Progesterone (P) maintains uterine quiescence in pregnancy, as evidenced by the observation that the onset of labor in most mammals occurs following a drop in maternal P. Though no measurable decrease in human P is noted with the onset of labor, two recent randomized, double-blind, placebo-controlled clinical trials demonstrated that P supplementation can reduce the reoccurrence of preterm birth (PTB) by 33-50% compared to placebo-treated pregnancies. These progestational agents represent the first therapy that addresses prevention of prematurity rather than optimization of care for the premature infant. The de novo synthesis of P from cholesterol in the placenta requires that cholesterol enter the mitochondria. P450 side chain cleavage (P450scc) and 3beta-hydroxysteroid dehydrogenase type I (3bHSD-1) act to convert cholesterol to P. MLN64 protein has been implicated in the initial cholesterol transport into the placental mitochondria for steroidogenesis. We hypothesize that a premature decrease in P synthesis in the placenta is a contributing factor in PTB, such that some women will need extra P to prevent PTB. Placental P450scc and 3bHSD-1 mRNA will be quantified using real-time RT-PCR and enzyme activity assays will be performed examining the conversion of cholesterol to pregnenolone and pregnenolone to progesterone, while protein levels will be assessed by western analysis and relative densitometry studies. Placental pregnenolone and P concentrations will be measured. MLN64 and its proteolytic variants which can enhance steroidogenesis will be studied in these same specimens by western analysis.The PTB and the 17P treated groups will be compared to gestationally age matched controls. We expect that decreased expression of the P pathway will be seen in women who respond successfully to 17P in preventing recurrent PTB. Determining the mechanism of 17P will allow therapy to specific women who are at risk for PTB without overtreatment of women who cannot respond.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Small Research Grants (R03)
Project #
5R03HD048525-02
Application #
7117014
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Signore, Caroline
Project Start
2005-09-01
Project End
2007-11-30
Budget Start
2006-09-01
Budget End
2007-11-30
Support Year
2
Fiscal Year
2006
Total Cost
$9,819
Indirect Cost
Name
University of Chicago
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637