Life Sciences, Vol . 25, pp . 1539-1550 Printed in the U.S .A .
Pergamon Press
MINIREVIEW ESTRAHYPOTHALAMIC THYROTROPIN RELEASING HORMONE (TRH) - ITS DISTRIBUTION AND ITS FUNCTIONS John E . Morley, MB, BCh . Endocrine-Metabolic Section, Minneapolis VA Medical Center, and Department of Medicine, University of Minnesota, Minneapolis, Minnesota, 55417
SUMMARY Thyrotropin releasing hormone (TRH) is distributed throughout the extxahypothalamic nervous system and spinal cord, in the retina, in the pancreas and gastrointestinal tract, in the placenta, in am niotic fluid, in the adrenals and in frog akin . TRH has been shown to have a variety of effects in the central nervous system, both on TRH interisolated neurones and in a number of in vivo situations . acts with endogenous and eaogenous opiates and it has been suggested that endogenous TRH may mediate part of the opiate withdrawal syndrome . The presence of TRH in the retina suggests the possibility that TRH plays a role in the visual process . TRH appears to be inThe role tegrally related to central thermoregulatory mechanisms . of TRB in psychiatric disorders is at present controversial . Recent studies suggest a role for TRH as a modulator of gastrointestinal and pancreatic function . The gastrointestinal actions of TRH include inhibition of gastric acid secretion and alterations in gastic motility . The high concentrations of TRH in the neonatal pancreas suggest a role for TRH in the early development of the pancreas . One of the metabolites of TRH histidyl-proline diketopiperazone, appears to have a number of extrahypothalamic actions and this suggèsts the need for further exploration of the effects of this compound both on the central nervous system and the gastrointestinal tract . The multiple extrahypothalamic actions of TRH have led to the concept that it is an ubiquitous neurotransmitter that has been co-opted by the pituitary as a releasing factor . Since the original isolation of thyrotropin releasing hormone (TRH) from the hypothalamus (1), it has become obvious that thyrotropin release from the pituitary is only one of many actions of TRH . It appears that the thyrotropin releasing action is predominately due to an adaptive process of the pituitary, in that the pituitary fails to make the enzymes necessary to degrade TRH (2), rather than due to an unique property of TRH. Studies with TRH antibodies (3, 4,5) suggest that TRH plays a role in the tonic release of TSH and possibly in the cold response (3) and diurnal rhythm (6,7) of TSH secretion . The major control of TSH secretion appears to be through direct feedback of thyroid hormones at the pituitary level (8,9) . Evidence of the multiple actions of TRH was originally obtained 1n man, when it was shown that TRH was at least equipotent in releasing prolactin from Sub the pituitary and that prolactin release precedes the release of TSH (10) . sequently it has been shown that exogenous TRH administration to man releases FSH (11,12) and norepinephrine (13) in normals and growth hormone in acromegaly (14), hypothyroidism (15), renal failure (16), anoreaia nervosa (17) and deprea0024-3205/79/181539-12$02 .00/0 Copyright (c) 1979 Pergamon Press Ltd
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and ACTH in Cuahing's and Nelson's syndromes (19) .
TRH is distributed throughout the extrahypothalamic central nervous system (20) and spinal cord (21), in the retina (22), in the pancreas and gastrointestinal tract (23, 24), in the placenta (25,26), in amniotic fluid (27), in breast milk (28,29) and to frog skin (30, 31) . Uncharacterized im,uunoreactivity has Phylobeen reported in kidney, liver and lung (23) and in the adrenals (32) . geaetic studies of TRH distribution have shown that TRH occurs in species such as the lamprey, which lacks TSH, and in a~mphigxus and in snail, species without pituitaries (33,34) . A preliminary report has suggested the presence of a TRHIt should be noted that immunolike substance in the vegetable kingdom (132) . reactive TRH concentrations are usually higher than the concentrations found after subjecting tissue TRH to chromatographic separation (7,35), suggesting a degree of non-apecifity for most TRH antibodies . The distribution of TRH, its rapid degradation in blood and tissue (36), its concentration in synaptosomes (37) and its demonstrated actions oa isolated neurones (vide infra), have led to the concept that TRH ie an ubiquitous neuro transmitter that has been co-opted by the pituitary as a releasing factor . CENTRAL NERVOUS SYSTEM ACTION OF TRH Using microiontophoretic techniques, TRH has been shown to have a depressant action on cortical and hypothalamic neurones (38,39) . TRH potentiatea the excitatory actions of acetylcholine oa cortical neurones (40) and has an excita tory action, similar to glutamate, when applied to frog spinal motoneurones (41) . Intraventricular and/or high dose parenteral administration of TRH has been shown to produce a number of behavioral alterations in rata . These include increased spontaneous motor activity (42), induction of heel-to-tail rotation (43), suppression of feeding and drinking activity (44), inhibition of condition-avoidance behavior (45) and alteration of sleep patterns (46) . In addition a number of pharmacobehavioral interactions of TRH have also been reported . TRH antagonizes the actions of sedative type drugs . It antagonizes barbiturate actions on Bleeping time (47), hypothermia (48) and lethality (49) and opposes the actions of ethanol (50), chloral hydrate (51) and diazepam (51) on sleeping time . Chlorpromazine-induced ~scle relaxation in mice is antagonized by TRH (58), ae is the depressant effect of a~methyl-p-tyrosine on motor activity (52) . TRH enhances convulsion time and lethality of strychnine (53) and potentiatea dope-induced hypermotility (54) and 5-hydroxy tryptamineinduced tremor (55) . It should be noted that the high concentrations of parenteral TRH required to produce central nervous system effects may well be physiological rather than pharmacological as TRH crosses the blood-brain barrier poorly (56) and the concentrations of TRH used are in the same range as the parenteral dose of GABA, a known neurotransmitter (57) . TRH AND CATECHOLAPfLNES There is a substantial body of literature ahawing that TRH enhances cerebral norepinephrine turnover, probably by releasing norepinephrine from nerve terminals . TRH (10 mg/kg) increases brain concentrations of the norepinephrine metabolite, 4-hydroay-3~methoayphen- .yiglycol (MOPED) (59) . TRH enhances catecholamine depletion produced following a~methyl-p-tyrosine as shown both by histochemical techniques demonstrating the accentuation of the diminution of green fluorescence, specific for catecholamines (60) and biochemically in thyroidectomized rata (61) .
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Tyrosine hydroxylase activity in the brain is enhanced by TRH suggesting increased catecholamine synthesis (62) and TRH increases brain 3H-norepinephrine Recently eaogenous TRH has been shown to increase blood norepinephrine (63) . levels (13) . Conversely it has been demonstrated that 3 H-TRH is released in vitro from mouse hypothalamic fragments by norepinephrine (64) and that norepinphrine releases TRH from frog skin (65) . These observations suggest that TRH and norepi nephrine may form a positive feedback loop in neural tissue . Cuenca et al (66) have shown that TRH enhances the noradrenaline response in the isolated vas deferens and in spinal cats potentiates the blood presque response to noradrenaline . TRH AND OPIATES A number of publications have suggested an interaction between TRH and the opiates . Morphine administration suppresses TSH, presumably through a hypothalamic mechanism (67) . TRH antagonizes morphine and ß-endorphin induced GH re lease (68,69) and TRA pre-treatment abolishes ß-endorphin- induced hypothermia, central depression and catalepsy in intact and hypohysectomized animals (69,70) . There is however no direct effect of TRH on binding to brain opiate receptor as demonstrated by the failure of TRH to displace either 3H-naloxone (69) or 3H-dihydromorphine (71) binding from opiate receptors . Behaviourally TRH is capable of producing a syndrome remarkably similar to The TRH-induced syndrome the classical 'met dog shakes" of morphine withdrawal . is characterized by head-shaking, paw tremor, lacrimation and intense shivering (72) . Brain areas where naloxone precipitates withdrawal O.~t&king : .i-n morphinedependent animals parallel the sites of TRIi-stimulated shaking and the endogenous sites of TRH-distribution (20,73) . Naloxone-induced morphine withdrawal produces a fall in cerebral cortical and diencephalic TRH content suggesting that during withdrawal therein TRH release (74) . These data, together withthe parallels between morphinerwithdrawal and TRH-induced shaking (Table 1), suggest that endogenous TRH may mediate part of the opiate withdrawal syndrome, particularly in regard to the thermoregulata tory alterations occurring during withdrawal . TRH may, in turn, being about its effects by acutely releasing norpinephrine from nerve terminals . TABLE I 1. 2.
3. 4. 5. 6. 7. 8.
Both TRH and morphine-withd=awal produce a chacteristic shaking behaviour in anaesthetized rats (72,76) . The brain areas were naloxone precipiates withdrawal shaking in opiate-dependent organisms, parallel the sites of TRH-stimulated shaking and endogenous sites of TRH distribution (20,72,73) . ß-endorphin antagonizes TRH-induced "wet dog shakes" (70) . TRH concentration in the diencephalon and cortex falls during acute morphine withdrawal (74) . TRH reverses ß-endorphin induced depression of motor activity (69) . TRH blocks ß-endorphin and morphine induced hypothermia (70) . TRH antagonizes morphine and ß-endorphin induced growth hormone release (68,69) . TRH diminishes the sialogogic effect of ß-endorphins (75) .
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TRH AND THE PINEAL TRH has been shown to be present in bovine, ovine, rat and frog pineals TRA in the frog pinewith both bio- and radioimmunoassay techniques (77,78,79) . al demonstrates a seasonal rhythmicity, with highest concentrations occurring in autumn (79) and in the rat pineal TRH has been shown to have a light-entrained rhythm similar to that in the retina and hypothalamus (82) . Arginine vasotocin is released from the cat pineal into the CSF by TRH (80) . Tsang and Martin (81) showed that TRH inhibits norepinephrine-stimulated accumulation of cyclic-AMP in the rat pineal (81) . As cyclic-AMP activation by nor epinephrine is thought to be the mechanism for stimulating N-acetyltransferase (the enzyme responsible for converting serotonin to melatonin) activity, we studied the effects of TRH on basal and isoproterenol stimulated acetyltransferase activity in pineal cultures, but could find no effect of TRH on this activity over a wide dose range (82) . TRH AND THE RETINA TRH has been shown to be present in the frog (32) and the rat retina (22) . Appreciable concentrations of TRH are also present in the retina of a number of fish (Marahak, Stell and Morley : Unpublished observations) . TRH in the retina appears to have a light-.entrained rhythm with the highest concentrations occurring during the day. Constant light elevates, and constant dark suppresses TRH concentrations in the retina . Somatostatin is also present in the retina (139) of the frog, goldfish and rat and appears to have a light entrained rhythm similar to that of TRH. There is a need for a series of physiological studies to delineate the rôle of these two peptides in the visula process . MISCELLANEOUS .CENTRAL NERVOUS SYSTEM EFFECTS OF TSH Cardiovascular : TRH administration produces a transient increase in blood pressure (83,13) in man. Intracranially administered TRH in rabbits produces a presaor response (84,85) . This reponse is blocked by spinal tranaections above T1 (85) and is not completely blocked by catecholamine antagonists . TRH also induces tachycardia in dogs (86) and in rats (87) . Same, hit not all of these findings, may be secondary to the increase in plasma norepinephrine levels following TRH (13) . Respiratory : Central administration of TRH produces tachypnea (58) . Administration of TRH to pregnant rabbits results in increased pulmonary surfactant production by the fetus (133) . Urinary Urgency : Exogenous administration of TRH produces an acute and transient sense of urinary urgency (88) . As a similar sensation was reported to follow TRH in a paraplegic patient, this is thought to be a centrally mediated effect (89) . Temperature Regulation : The acute rise in TSH following cold exposure in rats is thought to be secondary to an increase in TRH (3,90) . TRH increases body temperature in rats (91) and antagonizes hypothermia induced by barbiturates (48) and by opiates (70) . PSYCHIATRIC EFFECTS OF TRH IN MAN Originally there were a number of reports suggesting that TRH may be useful in depression, but subsequently a large number of adequately designed tri.8la have refuted this claim (Table II) . Overall there would appear to be no major
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TABLE II TRH AND DEPRESSION CLINICAL STUDIES NUMBER OF PATIENTS Prange and Wilson, 1972 (92)
7
DOSE
IMPROVEMENT
100-800 ug
++
tPrange, et al, 1972 (93)
10
600 ug
+
Rastin, et al, 1972 (96)
5
500 yg x 3 days
+
Vis Melsen and Wiener, 1972 (95)
1
40 mg p .o .
+
10
500 ug
+
*Wilson, et al, 1973 (96) Itil, et al, 1975 (97)
9
500-1000 ug 100 mg po x 3-5 days
+
*Takahahi, et al, 1973 (98)
14
500 ug 3/wk r. 3
-
*Ehrensing, et al, 1974 (99)
8
1000 ug x 3 days
-
10
600 ug x 3 days
-
600 pg a 3/15 days
-
*Coppen, et al, 1974 (100 Hollister, et al, 1974 (101) tTurek and Rocha, 1974 (102)
16
100 mg po
-
Mountjoy, et al, 1974 (103)
29
40 mg po x 7 days
-
tEvans, et al, 1975 (104)
10
500 ug
-
Maeda, et al, 1975 (105)
6
500 pg
-
*Lipton and Goodwin, 1975 (106)
13
600-1200 yg up to 14 days
-
*Riely, et al, 1976 (107)
11
200-300 mg po
-
tsingle blind *double blind
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therapeutic benefit of TRH in depression . However, many of the studies did reKieley, et port a mild increase in energy with a reversal o~ energy and apathy . al (107) had 5 out of 8 of their patients discontinue the study because of increased psychomotor activation and anxiety, restlessness and insomnia . After an original uncontrolled trail by Prangs et al (108) reporting improvement in schizophrenics receiving TRH, there followed a number of doubleblind studies which failed to demonstrate any benefit of TRH in schizophrenia (109-118) . A recent report from Japan (114) has demonstrated an improvement in motivation for work, emotional rapport, facial expression and psychomotor activity in a apeciably selected group of 143 schizophrenics, when they were given 4 The schizophrenics mg TRH orally for 14 days together with their other drugs . studied were a carefully chosen subset in that they all demonstrated loss of spontaneity, apathy, abulia and contact disturbance and none of them had paranoic symptoms . Two studies failed to show any effect of TRH in patients with Parkinson's disease (115,116) . Tiwary, et al (117,118) reported improvement in 3 hyperactive children given TRH. TRH IN THE GASTROINTESTINAL TRACT AND PANCREAS In keeping with Anthony Pearse's APUD theory (119), which suggests that endocrine cells in the gastrointestinal tract share a common origin with cells in the central nervous system, many peptide hormones which were originally thought to be either purely gastrointestinal or hypothalamic hormones have been found to In 1977, our group in America and Leppaluoto's be present in both regions (120) . group in Finland (23,24) reported the existence of TRH immuaoreactivity in the The distribution of TRH in pancreas and the gastrointestinal tract of the rat. the gastrointestinal tract is shown in Figure !. Highest concentrations were found in the pancreas and the large bowel . The evidence for TRH in the gastrointestinal tract is of clinical, imminoreactive, chromatographic and bioactive nature and is summarized in Table III . Burt and Snyder (125) have demonstrated low affinity binding sites for TRH in the liver . Martino, et al (124), in confirming the original work, showed that TRH concentrations were much higher in the pancreatic islets than in the rest of the pancreas . In a aeries of physiological experiments they showed that pancreatic TRH content is increased by starvation, not altered in hypothyroidism and markedly decreased by streptozotocin . They also demonstrated very high concentrations of TRH -in the pancreas of the neonatal rat (124) . Morley, et al (126) using the isolated perfused rat pancreas preparation have shown that TRH enhances arginine-induced glucagon release from the rat pancreas without altering insulin responses to either glucose or arginine . Argin ine infusion induced a phasic release of iTRH from the preparation. Transient nausea and occasional desire to defecate have been reported in man undergoing TRH testing (122) . TRH stimulates the guinea pig ileum in vitro (122) as well as rat antrum, pyloric sphincter and colon in vitro (121) . The TRH effect on antral motility is mediated through a non-cholinergic excitatory pathway and is inhibited by histamine antagonists (134) . Smith, et al (123) reported that intraventricular administration of TRH is the rabbit resulted in increased colonic activity, and suggested that, as intravenous administration was a less potent stimulus, the TRH effect on colonic motility was centrally mediated . In the dog, Morley, et al (127) have shown that TRH has no effect on basal or aecretin stimulated exocrine pancreatic function . TRH (bug/kg) markedly increased myoelectrical contractions as measured by electrodes in the antrum of
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TABLE III EVIDENCE POR THYROTROPIN RELEASING HORMONE (TRH) iN THE GASTROINTESTINAL TRACT A. B.
C. D.
CLINICAL 1. Nausea/desire to defecate in humans given TRH (122) . 2. Contracts gastrointestinal smooth muscle in vitro (121) . IIß~lIJNOREACTIVITY 1. Parallelism (23, 24, 124) . 2. Co-chromatography with TRH on Sephadex G-10 (23) . SP-Sephadex C-25 (23) . LH-20 (24) . Thin layer chromatography (24) . High pressure liquid chromatography (24) . 3. Immunoreactivity destroyed by sera (23) . BIOACTIV7ITY I. Activity in the modified mouse bioassay (23) . 2. Releases TSH from incubated pituitaries (124) . RECEPTORS 1. TRH receptors in liver (125) .
Figure 1 . Distribution of immunoreactive Thyrotropin Releeaing Hormone in the gaytrointeatinal tract .
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TRH transiently inhibits tetragastria stimulated acid the unanesthetized dog . TRH did not apex water absorption in dogs secretion from the dog's stomach . with Thirey-Vella loops . Dolva and his co-workers have extensively investigated the effects of TRH They have shown that TRH infusion inhibon gastrointestinal function in man. its absorption of glucose and xylose (128), inhibits gastric motility (129) . Recently, they have shown that TRH also inhibits the pancreatic polypeptide release seen during insulin-induced hypoglycemia (140) . TRH AND THE PLACENTA The placenta and brain have a common neuroectodermal origin (130), so it is not surprising that TRH has been demonstrated to be present in placentas of At present the evidence for TRH in the placenta comes rat and man (25,26) . In addition placenfrom immunoassay, bioassay and chromatographic techniques . tas can manufacture TRH from its constituent amino acids (25,26) . Synthetic exogenously administered TRH has been shaven to cross the feto-placental barrier in monkeys (131) . TRH AND AMNIOTIC FLUID Because of the presence of TRH in the placenta, we looked for 1`ßH in amniotic fluid . iTRH is present in amniotic fluid (27) and shows parallelism with synthetic TRA . The concentrations of iTRA in amniotic fluid increase with ges tational age and preliminary data suggests that low iTRH after 32 weeks gestation may be associated with subsequent neonatal distress . TRH AND BREAST MILK Both TRH and Luteinizing Hormone-Releasing Hormone have been shown to be present in human breast milk (28,29) . As TRH is absorbed from the gastrointestinal tract and in the newborn, serum TRH-degrading activity is very low, it is possible that TRH in maternal breast milk plays a role in the maturation of neonatal thyroid function . HISTIDYL-PROLINE DIKETOPIPERAZINE Prasad and his co-workers have shown that metabolism of TRH results in two products . One, pyroglutamyl-histidyl-proline (acid-TRH) is formed by the action of a TRH amidase and attempts to associate biological activity with this com pound have been uniformly negative (2) . TRH is also metabolised by a pyroglutamyl peptidase to form a cyclic dipeptide, HISTIDYL-PROLINE DIRETOPIPERAZINE (cyclo (His-Pro)) . This compound has been shown to be more potent than TRH in reducing ethanol-induced sleep in rata (136) . Cyclo (His-Pro) has also been demonstrated to produce hypothermia in rate (137) . This effect is antagonized by TRH. It appears that the hypothemic efforts observed on injection of TRH reflect its Ple.taboliam to cyclo (His-Pro) and that the primary effect of TRH is hyperthermic . Further evidence for this is that TRH is hyperthermic under ambient temperature conditions, while it is hypothermic at lower temperatures . Cyclo (His-Pro) has no effect at ambient temperatures eaerting its effects only at lower temperatures . Recently Bauer, et al (138) have shown that while TRH stimulates the secretion of prolactin by GR~ cells (a pituitary tumor cell line), cyclo (His-Pro) decreased the release o prolactin in a dose-related manner to approximately 50% of the control levels . In urethrane anethetized rats one micorgram of his-
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tidyl-proline-dtketopiperazine significantly depressed the TRH-stimulated prolactin, release . This exciting preliminary data available on the biological effects of the cyclised degradation product of TRH suggesx the need for a close evaluation of this substances effects ~ other areas where TRH has been shown to exert its extra-hypothalamic effects . CpNCI,U$ION TRH is ubiquitously distributed throughout the body and appears to have a number of physiological functions of which tonic control of TSH secretion from the pituitary is but one . There is a need to further define the role of extra hgpothalamic TRH and to look for TRH analogues which may be useful in altering retinal, central nervous system and gastrointestinal function . Finally, the name thyrotropin releasing hormone appears to be inappropriate, in that TRH ie not a hormone in the,claesical sense ; that thyrotropin release is but one of its many functions and that in the gastrointestinal tract same of TRH'e actions appear to be inhibitory . TRH is clearly a peptide in search of a new name . One possibility was Ubiquitous Regulatory Factor but I think that historically more justified would be the eponym - Guillemin-SchallyFactor (GSF) . REFERENCES 1. 2. 3. 4. 5. 6. 7. 8, 9. 10 . 11 . 12 . 13 . 14 . 15 . 16 . 17 . 18 . 19 .
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Pergamon Press
MINIREVIEW ESTRAHYPOTHALAMIC THYROTROPIN RELEASING HORMONE (TRH) - ITS DISTRIBUTION AND ITS FUNCTIONS John E . Morley, MB, BCh . Endocrine-Metabolic Section, Minneapolis VA Medical Center, and Department of Medicine, University of Minnesota, Minneapolis, Minnesota, 55417
SUMMARY Thyrotropin releasing hormone (TRH) is distributed throughout the extxahypothalamic nervous system and spinal cord, in the retina, in the pancreas and gastrointestinal tract, in the placenta, in am niotic fluid, in the adrenals and in frog akin . TRH has been shown to have a variety of effects in the central nervous system, both on TRH interisolated neurones and in a number of in vivo situations . acts with endogenous and eaogenous opiates and it has been suggested that endogenous TRH may mediate part of the opiate withdrawal syndrome . The presence of TRH in the retina suggests the possibility that TRH plays a role in the visual process . TRH appears to be inThe role tegrally related to central thermoregulatory mechanisms . of TRB in psychiatric disorders is at present controversial . Recent studies suggest a role for TRH as a modulator of gastrointestinal and pancreatic function . The gastrointestinal actions of TRH include inhibition of gastric acid secretion and alterations in gastic motility . The high concentrations of TRH in the neonatal pancreas suggest a role for TRH in the early development of the pancreas . One of the metabolites of TRH histidyl-proline diketopiperazone, appears to have a number of extrahypothalamic actions and this suggèsts the need for further exploration of the effects of this compound both on the central nervous system and the gastrointestinal tract . The multiple extrahypothalamic actions of TRH have led to the concept that it is an ubiquitous neurotransmitter that has been co-opted by the pituitary as a releasing factor . Since the original isolation of thyrotropin releasing hormone (TRH) from the hypothalamus (1), it has become obvious that thyrotropin release from the pituitary is only one of many actions of TRH . It appears that the thyrotropin releasing action is predominately due to an adaptive process of the pituitary, in that the pituitary fails to make the enzymes necessary to degrade TRH (2), rather than due to an unique property of TRH. Studies with TRH antibodies (3, 4,5) suggest that TRH plays a role in the tonic release of TSH and possibly in the cold response (3) and diurnal rhythm (6,7) of TSH secretion . The major control of TSH secretion appears to be through direct feedback of thyroid hormones at the pituitary level (8,9) . Evidence of the multiple actions of TRH was originally obtained 1n man, when it was shown that TRH was at least equipotent in releasing prolactin from Sub the pituitary and that prolactin release precedes the release of TSH (10) . sequently it has been shown that exogenous TRH administration to man releases FSH (11,12) and norepinephrine (13) in normals and growth hormone in acromegaly (14), hypothyroidism (15), renal failure (16), anoreaia nervosa (17) and deprea0024-3205/79/181539-12$02 .00/0 Copyright (c) 1979 Pergamon Press Ltd
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aion (18,
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and ACTH in Cuahing's and Nelson's syndromes (19) .
TRH is distributed throughout the extrahypothalamic central nervous system (20) and spinal cord (21), in the retina (22), in the pancreas and gastrointestinal tract (23, 24), in the placenta (25,26), in amniotic fluid (27), in breast milk (28,29) and to frog skin (30, 31) . Uncharacterized im,uunoreactivity has Phylobeen reported in kidney, liver and lung (23) and in the adrenals (32) . geaetic studies of TRH distribution have shown that TRH occurs in species such as the lamprey, which lacks TSH, and in a~mphigxus and in snail, species without pituitaries (33,34) . A preliminary report has suggested the presence of a TRHIt should be noted that immunolike substance in the vegetable kingdom (132) . reactive TRH concentrations are usually higher than the concentrations found after subjecting tissue TRH to chromatographic separation (7,35), suggesting a degree of non-apecifity for most TRH antibodies . The distribution of TRH, its rapid degradation in blood and tissue (36), its concentration in synaptosomes (37) and its demonstrated actions oa isolated neurones (vide infra), have led to the concept that TRH ie an ubiquitous neuro transmitter that has been co-opted by the pituitary as a releasing factor . CENTRAL NERVOUS SYSTEM ACTION OF TRH Using microiontophoretic techniques, TRH has been shown to have a depressant action on cortical and hypothalamic neurones (38,39) . TRH potentiatea the excitatory actions of acetylcholine oa cortical neurones (40) and has an excita tory action, similar to glutamate, when applied to frog spinal motoneurones (41) . Intraventricular and/or high dose parenteral administration of TRH has been shown to produce a number of behavioral alterations in rata . These include increased spontaneous motor activity (42), induction of heel-to-tail rotation (43), suppression of feeding and drinking activity (44), inhibition of condition-avoidance behavior (45) and alteration of sleep patterns (46) . In addition a number of pharmacobehavioral interactions of TRH have also been reported . TRH antagonizes the actions of sedative type drugs . It antagonizes barbiturate actions on Bleeping time (47), hypothermia (48) and lethality (49) and opposes the actions of ethanol (50), chloral hydrate (51) and diazepam (51) on sleeping time . Chlorpromazine-induced ~scle relaxation in mice is antagonized by TRH (58), ae is the depressant effect of a~methyl-p-tyrosine on motor activity (52) . TRH enhances convulsion time and lethality of strychnine (53) and potentiatea dope-induced hypermotility (54) and 5-hydroxy tryptamineinduced tremor (55) . It should be noted that the high concentrations of parenteral TRH required to produce central nervous system effects may well be physiological rather than pharmacological as TRH crosses the blood-brain barrier poorly (56) and the concentrations of TRH used are in the same range as the parenteral dose of GABA, a known neurotransmitter (57) . TRH AND CATECHOLAPfLNES There is a substantial body of literature ahawing that TRH enhances cerebral norepinephrine turnover, probably by releasing norepinephrine from nerve terminals . TRH (10 mg/kg) increases brain concentrations of the norepinephrine metabolite, 4-hydroay-3~methoayphen- .yiglycol (MOPED) (59) . TRH enhances catecholamine depletion produced following a~methyl-p-tyrosine as shown both by histochemical techniques demonstrating the accentuation of the diminution of green fluorescence, specific for catecholamines (60) and biochemically in thyroidectomized rata (61) .
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Tyrosine hydroxylase activity in the brain is enhanced by TRH suggesting increased catecholamine synthesis (62) and TRH increases brain 3H-norepinephrine Recently eaogenous TRH has been shown to increase blood norepinephrine (63) . levels (13) . Conversely it has been demonstrated that 3 H-TRH is released in vitro from mouse hypothalamic fragments by norepinephrine (64) and that norepinphrine releases TRH from frog skin (65) . These observations suggest that TRH and norepi nephrine may form a positive feedback loop in neural tissue . Cuenca et al (66) have shown that TRH enhances the noradrenaline response in the isolated vas deferens and in spinal cats potentiates the blood presque response to noradrenaline . TRH AND OPIATES A number of publications have suggested an interaction between TRH and the opiates . Morphine administration suppresses TSH, presumably through a hypothalamic mechanism (67) . TRH antagonizes morphine and ß-endorphin induced GH re lease (68,69) and TRA pre-treatment abolishes ß-endorphin- induced hypothermia, central depression and catalepsy in intact and hypohysectomized animals (69,70) . There is however no direct effect of TRH on binding to brain opiate receptor as demonstrated by the failure of TRH to displace either 3H-naloxone (69) or 3H-dihydromorphine (71) binding from opiate receptors . Behaviourally TRH is capable of producing a syndrome remarkably similar to The TRH-induced syndrome the classical 'met dog shakes" of morphine withdrawal . is characterized by head-shaking, paw tremor, lacrimation and intense shivering (72) . Brain areas where naloxone precipitates withdrawal O.~t&king : .i-n morphinedependent animals parallel the sites of TRIi-stimulated shaking and the endogenous sites of TRH-distribution (20,73) . Naloxone-induced morphine withdrawal produces a fall in cerebral cortical and diencephalic TRH content suggesting that during withdrawal therein TRH release (74) . These data, together withthe parallels between morphinerwithdrawal and TRH-induced shaking (Table 1), suggest that endogenous TRH may mediate part of the opiate withdrawal syndrome, particularly in regard to the thermoregulata tory alterations occurring during withdrawal . TRH may, in turn, being about its effects by acutely releasing norpinephrine from nerve terminals . TABLE I 1. 2.
3. 4. 5. 6. 7. 8.
Both TRH and morphine-withd=awal produce a chacteristic shaking behaviour in anaesthetized rats (72,76) . The brain areas were naloxone precipiates withdrawal shaking in opiate-dependent organisms, parallel the sites of TRH-stimulated shaking and endogenous sites of TRH distribution (20,72,73) . ß-endorphin antagonizes TRH-induced "wet dog shakes" (70) . TRH concentration in the diencephalon and cortex falls during acute morphine withdrawal (74) . TRH reverses ß-endorphin induced depression of motor activity (69) . TRH blocks ß-endorphin and morphine induced hypothermia (70) . TRH antagonizes morphine and ß-endorphin induced growth hormone release (68,69) . TRH diminishes the sialogogic effect of ß-endorphins (75) .
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TRH AND THE PINEAL TRH has been shown to be present in bovine, ovine, rat and frog pineals TRA in the frog pinewith both bio- and radioimmunoassay techniques (77,78,79) . al demonstrates a seasonal rhythmicity, with highest concentrations occurring in autumn (79) and in the rat pineal TRH has been shown to have a light-entrained rhythm similar to that in the retina and hypothalamus (82) . Arginine vasotocin is released from the cat pineal into the CSF by TRH (80) . Tsang and Martin (81) showed that TRH inhibits norepinephrine-stimulated accumulation of cyclic-AMP in the rat pineal (81) . As cyclic-AMP activation by nor epinephrine is thought to be the mechanism for stimulating N-acetyltransferase (the enzyme responsible for converting serotonin to melatonin) activity, we studied the effects of TRH on basal and isoproterenol stimulated acetyltransferase activity in pineal cultures, but could find no effect of TRH on this activity over a wide dose range (82) . TRH AND THE RETINA TRH has been shown to be present in the frog (32) and the rat retina (22) . Appreciable concentrations of TRH are also present in the retina of a number of fish (Marahak, Stell and Morley : Unpublished observations) . TRH in the retina appears to have a light-.entrained rhythm with the highest concentrations occurring during the day. Constant light elevates, and constant dark suppresses TRH concentrations in the retina . Somatostatin is also present in the retina (139) of the frog, goldfish and rat and appears to have a light entrained rhythm similar to that of TRH. There is a need for a series of physiological studies to delineate the rôle of these two peptides in the visula process . MISCELLANEOUS .CENTRAL NERVOUS SYSTEM EFFECTS OF TSH Cardiovascular : TRH administration produces a transient increase in blood pressure (83,13) in man. Intracranially administered TRH in rabbits produces a presaor response (84,85) . This reponse is blocked by spinal tranaections above T1 (85) and is not completely blocked by catecholamine antagonists . TRH also induces tachycardia in dogs (86) and in rats (87) . Same, hit not all of these findings, may be secondary to the increase in plasma norepinephrine levels following TRH (13) . Respiratory : Central administration of TRH produces tachypnea (58) . Administration of TRH to pregnant rabbits results in increased pulmonary surfactant production by the fetus (133) . Urinary Urgency : Exogenous administration of TRH produces an acute and transient sense of urinary urgency (88) . As a similar sensation was reported to follow TRH in a paraplegic patient, this is thought to be a centrally mediated effect (89) . Temperature Regulation : The acute rise in TSH following cold exposure in rats is thought to be secondary to an increase in TRH (3,90) . TRH increases body temperature in rats (91) and antagonizes hypothermia induced by barbiturates (48) and by opiates (70) . PSYCHIATRIC EFFECTS OF TRH IN MAN Originally there were a number of reports suggesting that TRH may be useful in depression, but subsequently a large number of adequately designed tri.8la have refuted this claim (Table II) . Overall there would appear to be no major
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TABLE II TRH AND DEPRESSION CLINICAL STUDIES NUMBER OF PATIENTS Prange and Wilson, 1972 (92)
7
DOSE
IMPROVEMENT
100-800 ug
++
tPrange, et al, 1972 (93)
10
600 ug
+
Rastin, et al, 1972 (96)
5
500 yg x 3 days
+
Vis Melsen and Wiener, 1972 (95)
1
40 mg p .o .
+
10
500 ug
+
*Wilson, et al, 1973 (96) Itil, et al, 1975 (97)
9
500-1000 ug 100 mg po x 3-5 days
+
*Takahahi, et al, 1973 (98)
14
500 ug 3/wk r. 3
-
*Ehrensing, et al, 1974 (99)
8
1000 ug x 3 days
-
10
600 ug x 3 days
-
600 pg a 3/15 days
-
*Coppen, et al, 1974 (100 Hollister, et al, 1974 (101) tTurek and Rocha, 1974 (102)
16
100 mg po
-
Mountjoy, et al, 1974 (103)
29
40 mg po x 7 days
-
tEvans, et al, 1975 (104)
10
500 ug
-
Maeda, et al, 1975 (105)
6
500 pg
-
*Lipton and Goodwin, 1975 (106)
13
600-1200 yg up to 14 days
-
*Riely, et al, 1976 (107)
11
200-300 mg po
-
tsingle blind *double blind
154 4
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therapeutic benefit of TRH in depression . However, many of the studies did reKieley, et port a mild increase in energy with a reversal o~ energy and apathy . al (107) had 5 out of 8 of their patients discontinue the study because of increased psychomotor activation and anxiety, restlessness and insomnia . After an original uncontrolled trail by Prangs et al (108) reporting improvement in schizophrenics receiving TRH, there followed a number of doubleblind studies which failed to demonstrate any benefit of TRH in schizophrenia (109-118) . A recent report from Japan (114) has demonstrated an improvement in motivation for work, emotional rapport, facial expression and psychomotor activity in a apeciably selected group of 143 schizophrenics, when they were given 4 The schizophrenics mg TRH orally for 14 days together with their other drugs . studied were a carefully chosen subset in that they all demonstrated loss of spontaneity, apathy, abulia and contact disturbance and none of them had paranoic symptoms . Two studies failed to show any effect of TRH in patients with Parkinson's disease (115,116) . Tiwary, et al (117,118) reported improvement in 3 hyperactive children given TRH. TRH IN THE GASTROINTESTINAL TRACT AND PANCREAS In keeping with Anthony Pearse's APUD theory (119), which suggests that endocrine cells in the gastrointestinal tract share a common origin with cells in the central nervous system, many peptide hormones which were originally thought to be either purely gastrointestinal or hypothalamic hormones have been found to In 1977, our group in America and Leppaluoto's be present in both regions (120) . group in Finland (23,24) reported the existence of TRH immuaoreactivity in the The distribution of TRH in pancreas and the gastrointestinal tract of the rat. the gastrointestinal tract is shown in Figure !. Highest concentrations were found in the pancreas and the large bowel . The evidence for TRH in the gastrointestinal tract is of clinical, imminoreactive, chromatographic and bioactive nature and is summarized in Table III . Burt and Snyder (125) have demonstrated low affinity binding sites for TRH in the liver . Martino, et al (124), in confirming the original work, showed that TRH concentrations were much higher in the pancreatic islets than in the rest of the pancreas . In a aeries of physiological experiments they showed that pancreatic TRH content is increased by starvation, not altered in hypothyroidism and markedly decreased by streptozotocin . They also demonstrated very high concentrations of TRH -in the pancreas of the neonatal rat (124) . Morley, et al (126) using the isolated perfused rat pancreas preparation have shown that TRH enhances arginine-induced glucagon release from the rat pancreas without altering insulin responses to either glucose or arginine . Argin ine infusion induced a phasic release of iTRH from the preparation. Transient nausea and occasional desire to defecate have been reported in man undergoing TRH testing (122) . TRH stimulates the guinea pig ileum in vitro (122) as well as rat antrum, pyloric sphincter and colon in vitro (121) . The TRH effect on antral motility is mediated through a non-cholinergic excitatory pathway and is inhibited by histamine antagonists (134) . Smith, et al (123) reported that intraventricular administration of TRH is the rabbit resulted in increased colonic activity, and suggested that, as intravenous administration was a less potent stimulus, the TRH effect on colonic motility was centrally mediated . In the dog, Morley, et al (127) have shown that TRH has no effect on basal or aecretin stimulated exocrine pancreatic function . TRH (bug/kg) markedly increased myoelectrical contractions as measured by electrodes in the antrum of
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TABLE III EVIDENCE POR THYROTROPIN RELEASING HORMONE (TRH) iN THE GASTROINTESTINAL TRACT A. B.
C. D.
CLINICAL 1. Nausea/desire to defecate in humans given TRH (122) . 2. Contracts gastrointestinal smooth muscle in vitro (121) . IIß~lIJNOREACTIVITY 1. Parallelism (23, 24, 124) . 2. Co-chromatography with TRH on Sephadex G-10 (23) . SP-Sephadex C-25 (23) . LH-20 (24) . Thin layer chromatography (24) . High pressure liquid chromatography (24) . 3. Immunoreactivity destroyed by sera (23) . BIOACTIV7ITY I. Activity in the modified mouse bioassay (23) . 2. Releases TSH from incubated pituitaries (124) . RECEPTORS 1. TRH receptors in liver (125) .
Figure 1 . Distribution of immunoreactive Thyrotropin Releeaing Hormone in the gaytrointeatinal tract .
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TRH transiently inhibits tetragastria stimulated acid the unanesthetized dog . TRH did not apex water absorption in dogs secretion from the dog's stomach . with Thirey-Vella loops . Dolva and his co-workers have extensively investigated the effects of TRH They have shown that TRH infusion inhibon gastrointestinal function in man. its absorption of glucose and xylose (128), inhibits gastric motility (129) . Recently, they have shown that TRH also inhibits the pancreatic polypeptide release seen during insulin-induced hypoglycemia (140) . TRH AND THE PLACENTA The placenta and brain have a common neuroectodermal origin (130), so it is not surprising that TRH has been demonstrated to be present in placentas of At present the evidence for TRH in the placenta comes rat and man (25,26) . In addition placenfrom immunoassay, bioassay and chromatographic techniques . tas can manufacture TRH from its constituent amino acids (25,26) . Synthetic exogenously administered TRH has been shaven to cross the feto-placental barrier in monkeys (131) . TRH AND AMNIOTIC FLUID Because of the presence of TRH in the placenta, we looked for 1`ßH in amniotic fluid . iTRH is present in amniotic fluid (27) and shows parallelism with synthetic TRA . The concentrations of iTRA in amniotic fluid increase with ges tational age and preliminary data suggests that low iTRH after 32 weeks gestation may be associated with subsequent neonatal distress . TRH AND BREAST MILK Both TRH and Luteinizing Hormone-Releasing Hormone have been shown to be present in human breast milk (28,29) . As TRH is absorbed from the gastrointestinal tract and in the newborn, serum TRH-degrading activity is very low, it is possible that TRH in maternal breast milk plays a role in the maturation of neonatal thyroid function . HISTIDYL-PROLINE DIKETOPIPERAZINE Prasad and his co-workers have shown that metabolism of TRH results in two products . One, pyroglutamyl-histidyl-proline (acid-TRH) is formed by the action of a TRH amidase and attempts to associate biological activity with this com pound have been uniformly negative (2) . TRH is also metabolised by a pyroglutamyl peptidase to form a cyclic dipeptide, HISTIDYL-PROLINE DIRETOPIPERAZINE (cyclo (His-Pro)) . This compound has been shown to be more potent than TRH in reducing ethanol-induced sleep in rata (136) . Cyclo (His-Pro) has also been demonstrated to produce hypothermia in rate (137) . This effect is antagonized by TRH. It appears that the hypothemic efforts observed on injection of TRH reflect its Ple.taboliam to cyclo (His-Pro) and that the primary effect of TRH is hyperthermic . Further evidence for this is that TRH is hyperthermic under ambient temperature conditions, while it is hypothermic at lower temperatures . Cyclo (His-Pro) has no effect at ambient temperatures eaerting its effects only at lower temperatures . Recently Bauer, et al (138) have shown that while TRH stimulates the secretion of prolactin by GR~ cells (a pituitary tumor cell line), cyclo (His-Pro) decreased the release o prolactin in a dose-related manner to approximately 50% of the control levels . In urethrane anethetized rats one micorgram of his-
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tidyl-proline-dtketopiperazine significantly depressed the TRH-stimulated prolactin, release . This exciting preliminary data available on the biological effects of the cyclised degradation product of TRH suggesx the need for a close evaluation of this substances effects ~ other areas where TRH has been shown to exert its extra-hypothalamic effects . CpNCI,U$ION TRH is ubiquitously distributed throughout the body and appears to have a number of physiological functions of which tonic control of TSH secretion from the pituitary is but one . There is a need to further define the role of extra hgpothalamic TRH and to look for TRH analogues which may be useful in altering retinal, central nervous system and gastrointestinal function . Finally, the name thyrotropin releasing hormone appears to be inappropriate, in that TRH ie not a hormone in the,claesical sense ; that thyrotropin release is but one of its many functions and that in the gastrointestinal tract same of TRH'e actions appear to be inhibitory . TRH is clearly a peptide in search of a new name . One possibility was Ubiquitous Regulatory Factor but I think that historically more justified would be the eponym - Guillemin-SchallyFactor (GSF) . REFERENCES 1. 2. 3. 4. 5. 6. 7. 8, 9. 10 . 11 . 12 . 13 . 14 . 15 . 16 . 17 . 18 . 19 .
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