The Menopause and Oxidative Stress

  • Lucky H. Sekhon
  • Ashok AgarwalEmail author
Part of the Oxidative Stress in Applied Basic Research and Clinical Practice book series (OXISTRESS)


Reproductive aging resulting in menopause is characterized by the permanent cessation of ovarian follicular activity. The signs and symptoms resulting from estrogen withdrawal can significantly disrupt a woman’s activities of daily living and sense of well being, while predisposing them to osteoporosis and heart disease. Current medical therapies are targeted at symptomatic relief or alleviating the hormonal deficiency itself to prevent its harmful sequelae. The progressive loss of estrogen and its protective effects, combined with deficient endogenous antioxidant, results in oxidative stress—which is implicated in the pathogenesis of vasomotor disturbances, loss of bone mass, and heart disease in menopause. The link between oxidative stress and estrogen deficiency has been demonstrated by numerous studies. Based on this, hormonal replacement therapy, antioxidant supplementation, and lifestyle modification have been investigated for their efficacy and safety in the treatment and prevention of menopause-related symptoms and chronic disease processes.


Reproductive aging  Menopause Antioxidant vitamins  Deficient endogenous antioxidant  Loss of estrogen  Herbal extracts  Vitamin C  Vitamin E  Vitamin A  Phytoestrogens  Curcuma longa  Lycopene  Grape polyphenols  Melatonin 


  1. 1.
    Arredondo FLJ (2007) Menopause. In: Falcone THW (ed) Clinical reproductive medicine and surgery. Mosby Elsevier, Philadelphia, pp 353–370Google Scholar
  2. 2.
    Lee SJ, Lenton EA, Sexton L, Cooke ID (1988) The effect of age on the cyclical patterns of plasma LH, FSH, oestradiol and progesterone in women with regular menstrual cycles. Hum Reprod 3(7):851–855PubMedGoogle Scholar
  3. 3.
    Lenton EA, Sexton L, Lee S, Cooke ID (1988) Progressive changes in LH and FSH and LH: FSH ratio in women throughout reproductive life. Maturitas 10(1):35–43PubMedCrossRefGoogle Scholar
  4. 4.
    Welt CK, McNicholl DJ, Taylor AE, Hall JE (1999) Female reproductive aging is marked by decreased secretion of dimeric inhibin. J Clin Endocrinol Metab 84(1):105–111PubMedCrossRefGoogle Scholar
  5. 5.
    Unfer TC, Conterato GM, da Silva JC, Duarte MM, Emanuelli T (2006) Influence of hormone replacement therapy on blood antioxidant enzymes in menopausal women. Clin Chim Acta 369(1):73–77PubMedCrossRefGoogle Scholar
  6. 6.
    Ayres S, Tang M, Subbiah MT (1996) Estradiol-17beta as an antioxidant: some distinct features when compared with common fat-soluble antioxidants. J Lab Clin Med 128(4):367–375PubMedCrossRefGoogle Scholar
  7. 7.
    Markides CS, Roy D, Liehr JG (1998) Concentration dependence of prooxidant and antioxidant properties of catecholestrogens. Arch Biochem Biophys 360(1):105–112PubMedCrossRefGoogle Scholar
  8. 8.
    Mendelsohn ME, Karas RH (1999) The protective effects of estrogen on the cardiovascular system. N Engl J Med 340(23):1801–1811PubMedCrossRefGoogle Scholar
  9. 9.
    Pansini F, Mollica G, Bergamini CM (2005) Management of the menopausal disturbances and oxidative stress. Curr Pharm Des 11(16):2063–2073PubMedCrossRefGoogle Scholar
  10. 10.
    Liehr JG (1996) Antioxidant and prooxidant properties of estrogens. J Lab Clin Med 128(4):344–345PubMedCrossRefGoogle Scholar
  11. 11.
    Becker BN, Himmelfarb J, Henrich WL, Hakim RM (1997) Reassessing the cardiac risk profile in chronic hemodialysis patients: a hypothesis on the role of oxidant stress and other non-traditional cardiac risk factors. J Am Soc Nephrol 8(3):475–486PubMedGoogle Scholar
  12. 12.
    Witteman JC, Grobbee DE, Kok FJ, Hofman A, Valkenburg HA (1989) Increased risk of artherosclerosis in women after the menopause. BMJ 298:642–644PubMedCrossRefGoogle Scholar
  13. 13.
    Vural P, Akgul C, Canbaz M (2006) Effects of hormone replacement therapy on plasma pro-inflammatory and anti-inflammatory cytokines and some bone turnover markers in postmenopausal women. Pharmacol Res 54(4):298–302PubMedCrossRefGoogle Scholar
  14. 14.
    Bittner V (2009) Menopause, age, and cardiovascular risk: a complex relationship. J Am Coll Cardiol 54(25):2374–2375PubMedCrossRefGoogle Scholar
  15. 15.
    Vural P, Canbaz M, Akgul C (2006) Effects of menopause and postmenopausal tibolone treatment on plasma TNFalpha, IL-4, IL-10, IL-12 cytokine pattern and some bone turnover markers. Pharmacol Res 53(4):367–371PubMedCrossRefGoogle Scholar
  16. 16.
    Signorelli SS, Neri S, Sciacchitano S, Pino LD, Costa MP, Marchese G et al (2006) Behaviour of some indicators of oxidative stress in postmenopausal and fertile women. Maturitas 53(1):77–82PubMedCrossRefGoogle Scholar
  17. 17.
    Naziroglu M, Simsek M, Simsek H, Aydilek N, Ozcan Z, Atilgan R (2004) The effects of hormone replacement therapy combined with vitamins C and E on antioxidants levels and lipid profiles in postmenopausal women with type 2 diabetes. Clin Chim Acta 344(1–2):63–71PubMedCrossRefGoogle Scholar
  18. 18.
    Mueck AO, Seeger H (2004) Estrogens acting as cardiovascular agents: direct vascular actions. Curr Med Chem Cardiovasc Hematol Agents 2(1):35–42PubMedCrossRefGoogle Scholar
  19. 19.
    Moreau KL, DePaulis AR, Gavin KM, Seals DR (2007) Oxidative stress contributes to chronic leg vasoconstriction in estrogen-deficient postmenopausal women. J Appl Physiol 102(3):890–895PubMedCrossRefGoogle Scholar
  20. 20.
    Moreau KL, Gavin KM, Plum AE, Seals DR (2005) Ascorbic acid selectively improves large elastic artery compliance in postmenopausal women. Hypertension 45(6):1107–1112PubMedCrossRefGoogle Scholar
  21. 21.
    Wassmann S, Baumer AT, Strehlow K, van Eickels M, Grohe C, Ahlbory K et al (2001) Endothelial dysfunction and oxidative stress during estrogen deficiency in spontaneously hypertensive rats. Circulation 103(3):435–441PubMedCrossRefGoogle Scholar
  22. 22.
    Arnal JF, Scarabin PY, Tremollieres F, Laurell H, Gourdy P (2007) Estrogens in vascular biology and disease: where do we stand today? Curr Opin Lipidol 18(5):554–560PubMedCrossRefGoogle Scholar
  23. 23.
    Moncada S, Palmer RM, Higgs EA (1991) Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 43(2):109–142PubMedGoogle Scholar
  24. 24.
    Gryglewski RJ (1994) Prostacyclin and nitric oxide. Acta Haematol Pol 25(2 Suppl 2):75–81PubMedGoogle Scholar
  25. 25.
    Cohen RA (1995) The role of nitric oxide and other endothelium-derived vasoactive substances in vascular disease. Prog Cardiovasc Dis 38(2):105–128PubMedCrossRefGoogle Scholar
  26. 26.
    Tinker AC, Wallace AV (2006) Selective inhibitors of inducible nitric oxide synthase: potential agents for the treatment of inflammatory diseases? Curr Top Med Chem 6(2):77–92PubMedCrossRefGoogle Scholar
  27. 27.
    Bednarek-Tupikowska G, Tupikowski K, Bidzinska B, Bohdanowicz-Pawlak A, Antonowicz-Juchniewicz J, Kosowska B et al (2004) Serum lipid peroxides and total antioxidant status in postmenopausal women on hormone replacement therapy. Gynecol Endocrinol 19(2):57–63PubMedCrossRefGoogle Scholar
  28. 28.
    Bednarek-Tupikowska G, Tworowska U, Jedrychowska I, Radomska B, Tupikowski K, Bidzinska-Speichert B et al (2006) Effects of oestradiol and oestroprogestin on erythrocyte antioxidative enzyme system activity in postmenopausal women. Clin Endocrinol (Oxf) 64(4):463–468Google Scholar
  29. 29.
    Leal M, Diaz J, Serrano E, Abellan J, Carbonell LF (2000) Hormone replacement therapy for oxidative stress in postmenopausal women with hot flushes. Obstet Gynecol 95(6 Pt 1):804–809PubMedCrossRefGoogle Scholar
  30. 30.
    Iqbal J, Sun L, Kumar TR, Blair HC, Zaidi M (2006) Follicle-stimulating hormone stimulates TNF production from immune cells to enhance osteoblast and osteoclast formation. Proc Nat Acad Sci USA 103(40):14925–14930PubMedCrossRefGoogle Scholar
  31. 31.
    Weiner CP, Lizasoain I, Baylis SA, Knowles RG, Charles IG, Moncada S (1994) Induction of calcium-dependent nitric oxide synthases by sex hormones. Proc Nat Acad Sci USA 91(11):5212–5216PubMedCrossRefGoogle Scholar
  32. 32.
    Hishikawa K, Nakaki T, Marumo T, Suzuki H, Kato R, Saruta T (1995) Up-regulation of nitric oxide synthase by estradiol in human aortic endothelial cells. FEBS Lett 360(3):291–293PubMedCrossRefGoogle Scholar
  33. 33.
    Sugioka K, Shimosegawa Y, Nakano M (1987) Estrogens as natural antioxidants of membrane phospholipid peroxidation. FEBS Lett 210(1):37–39PubMedCrossRefGoogle Scholar
  34. 34.
    Liao JK, Shin WS, Lee WY, Clark SL (1995) Oxidized low-density lipoprotein decreases the expression of endothelial nitric oxide synthase. J Biol Chem 270(1):319–324PubMedCrossRefGoogle Scholar
  35. 35.
    Wang MY, Liehr JG (1995) Induction by estrogens of lipid peroxidation and lipid peroxide-derived malonaldehyde-DNA adducts in male Syrian hamsters: role of lipid peroxidation in estrogen-induced kidney carcinogenesis. Carcinogenesis 16(8):1941–1945PubMedCrossRefGoogle Scholar
  36. 36.
    Cicinelli E, Ignarro LJ, Lograno M, Galantino P, Balzano G, Schonauer LM (1996) Circulating levels of nitric oxide in fertile women in relation to the menstrual cycle. Fertil Steril 66(6):1036–1038PubMedGoogle Scholar
  37. 37.
    Bednarek-Tupikowska G, Tworowska-Bardzinska U, Tupikowski K (2008) Effects of estrogen and estrogen-progesteron on serum nitric oxide metabolite concentrations in post-menopausal women. J Endocrinol Invest 31(10):877–881PubMedGoogle Scholar
  38. 38.
    Jokela H, Dastidar P, Rontu R, Salomaki A, Teisala K, Lehtimaki T et al (2003) Effects of long-term estrogen replacement therapy versus combined hormone replacement therapy on nitric oxide-dependent vasomotor function. J Clin Endocrinol Metab 88(9):4348–4354PubMedCrossRefGoogle Scholar
  39. 39.
    Rosselli M, Imthurn B, Keller PJ, Jackson EK, Dubey RK (1995) Circulating nitric oxide (nitrite/nitrate) levels in postmenopausal women substituted with 17 beta-estradiol and norethisterone acetate. A two-year follow-up study. Hypertension 25(4 Pt 2):848–853PubMedCrossRefGoogle Scholar
  40. 40.
    Kurtay G, Ozmen B, Erguder I (2006) A comparison of effects of sequential transdermal administration versus oral administration of estradiol plus norethisterone acetate on serum NO levels in postmenopausal women. Maturitas 53(1):32–38PubMedCrossRefGoogle Scholar
  41. 41.
    Imthurn B, Rosselli M, Jaeger AW, Keller PJ, Dubey RK (1997) Differential effects of hormone-replacement therapy on endogenous nitric oxide (nitrite/nitrate) levels in postmenopausal women substituted with 17 beta-estradiol valerate and cyproterone acetate or medroxyprogesterone acetate. J Clin Endocrinol Metab 82(2):388–394PubMedCrossRefGoogle Scholar
  42. 42.
    Archer DF (2007) Drospirenone and estradiol: a new option for the postmenopausal woman. Climacteric 10(Suppl 1):3–10PubMedCrossRefGoogle Scholar
  43. 43.
    Archer DF, Thorneycroft IH, Foegh M, Hanes V, Glant MD, Bitterman P et al (2005) Long-term safety of drospirenone-estradiol for hormone therapy: a randomized, double-blind, multicenter trial. Menopause 12(6):716–727PubMedCrossRefGoogle Scholar
  44. 44.
    Maffei S, Mercuri A, Prontera C, Zucchelli GC, Vassalle C (2006) Vasoactive biomarkers and oxidative stress in healthy recently postmenopausal women treated with hormone replacement therapy. Climacteric 9(6):452–458PubMedCrossRefGoogle Scholar
  45. 45.
    Vassalle C, Cicinelli E, Lello S, Mercuri A, Battaglia D, Maffei S (2011) Effects of menopause and tibolone on different cardiovascular biomarkers in healthy women. Gynecol Endocrinol 27(3):163–169PubMedCrossRefGoogle Scholar
  46. 46.
    Pines A, Sturdee DW, Birkhauser MH, Schneider HP, Gambacciani M, Panay N (2007) IMS updated recommendations on postmenopausal hormone therapy. Climacteric 10(3):181–194PubMedCrossRefGoogle Scholar
  47. 47.
    Mares P, Chevallier T, Micheletti MC, Daures JP, Postruznik D, De Reilhac P (2008) Coronary heart disease and HRT in France: MISSION study prospective phase results. Gynecol Endocrinol 24(12):696–700PubMedCrossRefGoogle Scholar
  48. 48.
    Wassmann S, Laufs U, Stamenkovic D, Linz W, Stasch JP, Ahlbory K et al (2002) Raloxifene improves endothelial dysfunction in hypertension by reduced oxidative stress and enhanced nitric oxide production. Circulation 105(17):2083–2091PubMedCrossRefGoogle Scholar
  49. 49.
    Oviedo PJ, Hermenegildo C, Tarin JJ, Cano A (2005) Therapeutic dosages of raloxifene do not modify myeloperoxidase and F2alpha-isoprostane levels in postmenopausal women. Fertil Steril 84(6):1789–1792PubMedCrossRefGoogle Scholar
  50. 50.
    Miyazaki H, Oh-ishi S, Ookawara T, Kizaki T, Toshinai K, Ha S et al (2001) Strenuous endurance training in humans reduces oxidative stress following exhausting exercise. Eur J Appl Physiol 84(1–2):1–6PubMedCrossRefGoogle Scholar
  51. 51.
    Bjarnason NH, Haarbo J, Byrjalsen I, Kauffman RF, Christiansen C (1997) Raloxifene inhibits aortic accumulation of cholesterol in ovariectomized, cholesterol-fed rabbits. Circulation 96:1964–1969PubMedCrossRefGoogle Scholar
  52. 52.
    Ozbasar D, Toros U, Ozkaya O, Sezik M, Uzun H, Genc H, Kaya H (2010) Raloxifene decreases serum malondialdehyde and nitric oxide levels in postmenopausal women with end-stage renal disease under chronic hemodiálisis therapy. J Obstet Gynaecol Res 36(1):133–137PubMedCrossRefGoogle Scholar
  53. 53.
    McArdle A, Jackson MJ (2000) Exercise, oxidative stress and ageing. J Anat 197(Pt 4):539–541PubMedCrossRefGoogle Scholar
  54. 54.
    Campbell PT, Gross MD, Potter JD, Schmitz KH, Duggan C, McTiernan A, Ulrich CM (2010) Effect of exercise on oxidative stress: a 12-month randomized, controlled trial. Med Sci Sports Exerc 42(8):1448–1453PubMedCrossRefGoogle Scholar
  55. 55.
    Pansini F, Cervellati C, Guariento A, Stacchini MA, Castaldini C, Bernardi A, Pascale G, Bonaccorsi G, Patella A, Bagni B (2008) Oxidative stress, body fat composition, and endocrine status in pre- and postmenopausal women. Menopause 15(1):112–118PubMedCrossRefGoogle Scholar
  56. 56.
    Mittal PC, Kant R (2009) Correlation of increased oxidative stress to body weight in disease-free postmenopausal women. Clin Biochem 42(10–11):1007–1011PubMedCrossRefGoogle Scholar
  57. 57.
    Karolkiewicz J, Michalak E, Pospieszna B, Deskur-Smielecka E, Nowak A, Pilacyznska-Szczesniak L (2009) Response of oxidative stress markers and antioxidant parameters to an 8-week aerobic physical activity program in healthy, postmenopausal women. Arch Gerontol Geriatr 49(1):e67–e71PubMedCrossRefGoogle Scholar
  58. 58.
    Mirzaiinjmabadi K, Anderson D, Barnes M (2006) The relationship between exercise, body mass index and menopausal symptoms in midlife Australian women. Int J Nurs Pract 12(1):28–34PubMedCrossRefGoogle Scholar
  59. 59.
    Villaverde-Gutierrez C, Araujo E, Cruz F, Roa JM, Barbosa W, Ruiz-Villaverde G (2006) Quality of life of rural menopausal women in response to a customized exercise programme. J Adv Nurs 54(1):11–19PubMedCrossRefGoogle Scholar
  60. 60.
    Attipoe S, Park JY, Fenty N, Phares D, Brown M (2008) Oxidative stress levels are reduced in postmenopausal women with exercise training regardless of hormone replacement therapy status. J Women Aging 20(1–2):31–45PubMedCrossRefGoogle Scholar
  61. 61.
    Kushi LH, Folsom AR, Prineas RJ, Mink PJ, Wu Y, Bostick RM (1996) Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. N Engl J Med 334(18):1156–1162PubMedCrossRefGoogle Scholar
  62. 62.
    Subbiah MT (2002) Estrogen replacement therapy and cardioprotection: mechanisms and controversies. Braz J Med Biol Res 35(3):271–276PubMedCrossRefGoogle Scholar
  63. 63.
    McSorley PT, Young IS, Bell PM, Fee JP, McCance DR (2003) Vitamin C improves endothelial function in healthy estrogen-deficient postmenopausal women. Climacteric 6(3):238–247PubMedGoogle Scholar
  64. 64.
    Waters DD, Alderman EL, Hsia J, Howard BV, Cobb FR, Rogers WJ et al (2002) Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial. JAMA 288(19):2432–2440PubMedCrossRefGoogle Scholar
  65. 65.
    Hallund J, Bugel S, Tholstrup T, Ferrari M, Talbot D, Hall WL et al (2006) Soya isoflavone-enriched cereal bars affect markers of endothelial function in postmenopausal women. Br J Nutr 95(6):1120–1126PubMedCrossRefGoogle Scholar
  66. 66.
    Ryan-Borchers TA, Park JS, Chew BP, McGuire MK, Fournier LR, Beerman KA (2006) Soy isoflavones modulate immune function in healthy postmenopausal women. Am J Clin Nutr 83(5):1118–1125PubMedGoogle Scholar
  67. 67.
    Engelman HM, Alekel DL, Hanson LN, Kanthasamy AG, Reddy MB (2005) Blood lipid and oxidative stress responses to soy protein with isoflavones and phytic acid in postmenopausal women. Am J Clin Nutr 81(3):590–596PubMedGoogle Scholar
  68. 68.
    Beavers KM, Serra MC, Beavers DP, Cooke MB, Willoughby DS (2009) Soymilk supplementation does not alter plasma markers of inflammation and oxidative stress in postmenopausal women. Nutr Res 29(9):616–622PubMedCrossRefGoogle Scholar
  69. 69.
    Oh HY, Lim S, Lee JM, Kim DY, Ann ES, Yoon S (2007) A combination of soy isoflavone supplementation and exercise improves lipid profiles and protects antioxidant defense-systems against exercise-induced oxidative stress in ovariectomized rats. BioFactors 29(4):175–185PubMedCrossRefGoogle Scholar
  70. 70.
    Ramirez-Bosca A, Soler A, Carrion MA et al (2000) An hydroalcoholic extract of Curcuma longa lowers the apo B/apo A ratio. Implications for artherogenesis prevention. Mech Ageing Dev 119(1):41–47PubMedCrossRefGoogle Scholar
  71. 71.
    Ramirez Bosca A, Soler A, Carrion-Gutierrez MA, Pamies Mira D, Pardo Zapata J, Diaz-Alperi J et al (2000) An hydroalcoholic extract of Curcuma longa lowers the abnormally high values of human-plasma fibrinogen. Mech Ageing Dev 114(3):207–210PubMedCrossRefGoogle Scholar
  72. 72.
    Kim OY, Yoe HY, Kim HJ, Park JY, Kim JY, Lee SH, Lee JH, Lee KP, Jang Y, Lee JH (2010) Independent inverse relationship between serum lycopene concentration and arterial stiffness. Artherosclerosis 208(2):581–586CrossRefGoogle Scholar
  73. 73.
    Misra R, Mangi S, Joshi S, Mittal S, Gupta SK, Pandey RM (2006) LycoRed as an alternative to hormone replacement therapy in lowering serum lipids and oxidative stress markers: a randomized controlled clinical trial. J Obstet Gynaecol Res 32(3):299–304PubMedCrossRefGoogle Scholar
  74. 74.
    Zern TL, Wood RJ, Greene C, West KL, Liu Y, Aggarwal D et al (2005) Grape polyphenols exert a cardioprotective effect in pre- and postmenopausal women by lowering plasma lipids and reducing oxidative stress. J Nutr 135(8):1911–1917PubMedGoogle Scholar
  75. 75.
    Lee S, Son D, Ryu J, Lee YS, Jung SH, Kang J et al (2004) Anti-oxidant activities of Acanthopanax senticosus stems and their lignan components. Arch Pharm Res. 27(1):106–110PubMedCrossRefGoogle Scholar
  76. 76.
    Lee YJ, Chung HY, Kwak HK, Yoon S (2008) The effects of A. senticosus supplementation on serum lipid profiles, biomarkers of oxidative stress, and lymphocyte DNA damage in postmenopausal women. Biochem Biophys Res Commun 375(1):44–48PubMedCrossRefGoogle Scholar
  77. 77.
    Behr GA, Schnorr CE, Moreira JC (2011) Increased blood oxidative stress in experimental menopause rat model: the effects of vitamin A low-dose supplementation upon antioxidant status in bilateral ovariectomized rats. Fundam Clin Pharmacol [Epub ahead of print]Google Scholar
  78. 78.
    Meyers DG, Maloney PA, Weeks D (1996) Safety of antioxidant vitamins. Arch Intern Med 156:925–935PubMedCrossRefGoogle Scholar
  79. 79.
    Scoglio S, Benedetti S, Canino C, Santagni S, Rattighieri E, Chierchia E, Canestrari F, Genazzani AD (2009) Effect of a 2-month treatment with klamin, a klamath algae extract, on the general well-being, antioxidant profile and oxidative status of postmenopausal women. Gynecol Endocrinol 25(4):235–240PubMedCrossRefGoogle Scholar
  80. 80.
    Baeza I, Fdez-Tresguerres J, Ariznavarreta C, De la Fuente M (2010) Effects of growth hormone, melatonin, oestrogens and phytoestrogens on the oxidized glutathione (GSSG)/reduced glutathione (GSH) ratio and lípid peroxidation in aged ovariectomized rats. Biogertontology 11(6):687–701CrossRefGoogle Scholar
  81. 81.
    Dilek M, Naziroglu M, Baha Oral H, Suat Ovey I, Kucukayaz M, Mungan MT, Kara HY, Sutcu R (2010) Melatonin modulates hippocampus NMDA receptors, blood and brain oxidative stress levels in ovariectomized rats. J Membr Biol 233(1–3):135–142PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Mount Sinai School of Medicine, OB/GYNNew YorkUSA
  2. 2.Lerner College of Medicine, Cleveland Clinic, Center for Reproductive MedicineClevelandUSA

Personalised recommendations