Effects of red clover on hot flash and circulating hormone concentrations in menopausal women: a systematic review and meta-analysis

Document Type : Review Article

Authors

1 Student Research Committee, Department of Midwifery and Reproductive Health, Nursing and Midwifery School, Mashhad University of Medical Science, Mashhad, Iran

2 Nuclear Medicine Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

3 Evidence-Based Care Research Centre, Department of Midwifery, School of Nursing and Midwifery, Mashhad University of Medical Sciences, Mashhad, Iran.

4 Department of Midwifery, School of Nursing and Midwifery, Mashhad University of Medical Sciences, Mashhad, Iran

5 Department of community of Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

6 Department of Midwifery, Islamic Azad University, Firuzabad, Fars, Iran,

7 Department of Midwifery, School of Nursing and Midwifery, Mashhad University of Medical Sciences, Mashhad, Iran Mashhad, Iran

Abstract

Objectives: To critically evaluate the effect of red clover on hot flash, endometrial thickness, and hormones status in postmenopausal and peri- and post-menopausal women.
Materials and Methods: MEDLINE (1966 to July 2014), Scopus (1990 to July 2014), and the Cochrane Central Register of Controlled Trials (The Cochrane Library issue 1, 2014) were searched for published randomized controlled Trials (RCTs).
Results: Of 183 relevant publication trials, 11 RCTs met the inclusion criteria. The mean hot flashes frequency in red clover was lower than the control groups (MD -1.99; p=0.067). There was larger decrease in FSH (SMD -0.812; CI: -1.93 to 0.312; p=0.157) and SHBG (SMD -0.128; CI-0.425 to 0.170; P=0.4) in red clover group, compared with placebo, which was not however statistically significant. LH (SMD 0.144; CI-0.097 to 0.384, p=0.242), estradiol (SMD 0.240; CI-0.001 to 0.482, p=0.051), testosterone (MD 0.083; CI: -0.560 to 0.726; p=0.901), and endometrial thickness (SDM 0.022; CI: -0.380 to 0.424, p=0.915) showed greater increase in red clover, compared with placebo, although the effect of estradiol was only significant.
Conclusion: Red clover had a positive effect of alleviating hot flash in menopausal women. Our data, however, suggested very slight changes in FSH, LH, testosterone, and SHBG and significant effect in estrogen status by red clover consumption. However, the interpretation of results of the current study is limited due to methodological flaws of the included studies, menopause status, and large heterogeneity among them. Further trials are still needed to confirm the current finding.

Keywords

Main Subjects


Atkinson C, Warren RM, Sala E, Dowsett M, Dunning AM, Healey CS, Runswick S, Day NE, Bingham SA.2004. Red-clover-derived isoflavones and mammographic breast density:a double –bilnd, randomaized , placebo- controlled trial. Breast Cancer Res, 6:R170-9.
Avis NE, Stellato R, Crawford S, Johannes C, Longcope C.2000. Is there an association between menopause status and sexual functioning?. Menopause, 7: 297-309.
Baber RJ, Templeman C, Morton T, Kelly GE, West L. 1999. Randomized placebo-controlled trial of an isoflavone supplement and menopausal symptoms in women. Climacteric, 2: 85-92.
Bu LH, Lephart ED. 2005. Effects of dietary phytoestrogens on core body temperature during the estrous cycle and pregnancy. Brain Res Bull, 65: 219-223.
Clifton-Bligh PB1, Baber RJ, Fulcher GR, Nery ML, Moreton T. 2001. The effect of isoflavones extracted from red clover (Rimostil) on lipid and bone metabolism. Menopause, 8:259-265.
Coon JT, Pittler MH, Ernst E. 2007. Trifolium pratense isoflavones in the treatment of menopausal hot flushes: a systematic review and meta-analysis. Phytomedicine, 14: 153-159.
del Giorno C, Fonseca AM, Bagnoli VR, Assis JS, Soares JM Jr, Baracat EC.2010. Effects of Trifolium pratense on the climacteric and sexual symptoms in postmenopause women. Rev Assoc Med Bras, 56: 558-62.
Ehsanpour S, Salehi K, Zolfaghari B, Bakhtiari S. 2012. The effects of red clover on quality of life in post-menopausal women. Iran J Nurs Midwifery Res, 17: 34-40.
Endogenous Hormones and Breast Cancer      Collaborative Group. Endogenous sex hormones and breast cancer postmenopausal
     women: reanalysis of nine prospective studies.2002. J Natl Cancer Inst, 94:606–616.
Freedman RR1, Blacker CM. 2002. Estrogen raises the sweating threshold in postmenopausal women with hot flashes. Fertil Steril, 77: 487-490.
Geller SE, Shulman LP, van Breemen RB, Banuvar S, Zhou Y, Epstein G, Hedayat S, Nikolic D, Krause EC, Piersen CE, Bolton JL, Pauli GF, Farnsworth NR. 2008. Safety and efficacy of black cohosh and red clover for the management of vasomotor symptoms: a randomized controlled trial. Menopause, 16:1156-1166.
Ghazanfarpour M, Sadeghi R, Latifnejad Roudsari R, (in press).2015. Red clover for treatment of hot flashes and menopausal symptoms: a systematic review and meta-analysis. J Obstet Gynaecol.
Gompel  A, Santen RJ. 2012. Hormone therapy and breast cancer risk 10 years after the WHI. Climacteric, 15: 241-249.
Habel LA, Dignam JJ, Land SR, Salane M, CapraAM, Julian TB.2004. Mammographic density and breast cancer after ductal carcinoma in situ. J Natl Cancer Inst, 96: 1467-1472.
Haghighi L, Zadmohammadi M, Hormon replacement therapy in menopusal women reffered to Iran University clinics during 2000-2001. RJMS,10:25-30.
Hale GE, Hughes CL, Robboy SJ, Agarwal SK, Bievre M. 2001. A double-blind randomized study on the effects of red clover isoflavone on the endometrium. Menopause, 8: 338-46.
Hidalgo LA, Chedraui PA, Morocho N, Ross S, San Miguel G. 2005. The effect of red clover isflavones on menopausal symptoms, lipids and vaginal cytology in menopausal women:a randomized, double-blind, placebo-controlled study. Gynecol Endocrinol, 21: 257-64.
Hooper L, Ryder JJ, Kurzer MS, Lampe JW, Messina MJ, Phipps WR, Cassidy A. 2009. Effects of soy protein and isoflavones on circulating hormone concentrations in pre-and post-menopausal women: a systematic review and meta-analysis. Hum Reprod Update, 4:423-40.
 
 Imhof M, Gocan A, Reithmayr F, Lipovac M,   Schimitzek C, Chedraui P, Huber J. 2006. Effects of a red clover extract (MF11RCE) on endometrium and sex hormones in postmenopausal women. Maturitas, 55: 76-81.
Jeri AR.2002. The use of an isoflavone supplement to relieve hot flashes. Female patient;27:35-37.
Knight DC, Howes JB, Eden JA. 1999. The effect of Promensil™, an isoflavone extract, on menopausal symptoms. Climacteric, 2:79-84.
Kotsopoulos D, Dalais FS, Liang YL, McGrath BP, Teede HJ. 2000. "The effects of soy
Krebs EE, Ensrud KE, MacDonald R, Wilt TJ. 2004. Phytoestrogens for treatment of menopausal symptoms: a systematic review. Obstet Gynecol,104: 824-836.
Lethaby AE, Brown J, Marjoribanks J, Kronenberg F, Roberts H, Eden J. 2007. Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst Rev:4.
Lipovac M, Chedraui P, Gruenhut C, Gocan A, Kurz C, Neuber B, Imhof M. 2012. The effect of red clover isoflavone  supplementation over vasomotore and menopausal symptoms in postmenopausal women. Gynecol Endocrinol, 28: 203-7.
Loprinzi CL, Kugler JW, Sloan JA, Mailliard JA, LaVasseur BI, Barton DL, Novotny PJ, Dakhil SR, Rodger K, Rummans TA, Christensen BJ. 2000. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet, 356: 2059-2063.
Maclennan AH, Broadbent JL, Lester S, Moore V. 2004. Oral oestrogen and combined oestrogen/Progestrog therapy versus placebo for hot flushes. Cochrane Database Syst Rev, 4.
Maki PM, Rubin LH, Fornelli D, Drogos L, Banuvar S, Shulman LP, Geller SE. 2009. Effects of botanicals and combined hormone therapy on cognition in postmenopausal women. Menopause, 16: 1167.
Meherishi S, Khandelwal S, Swarankar ML, Kaur P. 2010. Attitudes and practices of gynecologists in Jaipur toward management of menopause. J Midlife Health, 1: 74-8.
Menati L, Khaleghinezhad K, Tadayon M, Siahpoosh A. 2014. Evaluation of contexual and demographic factors on licorice effects on reducing hot flashes in postmenopause women. Health Care Women Int, 35: 87-99.
Nelson HD, Vesco KK, Haney E, Fu R, Nedrow A, Miller J, Nicolaidis C, Walker M, Humphrey L. 2006. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. Jama, 295: 2057-2071.
Salehi K, Ehsanpour S., Zolfaghari B, Salehi Z. Honagoo M. 2013. Effect of red clover isoflavone extract on menopausal symptoms.  J Gorgan Univ Med Sci, 15: 21-27.
Sites DS, Johnson NT, Miller JA, Torbush PH, Hardin JS, Knowles SS, Nance J, Fox TH, Tart RC. 2014. Controlled breathing with or without peppermint aromatherapy for postoperative nausea and/or vomiting symptom relief: a randomized controlled trial. J Perianesth Nurs, 29: 12-19.
Taavoni S, Shakeri F, Haghani H. Gooshegir S. 2012. Effect of red clover on vasomotor symptoms and heart discomfort of menopausal women . CMJA 3: 32-40.
Tice JA, Ettinger B, Ensrud K, Wallace R, Blackwell T, Cummings SR. 2003. Phytoestrogen supplements for the treatment of hot flashes: the Isoflavone Clover Extract (ICE) Study: a randomized controlled trial. Jama, 290: 207-214.
van de Weijer PH1, Barentsen R. 2002. Isoflavones from red clover (Promensil®) significantly reduce menopausal hot flush symptoms compared with placebo. Maturitas, 42:187-193.
Yavari Kia P, Safajou F, Shahnazi M, Nazemiyeh H. 2014. The effect of lemon inhalation aromatherapy on nausea and vomiting of pregnancy: a double-blinded, randomized, controlled clinical trial. Iran Red Crescent Med J, 16:e14360
Zheng W, Dai Q, Custer LJ, Shu XO, Wen WQ, Jin F, Franke AA.1999. Urinary excretion of isoflavonoids and the risk of breast cancer. Cancer Epidemiol Biomarkers Prev, 8: 35-40.