Oophorectomy, menopause, estrogen treatment, and cognitive aging: clinical evidence for a window of opportunity
Open accessAbstract
The neuroprotective effects of estrogen have been demonstrated consistently in cellular and animal studies but the evidence in women remains conflicted. We explored the window of opportunity hypothesis in relation to cognitive aging and dementia. In particular, we reviewed existing literature, reanalyzed some of our data, and combined results graphically. Current evidence suggests that estrogen may have beneficial, neutral, or detrimental effects on the brain depending on age at the time of treatment, type of menopause (natural versus medically or surgically induced), or stage of menopause. The comparison of women who underwent bilateral oophorectomy with referent women provided evidence for a sizeable neuroprotective effect of estrogen before age 50 years. Several case-control studies and cohort studies also showed neuroprotective effects in women who received estrogen treatment (ET) in the early postmenopausal stage (most commonly at ages 50-60 years). The majority of women in those observational studies had undergone natural menopause and were treated for the relief of menopausal symptoms. However, recent clinical trials by the Women's Health Initiative showed that women who initiated ET alone or in combination with a progestin in the late postmenopausal stage (ages 65-79 years) experienced an increased risk of dementia and cognitive decline regardless of the type of menopause. The current conflicting data can be explained by the window of opportunity hypothesis suggesting that the neuroprotective effects of estrogen depend on age at the time of administration, type of menopause, and stage of menopause. Therefore, women who underwent bilateral oophorectomy before the onset of menopause or women who experienced premature or early natural menopause should be considered for hormonal treatment until approximately age 51 years.
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Estradiol therapy is only partially protective against several domains of cognitive decline.
“Moreover, for those without contraindications who undergo RRSO before age 45, estradiol must be initiated soon after surgery to obtain the optimal protection against cognitive concerns, and studies indicate that estradiol therapy is only partially protective against several domains of cognitive decline [2,4,12,13].”
From Treating new-onset cognitive complaints after risk-reducing salpingo-oophorectomy: A randomized controlled crossover trial of lisdexamfetamine (2024) · cites this paper as [12]
Section 4 (page unavailable) reports that women who received estrogen treatment after premenopausal bilateral oophorectomy through age 50 or longer did not have an increased risk of cognitive impairment or dementia. This supports a protective effect, but the paper does not establish that estradiol is only partially protective across several distinct domains of cognitive decline. (LLM, conf=0.84)
Experimental — accuracy not yet measuredFor those without contraindications who undergo RRSO before age 45, estradiol must be initiated soon after surgery to obtain optimal protection against cognitive concerns.
“Moreover, for those without contraindications who undergo RRSO before age 45, estradiol must be initiated soon after surgery to obtain the optimal protection against cognitive concerns, and studies indicate that estradiol therapy is only partially protective against several domains of cognitive decline [2,4,12,13].”
From Treating new-onset cognitive complaints after risk-reducing salpingo-oophorectomy: A randomized controlled crossover trial of lisdexamfetamine (2024) · cites this paper as [12]
Section 4 reports that women who underwent bilateral oophorectomy before age 49 and received estrogen treatment through age 50 or longer did not have an increased risk of cognitive impairment or dementia. The Conclusions recommend considering hormonal treatment until the average age of natural menopause, but do not establish that estradiol must be started soon after RRSO before age 45 to obtain optimal protection. (LLM, conf=0.88)
Experimental — accuracy not yet measuredClinical studies by the Women's Health Initiative observed that a combination of progestin and estrogen at older ages of 65-79 and estrogen treatment alone exhibited a higher cause of perception decline and dementia.
“However, it was observed by the clinical studies conducted by the Women's Health Initiative (WHI) that a combination of progestin and estrogen at older ages of 65-79 and estrogen treatment alone exhibited a higher cause of perception decline and dementia [80] .”
From Phytotherapy: A promising approach for the treatment of Alzheimer's disease (2022) · cites this paper as [80]
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References 92 · Cited by 283
Research works printed but not linked: 1
- Writing Group for the Women’s Health Initiative, I 2002 Risks and benefits of estrogen plus progestin in healthy postmenopausal women JAMA 288 321 333 12117397
- Authors
- Rocca, W. A., Grossardt, B. R., & Shuster, L. T.
- Affiliations
- Mayo Clinic (US)
- Corresponding author
- Rocca, Walter A.
- Venue
- Brain Research
- Publisher
- Elsevier BV
- Published
- 2011-03
- Volume
- 1379
- Pages
- 188-198
- ISSN
- 0006-8993 (ISSN-L)
- PMC
- PMC3046246
- OpenAlex
- W2030997633
- Cited by
- 283
- References
- 92
- Citations by year
- 2026: 10 · 2025: 14 · 2024: 19 · 2023: 24 · 2022: 14 · 2021: 19 · 2020: 16 · 2019: 19 · 2018: 26 · 2017: 10 · 2016: 18 · 2015: 19 · 2014: 23 · 2013: 23 · 2012: 18
- FWCI
- 2.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NINDS (NS033978)
- NIA (AG034676)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- oophorectomy, menopause, estrogen therapy, cognitive aging, dementia, neuroprotection, natural menopause, surgical menopause, postmenopausal women, cognitive decline, Women's Health Initiative
- MeSH terms
- Age Factors, Aging, Animals, Cognition, Female, Humans, Menopause, Ovariectomy, Time Factors, Estrogen Replacement Therapy
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