratense),” Encyclopedia of Dietary Supplements, pp. 587–602, 2006.
[17]
E. M. Umland, “Treatment strategies for reducing the burden of menopause-associated vasomotor symptoms,” Journal of Managed Care Pharmacy, vol. 14, no. 3, pp. S14–S19, 2008.
[18]
C. Atkinson, J. E. Compston, N. E. Day, M. Dowsett, and S. A. Bingham, “The effects of phytoestrogen isoflavones on bone density in women: a double-blind, randomized, placebo-controlled trial1-3,” American Journal of Clinical Nutrition, vol. 79, no. 2, pp. 326–333, 2004.
[19]
M. Lipovac, P. Chedraui, C. Gruenhut, A. Gocan, M. Stammler, and M. Imhof, “Improvement of postmenopausal depressive and anxiety symptoms after treatment with isoflavones derived from red clover extracts,” Maturitas, vol. 65, no. 3, pp. 258–261, 2010.
[20]
L. A. Hidalgo, P. A. Chedraui, N. Morocho, S. Ross, and G. S. Miguel, “The effect of red clover isoflavones on menopausal symptoms, lipids and vaginal cytology in menopausal women: a randomized, double-blind, placebo-controlled study,” Gynecological Endocrinology, vol. 21, no. 5, pp. 257–264, 2005.
[21]
P. Chedraui, L. Hidalgo, G. S. Miguel, N. Morocho, and S. Ross, “Red clover extract (MF11RCE) supplementation and postmenopausal vaginal and sexual health,” International Journal of Gynecology and Obstetrics, vol. 95, no. 3, pp. 296–297, 2006.
[22]
M. M. Terzic, J. Dotlic, S. Maricic, T. Mihailovic, and B. Tosic-Race, “Influence of red clover-derived isoflavones on serum lipid profile in postmenopausal women,” Journal of Obstetrics and Gynaecology Research, vol. 35, no. 6, pp. 1091–1095, 2009.
[23]
J. E. Blümel, C. Castelo-Branco, P. A. Chedraui et al., “Patients' and clinicians' attitudes after the Women's Health Initiative study,” Menopause, vol. 11, no. 1, pp. 57–61, 2004.
[24]
B. Ettinger, D. Grady, A. N. A. Tosteson, A. Pressman, and J. L. Macer, “Effect of the Women's Health Initiative on women's decisions to discontinue postmenopausal hormone therapy,” Obstetrics and Gynecology, vol. 102, no. 6, pp. 1225–1232, 2003.
[25]
M. A. Schonberg and C. C. Wee, “Menopausal symptom management and prevention counseling after the Women's Health Initiative among women seen in an internal medicine practice,” Journal of Women's Health, vol. 14, no. 6, pp. 507–514, 2005.
[26]
R. J. Miksicek, “Commonly occurring plant flavonoids have estrogenic activity,” Molecular Pharmacology, vol. 44, no. 1, pp. 37–43, 1993.
[27]
R. J. Miksicek, “Interaction of naturally occurring nonsteroidal estrogens with expressed recombinant human estrogen receptor,” Journal of Steroid Biochemistry and Molecular Biology, vol. 49, no. 2-3, pp. 153–160, 1994.
[28]
E. Dornstauder, E. Jisa, I. Unterrieder, L. Krenn, W. Kubelka, and A. Jungbauer, “Estrogenic activity of two standardized red clover extracts (Menoflavon？) intended for large scale use in hormone replacement therapy,” Journal of Steroid Biochemistry and Molecular Biology, vol. 78, no. 1, pp. 67–75, 2001.
[29]
J. T. Coon, M. H. Pittler, and E. Ernst, “Trifolium pratense isoflavones in the treatment of menopausal hot flushes: a systematic review and meta-analysis,” Phytomedicine, vol. 14, no. 2-3, pp. 153–159, 2007.
[30]
P. Chedraui, G. S. Miguel, L. Hidalgo, N. Morocho, and S. Ross, “Effect of Trifolium pratense-derived isoflavones on the lipid profile of postmenopausal women with increased body mass index,” Gynecological Endocrinology, vol. 24, no. 11, pp. 620–624, 2008.
[31]
S. Stevenson and J. Thornton, “Effect of estrogens on skin aging and the potential role of SERMs,” Clinical Interventions in Aging, vol. 2, no. 3, pp. 283–297, 2007.
[32]
R. Paus and G. Cotsarelis, “The biology of hair follicles,” The New England Journal of Medicine, vol. 341, no. 7, pp. 491–497, 1999.
[33]
M. J. Thornton, L. D. Nelson, A. H. Taylor, M. P. Birch, I. Laing, and A. G. Messenger, “The modulation of aromatase and estrogen receptor alpha in cultured human dermal papilla cells by dexamethasone: a novel mechanism for selective action of estrogen via estrogen receptor beta?” Journal of Investigative Dermatology, vol. 126, no. 9, pp. 2010–2018, 2006.
[34]
M. P. Philpott, D. A. Sanders, and T. Kealey, “Effects of insulin and insulin-like growth factors on cultured human hair follicles: IGF-I at physiologic concentrations is an important regulator of hair follicle growth in vitro,” Journal of Investigative Dermatology, vol. 102, no. 6, pp. 857–861, 1994.
[35]
D. M. Klotz, S. C. Hewitt, K. S. Korach, and R. P. Diaugustine, “Activation of a uterine insulin-like growth factor I signaling pathway by clinical and environmental estrogens: requirement of estrogen receptor-α,” Endocrinology, vol. 141, no. 9, pp. 3430–3439, 2000.
[36]
J. Zhao, N. Harada, H. Kurihara, N. Nakagata, and K. Okajima, “Dietary isoflavone increases insulin-like growth factor-I production, thereby promoting hair growth in mice,” Journal of Nutritional Biochemistry, vol. 22, no. 3, pp. 227–233, 2011.
[37]
R. R. Torgerson, “Burning mouth syndrome,” Dermatologic Therapy, vol. 23, no. 3, pp. 291–298, 2010.
[38]
A. Forabosco, M. Criscuolo, G. Coukos et al., “Efficacy of hormone replacement therapy in postmenopausal women with oral discomfort,” Oral Surgery Oral Medicine and Oral Pathology, vol. 73, no. 5, pp. 570–574, 1992.
[39]
R. Leimola-Virtanen, H. Helenius, and M. Laine, “Hormone replacement therapy and some salivary antimicrobial factors in post- and perimenopausal women,” Maturitas, vol. 27, no. 2, pp. 145–151, 1997.
[40]
R. W. Wardrop, J. Hailes, H. Burger, and P. C. Reade, “Oral discomfort at menopause,” Oral Surgery Oral Medicine and Oral Pathology, vol. 67, no. 5, pp. 535–540, 1989.
[41]
H. V？limaa, S. Savolainen, T. Soukka et al., “Estrogen receptor-β is the predominant estrogen receptor subtype in human oral epithelium and salivary glands,” Journal of Endocrinology, vol. 180, no. 1, pp. 55–62, 2004.
[42]
C. M. Philpott, D. C. Wild, C. R. Wolstensholme, and G. E. Murty, “The presence of ovarian hormone receptors in the nasal mucosa and their relationship to nasal symptoms,” Rhinology, vol. 46, no. 3, pp. 221–225, 2008.
[43]
K. Tsukahara, H. Nakagawa, S. Moriwaki et al., “Ovariectomy is sufficient to accelerate spontaneous skin ageing and to stimulate ultraviolet irradiation-induced photoageing of murine skin,” British Journal of Dermatology, vol. 151, no. 5, pp. 984–994, 2004.
[44]
P. G. Sator, J. B. Schmidt, M. O. Sator, J. C. Huber, and H. H？nigsmann, “The influence of hormone replacement therapy on skin ageing: a pilot study,” Maturitas, vol. 39, no. 1, pp. 43–55, 2001.
[45]
T. J. Phillips, Z. Demircay, and M. Sahu, “Hormonal effects on skin aging,” Clinics in Geriatric Medicine, vol. 17, no. 4, pp. 661–672, 2001.
[46]
R. M. Brand and J. L. Jendrzejewski, “Topical treatment with (-)-epigallocatechin-3-gallate and genistein after a single UV exposure can reduce skin damage,” Journal of Dermatological Science, vol. 50, no. 1, pp. 69–72, 2008.
[47]
S. Widyarini, N. Spinks, A. J. Husband, and V. E. Reeve, “Isoflavonoid compounds from red clover (Trifolium pratense) protect from inflammation and immune suppression induced by UV radiation,” Photochemistry and Photobiology, vol. 74, no. 3, pp. 465–470, 2001.
[48]
E. Emmerson, L. Campbell, G. S. Ashcroft, and M. J. Hardman, “The phytoestrogen genistein promotes wound healing by multiple independent mechanisms,” Molecular and Cellular Endocrinology, vol. 321, no. 2, pp. 184–193, 2010.
[49]
A. Thielemann, W. Wuttke, M. Wuttke, and D. Seidlova-Wuttke, “Comparison of urodynamic effects of phytoestrogens equol, puerarin and genistein with these of estradiol 17β in ovariectomized rats,” Experimental Gerontology, vol. 45, no. 2, pp. 129–137, 2010.
[50]
I. U. Ahmad, J. D. Forman, F. H. Sarkar et al., “Soy isoflavones in conjunction with radiation therapy in patients with prostate cancer,” Nutrition and Cancer, vol. 62, no. 7, pp. 996–1000, 2010.
[51]
C. del Giorno, A. M. da Fonseca, V. R. Bagnoli, J. S. de Assis, J. M. Soares Jr., and E. C. Baracat, “Effects of Trifolium pratense on the climacteric and sexual symptoms in postmenopause,” Revista da Associa？？o Médica Brasileira, vol. 56, no. 5, pp. 558–562, 2010.
