Healthy Post-Menarchal Adolescent Girls Demonstrate Multi-Level Reproductive Axis Immaturity

Abstract

Context: Menstrual irregularity after menarche has been attributed to immature estrogen positive feedback activity (E+FB) but data are conflicting.

Objective: To determine the hypothalamic-pituitary-ovarian contributions to menstrual irregularity in adolescents.

Methods: Twenty-three healthy girls [aged 12.8 to 17.6 years; 0.4 to 3.5 years postmenarche; body mass index (BMI) percentile, 41.0 to 99.3] underwent serial hormone measurements and pelvic ultrasounds during two consecutive menstrual cycles. Hormones and follicle growth were compared with 65 adult historic controls with ovulatory cycles (OVs).

Results: Girls had anovulatory cycles (ANOVs; 30%), OVs with a short luteal phase (short OVs; 22%), or OVs with normal luteal phase (normal OVs; 48%) without differences in cycle length, chronologic or gynecologic age, or BMI. Adolescents showed a spectrum of E+FB [midcycle LH adjusted for preovulatory estradiol (E2)]; only normal OV girls were comparable to adults. All OV girls had lower E2, progesterone, and gonadotropins during the luteal phase and luteal-follicular transition compared with adults. Normal OV girls also had lower follicular phase LH and FSH levels, a longer follicular phase, a slower dominant follicle growth rate, and smaller estimated preovulatory follicle size than adults. Follicular phase E2 and inhibin B levels were lower in normal OV girls than in adults even after adjusting for differences in FSH and follicle size.

Conclusions: Early postmenarchal girls with normal OVs demonstrate mature E+FB but continue to have lower gonadotropin levels, diminished ovarian responsiveness, and decreased corpus luteum sex steroid synthesis compared with adults, indicating that reproductive axis maturity requires coordinated development of all components of the hypothalamic-pituitary-ovarian axis.

Trial registration: ClinicalTrials.gov NCT02486757.

Figures

Figure 1.

LH, FSH, E2, and P4 levels during two consecutive menstrual cycles in adolescent girls with either normal OV (left, n = 11) or short OV (right, n = 5) cycles. Levels represent serum or serum equivalents as determined from DBS or urine samples. Cycle days are centered to the MC LH peak of cycle 1 (day 0) and shown during the first week of cycle 2 (day 1 = menses). Adolescents: filled circles are arithmetic mean values and error bars are ±1 SE. Both groups are compared with historic adult controls (n = 65). Adults: Dashed line denotes arithmetic mean level and shaded area is ±1 SD. *P < 0.05; **P < 0.01; ***P < 0.001 for cycle phase (i.e., LFP, MC, LP, EFP). To convert E2 to SI units (pmol/L), multiply by 3.67; for P4 (nmol/L), multiply by 3.18.

Figure 2.

Dominant follicle diameter plotted against cycle day for adults and normal OV adolescents. Lines and 95% confidence bands were estimated from a linear mixed model. Adults, dashed line; normal OV adolescents, solid line. Filled circles are individual data points for normal OV adolescents. The slope of a line is the estimated follicle growth rate; the intercept at cycle day 0 is the estimated follicle size at ovulation. The dominant follicle grew more slowly in adolescent girls with normal OV cycles than in adults resulting in a smaller estimated follicle size at ovulation in cycle 1.

Figure 3.

INHB levels plotted against cycle day for adults and adolescents during the EFP of cycle 2. Adults: arithmetic mean levels, (○); dashed lines delineate ±1 SE. Adolescents: individual data points, normal OV (●), short OV (△), or ANOV (□). Adult and adolescent subjects each contributed data to only a subset of cycle days. INHB levels were lower in all adolescent groups compared with adults during the first 7 d of cycle 2. INHB values are equivalent in SI units (ng/L).