Outside the box signaling: Secreted factors modulate GnRH receptor-mediated gonadotropin regulation

•The existence of a complex regulatory network of locally secreted factors has implications for physiology and pathophysiology.•Exosignaling is emerging as a novel key mechanism in the regulation of gonadotropin expression.•Exosignaling may play an important role in GnRH pulse frequency decoding by the gonadotrope. Control of gene expression following activation of membrane receptors results from the regulation of intracellular signaling pathways and transcription factors. Accordingly, research to elucidate the regulatory control circuits and cellular data processing mechanisms focuses on intracellular mechanisms. While autocrine and paracrine signaling are acknowledged in endocrinology, secreted factors are not typically recognized as fundamental components of the pathways connecting cell surface receptors to gene control in the nucleus. Studies of the gonadotrope suggest that extracellular regulatory loops may play a central role in the regulation of gonadotropin gene expression by gonadotropin-releasing hormone (GnRH) receptor activation. We review emerging evidence for this phenomenon, which we refer to as exosignaling, in gonadotropin gene control and in other receptor-mediated signaling systems. We propose that basic signaling circuit modules controlling gene expression can be seamlessly distributed across intracellular and exosignaling components that together orchestrate the precise physiological control of gene expression.