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.

Introduction

Whether estrogen has beneficial neuroprotective effects on the brain of women remains controversial (Siegfried, 2007, Rocca et al., 2009, Henderson and Brinton, 2010, Hogervorst and Bandelow, 2010, Nejat and Chervenak, 2010, Rocca et al., 2010). The results of the Women's Health Initiative (WHI) clinical trials have created a situation of uncertainty with experimental studies showing detrimental effects of estrogen on the heart and brain, and observational studies showing beneficial effects (Writing Group for the Women's Health Initiative, I., 2002, Shumaker et al., 2003, Anderson et al., 2004, Shumaker et al., 2004, Manson et al., 2006).

The reaction of practicing clinicians and scientists to the results of the WHI trials has been mixed. Some have accepted the findings as final evidence and have discontinued the use of estrogen treatment in their practice or have opposed the funding of additional research on estrogen as a neuroprotectant. Other practicing clinicians and scientists have criticized the WHI findings and interpretations arguing that the effect of estrogen on the heart, brain, or other organs and tissues may vary by age at the time of administration, type of menopause, and stage of menopause. In addition, they suggested that the WHI data should be interpreted in light of the type (e.g. conjugated equine estrogens versus estradiol), regimen (e.g. oral versus transdermal), dosage (e.g. higher dose versus lower dose), and schedule of administration (e.g. continuous versus cyclic) of hormone therapy.

The idea that the beneficial or detrimental effects of estrogen treatment (ET) vary across women by age and stage of menopause has been called the “window of opportunity hypothesis” by some authors and the “timing hypothesis” by others (Manson et al., 2006, Mendelsohn and Karas, 2007, Siegfried, 2007, Brinton, 2008, Rocca et al., 2008, Rocca et al., 2009, Henderson and Brinton, 2010, Hogervorst and Bandelow, 2010, Rocca et al., 2010). We consider these two descriptions conceptually equivalent. From an epidemiologic perspective, the window of opportunity hypothesis can be described as an effect modification or an interaction (Szklo and Nieto, 2007, Porta and International Epidemiological Association, 2008).

In this review, we combine findings from both observational studies (case–control and cohort studies) and experimental studies (controlled clinical trials) to explore the window of opportunity hypothesis in relation to cognitive aging and dementia. However, this article does not review in depth the large body of experimental work on the effects of estrogen at the cellular level and in animal models.