"Ultrashort" control of hypothalamic hormones secretion: a brief history

Some 30 years ago we proposed that the synthesis of the hypothalamic releasing factors (RFs) might be influenced by changes of their own titers in the general circulation and in the hypothalamus. At that time the dominating concept was that there were two different hypothalamic RFs controling respectively follicle-stimulating hormone (FSHRF) and luteinizing hormone (LHRF). The possible existence of the first "ultrashort" feedback system was proposed on the basis of the observation that in male rats castrated, to eliminate the "long" feedback effect of testosterone, and then hypophysectomized, to abolish the possible "short" feedback effect of pituitary hormones on the hypothalamus, the intrahypothalamic levels of FSHRF resulted to be higher than in controls. Following a treatment with an hypothalamic extract, the intrahypothalamic stores of FSHRF returned to pre-operation levels, suggesting that a factor present in the hypothalamic extract might exert an inhibitory influence on the synthesis of FSHRF. In 1987, we confirmed these findings using an in vitro perfusion system of rat hypothalamic tissue, where the amount of gonadotropin-releasing hormone (GnRH) released was measured in the effluent. When a GnRH analog was added to the perfusion medium, both the spontaneous and the stimulated release of GnRH were totally obliterated. The presence of specific binding sites for GnRH has been clearly demonstrated in GnRH neurons. It is becoming consequently attractive the hypothesis that paracrine interactions might occur among GnRH neurons, entertaining an "ultrashort" feedback control of GnRH secretion.