The Effects and Action Mechanisms of Phytoestrogens on Vasomotor Symptoms During Menopausal Transition: Thermoregulatory Mechanism

Author(s): Haryati Ahmad Hairi , Ahmad Nazrun Shuid* , Nurul ‘Izzah Ibrahim , Jamia Azdina Jamal , Norazlina Mohamed , Isa Naina Mohamed .

Journal Name: Current Drug Targets

Volume 20 , Issue 2 , 2019

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Abstract:

Background: Phytoestrogens have recently been claimed to positively influence menopausal discomforts, including hot flashes. However, little is known about the influence of phytoestrogens on core body temperature during oestrogen fluctuation at menopause.

Objective: Previously published findings showed that phytoestrogens could relieve menopausal complaints, thus, the present review was aimed at assessing the effects of phytoestrogens on thermoregulatory mechanism during menopausal transition.

Results: The molecular mechanisms underlying hot flashes are complex. Oestrogen fluctuations cause hypothalamic thermoregulatory centre dysfunction, which leads to hot flashes during menopause. The phytoestrogens of interest, in relation to human health, include isoflavones, lignans, coumestans, and stilbenes, which are widely distributed in nature. The phytoestrogens are capable of reducing hot flashes via their oestrogen-like hormone actions. The potential effects of phytoestrogens on hot flashes and their molecular mechanisms of action on thermoregulatory centre are discussed in this review.

Conclusion: The effects of phytoestrogens on these mechanisms may help explain their beneficial effects in alleviating hot flashes and other menopausal discomforts.

Keywords: Phytoestrogen, vasomotor symptoms, hot flashes, thermoregulatory mechanism, molecular, perimenopause.

[1]
Umland EM. Treatment strategies for reducing the burden of menopause-associated vasomotor symptoms. J Manag Care Pharm 2008; 14: 14-9.
[2]
Burger HG, Dudley EC, Hopper JL, et al. Prospectively measured levels of serum follicle-stimulating hormone, estradiol, and the dimeric inhibins during the menopausal transition in a population based cohort of women. J Clin Endocrinol Metab 1999; 84: 4025-30.
[3]
Harlow SD, Gass MD, Hall JE, et al. Executive summary of the Stages of Reproductive Aging Workshop + 10: Addressing the unfinished agenda of staging reproductive aging. Menopause 2012; 19(4): 387-95.
[4]
Vliet EL. Menopause and perimenopause: the role of ovarian hormones in common neuroendocrine syndromes in primary care. Prim Care 2002; 29: 43-67.
[5]
Shaver JL, Paulsen VM. Sleep, psychological distress, and somatic symptoms in perimenopausal women. Fam Pract Res J 1993; 13: 373-84.
[6]
Biglia AN, Cagnacci AM, Gambacciani MS, et al. Vasomotor symptoms in menopause: a biomarker of cardiovascular disease risk and other chronic diseases? Climacteric 2017; 1-7.
[7]
Herbison AE. Estrogen regulation of GABA transmission in rat preoptic area. Brain Res Bull 1997; 4: 321-6.
[8]
Hart EC, Charkoudian N, Miller VM. Sex, hormones and neuroeffector mechanisms. Acta Physiol 2011; 203(1): 155-65.
[9]
Freedman RR, Krell W. Reduced thermoregulatory null zone in postmenopausal women with hot flashes. Am J Obstet Gynecol 1999; 181(1): 66-70.
[10]
Deecher DC. Thermoregulation and menopause: Understanding the basic pathophysiology of vasomotor Symptoms. Interface between Gynecology and Psychiatry 2009; 175: 77-87.
[11]
Kronenberg F. Hot flashes: epidemiology and physiology. Ann N Y Acad Sci 1990; 592: 52-86.
[12]
Rossouw JE1, Anderson GL, Prentice RL, et al. Women’s Health Initiative (WHI). Risk and benefits of estrogen plus progesterone in healthy post menopausal women. AMA 2002; 288(3): 321-33.
[13]
Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial. JAMA 2003; 289: 3243-53.
[14]
Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288: 321-33.
[15]
Nelson HD. Menopause. Lancet 2008; 371: 760-70.
[16]
Kober M. Guidance for Industry Estrogen and Estrogen/Progestin drug products to treat vasomotor symptoms and vulvar and vaginal atrophy symptoms—Recommendations for clinical evaluation Food and Drug Administration Center for Drug Evaluation and Research. CDER 2003.
[17]
Freedman RR, Subramanian M. Effects of symptomatic status and the menstrual cycle on hot flash-related thermoregulatory parameters. Menopause 2005; 12: 156-9.
[18]
Avis NE, Crawford SL, Greendale G, et al. Duration of menopausal vasomotor symptoms over menopause transition. AMA Intern Med 2015; 175(4): 531-9.
[19]
Deecher DC. Physiology of thermoregulatory dysfunction and current approaches to the treatment of vasomotor symptoms. Expert Opin Investig Drugs 2005; 14: 435-48.
[20]
Sievert LL, Morrison L, Brown DE, Reza AM. Vasomotor symptoms among Japanese-American and European-American women living in Hilo, Hawaii. Menopause 2007; 14(2): 261-9.
[21]
Huang AJ, Grady D, Jacoby VL, et al. Persistent hot flashes in older postmenopausal women. Arch Intern Med 2008; 168(8): 840-6.
[22]
Alexander C, Cochran CJ, Gallicchio L, et al. Serum leptin levels, hormone levels, and hot flashes in midlife women. Fertil Steril 2010; 94(3): 1037-43.
[23]
Elavsky S, McAuley E. Personality, menopausal symptoms, and physical activity outcomes in middle-aged women. Pers Individ Dif 2009; 46(2): 123-8.
[24]
Opas EE, Gentile MA, Kimmel DB, et al. Estrogenic control of thermoregulation in ERalphaKO and ERbetaKO mice. Maturitas 2006; 53: 210-621.
[25]
Crawshaw L, Grahn D, Wollmuth L, Simpson L. Central nervous regulation of body temperature in vertebrates: Comparative aspects. Pharmacol Ther 1985; 30(1): 19-30.
[26]
Morrison SF, Nakamura K. Central neural pathways for thermoregulation. Front Biosci 2011; 16: 74-104.
[27]
Stephenson LA, Kolka MA. Esophageal temperature threshold for sweating decreases before ovulation in premenopausal women. J Appl Physiol 1999; 86(1): 22-8.
[28]
Hui Z, Xiaoyan M, Mukun Y, et al. Effects of black cohosh and estrogen on the hypothalamic nuclei of ovariectomized rats at different temperatures. J Ethnopharmacol 2012; 142(3): 769-75.
[29]
Kallo I, Liposits Z, Flerko B, Coen CW. Immunocytochemical characterization of afferents to estrogen receptor-containing neurons in the medial preoptic area of the rat. Neuroscience 1992; 50: 299-308.
[30]
Charkoudian N, Stachenfeld N. Sex hormone effects on autonomic mechanisms of thermoregulation in humans. Auton Neurosci 2016; 196: 75-80.
[31]
Low DA, Hubing KA, Del Coso J, Crandall CG. Mechanisms of cutaneous vasodilation during the postmenopausal hot flash. Menopause 2011; 18(4): 359-65.
[32]
Duckles SP, Miller VM. Hormonal modulation of endothelial NO production. Pflugers Arch 2011; 459(6): 841-51.
[33]
Orshal JM, Khalil RA. Gender, sex hormones and vascular tone. Am J Physiol Regul Integr Comp Physiol 2004; 286(2): 233-49.
[34]
Charkoudian N. Skin blood flow in adult human thermoregulation: How it works, when it does not, and why. Mayo Clin Proc 2003; 78: 603-12.
[35]
Hosono T, Chen XM, Miyatsuji A, et al. Effects of estrogen on thermoregulatory tail vasomotion and heat-escape behavior in freely moving female rats. Am J Physiol Regul Integr Comp Physiol 2001; 280(5): R1341-7.
[36]
Abdelmawla AH, Langley RW, Szabadi E, Bradshaw CM. Comparison of the effects of venlafaxine, desipramine, and paroxetine on noradrenaline- and methoxamine-evoked constriction of the dorsal hand vein. Br J Clin Pharmacol 1999; 48: 345-54.
[37]
Le Saux M, Di PT. Changes in 5-HT1A receptor binding and G-protein activation in the rat brain after estrogen treatment: Comparison with tamoxifen and raloxifene. J Psychiatry Neurosci 2005; 30: 110-7.
[38]
Lu NZ, Bethea CL. Ovarian steroid regulation of 5-HT1A receptor binding and G protein activation in female monkeys. Neuropsychopharmacology 2002; 27: 12-4.
[39]
Gundlah C, Pecins-Thompson M, Schutzer WE, Bethea CL. Ovarian steroid effects on serotonin 1A, 2A and 2C receptor mRNA in macaque hypothalamus. Brain Res Mol Brain Res 1999; 63: 325-39.
[40]
Bethea CL, Lu NZ, Gundlah C, Streicher JM. Diverse actions of ovarian steroids in the serotonin neural system. Front Neuroendocrinol 2002; 23: 41-100.
[41]
Gundlah C, Kohama SG, Mirkes SJ, et al. Distribution of estrogen receptor beta (ERbeta) mRNA in hypothalamus, midbrain and temporal lobe of spayed macaque: Continued expression with hormone replacement. Brain Res Mol Brain Res 2000; 76: 191-204.
[42]
Serova LI, Maharjan S, Huang A, et al. Response of tyrosine hydroxylase and GTP cyclohydrolase I gene expression to estrogen in brain catecholaminergic regions varies with mode of administration. Brain Res 2004; 1015: 1-8.
[43]
Gundlah C, Lu NZ, Bethea CL. Ovarian steroid regulation of monoamine oxidase-A and -B mRNAs in the macaque dorsal raphe and hypothalamic nuclei. Psychopharmacology (Berl) 2002; 160: 271-82.
[44]
McEwen B. Estrogen actions throughout the brain. Recent Prog Horm Res 2002; 57: 357-84.
[45]
Joswig M, Hach-Wunderle V, Ziegler R, Nawroth PP. Postmenopausal hormone replacement therapy and the vascular wall: Mechanisms of 17 beta-estradiols effects’ on vascular biology. Exp Clin Endocrinol Diabetes 1999; 107: 477-87.
[46]
Albertazzi P. Noradrenergic and serotonergic modulation to treat vasomotor symptoms. J Br Menopause Soc 2006; 12(1): 7-11.
[47]
Freedman RR. Biochemical, metabolic, and vascular mechanisms in menopausal hot flushes. Fertil Steril 1998; 70: 1-6.
[48]
Cosmi S, Pawlyk AC, Alfinito PD, et al. Simultaneous telemetric monitoring of tail-skin and core body temperature in a rat model of thermoregulatory dysfunction. J Neurosci Methods 2009; 178(2): 270-5.
[49]
Bedell S, Nachtigall M, Naftolin F. The pro and cons of plant estrogens for menopause. J Steroid Biochem Mol Biol 2014; 139: 225-36.
[50]
Oseni T, Patel R, Pyles J, Jordan VC. Selective estrogen receptor modulators and phytoestrogens. Planta Med 2008; 74(13): 1656-65.
[51]
Kostelac D, Rechkemmer G, Briviba K. Phytoestrogens modulate binding response of estrogen receptors alpha and beta to the estrogen response element. J Agric Food Chem 2003; 51: 7632-5.
[52]
Kuiper GG, Lemmen JG, Carlsson B, et al. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology 1998; 139: 4252-63.
[53]
Bowers JL, Tyulmenkov VV, Jernigan SC, Klinge CM. Resveratrol acts as a mixed agonist/antagonist for estrogen receptors alpha and beta. Endocrinology 2000; 141(10): 3657-67.
[54]
Morton MS, Arisaka O, Miyake N, et al. Phytoestrogens concentration in serum Japanese men and women over forty years of age. J Nutr 2002; 132(10): 3168-71.
[55]
Khaodhiar L, Ricciotti HA, Li L, et al. Daidzein-rich isoflavoneaglycones are potentially effective in reducing hot flashes in menopausal women. Menopause 2008; 15(1): 125-32.
[56]
Bu L, Lephart ED. Effects of dietary phytoestrogens on core body temperature during the estrous cycle and pregnancy. Brain Res Bull 2005; 65(3): 219-23.
[57]
Axelson M, Sjovall J, Gustafsson BE, et al. Soya- a dietary source of the non-steroidal estrogen equol in man and animals. J Endocrinol 1984; 102: 49-56.
[58]
Setchell KD. Phytoestrogens: The biochemistry, physiology, and implications for human health of soy isoflavones. Am J Clin Nutr 1998; 68: 1333S-46S.
[59]
Setchell KD, Brown NM, Lydeking-Olsen E. The clinical importance of the metabolite equol-a clue to the effectiveness of soy and its isoflavones. J Nutr 2002; 132(12): 3577-84.
[60]
Howes LG, Howes JB, Knight DC. Isoflavonetheapy for menopausal flushes: A systematic review and meta-analysis. Maturitas 2006; 55: 203-11.
[61]
Messina M, Caan BJ, Abrams DI, et al. It’s time for clinicians to reconsider: their proscription against the use of soy foods by breast cancer patients. Oncology 2013; 430-7.
[62]
Chambliss KL, Shaul PW. Estrogen modulation of endothelial nitric oxide synthase. Endocr Rev 2002; 23: 665-86.
[63]
Si H, Liu D. Genistein, a soy phytoestrogen, upregulates the expression of human endothelial nitric oxide synthase and lowers blood pressure in spontaneously hypertensive rats. J Nutr 2008; 138: 297-304.
[64]
Williamson-Hughes PS, Flickinger BD, Messina MJ, et al. Isoflavone supplements containing predominantly genistein reduce hot flash symptoms: A critical review of published studies. Menopause 2009; 13(5): 831-9.
[65]
Han KK, Soares JM Jr, Haidar MA, et al. Benefits of soy isoflavone therapeutic regimen on menopausal symptoms. Obstet Gynecol 2002; 99: 389-94.
[66]
Crisafulli A, Marini H, Bitto A, et al. Effects of genistein on hot flushes in early postmenopausal women: a randomized, double-blind EPT- and placebo-controlled study. Menopause 2004; 11: 400-4.
[67]
Muthyala RS, Ju YH, Sheng S, et al. Equol, a natural estrogenic metabolite from soy isoflavones: Convenient preparation and resolution of R- and S-equols and their differing binding and biological activity through estrogen receptors alpha and beta. Bioorg Med Chem 2004; 12: 1559-67.
[68]
Akaza H, Miyanaga N, Takashima N, et al. Comparisons of percent equol producers between prostate cancer patients and controls: case controlled studies of isoflavones in Japanese, Korean and American residents. J Clin Oncol 2004; 34: 86-9.
[69]
Fanti P, Sawaya BP, Custer LJ, et al. Serum levels and metabolic clearance of the isoflavones genistein and daidzeinin hemodialysis patients. J Am Soc Nephrol 1999; 10: 864-71.
[70]
Ohkura Y, Obayashi S, Yamada K, et al. S-equol partially restored endothelial nitric oxide production in isoflavone-deficient ovariectomized rats. J Cardiovasc Pharmacol 2015; 65: 500-7.
[71]
Yee S, Burdock GA, Kurata Y, et al. Acute and subchronic toxicity and genotoxicity of SE5-OH, an equol-rich product produced by Lactococcus garvieae. Food Chem Toxicol 2008; 46: 2713-20.
[72]
Yoneda T, Ueno T, Uchiyama S. S-equol and the fermented soy product SE5-OH containing S-equol similarly decrease ovariectomy-induced increase in rat tail skin temperature in an animal model of hot flushes. Menopause 2011; 18(7): 814-20.
[73]
Newton KM, Reed SD, Uchiyama S, et al. A cross-sectional study of equol producer status and self-reported vasomotor symptoms. Menopause 2015; 22(5): 489-95.
[74]
Davinelli S, Scapagnini G, Marzatico V, et al. Influence of equol and resveratrol supplementation on health-related quality of life in menopausal women: A randomized, placebo-controlled study. Maturitas 2017; 77-83.
[75]
Utian W. The role of soy isoflavones in menopausal health: Report of The North American Menopause Society. Translational Science Symposium in Chicago, IL (October 2010). Menopause 2011; 18: 732-53.
[76]
Voloshyna I, Hussaini SM, Reiss AB. Resveratrol in cholesterol metabolism and atherosclerosis. J Med Food 2012; 15(9): 763-73.
[77]
Gehn BD, McAndrews JM, Chien P, et al. Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proc Natl Acad Sci 1997; 94(25): 14138-43.
[78]
Robb EL, Stuart JA. Resveratrol interacts with estrogen receptor-β to inhibit cell replicative growth and enhance stress resistance by upregulating mitochondrial superoxide dismutase. Free Radic Biol Med 2011; 50(7): 821-31.
[79]
Xia N, Daiber A, Habermeier A, et al. Resveratrol reverses endothelial nitric-oxide synthase uncoupling in apolipoprotein e knockout mice. J Pharmacol Exp Ther 2010; 335(1): 149-54.
[80]
Nakata R, Takahashi S, Inoue H. Recent advances in the study on resveratrol. Biol Pharm Bull 2012; 35(3): 273-9.
[81]
Herbalust RU. American herbal pharmacoporia and therapeutic compendium: black cohosh rhizome. Standards of analysis, quality control and therapeutics. Santa Cruz (CA). AHP 2002; 15: 200-15.
[82]
Margaret R. Alternative treatments for the menopause. Best Practice & Research Clinical Obstetrics and Gynaecology 2009; 23: 151-61.
[83]
Seidlova-Wuttke D, Hesse O, Jarry H, et al. Evidence for selective estrogen receptor modulator activity in a black cohosh (Cimicifuga racemosa) extract: comparison with estradiol-17 beta. Eur J Endocrinol 2003; 149(4): 351-62.
[84]
Burdette JE, Liu J, Chen SN, et al. Black cohosh acts as a mixed competitive ligand and partial agonist of the serotonin receptor. J Agric Food Chem 2003; 51(19): 5661-70.
[85]
Lin MT, Tsay HJ, Su WH, Chueh FY. Changes in extracellular serotonin in rat hypothalamus affect thermoregulatory function. Am J Physiol 1998; 274(5 Pt 2): R1260-7.
[86]
Mize AL, Young LJ, Alper RH. Uncoupling of 5-ht1a receptors in the brain by estrogens: Regional variations in antagonism by ici 182,780. Neuropharmacology 2003; 44: 584-91.
[87]
Vitale ML, Chiocchio SR. Serotonin, a neurotransmitter involved in the regulation of luteinizing hormone release. Endocr Rev 1993; 14: 480-93.
[88]
Siddiqui A, Kotecha K, Salicioni AM, et al. Serotonin inhibits luteinizing hormone release via 5-HT1A receptors in the zonaincerta of ovariectomised, anaesthetised rats primed with steroids. Neuroendocrinology 2000; 72: 272-83.
[89]
Loprinzi CL, Sloan JA, Perez EA, et al. Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol 2002; 20: 1578-83.
[90]
Duker EM, Kopanski L, Jarry H, Wuttke W. Effects of extracts from Cimicifugaracemosa on gonadotropin release in menopausal women and ovariectomized rats. Planta Med 1991; 57: 420-4.
[91]
Ma X, Zhang H, Wang K, et al. Effects of an isopropanolic-aqueous black cohosh extract on central body temperature of ovariectomized rats. J Ethnopharmacol 2011; 138(1): 156-61.
[92]
Wuttke W. Efficacy and tolerability of the black cohosh (Actaea racemosa) ethanolic extract BNO 1055 on climacteric complaints: A double-blind, placebo- and conjugated estrogens-controlled study. Maturitas 2006; 55: S83-91.
[93]
Bai W. Efficacy and tolerability of a medicinal product containing an isopropanolic black cohosh extract in Chinese women with menopausal symptoms: A randomized, double blind, parallel-controlled study versus tibolone. Maturitas 2007; 58: 31-41.
[94]
Borrelli F, Ernst E. Black cohosh (Cimicifuga racemosa): a systematic review of adverse events. American Journal of Obstetrics and Gynecology 2008; 11: 455-66.
[95]
Stevens JF, Taylor AW, Deinzer ML. Quantitative analysis of xanthohumol and related prenylflavonoids in hops and beer by liquid chromatography tandem mass spectrometry. J Chromatogr A 1999; 832: 97-107.
[96]
Overk CR, Yao P, Chadwick LR, et al. Comparison of the in vitro estrogenic activities of compounds from hops (Humulus lupulus) and red clover (Trifolium pratense). J Agric Food Chem 2005; 53: 6246-53.
[97]
Roelens F, Heldring N, Dhooge W, et al. Subtle side-chain modifications of the hop phytoestrogen 8-prenylnaringenin result in distinct agonist/antagonist activity profiles for estrogen receptors alpha and beta. J Med Chem 2006; 49: 7357-65.
[98]
Schaefer O, Humpel M, Fritzemeier KH, et al. 8-Prenyl naringenin is a potent ERalpha selective phytoestrogen present in hops and beer. J Steroid Biochem Mol Biol 2003; 84: 359-60.
[99]
Christoffel J, Rimoldi G, Wuttke W. Effects of 8-prenylnaringenin on the hypothalamo-pituitary-uterine axis in rats after 3-month treatment. J Endocrinol 2006; 188(3): 397-405.
[100]
Hümpel M, Isaksson P, Schaefer O, et al. Tissue specificity of 8-prenylnaringenin: protection from ovariectomy induced bone loss with minimal trophic effects on the uterus. J Steroid Biochem Mol Biol 2005; 97(3): 299-305.
[101]
Bowe J, Li XF, Kinsey-Jones J, et al. The hop phytoestrogen, 8-prenylnaringenin, reverses the ovariectomy-induced rise in skin temperature in an animal model of menopausal hot flushes. J Endocrinol 2006; 191(2): 399-405.
[102]
Rad M, Hümpel M, Schaefer O, et al. Pharmacokinetics and systemic endocrine effects of the phyto-oestrogen 8-prenylnaringenin after single oral doses to postmenopausal women. Br J Clin Pharmacol 2006; 62: 288-96.
[103]
Heyerick A, Vervarcke S, Depypere H, et al. A first prospective, randomized, double-blind, placebo-controlled study on the use of a standardized hop extract to alleviate menopausal discomforts. Maturitas 2006; 54: 164-75.


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VOLUME: 20
ISSUE: 2
Year: 2019
Page: [192 - 200]
Pages: 9
DOI: 10.2174/1389450118666170816123740
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