Oophorectomy, menopause, estrogen treatment, and cognitive aging: clinical evidence for a window of opportunity

Abstract

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.

Fig. 1

Graphic representation of ovarian function and menstrual activity in relation to menopause. Fig. 1A – For women who experience natural menopause, ovarian function, and menstrual activity decline gradually in a synchronized fashion (gradual shading of bars). Fig. 1B – Women who undergo hysterectomy with one or both ovaries conserved experience an abrupt cessation of menses at the time of the surgery (solid bar) but a gradual decline in ovarian function (gradual shading of bar). These women experience a lag time between hysterectomy and cessation of ovarian function that may last 10 or more years and may be difficult to measure correctly in the clinical setting. *In this figure, we are assuming that the removal of the uterus or of one ovary have no consequences on the remaining ovarian function (one or two conserved ovaries). In fact, removal of the uterus or of one ovary may lead to an earlier cessation of ovarian function by approximately 4 years (Farquhar et al., 2005; Rocca et al., 2007; Phung et al., 2010). Fig. 1C – Women who undergo bilateral oophorectomy with or without hysterectomy experience an abrupt cessation of both ovarian function and menstrual activity at the time of surgery (solid bars).

Fig. 2

Risk of cognitive impairment or dementia by age at bilateral oophorectomy and by age at estrogen deficiency in the Mayo Clinic Cohort Study of Oophorectomy and Aging (relative risk estimated by a hazard ratio and 95% confidence intervals, logarithmic scale). The hazard ratio increased linearly with decreasing age at oophorectomy (p for trend = 0.02) and with decreasing age at estrogen deficiency (p for trend = 0.02). ^aAge at estrogen deficiency = age at oophorectomy plus total duration of subsequent estrogen treatment. ^bBilateral oophorectomy in women younger than age 49 years.

Fig. 3

Three possible explanations for the association of bilateral oophorectomy with increased risk of cognitive impairment or dementia. Fig. 3A – Possible confounding by genetic variants and possible confounding by non-genetic factors (red arrow). Fig. 3B – Confounding by accelerated aging (red arrow). Fig. 3C – Chain of causality in which genetic variants or non-genetic factors are effect modifiers (or interaction variables; blue arrow) rather than confounders.

Fig. 4

The effect of estrogen on the risk of cognitive decline or dementia varies with age at the time of treatment, type of menopause, and stage of menopause (relative risk estimated by an odds ratio or a hazard ratio and 95% confidence intervals, logarithmic scale). Women with ovarian conservation have a reduced long-term risk of cognitive decline or dementia compared to women who underwent bilateral oophorectomy before menopause (most commonly before age 50 years). Treatment with estrogen in the early postmenopausal stage (most commonly at ages 50–60 years) is associated with a reduced long-term risk of cognitive decline or dementia. However, initiation of estrogen treatment in the late postmenopausal stage (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; WHI = Women’s Health Initiative Study (Yaffe et al., 1998; Waring et al., 1999; Hogervorst et al., 2000; LeBlanc et al., 2001; Zandi et al., 2002; Shumaker et al., 2003; Shumaker et al., 2004; Rocca et al., 2007) [Modified from W.A. Rocca et al., Neurodegenerative Dis 2010;7:163–166]. ^aThese three publications were meta-analyses.