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THYROTROPIN-RELEASING HORMONE:
SHEDDING NEW LIGHT ON THE HYPOTHALAMIC-PITUITARY THYROID AXIS*
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Leonidas H. Duntas
1Endocrine Unit, Evgenidion Hospital, University of Athens, Medical School, Greece
Charles Emerson
University of Massachussetts School of Medicine, Worcester, MA, USA
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Editorial 2009
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*Dedicated to all those who contributed to the discovery of TRH
The authors declare no conflict of interest related to this article.
Correspondence to:
Leonidas H. Duntas, M.D.
Endocrine Unit, Evgenidion Hospital
University of Athens
20 Papadiamantopoulou St.
115 28 Athens, Greece. Email: ledunt@otenet.gr
ABSTRACT
Thyrotropin-releasing hormone (TRH) is the dominant constituent of the hypothalamic-pituitary thyroid
axis (HPT) and exerts various effects throughout the central nervous system. It has recently been
reported that tanycyte pyroglutamyl peptidase II, one of the enzymes that degrade TRH, is regulated
by thyroid hormones and is therefore a candidate for mediation of the feedback regulation of the HPT
axis. In parallel, TRH has been found in the gastrointestinal tract, especially in the pancreas where it
plays a regulatory role in the secretion of insulin, in the Leydig cells and in the prostate where it is
modulated by testosterone. Of special significance are its newly identified glucoregulatory and
antidiabetic effects that make the tripeptide and its analog potential targets for therapeutic
intervention, while equally noteworthy are recent studies showing TRH receptor gene mutations to be
the etiology of central hypothyroidism. The first family with complete resistance to TRH has also been
documented of late. Forty years after its discovery, TRH continues to present us with an exceptionally
wide field of research which will surely provide both exciting new challenges and enlightening
perspectives in the in the coming years.
“TRF is such a simple molecule for all these years of work!” Roger Guillemin, 1969
Introduction
The isolation of Thyrotropin-Releasing Hormone (TRH), the epitome of a scientific odyssey
that was passionately conducted by Roger Guillemin and Andrew Schally and their teams for almost a
decade, resulted in the identification of the first hypothalamic-releasing factor and thereby the
establishment of modern Neuroendocrinology (1). Subsequent to the historical pinpointing of TRH as
the main physiological regulator of TSH synthesis and secretion, the description of the isolation and
properties of porcine TRH was published by A. Schally on 10 August, 1969, and the structure of
porcine and bovine TRH was published by J. Boler and R. Burgus on 6 and 12 November, 1969,
respectively (2-4).
TRH is a tripeptide (pyroGlu-His-Pro-NH2). It is present in a number of brain regions but of
paramount importance for the hypothalamic-pituitary thyroid (HPT) axis is its secretion by the nerve
terminals of the paraventricular nucleus (PVN). TRH is a tripeptide (pyroGlu-His-Pro-NH2: the
structure of TRH is presented in Figure 1) that is present in a number of brain regions.
Figure 1: Chemical Structure of Thyrotropin-Releasing Hormone
However, of paramount importance for the hypothalamic-pituitary thyroid (HPT) axis is its
secretion by the nerve terminals of the paraventricular nucleus (PVN). These have their cell bodies in
the periventricular region known as the “thyrotropic area” which extends into the median eminence.
The main action of TRH is to stimulate the synthesis and release of TSH. The description of the
structure of TRH was followed by its synthesis and subsequently by its extensive use in clinical
medicine. For more than two decades the TRH-test has comprised the prime diagnostic tool for
detection of thyroid disease.
The aim of this review is to summarize the old and outline the many new findings with regard
to TRH, a peptide which is characterized not only by its dominant role in the HPT but also by its wide
range of extrahypothalamic sources and numerous actions.
Biosynthesis and metabolism
The introduction of the polymerase chain reaction and cDNA cloning methodology in the ΄80s
made possible the elucidation of the biosynthesis of TRH. TRH is derived from the prepro-TRH
peptide, which is composed of 242 amino acids in man, compared to 255 amino acids in the rat, and
contains multiple copies of the TRH progenitor sequence Gln-His-Pro-Gly (5-7). Each of these
sequences is flanked by paired amino acid residues that yield, via proteolytic cleavage, five copies of
TRH and seven cryptic peptides, which actively participate in the intracellular routing of the precursor
(8,9). For instance, the connecting peptide prepro-TRH-(160-169) (Ps4) was demonstrated to be coreleased
with TRH and to modulate its biological effects; Ps4 has no direct effect on TSH secretion
but it potentiates TRH-mediated TSH release in a dose-dependent manner (9). However,
immunochemical and immunocytochemical studies suggest that the maturation of pro-TRH, a high
molecular weight immunoreactive TRH precursor form in the developing mouse hypothalamus, is a
continuum starting in the endoplasmatic reticulum and ending as a post-Golgi event (10).
Hypothyroidism selectively increases the synthesis of pro-TRH mRNA and the prohormone in PVN. In
vitro studies demonstrated a reduced content and increased release of pro-TRH from the median
eminence (11). At least three enzymes have been observed to degrade synthetic TRH. These are a
prolyl endopeptidase (post proline cleaving enzyme, TRH deamidase), which is present in brain and
lacks substrate specificity for TRH, and two pyroglutamyl aminopeptidases (PPAs). Prolyl
endopeptidase, as its name indicates, converts TRH to pGlu-His-Pro, while PPAs I and II convert
TRH to His-ProNH2. PPAs II has substrate specificity for TRH and is the only one of the enzymes with
TRH degrading activity that is currently listed in the International Union of Biochemistry and Molecular
Biology (IUBMB) Nomenclature Database (EC 3.4.19.6) (Figure 2).
Figure 2: The metabolism of TRH. A schematic diagram of the prepro-TRH cDNA. The shaded area above left
represents the signal peptide encoding region. The blue solid boxes represent the TRH coding sequences. In
the posttranslational process, TRH will be at different sites by the action of pyroglutamyl-peptidases I and II
degraded to its main metabolite His-Pro-NH2, which can be spontaneously converted to cyclo (His-Pro), and by
the action of prolyl endopeptidase (TRH desamidase) to desamidated pyro-Glu-His-Pro-OH.
His-ProNH2 can spontaneously convert to cyclo His-Pro (histidyl- proline diketopiperazine).
Biological activity has been reported for cyclo (His-Pro) including regulation of body temperature and,
acting at variance with its pre-hormone, it has been reported to inhibit prolactin secretion in vitro (12)
but not in vivo (13). Elsewhere, its co-release with glucagons by the pancreatic α-cells suggests
possible exertion of modulatory actions in the insular physiology (14). Interestingly, Perry et al.
identified cyclo (His-Pro) in human urine in 1965, even before the elucidation of the structure of TRH,
and attributed its presence to dietary sources (15).
Following its release into the portal circulation, TRH is probably rapidly degraded by serum
and perhaps by tissue membrane bound PPAs activities in tanycytes (16-18). Divergent results have
been reported regarding the influence of thyroid status on serum and brain PPAs activities with the
ultimate aim of producing synthetic TRH (18-21). These differences are likely due to differences in
species and tissues examined rather than to methodology. In the adenohypophysis, PPAs II is mainly
regulated by thyroid hormone (TH), being decreased within a few days in animals rendered
hypothyroid, while it is rapidly increased after 4-6h following an injection of T3 (22). Estradiol
decreases the activity of the adenohypophyseal enzyme. Ovariectomy in rats induces increase of the
enzymatic activity, while treatment with estradiol benzoate leads to significant decrease (22). Thus,
PPAs II exerts its influence on the adenohypophyseal function by regulating TRH catabolism in
relation to hormonal status.
Two studies have recently emerged, one referring for the first time to an inactivating mutation
of the TRH receptor gene causing isolated central hypothyroidism in a 9-year-old boy (23,24) and the
second constituting the first report on a family with complete resistance to the action of TRH due to a
nonsense mutation in the TRH receptor gene causing central hypothyroidism (25). In both cases the
patients were diagnosed with isolated hypothyroidism marked by delayed growth, short stature,
lethargy and fatigue. In the second case, by contrast, the pregnant sister of the proband, diagnosed
with central hypothyroidism based on genetic testing of the family members, delivered two babies at
term, who were subsequently both breast-fed, this indicating that TRH action is not mandatory either
for female fertility and lactation nor for TSHβ and PRL genes expression. It is noteworthy that the
TSH action on the thyroid was not completely absent, since withdrawal of LT4 stimulated circulating
TSH and thus resulted in increased endogenous thyroid hormone levels, this, however, insufficient to
maintain euthyroidism in the absence of TRH action (25). The rhythmic pituitary function is well
preserved, pointing to the fact that non-TRH signals and some other factors, such as possibly
thyrostimulin, may be involved in the pituitary regulation in this case.
The setpoint and the regulation of TRH neurons
Although TRH was discovered four decades ago, it is only in the last few years that the
topography of TRH-containing cells in the brain has been described, this permitting the acquisition of
ever more specific data on its function and regulating activities (Figure 3).
Figure 3: TRH is secreted by the hypothalamic paraventricular nucleus (PVN); it reaches the median eminence
through axonal transport and is relocated via the hypothalamic portal vein to the anterior pituitary thyrotroph,
where it binds to TRH receptors regulating TSH production. The arcuate nucleus (AN) is an important “relaystation”
for the maintenance of energy homeostasis. Leptin signals from the periphery have an access to AN
which is relayed to PVN via pre-autonomic neurons containing NPY/AgRP and POMC/CART peptides (see
text).
The neurons synthesizing TRH, which are mainly located in the dorsocaudal region of the
hypothalamic PVN, constitute the central regulatory unit, i.e. the setpoint, of the hypothalamic-pituitary thyroid axis. TRH plays a major role in the posttranslational maturation of TSH oligosaccharide chains
and is required for the secretion of TSH with full biological activity (26). The synthesis and release of
TRH in the hypothalamus is under negative feedback regulation by TH that inhibits at the
transcriptional level both TRH and TSH subunit genes (11). Hypothyroidism strongly stimulates the
synthesis of pro-TRH, the release of TRH and the pro-TRH derived peptides in the hypothalamus
(27). Hypothyroidism strongly stimulates the synthesis of pro-TRH as well as the release of TRH and
of the pro-TRH derived peptides in the hypothalamus (27). Contrary to the general view that TH is
the main regulator of the HPT-axis, recent data from transgenic animals have clearly revealed that
TRH has the dominant role in the regulation of the HPT-axis and determination of the setpoint (28).
Thus, central regulation of the pituitary-thyroid axis by TRH is essential for normal function. Recently
it has been demonstrated that mRNA for PPAs II extends from the tanycyte cell bodies in the base of
the third ventricle to the external zone of the median eminence in apposition to pro-TRH containing
axon terminals (29). PPAs II activity is up-regulated by TH in the tanycyte, resulting in enhanced
degradation of extracellular TRH, whereas PPAs II inhibition leads to increased TRH secretion (29).
These novel and significant results indicate that tanycyte PPAs II may be an important mediator in the
regulation of the HPT as far as feedback inhibition by TH is concerned.
Specific conditions, however, such as prolonged cold exposure and fasting or clinical
conditions such as infection, critical illness and psychiatric disorders may alter the setpoint for
negative feedback. Cold exposure induces stimulation of the HPT axis via adrenergic neurons, while
fasting decreases TRH mRNA in hypothalamic neurons and enhances the sensitivity to the negative
feedback by TH (30). Infection induces, via cytokines, activation of type 2 iodothyronine deiodinase
(D2), which is the enzyme responsible for the conversion of T4 to T3 in the brain and, once
stimulated, it leads to local hyperthyroidism and subsequent inhibition of hypophysiotropic TRH (31).
Recent results from neuroanatomical studies using quantitative in situ hybridization have
proposed a different mechanism for thyroid setpoint regulation in pathological conditions (32). In postmortem
specimens, it was found that TRH neurons in the PVN express the thyroid transporter
monocarboxylase transporter 8 (MCT8), thyroid hormones receptors and inner ring iodothyronine
deiodinase 3 (D3), while outer ring iodothyronine deiodinase (D2) activity was detected in the region of the median eminence, in the glial cells and in the tanycytes which demarcate the third ventricle
(32). Following this line of evidence, it has been proposed that T4 is taken up by the hypothalamic
glial cells and converted into T3, which is subsequently transported to TRH neurons to be bound to
TH receptors or be metabolized into inactive iodothyronines by D3 (32). These novel findings, via the
application of immunohistochemistry, mRNA in situ hybridization and enzyme activity assays, have
contributed considerably to identification of the determinants of the setpoint for TH regulation of TSH
secretion and have underlined the significance of the glial cells and tanycytes. In critical illness,
altered metabolism of T4 due to reduced hypothalamic deiodinase activity results in decreased TRH
mRNA. However, the decreased TH concentration does not raise the TSH levels, suggesting altered
feedback regulation at the hypothalamic/pituitary level (32). Notably, these findings have recently
been partly confirmed by experimental studies on prolonged critically ill animals showing that TRH
mRNA in the hypothalamus was decreased and, although MCT8 and MCT10 were increased, TH
concentration and receptors were not elevated (33). The evident conclusion is therefore that the
decreased TRH gene expression and the low TSH and T3 concentrations during prolonged critical
illness are not solely due to hypothalamic thyrotoxicosis but that additionally other factors are
involved.
Hypothalamic and extrahypothalamic functions of TRH neuron
Besides being localized in the hypothalamus, where it represents only a small fraction of the
entire brain TRH, TRH has been detected throughout the CNS in the brainstem, medulla oblongata
and spinal cord (34). It is therefore conjectured to be a peptide ubiquitously distributed in the CNS
where it mainly functions as neurotransmitter or neuromodulator.
The hypothalamic TRH neuron is a regulator of energy homeostasis through its impact on
thyroid function, by stimulating TSH release, and on feeding behavior (35). TRH is an anorexigenic
peptide suppressing, by means of central effects, food intake in normal, fasting and stressed animals.
Although the precise mechanism remains unknown, the presence has been established of an
interplay between TRH neurons and the leptin regulating system in the arcuate nucleus.
TRH cells in the PVN receive projections from leptin-responsive neurons that are located in
the arcuate nucleus of the hypothalamus. These neurons contain the anorexigenic peptides alphamelanocyte
stimulating hormone (alpha-MSH), the cocaine and amphetamine regulated transcript
(CART) and the orexigenic neuropeptide Y (NPY), and the agouti-related protein (AGRP) peptides,
which promote obesity and reduce energy expenditure (36). Prolonged fasting suppresses leptin,
serum T4 and TSH levels as well as proTRH mRNA in the hypothalamic PVN, presumably 1) by
increasing NPY, that suppresses pro-TRH mRNA in the PVN, and 2) by decreasing prohormone
convertases 1 and 2 genes, the enzymes that regulate TRH proteolysis cleavage in the PVN and
median eminence (37-38). The systemic administration of leptin may entirely reverse these changes,
this showing that leptin influences the setpoint for feedback inhibition of TH and that it also partially
controls the biosynthesis of TRH in the PVN.
TRH exerts various effects on the central nervous system, contributing to the regulation of
thermogenesis and influencing arousal and locomotor activation, while also exerting various analeptic
and antidepressant effects. It controls the cephalic phase of digestion by acting, via cholinergic and
dopaminergic mechanisms, on the septum and nucleus accumbens, respectively (39). Centrally
administered TRH increases gastric secretion via vagal pathways, including the dorsal motor nucleus
of the vagus (DMN), while it also stimulates gastric myenteric cholinergic neurons and colonic activity
(40). Moreover, through the raphe pallidus neurons, medullary TRH innervates vagal preganglionic
motor neurons in the dorsal vagal complex and regulates gastric functions and pancreatic insulin
secretion (41).
Peripheral TRH
TRH has been localized in considerable amounts outside the CNS, as in the gastrointestinal
tract, in the pancreas and in the reproductive tracts of male rats, including the rat prostate where it
may have a physiological role and be modulated by testosterone (42). Further research is needed to
elucidate this matter (43).
TRH is synthesized in the β-cells of the Lagherhans islets from a pro-TRH mRNA, similar to
that present in the hypothalamus, and is involved as a local modulator in the pancreatic physiology (44). Exogenous TRH increases basal glucagon secretion, suggesting a direct effect on alpha-cell
secretion and a glucoregulatory role in the pancreas (45). Glucagon in contrast to arginine does not
stimulate TRH release from the isolated perfused rat pancreas (46). In the neonate rat, while TRH is
elevated in the pancreatic β-cells, the TRH-degrading activity is absent, appearing on day 14 and
reaching adult levels on day 21 (47). A developmental role of TRH in the embryonic pancreas has
been proposed by current data showing that TRH treatment of human islet-derived precursor cells for
several days promotes programmed cell death, a normal pathway of human embryonic development
(48). It has been proposed that TRH is a marker of insulin expressing cell, recent studies having
revealed that TRH administered to rats rendered severely diabetic with streptozotocin completely
reverses the hyperglycemia (49,50). In humans, following the oral glucose tolerance test, oral TRH
inhibits in normal subjects the first hour increase in blood glucose, insulin and proinsulin, presumably
via inhibition of gastric motility and/or paracrine actions (51). Moreover, targeted prepro-TRH gene
disruption causes hypothyroidism and hyperglycemia (52), demonstrating that prepro-TRH as well as
its derived peptides and their receptors are crucial not only for the functioning of various local systems
but for the homeostasis of the entire organism. These results are corroborated by those of studies
using mice that are lacking TRH (TRH-/-). TRH-/- mice, though viable and fertile, show signs of
hypothyroidism with elevated serum TSH and diminished TSH bioactivity, which are reversed via TRH
supplementation but not by thyroid hormone administration. Moreover, they exhibit severe
hyperglycemia and impaired insulin response to glucose administration, suggesting that TRH is
involved not only in thyrotroph but also in insulin regulation (53).
TRH has demonstrated a considerable inhibitory action on the gastrointestinal tract and the
exocrine pancreas; an infusion of 200 μg TRH resulted in inhibition of lipase and chymotrypsin
secretion up to 44% (54).
TRH has furthermore been implicated in a range of systems whereby it exerts a wide
spectrum of actions. For example, it has recently been reported that TRH and TRH receptor are
expressed in the epithelium of human hair-follicles (55). TRH acts as a hair growth stimulator by
promoting hair-shaft elongation, prolonging the hair cycle growth (anagen) while antagonizing its
termination via TGF-β activity (55).
Finally, TRH is expressed by melanoma and its presence in nevi may be considered as a
predictor for melanoma functioning as an autocrine growth factor (56). These latter findings, however,
require further confirmation by means of additional research regarding TRH implication in the
formation and development of melanoma.
Clinical use
The demonstration that TRH releases thyrotropin from the anterior pituitary and the
subsequent synthesis of TRH led to its use as what came to be known as the TRH-test, which has
been regarded for almost a quarter of century as the “Golden Test” for the study of the release of TSH
and subsequently that of thyroidal status after stimulation of the thyrotroph with TRH (57-59). A
suppressed TSH response to TRH indicates hyperthyroidism, while a high response evidences
hypothyroidism.
In a variety of endocrine disorders, serum TSH response to TRH has been reported blunted,
such as in acromegaly and hypercortisolism, or exaggerated as in Klinefelter’s syndrome and
Turner’s syndrome (60). In acromegaly, TRH administration elicits a significant increase of GH in 50%
of the patients; however, the increase is not dependent on basal GH and TSH levels (61,62). In
Cushing’s disease and Nelson’s syndrome, TRH-testing induces a rise of plasma ACTH levels in
about 30% of the patients, probably due to expression of TRH receptors on the corticotrophs (63).
TRH administration induces a 5-10 fold increase in serum prolactin (PRL), especially in
women during the fertile years. However, in microprolactinomas the PRL response is rather poor,
while increased response usually occurs in patients with hypothalamic or stalk lesions (64).
Elevations in serum FSH, LH or even α-SU after TRH administration have been observed in patients
with gonadotropinomas, and very occasionally in functionless pituitary adenomas, the rise being
independent of the basal levels of the gonadotrophins (65). Increased FSH and LH response to the
TRH-test was also observed in patients with acromegaly, this possibly indicating plurihormonal tumor.
. The TRH-test has been performed as an adjuvant in the diagnosis and evaluation of treatment
of depression (66). Human depression is characterized by an impairment of the inhibitory
glucocorticoid feedback from the hippocampus to the hypothalamus, leading to increased cortisol levels and activation of the TRH neuron. This results in increased TRH levels and down-regulation of
the TRH receptor on the thyrotroph and in the typically blunted TSH response to TRH in depression
(67). Administration of TRH has been reported to enhance mood and ameliorate the psychological
state. This is probably due to the excitatory action of TRH throughout the neuroaxis following the
blocking of various K+ channels linked to TRH receptors in different TRH-innervated neuroanatomical
pathways and leading to increased secretory output of TRH regulatory circuits that modulate
neurobehavior (68).
TRH has been therapeutically applied in patients with amyotrophic lateral sclerosis (69), ataxia
cerebellaris, and experimental endotoxin shock (70), sometimes but not always with favorable
results. Due to its short-half life, which amounts to 6.5 min following intravenous administration
(71,72), TRH probably needs to be evaluated by administering it at a constant rate for a prolonged
period. Another approach would be to develop analogs of TRH, ideally have the same neurotrophic
and/or glucoregulatory properties as TRH but without hypophysiotropic activity.
Epicrisis
Four decades have passed since the ground-breaking discovery of TRH, a period marked by
our constantly growing understanding of its broad spectrum of vital actions, including control of thyroid
function and energy homeostasis and its influence on behavior. Its wide range of application is hence
unsurprising and certainly justifies the continuing interest of the scientific community in this truly
impressive molecule. Meanwhile, the constantly accumulating experience of its clinical and
neurobiological effects warrants our sustained endeavor for the development of TRH agonistic drugs
that can alleviate numerous diseases and symptoms. Forty years after its discovery TRH remains a
unique and extraordinary peptide.
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Address:
THYROTROPIN-RELEASING HORMONE:
SHEDDING NEW LIGHT ON THE HYPOTHALAMIC-PITUITARY THYROID AXIS* |
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Title: Hot Thyroidology; Abbreviated key title: Hot Thyroidol.; Online ISSN: 2075-2202
Legal Note: © All rights reserved European Thyroid Association 2009
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