Progesterone prolongs time to delivery and attenuates blood pressure possibly by improving inflammation and endothelial function in response to preeclampsia.

Preeclampsia (PE), new onset hypertension during pregnancy, affects 5-7% of all pregnancies in the U.S. and is associated with reduced fetal weight, increased inflammation, vascular endothelial dysfunction (increased endothelin-1 (ET-1) and decreased nitric oxide (NO)) and hypertension. To date the best treatment remains early delivery of the feto-placental unit. Activated lymphocytes during normal pregnancy (NP) express progesterone receptors, which stimulate a protein called Progesterone Induced Blocking Factor (PIBF) that is reduces during hypertensive pregnancy disorders. Therefore, this study was designed to test the hypothesis that progesterone, in the form of 17-hydroxyprogesterone caproate (17-OHPC), reduces inflammation, markers of endothelial dysfunction while reducing blood pressure and prolong time to delivery in PE women. In our ongoing clinical trial, PE participants received 17-OHPC (250 mg, I.M.) with blood draws before and after injection. Placentas were collected at delivery. PIBF was 18.6 +/-1.0 pg/mL in NT (n=4), 14.53 +/- 1.0 pg/mL in PE (n=10, p<0.05), and 15.78 +/-0.85 in PE+17-OHPC (n=6). Placental CD4+ T cells were 6.5+/- 2.7 in PE (n=3), 4.6+/- 2.0 in PE +17-OHPC (n=4). Circulating CD4+ T cells were 18.23 +/-4.8 in PE (n=4), 14.4+/-1.2 % gate in PE+17-OHPC (n=5). Placental TH2 cells were 81.7+/-10.6% gate in PE and 84.7+/-11.0 in PE+17-OHPC. Placental and circulating NK cells were 20.84 +/- 6.8 % gate, 7.2 +/- 2.0 in PE which reduced to 4.7+/-1.03, 5.3 +/- 1.5 % gate in PE+17-OHPC. Circulating TNF-alpha was 32.0 +/- 3.4 pg/mL in PE (n=8), which decreased to 21.1+/-5.5 in PE+17OHPC (n=4). Circulating ET-1 was 2.53+/- 0.4 pg/mL in healthy normal pregnant (NP, n=5), 6.7 +/- 1.4 in PE (n=18, p<0.05) and 4.9 +/- 1.3 in PE+17-OHPC. Placenta preproendothelin -1 (PPET-1) increased 1.5 fold change in PE (n=4) compared to NP, which was reduced to 0.96 in PE+17-OHPC (n=4). Importantly, endotheling-1 measured in HUVECS media treated with PE sera was 68 +/- 22 pg/mg of protein in PE which reduced to 57 +/-19 in PE+17OHPC (n=6). Moreover, circulation nitrate-nitrite was 50 +/- 9 uM in PE and significantly increased to 94 +/-14 in PE+17-OHPC. 17-OHPC prolonged time of delivery beyond 72h on average and average systolic blood pressure was 151 +/- 5 mmHg in PE (n=18) and 137+/-4 in PE+17-OHPC (n=13). Our results suggest that 17-OHPC reduced inflammation, markers of endothelial dysfunction, lowered blood pressure and prolonged time do delivery in PE women.