The Relationship Between Progesterone, Sleep, and LH and FSH Secretory Dynamics in Early Postmenarchal Girls

Abstract

Context: During puberty, LH pulse frequency increases during sleep; in women, LH pulse frequency slows during sleep in the early/middle follicular phase (FP) of the menstrual cycle. The origin and significance of this developmental transition are unknown.

Objective: To determine the relationship between progesterone (P4) exposure, sleep-related slowing of LH pulses in the FP, and the intercycle FSH rise, which promotes folliculogenesis, in early postmenarchal girls.

Methods: 23 girls (gynecologic age 0.4 to 3.5 years) underwent hormone measurements and pelvic ultrasounds during two consecutive cycles and one frequent blood sampling study with concurrent polysomnography during the FP.

Results: Subjects demonstrated one of four patterns during cycle 1 that represent a continuum of P4 exposure: ovulatory cycles with normal or short luteal phase lengths or anovulatory cycles ± follicle luteinization. Peak serum P4 and urine pregnanediol (Pd) in cycle 1 were inversely correlated with LH pulse frequency during sleep in the FP of cycle 2 (r = -0.5; P = 0.02 for both). The intercycle FSH rise and folliculogenesis in cycle 2 were maintained after anovulatory cycles without P4 or Pd exposure or nocturnal slowing of LH pulse frequency in the FP.

Conclusions: During late puberty, rising P4 levels from follicle luteinization and ovulation may promote a slower LH pulse frequency during sleep in the FP. However, a normal FSH rise and follicle growth can occur in the absence of P4-associated slowing. These studies therefore suggest that an immature LH secretory pattern during sleep is unlikely to contribute to menstrual irregularity in the early postmenarchal years.

Trial registration: ClinicalTrials.gov NCT02486757.

Figure 1.

Study protocol schema. Subjects were monitored during specific phases of two consecutive menstrual cycles. In this hypothetical subject, an LH peak on cycle day 14 was followed by a 14-day luteal phase (28-day cycle), and monitoring continued into the late follicular phase of cycle 2 (cycle day 14 or 28 days since cycle 1 LH peak). Intercycle FSH dynamics were determined after centering to days since the LH peak in cycle 1 and excluding the midcycle FSH peak in cycle 2. A sleep study with concurrent frequent blood sampling was performed between days 2 and 9 of cycle 2. Solid line, LH; dotted line, FSH. PSG, polysomnography.

Figure 2.

Observed and fitted FSH levels during the transition from cycle 1 to cycle 2 in three representative subjects with either normal ovulatory (OV) cycles, short OV cycles, or anovulatory (ANOV) cycles (with luteinization) in cycle 1. Data are centered to the midcycle LH peak in cycle 1 (day 0). Gray circles indicate observed FSH values, and dashed line represents fitted FSH trajectories based on smoothing splines. Fitted trajectories were used to calculate the FSH minimum, FSH maximum, slope of the FSH rise, and number of days spent above the FSH threshold (~4.2 IU/L) after the FSH rise.

Figure 3.

Sleep stages (wake, REM, N1, N2, and N3, in descending order) and pulsatile LH secretion in representative subjects from the four progesterone exposure groups, demonstrating the relationship between P4 level and LH pulse frequency during sleep. Studies were performed on day 5 or 6 of cycle 2. P4 = maximum serum progesterone detected in cycle 1. Inverted triangles indicate LH pulse nadirs.