Our findings indicate that three months of HT administration with transdermal 17β-estradiol had significant favorable effects on semantic memory (Boston Naming Test) and visual memory (Figural Memory Test) in postmenopausal women with AD. These findings, consistent with our earlier reports and the reports of others [4
], indicate that short-term HT that includes transdermal 17 β-estradiol may augment some cognitive abilities in older postmenopausal women with AD. Given the small sample size and short duration of treatment, the clinical relevance of the present and other similar studies needs to be confirmed in larger clinical trials of HT over extended periods of time.
Presently, drugs designed to treat AD mainly include cholinesterase inhibitors, which work by preventing the synaptic breakdown of acetylcholine in the brain. However, cholinesterase inhibitors attenuate only some AD symptoms and a positive treatment response is seen in a considerably small subset of the affected population. An ideal pharmacologic treatment for AD should be directed towards multiple pathophysiological mechanisms, have the potential to favorably alter disease neurobiology, be associated with minimum toxicity, and result in clinically significant improvements in AD symptoms. Short-term use of HT with estradiol may represent one such alternative treatment to improve cognitive symptoms associated with AD in older postmenopausal women. Unlike cholinergic drugs that primarily enhance cholinergic neurotransmission [59
], estrogen exerts multiple salutary effects on the brain that have the potential to both enhance cognition and favorably alter AD pathology (for a comprehensive review, see [60
]). Among others, some of these salutary effects include enhanced serotonergic, cholinergic and dopaminergic neurotransmission, anti-inflammatory effects, antioxidative efficacy, an ability to favorably alter amyloid-β protein precursor metabolism, multiple neurotrophic effects (e.g., increased synaptogenesis and dendritic spine density), and an ability to enhance glucose metabolism in areas known to be afflicted by AD pathology and involved in memory (e.g., the hippocampus) [61
]. Findings from clinical studies suggest that, in addition to improving cognition, HT enhances cerebral blood flow and glucose utilization [64
The results of the current study not only replicate our previous findings, but also are consistent with other reports demonstrating cognitive improvement associated with increased endogenous estradiol levels in younger women and exogenous levels via HT in healthy older women [68
]. Cognitive assessment was obtained using a comprehensive battery of well-established tests, across multiple cognitive domains pertinent to HT and AD. Together, these findings provide further support for a favorable effect of estradiol for healthy and pathological aging. This conclusion is not without controversy, as others have failed to show a beneficial effect on cognitive function [17
]. The lack of a clinical consensus likely relates to a variety of complex financial, social, psychological, and scientific issues, including several important methodological inconsistencies between studies, such as formulation and route of estrogen administration, hysterectomy status, age at time of exposure, exposure duration, sensitivity of cognitive tests administered, and inter-individual differences in hormone levels achieved following HT.
Our findings provide preliminary evidence to suggest that opposed 17 β-estradiol administration may confer greater benefits for visual memory than unopposed therapy. This finding is surprising, given recent evidence that MPA is neurotoxic and could further worsen cognitive performance [70
]. When the current study was designed, MPA was the most commonly used progesterone to oppose estrogen. Unlike natural progesterone, MPA binds to glucocorticoid receptors with a much higher affinity and may have a greater impact on the hypothalamic–pituitary–adrenal axis, basal forebrain and limbic areas such as the amygdala and hippocampus, areas of the brain that are particularly stress-sensitive [71
]. It is possible that the MPA-induced androgenic and progestogenic actions may result in short-term improvements on visuospatial ability, which may also explain reports that CEE + MPA was associated with a trend toward beneficial effects on figural memory in the Women’s Health Initiative Study of Cognitive Aging (WHISCA) study [72
]. Taken together, these results suggest that the potential negative cognitive effects associated with MPA administration likely take longer than 3 months to manifest.
The primary limitation of the present study relates to attrition. Published risks from the WHI and WHIMS significantly increased attrition of participants in our study relative to attrition rates observed in our previous HT trials and adversely affected the overall recruitment resulting in a smaller than anticipated sample size. In a retrospective analysis of 29,718 new HT users, 54.4% were non-adherent after one year [73
]. Moreover in women over 65 years of age, 62% discontinued HT within 12 months compared to 48% of younger women 50 to 55 years [74
]. To minimize the potential impact on power or bias caused by such limitations, we performed analyses only on data collected up to month 3 for comparison groups collapsed across HT dose (i.e., any HT, versus placebo; opposed versus unopposed). A second important limitation relates to the mandated IRB modification to the randomization scheme in the wake of the WHI and WHIMS reports. That is, hysterectomized women were assigned equally to unopposed HT or placebo and non-hysterectomized women received opposed HT or placebo. As a result, the potential effects of hysterectomy status on cognitive response to HT could not be evaluated. Type of hysterectomy and duration since surgery is now recognized as an important factor and has been associated with an increased risk of cognitive impairment [75
]. Finally, we were not able to address whether variables such as type of hysterectomy, duration and type of HT for prior users, cardiovascular history, and smoking history modulated response to HT as this information was not collected in our study.
In summary, our findings indicate favorable effects of short-term HT that includes estradiol on cognitive function in older postmenopausal women with AD. Future, larger trials to examine the cognitive effects of HT for older women with AD will be essential to further investigate the short-term therapeutic benefit of estradiol HT.