After more than four decades of assisted reproductive technology (ART) practice worldwide, today more than 60% of women undergoing in vitro fertilization (IVF) treatments fail to become pregnant after the first embryo transfer and nearly 20% of patients are suffering from unexplained recurrent implantation failures (RIFs) and repeated pregnancy loss (RPL). The literature reported different causes of RIF–RPL, mainly multifactorial, endometrial and idiopathic. RIF remains a black box because of the complicated categorization and causes of this physio-pathological dysregulation of implantation and pregnancy process after ovarian stimulation. Many options were suggested as solutions to treat RIF–RPL with controversial results on their usefulness. In this article, we reviewed different possible therapeutic options to improve implantation rates and clinical outcomes. Based on our experience we believe that endometrium immunomodulation after intrauterine insemination of activated autologous peripheral blood mononuclear cells (PBMCs) or platelet-rich plasma (PRP) can be a promising therapeutic solution. On the other hand, peripheral lymphocyte balance typing, specific cytokines and interleukins profiling can be proposed as predictive biomarkers of implantation before embryo transfer.

Growth hormone (GH) has gained attention as an anti-aging compound enhancing oocyte quality. In fact, GH is known to activate intrafollicular metabolic events for oocyte maturation. Insulin growth factor I (IGF1) is another ovarian growth factor that mediates the FSH and GH actions. Cytokines could also increase IVF outcomes. Indeed, IL-6 is a pleiotropic cytokine with multiple cellular effects that can vary based on the physiological environment. IL-6 may also play an important role in follicular development (Yang et al., J Assist Reprod Genet, 2020, 37 (5), 1171–1176). Clinical studies have been performed to explore the potential role of IL-6 in human oocyte maturation and subsequent embryonic development. To date, the answers are not conclusive. During peri-implantation, many cytokines balances are regulated like pro-inflammatory and anti-inflammatory interleukins. The pro-inflammatory properties of IL-17 and its impact on the tumor microenvironment or autoimmune diseases are characterized, but new dimensions of IL-17 activity that promotes embryo implantation are not well explored. In the search for answers, our study compared concentrations of growth factors IGF1, GH, and interleukins IL-6 and IL-17 in the follicular fluid (FF) from 140 women divided into two groups depending on bad (G1) or good prognosis (G2) and investigated the relationships between these FF components’ levels and the main parameters of IVF. GH, IGF1, and IL-6 were significantly higher for G2. For GH, it was negatively correlated to patient age and positively correlated to maturity rate and IGF1. Moreover, GH and IGF1 were correlated to the top embryo rate and cumulative pregnancy rate. Regarding IL-6, it was correlated to IGF1 level, endometrium thickness, and implantation rate. As for IL-17, it was only correlated to IL-6. Consequently, all these FF components were predictive of oocyte quality except IL-17. GH seemed to be the best biomarker of this quality.