Cited by 779Menopause: Health Impacts and TreatmentsEstrogen and related hormone effectsHormonal and reproductive studies

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Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol

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Hodis, Howard N., Mack, Wendy J., Henderson, Victor W., Shoupe, Donna, Budoff, Matthew J., Hwang-Levine, Juliana, Li, Yanjie, Feng, Mei, Dustin, Laurie, Kono, Naoko, Stanczyk, Frank Z., Selzer, Robert H., Azen, Stanley P.·2016·New England Journal of Medicine

DOI 10.1056/nejmoa1505241PMC PMC4921205

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Abstract

BACKGROUND: Data suggest that estrogen-containing hormone therapy is associated with beneficial effects with regard to cardiovascular disease when the therapy is initiated temporally close to menopause but not when it is initiated later. However, the hypothesis that the cardiovascular effects of postmenopausal hormone therapy vary with the timing of therapy initiation (the hormone-timing hypothesis) has not been tested. METHODS: A total of 643 healthy postmenopausal women were stratified according to time since menopause (<6 years [early postmenopause] or ≥10 years [late postmenopause]) and were randomly assigned to receive either oral 17β-estradiol (1 mg per day, plus progesterone [45 mg] vaginal gel administered sequentially [i.e., once daily for 10 days of each 30-day cycle] for women with a uterus) or placebo (plus sequential placebo vaginal gel for women with a uterus). The primary outcome was the rate of change in carotid-artery intima-media thickness (CIMT), which was measured every 6 months. Secondary outcomes included an assessment of coronary atherosclerosis by cardiac computed tomography (CT), which was performed when participants completed the randomly assigned regimen. RESULTS: After a median of 5 years, the effect of estradiol, with or without progesterone, on CIMT progression differed between the early and late postmenopause strata (P=0.007 for the interaction). Among women who were less than 6 years past menopause at the time of randomization, the mean CIMT increased by 0.0078 mm per year in the placebo group versus 0.0044 mm per year in the estradiol group (P=0.008). Among women who were 10 or more years past menopause at the time of randomization, the rates of CIMT progression in the placebo and estradiol groups were similar (0.0088 and 0.0100 mm per year, respectively; P=0.29). CT measures of coronary-artery calcium, total stenosis, and plaque did not differ significantly between the placebo group and the estradiol group in either postmenopause stratum. CONCLUSIONS: Oral estradiol therapy was associated with less progression of subclinical atherosclerosis (measured as CIMT) than was placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause. Estradiol had no significant effect on cardiac CT measures of atherosclerosis in either postmenopause stratum. (Funded by the National Institute on Aging, National Institutes of Health; ELITE ClinicalTrials.gov number, NCT00114517.).

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Influential
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Background
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The impact of sex on stroke care: From epidemiology to outcome
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Diretriz Brasileira sobre a Saúde Cardiovascular no Climatério e na Menopausa – 2024
de Oliveira, G. M. M., de Almeida, M. C. C., Artucio, C., Espíndola, L. N., Rivera, M. A. M., Filho, A. L. D. S., Marques-Santos, C., Fernandes, C. E., Albuquerque, C. J. D. M., Freire, C. M. V., et al. (2024) · Arquivos Brasileiros de Cardiologia · doi:10.36660/abc.20240478 · Cited by 24
Menopausal Hormone Therapy: Its Role in the Prevention of Cardiovascular Diseases and the Risk of Breast Cancer in Women
Tran, T. T. T., Phung, T. M., Do, A. T. M., Ly, Q. T. M., & Nguyen, T. H. (2025) · Clinical and Experimental Obstetrics & Gynecology · doi:10.31083/ceog26813 · Cited by 4
A review of the common causes of acute coronary syndrome (ACS) in females, and the role of estrogen on its pathologies and risk factors—review article
Namkoong, J., & Minhas, K. (2025) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/cjpp-2023-0425 · Cited by 4
Impact of sex and menopausal hormonal therapy on cardiovascular diseases in people with diabetes or prediabetes
Song, D. K., Sung, Y., Hong, Y. S., Kim, M. H., & Lee, H. (2025) · Scientific Reports · doi:10.1038/s41598-025-01768-8 · Cited by 6
“However, this benefit was not observed in women who began therapy 10 or more years after menopause 32 .”
The Prevention, Diagnosis and Treatment of Ischemic Heart Disease in Women
Brewer, L. C., Adigun, R. O., & Mulvagh, S. L. (2018) · Springer eBooks · doi:10.1007/978-3-319-71135-5_12 · Cited by 4
Hormones endogènes et exogènes
Bejan‐Angoulvant, T., & Arnal, J. (2019) · La Presse Médicale · doi:10.1016/j.lpm.2019.10.008 · Cited by 4
Premature ovarian insufficiency in children: Etiology, clinical management and treatment
Yuan, K., & Wang, C. L. (2020) · Journal of Advanced Pediatrics and Child Health · doi:10.29328/journal.japch.1001017 · Cited by 5
Traitement hormonal de ménopause et risque cardiovasculaire. RPC Les femmes ménopausées du CNGOF et du GEMVi
Plu‐Bureau, G., & Mounier‐Véhier, C. (2021) · Gynécologie Obstétrique Fertilité & Sénologie · doi:10.1016/j.gofs.2021.03.017 · Cited by 6
Le traitement hormonal de la ménopause en pratique. RPC Les femmes ménopausées du CNGOF et du GEMVi
Gosset, A., Robin, G., Letombe, B., Pouillès, J. M., & Trémollières, F. (2021) · Gynécologie Obstétrique Fertilité & Sénologie · doi:10.1016/j.gofs.2021.03.019 · Cited by 4
Prevention of Coronary Artery Disease in Women
Liu, E., Bigeh, A., Ledingham, L., & Mehta, L. S. (2022) · Current Cardiology Reports · doi:10.1007/s11886-022-01721-5 · Cited by 4
17β-estradiol reduces NF-κB expression induced by increased crosstalk between KLF5 and ERα in murine vascular smooth muscle cells
Zhang, M., Zhang, M., Wang, W., Chen, H., Wang, X., Li, X., Li, L., & Tong, F. (2022) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2022.07.054 · Cited by 4
Integrating multiple brain imaging modalities does not boost prediction of subclinical atherosclerosis in midlife adults
Sentis, A. I., Rasero, J., Gianaros, P. J., & Verstynen, T. (2022) · NeuroImage Clinical · doi:10.1016/j.nicl.2022.103134 · Cited by 4
Carotid Atherosclerosis Progression in Postmenopausal Women Receiving a Mixed Phytoestrogen Regimen: Plausible Parallels with Kronos Early Estrogen Replacement Study
Kirichenko, T. V., Myasoedova, V. A., Ravani, A. L., Sobenin, I. A., Orekhova, V. A., Romanenko, E. B., Poggio, P., Wu, W., & Orekhov, A. N. (2020) · Biology · doi:10.3390/biology9030048 · Cited by 4
“ELITE (Early versus Late Intervention Trial of Estradiol) study showed a significant effect of HT on carotid intima media thickness (cIMT) progression in early postmenopausal period (within 6 years after menopause) but not in late postmenopausal period (more than 10 years after menopause) [11].”
Background
Risk of cardiovascular disease after preventive salpingo-oophorectomy
Johansen, N., Tonstad, S., Liavaag, A. H., Selmer, R. M., Tanbo, T. G., & Michelsen, T. M. (2020) · International Journal of Gynecological Cancer · doi:10.1136/ijgc-2019-000856 · Cited by 4
Women’s Heart Programs
Aggarwal, N. R., & Mulvagh, S. L. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-819369-3.00002-2 · Cited by 4
Østrogener i menopausen – på tide å endre anbefalingene?
Eriksen, E. F., Moen, M. H., & Iversen, O. E. (2018) · Tidsskrift for Den norske legeforening · doi:10.4045/tidsskr.17.1059 · Cited by 4
A review of menopausal hormone therapy: recalibrating the balance of benefit and risk
Rajan, S., & Kreatsoulas, C. (2019) · Polskie Archiwum Medycyny Wewnętrznej · doi:10.20452/pamw.4412 · Cited by 4
Measures of association in clinical trials: definition and interpretation.
Carneiro, A. V. (2003) · PubMed · Cited by 4
Genome-wide association study and multi-ancestry meta-analysis identify common variants associated with carotid artery intima-media thicknessPreprint
Meena, D., Huang, J. V., Zare, M., Hasbani, N. R., Boua, P. R., Mustafa, R., van der Laan, S. W., Xu, H., Terry, J. G., Bis, J. C., et al. (2025) · medRxiv · doi:10.1101/2025.04.11.25325582 · Cited by 3
“…to examine the genetic basis of coronary artery disease and insulin resistance in Mexican-Americans using a family-based design. cIMT was measured using standardized procedures and technology developed specifically for longitudinal measurement of atherosclerosis 38 (Patents 2005, 2006, 2011).”
Cardiovascular Health in Women—Across the Lifespan
Chandrasekhar, J., Yao, J. V., Gong, S., Wijayarathne, P. M., Watts, M., & Mukherjee, S. (2025) · Clinical Endocrinology · doi:10.1111/cen.70027 · Cited by 5
Estrogen Alleviates Sevoflurane‐Induced Neurotoxicity by Inhibiting ERα‐Tau Binding
Li, F., Gong, B., Song, Z., Yang, N., Liu, Y., Zhang, J., Li, D., Yang, Y., & Yu, Y. (2025) · Advanced Science · doi:10.1002/advs.202508568 · Cited by 3
Sex Hormone Supplementation and Cardiovascular Disease Risk
Kampka, Z., Balwierz, M., & Wybraniec, M. T. (2026) · Medicina · doi:10.3390/medicina62010134 · Cited by 5
“Furthermore, no such effect was noted in women more than 10 years after menopause [43].”
Russian eligibility criteria for prescription of menopausal hormone therapy to patients with cardiovascular and metabolic diseases. Agreement document of RKO, ROAG, RAE, EAT, AFR, RNMOT, RAGG
Shlyakhto, E. V., Dedov, I. I., Serov, V. N., Sukhikh, G. T., Arutyunov, G. P., Suchkov, I. A., Drapkina, O. M., Tkacheva, O. N., Orlova, Y. A., Baranov, I. A., et al. (2026) · Problems of Endocrinology · doi:10.14341/probl13694 · Cited by 3
“В другом наблюдательном исследовании определено, что МГТ независимо от ее выбора снижает риск развития атеросклероза периферических артерий на 20% [144].”
Menopausal hormone therapy and breast cancer: Balancing risks and benefits
Bollam, R., Karam, J., SHUFELT, C. L., & Faubion, S. S. (2026) · Maturitas · doi:10.1016/j.maturitas.2026.108894 · Cited by 3
Hormone Replacement Therapy for Menopausal Symptoms and the Risk of Cardiometabolic Disease: Current Evidence and Future Directions
Dong, J., Hillman, S., Dixon, S., Shah, A., Venkatakrishnan, R., & Tomlinson, J. (2026) · BJOG An International Journal of Obstetrics & Gynaecology · doi:10.1111/1471-0528.70214 · Cited by 4
Women’s midlife: the front line of Alzheimer prevention
Mosconi, L. (2026) · Journal of Clinical Investigation · doi:10.1172/jci199832 · Cited by 9
Posicionamiento AEEM-SEGO sobre la terapia hormonal de la menopausia
Sánchez‐Borrego, R., Coto, P. L., de Guevara, N. M. L., Delgado, R. C., Barriendos, J. F., Baquedano, L., Jurado, A. R., Manubens, M., García-Ramos, B. O., López, D. M. L., et al. (2019) · Progresos de Obstetricia y Ginecología · doi:10.20960/j.pog.00094 · Cited by 3
Women: Diet, Cardiometabolic Health, and Functional Medicine
Gottfried, S. (2022) · Physical Medicine and Rehabilitation Clinics of North America · doi:10.1016/j.pmr.2022.04.005 · Cited by 3
Factors Affecting the Risk of Cardiovascular Disease in Postmenopausal Women: A Postmenopausal Period-Stratified Analysis
Kim, J., & Choi, H. (2023) · Research in Community and Public Health Nursing · doi:10.12799/rcphn.2022.00297 · Cited by 3
Postmenopausal hormone therapy in prior pre-eclamptic women: a nationwide cohort study in Finland
Venetkoski, M., Ylikorkala, O., Joensuu, J., Gissler, M., Mikkola, T. S., & Savolainen-Peltonen, H. M. (2023) · Climacteric · doi:10.1080/13697137.2023.2228687 · Cited by 3
“…in the primary prevention of coronary heart disease when started before age 60 years, prior to the development of established atherosclerosis [9,23–25]. these results are parallel to our previous data on the reduced risk of cardiovascular disease death in Finnish Ht users [20,26]. thus, the…”
Result
Summary of the 2023 Thai Menopause Society Clinical Practice Guideline on Menopausal Hormone Therapy
Chaikittisilpa, S., Orprayoon, N., Vallibhakara, O., Vallibhakara, S. A.-O., Tanmahasamut, P., Somboonporn, W., Rattanachaiyanont, M., Techatraisak, K., & Jaisamrarn, U. (2024) · Journal of Menopausal Medicine · doi:10.6118/jmm.24006 · Cited by 3
“For cardiovascular risk, a subgroup analysis of the WHI study showed that initiating MHT at 60 years or within 10 years after menopause may be beneficial for atherosclerotic plaque prevention [84].”
Background
Drug repurposing for personalized medicine
Hora, J., Rambhia, N., & Mani, I. (2024) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2024.02.007 · Cited by 3
Hormone replacement therapy after myocardial infarction: British Menopause Society Tool for Clinicians
Stevenson, J. C., Collins, P. D., Hodis, H. N., & in collaboration with the medical advisory council of the British Menopause Society (2024) · Post Reproductive Health · doi:10.1177/20533691241252300 · Cited by 3
“4,5 In some HRT preparations, the vascular bene ﬁ ts of estrogen may be attenuated by the addition of oral androgenic progestogens such as medroxyprogesterone acetate 6 or norgestrel (transdermal or vaginal progestogen administration may not have this adverse effect) but not by the addition of…”
Background
Brazilian Guideline on Menopausal Cardiovascular Health – 2024
de Oliveira, G. M. M., de Almeida, M. C. C., Artucio, C., Espíndola, L. N., Rivera, M. A. M., Filho, A. L. D. S., Marques-Santos, C., Fernandes, C. E., Albuquerque, C. J. D. M., Freire, C. M. V., et al. (2024) · Revista Brasileira Ginecologia e Obstetrícia · doi:10.61622/rbgo/2024rbgo100 · Cited by 7
Menstruation: An Important Indicator for Assessing Stroke Risk and Its Outcomes
Seitz, A., & Raval, A. P. (2024) · Stroke · doi:10.1161/strokeaha.124.048869 · Cited by 5
“73 Overall, findings suggested harm with hormone therapy in older women and inconclusive results in younger women.”
Hormone therapy and venous thromboembolism risk in women of menopausal age: a target trial emulation
Yeh, Y.-C., Yin, C., Chang, C. Y., & Chen, P. (2024) · European Journal of Epidemiology · doi:10.1007/s10654-024-01181-x · Cited by 4
“Notably, the subgroup analysis was based on only two trials with a total of 14 VTE events [25 , 26 ].”
HRT for the Primary Prevention of Coronary Heart Disease
Stevenson, J. C. (2019) · ISGE series · doi:10.1007/978-3-030-11355-1_17 · Cited by 3
Premature ovarian insufficiency – to treat or not to treat?
Загородня, О. С., Венцківська, І. Б., & Kazak, A. (2019) · Reproductive Endocrinology · doi:10.18370/2309-4117.2019.50.12-16 · Cited by 3
Early versus late initiation of GH replacement in adult-onset hypopituitarism
Postma, M. R., Burman, P., & van Beek, A. P. (2020) · Endocrine Connections · doi:10.1530/ec-20-0098 · Cited by 3
Reproductive factors and breast arterial calcification: a systematic review and meta-analysis
Lee, S. C., Pirikahu, S., Phillips, M. R., Bellinge, J. W., Stone, J., Wylie, E. J., Stuckey, B. G. A., & Schultz, C. J. (2021) · Climacteric · doi:10.1080/13697137.2021.1985991 · Cited by 3
A multicenter, randomized, open, controlled trial to evaluate the efficacy of Honglilai Vaginal Cream and Premarin Vaginal Cream for Genitourinary Syndrome of Menopause in different subgroups of Chinese postmenopausal women
Yang, M., Lin, S., Zheng, S., Sun, A., Bian, M., Li, S., Liu, J., Hu, L., Ning, H., Zhong, J., et al. (2022) · Gynecological Endocrinology · doi:10.1080/09513590.2022.2118710 · Cited by 3
“For cardiovascular diseases, an increasing number of studies have confirmed the ‘window of opportunity’ to initiate MHT [22].”
BackgroundInfluential
Cardiovascular impact of near complete estrogen deprivation in premenopausal women with breast cancer: The CROWN study
Thomas, A., O'Connell, N. S., Douglas, E. H., Hatcher, S., Park, C. J., Dent, S. F., Ansley, K. C., Klem, I., Bansal, R., Westbrook, K. E., et al. (2023) · American Heart Journal · doi:10.1016/j.ahj.2023.10.007 · Cited by 4
Red Clover (Trifolium pratense) as a Source of Phytoestrogens in Beer
Habschied, K. J., Babić, M. K., Horvat, D., Arapović, M., Puljić, L., Kajić, N., Krstanović, V., & Mastanjević, K. M. (2024) · Fermentation · doi:10.3390/fermentation10080423 · Cited by 3
The Postmenopausal Women
Roeca, C. M., Al-Safi, Z. A., & Santoro, N. F. (2015) · Cited by 3

Authors: Hodis, H. N., Mack, W. J., Henderson, V. W., Shoupe, D., Budoff, M. J., Hwang-Levine, J., Li, Y., Feng, M., Dustin, L., Kono, N., Stanczyk, F. Z., Selzer, R. H., & Azen, S. P.
Affiliations: General Department of Preventive Medicine (VN)
Stanford University (US)
University of California, Los Angeles (US)
ORCID: Mack, Wendy J.
Henderson, Victor W.
Budoff, Matthew J.
Li, Yanjie
Stanczyk, Frank Z.
Venue: New England Journal of Medicine
Publisher: Massachusetts Medical Society
Published: 2016-03-31
Volume: 374
Issue: 13
Pages: 1221-1231
ISSN: 0028-4793 (ISSN-L)
1533-4406
DOI: 10.1056/nejmoa1505241
PMC: PMC4921205
OpenAlex: W2330799317
Cited by: 779
References: 42
Citations by year: 2026: 95 · 2025: 67 · 2024: 54 · 2023: 72 · 2022: 80 · 2021: 83 · 2020: 65 · 2019: 77 · 2018: 73 · 2017: 74 · 2016: 36
FWCI: 86.77
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: New England Journal of Medicine (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
eScholarship (California Digital Library) (submittedVersion)
Funders: National Institute on Aging (R01-AG024154-S2, R01AG-024154-01-05, R01AG024154, R01AG-024154-06-08)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
Keywords: hormone replacement therapy, estradiol, timing of hormone therapy initiation, carotid intima-media thickness, subclinical atherosclerosis, coronary artery calcium, coronary artery stenosis, coronary plaque, cardiovascular risk, menopause, progesterone, oral estradiol, cardiac CT, cardiovascular disease prevention, postmenopausal women
MeSH terms: Administration, Intravaginal, Administration, Oral, Carotid Arteries, Coronary Artery Disease, Drug Administration Schedule, Estradiol, Female, Humans, Middle Aged, Progesterone, Estrogen Replacement Therapy, Linear Models, Postmenopause, Disease Progression, Atherosclerosis, Carotid Intima-Media Thickness

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Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol

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