Background The association between hormone treatment (HT) and mortality remains controversial. This study aimed to determine whether the risk of mortality associated with HT use varies depending on the specific characteristics of treatment and genetic variability in terms of the estrogen receptor. Methodology/Principal Findings A prospective, population-based study of 5135 women aged 65 years and older who were recruited from three cities in France and followed over six years. Detailed information related to HT use was obtained and five estrogen receptor polymorphisms were genotyped. The total follow-up was 25,436 person-years and during this time 352 women died. Cancer (36.4%) and cardiovascular disease (19.3%) were the major causes of death. Cox proportional hazards models adjusted for age, education, centre, living situation, comorbidity, depression, physical and mental incapacities, indicated no significant association between HT and mortality, regardless of the type or duration of treatment, or the age at initiation. However, the association between HT and all-cause or cancer-related mortality varied across women, with significant interactions identified with three estrogen receptor polymorphisms (p-values = 0.004 to 0.03) in adjusted analyses. Women carrying the C allele of ESR1 rs2234693 had a decreased risk of all-cause mortality with HT (HR: 0.42, 95% CI: 0.18–0.97), while in stark contrast, those homozygous for the T allele had a significantly increased risk of cancer-related mortality (HR: 3.18, 95% CI: 1.23–8.20). The findings were similar for ESR1 rs9340799 and ESR2 rs1271572. Conclusions/Significance The risk of mortality was not associated with HT duration, type or age at initiation. It was however not equal across all women, with some women appearing genetically more vulnerable to the effects of HT in terms of their estrogen receptor genotype. These findings, if confirmed in another independent study, may help explain the differential susceptibility of women to the beneficial or adverse effects of HT.
References
[1]
Freeman EW, Sherif K (2007) Prevalence of hot flushes and night sweats around the world: a systematic review. Climacteric 10: 197–214.
[2]
Welton AJ, Vickers MR, Kim J, Ford D, Lawton BA, et al. (2008) Health related quality of life after combined hormone replacement therapy: randomised controlled trial. BMJ 337: a1190.
[3]
Farquhar C, Marjoribanks J, Lethaby A, Suckling JA, Lamberts Q (2009) Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev 15: CD004143.
[4]
Canonico M, Oger E, Plu-Bureau G, Conard J, Meyer G, et al. (2007) Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation 115: 840–845.
[5]
Cauley JA, Seeley DG, Browner WS, Ensrud K, Kuller LH, et al. (1997) Estrogen replacement therapy and mortality among older women. The study of osteoporotic fractures. Arch Intern Med 157: 2181–2187.
[6]
Paganini-Hill A, Corrada MM, Kawas CH (2006) Increased longevity in older users of postmenopausal estrogen therapy: the Leisure World Cohort Study. Menopause 13: 12–18.
[7]
Petitti DB, Perlman JA, Sidney S (1987) Noncontraceptive estrogens and mortality: long-term follow-up of women in the Walnut Creek Study. Obstet Gynecol 70: 289–293.
[8]
Rodriguez C, Calle EE, Patel AV, Tatham LM, Jacobs EJ, et al. (2001) Effect of body mass on the association between estrogen replacement therapy and mortality among elderly US women. Am J Epidemiol 153: 145–152.
[9]
Chilvers CE, Knibb RC, Armstrong SJ, Woods KL, Logan RF (2003) Post menopausal hormone replacement therapy and risk of acute myocardial infarction–a case control study of women in the East Midlands, UK. Eur Heart J 24: 2197–2205.
[10]
Grodstein F, Manson JE, Stampfer MJ (2006) Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. J Womens Health (Larchmt) 15: 35–44.
[11]
Sourander L, Rajala T, Raiha I, Makinen J, Erkkola R, et al. (1998) Cardiovascular and cancer morbidity and mortality and sudden cardiac death in postmenopausal women on oestrogen replacement therapy (ERT). Lancet 352: 1965–1969.
[12]
Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, et al. (2004) Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 291: 1701–1712.
[13]
Cherry N, Gilmour K, Hannaford P, Heagerty A, Khan MA, et al. (2002) Oestrogen therapy for prevention of reinfarction in postmenopausal women: a randomised placebo controlled trial. Lancet 360: 2001–2008.
[14]
Hulley S, Grady D, Bush T, Furberg C, Herrington D, et al. (1998) Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 280: 605–613.
[15]
Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, et al. (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 288: 321–333.
[16]
Vickers MR, MacLennan AH, Lawton B, Ford D, Martin J, et al. (2007) Main morbidities recorded in the women's international study of long duration oestrogen after menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women. BMJ 335: 239.
[17]
Rossouw JE, Prentice RL, Manson JE, Wu L, Barad D, et al. (2007) Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 297: 1465–1477.
[18]
L'Hermite M, Simoncini T, Fuller S, Genazzani AR (2008) Could transdermal estradiol+progesterone be a safer postmenopausal HRT? A review. Maturitas 60: 185–201.
[19]
Schumacher M, Guennoun R, Ghoumari A, Massaad C, Robert F, et al. (2007) Novel perspectives for progesterone in hormone replacement therapy, with special reference to the nervous system. Endocr Rev 28: 387–439.
[20]
Prentice RL, Langer R, Stefanick ML, Howard BV, Pettinger M, et al. (2005) Combined postmenopausal hormone therapy and cardiovascular disease: toward resolving the discrepancy between observational studies and the Women's Health Initiative clinical trial. Am J Epidemiol 162: 404–414.
[21]
Gompel A, Rozenberg S, Barlow DH (2008) The EMAS 2008 update on clinical recommendations on postmenopausal hormone replacement therapy. Maturitas 61: 227–232.
[22]
Hodis HN, Mack WJ (2009) Coronary heart disease and hormone replacement therapy after the menopause. Climacteric 12: Suppl 171–75.
[23]
Abbas S, Brauch H, Chang-Claude J, Dunnebier T, Flesch-Janys D, et al. (2010) Polymorphisms in genes of the steroid receptor superfamily modify postmenopausal breast cancer risk associated with menopausal hormone therapy. Int J Cancer 126: 2935–2946.
[24]
Herrington DM, Howard TD, Hawkins GA, Reboussin DM, Xu J, et al. (2002) Estrogen-receptor polymorphisms and effects of estrogen replacement on high-density lipoprotein cholesterol in women with coronary disease. N Engl J Med 346: 967–974.
[25]
Silvestri S, Thomsen AB, Gozzini A, Bagger Y, Christiansen C, et al. (2006) Estrogen receptor alpha and beta polymorphisms: is there an association with bone mineral density, plasma lipids, and response to postmenopausal hormone therapy? Menopause 13: 451–461.
[26]
Almeida S, Hutz MH (2007) Genetic variation of estrogen metabolism and the risks of cardiovascular disease. Curr Opin Investig Drugs 8: 814–820.
[27]
Katzenellenbogen BS (1980) Dynamics of steroid hormone receptor action. Annu Rev Physiol 42: 17–35.
[28]
Herrington DM (2003) Role of estrogen receptor-alpha in pharmacogenetics of estrogen action. Curr Opin Lipidol 14: 145–150.
[29]
The 3C Study Group (2003) Vascular factors and risk of dementia: Design of the three city study and baseline characteristics of the study population. Neuroepidemiology 22: 316–325.
[30]
Alperovitch A, Bertrand M, Jougla E, Vidal JS, Ducimetiere P, et al. (2009) Do we really know the cause of death of the very old? Comparison between official mortality statistics and cohort study classification. Eur J Epidemiol 24: 669–675.
[31]
Ioannidis JP, Stavrou I, Trikalinos TA, Zois C, Brandi ML, et al. (2002) Association of polymorphisms of the estrogen receptor alpha gene with bone mineral density and fracture risk in women: a meta-analysis. J Bone Miner Res 17: 2048–2060.
[32]
Shearman AM, Cupples LA, Demissie S, Peter I, Schmid CH, et al. (2003) Association between estrogen receptor alpha gene variation and cardiovascular disease. JAMA 290: 2263–2270.
[33]
Slattery ML, Sweeney C, Herrick J, Wolff R, Baumgartner K, et al. (2007) ESR1, AR, body size, and breast cancer risk in Hispanic and non-Hispanic white women living in the Southwestern United States. Breast Cancer Res Treat 105: 327–335.
[34]
Alonso P, Gratacos M, Segalas C, Escaramis G, Real E, et al. (2011) Variants in estrogen receptor alpha gene are associated with phenotypical expression of obsessive-compulsive disorder. Psychoneuroendocrinology 36: 473–483.
[35]
Maruyama H, Toji H, Harrington CR, Sasaki K, Izumi Y, et al. (2000) Lack of an association of estrogen receptor alpha gene polymorphisms and transcriptional activity with Alzheimer disease. Arch Neurol 57: 236–240.
[36]
Rexrode KM, Ridker PM, Hegener HH, Buring JE, Manson JE, et al. (2007) Polymorphisms and haplotypes of the estrogen receptor-beta gene (ESR2) and cardiovascular disease in men and women. Clin Chem 53: 1749–1756.
[37]
Radloff L (1977) The CES-D scale: a self-report depression scale for research in the general population. Appl Psychol Measurement 1: 385–401.
[38]
Lawton MP, Brody EM (1969) Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 9: 179–186.
[39]
Folstein MF, Folstein SE, McHugh PR (1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12: 189–198.
[40]
Commenges D, Letenneur L, Joly P, Alioum A, Dartigues JF (1998) Modelling age-specific risk: application to dementia. Stat Med 17: 1973–1988.
[41]
Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, et al. (2005) Estrogen therapy and risk of cognitive decline: results from the Women's Estrogen for Stroke Trial (WEST). Am J Obstet Gynecol 192: 387–393.
[42]
Fournier A, Mesrine S, Boutron-Ruault MC, Clavel-Chapelon F (2009) Estrogen-progestagen menopausal hormone therapy and breast cancer: does delay from menopause onset to treatment initiation influence risks? J Clin Oncol 27: 5138–5143.
[43]
Prentice RL, Manson JE, Langer RD, Anderson GL, Pettinger M, et al. (2009) Benefits and risks of postmenopausal hormone therapy when it is initiated soon after menopause. Am J Epidemiol 170: 12–23.
[44]
Chen GG, Zeng Q, Tse GM (2008) Estrogen and its receptors in cancer. Med Res Rev 28: 954–974.
[45]
Kobayashi N, Fujino T, Shirogane T, Furuta I, Kobamatsu Y, et al. (2002) Estrogen receptor alpha polymorphism as a genetic marker for bone loss, vertebral fractures and susceptibility to estrogen. Maturitas 41: 193–201.
[46]
Domingues-Montanari S, Subirana I, Tomas M, Marrugat J, Senti M (2008) Association between ESR2 Genetic Variants and Risk of Myocardial Infarction. Clin Chem 54: 1183–1189.
[47]
Ryan J, Carriere I, Scali J, Ritchie K, Ancelin ML (2008) Lifetime hormonal factors may predict late-life depression in women. Int Psychogeriatr 20: 1203–1218.
