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

J Clin Endocrinol Metab. 2019 Feb 1;104(2):613-623. doi: 10.1210/jc.2018-00595.


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: NCT02486757.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adolescent
  • Adolescent Development / physiology*
  • Adult
  • Child
  • Cohort Studies
  • Estradiol
  • Female
  • Follicle Stimulating Hormone / blood
  • Follicle Stimulating Hormone / metabolism
  • Humans
  • Hypothalamo-Hypophyseal System / metabolism*
  • Inhibins / blood
  • Inhibins / metabolism
  • Luteinizing Hormone / blood
  • Luteinizing Hormone / metabolism
  • Menarche / physiology*
  • Menstrual Cycle / physiology*
  • Ovary / metabolism*
  • Ovulation / physiology
  • Progesterone / blood
  • Progesterone / metabolism


  • inhibin B
  • Progesterone
  • Estradiol
  • Inhibins
  • Luteinizing Hormone
  • Follicle Stimulating Hormone

Associated data