0013.7227/92/1315-2042$03.00/0 Endocrinology Copyright 0 1992 by The Endocrine
Society
:-, .0 75
Vol. 131, No. 5 Printed in U.S.A.
th
YEAR
Remembrance: The Discovery of Growth Hormone (GH)Releasing Hormone and GH Release-Inhibiting Hormone In contrast to the other pituitary hormones, there was little information pertaining to a possible hypothalamic control of GH. In 1961, Reichlin (1) reported that basal hypothalamic lesions in rats interfered with growth and lowered the content of GH in the pituitary gland which suggested hypothalamic control. Before that time, in the mid 195Os, the argument continued to swirl as to whether or not vasopressin was a CRF, and whether there was an additional factor called CRF. At that time I was asked by Schering Corporation (Bloomfield, NJ) to serve as a consultant in the search for a GRF. I made four trips to their laboratories in 1958 and spent a half day each time discussing methods to discover such a factor. After that time, I heard no more about the matter for several years. In the early 1960s we were purifying the various releasing factors. We had obtained evidence for a GRF in crude extracts of pituitary stalk-median eminence tissue by measuring the effect of systemic injection of these extracts on the GH content of the pituitary as estimated by the only bioassay available; i.e. the tibia1 epiphyseal cartilage assay in hypophysectomized rats (2). By this time we had already shown that injections of GH depleted pituitary GH and had postulated a shortloop feedback of GH to suppress its own release (3). We concluded that this action was at least partly at the hypothalamic level because we could also deplete pituitary GH and reduce anterior pituitary weight of rats by implanting GH into the region of the median eminence (4).
By 1964 we had fractionated large batches of stalkmedian eminence extracts from sheep using a long Sephadex G-25 column and assayed the fractions for releasing factors which included LHRF, FSH-releasing factor, PRL-inhibiting factor, CRF, vasopressin, and GRF. The first paper on the purification of GRF was presented at the plenary session of The Endocrine Society in June 1965 (5) in New York and published in Endocrinology in that year (6). In early 1965, I received two peptides, stated to be almost pure, from Schering for testing for releasing factor activity. We screened both of these peptides and one of them released only GH. We were very excited about the Received May 4, 1992. “Remembrance” articles discuss people and events as remembered the author. The opinion(s) expressed are solely those of the writer do not reflect the view of the Journal or The Endocrine Society.
by and
results and proposed to Schering a joint publication on the purification of GRF; however, we never heard anything further about the matter. When we were writing up the results, we discovered a prior paper on GRF published in 1962 by Franz, Haselbach, and Leibert (7). They reported that a purified GRF obtained from Schering Corporation would enhance growth of rats and cause the release of GH into the medium of pituitaries incubated in vitro. In 1964, Deuben and Meites (8) demonstrated that median eminence extracts released GH from hemipituitaries incubated in uitro, whereas cerebral cortex extracts were ineffective. The in vitro studies of Meites and colleagues (8) which showed that hypothalamic but not cerebral cortical extracts released various pituitary hormones convinced us to switch to an in vitro bioassay using hemipituitaries. The key was the use of preincubation to eliminate the large background hormone release during the initial incubation of the glands. Using the in vitro system, we confirmed the location of GRF in several sequential fractions from the Sephadex column. By this time (1967), we had moved from Philadelphia to Dallas and Krulich had come back to work on the problem. One Friday he came to me very excited stating that we had an inhibitor in fractions which emerged from the column shortly after GRF. I was extremely skeptical and thought that this might be a toxic contaminant in the tubes. He confirmed the activity and we then ran three additional Sephadex columns where we found the activity in the same location. This convinced us that the inhibitor was real and we submitted the first paper on GH-inhibiting factor (GIF) and also demonstrated its separation from GRF (9). We further purified GRF and GIF on carboxymethyl cellulose (6,lO). We went on to study the effect of these factors on the content as well as the release of GH from pituitaries incubated in vitro and the effect of coaddition of the GRF and GIF, showing that they could antagonize each other (11). We also demonstrated that the factors acted only on GH, and not on other pituitary hormones (12,13). In the meantime, the existence of both of these factors was not widely accepted. Schally’s group obtained highly purified GRF (14); however, Guillemin and collaborators reported (15) that they could find neither GRF nor GIF after purification of basic hypothalamic extracts by gel filtration on Sephadex G-25. Basic extracts were not
2042
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 20 November 2015. at 03:20 For personal use only. No other uses without permission. . All rights reserved.
REMEMBRANCE
generally used before, or since, to extract peptides of this type and may have been used in this instance because these fragments were collected by John Beck in Canada; he was primarily interested in extracting GH from the pituitary which does require basic conditions. It was my view that they might have pooled the fractions containing GRF and GIF, thereby extinguishing the activities of both factors. At the Tucson meeting on Releasing Factors in 1969, the existence of both GRF and GIF was called to question. It was claimed that these were artifacts of the tibia1 epiphyseal cartilage assay (16). At that time, we had already sent media from fractions incubated with hemipituitaries in vitro to Peake in Daughaday’s laboratory, who had confirmed the GRF activity of the fractions by RIA of GH (17). After this meeting we confirmed and purified both activities by RIA of the GH released from the incubated pituitaries (18). To localize the activities in the hypothalamus, frozen sections were cut through the hypothalamus in three planes at right angles to each other, extracted, and bioassayed for the various releasing factors and inhibiting factors. By this means GRF was located in the region of the arcuate-ventromedial nucleus and GIF in the median eminence and also in the suprachiasmatic region (18). These localizations were subsequently shown to be correct; the observations antedated the definitive localizations by immunocytochemistry (19,20). Guillemin’s group was very fortunate to be able to isolate and determine the structure of GIF using extract from only 500,000 sheep hypothalami. This was made possible by the development by Brazeau et al. (21) of an assay which was excruciatingly sensitive to the inhibitor, namely the 4-day monolayer cultured pituitary cell assay. Both Guillemin and I were members of an international committee to rename peptide hormones and the names liberin for stimulatory factors and sequestrin for inhibitors had been proposed. Therefore, it was not surprising that Guillemin renamed GIF, somatostatin (SRIF) (21). It has never been shown to produce growth stasis, as expected from the name, since it is a very labile molecule. Thus, somatostatin is a misnomer. Because of its marked inhibitory action at many sites throughout the body, we proposed an alternative name, panhibin (22). Finally, the recently developed, long acting, highly potent analog of the peptide can produce growth stasis. The breakthrough in GRF research was provided by Frohman, who discovered an extra-hypothalamic tumor which secreted GRF. Unfortunately, he did not isolate and determine structure of the peptide. Thorner uncovered a similar tumor and sent it to Vale at the Salk Institute for fractionation. Since this tumor contained manyfold more GRF than the hypothalamus and lacked SRIF and with the advances in peptide chemistry in the intervening years, Rivier, Vale, and their co-workers (23)
2043
were able to determine the structure of the human pancreatic GRF in 1982. However, Guillemin was fortunate to secure a similar tumor in France which he brought back to his laboratory also at the Salk Institute. His group (24) determined the structure from this tumor, which was identical to that obtained by Rivier et al. (23) except for the addition of four amino acids at the Cterminal end of the molecule. That compound constitutes the bulk of the GRH found in the human hypothalamus, although there is a small amount of the 40 amino acid GRH as well. Finally, 12 yr after the discovery of the structure of SRIF, the structure of GRH had been revealed. Samuel M. McCann Department of Physiology Neuropeptide Division The University of Texas Southwestern Medical Center
References 1.
Reichlein S 1961 Growth
hormone content of pituitaries from rats Endocrinology 69:225-230 Krulich L, Dhariwal AL’S, McCann SM 1965 Growth hormonereleasing activity of crude ovine hypothalamic extracts. Proc Sot Exp Biol Med 120:180-184 Krulich L, McCann SM 1966 Influence of growth hormone (GH) on content of GH in the pituitaries of normal rats. Proc Sot Exp Biol Med 121:1114-1117 Katz SH, Molitch M, McCann SM 1969 The effect of hypothalamic implants of growth hormone (GH) on anterior pituitary weight and GH concentration. Endocrinology 85:725-734 Krulich L, Dhariwal AL’S, McCann SM, Hypothalamic control of growth hormone (GH) secretion. Program of the 47th Annual Meeting of the Endocrine Society, New York, 1965, p 21 (Abstract) Dhariwal AT’S, Krulich L, Katz S, McCann SM 1965 Purification of growth hormone-releasing factor (GH-RF). Endocrinology 771932-936 Franz J, Haselbach CH, Libert 0 1962 Studies of the effect of hypothalamic extracts on somatotrophic pituitary function. Acta Endocrinol (Copenh) 41:336-350 Deuben RR, Meites J 1964 Stimulation of pituitary growth hormone release by a hypothalamic extract in vitro. Endocrinology 74:408414 Krulich L, Dhariwal AL’S, McCann SM 1968 Stimulatory and inhibitory effects of purified hypothalamic extracts on growth hormone release from rat pituitary in vitro. Endocrinology 83:783-790 Dhariwal APS, Krulich L, McCann SM 1969 Purification of a growth hormone inhibiting factor (GIF) from sheep hypothalamus, Neuroendocrinology 4:282-288 Krulich L, McCann SM 1969 Effect of GRF and GIF on the release and concentration of GH in pituitaries incubated in vitro. Endocrinology 85:319-324 Crighton DB, Schneider HPG, McCann SM 1969 A study of the possible interaction of LRF with other hypothalamic releasing factors at the level of the pituitary gland. J Endocrinol 44:405-410 McCann SM, Dhariwal APS, Porter JC 1968 Regulation of the adenohypophysis. Ann Rev Physiol30:589-640 with
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13. 14.
hypothalamic
lesions.
Ali AV, Arimura A, Wakabashyi I, Sawano S, Barrett JF, Bowers CY, Redding TW, Mittler JC, Saito A 1970 The chemistry of hypothalmic growth hormone-releasing J (ed) Hypophysiotropic Hormones and Chemistry. Williams & Wilkins 226
hormone (GRH). of the Hypothalamus: Company, Baltimore,
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 20 November 2015. at 03:20 For personal use only. No other uses without permission. . All rights reserved.
In: Meites Assay pp 20%
2044
REMEMBRANCE
15. Roger NW, Beck JC, Burgus R, Guillemin R 1969 Variability of response in the bioassay for hypothalamic somatotropin-releasing factor based on rat pituitary growth hormone content. Endocrinology 84:1373-1383 16. Daughaday WH, Peake GT, Machlin LJ 1970 Assay of the growth hormone releasing factor. In: Meites J (ed) Hypophysiotropic Hormones of the Hypothalamus: Assay and Chemistry. Williams & Wilkins Company, Baltimore, pp 151-170 17. McCann SM 1970 In: Meites J (ed). Hypophysiotropic Hormones of the Hypothalamus: Assay and Chemistry. Williams & Wilkins Company, Baltimore. Discussion to Ref. 16, pp 163-165 L, Illner I’, Fawcett CP, Quijada M, McCann 1972 Dual 18. Krulich hypothalamic regulation of growth hormone secretion. In: Pecile A, Muller EE (eds) Growth and Growth Hormone. Excerpta Medica International Congress Series, no 244, pp 306-316 19. Elde R, Hokfelt T 1979 Localization of hypophysiotropic peptides and other biologically active peptides within the brain. Ann Rev Physiol41:587-602
Endo. Voll31.
1992 No 5
20. Bloch B, Brazeau P, Ling N, Bohlen P, Esch F, Wehrenberg WB, Benoit R, Bloom F, Guillemin R 1983 Immunohistochemical detection of growth hormone-releasing factor in brain. Nature 301:607-608 21. Brazeau P, Vale W, Burgus R, Ling N, Butcher M, Rivier J, Guillemin R 1973 Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science 179:77-79 ._ -._... 22. McCann SM, Krulich L, Negro-Vilar A, Ojeda SR, Vijayan E 1980 Regulation and function of panhibin (somatostatin). In: Costa E, Trab&hi M (eds) Neural Peptides and‘Neurona1 Communication. Advances in Biochemical Psychopharmacology. Raven Press, New York, pp 131-143 23. Rivier J, Spiess J, Thorner M, Vale W 1982 Characterization of a growth hormone-releasing factor from a human pancreatic islet tumour. Nature 300:276-278 24. Guillemin R, Brazeau P, Bohlen P, Esch F, Ling N, Wehrenberg WB 1982 Growth hormones-releasing factor from a human pancreatic tumor that caused acromegaly. Science 218:585-587
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 20 November 2015. at 03:20 For personal use only. No other uses without permission. . All rights reserved.
Society
:-, .0 75
Vol. 131, No. 5 Printed in U.S.A.
th
YEAR
Remembrance: The Discovery of Growth Hormone (GH)Releasing Hormone and GH Release-Inhibiting Hormone In contrast to the other pituitary hormones, there was little information pertaining to a possible hypothalamic control of GH. In 1961, Reichlin (1) reported that basal hypothalamic lesions in rats interfered with growth and lowered the content of GH in the pituitary gland which suggested hypothalamic control. Before that time, in the mid 195Os, the argument continued to swirl as to whether or not vasopressin was a CRF, and whether there was an additional factor called CRF. At that time I was asked by Schering Corporation (Bloomfield, NJ) to serve as a consultant in the search for a GRF. I made four trips to their laboratories in 1958 and spent a half day each time discussing methods to discover such a factor. After that time, I heard no more about the matter for several years. In the early 1960s we were purifying the various releasing factors. We had obtained evidence for a GRF in crude extracts of pituitary stalk-median eminence tissue by measuring the effect of systemic injection of these extracts on the GH content of the pituitary as estimated by the only bioassay available; i.e. the tibia1 epiphyseal cartilage assay in hypophysectomized rats (2). By this time we had already shown that injections of GH depleted pituitary GH and had postulated a shortloop feedback of GH to suppress its own release (3). We concluded that this action was at least partly at the hypothalamic level because we could also deplete pituitary GH and reduce anterior pituitary weight of rats by implanting GH into the region of the median eminence (4).
By 1964 we had fractionated large batches of stalkmedian eminence extracts from sheep using a long Sephadex G-25 column and assayed the fractions for releasing factors which included LHRF, FSH-releasing factor, PRL-inhibiting factor, CRF, vasopressin, and GRF. The first paper on the purification of GRF was presented at the plenary session of The Endocrine Society in June 1965 (5) in New York and published in Endocrinology in that year (6). In early 1965, I received two peptides, stated to be almost pure, from Schering for testing for releasing factor activity. We screened both of these peptides and one of them released only GH. We were very excited about the Received May 4, 1992. “Remembrance” articles discuss people and events as remembered the author. The opinion(s) expressed are solely those of the writer do not reflect the view of the Journal or The Endocrine Society.
by and
results and proposed to Schering a joint publication on the purification of GRF; however, we never heard anything further about the matter. When we were writing up the results, we discovered a prior paper on GRF published in 1962 by Franz, Haselbach, and Leibert (7). They reported that a purified GRF obtained from Schering Corporation would enhance growth of rats and cause the release of GH into the medium of pituitaries incubated in vitro. In 1964, Deuben and Meites (8) demonstrated that median eminence extracts released GH from hemipituitaries incubated in uitro, whereas cerebral cortex extracts were ineffective. The in vitro studies of Meites and colleagues (8) which showed that hypothalamic but not cerebral cortical extracts released various pituitary hormones convinced us to switch to an in vitro bioassay using hemipituitaries. The key was the use of preincubation to eliminate the large background hormone release during the initial incubation of the glands. Using the in vitro system, we confirmed the location of GRF in several sequential fractions from the Sephadex column. By this time (1967), we had moved from Philadelphia to Dallas and Krulich had come back to work on the problem. One Friday he came to me very excited stating that we had an inhibitor in fractions which emerged from the column shortly after GRF. I was extremely skeptical and thought that this might be a toxic contaminant in the tubes. He confirmed the activity and we then ran three additional Sephadex columns where we found the activity in the same location. This convinced us that the inhibitor was real and we submitted the first paper on GH-inhibiting factor (GIF) and also demonstrated its separation from GRF (9). We further purified GRF and GIF on carboxymethyl cellulose (6,lO). We went on to study the effect of these factors on the content as well as the release of GH from pituitaries incubated in vitro and the effect of coaddition of the GRF and GIF, showing that they could antagonize each other (11). We also demonstrated that the factors acted only on GH, and not on other pituitary hormones (12,13). In the meantime, the existence of both of these factors was not widely accepted. Schally’s group obtained highly purified GRF (14); however, Guillemin and collaborators reported (15) that they could find neither GRF nor GIF after purification of basic hypothalamic extracts by gel filtration on Sephadex G-25. Basic extracts were not
2042
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 20 November 2015. at 03:20 For personal use only. No other uses without permission. . All rights reserved.
REMEMBRANCE
generally used before, or since, to extract peptides of this type and may have been used in this instance because these fragments were collected by John Beck in Canada; he was primarily interested in extracting GH from the pituitary which does require basic conditions. It was my view that they might have pooled the fractions containing GRF and GIF, thereby extinguishing the activities of both factors. At the Tucson meeting on Releasing Factors in 1969, the existence of both GRF and GIF was called to question. It was claimed that these were artifacts of the tibia1 epiphyseal cartilage assay (16). At that time, we had already sent media from fractions incubated with hemipituitaries in vitro to Peake in Daughaday’s laboratory, who had confirmed the GRF activity of the fractions by RIA of GH (17). After this meeting we confirmed and purified both activities by RIA of the GH released from the incubated pituitaries (18). To localize the activities in the hypothalamus, frozen sections were cut through the hypothalamus in three planes at right angles to each other, extracted, and bioassayed for the various releasing factors and inhibiting factors. By this means GRF was located in the region of the arcuate-ventromedial nucleus and GIF in the median eminence and also in the suprachiasmatic region (18). These localizations were subsequently shown to be correct; the observations antedated the definitive localizations by immunocytochemistry (19,20). Guillemin’s group was very fortunate to be able to isolate and determine the structure of GIF using extract from only 500,000 sheep hypothalami. This was made possible by the development by Brazeau et al. (21) of an assay which was excruciatingly sensitive to the inhibitor, namely the 4-day monolayer cultured pituitary cell assay. Both Guillemin and I were members of an international committee to rename peptide hormones and the names liberin for stimulatory factors and sequestrin for inhibitors had been proposed. Therefore, it was not surprising that Guillemin renamed GIF, somatostatin (SRIF) (21). It has never been shown to produce growth stasis, as expected from the name, since it is a very labile molecule. Thus, somatostatin is a misnomer. Because of its marked inhibitory action at many sites throughout the body, we proposed an alternative name, panhibin (22). Finally, the recently developed, long acting, highly potent analog of the peptide can produce growth stasis. The breakthrough in GRF research was provided by Frohman, who discovered an extra-hypothalamic tumor which secreted GRF. Unfortunately, he did not isolate and determine structure of the peptide. Thorner uncovered a similar tumor and sent it to Vale at the Salk Institute for fractionation. Since this tumor contained manyfold more GRF than the hypothalamus and lacked SRIF and with the advances in peptide chemistry in the intervening years, Rivier, Vale, and their co-workers (23)
2043
were able to determine the structure of the human pancreatic GRF in 1982. However, Guillemin was fortunate to secure a similar tumor in France which he brought back to his laboratory also at the Salk Institute. His group (24) determined the structure from this tumor, which was identical to that obtained by Rivier et al. (23) except for the addition of four amino acids at the Cterminal end of the molecule. That compound constitutes the bulk of the GRH found in the human hypothalamus, although there is a small amount of the 40 amino acid GRH as well. Finally, 12 yr after the discovery of the structure of SRIF, the structure of GRH had been revealed. Samuel M. McCann Department of Physiology Neuropeptide Division The University of Texas Southwestern Medical Center
References 1.
Reichlein S 1961 Growth
hormone content of pituitaries from rats Endocrinology 69:225-230 Krulich L, Dhariwal AL’S, McCann SM 1965 Growth hormonereleasing activity of crude ovine hypothalamic extracts. Proc Sot Exp Biol Med 120:180-184 Krulich L, McCann SM 1966 Influence of growth hormone (GH) on content of GH in the pituitaries of normal rats. Proc Sot Exp Biol Med 121:1114-1117 Katz SH, Molitch M, McCann SM 1969 The effect of hypothalamic implants of growth hormone (GH) on anterior pituitary weight and GH concentration. Endocrinology 85:725-734 Krulich L, Dhariwal AL’S, McCann SM, Hypothalamic control of growth hormone (GH) secretion. Program of the 47th Annual Meeting of the Endocrine Society, New York, 1965, p 21 (Abstract) Dhariwal AT’S, Krulich L, Katz S, McCann SM 1965 Purification of growth hormone-releasing factor (GH-RF). Endocrinology 771932-936 Franz J, Haselbach CH, Libert 0 1962 Studies of the effect of hypothalamic extracts on somatotrophic pituitary function. Acta Endocrinol (Copenh) 41:336-350 Deuben RR, Meites J 1964 Stimulation of pituitary growth hormone release by a hypothalamic extract in vitro. Endocrinology 74:408414 Krulich L, Dhariwal AL’S, McCann SM 1968 Stimulatory and inhibitory effects of purified hypothalamic extracts on growth hormone release from rat pituitary in vitro. Endocrinology 83:783-790 Dhariwal APS, Krulich L, McCann SM 1969 Purification of a growth hormone inhibiting factor (GIF) from sheep hypothalamus, Neuroendocrinology 4:282-288 Krulich L, McCann SM 1969 Effect of GRF and GIF on the release and concentration of GH in pituitaries incubated in vitro. Endocrinology 85:319-324 Crighton DB, Schneider HPG, McCann SM 1969 A study of the possible interaction of LRF with other hypothalamic releasing factors at the level of the pituitary gland. J Endocrinol 44:405-410 McCann SM, Dhariwal APS, Porter JC 1968 Regulation of the adenohypophysis. Ann Rev Physiol30:589-640 with
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13. 14.
hypothalamic
lesions.
Ali AV, Arimura A, Wakabashyi I, Sawano S, Barrett JF, Bowers CY, Redding TW, Mittler JC, Saito A 1970 The chemistry of hypothalmic growth hormone-releasing J (ed) Hypophysiotropic Hormones and Chemistry. Williams & Wilkins 226
hormone (GRH). of the Hypothalamus: Company, Baltimore,
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 20 November 2015. at 03:20 For personal use only. No other uses without permission. . All rights reserved.
In: Meites Assay pp 20%
2044
REMEMBRANCE
15. Roger NW, Beck JC, Burgus R, Guillemin R 1969 Variability of response in the bioassay for hypothalamic somatotropin-releasing factor based on rat pituitary growth hormone content. Endocrinology 84:1373-1383 16. Daughaday WH, Peake GT, Machlin LJ 1970 Assay of the growth hormone releasing factor. In: Meites J (ed) Hypophysiotropic Hormones of the Hypothalamus: Assay and Chemistry. Williams & Wilkins Company, Baltimore, pp 151-170 17. McCann SM 1970 In: Meites J (ed). Hypophysiotropic Hormones of the Hypothalamus: Assay and Chemistry. Williams & Wilkins Company, Baltimore. Discussion to Ref. 16, pp 163-165 L, Illner I’, Fawcett CP, Quijada M, McCann 1972 Dual 18. Krulich hypothalamic regulation of growth hormone secretion. In: Pecile A, Muller EE (eds) Growth and Growth Hormone. Excerpta Medica International Congress Series, no 244, pp 306-316 19. Elde R, Hokfelt T 1979 Localization of hypophysiotropic peptides and other biologically active peptides within the brain. Ann Rev Physiol41:587-602
Endo. Voll31.
1992 No 5
20. Bloch B, Brazeau P, Ling N, Bohlen P, Esch F, Wehrenberg WB, Benoit R, Bloom F, Guillemin R 1983 Immunohistochemical detection of growth hormone-releasing factor in brain. Nature 301:607-608 21. Brazeau P, Vale W, Burgus R, Ling N, Butcher M, Rivier J, Guillemin R 1973 Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science 179:77-79 ._ -._... 22. McCann SM, Krulich L, Negro-Vilar A, Ojeda SR, Vijayan E 1980 Regulation and function of panhibin (somatostatin). In: Costa E, Trab&hi M (eds) Neural Peptides and‘Neurona1 Communication. Advances in Biochemical Psychopharmacology. Raven Press, New York, pp 131-143 23. Rivier J, Spiess J, Thorner M, Vale W 1982 Characterization of a growth hormone-releasing factor from a human pancreatic islet tumour. Nature 300:276-278 24. Guillemin R, Brazeau P, Bohlen P, Esch F, Ling N, Wehrenberg WB 1982 Growth hormones-releasing factor from a human pancreatic tumor that caused acromegaly. Science 218:585-587
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 20 November 2015. at 03:20 For personal use only. No other uses without permission. . All rights reserved.
