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Premature menopause or early menopause and risk of ischemic stroke
Open accessAbstract
In Brief Objective The general consensus has been that estrogen is invariably a risk factor for ischemic stroke (IS). We reviewed new observational studies that challenge this simple conclusion. Methods This was a review of observational studies of the association of premature or early menopause with stroke or IS published in English from 2006 through 2010. Results Three cohort studies showed an increased risk of all types of stroke in women who underwent bilateral oophorectomy compared with women who conserved their ovaries before age 50 years. The increased risk of stroke was reduced by hormone therapy in one of the studies, suggesting that estrogen deprivation is involved in the association. Four additional observational studies showed an association of all types of stroke or IS with the early onset of menopause or with a shorter life span of ovarian activity. In three of the seven studies, the association was restricted to IS. Age at menopause was more important than type of menopause (natural vs induced). Conclusions The findings from seven recent observational studies challenge the consensus that estrogen is invariably a risk factor for IS and can be reconciled by a unifying timing hypothesis. We hypothesize that estrogen is protective for IS before age 50 years and may become a risk factor for IS after age 50 years or, possibly, after age 60 years. These findings are relevant to women who experienced premature or early menopause or to women considering prophylactic bilateral oophorectomy before the onset of natural menopause. The findings from seven recent observational studies challenge the consensus that estrogen is invariably a risk factor of ischemic stroke. In this study, a unifying theory is proposed, in which estrogen is protective before approximately age 50 years and may become a risk factor of ischemic stroke after age 50 years or, possibly, after age 60 years.
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“Treatment with estrogens until age 45 years or longer may reduce the risk of cardiovascular disease and mortality (47,49,51).”
From Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline (2016) · cites this paper as [49]
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“Treatment with estrogens through age 45 years or longer may reduce the risk of cardiovascular disease and mortality (47,49,51).”
From Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline (2016) · cites this paper as [49]
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Watson, J. M., Rice, P. F. S., Utzinger, U., Barton, J. K., Marion, S. L., Hoyer, P. B., BREWER, M. A., Davis, J. R., & Rodrı́guez, J. J. (2012) · Journal of Biomedical Optics · doi:10.1117/1.jbo.17.7.076002 · Cited by 34
Yang, H. J., Suh, P. S., Kim, S. J., & Lee, S. Y. (2015) · Journal of Preventive Medicine and Public Health · doi:10.3961/jpmph.15.021 · Cited by 30
“Menopause is also associated with dyslipidemia [3], hypertension [4], and ischemic stroke [5].”
BackgroundTime Trends in Unilateral and Bilateral Oophorectomy in a Geographically Defined American Population
Erickson, Z., Rocca, W. A., Smith, C. Y., Rocca, L. G., Stewart, E. A., Laughlin-Tommaso, S. K., & Mielke, M. M. (2022) · Obstetrics and Gynecology · doi:10.1097/aog.0000000000004728 · Cited by 28
Self-citationAortic hemodynamics and white matter hyperintensities in normotensive postmenopausal women
Barnes, J. N., Harvey, R. E., Zuk, S. M., Lundt, E. S., Lesnick, T. G., Gunter, J. L., Senjem, M. L., Shuster, L. T., Miller, V. M., Jack, C. R., et al. (2017) · Journal of Neurology · doi:10.1007/s00415-017-8476-1 · Cited by 27
“During the transition to and after menopause, the risk of developing hypertension, ischemic heart disease, and stroke increases in women [21].”
BackgroundSelf-citationRofaeil, R. R., Sharata, E. E., Attya, M. E., Abo‐Youssef, A. M., Hemeida, R. A. M., & Khalaf, M. M. (2025) · Food and Chemical Toxicology · doi:10.1016/j.fct.2025.115406 · Cited by 24
Sehl, M. E., & Ganz, P. A. (2018) · JNCI Cancer Spectrum · doi:10.1093/jncics/pky035 · Cited by 24
“In addition, the Mayo Clinic Study of Oophorectomy and Aging revealed higher rates of stroke (126) and multimorbidity in women undergoing oophorectomy for a noncancer indication (4), with an increased risk of depression,”
BackgroundAge at natural menopause impacts cerebrovascular reactivity and brain structure
Moir, M. E., Corkery, A. T., Senese, K. A., Miller, K. B., Pearson, A. G., Loggie, N. A., Howery, A. J., Gaynor‐Metzinger, S. H. A., Cody, K. A., Eisenmenger, L. B., et al. (2023) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00228.2022 · Cited by 24
Menstrual Factors and Stroke Incidence in Japanese Postmenopausal Women: The Ohasama Study
Murakami, K., Metoki, H., Satoh, M., Asayama, K., Hosaka, M., Matsuda, A., Inoue, R., Tsubota‐Utsugi, M., Murakami, T., Nomura, K., et al. (2016) · Neuroepidemiology · doi:10.1159/000452220 · Cited by 22
Podfigurna, A., & Męczekalski, B. (2018) · Menopause Review/Przegląd Menopauzalny · doi:10.5114/pm.2018.78551 · Cited by 22
“However, at this time, evidence is insufficient to recommend hormone replacement therapy for the sole purpose of preventing cardiovascular disease or stroke [16].”
BackgroundMenopausal syndrome limited to hot flushes and sweating a representative survey study
Weidner, K., Croy, I., Siepmann, T., Brähler, E., Beutel, M. E., & Bittner, A. (2017) · Journal of Psychosomatic Obstetrics & Gynecology · doi:10.1080/0167482x.2017.1291624 · Cited by 21
Cordova, R., Kiekens, K. C., Burrell, S. L., Drake, W. K., Kmeid, Z., Rice, P. F. S., Rocha, A. D., Diaz, S., Yamada, S., Yozwiak, M. L., et al. (2021) · Journal of Biomedical Optics · doi:10.1117/1.jbo.26.7.076001 · Cited by 20
Pulsed administration for physiological estrogen replacement in mice
Corciulo, C., Scheffler, J. M., Gustafsson, K. L., Drevinge, C., Humeniuk, P., Pons, A., POUTANEN, M. H., Ohlsson, C., Lagerquist, M. K., & Islander, U. (2021) · F1000Research · doi:10.12688/f1000research.54501.1 · Cited by 20
Craniopharyngioma—An update on metabolic and cognitive complications and new therapy
Erfurth, E. M. (2023) · Journal of Internal Medicine · doi:10.1111/joim.13684 · Cited by 21
The Relationship of Fertility, Lifestyle, and Longevity Among Women
Lockhart, P., Martin, P., Johnson, M. A., Shirtcliff, E. A., & Poon, L. W. (2016) · The Journals of Gerontology Series A · doi:10.1093/gerona/glw158 · Cited by 20
“In a study out of Japan, there was a 21% increased risk of stroke in women who had begun menopause under the age of 44 years, regardless of whether it was natural or induced (30).”
BackgroundLi, Y., Zhao, D. H., Wang, M., Sun, J., Liu, J., Qi, Y., Hao, Y., Deng, Q., Liu, J., Liu, J., et al. (2021) · BMC Cardiovascular Disorders · doi:10.1186/s12872-021-01919-5 · Cited by 25
“A previous review of observational studies reported that premature or early menopause was associated with an increased risk of ischemic stroke and that hormonal therapy before age 50 years may partly offset the increased risk; the authors suggested that estrogen may be a protective factor for ischemic stroke before ag…”
BackgroundTerra, L., Hooning, M. J., Heemskerk‐Gerritsen, B. A. M., van Beurden, M., van Lennep, J. E. R., van Doorn, H. C., de Hullu, J. A., Mom, C. H., van Dorst, E. B. L., Mourits, M. J. E., et al. (2020) · JMIR Research Protocols · doi:10.2196/24414 · Cited by 21
Genetic Polymorphisms in the ESR1 Gene and Cerebral Infarction Risk: A Meta-Analysis
Gao, H., Gao, L., & Wen, J. (2014) · DNA and Cell Biology · doi:10.1089/dna.2013.2270 · Cited by 18
“Indeed, estrogen is protective for cerebral infarction in women younger than 50 years, where women did not experience premature or early menopause or considering no prophylactic bilateral oophorectomy before the onset of natural menopause (Lisabeth et al. , 2009; Rocca et al. , 2012).”
Kim, J., Choe, J.-P., Park, J.-H., Yoo, E., & Lee, J. M. (2021) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph18147256 · Cited by 18
“In particular, early menopause has been announced to be related to all-cause mortality [11,12] and has a lot of negative effects on cardiovascular disease [13], neurological diseases, and osteoporosis [14].”
BackgroundPrimary Prevention of Cardiovascular Disease with HRT
Maclaran, K., & Stevenson, J. C. (2011) · Women s Health · doi:10.2217/whe.11.87 · Cited by 18
“Furthermore, menopause is associated with a number of adverse changes to classical cardiovascular risk factors, and women experiencing premature loss of ovarian function have an increased risk of ischemic heart disease [3,4] and possibly stroke [5].”
BackgroundFrom head to toe: Sex and gender differences in the treatment of ischemic cerebral disease
Falsetti, L., Viticchi, G., Buratti, L., Balucani, C., Marra, A. M., & Silvestrini, M. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.05.006 · Cited by 19
“An early menopause has also been associated to an increased rate of cardiovascular events and vascular death[9,10] and the risk increases further in the presence of hormone therapy [11].”
BackgroundDamiati, S. (2018) · Journal of Medical Biochemistry · doi:10.2478/jomb-2018-0025 · Cited by 16
“By assuming that 50 years of age is approximately the age of onset of menopause in women (30, 31), it has been shown that ADMA levels increased with the onset of menopause, which may be attributed to changes in sex hormones concentrations as an important factor in the menstrual cycle (32).”
BackgroundRuberti, O. M., & Rodrigues, B. L. (2019) · Current Cardiology Reviews · doi:10.2174/1573403x15666190729153026 · Cited by 17
“For example, the Mayo Clinic Cohort Study of Aging Oophorectomy revealed that early surgical induction of menopause increased the risk of ischemic stroke, Parkinson's disease, doubled the risk of dementia, increased risk of depression and anxiety as well as the risk of mortality due to neurological disorders increased…”
BackgroundRYMER, J. M., Brian, K., & Regan, L. (2019) · BMJ · doi:10.1136/bmj.l5928 · Cited by 17
Miller, V. M., & Manson, J. E. (2013) · Current Cardiovascular Risk Reports · doi:10.1007/s12170-013-0305-1 · Cited by 14
“Indeed, the “window of opportunity” for stroke prevention may not be comparable to that for cardiac events [19].”
Self-citationMossa, F., Latham, K. E., Ireland, J. J., & Veiga‐Lopez, A. (2019) · Molecular Reproduction and Development · doi:10.1002/mrd.23239 · Cited by 13
“Consistent with these associations, CVD is linked to a diminished ovarian reserve (Verit et al., 2014), the single greatest contributor to infertility in women (SART, 2013), and to menopause (Kannel, Hjortland, McNamara, & Gordon, 1976; Rocca et al., 2012).”
BackgroundReproductive hormones in relation to white matter hyperintensity volumes among midlife women
Thurston, R. C., Chang, Y.-F., Wu, M., Harrison, E. M., Aizenstein, H. J., Derby, C. A., Barinas‐Mitchell, E., & Maki, P. M. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.14093 · Cited by 12
“7,8 Research links an earlier natural menopause or younger/premenopausal oophorectomy with elevated stroke risk 9–11 and a longer reproductive lifespan with lowerstrokerisk.”
BackgroundCardiovascular Disease After Hysterectomy in the Nurses' Health Study and Nurses' Health Study II
Thao, V., Borah, B. J., Stewart, E. A., Farland, L. V., Laughlin-Tommaso, S. K., Khan, Z., Coutinho, T., & Rassier, S. L. C. (2025) · Obstetrics and Gynecology · doi:10.1097/aog.0000000000005902 · Cited by 13
Hsieh, Y., Jeng, J., Lin, H., Hu, C., Yu, C.-C., Lien, L., Peng, G., Chen, C.-I., Tang, S., Chi, N., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0047773 · Cited by 12
“Previous population-based epidemiological studies reported stroke incidence rate to be lower in women during midlife than that in either older aged women or men [1,2].”
BackgroundResultSexuality and Intimacy Among Older Women Living with HIV: a Systematic Review
Stanton, A. M., Goodman, G. R., Looby, S. E. D., Robbins, G. K., & Psaros, C. (2019) · Current Sexual Health Reports · doi:10.1007/s11930-019-00227-6 · Cited by 12
The association between chronic diseases and the age at natural menopause: a systematic review
Tehrani, F. R., & Amiri, M. (2021) · Women & Health · doi:10.1080/03630242.2021.1992067 · Cited by 12
“Earlier studies have documented that early age at natural menopause (ANM) can be related to numerous health outcomes, such as increased risks of cardiovascular disease, neurological disorders, psycho-emotional disturbances, and osteoporosis (Cancer 2012; Fu et al. 2016; Georgakis et al. 2016; McPherson et al. 1996; Ra…”
BackgroundFactors associated with early menopause among women in Nigeria
Agaba, P. A., Meloni, S., Sule, H. M., Ocheke, A. N., Agaba, E. I., Idoko, J. A., & Kanki, P. J. (2017) · Journal of Virus Eradication · doi:10.1016/s2055-6640(20)30333-2 · Cited by 14
Mittal, M., Savvas, M., Narvekar, N. N., Panay, N., & Hamoda, H. (2014) · Post Reproductive Health · doi:10.1177/2053369114540883 · Cited by 11
“A review of seven observational studies showed an increased risk of all stroke including ischaemic stroke in women who underwent an early menopause before the age of 50 years, with the risk reduced in women who received hormone therapy.(19) All routes of estrogen administration can effectively treat menopausal symptom…”
BackgroundBarboza, L. N., Prando, T. B. L., Dalsenter, P. R., Gasparotto, F. M., Gasparotto, F., Jacomassi, E., Araújo, V. D. O., Lourenço, E. L. B., & Gasparotto, A. (2014) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2014/958291 · Cited by 10
“Usually it occurs between 45 and 54 years of age and can present a number of comorbidities (mainly bone loss and cardiovascular disease) influenced by lifestyle, age, and genetic characteristics [1].”
BackgroundWyse, Â. T. D. S., Siebert, C., Bobermin, L. D., dos Santos, T. M., & Quincozes‐Santos, A. (2019) · Neurotoxicity Research · doi:10.1007/s12640-019-00128-5 · Cited by 9
Metadata
- Authors
- Rocca, W. A., Grossardt, B. R., Miller, V. M., Shuster, L. T., & Brown, R. D.
- Affiliations
- Mayo Clinic (US)
- Department of Medical Sciences (BY)
- Corresponding author
- Rocca, Walter A.
- Venue
- Menopause
- Published
- 2012-03
- Volume
- 19
- Issue
- 3
- Pages
- 272-277
- ISSN
- 1072-3714 (ISSN-L)
- PMC
- PMC3258468
- OpenAlex
- W2016373832
- Semantic Scholar
- 5046b0fb75f713a0ec75734faf7bbf9842dc66db
- Cited by
- 188
- References
- 53
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 9 · 2023: 12 · 2022: 5 · 2021: 10 · 2020: 11 · 2019: 31 · 2018: 11 · 2017: 14 · 2016: 15 · 2015: 11 · 2014: 17 · 2013: 13 · 2012: 12
- FWCI
- 1.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Menopause The Journal of The North American Menopause Society (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG034676, AG-034676)
- National Institute of Neurological Disorders and Stroke (NS 033978, R01NS033978)
- 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 › Clinical Neurology › Acute Ischemic Stroke Management
- Keywords
- premature menopause, early menopause, ischemic stroke, estrogen, estrogen deprivation, bilateral oophorectomy, hormone therapy, timing hypothesis, ovarian function
- MeSH terms
- Female, Humans, Menopause, Premature, Ovariectomy, Risk, Cohort Studies, Hormone Replacement Therapy, Stroke
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