A comparison of progestins within three classes: Differential effects on learning and memory in the aging surgically menopausal rat

Abstract

Introduction: For decades, progestins have been included in hormone therapies (HT) prescribed to women to offset the risk of unopposed estrogen-induced endometrial hyperplasia. However, the potential effects on cognition of subcategories of clinically used progestins have been largely unexplored.

Methods: In two studies, the present investigation evaluated the cognitive effects of norethindrone acetate (NETA), levonorgestrel (LEVO), and medroxyprogesterone acetate (MPA) on the water radial-arm maze (WRAM) and Morris water maze (MM) in middle-aged ovariectomized rats.

Results: In Study 1, six-weeks of a high-dose NETA treatment impaired learning and delayed retention on the WRAM, and impaired reference memory on the MM. Low-dose NETA treatment impaired delayed retention on the WRAM. In Study 2, high-dose NETA treatment was reduced to four-weeks and compared to MPA and LEVO. As previously shown, MPA impaired working memory performance during the lattermost portion of testing, at the highest working memory load, impaired delayed retention on the WRAM, and impaired reference memory on the MM. NETA also impaired performance on these WRAM and MM measures. Interestingly, LEVO did not impair performance, but instead enhanced learning on the WRAM.

Conclusions: The current study corroborates previous evidence that the most commonly prescribed FDA-approved progestin for HT, MPA, impairs learning and memory in the ovariectomized middle-aged rat. When progestins from two different additional subcategories were investigated, NETA impaired learning and memory similarly to MPA, but LEVO enhanced learning. Future research is warranted to determine LEVO's potential as an ideal progestin for optimal health in women, including for cognition.

Keywords: Aging; Cognition; Hormone therapy; Memory; Menopause; Progestin.

Figure 1

Chemical structures of progesterone-resembling progestogens: (a) progesterone (b) medroxyprogesterone acetate (MPA), and testosterone-resembling progestins: (c) norethindrone acetate (NETA) (d) levonorgesterel (LEVO). Timeline for (e) Study 1 and (f) Study 2 summarizing duration of treatment and behavior testing.

Figure 2

Study 1 Mean error scores (+SE) collapsed across all trials on the water radial-arm maze during the learning (Days 2–6) and asymptotic (Days 7–12) testing phases: (a) Working Memory Correct errors, (b) Working Memory Incorrect errors, and (c) Reference Memory errors. (d) Mean Working Memory Correct error scores (+SE) for baseline (last day of regular testing trial 3) vs. delay (trial 3 immediately following a 6 hour delay). *p < 0.05; ^p < 0.05 Baseline vs. Delay

Figure 3

Study 1 Morris maze mean (+SE) (a) Distance scores in centimeters and (b) Latency scores in seconds across all days of testing (Days 1–3). (c) Mean percent Distance in the target NE quadrant as compared to the opposite SW quadrant during the probe trial. *p <.05; ^#p <.10; ***p <.0001 NE quadrant vs. SW quadrant

Figure 4

Study 2 (a) Mean error scores (+SE) collapsed across all trials on the water radial-arm maze during the learning (Days 2–6) and asymptotic (Days 7–14) testing phases for Working Memory Incorrect errors. Working memory load effect during the learning testing phase (Days 2–6) for (b) Working Memory Correct errors and (c) Working Memory Incorrect errors, and (d) during the last day of regular testing (Day 14) for Working Memory Correct errors. (e) Mean Working Memory Correct error scores (+SE) for baseline (last day of regular testing trial 3) vs. delay (trial 3 immediately following a 4 hour delay). *p ≤ 0.05; ^#p <.10; ^p < 0.05 Baseline vs. Delay

Figure 5

Study 2 Morris maze mean (+SE) (a) Distance scores in centimeters and (b) Latency scores in seconds across all days of testing (Days 1–3). (c) Mean percent Distance in the target NE quadrant as compared to the opposite SW quadrant during the probe trial. *p < 0.05; ^#p <.10; ***p < 0.001 NE quadrant vs. SW quadrant