Download Thyroid-Stimulating Hormone

Clinical Science and Molecular Medicine (1978) 55,l-I0
EDITORIAL REVIEW
Thyroid-stimulating hormone: Neuroregulation and clinical
applications
PART 1
M . F. S C A N L O N , B. R E E S S M I T H A N D R . H A L L
Endocrine Unit, Departments of Medicine and Clinical Biochemistry, Royal Victoria Infirmary, Newcastle upon Tynr, U.K.
Abbreviations: FSH, follicle-stimulating hormone;
GH-RIH, growth hormone-release-inhibiting
hormone; hCG, human chorionic gonadotrophin; LH, luteinizing hormone; T,, triiodothyronine;
T,,
thyroxine;
TRH,
thyrotrophin-releasing hormone; TSH, thyrotr ophin .
trophins are determined by the b-subunit, but that
the active sites of the hormones can only be formed
when the a- and b-subunits are combined. In
addition to conferring biological specificity, the
b-subunits of the hormones are also the major
antigenic sites and this is important in the preparation of specific antisera (Pierce, 1971).
Thyrotrophin
The TSH receptor
Thyroid-stimulating hormone (TSH or thyrotrophin) is responsible for the control of thyroid
function in normal man. The hormone is synthesized and secreted by basophilic cells (thyrotrophs) in the anterior pituitary. When extracted
from the pituitary, TSH is in the form of a
glycoprotein with a molecular weight of about
30 000. The molecule, which contains about 15%
carbohydrate, is composed of two similarly sized
reptide chains (designated a and p) linked by noncovalent bonds (Pierce, 197 1).
The structure of TSH is closely related to that of
the gonadotrophins, luteinizing hormone (LH),
follicle-stimulating hormone (FSH) and human
chorionic gonadotrophin (hCG). The three gonadotrophins and TSH share a common a-subunit
whereas the b-subunits of TSH, L H and FSH are
different. LH and h C G have structurally similar bsubunits except that the P-subunit of hCG has an
additional C-terminal peptide. Isolated subunits of
TSH and the gonadotrophins do not show any
biological activity but when a- and b-subunits are
recombined to form intact molecules, the reconstituted proteins have biological activity (Pierce,
1971).
These observations indicate that the biological
activity and specificity of TSH and the gonado-
The first stage in the action of TSH on the
thyroid is the formation of a complex between TSH
and a thyroid cell-surface receptor. Kinetic studies
with 1251-labelled TSH indicate that contact between TSH and its receptor is transient; both
association and dissociation reactions being fairly
rapid (Rees Smith, Pyle, Petersen & Hall, 1977).
Experiments with detergents suggest that the
receptor for TSH consists of a molecule with a
hydrophobic region and a hydrophilic region
(Manley, Bourke & Hawker, 1974; Petersen,
Dawes, Rees Smith & Hall, 1977). The hydrophilic
region is in contact with the external environment
of the cell and appears to contain the TSH-binding
site. The hydrophobic region, however, is buried in
the hydrophobic interior of the cell membrane and
may provide a contact with such components as
adenylate cyclase which is located on the inner
surface of the cell membrane. It has been suggested
that gangliosides form an integral part of the TSH
receptor (Meldolesi, Fishman, Alej, Ledley, Lee,
Bradley, Brady & Kohn, 1977) but further work
and confirmatory studies are required before this
can be generally accepted. Preliminary studies with
detergent extracts of human thyroid membranes
suggest that the human TSH receptor molecule has
an isoelectric point of about pH 4 and is associated
with a 50 000 molecular-weight protein fraction
(Dawes, Petersen, Rees Smith & Hall, 1978).
The interaction of TSH with its receptor leads to
Correspondence: Dr Maurice F. Scanlon, Endocrine Unit,
The Royal Victoria Infirmary, Queen Victoria Road, Newcastle
upon Tyne, NEI 4LP, U.K.
I
M . F. Scanlon, B. Rees Smith and R. Hall
2
are required before the receptor assay can be used
activation of membrane-bound adenylate cyclase
to measure TSH in serum (B. Rees Smith &
and an increase of intracellular cyclic adenosine
R. Hall, unpublished observation). The TSH
monophosphate (cyclic AMP) which in turn
receptor assay, therefore, at least in its present
dissociates the regulatory and catalytic compoform, does not appear to be useful for routine
nents of a series of enzymes termed protein kinases
serum TSH measurements. It is, however, in(Field, 1975). The activated protein kinases then
valuable for monitoring the TSH receptor antiphosphorylate a number of substrates, which are
bodies (thyroid-stimulating antibodies or TSAb),
responsible for the actions of TSH on iodide
which appear to be responsible for the hypertrapping, organscation of iodine, tri-iodothyronine
thyroidism of Graves’ disease (Mukhtar, Rees
(T,) and thyroxine (T,) synthesis, pinocytosis of
Smith, Pyle, Hall & Vice, 1975; Clague, Mukhtar,
coiloid and thyroid hormone release. Not all the
Pyle, Nutt, Clark, Scott, Evered, Rees Smith &
effects of TSH on the thyroid appear to be
Hall, 1976).
mediated by cyclic AMP, e.g. the effects of TSH on
The only assay method sufficiently sensitive to
32P incorporation into phospholipid (Pastan &
readily measure normal and subnormal TSH levels
Macchia, 1967) and other effects of TSH such as
is the cytochemical bioassay (Bitensky, Alaghband,
the rapid stimulation of iodide release can be
Zadeh & Chayen, 1974; Petersen, Rees Smith &
demonstrated to occur before there are any
Hall, 1975). This technique is extremely sensitive,
detectable changes in intracellular cyclic AMP
being able to measure as little as lo-’’ mol/l TSH.
concentrations (Povey, Rees Smith, Davies & Hall,
The method depends on the ability of TSH to
1976).
induce increases in the permeability of thyroid cell
lysosomes in segments of thyroid tissue. The
TSH measurement
increase in lysosomal permeability is then monitored colorimetrically by using an appropriate
The most convenient method of measuring TSH
lysosomal enzyme substrate. The technique is
is by radioimmunoassay. The concentration of
tedious and only a few samples per week can be
TSH in normal human serum, however, is exhandled. Recently, however, a modification of the
tremely low, being in the region of 1 munit/l
assay based on sections rather than segments of
mol/l) and this is close to the limit of sensitivity of
thyroid tissue has been developed (Gilbert, Besser,
most radioimmunoassays. Consequently, radioBitensky & Chayen, 1978). With the section
immunoassay is of limited value in studies of
system, relatively large numbers of samples can be
normal TSH concentrations. However, TSH
assayed and the feasibility of using the cytomeasurements by radioimmunoassay are parchemical method on a routine basis is now
ticularly useful diagnostically in conditions where
considerably increased.
TSH levels are elevated. In addition, the technique
is invaluable in monitoring the TSH response to
TRH in the now classical TRH test.
T S H heterogeneity
Recently, radioreceptor assays for TSH have
Different proportions of intact TSH and its a been described (Manley et al., 1974; Smith & Hall,
and /%subunits may be secreted in a variety of
1974). These are based on the interaction between
different pathophysiological conditions and there is
1251-labelledTSH and TSH receptors in thyroid
also increasing evidence for the secretion of TSH
membranes; however, in practice the radioreceptor
with reduced biological activity.
assay has several disadvantages when compared
Isolated a- and /3-subunits of TSH can be
with the radioimmunoassay. In particular, the
measured in the circulation by specific radiosensitivity of the receptor assay is limited by the
immunoassay even in the presence of elevated
association constant of the hormone-receptor
concentrations of TSH (Kourides, Weintraub,
interaction and this is in the region of lo9 l/mol.
Levko & Maloof, 1974; Binoux, Pierce & Odell,
Good TSH antisera, however, can have association
1974). From such studies it is clear that increased
constants as high as 10” I/mol (D. R. Weightman,
levels of free TSH-a and TSH-B are present in
B. Rees Smith & R. Hall, unpublished observation)
patients with primary hypothyroidism, are released
and this results in a correspondingly superior
from the pituitary after administration of
sensitivity. In addition, the hormone-receptor
thyrotrophin-releasing hormone (TRH) and are
binding system is particularly sensitive to nondecreased by administration of T, and in
specific interference from serum samples and
hyperthyroidism due to Graves’ disease or toxic
consequently complex serum-extraction procedures
Thyroid-stimulating hormone: Neuroregulation and clinical applications
nodules (Kourides, Weintraub, Ridgway &
Maloof, 1973, 1975). The TSH subunits in serum
are not derived from peripheral metabolism of
intact TSH, but are secreted as such by the
pituitary (Kourides et al., 1975; Edmonds,
Molitch, Pierce & Odell, 1975). Elevated serum asubunits can also be detected in some patients with
pituitary tumours (Kourides, Weintraub, Rosen,
Ridgway, Kliman & Maloof, 1976) and further
studies by Kourides, Ridgway, Weintraub, Bigos,
Gerghengorn & Maloof (1977) in six patients
with TSH-induced hyperthyroidism have shown
that the finding of elevated a-subunits and undetectable TSH-P may serve to identify those with
pituitary tumours. Furthermore, in certain patients
the reduction in serum a-subunit levels may reflect
the adequacy of therapy. Recent studies indicate
that physical and chemical microheterogeneity may
also exist within individual subunits. Weintraub,
Stannard & Rosen (1977) report that only certain
species of immunologically identical a-subunits are
capable of physically combining with P-subunits
and of these even fewer are capable of expressing
the receptor-binding activity specified by the P-subunit. Giudice & Pierce (1977) have identified two
radioimmunologically identical components of
TSH P-subunits, of which one does not recombine
with a-subunits and thus represents a nonfunctional form of TSH-P. Whether such structural
and hence functional microheterogeneity is artifactual, occurring during the preparation and
purification of the subunits, or biologically relevant
remains to be defined.
Serum immunoreactive TSH levels are elevated
or are at the upper end of the normal range in some
hypothyroid patients with hypothalamic-pituitary
disease and the TSH response to TRH may be
normal, exaggerated or delayed. Before concluding
that such TSH is biologically inactive, it is
necessary to exclude primary thyroid disease by
confirming the absence of thyroid autoantibodies,
by demonstrating a rise in thyroidal radioiodine
uptake in response to exogenous TSH and by
showing that T, and T, levels fail to rise in response
to endogenous TSH released by administration of
TRH. Illig, Krawczynska, Torresani & Prader
(1975) detected slightly elevated basal TSH levels
and clinical hypothyroidism in six children with
documented growth hormone deficiency. The TSH
response to T R H was exaggerated and followed by
a rise in T, levels, suggesting that TRH may have
increased the secretion of TSH molecules of higher
biological activity than that normally circulating in
the patients. Confirmation of the low biological
3
activity of the patient’s TSH can only be achieved
by using the highly sensitive cytochemical bioassay
(Bitensky et al., 1974; Belchetz & Elkeles, 1976;
Petersen, McGregor, Belchetz, Elkeles & Hall,
1978). A possible dissociation of biological and
radioimmunological activity was found by Van
Haelst, Bonnyns & Golstein-Golaire (1975), who
studied the TSH content of the pituitaries of 22
patients with atrophic thyroiditis. Increased
amounts of TSH were demonstrated with the
McKenzie bioassay but these increases were not
evident when measurements were made by radioimmunoassay. Furthermore, the slopes of the
dilution curves of pituitary TSH were not parallel
to TSH standards. The authors suggested that
there may exist a species of TSH molecule with
much higher biological activity than previously
recognized.
Further studies are required to elucidate the
relationship between structure and function in the
TSH molecule and the possible modification of
TSH structure by factors involved in the control of
TSH synthesis and secretion.
Regulation of thyrotrophin synthesis and secretion
The hypothalamus exerts a dominant stimulatory
action over TSH synthesis and secretion since
hypothyroidism follows pituitary stalk section
(Turkington, Underwood & Van Wyk, 1971).
Thyroid hormones exert a powerful negative feedback control over TSH release acting at both
pituitary and hypothalamic levels. However, recent
evidence indicates that the central neurotransmitter dopamine has a physiological inhibitory
control over TSH release in man and there is
circumstantial evidence to suggest a similar role for
somatostatin (growth hormone-release inhibiting
hormone; GH-RIH). Thus hypothalamic control
over TSH synthesis and release in man is more
complex than previously envisaged and has both
stimulatory and inhibitory components.
Thyrotrophin-releasing hormone
Although the existence of a thyrotrophinreleasing hormone (TRH) was first suggested more
than two decades ago (Greer, 195 1) it was not until
15 years later that Schally, Bowers, Redding &
Barrett (1966) isolated a porcine hypothalamic
extract with TSH-releasing properties.
Structure,
analogues
and
metabolism.
Elucidation of the structure and subsequent synthesis of porcine (Folkers, Enzman, Boler, Bowers
& Schally, 1969) and ovine (Burgus, Dunn,
4
M . F. Scaiilon, B. Rees Smith and R . Hall
is widely distributed in the hypothalamus although
higher concentrations are found in the median
eminence than in other hypothalamic areas
(Jackson & Reichlin, 1974; Brownstein, Palkovits,
Saavedra, Bassiri & Utiger, 1974; Brownstein,
Utiger, Palkovits & Kizer, 1975). However,
immunoreactive TRH can also be detected in many
other brain areas (Jackson & Reichlin, 1974;
FIG.1. Structure of thyrotrophin-releasing hormone (TRH).
Winoku & Utiger, 1974) and in the rat spinal cord
(Hokfelt, Fuke, Johansson, Jeffcoate & White,
Desiderio, Ward, Vale & Guillemin, 1970) TRH
1975). Indeed, about two-thirds of brain TRH is
established its nature as a weakly basic tripeptide,
located outside the hypothalamus (Winoku &
L-pyro-Glu-L-His-L-Pro-amide
(Fig. 1).
Utiger, 1974). Extra-hypothalamic T R H is not
The presence of three ring structures in the
produced by hypothalamic neurosecretory cells
molecule reduces enzyme access to its amide bonds
since hypothalamic deafferentation decreases only
and this may explain why TRH is active after oral
hypothalamic and not extra-hypothalamic TRH
administration (Pittmann, 1974). In the circulation
(Brownstein et al., 1975). This wide distribution
TRH has a half-life of about 4 min (Redding &
supports the concept that TRH may have some
Schally, 1969, 1971), being inactivated by enneurotransmitter functions in addition to its known
zymatic cleavage of the amide group (Nair,
pituitary actions though there is no direct evidence
Redding & Schally, 1971) and excreted by the
for this in man.
kidney and liver.
TRH radioimmunoassay in serum and urine is
It has been shown that synthetic TRH has
technically more difficult and has provided conflictidentical biological activity to the natural material
ing data. Because of the rapid degradation of TRH
and has full biological activity in all animaf species
in serum precautions must be taken to prevent this
so far studied. It thus exhibits a lack of phyloin samples for assay (Jeffcoate et al., 1974). In rats,
genetic specificity which is common to the other
cold exposure (which is known to cause TSH
hypothalamic regulatory hormones. An intact
release in this species) has been reported both to
amide group and the cyclic glutamic acid terminus
increase (Montoya, Seibel & Wilber, 1975) and to
are essential for biological activity (Reichlin, 1974).
have no effect on (Emerson & Utiger, 1975)
Many analogues of TRH have been synthesized
plasma TRH levels. Such conflicting findings reflect
although most have absent or reduced biological
the methodological difficulties involved in TRH
activity. One analogue in which histidine is methylradioimmunoassay. Caution must also be exercised
ated in position C-3 has eight times higher potency
in interpreting results of TRH radioimmunoassay
(Vale, Rivier & Burgus, 1971). Inhibitory TRH
in urine. A recent study by Emerson, Frohman,
analogues have not yet been synthesized although
Szabo & Thakkar (1977) indicates that TRH
dissociation between brain and pituitary actions of
TRH has been found with ~-pyrazolyl-3-Ala2)- immunoreactivity in human urine, even after
concentration by affinity chromatography, may be
TRH and TRH-D-alanine (Prange, Breese, Jahnke,
due to cross-reacting substances rather than TRH.
Martin, Cooper, Cott, Wilson, Alltop, Lipton,
Therefore results of TRH radioimmunoassay in
Bissette, Nemeroff & Loosen, 1975). Thus the
urine and other biological fluids must still be
brain response to each of these analogues is similar
interpreted with caution.
whereas the TSH response is greatly reduced.
Mechanism ofaclion. TRH is synthesized within
Measurement and distribution. The presence of
so-called ‘peptidergic’ neurons in the hypothalamus
TRH in hypothalamic extracts was initially
and transported to the median eminence where it is
assessed with bioassays which depended on the
stored. From here it is secreted into the
release of TSH from pituitary tissue (Schally,
hypophyseal portal venous system and carried to
Bowers, Redding & Barrett, 1966; Guillemin,
the anterior pituitary gland (Redding, Schally,
Burgus & Vale, 197 1). Subsequent purification,
Arimura & Matsuo, 1972). Radioligand-binding
characterization and synthesis of the tripeptide
studies with Wlabelled T R H have demonstrated
have led to the development of radiospecific binding to anterior pituitary plasma memimmunoassays, which, though fraught with methodbranes (Grant, Vale & Guillemin, 1972; Labrie,
-ological difficulties (Jeffcoate, White, Fraser &
Barden, Pokier & De Lean, 1972; Wilber & Siebel,
Gunn, 1974), have been applied to the study of the
1973; De Lean, Ferland, Drouin, Kelly & Labrie,
tissue distribution of TRH. Immunoreactive TRH
Thyroid-stimulating hormone: Neuroregulation and clinical applications
5
1977) and a high degree of specificity of the TRH
related since oestrogen administration to males
receptor is suggested by the absence of competitive
leads to enhancement of the TSH response to TRH
binding by other hypothalamic peptides and polywithout any alteration in basal TSH levels (Faglia,
peptide hormones (Labrie, Barden, Poirier & De
Beck-Peccoz, Ferrari, Ambrosi, Spada &
Travaglini, 1973a; Mortimer, Besser, Goldie, Hook
Lean, 1972). Furthermore, there is a close cor& McNeilly, 1974). Furthermore, oestrogenrelation between the ability of a wide variety of
containing ovulatory suppressants increase basal
TRH analogues to inhibit 3H-labelled T R H binding and to stimulate TSH release (Grant, Vale &
TSH levels (Weeke & Hansen, 1975) and enhance
the TSH response to TRH (Ramey, Burrow,
Guillemin, 1973). TRH binding to its receptor leads
Polackwich & Donabedian, 1975). Recently, De
to activation of membrane-bound adenylate cyclase and intracellular accumulation of cyclic AMP
Lean et al. (1977) have clearly demonstrated that
(Borgeat, Chavancy, Dupont, Labrie, Arimura &
oestrogens increase binding of TRH to anterior
Schally, 1972; Kaneko, Saito, Oka, Oda &
pituitary cell membranes although the physioYanaihara, 1973). It has been appreciated for some
logical significance of this remains to be demonstrated.
time that both cyclic AMP and theophylline (an
Actions on other pituitary hormones. Although it
inhibitor of cyclic nucleotide phosphodiesterase)
is reasonable to assume that TRH has a physioenhance TSH release in vitro (Wilber, Peake &
logical control over TSH synthesis and release in
Utiger, 1969) and it is now generally agreed that
man, the hypophysiotropic actions of TRH are not
the actions of TRH on TSH release are mediated
by cyclic AMP.
limited to TSH. TRH consistently stimulates
prolactin release when administered to both
In addition to stimulating TSH release, TRH
animals and man (Jacobs, Snyder, Wilber, Utiger
also stimulates TSH synthesis (Mittler, Redding &
& Daughaday, 1971; Jacobs, Snyder, Utiger &
Pchally, 1969). A biphasic pattern of TSH release
Daughaday, 1973) and studies with cultured
is seen after prolonged intravenous infusion of
pituitary cells in vitro indicate a direct action of
T R H in man (Chan & Wang, 1977); the early
T R H on the lactotroph (Meites, 1973). Prolactin
phase may well reflect the release of a readily
release is stimulated not only by single intravenous
releasable pool of stored TSH within the thyinjections but also by continuous infusions of TRH
i'rotrophs, whereas the later phase could be due to
release of newly synthesized TSH produced under
(Noel, Dimond, Wartofsky, Earll & Frantz, 1974;
the influence of increased TRH drive. A similar
Mortimer, Besser, Goldie, Hook & McNeilly,
pattern of events has been postulated for the
1974). Three micrograms of TRH is the minimal
&nthesis and release of luteinizing hormone after
effective dose for the release of both TSH and
prolactin. Thus the smallest increase in TRH
administration of gonadotrophin-releasing horcapable of inducing an increase in serum TSH also
mone (Bremner & Paulsen, 1974).
increases the serum prolactin levels. This finding
Actions on TSH. Intravenous administration of
indicates that TRH may have a physiological role
15-500 pg of TRH to humans causes a doserelated release of TSH from the pituitary (Bowers,
in the control of prolactin release in man (Noel et
Schally, Schalch, Gual, Kastin & Folkers, 1970;
al., 1974). Such a concept will remain questionable,
Hall, Amos, Garry & Buxton, 1970). T o induce a
however, until there are more direct and reliable
similar effect by oral, subcutaneous or intramethods of assessing the effects of physiological
muscular administration requires larger doses of
alteration in endogenous TRH levels. CertainTRH. The TSH response to 200 pg of T R H given
ly,TRH cannot be the only factor involved in the
intravenously to normal subjects is detectable by
control of prolactin secretion since the release of
radioimmunoassay within 2-5 min, and is maximal
TSH and prolactin appear to be dissociated in a
at 20-30 min with a return to basal levels by 2-3 h.
variety of physiological situations. In particular the
An elevation in thyroid hormone levels in response
prolactin responses to suckling (Gautvik,
to T R H is also seen with T, peaking at 3 h and T,
Weintraub, Graeber, Maloof, Zuckerman & Tashat 8 h (Lawton, 1972). Females show a greater
jian, 1973) and stress (Noel et al. 1972; Meites,
TSH response to TRH than males (Ormston,
1973) in man are not accompanied by elevations in
Garry, Cryer, Besser & Hall, 1971) and also show
serum TSH levels. The situation is complicated by
a greater response during the follicular phase of
species variations, however, as Burnet & Wakerly
the menstrual cycle (Sanchez-Franco, Garcia,
(1976) have clearly shown in rats that the prolactin
Cacicedo, Martin-Zurro & Escobar del Rey, 1973).
response to suckling is paralleled by a tenfold rise
It is likely that this sex difference is oestrogenin TSH levels.
6
M . F. Scanlon, B . Rees Smith and R . Hall
In man T R H produces a small but consistent
release of follicle-stimulating hormone (Mortimer,
Besser, McNeilly, Tunbridge, Gomez-Pan & Hall,
1973) and this effect is abolished by prior treatment
with oestrogens (Mortimer, Besser, Goldie, Hook
& McNeilly, 1974). TRH also releases lutehizing
hormone in some females at midcycle (Franchimont, 1972).
TRH administration causes growth hormone
release in several pathophysiological conditions but
not in normal individuals. Such growth hormone
release has been demonstrated in some patients
with chronic renal failure (Gonzalez-Barcena,
Kastin, Schalch, Torres-Zamora, Perez-Pasten,
Kato & Schally, 1973; Gomez-Pan, Alvarez-Ude,
Evered, Duns, Hall & Kerr, 1975a), in acromegaly
(Irie & Tsushima, 1972; Faglia, Beck-Peccoz,
Ferrari, Travaglini & Ambrosi, 1973b; GomezPan, Tunbridge, Duns, Hall, Besser, Coy, Schally
& Kastin, 1975b), in anorexia nervosa (Maeda,
Kato, Yamaguchi, Chihara, Ohgo, Iwasaki,
Yoshimoto, Moridera, Kuromaru & Imura, 1976),
in some patients with depression (Maeda, Kato,
Ohgo,
Chihara,
Yoshimoto,
Yamaguchi,
Kuromaru & Imura, 1975) and in some children
with hypothyroidism (Collu, Leboeuf, Letarte &
Ducharme, 1977). Such disturbances may well be
associated with a more generalized central neurotransmitter imbalance. The TRH-induced G H
release in acromegaly is not mediated by TSH or
prolactin and may reflect a loss of specificity of
receptor sites on the somatotroph in this condition.
This effect can be blocked by growth hormonerelease-inhibiting hormone (Gomez-Pan, 1975b).
In acromegalic patients showing a GH response to
TRH, complete suppression of G H levels with
bromocriptine (2-bromo-cc-ergocryptine; CB 154)
does not abolish the TRH-mediated G H release
(Gomez-Pan, Sachdev, Duns, Tunbridge & Hall,
1975c; Ishibashi, Yamaji & Kosaka, 1977).
Negativefeedback control by thyroid hormones
Whilst the dominant hypothalamic control over
TSH is stimulatory via TRH, thyroid hormones
exert a powerful, dose-related negative feedback
control over TSH release (Snyder & Utiger, 1972).
Just as small increases in serum T, and T, levels
reduce basal and TRH-stimulated levels, small
decreases in T, and T, levels induced by short-term
administration of pharmacological doses of iodide
lead to elevation in basal and TRH-stimulated TSH
levels (Saberi & Utiger, 1975; Ikeda & Nagataki,
1976; Jubiz, Carlile & Lagerquist, 1977).
The direct pituitary action of T, on the
suppression of basal and TRH-stimulated TSH
release has been clearly demonstrated in many
studies but investigation of the precise role of T, in
the negative feedback pathway has yielded conflicting results. Thus Chopra, Carlson & Solomon
(1976) concluded from the results of studies in
vitro that T, had an intrinsic role in the suppression
of TSH release from the pituitary and this is
supported by recent studies in normal adult men:
the peak TSH response to TRH showed a
significant negative correlation with circulating T,
rather than T, levels (Sawin & Hershman, 1976)
and T, administration to euthyroid men at a dose
which increased circulating T,, but not T,, levels
abolished the TSH response to T R H (Sawin,
Hershman & Chopra, 1977). However, a recent
study by Lewis, Yeo, Green & Evered (1977), in
which physiological concentrations of T, and T,
were applied to cultures of rat anterior pituitary
cells, suggested that T, per se has no feedback
action, its effects being due to its peripheral
monodeiodination to T,. Furthermore, goo&
evidence has recently been presented which suggests that suppression of TSH release in hypothyroid rats occurs by interaction of T, with the
nuclear receptor of the thyrotroph and, after T,
injection, the T, found in the nucleus is derived
from rapid intrapituitary monodeiodination (Silva
& Larsen, 1977). This view is consistent with the
findings in vivo of Escobar del Rey, Garcia, Bernal
& Morreale de Escobar (1974). Acute elevation in
serum T, levels after administration of exogenous
T, to both euthyroid and hypothyroid subjects does
not cause immediate suppression of basal and
TRH-stimulated TSH levels (Saberi & Utiger,
1974; Wartofsky, Dimond, Noel, Frantz & Earll,
1976; Burrow, May, Spaulding & Donabedian,
1977). Indeed, after administration of a single dose
of T, there is increasing inhibition of TRHstimulated TSH release, which is maximal at about
3 days after ingestion but only after the early
elevation in serum T, levels has returned to normal
(Azizi et al., 1975). There are several possible
explanations for the observed time lag between
peak serum T, levels and maximal TSH
suppression. The inhibitory action of T, on TSH
release from cultured anterior pituitary cells can be
blocked by prior treatment with inhibitors of
protein synthesis (Bowers, Lee & Schally, 1968). It
appears, therefore, that at least part of the
inhibitory action of T, is mediated by the induction
of a protein suppressor in the thyrotroph. Thus the
time lag may reflect in part the time taken for new
Thyroid-stimulating hormone: Neuroregulation and clinical applications
7
protein synthesis. Takaishi, Miyachi & Shishiba
thyroid hormones and TRH-secreting peptidergic
(1975) detected a 7-12 h delay in equilibration
neurons.
between serum and pituitary T, levels after adPart 2 will appear in the next number (55, number
ministration of single doses of T, to mice, whereas
2, August 1978) of Clinical Science and Molecular
equilibration between serum and liver was almost
Medicine
immediate. Since the pituitary gland has direct
connections with the systemic circulation and thus
References (Part 1)
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A.G., INGBAR,
S.H. & BRAVERMAN,
L.
unlikely that the observed delay in equilibration is
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