GnRH drives an inflammatory process with concomitant SAT1 upregulation through ERK/PI3K signaling pathways in pituitary gonadotrope cells during the preovulatory surge

Abstract Pituitary gonadotrope cells are central regulators of reproduction through the secretion of gonadotropins under the control of gonadotropin-releasing hormone (GnRH). While the preovulatory surge of GnRH is known to trigger massive gonadotropin release, the molecular mechanisms supporting this process remain incompletely understood. Here, we demonstrate, using single-cell and temporal analyses on rat pituitary gland combined with in situ and in vitro analyses, that the preovulatory period is associated with a transient inflammatory-like response. This response is characterized by increased expression of pro-inflammatory mediators ( Tnf , Il6 , Ptgs2 ) without evidence of increased pituitary leukocyte infiltration. We further demonstrated a decreased expression of the anti-inflammatory gene Elovl2 concomitant with a rise in Sat1 , encoding the rate-limiting enzyme of polyamine catabolism. Gonadotrope cells were identified as key contributors to this process. Indeed, in LβT2 gonadotrope cells, GnRH directly induces inflammatory gene expression via ERK and PI3K signaling pathways, with distinct sensitivity to pulsatile patterns. Notably, sustained GnRH exposure, mimicking the preovulatory surge, is required to induce a subset of inflammatory-related genes, including Sat1 . Promoter analyses reveal that GnRH regulates Sat1 transcription through a proximal region involving FOXO transcription factors, acting as repressors relieved upon GnRH signaling. Functionally, although modulation of polyamine metabolism does not affect gonadotropin secretion, SAT1 contributes to GnRH-induced expression of inflammatory mediators as evidenced by SAT1 loss-of-function and pharmacological experiments. Together, these findings uncover a previously unrecognized regulation of polyamine metabolism and inflammatory pathways by GnRH in gonadotrope cells, suggesting that a controlled inflammatory-like state contributes to pituitary plasticity during ovulation.