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



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



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



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.



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.



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.
Department of Obstetrics and Gynecology, University of Kentucky College of Medicine, Lexington, Kentucky 40536.
Yohan
Y
Choi
Department of Obstetrics and Gynecology, University of Kentucky College of Medicine, Lexington, Kentucky 40536.
Kalin
K
Wilson
Department of Obstetrics and Gynecology, University of Kentucky College of Medicine, Lexington, Kentucky 40536.
Patrick R
PR
Hannon
Department of Obstetrics and Gynecology, University of Kentucky College of Medicine, Lexington, Kentucky 40536.
Katherine L
KL
Rosewell
Department of Obstetrics and Gynecology, University of Gothenburg, 405 30 Gothenburg, Sweden.|Stockholm IVF, 112 81 Stockholm, Sweden.
Mats
M
Brännström
Bluegrass Fertility Center, Lexington, Kentucky 40503.
James W
JW
Akin
Department of Obstetrics and Gynecology, University of Kentucky College of Medicine, Lexington, Kentucky 40536.
Thomas E
TE
Curry
Department of Obstetrics and Gynecology, University of Kentucky College of Medicine, Lexington, Kentucky 40536.
Misung
M
Jo
D000328:Adult; D066258:Amphiregulin / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D005260:Female; D005307:Fertilization in Vitro; D020869:Gene Expression Profiling; D006107:Granulosa Cells; D006801:Humans; D007150:Immunohistochemistry; D008184:Luteal Cells; D007986:Luteinizing Hormone; D027361:Organic Anion Transporters / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D006080:Ovarian Follicle / Q000378:metabolism*; D010060:Ovulation; D016133:Polymerase Chain Reaction; D011374:Progesterone / Q000378:metabolism*; D000071876:Prostaglandin-E Synthases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011980:Receptors, Progesterone / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism
C587848:AREG protein, human; D066258:Amphiregulin; D006063:Chorionic Gonadotropin; D027361:Organic Anion Transporters; D011453:Prostaglandins; D012333:RNA, Messenger; D011980:Receptors, Progesterone; C503526:SLCO2A1 protein, human; D011374:Progesterone; D004815:Epidermal Growth Factor; D007986:Luteinizing Hormone; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases