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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) lies outside the blood-brain barrier, it seems AZIZI,F., VAGENAKIS, A.G., INGBAR, S.H. & BRAVERMAN, L. unlikely that the observed delay in equilibration is E. (1975) The time course of changes in TRH responsiveness due to slower transport of thyroid hormones to the in man following a single dose of liothyronine. Metabolism, anterior pituitary gland. It is possibly more related 24,69 1-694. BELCHETZ, P.E. & ELKELES, R.S. (1976) Idiopathic to the binding affinity of nuclear receptors in hypopituitarism with biologically inactive TSH. Proceedings anterior pituitary cells for T, and this may well of the Royal Society of Medicine, 69,428-429. BINOUX,M., PIERCE,J.G. & ODELL, W.D. (1974) Radiovary between different tissues. immunological characterisation of human thyrotropin and its Other workers, however, using higher doses of subunits: applications for the measurement of human TSH. T,, have reported much more rapid inhibition of Journal of Clinical Endocrinology & Metabolism, 38, 674682. TSH release in studies with hypothyroid rats BITENSKY,L., ALAGHBAND-ZADEH, J. & CHAYEN,J. (1974) (Surks & Oppenheimer, 1976) and man (Utiger, Studies on thyroid stimulating hormone and long-acting 1965; Odell, Vanslager & Bates, 1968) and the rate thyroid stimulating hormone. Clinical Endocrinology, ‘3, 363-374. of TSH suppression was shown to be dose-related BORGEAT, P., CHAVANCY,G., DUPONT, A., LABRIE, F., (Odell et al., 1968). In recent detailed studies both ARIMURA,A. & SCHALLY,A.V. (1972) Stimulation of adenosine 3‘ :5’-cyclic monophosphate accumulation in rapid and slow components in the pattern of TSH anterior pituitary gland in vitro by synthetic luteinising suppression have been clearly demonstrated in hormone-releasing hormone. Proceedings of the National hypothyroid (Surks & Oppenheimer, 1976) and Academy of Sciences USA., 69,2677-2681. BOWERS,C.Y., LEE, K.L. & SCHALLY,A.V. (1968) A study on euthyroid rats (Surks & Lifschitz, 1977). After the interaction of the thyrotropin-releasing factor and Lacute administration of a single pharmacological triiodothyronine: Effects of puromycin and cycloheximide. dose of T, there is rapid suppression of TSH to Endocrinology, 8 2 , 7 5 4 2 . BOWERS,C.Y., SCHALLY,A.V., SCHALCH,D.S., GUAL, C., 10% of pretreatment levels by 5 h after T, K. (1970) Activity and specificity KASTM,A.J. & FOLKERS, administration. Thereafter TSH suppression occurs of synthetic thyrotrophin-releasing hormone in man. Biochemical and Biophysical Research Communications, 39, much more slowly and only after chronic treatment 352-355. with T,. It seems likely that a similar pattern of BREMNER,W.J. & PAULSEN,C.A. (1974) Two pools of events occurs in man, although this has not yet luteinising hormone in the human pituitary: evidence from constant administration of luteinising hormone-releasing been clearly demonstrated. hormone. Journal of Clinical Endocrinology and Metabolism, In addition to any direct inhibitory effects on 39,8 11-8 15. TSH synthesis and release, thyroid hormones may BROWNSTEM, M.J., UTIGER, R.D., PALKOVITS, M. & KIZER, J.S. (1975) Effect of hypothalamic deafferentation on have a physiological role in regulating the TRH thyrotropin releasing hormone levels in rat brain. Proceedings receptor density on the thyrotroph cell, and recent of the National Academy of Sciences U S A . , 12,4177-4179. BROWNSTEIN, M., PALKOVITS, M., SAAVEDRA, J.M., BASSIRI, studies in vitro (De Lean et al., 1977) have R.M. & UTIGER,R.D. (1974) Thyrotropin releasing hormone demonstrated a twofold increase in T R H binding in in specific nuclei of the brain. Science, 185,267-269. hypothyroid animals, which can be reduced by BURGUS,R., DUNN,T.F., DESIDERIO,D., WARD,D.N., VALE, W. & GUILLEMIN,R. (1970) Characterisation of the thyroid hormone replacement. Such a finding raises hypothalamic hypophysiotropic TSH-releasing factor (TRF) the possibility that, in states of primary thyroid of ovine origin. Nature (London),226,321-325. failure, T R H action may be regulated without the BURNET,F.R. & WAKERLEY, J.B. 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