Progesterone inhibits basal and TNF-alpha-induced apoptosis in fetal membranes: a novel mechanism to explain progesterone-mediated prevention of preterm birth.
OBJECTIVE
Progesterone supplementation prevents preterm birth (PTB) in some high-risk women, but its mechanism of action is not known. One third of PTB is associated with preterm premature rupture of membranes (PPROM). We hypothesize that progesterone may block proinflammatory cytokine-induced apoptosis of fetal membrane, thereby preventing PPROM and PTB.


METHODS
Fetal membranes were collected at elective repeat cesarean at term (no labor, no infection [n = 12]), washed, and cultured with/ without progesterone (125-500 ng/mL), 17alpha-hydroxyprogesterone caproate (125-500 ng/mL [17P]), or medroxyprogesterone acetate (10(-7)-10( -6) mol/L [MPA]) for 24 hours. Membranes were then treated with/without lipopolysaccharide ([LPS] 100 ng/mL) or tumor necrosis factor alpha ([TNF-alpha] 50 ng/ mL) for 24 to 72 hours, harvested, and homogenized. Apoptosis was determined by evaluating caspase-3, -8, and -9 activities. Caspase activity in relative light units was measured on a luminometer and corrected for total protein.


RESULTS
Both TNF-alpha and LPS significantly increased caspase-3, -8, and -9 activity in term fetal membranes in a time-dependent fashion. Progesterone, 17P, and MPA significantly reduced TNF-alpha, but not LPS, induced caspase-3 activity. Interestingly, progesterone and MPA, but not 17P, also inhibited basal caspase-3 activity.


CONCLUSIONS
Progesterone inhibits basal and TNF-alpha-induced apoptosis in term fetal membranes. This novel observation may explain in part the mechanism by which progesterone supplementation prevents PPROM and PTB in some high-risk women. The effect of progesterone on the basal levels of apoptosis suggests that this mechanism may also be important for normal labor at term.
Luo
Guoyang
G
Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Abrahams
Vikki M
VM
Tadesse
Serkalem
S
Funai
Edmund F
EF
Hodgson
Eric J
EJ
Gao
Jinsong
J
Norwitz
Errol R
ER
D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D005321:Extraembryonic Membranes / Q000166:cytology / Q000187:drug effects*; D005260:Female; D005322:Premature Rupture of Fetal Membranes / Q000517:prevention & control; D006801:Humans; D011247:Pregnancy; D047928:Premature Birth / Q000517:prevention & control*; D011374:Progesterone / Q000494:pharmacology* / Q000627:therapeutic use; D011372:Progestins / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000633:toxicity*
D011372:Progestins; D014409:Tumor Necrosis Factor-alpha; D011374:Progesterone