Even before the identities and structures of many hormones were established, endocrinologists and physiologists had speculated about the mechanism of their action. A hundred years later, we are still struggling to establish in molecular and cellular terms the mode of physiological action of a given hormone. Two major reasons account for this situation: i) the failure to recognise that hormones as signalling molecules have been highly conserved during evolution but that their physiological actions vary enormously in different organisms or from one tissue to another in the same species; ii) that most investigations aiming to reveal the mechanism of action have been technology-driven and not hypothesis-based, as will be illustrated with a few time-lines.
Despite these shortcomings, a major advance was made with the introduction of the concept of hormone receptors, which, thanks to the advent of gene cloning technologies, are now molecularly and structurally well defined as key elements of hormone action. They are cellular homologues of the oncogenes c-erbB or c-erbA, located in the cell membrane or as transcription factors in the nucleus, respectively. Current thinking on understanding of how hormones act at the cellular and molecular levels is now focused on convergence of signalling pathways from different cellular locations, attempts to understand the immediate consequence of hormone-receptor interaction and the wider involvement of genomic and non-genomic networks.
In view of what may sound as a rather negative account, one may well ask: Is it worth continuing to look for mechanisms of hormone action? The answer is most emphatically yes. So many concepts of cellular signalling mechanisms have emerged from work on hormone action. Just consider the discovery of cyclic AMP and the functions of several transcription factors.