Prof. Clin. Physiol. Laboratory for Endocrinology and Metabolism, Illrd Med. Dept., lst Sch. of Med., Charles University (General University Hospital), Prague 128 21, Czech Republic
Almost 50 years ago Harris (1947) disclosed the flow of blood from the hypothalamus to the adenohypophysis and elaborated the "neurovascular theory" of pituitary regulation (Harris 1955). He was especially interested in TSH regulation (Harris 1959). Earlier (1948) he presented evidence that adenohypophyseal function was controlled by hypothalamic humoral factor (or factors). I shall never forget the excitement which this hypothesis roused in me (as a medical student) and my surprise that neither Harris nor anybody else had tested it by classic endocrinological methods, i.e. by extraction and injection - not to speak about in vitro methods (we are in the year 1948).
I started with such experiments in 1949, than they were forcefully interrupted for the period 1950-1955, retested in 1956 and that all was reviewed previously (Schreiber 1967, 1978). By any means I still believe, that the first physiological demonstration of TRH activity in vitro was published from our laboratory (Schreiber 1961).
It was not easy at that times. Endocrinology was declared as an capitalistic nonscience in the former Czechoslovakia. What more: at an international symposium held in Miami in 1961 (Nalbandov 1963) it was said: The oddity of the situation with respect to the hypothalamic X substances is that never before, to my knowledge, except for the monster of Loch Ness and the abominable Snowman of the Himalayas, has the existence of hypothetical object been indicated by so much imposing circumstantial evidence. Soon it was, however, shown, that the hypothalamic hormones are not "watery illusions" nor "some plain old minnows of the genus Octopepdidarius" - they seemed , however, to possess some qualities of Proteus and had expanded or contracted their body size. This was especially the case with TRH (for review, see Schreiber 1967).
In 1966 I agreed to a reciprocal exchange of TRF samples with a well-known laboratory abroad. Their sample arrived and was active in my laboratory, and I sent a report to that effect. Apart from being informed that my sample had arrived and that it was hygroscopic and brown, I learned nothing more. A year later, when visiting the laboratory concerned, I inquired and was told that the laboratory was not interested in testing TRF samples, which were not sufficiently pure. The reader will no doubt appreciate that this was a source of amusement to me rather than bitterness. Imagine Prague in the early sixties!
For some time (Schreiber 1967) TRF was considered not to be a peptide, even by the most renowned laboratories. This is why I ascribed to it a Protean nature. Anyway Schally (for review see Schally 1978) and Guillemin (for review see Guillemin 1978) righfully shared a quarter of Nobel Prize, each, for the discovery of TRH structure. One half of the prize was ascribed - again rightfully - to Rosalyn Yellow, for the discovery of radioimmunoassay.
The modification of the peptide molecule - i. e. pyroglutamyl-histidyl-prolineamide and TRH formation as a pre-pro-hormone, containing 242 amino acids and six copies of TRH (Tyrrell et al. 1994) were the source of a confusion. TRH-secreting neurones are localised in the medial portions of the paraventricular nuclei and their axons terminate in the median eminence. Here, TRH is delivered into the portal blood for the adenohypophysis, to stimulate TSH (and PRL) secretion.
But is that all? TRH is localised in the brain and in the gastrointestinal system. -. There is more TRH in the brain areas outside the hypothalamus than in the hypothalamus (Baxter 1994) - the neurotransmitter actions of TRH include increased motor activity, arousal, tremor, and enhanced peripheral sympathetic activity. For some time, TRH was considered as a drug for depression. TRH is detectable in a variety of tumors, mostly of the neuroendocrine type (Benz and Lewin, 1994). It also stimulates the secretion of prolactin (Greenspan 1994). Soon we shall hear about other extrahypophyseal activities of TRH and TRH- like peptides.
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Nalbandov A. V. (Ed): Advances in neuroendocrinology, p. 511.University of Illinois Press, Urbana 1963.
Schally A. V.: In the pursuit of hypothalamic hormones. In: Pioneersin Neuroendocrinology 11, Meites J., Donovan B. T., McCann S. M. Eds., Plenum Press, New York and London, 1978.
Schreiber V., Eckertova A., Franz Z., Koci J., Rybak M., Kmentova V.: Effect of a fraction of bovine hypothalamic extract on the release ofTSH by rat adenohypophyses in vitro. Experientia 17: 264, 1961.
Schreiber V.: Thyrotropin-releasing factor: purification, mechanismand blockage of action. Neuroendocrinology 2: 175, 1967.
Schreiber V.: Being an outsider. In: Pioneers in Neuroendocrinology 11, Meites J., Donovan B. T., McCann S. M. (Eds) Plenum Press, NewYork and London, 1978.
Tyrrel J. B., Findling J. W., Aron D. C.: Hypothalamus and pituitary. In: Basic and Clinical Endocrinology. A Lange medical book. FourthEdition. Greenspan F. S., Baxter J. D. (Eds) Appleton and Lange, Norwalk, Conn., 1994.
