Effects of Hormone Therapy on List and Story Recall in Post-Menopausal Women

ABSTRACT

Background/Study Context: A number of longitudinal randomized controlled trials (LRCT) have used free verbal recall tests to study the effects of post-menopausal estrogen hormone therapy (HT) on episodic memory, but none have explicitly explored contrasts between list and story recall, in spite of cognitive differences between the tasks. For example, list recall provides little support for the use of gist, while story recall emphasizes it, and there is evidence that estrogen produces gist bias. Moreover, we present a literature tabulation that also suggests a task-specific HT effect.

Methods: In an LRCT with up to eight yearly test sessions, post-menopausal women were randomly assigned either to placebo (N = 56) or to an estrogen formulation (N = 44); subgroups received either estrogen alone (hysterectomy; E-alone; N = 16) or with progestin (intact uterus; E + P; N = 28). Participants were tested on the immediate and delayed list and story recall at each session.

Results: Linear mixed effects analyses of longitudinal trajectories showed that relative to placebo, the HT group declined significantly faster on immediate list recall and slower on immediate story recall. Separate analyses produced a sharpened version of this pattern for the E-alone subgroup but found no significant effects for the E + P subgroup. No significant effects were found in delayed testing.

Conclusion: The dissociation we found for immediate list and story recall is similar to the pattern of results in our literature tabulation. Fuzzy-Trace Theory posits parallel verbatim and gist traces plus a meta-cognitive review which becomes more gist-biased with age. Our results suggest that: (1) estrogen increases gist bias, hastening the normal age-related decline of list recall but slowing the decline of story recall relative to placebo; (2) decay of the verbatim trace over time generally causes a shift to gist, thereby accounting for the absence of a delayed recall difference; and (3) progestin weakens the effects of estrogen, thereby accounting for why the dissociation found in E-alone was absent in the E + P subgroup.

Study Background

The Women‘s Health Initiative (WHI) estrogen study was a double-blind placebo-based longitudinal study of the effects of HT in women 65+ years old (Women‘s Health Initiative Steering Committee, 2004; Writing Group for the Women‘s Health Initiative Investigators, 2002). In the WHI study, women with an intact uterus were given either estrogen + progestin (E+P) or placebo, and women with no uterus were given estrogen (E-alone) or placebo, with annual follow-ups. A subset of 7,340 WHI participants was enrolled in an ancillary study focused on dementia, the WHI Memory Study (WHIMS). These participants were tested annually for changes in global cognition with the Modified Mini-Mental State Examination (3MS; Teng & Chui, 1987). The WHI E+P branch was halted prematurely in 2002 after an average of 5.2 years of follow-up due to increased risk of coronary heart disease and invasive breast cancer, and the E-alone branch was stopped in 2004, in part because of increased risk of stroke (Women‘s Health Initiative Steering Committee, 2004; Writing Group for the Women‘s Health Initiative Investigators, 2002).

Soon after the WHIMS study began, the first author received WHI authorization to conduct an ancillary study, “Longitudinal assessment of memory functioning in an elderly normal subsample of the Women‘s Health Initiative clinical trial enrollees”. This ancillary study, which included both list and story verbal recall tasks, assessed participants from September of 1996 through July of 2004.

Recruitment into Current Study

One hundred WHIMS participants enrolled in our WHI ancillary study and came to at least one session, having been assigned per hysterectomy status to E-alone or E+P, and assigned randomly to placebo versus treatment. Note that at the time this was done, WHIMS researchers expected to find no cognitive differences due to E-alone versus E+P (e.g., Shumaker et al., 1998), so it was expected that all of our study participants receiving HT would be combined into a single treatment group. (Note that due to progestin-related differences reported since then, the current paper analyses the combined HT group as well as separate E-alone and E+P subgroups). As a result, there was no attempt to balance the size of the two subgroups. Criteria for acceptance into our study were that participants be enrolled in WHIMS and be willing to undergo a total of seven additional annual assessments. The WHIMS criteria (Shumaker et al., 1998) required active enrollment in WHI and also included a specific age range (65 to 79 years) plus readiness to participate in cognitive assessments for four to six years. The WHI criteria were quite open: they accepted any postmenopausal woman age 50 to 79 who resided near a study center, except for a set of specific exclusion criteria (Appendix A of Shumaker et al., 1998) such as dementia, mental illness including depression, dependence on alcohol or drugs, and a number of serious medical problems. All participants came to us via referral from the UC Davis WHI Clinical Center, where they were asked whether they were willing to volunteer for an additional cognitive study. Before the WHI Study of Cognitive Aging (WHISCA; Resnick et al., 2004) began, all volunteers were referred to us; after WHISCA began, referrals were made to both studies with priority given to WHISCA. We did not receive information about placebo participants‘ hysterectomy history.

Attrition and Compliance: number of participants per year of study

Table

Mean raw verbal recall testing results for Sessions 1-7

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Additional information

Funding

The project described was supported by the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), through grant #UL1 TR001860. We thank John Robbins, M.D., and the staff of the UC Davis Women’s Health Initiative (WHI) Clinical Center for their assistance, and we thank the WHI Memory Study (WHIMS) for referring participants to us. The findings reported here are distinct from and do not involve data from the WHI and WHIMS datasets. Portions of this research were presented as a poster at the Cognitive Neuroscience Society Annual Meeting, April 16, 2013, in San Francisco.