The development of the releasing factor concept.

After four decades of intense and competitive research, three hypothalamic releasing hormones (formerly factors) have recently been isolated and characterized. These are the decapeptide gonadotrophin releasing hormone (GnRH), tripeptide thyrotrophin releasing hormone (TRH), and the tetradecapeptide somatostatin. Some aspects of these hormones are discussed, and GnRH is considered in greater detail to demonstrate the difficulties involved in fulfilling completely the criteria which determine whether a substance can be accepted as a physiological releasing hormone. A substance immunologically similar to GnRH is present in rat hypophysial portal vessel blood, but, while the amount of this substance released into the portal circulation can be increased significantly by electrical stimulation of the preoptic area, no significant changes occur during the oestrous cycle or after long-term castration. This may be due to interference with the normal secretion of GnRH by the trauma and anaesthesia which necessarily accompany exposure of the pituitary stalk. However, the possibility exists that our preconceived notions regarding the changes in plasma levels of releasing hormones under physiological conditions may be incorrect. Thus it seems likely that changes in the rate of secretion of thyrotrophin is effected by throid hormones modulating the responsiveness of the thyrotrophs to a steady input of TRH. Evidence is presented for the existence of a similar mechanism for gonadotrophin secretion, and the role of steroid hormones and the priming effect of GnRH in modulating the responsiveness of the gonadotrophs is considered. The intrinsic connexions of the hypothalamus, the role of the hypothalamic aminergic systems and the autonomy of the hypothalamus with respect to anterior pituitary control present many problems which will prove difficult to solve.