Effect of Ovarian Hormone Therapy on Cognition in the Aged Female Rhesus Macaque

Abstract

Studies of the effect of hormone therapy on cognitive function in menopausal women have been equivocal, in part due to differences in the type and timing of hormone treatment. Here we cognitively tested aged female rhesus macaques on (1) the delayed response task of spatial working memory, (2) a visuospatial attention task that measured spatially and temporally cued reaction times, and (3) a simple reaction time task as a control for motor speed. After task acquisition, animals were ovariectomized (OVX). Their performance was compared with intact controls for 2 months, at which time no group differences were found. The OVX animals were then assigned to treatment with either a subcutaneous sham implant (OVX), 17-β estradiol (E) implant (OVX+E) or E implant plus cyclic oral progesterone (OVX+EP). All groups were then tested repeatedly over 12 months. The OVX+E animals performed significantly better on the delayed response task than all of the other groups for much of the 12 month testing period. The OVX+EP animals also showed improved performance in the delayed response task, but only at 30 s delays and with performance levels below that of OVX+E animals. The OVX+E animals also performed significantly better in the visuospatial attention task, particularly in the most challenging invalid cue condition; this difference also was maintained across the 12 month testing period. Simple reaction time was not affected by hormonal manipulation. These data demonstrate that chronic, continuous administration of E can exert multiple beneficial cognitive effects in aged, OVX rhesus macaque females.

Significance statement: Hormone therapy after menopause is controversial. We tested the effects of hormone replacement in aged rhesus macaques, soon after surgically-induced menopause [ovariectomy (OVX)], on tests of memory and attention. Untreated ovarian-intact and OVX animals were compared with OVX animals receiving estradiol (E) alone or E with progesterone (P). E was administered in a continuous fashion via subcutaneous implant, whereas P was administered orally in a cyclic fashion. On both tests, E-treated animals performed better than the other 3 experimental groups across 1 year of treatment. Thus, in this monkey model, chronic E administered soon after the loss of ovarian hormones had long-term benefits for cognitive function.

Keywords: aging; cognition; hormones.

Figure 1.

Experimental design: Gonad-intact, aged rhesus females were trained to criteria during task acquisition. All but 6 of the animals were then bilaterally ovariectomized, and all 28 were retested after 1 week, 1 month, and 2 months during the acute OVX testing phase. Longitudinal hormone replacement began thereafter, and all groups were retested at 1 week and at 1, 2, 4, 6, 9, and 12 months.

Figure 2.

The percentage change in delayed response performance, during the 2 month, post-OVX washout period and during 12 months of HT. During the washout period, the percentage change was calculated from baseline values, whereas for the HT period, comparisons were reset at the start of HT. Left, During the 2 month post-OVX washout phase, there was no difference between intact or OVX groups. Right, During the HT period, the OVX+E animals performed significantly better than the gonad-intact, OVX, or OVX+EP groups. ^aSignificantly different from intact (p < 0.05, or at a greater significance level). ^bSignificantly different from OVX (p < 0.05, or at a greater significance level). ^cSignificantly different from OVX+EP (p < 0.05, or at a greater significance level). Note different y-axis scales for the left and right panels.

Figure 3.

The effect of HT on overall delayed response performance. When just examining the effect of treatment, collapsing the data across delay and time, the OVX+E group significantly performed better than the intact, OVX, or OVX+EP-treated animals. In all pairwise comparison, none of the other three groups was significantly different from each other in performance.

Figure 4.

The interaction of delay and treatment on delayed response performance. A significant interaction of delay × treatment was found (p < 0.0001), and comparisons are presented for each delay. Although there were no group differences in performance for the 1 s delay, at 5 s delays both the OVX and OVX+E groups outperformed gonad-intact and OVX+EP animals. For the 15 s delay, the OVX+E group performed significantly better than all other groups. At the 30 s delay, OVX+E again resulted in significantly improved performance versus all other groups. However, in this case, the OVX+EP group performance was superior to that of gonad-intact and OVX animals, but still below that of OVX+E animals. All significant comparisons exceeded p < 0.05, with different letters for any treatment group denoting a significant pairwise difference. Data represent mean ± SEM.

Figure 5.

The effect of HT on RT for each cue condition during the 2 month, post-OVX period (left panel of each graph) and during 12 months of HT (right panel). Results are shown separately for valid, invalid, no cue, and neutral cue conditions, with the y-axis representing the change in RT from the baseline condition for each phase of the study. There was no effect of treatment during the 2 month OVX period (Phase 1) for any of the cue conditions. However, in the Phase 2 test of HT, post hoc analyses at each time point revealed that the OVX+E group had faster RTs in the invalid cue condition starting at 2 months, with neutral cues starting at 4 months, and in invalid or no cue conditions starting at 9 months, with all effects persisting through 12 months. ^aSignificantly different from intact (p < 0.05). ^bSignificantly different from OVX (p < 0.05). ^cSignificantly different from OVX+EP (p < 0.05). Data represent mean ± SEM.