Metabolites of progesterone and the pregnane X receptor: a novel pathway regulating uterine contractility in pregnancy?
OBJECTIVE
The purpose of this study was to determine the role of 5beta-dihydroprogesterone (5beta-DHP), acting through the nuclear receptor pregnane X receptor (PXR), in regulating uterine contractility.


METHODS
Uterine contractility was studied in tissues from women, rats, and mice. Messenger RNA was assessed using reverse transcriptase-polymerase chain reaction (RT-PCR), and protein was measured using enzyme assays, immunofluorescence microscopy, and Western analyses.


RESULTS
Human and rat uterine tissues contain mRNA and protein for 5beta-reductase and for PXR. Acute in vitro treatment with 5beta-DHP causes rapid uterine relaxation that is not mediated by PXR. Chronic in vivo administration of 5beta-DHP to mice with intact PXR, but not in mice with disrupted PXR, causes an increased effect of 1400W, a specific inhibitor of inducible nitric oxide synthase (iNOS). This suggests that 5beta-DHP increased iNOS-modulated uterine tone, as occurs during pregnancy.


CONCLUSIONS
These data support the hypothesis that metabolites of progesterone may act chronically through a PXR-mediated mechanism to regulate uterine contractility.
Mitchell
Bryan F
BF
Department of Obstetrics and Gynecology, Perinatal Research Centre, University of Alberta, Edmonton, Alberta, Canada. brymitch@ualberta.ca
Mitchell
Jana M
JM
Chowdhury
Jeeshan
J
Tougas
Michelle
M
Engelen
Sanne M E
SM
Senff
Nancy
N
Heijnen
Iris
I
Moore
John T
JT
Goodwin
Bryan
B
Wong
Susan
S
Davidge
Sandra T
ST
D000704:Analysis of Variance; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D023421:Models, Animal; D008969:Molecular Sequence Data; D009215:Myometrium / Q000187:drug effects / Q000378:metabolism; D009924:Organ Culture Techniques; D011247:Pregnancy; D011270:Pregnancy, Animal; D000077297:Pregnane X Receptor; D011336:Probability; D011374:Progesterone / Q000378:metabolism* / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000378:metabolism; D011987:Receptors, Steroid / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity; D015854:Up-Regulation; D014590:Uterine Contraction / Q000187:drug effects* / Q000502:physiology
D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D011374:Progesterone