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

Abstract

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.

Stable adrenomedullin analog mitigates placental ischemia-induced hypertension and fetal growth restriction in rats

“…Although calcium, selenium, and melatonin supplementation may lower the relative risk of preeclampsia [19][20][21], starting low-dose acetylsalicylic acid (ASA) before 16 weeks of gestation has been shown to reduce the risk of preeclampsia in high-risk women, likely due to its antioxidant and anti-inflammatory effects [22][23][24][25][26]. Additionally, progesterone can extend the time to delivery [27]. However, there is no evidence that any of these measures can substantially lengthen gestation by more than a few days once the disorder sets in [6,28,29].…”