Oophorectomy, menopause, estrogen, and cognitive aging: the timing hypothesis

Abstract

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.

Conclusion: The neuroprotective effects of estrogen depend on age, type of menopause, and stage of menopause (timing hypothesis).

Fig. 1

Four possible clinical situations relevant to the timing hypothesis of estrogen neuroprotection. a Women who underwent bilateral oophorectomy early in life experienced premature estrogen deficiency and increased risk of cognitive impairment or dementia. b Women who underwent bilateral oophorectomy and were treated with estrogen through age 50 years or later had the same risk of cognitive impairment or dementia as the general population. c Women who underwent natural menopause and were treated with estrogen in the early postmenopausal phase (most commonly at ages 50–60 years) had a reduced risk of cognitive impairment or dementia. d Women who underwent natural menopause or surgical menopause (hysterectomy with or without bilateral oophorectomy) and initiated estrogen treatment (ET) at ages 65–79 years had an increased risk of cognitive impairment and dementia. The apparent paradox of these four clinical situations is resolved by postulating an interaction between timing and ET (timing hypothesis).

Fig. 2

The effect of estrogen on the risk of cognitive decline or dementia varies with age, type of menopause, and stage of menopause (relative risk estimated by an odds ratio or a hazard ratio and 95% confidence intervals; logarithmic scale). a Women with ovarian conservation before menopause (most commonly before age 50 years) have a reduced long-term risk of cognitive decline or dementia compared to women who underwent bilateral oophorectomy. b Treatment with estrogen in the early postmenopausal phase (most commonly at ages 50–60 years) is associated with a reduced long-term risk of cognitive decline or dementia. c Initiation of ET in the late postmenopausal phase (ages 65–79 years) is associated with an increased risk of cognitive impairment or dementia. CEE = Conjugated equine estrogen; HR = hazard ratio; MPA = medroxyprogesterone acetate; OR = odds ratio.