Women's Health Initiative Study of Cognitive Aging - Extension Study

妇女健康倡议（WHI）激素治疗（HT）的随机、安慰剂对照临床试验旨在检验单独使用结合马雌激素（CEE）或与醋酸甲羟孕酮（CEE+MPA）联合使用可保护绝经后妇女免受心脏病发展的假设。 WHI记忆研究（WHIMS）是WHI试验的一项辅助研究，该研究包括在子宫切除或子宫切除后的女性中分别进行的0.625 mg/d CEE治疗（联合或不联合2.5 mg/d MPA）的平行安慰剂对照随机临床试验。 WHIMS研究了CEE单独和CEE+MPA对65岁及以上女性可能痴呆和轻度认知障碍风险的影响，以及这些治疗对整体认知功能的影响。WHIMS对参与HT试验的40个WHI临床试验点中的38个的7479名妇女进行了随访。 WHI认知老化研究（WHISCA）是WHIMS的辅助研究，旨在研究HT对非痴呆女性特定领域认知功能的影响。 基于我们小组和其他人的观察性研究以及手术绝经后年轻女性的随机试验，我们假设绝经后女性的激素治疗（HT）将有益于记忆和其他认知功能。WHISCA在14个WHIMS研究中心招募了2305名女性，分布在两个平行试验中。WHISCA在WHI随机化后平均3年开始，主要结局是HT对认知变化率的影响，根据随机化后的时间进行调整。 通过主要的WHI研究和WHIMS，中风，可能的痴呆和轻度认知障碍（MCI）的事件诊断可供WHISCA参与者使用。 WHIMS CEE+MPA试验因主要WHI试验中的不良风险-获益特征而提前终止（2002年7月）。 随后，WHI CEE单独试验也提前终止（2004年2月）。 WHIMS试验的结果表明，单独使用CEE或CEE+MPA会增加老年痴呆症的风险，并对65岁或以上女性的整体认知产生不利影响。 HT也被证明会增加65岁及以上女性临床中风的风险。 WHISCA研究结果的初步报告（Resnick等人，临床内分泌学和代谢杂志，2006年）包括1416名无可能痴呆的妇女，她们被随机分配到CEE+MPA或安慰剂组，并在主要WHI试验提前终止前随访了1.35年，因为HT治疗的妇女患乳腺癌的风险增加和不利的风险-获益特征。 对特定认知功能和情感的年变化率进行分析，调整自随机化以来的时间，显示与安慰剂相比，CEE + MPA对语言记忆有负面影响（p < 0.01），随着时间的推移，对图形记忆有积极影响的趋势（p = 0.012），对其他认知领域没有影响。 此外，这些效果只有在长期治疗后才明显。CEE + MPA没有显着影响积极情绪，消极情绪，或抑郁症状。这些发现表明，HT可能在不同的认知领域有不同的影响。 在子宫切除术后随机接受CEE或安慰剂的妇女中进行的CEE单独试验的结果目前正在临床内分泌学和代谢杂志上发表。 最近，通过相关的WHIMS-MRI研究，我们与我们的WHIMS合作者报告说，HT与1400多名女性的海马和额叶区域脑体积减少有关，这些女性在试验后进行了脑部MRI扫描。 HT对海马体积的不利影响在WHI基线时整体认知功能评分最低的女性中最为明显。

The Womens Health Initiative (WHI) randomized, placebo-controlled clinical trials of hormone therapy (HT) were designed to test the hypothesis that conjugated equine estrogens alone (CEE-Alone) or in combination with medroxyprogesterone acetate (CEE+MPA) protected postmenopausal women against the development of heart disease. The WHI Memory Study (WHIMS)was an ancillary study to the WHI trials, which consisted of parallel placebo-controlled randomized clinical trials of 0.625 mg/day CEE therapy with and without 2.5 mg/day MPA in women with a uterus or post-hysterectomy, respectively. WHIMS investigated the effect of CEE-Alone and CEE+MPA on risk for probable dementia and mild cognitive impairment in women age 65 and older, as well as the effects of these treatments on global cognitive function. WHIMS followed 7479 women at 38 of the 40 WHI clinical sites participating in the HT trial. The WHI Study of Cognitive Aging (WHISCA), an ancillary study to WHIMS, was developed to investigate the effects of HT on domain-specific cognitive function in women without dementia. Based on observational studies from our group and others and randomized trials of younger women following surgical menopause, we hypothesized that hormone therapy (HT) in postmenopausal women would benefit memory and possibly other cognitive functions. WHISCA enrolled 2305 women at 14 of the WHIMS sites, distributed across the two parallel trials. WHISCA was initiated on average 3 years after WHI randomization and the primary outcome was the effect of HT on rates of cognitive change, adjusted for time since randomization. Through the main WHI study and WHIMS, incident diagnoses of stroke, probable dementia, and mild cognitive impairment (MCI) are available for WHISCA participants. The WHIMS CEE+MPA trial terminated earlier than planned (July, 2002) due to an adverse risk-to-benefit profile in the main WHI trial. Subsequently, the WHI CEE-Alone Trial also was terminated early (February, 2004). Results from the WHIMS trials showed that CEE-Alone or CEE+MPA increase the risk of dementia and have adverse effects on global cognition in women aged 65 years or older. HT also has been shown to increase the risk of clinical stroke in women 65 years and older. The initial report of WHISCA findings (Resnick et al., Journal of Clinical Endocrinology and Metabolism, 2006) included 1416 women free of probable dementia who were randomized to CEE+MPA or placebo and followed for a 1.35 yr prior to the early termination of the main WHI trial due to an increase in risk for breast cancer in HT-treated women and an adverse risk-benefit profile. Analysis of annual rates of change in specific cognitive functions and affect, adjusted for time since randomization, showed that CEE + MPA had a negative impact on verbal memory (p < 0.01) and a trend to a positive impact on figural memory (p = 0.012) over time compared with placebo with no effect on other cognitive domains. In addition, these effects were evident only after long-term therapy. CEE + MPA did not significantly influence positive affect, negative affect, or depressive symptoms. These findings suggest that HT may have different effects across different cognitive domains. The results of the CEE-Alone Trial in women with prior hysterectomy who were randomized to CEE or placebo are currently in press in Journal of Clinical Endocrinology and Metabolism. More recently, through the related WHIMS-MRI study, we have reported with our WHIMS collaborators that HT was associated with decreased hippocampal and frontal regional brain volumes in more than 1400 women evaluated post-trial with brain MRI scans. This adverse effect of HT on hippocampal volume was most pronounced in women who had the lowest scores on a measure of global cognitive function at WHI baseline.