Influence of Sleep Stage on LH Pulse Initiation in the Normal Late Follicular Phase and in Polycystic Ovary Syndrome

Abstract

Objective: During the early follicular phase, sleep-related luteinizing hormone (LH) pulse initiation is positively associated with brief awakenings but negatively associated with rapid eye movement (REM) sleep. The relationship between sleep architecture and LH pulse initiation has not been assessed in other cycle stages or in women with polycystic ovary syndrome (PCOS).

Design and methods: We performed concomitant frequent blood sampling (LH pulse analysis) and polysomnography on 8 normal women (cycle day 7-11) and 7 women with PCOS (at least cycle day 7).

Results: In the normal women, the 5 min preceding LH pulses contained more wake epochs and fewer REM epochs than the 5 min preceding randomly determined time points (wake: 22.3 vs. 9.1%, p = 0.0111; REM: 4.4 vs. 18.8%, p = 0.0162). However, LH pulse initiation was not related to wake or REM epochs in PCOS; instead, the 5 min preceding LH pulses contained more slow-wave sleep (SWS) than the 5 min before random time points (20.9 vs. 6.7%, p = 0.0089). Compared to the normal subjects, the women with PCOS exhibited a higher REM-associated LH pulse frequency (p = 0.0443) and a lower proportion of wake epochs 0-5 min before LH pulses (p = 0.0205).

Conclusions: Sleep-related inhibition of LH pulse generation during the later follicular phase is normally weakened by brief awakenings and strengthened by REM sleep. In women with PCOS, LH pulse initiation is not appropriately discouraged by REM sleep and may be encouraged by SWS; these abnormalities may contribute to a high sleep-related LH pulse frequency in PCOS.

Keywords: Gonadotropin-releasing hormone; Luteinizing hormone; Polycystic ovary syndrome; Sleep.

Figure 1.. Example of aligned LH and PSG data.

In deconvolution, the rate of LH secretion from the anterior pituitary during a pulse is assumed to exhibit a Gaussian pattern; and deconvolution results include the pulse position—the center of the underlying secretory event (i.e., time of peak LH secretion rate)—and a secretory standard deviation (SD). The precise timing of sleep-associated LH pulse initiation (denoted by dashed vertical lines) was defined as two secretory SDs before pulse position.

Figure 2.. Depiction of sensitivity analyses.

Panel A. In the first sensitivity analysis, we paired (a) sleep stage proportions before each LH pulse to (b) average sleep stage proportions during the same time block for all other admissions. For each group (normal, PCOS), paired data were analyzed for consistent differences using Wilcoxon signed rank tests. Panel B. In the second sensitivity analysis, we paired (a) the average proportion of sleep stages before all LH pulses during an admission to (b) the proportion of sleep stages occupying the entire sleep period (same admission). For each group (normal, PCOS), paired data were analyzed for consistent differences using Wilcoxon signed rank tests.

Figure 3:. Primary analyses, normal women.

Panel A: Proportion of LH pulses (solid bars) vs. random time points (open bars) instantaneously associated with various sleep stages, calculated as the number of LH pulses (or random time points) instantaneously associated with a sleep stage divided by the total number of LH pulses (or random time points). Panel B: Proportion of time frame 0-5 minutes before LH pulses (solid bars) vs. random time points (open bars) occupied by each sleep stage. Data are expressed as mean ± standard error of the mean. * p < 0.05.

Figure 4:. Sensitivity analyses, normal women.

Panel A: First sensitivity analysis: Proportion of sleep stage before LH pulse initiation (solid bars) vs. average proportion of the same sleep stage occurring at the same clock times in other admissions in normal subjects (open bars). Panel B: Second sensitivity analysis: Average proportion of sleep stage before all LH pulses in an admission (solid bars) vs. proportion of the same sleep stage during the same admission’s sleep period. Data are presented as mean ± standard error of the mean. * p < 0.05; *** p < 0.001.

Figure 5:. Primary analyses, women with PCOS.

Panel A: Proportion of LH pulses (solid bars) vs. random time points (open bars) instantaneously associated with various sleep stages. Panel B: Proportion of time frame 0-5 minutes before LH pulses (solid bars) vs. random time points (open bars) occupied by each sleep stage. Data are presented as mean ± standard error of the mean. ** p < 0.01.

Figure 6:. Sensitivity analyses, women with PCOS.

Panel A: First sensitivity analysis: Proportion of sleep stage before LH pulse initiation (solid bars) vs. average proportion of the same sleep stage occurring at the same clock times in other subjects with PCOS (open bars). Panel B: Second sensitivity analysis: Average proportion of sleep stage before all LH pulses in an admission (solid bars) vs. proportion of the same sleep stage during the same admission’s sleep period. Data are presented as mean ± standard error of the mean.

Figure 7:. Normal vs. PCOS.

Panel A: LH pulse frequency for a given sleep stage was calculated as the number of LH pulses instantaneously associated with the sleep stage divided by the percentage of total sleep period (in hours) occupied by that sleep stage. For women studied during two overnight admissions, sleep stage-associated LH pulse frequencies were calculated for both admissions and results averaged. Panel B: “Normalized” sleep stage proportions in the 0-5 minutes before LH pulses, defined as the average sleep stage proportion 0-5 minutes before all sleep-related LH pulses in an admission divided by the corresponding sleep stage proportion for the sleep period. Both panels: For subjects with two overnight admissions, results were calculated for each admission and averaged. Data are presented as mean ± standard error of the mean. * p < 0.05.

Figure 8.. Hypothetical model.

We speculate that progesterone action—including lingering effects of recent progesterone exposure—strengthens (a) the positive relationship between wake epochs and GnRH pulse initiation, (b) the negative relationship between REM sleep and GnRH pulse initiation, and (c) the negative relationship between slow wave sleep (SWS) and GnRH pulse initiation. In contrast, the absence of substantial progesterone action may be associated with partial or full reversal of these relationships. Instead of a negative relationship between SWS and GnRH pulse initiation, as observed in the early follicular phase (adults), a positive relationship between SWS and GnRH pulse initiation is observed in PCOS and early puberty. Similarly, instead of the positive relationship between wake epochs and GnRH pulse initiation observed in the early and late follicular phases (adults), no relationship or a negative relationship is observed in PCOS and early puberty, respectively. Other factors could also play important roles in the relationship between sleep architecture and GnRH pulse initiation. For example, hyperandrogenemia may antagonize the effects of progesterone on these relationships.