Accumulated deep sleep is a powerful predictor of LH pulse onset in pubertal children

Abstract

Context: During puberty, reactivation of the reproductive axis occurs during sleep, with LH pulses specifically tied to deep sleep. This association suggests that deep sleep may stimulate LH secretion, but there have been no interventional studies to determine the characteristics of deep sleep required for LH pulse initiation.

Objective: The objective of this study was to determine the effect of deep sleep fragmentation on LH secretion in pubertal children.

Design and setting: Studies were performed in a clinical research center.

Subjects: Fourteen healthy pubertal children (11.3-14.1 y) participated in the study.

Interventions: Subjects were randomized to two overnight studies with polysomnography and frequent blood sampling, with or without deep sleep disruption via auditory stimuli.

Results: An average of 68.1 ±10.7 (± SE) auditory stimuli were delivered to interrupt deep sleep during the disruption night, limiting deep sleep to only brief episodes (average length disrupted 1.3 ± 0.2 min vs normal 7.1 ± 0.8 min, P < .001), and increasing the number of transitions between non-rapid eye movement (NREM), REM, and wake (disrupted 274.5 ± 33.4 vs normal 131.2 ± 8.1, P = .001). There were no differences in mean LH (normal: 3.2 ± 0.4 vs disrupted: 3.2 ± 0.5 IU/L), LH pulse frequency (0.6 ± 0.06 vs 0.6 ± 0.07 pulses/h), or LH pulse amplitude (2.8 ± 0.4 vs 2.8 ± 0.4 IU/L) between the two nights. Poisson process modeling demonstrated that the accumulation of deep sleep in the 20 minutes before an LH pulse, whether consolidated or fragmented, was a significant predictor of LH pulse onset (P < .001).

Conclusion: In pubertal children, nocturnal LH augmentation and pulse patterning are resistant to deep sleep fragmentation. These data suggest that, even when fragmented, deep sleep is strongly related to activation of the GnRH pulse generator.

Figure 1.

Sleep disruption led to a decrease in the amount of time spent in deep sleep (N3) (P < .001) and an increase in the amount of time spent in stages N1 (P = .01) and N2 (P < .01) relative to the normal sleep night but no change in time spent in REM or time awake after sleep onset (WASO).

Figure 2.

Representation of sleep stages (wake, REM, N1, N2, and N3, in descending order) and LH values in two subjects studied during one night of normal (right panel) and one night of disrupted (left panel) sleep spaced 2 months apart. Note the consolidated periods of deep sleep across the night during normal sleep in contrast to the frequent sleep stage transitions during the disrupted sleep night. The nadir of each LH pulse is marked by a triangle. A, In this 11-year-old early pubertal boy (subject 8), sleep disruption was associated with a decrease in LH pulse amplitude (2.5 to 1.7 IU/L), resulting in a decrease in mean LH levels (3.7 to 2.6 IU/L). B, In this 12.5-year-old premenarcheal girl (subject 5), sleep disruption was associated with one additional pulse and a small decrease in LH pulse amplitude (1.8 to 1.2 IU/L) but no difference in mean LH levels (1.3 to 1.4 IU/L).

Figure 3.

A, Sleep disruption in pubertal children did not diminish LH pulse frequency, LH pulse amplitude, or mean LH levels (mean ± SE). B, Individual data for the 14 subjects demonstrates the heterogeneity of the LH responses to sleep disruption.

Figure 4.

Influence of fraction of time spent in N3, controlled for instantaneous N3, on the probability of an LH pulse in windows of increasing duration (x-axis). The figure shows the χ² test P values (ie, the difference between models 1 and 2 described in Table 2; y-axis) for improvement in predicting an LH pulse as a function of the fraction of time spent in N3 in windows of increasing duration. The dashed line marks the 0.05 significance level. The fraction of time spent in N3 over a 20-minute window before an LH pulse is most significantly associated with pulse onset (denoted by inverted arrow at time zero).