While clinical trials of HRT in women can correct for selection bias and confounding inherent in observational studies, they have demonstrated limited efficacy of HRT on maintenance of cognitive function, primarily assessed as verbal memory, or on risk for AD. Overall, they show a neutral effect of estrogen alone and a negative effect of combined estrogen-progestogen treatment on verbal memory. It is helpful to group study results by population and HRT formulation in order to evaluate result trends.
Several randomized, placebo-controlled trials of unopposed estrogen therapy on episodic verbal memory in women younger than 65 years old demonstrated improvement in test scores of verbal recall in women less than 65 years of age receiving estrogen only supplementation (22
). Results were limited by sample sizes of fifty women or less and most or all of the women in these studies were surgically menopausal. Despite the small study samples and design limitations, the results of these studies support the hypothesis that estrogen alone either enhances or has no effect on verbal memory in younger women in short-term follow-up. Results of unopposed estrogen therapy in older women have been neutral. Randomized, placebo-controlled trials of estrogen and cognition in women with a mean age greater than 65 years old have each employed a different estradiol formulation(25
While unopposed estrogen therapy has demonstrated positive effects on cognitive outcomes in younger women and neutral effects in older women, the results from combination estrogen-progestogen treatment trials are less encouraging in both groups. The largest study of any form of hormone therapy on verbal memory in women younger than age 65 was the Cognitive Complaints in Early Menopause Trial (28
), which indicated a non-significant trend for conjugated equine estrogen/medroxyprogesterone acetate (CEE/MPA) to be associated with decline in both short- and long-delay free recall compared with placebo (p<0.07). A second study in younger women found that combined therapy with estrogen plus progestogen (dienogest) enhanced verbal memory compared with both placebo and estradiol (29
). The two studies suggest that different forms of progestogens may have different effects on cognitive function in younger women, with negative effects of MPA on verbal memory and positive effects of dienogest, a progestogen with anti-androgenic effects.
A number of trials have evaluated combined estrogen/progestogen treatment in women over 65 years of age. Out of four trials evaluating combined therapy on cognition in postmenopausal women, three showed either a negative effect of HRT on verbal memory (30
), or a trend of negative effect on verbal memory (32
) (p<0.06). These findings suggest a consistent, detrimental effect of combined hormone therapy on verbal memory. The largest trial to date is the Woman’s Health Initiative Memory Study (WHIMS) (33
), which examined the impact of CEE in women with prior hysterectomy, and the impact of CEE/MPA in naturally post-menopausal women, on the incidence of dementia in women age 65 or older. In the combined therapy arm, CEE/MPA doubled the risk for all-cause dementia (HR=2.01; 95th
% confidence interval= 1.21–3.48) (34
). In the estrogen-alone arm there was no evidence that CEE changed the risk of all-cause dementia (HR= 1.49; 95%
confidence interval =0.83–2.66) (35
). However, the negative effects of the WHIMS trials may be related to the timing of treatment, the specific formulation of HRT provided and schedule used. Interestingly, analysis of prior HRT use in the perimenopausal period in the WHIMS population was associated with a lower rate of developing dementia regardless of the treatment arm. When AD was analyzed apart from other causes of dementia, prior HRT was associated with a 64% reduction in incidence. In sum, results of clinical trials of HRT vary depending of the type of therapy used and the age of initiation. The true effects of combination HRT on brain function are complicated by the finding that certain forms of progestogen, such as MPA, but not others, may antagonize the effects of estrogen on the hippocampus (36
). This provides a motivation for exploring the impact of different estrogen/ progestogen combinations and dosages on verbal memory. Modes of HRT delivery also need to be evaluated. Transdermal HRT application, which bypasses first-pass metabolism, may have a different effect on hormone delivery and therefore on cognitive outcome. Additionally, the critical window hypothesis highlights the need to define the time period of effective intervention in order to optimize the timing of early hormone therapy on cognition. Finally, it should be determined how long HRT must be used to confer benefits. The answer to this question may be provided in part by the results of PREPARE (PREventing Post-menopausal Alzheimer’s Disease with Replacement Estrogens) an HRT trial in women 65 years of age or older with a family history of dementia in a first-degree relative, which was designed to determine if HRT delays AD or memory loss in women at increased risk for cognitive change (37*
). While active study treatment was discontinued in response to the WHI Memory Study report, the study continues to follow participants for a total of five years blind to the original medication assignment. Future results will address whether there are lasting or delayed effects of HRT on cognition after treatment cessation.
Two large clinical trials may provide important information on the effect of HRT on cognitive function in younger and older postmenopausal women. The Kronos Early Estrogen Prevention Study (KEEPS) is a five year, multicenter clinical trial that will enroll women who are within 36 months of their final menstrual period. Participants will be randomized to receive oral CEE plus micronized progesterone, transdermal estradiol plus micronized progesterone, or placebo. The trial was designed to address the dual concerns that the older mean age of the WHI population may have affected response to HRT, and that the mode of HRT administration may impact health outcome (38**
). Cognitive outcome tracking will be part of a secondary analysis, and women included in the study must have an MMSE>=23. The Early versus Late Intervention Trial with Estradiol (ELITE) at UCLA is a single site clinical trial that will enroll a total of 504 post-menopausal women who are less than six years from menopause (early) versus 10 years or more from menopause (late) to receive either oral estradiol or placebo (39
). Both KEEPS and ELITE will examine verbal memory as a primary outcome and focus on naturally menopausal women.