ReviewOophorectomy, menopause, estrogen treatment, and cognitive aging: Clinical evidence for a window of opportunity
Research Highlights
► Estrogen effects on the brain vary by age. ► Estrogen is protective for cognitive aging before age 50 years. ► Estrogen may be beneficial for cognitive aging in the early postmenopausal stage. ► Estrogen is deleterious when initiated after age 65 years. ► Women who experience premature or early menopause should be treated.
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.
Section snippets
Classification of women in relation to menopause
There is some confusion in the literature regarding age at the time of estrogen administration and type of menopause. To reduce this confusion, we suggest to first distinguish women who experienced natural menopause from those who underwent medically induced menopause primarily via surgery (Table 1, Fig. 1). Natural menopause is defined as cessation of menses for 12 continuous months or more in the absence of a medical or surgical cause (Utian, 2001), and the median age at natural menopause is
Evidence of neuroprotective effects of estrogen in animal experiments
The mechanisms of action of estrogen on the brain are only briefly summarized here, and the readers are referred to some recent reviews and original reports of cellular or animal studies (Mendelsohn and Karas, 2005, Morrison et al., 2006, Umetani et al., 2007, Gibbs, 2010, Henderson and Brinton, 2010).
Most animal experiments on the neuroprotective effects of estrogen involved the removal of both ovaries and the subsequent administration of estrogen. Most of the studies utilized female rodents;
Evidence of neuroprotective effects of estrogen in women before the age of natural menopause
Important observations on the effects of estrogen in younger women came from studies of women who underwent bilateral oophorectomy before reaching natural menopause. The hormonal changes occurring after bilateral oophorectomy in premenopausal women are different from those occurring during natural menopause or after bilateral oophorectomy in women who already experienced natural menopause (Table 1, Fig. 1). In particular, bilateral oophorectomy before menopause causes an abrupt decline of
Difference between confounding and interaction
There is some disagreement on the interpretation of the findings from the Mayo Clinic cohort study (Hogervorst and Bandelow, 2007, Rocca et al., 2009). Bilateral oophorectomy may be a true risk factor for the subsequent increased risk of cognitive impairment or dementia or the association may be spurious and caused by confounding. For example, there may be confounding by genetic factors (e.g. genetic variants), confounding by non-genetic factors, and confounding by accelerated aging (Fig. 3).
Evidence of neuroprotective effects of estrogen in women in the early postmenopausal stage
Case–control and cohort studies have consistently shown a beneficial effect of estrogen on cognition when ET was started in early postmenopause (most commonly at ages 50–60 years, Fig. 4) (Yaffe et al., 1998, Waring et al., 1999, Hogervorst et al., 2000, LeBlanc et al., 2001, Zandi et al., 2002). However, some studies did not confirm the beneficial effect (Roberts et al., 2006, Petitti et al., 2008). The majority of women in these observational studies had undergone natural menopause and were
Evidence of deleterious effects of estrogen initiated in the late postmenopausal stage
The WHI clinical trials showed an increased risk of dementia or mild cognitive impairment (MCI) among women who initiated treatment with estrogen alone or in combination with progestin at ages 65–79 years (Fig. 4) (Rapp et al., 2003b, Shumaker et al., 2003, Espeland et al., 2004, Shumaker et al., 2004). However, these trials focused on the effects of ET initiated many years after the onset of natural or surgical menopause, and the discrepancy between the WHI results and observational data may be
History of the window of opportunity hypothesis
Table 2 provides a brief history of the window of opportunity hypothesis (or timing hypothesis) from a broad perspective including several outcome diseases and overall mortality. We organized the events and the publications in chronological order and grouped them into four periods: 1) a phase of great optimism and expectation for estrogen treatment that was abruptly terminated by the premature interruption of the WHI trials; 2) a phase of introduction and support of the window of opportunity
Conclusions
A combination of current scientific evidence from animal studies and from both observational studies and clinical trials suggests that estrogen is neuroprotective; however, the neuroprotective effects are dependent on age at the time of initiation, type of menopause, and stage of menopause. The apparent contradiction of results from observational studies versus results from clinical trials may be explained by the window of opportunity hypothesis (or timing hypothesis, Fig. 4).
The results from
Acknowledgments
This research was supported by grants from the NINDS NS033978 and NIA AG034676.
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