Aberrations in the progesterone pathway and the Th1/Th2 cytokine dichotomy - An evaluation of RPL predisposition in the northeast Indian population.

Abstract

Recurrent pregnancy loss (RPL) is the spontaneous loss of two or more consecutive pregnancies prior to 20weeks of gestation, occurring in 1% of the reproductive-age population. It is a major cause of infertility in India with a staggering 7.46% prevalence rate. Blood and product of conception (POCs) from RPL cases (n=65) were enrolled for this study, along with cases of medically terminated pregnancy (MTP, n=80) and term delivery cases (n=90) as control. ELISA for progesterone and progesterone induced blocking factor (PIBF) levels was carried out, followed by mRNA expression analysis of progesterone receptor isoform B (PR-B) and its downstream immunomodulatory effectors, namely, PIBF, IL-10 and IL-12. Screening of PROGINS haplotype of PR gene and PIBF polymorphism were also conducted to correlate with their respective gene expression profiles. Serum progesterone level was found to be comparable in the RPL and MTP cases. Although the mRNA expression of PR-B was found to be downregulated in the RPL cases, no significant PROGINS haplotype was observed. Presence of a single nucleotide polymorphism (SNP) in the PIBF gene (rs1372000) was more in healthy controls compared to RPL cases. Serum PIBF levels were found to be lower in the RPL cases with a resultant increase in IL-12 and a decrease in IL-10 mRNA expression in these cases. This study indicates that progesterone, acting through PIBF, modulates the immunological state of pregnancy to be Th1-biased in RPL, indicative of a pro-inflammatory, labour-like state not desired for a healthy pregnancy.