Download Thyroid-Stimulating Hormone: Neuroregulation and Clinical

Clinical Science and Molecular Medicine (1978) 55,129-138
EDITORIAL RE VIEW
Thyroid-stimulating hormone: neuroregulation and clinical
applications
PART 2
M. F. S C A N L O N , B. R E E S S M I T H
AND
R. H A L L
Endocrine Unit, Departments of Medicine and Clinical Biochemistry, Royal Victoria Infirmary, Newcastle upon Tyne. UX.
Regulation of thyrotrophin synthesis and secretion
(continued)
Role of catecholamines and serotonin
Animal studies with central neurotransmitter
agonist and antagonist drugs 'have indicated the
existence of stimulatory a-noradrenergic and
inhibitory dopaminergic pathways in the control of
thyrotrophin (TSH) secretion in the rat (Tuomisto,
Ranta, Mannisto, Saarinen & Leppaluoto, 1975;
Mueller, Simpkins, Meites & Moore, 1976; Ranta.
Mannisto & Tuomisto, 1977; Krulich, Giachetti,
Marchlewska-Koj, Hefco & Jameson, 1977).
However, Chen & Meites (1975), using the
catecholamine precursor drug L-dopa, were unable
to find any significant catecholamine effects on
TSH release. Conflicting results have also been
obtained with regard to the role of serotonin.
Grimm & Reichlin (1973) found that the serotonin
precursor 5-hydroxytryptophan inhibited the
release of thyrotrophin-releasing hormone (TRH)
radioactivity from mouse hypothalamic slices and
suggested that serotonin was an inhibitory neurotransmitter in the control of TRH release. TSH
suppression was also found after intrahypothalamic implantation of serotonin in rats (Mess &
Peter, 1975). This was supported by the findings in
vivo of Tuomisto et al. (1975) but conflicts with
the findings in uivo of Chen & Meites (1975),
who found direct evidence for a stimulatory serotoninergic pathway in the control of TSH release.
Such conflicting findings are dimcult to interpret
and may well reflect in part the technical difficulties
involved in the administration in uivo of centrally
Abbreviations: LHRH, luteinizing hormone-releasing hormone; T,,tri-iodothyronine; T,, thyroxine; TRH, thyrotrophinreleasing hormone; TSH, thyrotrophin.
Correspondence: Dr M. F. Scanlon, Endocrine Unit, Department of Medicine, Royal Victoria Infirmary, Newcastle upon
Tyne, NEl4LP, U.K.
9
active drugs to animals in which stress itself is
known to inhibit TSH release. There is also
considerable variation in standardization and
methodology between different laboratories, making direct comparison of results dimcult. Despite
this, however, the most consistent findings are in
favour of stimulatory a-noradrenergic and
inhibitory dopaminergic pathways, although the
site of action of such putative regulators of TSH
release remains to be determined.
In man, there is as yet no definite evidence of
direct noradrenergic regulation of TSH release
(Woolf, Lee & Schalch, 1972; Birk Lauridsen,
Faber, Friis, Kirkegaard & Nerup, 1976), and the
TSH suppression in hyperthyroidism is unrelated to
any increase in central adrenergic activity (Epstein,
Pimstone, Vinik & Meharen, 1975; Wartofsky,
Dimond, Noel, Frantz & Earll, 1975). ,&Adrenoreceptor-blocking drugs lead indirectly to a slight
elevation in basal TSH levels but this presumably
reflects the known peripheral action of such drugs
in reducing the conversion of T, and T, and hence
the degree of negative feedback inhibition of TSH
release (Wiersinga & Touber, 1977).
There is now clear evidence of a physiological
inhibitory role for dopamine in the control of TSH
release in man. The initial studies of Besses,
Burrow, Spaulding & Donabedian (1975) demonstrated that dopamine infusion inhibited the TSH
response to TRH and this has now been confirmed
(Burrow, May, Spaulding & Donabedian, 1977).
Furthermore, dopamine infusion lowers basal TSH
levels in both euthyroid and hypothyroid subjects
(Camanni, Massara, Belforte, Vergano &
Molinatti, 1977; Delitala, 1977); although acute Ldopa administration has no effect on TSH levels,
chronic administration to patients with Parkinsonism leads to suppression of the TSH response to
TRH (Spaulding, Burrow, Donabedian & Van
129
M . F. Scanlon. B. Rees Smith and R. Hall
130
Woert, 1972). Similarly, dopamine receptor
stimulation with bromocriptine lowers the elevated
basal TSH levels in hypothyroid patients (Miyai,
Onishi, Hosokawa, Ishibashi & Kumahara, 1974;
Felt & Nedvidkova, 1977) and suppresses acutely
the TSH response when administered 2 h before
TRH (Garcia Centenera, Buxeda Paz, Hervas
Olivares, Perez Merida, Pozuelo Escudero &
Gomez-Pan, 1977). Fusaric acid is an inhibitor of
dopamine /3-hydroxylase, which converts dopamine
into noradrenaline. Administration of fusaric acid
thus leads to a relative increase in endogenous
dopamine levels and lowers the elevated basal TSH
levels in patients with primary hypothyroidism
(Yoshimura, Hachiya, Ochi, Nagasaka, Takeda,
Hidaka, Refetoff & Fang, 1977).
Whilst such findings suggest an inhibitory role
for dopamine, they provide no indication of the
physiological relevance of dopaminergic pathways
in the control of TSH release. In previous studies in
which dopamine receptor-blocking drugs such as
metoclopramide and chlorpromazine were administered to euthyroid subjects, no effect on TSH
release was detected (Delitala, Masala, Alagna
& Devilla, 1975; Onishi, Miyai, Izumi, Nakanishi
& Kumahara, 1975; Judd, Lazarus & Smythe,
1976), suggesting that there was no significant
physiological dopaminergic inhibition of TSH
release in man. In the light of recent findings, such
a conclusion must be regarded as invalid, since
there is marked elevation in basal TSH levels after
metoclopramide administration to patients with
primary thyroid failure (Scanlon, Weightman,
Mora, Heath, Shale, Snow & Hall, 1977; Fig. 1).
Thus, in euthyroid subjects, TSH release after
dopamine antagonist drugs may be masked by the
dominant inhibitory effects of normal circulating
levels of thyroid hormones. However, even after
metoclopramide administration to euthyroid subjects, a relatively small but highly significant rise in
basal TSH levels can be detected by using a
sensitive and precise radioimmunoassay for human
TSH and adequate control studies (Scanlon,
Weightman, Shale, Mora, Heath, Snow & Hall,
1978; Fig. 2). Such findings in euthyroid subjects
are in agreement with the recent reports of
others (Sowers, McCallum, Hershman, Carlson,
Sturdevant & Meyer, 1976; Healy & Burger, 1977).
Metoclopramide
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60
90
120
150
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FIG.1. Thyrotrophin (TSH) response to metoclopramide (10
rng orally) and placebo in hypothyroid patients. Mean values ?
SEM are shown.
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30
60
90
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120
150
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180
Time (min)
FIG.2. Thyrotrophin (TSH) response to metoclopramide (10
mg orally) and placebo in 10 euthyroid males ( 0 ) and 10
euthyroid females (0).Mean values are shown.
Thyroid-stimulating hormone-Part 2
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131
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F1c.4. Correlation of basal thyrotrophin (TSH) with ATSH
after metoclopramide (10 mg orally) in euthyroid men (10) and
women (10).r=-0~602-00.60;P<0.01.
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cross the blood-brain barrier and therefore the welldocumented TSH suppression during dopamine
infusion is likely to be due to a direct action of
dopamine on the pituitary or median eminence,
tissues which have direct connections with the
systemic circulation. Furthermore, dopamine
receptors have now been identified on anterior
pituitary cells but not in median eminence tissue
(Brown, Seeman & Lee, 1976). Further study is
required to establish which pituitary cell types
possess dopamine receptors.
Any role of serotonin in the control of TSH
release in man is less clear. Yoshimura, Ochi,
Miyazaki, Shiomi & Hachiya (1973) reported
lowering of basal TSH levels in hypothyroid but
not in euthyroid patients after administration of 5hydroxytryptophan. Woolf & Lee (1977) found
that L-tryptophan had no effect on basal TSH in
euthyroid subjects. On the other hand, cyproheptadine, a drug which blocks serotonin receptors,
produces suppression of the TSH response toTRH
in euthyroid subjects (Ferrari, Paracchi, Rondena,
Beck-Peccoz & Faglia, 1976; Egge, Rogol, Varma
& Blizzard, 1977). However, this effect on TSH is
unlikely to be related to serotonin since metergoline, a more specific serotonin antagonist, has no
effect on TRH-induced TSH release (Ferrari et al.,
1976).
Role of somatostatin
Somatostatin is a cyclic tetradecapeptide found
in highest concentrations in the hypothalamus. The
132
M . F. Scanlon, B. Rees Smith and R . Hall
hormone is thought to have a physiological
inhibitory control over growth hormone release.
However, recent studies in vitro and in vivo suggest
that somatostatin may also be a physiological
inhibitor of TSH release. Administration of
somatostatin antisera to cultured anterior pituitary
cells causes elevation of both growth hormone and
TSH levels in the medium (Tanjasiri, Kozbur &
Florsheim, 1976), and administration of the antisera to intact rats produces enhanced TSH
responses to both cold stress and T R H as well as
elevation of basal growth hormone and TSH levels
(Arimura, Gordin & Schally, 1976; Ferland,
Labrie, Jobin, Arimura & Schally, 1976). Such
responses after antagonism of endogenous
somatostatinergic activity provide strong evidence
of a physiological inhibitory role for somatostatin
in the control of these two hormones. There is no
such direct evidence in man, although somatostatin
infusion lowers the elevated basal TSH levels in
patients with primary thyroid failure (Lucke,
Hornten & Von zur Muhlen, 1975), suppresses the
TSH response to TRH (Siler, Yen, Vale &
Guillemin, 1974); Carr, Gomez-Pan, Weightman,
Roy, Hall, Besser, Thorner, McNeilly, Schally,
Kastin & Coy, 1975) and abolishes the nocturnal
elevation in basal TSH levels (Weeke, Hansen &
Lundbaek, 1975).
Other influences on thyrotrophin secretion
In the light of the neuroregulatory pathways outlined above and in Part 1 (Scanlon, Rees Smith &
Hall, 1978), it is now possible to consider other
factors which modify TSH secretion in man.
Circadian variation
It has now been clearly established that there is a
circadian rhythm of TSH secretion in both animals
(Bakke & Lawrence, 1965) and man (Nicoloff,
Fisher & Appleman, 1970; Patel, Alford & Burger,
1972; Weeke, 1973). This is not entirely sleeprelated since TSH levels begin to rise during the
evening before the onset of sleep, reaching a peak
at about 23.00 hours, when the TSH response to
TRH is also enhanced. Levels remain elevated
overnight and gradually decline over the ensuing
morning, reaching a nadir around 11.00 hours
(Weeke, 1973).
The neuroendocrine mechanisms underlying this
circadian rhythm are unknown. Administration of
pharmacological doses of glucocorticoids abolishes
the nocturnal elevation (Nicoloff et al., 1970; Patel
et al., 1972) and reduces both basal and TRHstimulated TSH levels (Re, Kourides, Ridgway,
Weintraub & Maloof, 1976; Sowers, Carlson,
Brautbar & Hershman, 1977). It has therefore been
suggested that the circadian TSH variation may be
secondary to the circadian changes in adrenocortical function. In support of this suggestion Re et
al. (1976) found a slight elevation in basal TSH
levels in normal subjects treated with metyrapone,
which lowers plasma cortisol levels by blocking 11hydroxylation. This finding requires confirmation
but does suggest that physiological levels of glucocorticoids can suppress TSH release. However,
Patel, Baker, Burger, Johns & Ledinek (1974) did
not find any close correlation between circadian
cortisol and TSH rhythms.
There is little, if any, circadian variation in basal
TSH levels in patients with severe hypothyroidism
(Weeke & Laurberg, 1976) and the dopaminergic
inhibition of TSH release also decreases with
increasingly severe hypothyroidism (Scanlon el al.,
1977). Again, both the circadian rhythm of TSH
secretion and the TSH response to dopamine
receptor blockade are restored after partial thyroid
hormone treatment of severely hypothyroid
patients (Weeke & Laurberg, 1976; M. F. Scanlon,
unpublished work). Furthermore, in euthyroid
subjects, the degree of TSH response to dopamine
receptor blockade is inversely related to basal TSH
levels (Fig. 4), suggesting that dopamine may be a
determinant of low daytime TSH levels and is thus
implicated in the circadian rhythm of TSH secretion. Whether the nocturnal elevation in TSH
levels reflects reduced dopaminergic inhibition of
TSH or the activity of another stimulus to TSH
secretion remains to be determined.
Effects of cold stress
Environmental cooling is a potent stimulus to
TSH release in both laboratory animals (Itoh,
Hiroshige, Koseki & Nakatsugawa, 1966;
Tuomisto, Ranta, Saarinen, Mannisto & Leppaluoto, 1973) and human neonates (Fisher &
Odell, 1969; Wilber & Baum, 1970). The TSH
response to cold stress in adult man is much less
striking (Odell, Vanslager & Bates, 1968;
Tuomisto, Mannisto, Lamberg & Linnoila, 1976).
Reichlin (1966) has suggested that, in rats, cold
stress causes release of T R H since the effect could
be abolished by appropriately placed hypothalamic lesions. More recent studies based on
urinary TRH measurements in cold-exposed
animals have provided conflicting results (Emmerson & Utiger, 1975; Montoya, Seibel & Wilber,
1975). However, in a recent report Muller, Franco,
Thyroid-stimulating hormone-Part 2
Reichlin & Jackson (1977) have described
suppression of the TSH response to cold stress in
rats by pretreatment with antibodies to TRH. Such
a finding provides the most direct evidence for a
physiological role for TRH in the TSH response to
cold.
On the basis of animal studies it seems likely that
cold stress leads to increased a-noradrenergic
activity (Krulich et al., 1977) and consequent TRH
release (Mueller et al., 1977). Serotoninergic
pathways appear to have an inhibitory effect on the
TSH response to cold, possibly through inhibition
of TRH release (Tuomisto et al., 1975). The neurotransmitter pathways involved in the slight TSH
response to environmental cooling in adult man are
unknown.
Effects of calorie restriction
Calorie restriction in man leads to impaired
peripheral conversion of T, into T,, resulting in low
total and free T,, normal T, and normal or slightly
elevated free T, levels (Portnay, O’Brian, Bush,
Vagenakis, Azizi, Arky, Ingbar & Braverman,
1974; Vagenakis, Burger, Portnay, Rudolph,
O’Brian, Azizi, Arky, Nicod, Ingbar & Braverman,
1975;Croxson, Hall, Kletzky, Jaramillo & Nicoloff,
1977). Furthermore it has recently been reported
that in rats starvation also decreases the nuclear
T, receptor content (Schussler & Orlando, 1978).
In addition, short-term fasting produces
suppression of basal and TRH-stimulated TSH
levels (Vinik, Kalk, McLaren, Hendricks &
Pimstone, 1975; Croxson et al., 1977), although
TSH responsiveness after more prolonged fasting
over 3-4 weeks is normal or only minimally
decreased (Rothenbuchner, Loos, Kiessling, Birk
& Pfeiffer, 1973; Portnay et al., 1974). The initial
fall of TSH and the subsequent failure of the
response to TRH in the face of low levels of T,
suggests inhibition of TSH release. Croxson et al.
(1977) could detect no alteration in the daily
excretion of 17-hydroxycorticosteroidsor urinary
cortisol, or in the diurnal pattern of serum cortisol.
Furthermore, metyrapone administration did not
reverse the inhibitory effects of fasting on TSH
release. It seems unlikely, therefore, that glucocorticoids mediate the TSH suppression of fasting. The
possible role of dopamine in this context is currently
being investigated.
The pattern of TSH response to TRH varies in
different types of calorie restriction: in proteincalorie malnutrition the TSH response to TRH is
enhanced (Becker, Vinik, Pimstone & Paul,
133
1975), whereas patients with anorexia nervosa
frequently show a delayed or ‘hypothalamic pattern’ of TSH response to TRH (Miyai, Yamamoto,
Azukizawa, Ishibashi & Kumahara, 1975). The
reason for this difference is unknown. However,
there is increasing evidence of TSH suppression in
some patients with anorexia nervosa leading to
decreased thyroid release of T,. Such patients also
show a loss of the diurnal rhythm of thyroidal
iodide release which reflects a loss of diurnal TSH
variation (Croxson & Ibbertson, 1977). This
suppression could explain the low or low-normal
TSH levels seen in such patients in the face of
reduced serum T, levels, but the exact mechanism
is unknown. However, in view of the recently
demonstrated physiological inhibitory role of
dopamine in the control of TSH release, it is
tempting to speculate that one component of the
anorexia nervosa syndrome may be dopaminergic
hyperactivity.
Role ofprostaglandins
Prostaglandins are widely distributed in the
central nervous system, including the hypothalamus (Holmes & Horton, 1968) and prostaglandin E can activate pituitary adenylate cyclase
(Zor, Kaneko, Schneider, McCann & Field, 1970).
They may therefore be involved in the control of
anterior pituitary function at either extra- or intracellular levels.
Several studies in vitro have indicated that
prostaglandins can increase both basal and TRHstimulated TSH release from anterior pituitary cells
(Kudo, Rubinstein, McKenzie & Beck, 1972;
Brown & Hedge, 1974). Furthermore, indomethacin, a prostaglandin synthetase inhibitor, abolished
the TSH response to TRH in vitro (Dupont &
Chavancy, 1972). Other workers, however, have
found no effect of prostaglandins on TSH release in
vitro (Tal, Szabo & Burke, 1974). Studies in vivo in
animals are equally conflicting: prostaglandin
E, had no effect on TSH release when administered
intraventricularly to rats (Eskay, Warberg, Mical
& Porter, 1975) whereas prostaglandin E,
given to pregnant rats caused a significant elevation
in maternal TSH levels (D’Angelo, Wall & Bowers,
1975).
There is, as yet, no evidence for TSH stimulation
by prostaglandins in man. Indomethacin pretreatment had no effect on TRH-stimulated TSH release
in men, even though plasma prostaglandin E and F
levels were significantly lowered (Ramey, Burrow,
Spaulding, Donabedian, Speroff & Frantz, 1976).
134
M. F. Scanlon. B. Rees Smith and R . Hall
In the same study, aspirin (another prostaglandin
synthetase inhibitor) did suppress TRH-induced
TSH release but this was probably due to its known
effect in increasing the fraction of unbound thyroid
hormones (Larsen, 1972). There are no reports of
the effects of prostaglandin synthetase inhibitors on
the elevated basal TSH levels in patients with
primary hypothyroidism but the available indirect
evidence does not suggest any significant action at
this level.
Clinical applications of thyrotrophin measurements
Measurement of basal and TRH-stimulated TSH
levels are of established value in the diagnosis of
disorders of the hypothalamus-pituitary-thyroid
axis, and the degree of TSH release after administration of dopamine antagonist drugs could
also prove to be a more refined test of the integrity
of this axis.
Basal TSH levels
Patients with hypothyroidism due to primary
thyroid failure have elevated basal TSH levels (>6
munits/l) and this is usually sufficient evidence to
confirm the diagnosis. However, hypothyroidism is
a graded phenomenon and there are many patients
with primary thyroid disease who have normal or
low-normal thyroid hormone levels and an
elevated basal TSH in the absence of any
symptoms attributable to thyroid hormone insufficiency (Evered, Clark & Petersen, 1973). A
variety of names have been given to such conditions, including compensated euthyroidism, premyxoedema (Fowler, Swale & Andrews, 1970) and
subclinical hypothyroidism (Evered, Ormston,
Smith, Hall & Bird, 1973). It seems likely that
thyroid function is fully compensated by the
increased TSH drive in some of these patients,
whereas in others circulating thyroid hormone
levels are suboptimal and treatment with thyroxine
might be beneficial. At present there is no way of
distinguishing between such patients and thyroxine
replacement therapy is usually restricted to patients
with mild and overt clinical hypothyroidism.
Replacement therapy with L-thyroxine is generally
regarded as adequate when the patient’s symptoms
of hypothyroidism are relieved and the basal TSH
level is reduced to the normal range ((6 munits/l).
Elevated basal TSH levels in the presence of
clinical and biochemical hyperthyroidism indicate
the rare condition of hypothalamic-pituitary
hyperthyroidism due to excessive TSH secretion.
As previously mentioned, specific TSH a-subunit
measurements in such patients may serve to
identify those patients with a pituitary adenoma
and serial estimations of a-subunit levels may
better indicate the adequacy of therapy.
Measurements of TSH in cord blood or on filterpaper spots taken some 5 days after birth have
indicated that, in North America and in certain
areas of Europe, the prevalence of neonatal
hypothyroidism is in the region of 1/3000 to
1/6000 live births (Klein, Agustin & Foley, 1974;
Dussault, Coulombe, Laberge, Letarte, Guyda &
Khoury, 1975; Walfish, 1975; Illig & Rodriguez de
Vera Roda, 1976). This is about two to three times
the prevalence of phenylketonuria, for which there
is an established screening programme based on
the Guthrie spot. TSH measurements can easily be
grafted on to the existing phenylketonuria screen,
TSH being measured on the filter-paper spots (Illig
& Rodriguez de Vera Roda, 1976). Advantages of
TSH over T, measurements are a lower false
positive rate (most cretins diagnosed so far have
TSH values greater than 100 munits/l). Hypothalamic-pituitary hypothyroidism may be responsible for about 10% of cases of neonatal
hypothyroidism and they would be missed by TSH
measurements (Dussault, Parlow, Letarte, Guyda
& Laberge, 1976). Further information is required
about the frequency and severity of this variety of
cretinism. It seems likely that screening programmes will be set up in most developed countries
but some time will have to elapse before the
probable benefits of early therapy can be
demonstrated.
TSH levels after TRH stimulation
The standard intravenous T R H test (Ormston,
Garry, Cryer, Besser & Hall, 1971) now has an
established role in the diagnosis of disorders of the
hypothalamus-pituitary-thyroid axis. Two hundred
micrograms of T R H are given as an intravenous
bolus and TSH levels are measured in blood
samples taken at 0, 20 and 60 min. Basal routine
thyroid-function tests (T3, T,, a thyroid hormonebinding test, and thyroid autoantibodies are also
estimated in the 0 sample). The test is free from
significant side effects, although about half the
patients experience a transient metallic taste, deep
urethral sensation, facial flushing and mild nausea,
all of which pass off within a few minutes of the
injection. Although the 60 min sample is helpful to
detect delayed responses, in routine clinical practice the peak sample (20 min) is sufficient to
confirm the diagnosis of thyroid disease. It is now
Thyroid-stimulating hormone-Part 2
our practice to perform the TRH test during the
initial outpatient visit when indicated. For
diagnostic purposes, the greater TSH response
during the follicular phase of the cycle in females,
or the diurnal variations observed in a given
subject, may be disregarded when the TRH test is
performed at a routine clinic visit, and, in addition,
the patient need not be fasting or recumbent. The
TRH test can be performed in conjunction with the
LHRH and insulin tolerance tests since there is no
interaction between the various hormones released
(Besser, Ratcliffe, Kilborn, Ormston & Hall, 1971;
Mortimer, Besser, McNeilly, Tunbridge, GomezPan & Hall, 1973). This procedure provides a test
of pituitary reserve of the gonadotrophins, TSH,
prolactin, growth hormone and corticotrophin.
Results in hyperthyroidism. Patients with
hyperthyroidism fail to respond to TRH because
of the suppressive effects of elevated circulating
levels of thyroid hormones. A normal TSH
response to a 200 pg dose of TRH absolutely
excludes a diagnosis of hyperthyroidism. The main
diagnostic application of the TRH test is the
exclusion of mild or subclinical hyperthyroidism.
However, it must be emphasized that an impaired
or absent response to TRH is not in itself indicative
of hyperthyroidism since it can be seen in patients
with ophthalmic Graves’ disease (Ormston, Alexander, Evered, Clark, Bird, Appleton & Hall, 1973),
in multinodular goitres and autonomous thyroid
adenomata (Evered et al., 1974), in some non-toxic
diffuse goitres, in patients with a variety of pituitary
diseases with or without hypothyroidism (Hall,
Besser, Ormston, Cryer & McKendrick, 1972),
in Cushing’s disease and acromegaly, in states of
supraphysiological replacement with T, or T, for
hypothyroidism and in some subjects rendered
clinically and biochemically euthyroid for several
months after treatment of hyperthyroidism (Von
Zur Muhlen, Hesch & Kobberling, 1975; SanchezFranco, Garcia, Cacicedo, Martin-Zurro, Escobar
Del Rey & Morreale de Escobar, 1974). This
sustained delay in the restoration of a normal TSH
response to TRH renders the TRH test unreliable
in the follow-up and monitoring of antithyroid
therapy for a period of up to 9 months after clinical
remission has occurred. Although the TSH response to TRH correlates well with suppressibility
by T, of thyroidal radioisotope uptake (Ormston et
al., 1973) a number of discrepancies have been
observed between the two tests, which are still not
fully understood. Despite this lack of absolute
correlation between these tests, the TRH test has
now replaced the outdated T, suppression test. It is
135
more rapid, less expensive, safer and does not
require administration of radioisotopes or a potentially dangerous drug to the patient.
Results in hypothalamic-pituitary disease. The
TRH test has limited value in the assessment of
pituitary reserve (Hall et al., 1972). A suboptimum
TSH response is associated with secondary
hypothyroidism in about 40% of the cases studied.
Patients with hypothyroidism due to pituitary
disease usually fail to respond to TRH. Patients
with hypothalamic disease may show a characteristic ‘delayed’ response in which the 60 min TSH
value is higher than that obtained at 20 min. Such a
response may also be seen in patients with primary
pituitary disease, although the pressure effects of
the tumour or the effect of previous therapy may
play a role in causing hypothalamic disturbance. In
patients with anorexia nervosa, a ‘hypothalamic’
type of response is often seen, which returns to
normal after restoration of body weight.
Results in chronic renal failure. The TRH test
provides unreliable information in patients with
impaired renal function. An exaggerated response
may be due to poor renal clearance of TRH
(Gonzalez-Barcena, Kastin, Schalch, TorresZamora, Perez-Pasten, Kato & Schally, 1973) and
impaired, absent or delayed TSH responses during
the standard TRH test may be observed in patients
with chronic renal failure, without any evidence
of hypothalamic-pituitary or thyroid disease
(Gomez-Pan, Sachdev, Duns, Tunbridge & Hall,
1975).
TSH levels after dopamine antagonism
The finding that serum TSH levels rise after
dopamine-receptor blockade in both euthyroid and
hypothyroid subjects suggests that this mechanism
might be of potential value as a more refined test of
the integrity of the hypothalamic-pituitarythyroid axis. It may prove possible to distinguish
compensated from uncompensated thyroid function in patients who are currently labelled as
mildly or subclinically hypothyroid on the basis of
their degree of TSH response to dopamine-receptor
blockade. Patients in this category have elevated
basal TSH levels and all show an exaggerated TSH
response to TRH and therefore the TRH test is of
no diagnostic value in this context. However,
patients whose thyroid function is truly compensated by their increased TSH drive might be
expected to show no greater TSH response to
dopamine-receptor blockade than a euthyroid
subject, regardless of the basal TSH levels. The
validity of this hypothesis depends critically on the
136
M . F. Scanlon, B. Rees Smith and R . Hall
relationship between basal TSH and the degree of
dopaminergic inhibition of TSH. The hypothesis is
supported by the finding of an inverse relationship
between basal TSH and the degree of dopaminergic
inhibition of TSH release in euthyroid subjects in
daytime hours. However, further work is required
to clarify the situation in patients with mild and
subclinical hypothyroidism.
Therapeutic applications of TRH
So far, no definite therapeutic applications have
been described for TRH. It has already been
indicated that the value of the TRH test in
monitoring antithyroid therapy is limited by the
delay in restoration of pituitary responsiveness to
TRH after hyperthyroidism. It is of no value in the
treatment of depression (Mountjoy et al., 1974).
The role of TRH as a tool in the treatment of
thyroid carcinoma (by increasing uptake of the
therapeutic dose of radioiodine by the tumour:
Fairclough, Cryer, MacAllister, Hawkins, Jones,
McKendrick, Hall & Besser, 1973) has been
described. TRH can be used in the treatment of
hypothalamic (tertiary) hypothyroidism, but it does
not offer any advantage over thyroid hormone
replacement. We have not observed any beneficial
effect of TRH in regenerating thyroid remnants
after surgery.
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