Oophorectomy, menopause, estrogen, and cognitive aging: the timing hypothesis.
BACKGROUND
The concept of neuroprotective effects of estrogen in women remains controversial.


OBJECTIVE
To explore the timing hypothesis in relation to cognitive aging and dementia.


METHODS
We reviewed existing literature, conducted some reanalyses, and combined results graphically.


RESULTS
Current evidence suggests that estrogen may have either protective effects or harmful effects on the brain depending on age, type of menopause (natural versus surgical), or stage of menopause. The comparison of women with ovarian conservation versus women who underwent bilateral oophorectomy provided evidence for a sizeable neuroprotective effect of estrogen in women in the premenopausal years (most commonly before age 50 years). Several case-control studies and cohort studies also showed a neuroprotective effect in women who received estrogen treatment in the early postmenopausal phase (most commonly at ages 50-60 years). However, recent clinical trials showed that women who initiated estrogen treatment in the late postmenopausal phase (ages 65-79 years) experienced an increased risk of dementia and cognitive decline.


CONCLUSIONS
The neuroprotective effects of estrogen depend on age, type of menopause, and stage of menopause (timing hypothesis).
Rocca
Walter A
WA
Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. rocca@mayo.edu
Grossardt
Brandon R
BR
Shuster
Lynne T
LT
D000375:Aging / Q000187:drug effects* / Q000473:pathology / Q000523:psychology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology; D004967:Estrogens / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008593:Menopause / Q000187:drug effects* / Q000523:psychology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010052:Ovariectomy / Q000009:adverse effects*; D016387:Women's Health
D004967:Estrogens; D018696:Neuroprotective Agents