Progesterone-Mediated Inhibition of the GnRH Pulse Generator: Differential Sensitivity as a Function of Sleep Status

Abstract

Context

During normal, early puberty, luteinizing hormone (LH) pulse frequency is low while awake but increases during sleep. Mechanisms underlying such changes are unclear, but a small study in early pubertal girls suggested that differential wake-sleep sensitivity to progesterone negative feedback plays a role.

Objective

To test the hypothesis that progesterone acutely reduces waking LH pulse frequency more than sleep-associated pulse frequency in late pubertal girls.

Design

Randomized, placebo-controlled, double-blinded crossover study.

Setting

Academic clinical research unit.

Participants

Eleven normal, postmenarcheal girls, ages 12 to 15 years.

Intervention

Subjects completed two 18-hour admissions in separate menstrual cycles (cycle days 6 to 11). Frequent blood sampling for LH assessment was performed at 1800 to 1200 hours; sleep was encouraged at 2300 to 0700 hours. Either oral micronized progesterone (0.8 mg/kg/dose) or placebo was given at 0700, 1500, 2300, and 0700 hours, before and during the first admission. A second admission, performed at least 2 months later, was identical to the first except that placebo was exchanged for progesterone or vice versa (treatment crossover).

Main Outcome Measures

LH pulse frequency during waking and sleeping hours.

Results

Progesterone reduced waking LH pulse frequency by 26% (P = 0.019), with no change observed during sleep (P = 0.314). The interaction between treatment condition (progesterone vs placebo) and sleep status (wake vs sleep) was highly significant (P = 0.007).

Conclusions

In late pubertal girls, progesterone acutely reduced waking LH pulse frequency more than sleep-associated pulse frequency. Differential wake-sleep sensitivity to progesterone negative feedback may direct sleep-wake LH pulse frequency changes across puberty.