Estradiol and progesterone modulate spontaneous sleep patterns and recovery from sleep deprivation in ovariectomized rats

Abstract

Study objectives: Women undergo hormonal changes both naturally during their lives and as a result of sex hormone treatments. The objective of this study was to gain more knowledge about how these hormones affect sleep and responses to sleep loss.

Design: Rats were ovariectomized and implanted subcutaneously with Silastic capsules containing oil vehicle, 17 beta-estradiol and/or progesterone. After 2 weeks, sleep/wake states were recorded during a 24-h baseline period, 6 h of total sleep deprivation induced by gentle handling during the light phase, and an 18-h recovery period.

Measurements and results: At baseline and particularly in the dark phase, ovariectomized rats treated with estradiol or estradiol plus progesterone spent more time awake at the expense of non-rapid eye movement sleep (NREMS) and/or REMS, whereas those given progesterone alone spent less time in REMS than ovariectomized rats receiving no hormones. Following sleep deprivation, all rats showed rebound increases in NREMS and REMS, but the relative increase in REMS was larger in females receiving hormones, especially high estradiol. In contrast, the normal increase in NREMS EEG delta power (an index of NREMS intensity) during recovery was attenuated by all hormone treatments.

Conclusions: Estradiol promotes arousal in the active phase in sleep-satiated rats, but after sleep loss, both estradiol and progesterone selectively facilitate REMS rebound while reducing NREMS intensity. These results indicate that effects of ovarian hormones on recovery sleep differ from those on spontaneous sleep. The hormonal modulation of recovery sleep architecture may affect recovery of sleep related functions after sleep loss.

Figure 1

Amount (mean + SEM, min) of wake (A, B), NREMS (C, D), and REMS (E, F), and REMS as a percentage of total sleep (G, H), during baseline recording for the full 24-h period (left) and during the 12-h light and 12-h dark phases (right) in ovariectomized female rats treated with Oil (solid bars), low estradiol (LE), high estradiol (HE), low progesterone (LP), or low estradiol plus low progesterone (LEP), and in intact males (M; white bars) (n = 8 per group). The background shading indicates the dark phase. Treatments with estradiol alone (LE and HE) or combined with progesterone (LEP) increased wake and decreased NREMS and/or REMS, while treatments with progesterone alone (LP) selectively decreased REMS. These effects were more prominent during the dark phase. *Different from light phase; ^adifferent from Oil; ^bdifferent from LE; ^cdifferent from HE; ^ddifferent from LP; all P < 0.05 (Fisher LSD post hoc comparisons).

Figure 2

Amount (mean + SEM, min) of NREMS (A) and REMS (B) during the 18-h recovery period after 6 h of sleep deprivation and during the equivalent 18 h of baseline recording (left) in the Oil (solid bars), LE, HE, LP, LEP, and M (white bars) groups (n = 7 or 8 because a complete sleep recording was not available for every animal). All groups showed NREMS and REMS rebound following sleep deprivation, reaching similar absolute levels for NREMS and REMS, with the exception of the LP group, which had less absolute recovery of REMS amounts than the Oil, LE, and M groups. *Different from corresponding baseline; ^adifferent from Oil; ^bdifferent from LE; ^cdifferent from HE; ^ddifferent from LP; all P < 0.05 (Fisher LSD post hoc comparisons).

Figure 3

Time course of NREMS amount (min) in 2-h intervals across the 24-h baseline period (white circles), during 6 h of sleep deprivation (Sleep Dep in top left panel), and during the 18 h recovery period (black circles) in the Oil, LE, HE, LP, LEP, and M groups. Data are shown as means ± SEM, with n = 7-8 per group. In all groups, NREMS amounts increased greatly during the first 2 h after sleep deprivation, then declined but remained elevated at most time points for the rest of the dark phase. During the subsequent light phase, NREMS amounts returned to baseline levels in all groups except the LEP group. *Different from corresponding baseline, P < 0.05 (Fisher LSD post hoc comparisons). Background shading indicates dark phase.

Figure 4

Time course of REMS amount (min) in 2-h intervals across the 24-h baseline period (white circles), during 6 h of sleep deprivation (Sleep Dep in top left panel), and during the 18-h recovery period (black circles) in the Oil, LE, HE, LP, LEP, and M groups. Data are shown as means ± SEM, with n = 7-8 per group. Like NREMS (Fig. 3), in all groups except for the Oil group, REMS amounts increased greatly during the first 2 h following sleep deprivation, after which they declined but remained elevated at most time points during the rest of the dark phase. The Oil group showed only intermittent elevations during the same period. During the subsequent light phase, REMS amounts returned to baseline levels in all groups. *Different from corresponding baseline, P < 0.05 (Fisher LSD post hoc comparisons). Background shading indicates dark phase.

Figure 5

Percentage of NREMS (A) and REMS (B) recovered after 6 h of sleep deprivation in the Oil (solid bars), LE, HE, LP, LEP, and M (white bars) groups. The percentage was calculated by dividing the difference between NREMS or REMS amounts during the 18-h baseline and recovery periods by the duration of NREMS or REMS lost during the 6 h deprivation period. Data are shown as means + SEM (n = 7-8 per group). The percentage gain of REMS during recovery relative to lost REMS was greater in the LE and HE groups than in the Oil group, while the percentage gain of NREMS was not significantly different among groups. ^aDifferent from Oil; ^cdifferent from HE. All P < 0.05 (Fisher LSD post hoc comparisons).

Figure 6

Time course of normalized NREMS delta power in 2-h intervals across the 24-h baseline period (white circles) and during the 18-h recovery period (black circles) in the Oil, LE, HE, LP, LEP, and M groups after 6 h of sleep deprivation. EEG power was normalized to the 24 h baseline average at 2-h intervals in each animal. Data are shown as means ± SEM (n = 7-8 per group). During the first 2 h after sleep deprivation, the Oil group showed more normalized NREMS delta power than the other female groups, and continued to show elevated values throughout the first 8 h of recovery, while the increased NREMS delta power persisted only for 4 h in all other groups. A decrease in delta power below baseline levels was observed 10-12 h post-deprivation in the LE and HE groups. *Different from corresponding baseline, P < 0.05 (Fisher LSD post hoc comparisons). Background shading indicates dark phase.