Coordinated Regulation Among Progesterone, Prostaglandins, and EGF-Like Factors in Human Ovulatory Follicles

J Clin Endocrinol Metab. 2017 Jun 1;102(6):1971-1982. doi: 10.1210/jc.2016-3153.


Context: In animal models, the luteinizing hormone surge increases progesterone (P4) and progesterone receptor (PGR), prostaglandins (PTGs), and epidermal growth factor (EGF)-like factors that play essential roles in ovulation. However, little is known about the expression, regulation, and function of these key ovulatory mediators in humans.

Objective: To determine when and how these key ovulatory mediators are induced after the luteinizing hormone surge in human ovaries.

Design and participants: Timed periovulatory follicles were obtained from cycling women. Granulosa/lutein cells were collected from in vitro fertilization patients.

Main outcome measures: The in vivo and in vitro expression of PGR, PTG synthases and transporters, and EGF-like factors were examined at the level of messenger RNA and protein. PGR binding to specific genes was assessed. P4 and PTGs in conditioned media were measured.

Results: PGR, PTGS2, and AREG expressions dramatically increased in ovulatory follicles at 12 to 18 hours after human chorionic gonadotropin (hCG). In human granulosa/lutein cell cultures, hCG increased P4 and PTG production and the expression of PGR, specific PTG synthases and transporters, and EGF-like factors, mimicking in vivo expression patterns. Inhibitors for P4/PGR and EGF-signaling pathways reduced hCG-induced increases in PTG production and the expression of EGF-like factors. PGR bound to the PTGS2, PTGES, and SLCO2A1 genes.

Conclusions: This report demonstrated the time-dependent induction of PGR, AREG, and PTGS2 in human periovulatory follicles. In vitro studies indicated that collaborative actions of P4/PGR and EGF signaling are required for hCG-induced increases in PTG production and potentiation of EGF signaling in human periovulatory granulosa cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Amphiregulin / genetics*
  • Amphiregulin / metabolism
  • Blotting, Western
  • Cells, Cultured
  • Chorionic Gonadotropin / pharmacology
  • Cyclooxygenase 2 / drug effects
  • Cyclooxygenase 2 / genetics*
  • Cyclooxygenase 2 / metabolism
  • Epidermal Growth Factor / metabolism
  • Female
  • Fertilization in Vitro
  • Gene Expression Profiling
  • Granulosa Cells
  • Humans
  • Immunohistochemistry
  • Luteal Cells
  • Luteinizing Hormone
  • Organic Anion Transporters / drug effects
  • Organic Anion Transporters / genetics*
  • Organic Anion Transporters / metabolism
  • Ovarian Follicle / metabolism*
  • Ovulation
  • Polymerase Chain Reaction
  • Progesterone / metabolism*
  • Prostaglandin-E Synthases / drug effects
  • Prostaglandin-E Synthases / genetics
  • Prostaglandin-E Synthases / metabolism
  • Prostaglandins / metabolism*
  • RNA, Messenger / metabolism
  • Receptors, Progesterone / drug effects
  • Receptors, Progesterone / genetics*
  • Receptors, Progesterone / metabolism


  • AREG protein, human
  • Amphiregulin
  • Chorionic Gonadotropin
  • Organic Anion Transporters
  • Prostaglandins
  • RNA, Messenger
  • Receptors, Progesterone
  • SLCO2A1 protein, human
  • Progesterone
  • Epidermal Growth Factor
  • Luteinizing Hormone
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • PTGES protein, human
  • Prostaglandin-E Synthases