regulation of thyroid function - pennsylvania state university
TRANSCRIPT
Regulation of Thyroid Function
International Thyroid Symposion Düsseldorf, Federal Republic of Germany
October 3rd and 4th, 1975
Edited by
Prof. Dr. E. Klein, Bielefeld Prof. Dr. D. Reinwein, Essen
Assisted by Dr. D. Beysel, Darmstadt
With 49 Figures and 18 Tables
F. K. SCHATTAUER V E R L A G • STUTTGART - NEW YORK
CIP-Kurztitclaufnahmc der Deutschen Bibliothek
Regulation of thyroid function Internat. Thyroid Symposion, D ü s s e l d o r f , Föderal Republic of Gennany, October ?>. and 4., 1975. F.d. by F.. Klein ; D. Reinwein. Assisted by D. Beysel. - l . Aufl. -Stuttgart, New York: Schattauer, 1976.
ISBN 5-~945-(h~M-h
N F : Klein, 1 rich jHrsg.j; International Thyroid Symposion 02, 19~*5, D ü s s e l d o r f
The reproduetion of general descriptive names, trade names, trade marks etc. in this publication, even when there is no special identification mark, is not to be taken as a sign that such names, as understood bv the
Trade Marks and Merchandise Marks Law, may accordingly be freely used by anyone.
A l l rights reserved. N o part of this book may be translated or reproduced in any form without written per-mission from the Schattauer Verlag.
© 1976 by F. K. Schattauer Verlag G m b H . , Stuttgart, Germany
Printed in Germany
Composing and printing: S V - D R U C K , 7302 Ostfildern 1
ISBN 3 7945 0564 6
Contents
E. K L E I N : Introduction 1
D . R E I N W E I N : Introductory Survey on theRegulatory System 3
Central regulatory components M . A . G R E E R and H . F U K U D A : Hypothalamic control of T S H Secretion 15
A . V O N Z U R M Ü H L E N : Thyreotropin Releasing Hormon 27 P. C. S C R I B A , F. E R H A R D T , H . G . H E I N Z E , K . H O R N , I. M A R S C H N E R
and C R . P I C K A R D T : Anterior Pituitary and T S H 3 5
Intrathyroid regulatory components J . E . D U M O N T , R . P O C H E T and D . H . D E S M E D T : M o d e s o f A c t i o n o f T S H . . . . 4 9
J. W O L F F : IodineHomeostasis 65
D. A . K O U T R A S : T 4 / T 3 Ratio and Enzyme Activities 83
Peripheral regulatory components J . E. R A L L : Protein Binding of Thyroid Hormones as a Regulatory Mechanism 97 G . M O R R E A L E D E E S C O B A R : Conversion of T 4 to T 3 and its Relation
to Hormonal Activity 109 J. H . O P P E N H E I M E R , M . I. S U R K S , H . L . S C H W A R T Z , D . H . K O E R N E R
and W . D I L L M A N N : Evidence in Support of a Nuclear Site for the Initiation of Thyroid Hormone Action 131
B . -A . L A M B E R G : Pathological Regulatory Factors in Thyroid Disease 143 H . S C H L E U S E N E R : Thyroid Stimulating Immunoglobulins in Graves'Disease . . . 159
List of Participants
A D E L K O F E R , F . , Pr iv .-Doz. Dr . Klinikum Steglitz der Freien U n i v e r s i t ä t Berlin, 1000 Berlin 45, Hindenburgdamm 30, W . Germany
A L M Q U I S T , S. G . , D r . Medical Cl inic , Section of Endocrinology, Regionsjukhuset, L i n k ö p i n g 2, Sweden
A N D R E O L I , M . , Prof. Dr . Centro di Fisiopatologia Tiroidea, Policlinico Umberto I, Universita di Roma, 001 Roma, Italy
B A L D E T , L . , D r . Cliniques des Maladies Metaboliques et Endocriniennes - Hopital Saint-Eloi, 34059 Montpellier Cedex
(67), France
B A S T E N I E , P. A . , Prof. Dr . Laboratoire de Medecine Experimentale, Universite Libre de Bruxelles, Boulevard de Waterloo, 115,
1000 Bruxelles, Belgium
B E C K E R S , C . , Prof. D r . Centre de Medecine Nucleaire, Brusselsestraat 69, 3000 Leuven, Belgium
B E T H G E , H . , Prof. D r . 6100 Darmstadt, Frankfurter S t r a ß e 250, W . Germany
B E Y S E L , D . , D r . 6100 Darmstadt, Frankfurter S t r a ß e 250, W . Germany
B Ö R N E R , W . , Prof. Dr . Abteilung für Nuclearmedizin im Klinikum der U n i v e r s i t ä t W ü r z b u r g , Luitpoldkrankenhaus, 8700 W ü r z b u r g , W . Germany
C O S T A , A . , Prof. Dr . Ospedale Mauriziano, Corso Galileo Ferraris, 51, 10128 Tor ino , Italy
C R O O K S , J., Prof. Dr . Department of Pharmacology and Therapeutics, University of Dundee, Dundee, D D 2 1 U D , England
D U M O N T , J. E . , Prof. Dr . Institut de Recherche Interdisciplinaire, Universite Libre, Boulevard de Waterloo, 115, 1000 Bruxelles,
Belgium
E B E R , O . , Prof. D r . II. Innere Abteilung, Krankenhaus der Barmherzigen B r ü d e r , B e r g s t r a ß e 27, 8020 Graz-Eggenberg,
Austria
X List ot Participants
E I C K E N B U S C H , W . , Priv .-Doz. Dr . Medizinische Klinik, Allgemeines Krankenhaus, 5800 Hagen, B u s c h e y s t r a ß e 15a, W. German)
E M R I C H , D . , Prof. Dr . Nuklearmedizinischc Abteilung der Medizinischen und Radiologischen Klinik der U n i v e r s i t ä t , 3400 G ö t t i n g e n , Humboldtallee 1, W . Germany
G E H R I N G , D . , Pr iv .-Doz. Dr . Abteilung für klinische Nuklearmedizin der U n i v e r s i t ä t , 7800 Freiburg, Hugstetter S t r a ß e 55, W . Ger
many
G R E E R , M . A . , Prof. Dr . Department of Medicine, Division of Endocrinology, University of Oregon Medical School, 3181 S. W . Sam Jackson Park Road, Portland, Oregon 97201, U S A
G U I N E T , P. , Prof. Dr . Clinique Endocrinologique, H ö p i t a l de L'Antiquaille, Rue de L'Antiquaille, L y o n , France
H A C K E N B E R G , K . , Pr iv .-Doz. D r . Medizinische U n i v e r s i t ä t s k l i n i k , Abt . Kl in . Endokrinologie, 4300 Essen 1, H u f e l a n d s t r a ß e 55, \V .
Germany
H E R R M A N N , J . , Prof. Dr . 2. Medizinische U n i v e r s i t ä t s - K l i n i k , 4000 D ü s s e l d o r f , M o o r e n s t r a ß e 5, W . Germany
H E S C H , R. D . , Pr iv .-Doz. Dr . Abteilung für klinische Endokrinologie, Medizinische Hochschule, 3000 Hannover-Kleefeld, Karl-
Wiechert-Allee 9, W . Germany
H Ö F E R , R., Prof. Dr . IL Medizinische U n i v e r s i t ä t s - K l i n i k , Abt . für Nuklearmedizin, Garnisongasse 13, 1090 Wien, Austria
H O R S T , W . , Prof. D r . U n i v e r s i t ä t s k l i n i k und Poliklinik für Nuklearmedizin, Kantonsspital, R ä m i s t r a ß e 100, 8006 Z ü r i c h ,
Switzerland
H O R S T E R , F . A . , Prof. Dr . 2. Medizinische U n i v e r s i t ä t s - K l i n i k , 4000 D ü s s e l d o r f , M o o r e n s t r a ß e 5, W . Germany
J A F F I O L , C . , Prof. Dr . Clinique des Maladies Metaboliques et Endocriniennes, H ö p i t a l Saint-Eloi, 34059 Montpellier Cedex (67), France
J O S E P H , K . , Prof. Dr. . Klinik und Poliklinik für Nuklearmedizin der U n i v e r s i t ä t , 3550 Marburg/Lahn, B a h n h o f s t r a ß e 7, W .
Germany
J U N G E - H Ü L S I N G , G . , Prof. Dr . Medizinische Klinik der Stadt. Kliniken, 4500 O s n a b r ü c k , Natruper-Tor-Wall 1, W . Germany
List of Participants X I
K L E I N , E . , Prof. D r . S t ä d t i s c h e Krankenanstalten, 4800 Bielefeld, O e l m ü h l e n s t r a ß e 26, W . Germany
K O U T R A S , D . A . , Prof. Dr . Thyro id Section of the Alexandra Hospital, 35, Vasilissis Sofias Ave . , Athens 139, Greece
K R A C H T , J., Prof. Dr . Zentrum für Pathologie der U n i v e r s i t ä t , 6300 G i e ß e n , L a n g h a n s s t r a ß e 10, W . Germany
K R Ü S K E M P E R , H . L . , Prof. Dr . 2. Medizinische U n i v e r s i t ä t s - K l i n i k , 4000 D ü s s e l d o r f , M o o r e n s t r a ß e 5, W . Germany
K U T Z I M , H . , Prof. D r . Nuklearmedizinische Abteilung der U n i v e r s i t ä t , 5000 K ö l n 41, W . Germany
L A B H A R T , A . , Prof. Dr . Medizinische Klinik der U n i v e r s i t ä t , Kantonsspital Z ü r i c h , R ä m i s t r a ß e 100, 8006 Z ü r i c h , Switzerland
L A M B E R G , B . - A . , Prof. Dr . Endokrinologisches Laboratorium, U n i v e r s i t ä t Helsinki - Minervastiftung, P. O . Box 819, 00101 He l sinki 10, Finland
L E M A R C H A N D - B E R A U D , T h . , Pr iv .-Doz. Dr . Departement de Biochimie, Clinique H ö p i t a l Cantonal Universitaire, 1011 Lausanne, Switzerland
L E W I T U S , Z . , Prof. Dr . Division of Medicine, Beilinson Hospital, Bloch Str. 32, Te l -Aviv , Israel
M O R R E A L E D E E S C O B A R , G . , Dr . Instituto G . Maranon, Departamento de Endocrinologia Experimental, Arzobispo Morcil lo, S/n, M a
drid 34, Spain
V O N Z U R M Ü H L E N , A . , Prof. D r . Medizinische Hochschule Hannover, Abt . für Kl in . Endokriologie, 3000 Hannover-Kleefeld, Karl-
Wiechert-Allee 9, W . Germany
O B E R D I S S E , K . , Prof. D r . 4000 D ü s s e l d o r f 1, S c h l o ß m a n n s t r a ß e 32, W . Germany
O P P E N H E I M E R , J. H . , Prof. Dr . Montefiore Hospital and Medical Center, III East 2lOth Street, Bronx, New York 10467, U S A
P F A N N E N S T I E L , P. , Prof. D r . Deutsche Klinik für Diagnostik, 6200 Wiesbaden, Aukammallee 33, W . Germany
P I C K A R D T , C . R., Pr iv .-Doz. D r . II. Medizinische Klinik, 8000 M ü n c h e n 2, Z i e m s s e n s t r a ß e 1, W . Germany
P I N C H E R A , A . , Prof. Dr . Patologia Speciale Medica II, Via Bonanno, 48, Pisa 56100, Italy
XII List ot Participants
R A L L , J. E. , M . D . , Ph. D . Department of Health, Education and Weifare, National Institute of Health, Bethesda, Maryland 20014, U S A
R E I N W E I N , D . , Prof. Dr . Medizinische U n i v e r s i t ä t s k l i n i k , 4300 Essen 1, H u f e l a n d s t r a ß e 55, W . Germany
R I C C A B O N A , G . , Prof. Dr . Lehrkanzel für Nuklearmedizin, Chirurgische U n i v e r s i t ä t s k l i n i k , A n i c h s t r a ß e 35, 6020 Innsbruck,
Austria
S A L V A T O R E , G . , Prof. D r . Instituto di Patologia Generale, Universita di Napoli , Via Sergio Pausini, 80131 Napoli , Italy
S C H E M M E L , K . , Prof. Dr . Innere Abteilung des Kreiskrankenhauses, 2240 Heide, Holstein, W . Germany
S C H L E U S E N E R , H . , Prof. Dr . Freie U n i v e r s i t ä t Berlin, Kl inikum Steglitz, 1000 Berlin 45, Hindenburgdamm 30, W . Germany
S C R I B A , P. C . , Prof. Dr . IL Medizinische Klinik der U n i v e r s i t ä t , 8000 M ü n c h e n 2, Z i e m s s e n s t r a ß e 1, W . Germany
S K R A B A L O , Z . , Prof. D r . Institut für Diabetes der U n i v e r s i t ä t , Petrinjska 34, 4100 Zagreb, Jugoslavia
S T A U B , J. J., D r . Endokrinologische Station der Medizinischen U n i v e r s i t ä t s p o l i k l i n i k und Nuklearmedizinischen Abtei
lung, Kantonsspital Basel, 4004 Basel, Switzerland
V A N N O T T I , A . , Prof. D r . Clinique Medicale Valmont, 1823 Gl ion s/Montreux-Suisse, Switzerland
W I L D M E I S T E R , Pr iv .-Doz. W . , Dr . 2. Medizinische U n i v e r s i t ä t s - K l i n i k , 4000 D ü s s e l d o r f , M o o r e n s t r a ß e 5, W . Germany
W O L F F , J., M . D . , Ph. D . National Institute of Health, Bethesda, Maryland 20014, U S A
Anterior Pituitary and TSH*
P . C . S C R I B A , F . E R H A R D T , H . G . H E I N Z E , K . H O R N , I. M A R S C H N E R ,
C . R. P I C K A R D T
In 1971, at the Laurentian Hormone Conference, Dr . R E I C H L I N (82) has reviewed the evidence in favour of positive feedback regulation of T R H synthesis by thyroid hor-mones. In the introduction to this outstanding review two factors Controlling d i r e c t l y the secretion of T S H were classified as p r i m a r y regulators: 1. the negative feedback inhibition by thyroid hormones and 2. the stimulatory effect of T R H .
Several factors act probably indirectly in the control of T S H secretion (82), including the peripheral degradation of T S H , of thyroid hormones and of T R H , the physioche-mical State of the circulating thyroid hormones, and the pituitary conversion of T 4 to T 3 (2,39, 84 a, 89, 98). Even with the additional consideration of thecircadian rhythms (14, 66, 67, 94), the role of liver and kidney for the production rates and metabolism of T R H , T S H and thyroid hormones ( 3, 10, 13, 33, 50), and of inducable changes of T B G levels as one possible alteration of the physiochemical State of the thyroid hormones, it is probably justified to classify these factors as of secondary importance for the T S H regulation (82, 85, 87). Therefore, this review will concentrate on: 1. Problems of T S H structure, 2. recent developments in T S H assays, 3. deficiency and excess of T R H and 4. deficiency and excess of thyroid hormones.
1. Structure and heterogeneity of TSH
The T S H molecule can be dissociated by the treatment with propionic acid into the subunits a and/?. As it has been shown for other glycoproteohormones, the/3-subunit carries the immunological and biological confirmation specific for T S H .
::" Supporten1 by the Deutsche Forschungsgemeinschaft (SFB 51).
36 P. C . Scriba, F. Erhardt, H . G . Heinze, K. H o r n , I. Marschner, C . R. Pickardt
Radioimmunoassays specific for tbese s u b u n i t s have been developed (6, 47, 48). So far, the/3-hTSH radioimmunoassay represents no improvement in terms of specificity and sensitivity as compared to the widely used homologous radioimmunoassay for hTSH (6). More important, K O U R I D E S et al. (49) have provided evidence that/3-TSH subunits are secreted by the pituitary gland(16), but that/3-TSH is not detectable in se-rum of euthyroids or in patients with Graves' disease, respectively. In addition, the elevated levels of ß-TSH in primary hypothyroidism were suppressed by thyroxine administration. The finding of a normal regulation of/3-subunit secretion in terms of a negative feedback inhibition by thyroxine (49) is of interest w i t h respect to the studies of K O H N and W I N A N D (45, 46). These authors have claimed receptors in the retroorbi-tal tissue capable of binding of bovine T S H , of/3-TSH and of an exophthalmogenic product formed by pepsin digestion of bovine T S H , the binding being enhanced by y-globulins from patients w i t h Graves' disease. The pathophysiological involvement of human ß-TSH or other T S H related factors in Graves' ophthalmopathy remains however to be established, if the Observation of K O U R I D E S (49) is conf i rmed.
In addition to the data on subunits, the earlier work (15) about s/ze h e t e r o g e n e i t y of T S H circulating in primary hypothyroidism has been extended by G O L S T E I N and V A N H A E L S T (26). Using a radioimmunoassay System for ß-TSH, these authors ob-served a high molecular weight fraction in the serum of patients with pr imary
hypothyroidism. Taking a somewhat different approach, E R H A R D T (20) has obtained a high molecular weight, T S H immunoreactive preparation from human pituitaries, using Sephadex G-100 filtration and subsequently affinity chromatography with se-pharose linked anti-TSH. The material constitutes 1 - 3 % of the total T S H immunore-activity in human pituitaries. The Information about this material is still preliminary. We know however, that " b i g " T S H is stable upon rechromatography, has an appro-ximate molecular weight of 200 000 on Sephadex G-200, shows paralellism in the T S H radioimmunoassay System ( M R C Standard), has a R N A content below the limits of detection (ethidium bromide fluorescence), is stable in 6 M guanidine-HCl p H 5.1, 0.25% Triton X 100 (37° C , lh) , and shows formation of regulär size immunoreactive T S H by trypsin digestion. - It appears therefore likely, that the chapter of T S H structure and its relation to human pathophysiology is not yet closed.
2. Recent developments in T S H assays
The information about the regulation of the secretion of T S H depends obviously on the methods available for the determination of T S H .
Recently, the principle of the highly sensitive c y t o c h e m i c a l assay has been applied to T S H determinations, using the induced lysosomal instability (7, 29) . P E T E R S E N repor-ted in Boston and elsewhere (71), that the T S H level of 0.31 / / U / m l in one normal sub-
Anterior Pituitary and T S H 37
ject was suppressed by daily administrations of 120//g T 3 to 0.17 / /U/ml after 4 days and to 0.02//U/ml after 8 days. The latter values are lower than the " T S H " levels of 0.28//U/ml measured in untreated Graves' disease by this method (71). However, it may be too early to aeeept fully the differentiation between T S H and L A T S made me-rely on the basis of different reaction kinetics in the cytochemical assay (71). A T R H Stimulation test increased the T S H level of euthyroid controls from 0.6 to 7.0//U/ml in this assay (71). These values are in good agreement with data obtained by the radioimmunoassay.
I have to omit any comments on radioreeeptor assays (29), which are at present in de-velopment or in use in several laboratories (cf. S C H L E U S E N E R ) . - Instead, I should like to discuss briefly two aspects of the r a d i o i m m u n o a s s a y for T S H . This method has ra-pidly become a valuable tool for the clinical judgement of thyroid patients (1, 18, 19, 28, 29, 70). A vast number of modifications and commercial kits favours its wide-spread use. However, in addition to the obvious limitations of the T S H radioimmunoassay in terms of sentitivity and speeificity, we have to realize, that this method lacks adequate interlaboratory comparability. This may be concluded from a recent "Ringversuch" or collaborative survey, performed under the auspices of the Thyroid Section of the German Endocrine Society (56).
Abgelesen auf
Standard kurve
22 H E p
23 8 E E H
5 6 4
5 - 957. = 32 ,4 VK = 127.6 = 22,9 VK= 63,7
BT B l 19, W 1
10 20 30 40 50 60
T S H / m l
211,3
Wiederlindekurve P 27
P 27
E
19
18 x = 18,0 VK = 31,0
a ! 8
5-95 7c * 17,3 VK = 21, 8
p 25
B 16 6 E
2 o B E
U H
L H
23 E
5 E 3 0 E
3 B 3 2 , E
B l E l 81 B l 1 E l 28 |7 |9 |29 | , |32 1
10 20 30 40 50 6 0 ^JE T S H / m l
Fig. [ . " R i n g v e r s u c h " , i . e. c o l l a b o r a t i v e s u r v e y o n t h e r a d i o i m m u n o a s s a y f o r T S H . The individual means of triplicate determinations of one of 8 unknown samples obtained from 24 partieipa-ting laboratcries may be read on the abscissas of the histogram. "Wiederfindekurve" Stands for Standards in "hormone free" serum. Each rectangle depicts the number of the partieipant and a symbol for the method used. The imerlaboratory means (x) and coefficients of Variation (VK) are given for all participants and for
the group between 5 and 95 % of the Gaussian curvc (mean ± 1.7 SD), respectively (56).
38 P. C . Scriba, F. Erhardt, H . G . Heinze, K. H o r n , 1. Marschner, C . R. Pickardt
As shown in Fig. 1, the better 90% of 24 participants produced a mean of 22.9//L7ml for the first of the unknowns, using their own Standard curves. There was a wide Variation of the single laboratories between 8 and 6 0 / / U / m l , with a coefficient of Variation of 64%. Using common Standards in "hormone free" serum (18, 21, 70), the results were definitely improved with a more correct mean of 17.3//U/ml and with a reasona-ble coefficient of Variation of 21.8% between laboratories. Some commercial kits have since been improved as a consequence of this study (56).
The second point, which I would like to discuss, is the need for automation of the radioimmunoassay for T S H , as for other hormones. We have developed a modular ana-lyzer System (57), for which the working instruetions for T S H include as the impor-tant points: Standards i n hormone free serum, " c o l d " preineubation of antibody with non - labeled hormone , tracer of rather low specific activity, classical double antibody method with discontinuous filtration for b/f Separation etc. (57). - In summary, the proper radioimmunoassay for T S H has turned out to be relatively simple, reliable and satisfactory for diagnostic purposes.
a) T R H Stimulation test
Today, the intravenous T R H Stimulation test has been widely aeeepted as a valuable extension (28, 78, 87, 97, 103) of the diagnostic possibilities provided by the T S H radioimmunoassay. In our hands, the normal ränge of 2.7 to 23.6//U/ml (18, 19) for the T S H increment 30 min after injection of 200//gTRH has been satisfactory for diagnostic purposes. Numerous and sometimes conflicting reports have been published a-bout sex and age dependence of the T S H response (51, 68, 97), about other T R H doses recommended (5), about the effects of the menstrual cycle and of antiovulatory Steroids (23, 51, 63, 81, 96, 97), and other drugs (17, 83, 102), particularly cortieoids (69), of stressful situations and cold (12, 25, 58), of malnutrition respectively anorexia nervosa (53, 62, 64), of 2-Br-a-ergocriptine (61), somatostatin (4, 90, 93, 95), Prostaglandins (9) and of diseases of the liver and the kidneys (3, 10, 13, 33). However, time does not allow to discuss all these data. In general, all these factors rarely diminish the diagnostic usefulness of the normal ränge mentioned.
3 . Deficiency and excess of T R H
A t first, the regulation of the T S H secretion in t h e a b s e n c e of endogenous T R H has to be considered.
In a series of elegant experiments, R E I C H L I N et al. (82) have shown, that in rats with lesions in the hypothalamic thyrotropic area, the sensitivity of the pituitary "thyro-
Anterior Pituitary and T S H 39
stat" towards t h y r o i d hormones is changed. A diminished increase of T S H levels was
only observed as late as 40 days after thyro idec tomy. In addit ion to this decreased sen-
sitivity of the T S H secretion towards a deficiency in t h y r o i d hormones , the threshold
for T S H suppression by t h y r o i d hormones was lowered in the rats carrying the h y p o -
thalamic lesions. These experimental data are in agreement wi th the cl inical Observa
tion of usual ly m i l d h y p o t h y r o i d i s m wi th l o w , but definitely measurable T S H levels in
patients w i t h hypotha lamic hypopi tu i t a r i sm. It has been repeatedly documented (28,
60, 74, 75, 78, 87, 92) that T R H Stimulation tests in patients wi th suprasellar disease
and secondary h y p o t h y r o i d i s m result in normal or supranormal T S H increases. In ad
d i t ion , we also observed a normal St imulation of T S H secretion by T R H in most pa
tients w i t h pi tui tary adenoma and secondary h y p o t h y r o i d i s m (74, 75). It w o u l d there-
fore appear, that in pi tui tary tumor patients, the hypothalamic T R H product ion or the
T R H transport via the portal vessels of the pituitary stalk are more susceptible to d i -
sturbance than the T S H produc ing thyrotrophs of the anterior pituitary themselves.
T R H was s h o w n to be present i n human cerebrospinal f l u i d , and appears subse-
quently to its injection into the third ventricle of rats in the portal vessels of the p i tu i
tary stalk (27, 44, 79, 88). This Observation a l lowed the further study of the problem
mentioned above. F A H L B U S C H and P I C K A R D T (24) compared the normal T S H incre-
ment in patients after intravenous T R H w i t h the T S H response, when 50//g T R H were
injected into the 3rd or lateral ventricle o n the occasion of diagnostic or therapeutic
puncture of the ventricles. In " c o n t r o l s " , the T S H response to intraventricular T R H
was lower as compared to i . v . T R H , and was maximal only at 40 m i n or later. In cases
wi th tumors in the 3rd ventricle or w i t h pituitary adenomata expanding into the supra
sellar reg ion, no T S H response was seen after intraventricular T R H , whereas the res
ponse to i . v. T R H was regularly obtained. Hence, " p o r t a l vessel o c c l u s i o n " (74, 75)
may wel l be a pathophysiologica l mechanism for " h y p o t h a l a m i c " or secondary h y p o
pituitarism in cases wi th pituitary adenoma.
I should n o w like to discuss briefly the effects of prolonged exogenous T R H excess. Repeated administrat ion of T R H leads to a rapid declinc of the T S H responses of the
pituitary (65, 80, 91). This Observation is of some cl inical interest, since oral T R H
treatmentplays a role in certain Psychiatric diseases, namely depression. Interestingly,
M A E D A eta l . (54), have recently s h o w n in depressed patients, that single T R H Stimula
t ion is f o l l owed by an abnormal increase of g rowth hormone , wi th concomitant ly en-
hanced pro lact in responses, but blunted T S H responses.
Repeated oral administrat ion of 40 mg T R H per day causes only transitory increases
of T 3 and T 4 , w i t h i n the normal ränge (39, 80, 91). Daily application of 40 mg T R H
over a per iod of 4 weeks leads f inally to d iminished basal T S H levels and to a blunted
TSH response to 200//g T R H i . v . (Table 1). This indicates, that the suppressive effect
of ini t ia l ly ris ing t h y r o i d hormone levels on T S H release is more potent than the s t imu-
lating effect of cont inued oral T R H (40).
40 P. C . Scriba, F. Erhardt, H . G . Heinze, K. H o r n , L Marschner, C . R. Pickardt
Table 1. Effect-oi oral T R H application to healthy subjects ( N = 12; 40 mg per day over a period of four weeks), from H O R N et al. (39, 40).
Before T R H After T R H
Serum T S H basal 2.0 ± 0.8 1.0 ± 0.5:;-
(z/U/ml) A T S H 30 min 8.1 ± 3.0 3.0 ± 1.9*
Serum T 4 6.2 ± 1.9 6.5 ± 1.8
(//g/100 ml)
Serum T 3 112 ± 22 109 ± 32 (ng/100 ml)
Significance p < 0.005
Table 2. T S H and P R L producing pituitary adenoma.
- Female, 22 y . , enlarged sella. - Recurrent goiter and thyrotoxicosis. - Galactorrhea-amenorrhea S y n d r o m e .
- T S H (12 - 29//U/ml) and P R L (200 - 300 ng/ml) refractory to exogenous thyroid hormones and to T R H Stimulation (200 //g i. v.).
- T S H ans P R L suppressed bv bromoeriptine (5 mg p. o.) - Identification of "thyrotrophs" and "lactotrophs" evenly distributed throughout the adenoma
(electronmicroscopy, immunolluorescence).
H O R N , K. et al., Proceed. Int. Thyroid Conf . , Boston, 1975 (40).
The fact, that continued oral application of excess T R H failed to induce hyperthy-roidism, may be taken as another strong argument against any hypothalamic form of thyrotoxicosis.
Finally, the effect of primary pituitary T S H excess should be briefly considered. A T S H producing adenoma of the pituitary gland is a rare finding; I am only aware of three well documented cases published in the literature (22, 31, 52). Recently we had the opportunity to study a patient with a so far unique adenoma producing both, T S H and prolactin concomitantly (40). Table 2 summarizes the findings in this patient. It may be concluded, that the "thyrotrophs" of this T S H producing adenoma lack the adequate reeeptor or sensitivity for negative feedback inhibition by thyroid hormones and for T R H Stimulat ion, respectively. This corresponds to other hormonally active pituitary adenomata, in which the phenomenon of "reeeptor degeneration" (99) has been demonstrated.
4. Deficiency and excess of thyroid hormones
The remainder of this contribution will be devoted to regulatory T S H increases and decreases by the thyroid hormone negative feedback mechanism. Obviously, most of
Anterior Pituitarv and T S H 41
the diagnostic information obtained by T S H radioimmunoassay is derived from patients with primary thyroid disease, since it has been realized, that feedback alteration of the T S H secretion currently represents the most sensitive indicator for lack or excess of thyroid hormones (72, 82, 87). Innumerous studies dealing with different aspects of this field have been published and cannot be reviewed within the limitations of time. Also, the interesting questions of intrapituitary conversion of T 4 to T 3 , of pituitary preferential T3-receptors, and of the relative contributions of T 4 and T 3 in the circula-tion to the negative feedback regulation of T S H secretion (2, 39, 84a, 89, 98) have to be left to the discussion. Instead, we thought it worthwhile to discuss briefly and as a clinical example some problems related to endemic goiter. Nontoxic goiter is known to be the most frequent thyroid disease in the Federal Republic of Germany, which has recently again been shown to be as a whole an area of endemic goiter (41) and of sub-stantial iodine deficiency (30, 86).
D e f i c i e n c y i n t h y r o i d h o r m o n e s is known to give rise to elevated basal T S H levels, an Observation which may be further elucidated by the Observation of increased T S H responses to i . v . T R H Stimulation tests. I should like to leave possible controversies a-bout the term "subclinical hypothyroidism" (68, 72) to the discussion. I would rather emphasize, that T S H radioimmunoassays have already been used for Screening pro-grams e. g. for neonatal hypothyroidism (36).
Approximately 20% of the iodine deficiency goiter patients of Munich (72, 73, 77) were shown to display an increased T S H response to T R H Stimulat ion. This increase above the Upper limit of normal, usually shown in a logarithmic scale, is quite remark-able in some patients. This finding has been confirmed for Essen and Göttingen (100). The elevated T S H levels are obviously not related to the tendencies of these patients towards low-normal or slightly decreased T 4 levels and towards normal or slightly elevated T 3 levels (Fig. 2). The latter phenomenon is known as preferential T 3 secretion in iodine deficiency states (37, 39, 72). The elevated T S H secretion in 1/5 of the goiter patients may be interpreted as evidence for 1. slight thyroid hormone deficiency in this group and/or 2. a phase of further growth of the already enlarged thyroid.
The fact, that 80% of our patients have normal T S H responses despite their thyroid enlargement, may be interpreted als indicative for 1. no actual progression of their goiter and/or, 2. if there is further goitral growth, this might indicate an enhanced thyroid sensitivity
to normal circulating levels of T S H as proposed by B R A Y (8). Interestingly, the thyroidal adaptation to iodine deficiency in terms of an elevated serum T 3 / T 4 ratio is reversible without measurable alteration of the T S H secretion. H O R N et al. (38) have shown, that administration of 200^g iodine per day as potassium iodide tablets over a period of four weeks reduced the elevated T 3 / T 4 ratio towards normal. Since the mean basal T S H levels and the T S H responses to 200//g T R H i . v.
42 P. C . Scriba, F. Erhardt, H . G . Heinze, K. H o r n , I. Marschner, C . R. Pickardt
• = Blande Struma \ TSH normal
• = Blande Struma A TSH A TSH erhöht u,E/ml A = Rezidivstruma
Fig. 2. T o t a l s e r u r n TA and as related t o t h e T S H response (A T S H 30 m i n ) t o 2 0 0 //g T R H i . v. 'Blande Struma" is synonymous with nontoxic goiter, "Rezidivstruma" with recurrent goiter after Opera
tion (37, 39, 73, 78).
were the same prior to and after 4 weeks on 200/ /g iodine per day, it was concluded, that this may represent an example of thyroidal autoregulation (42) .
The treatment of goiters with T S H suppressive doses of thyroid hormones may rea-dily be controlled by T R H Stimulation tests and radioimmunoassay for T S H (77, 78 , 103).
Finally, we have to focus on the impact of t h y r o i d h o r m o n e excess on the T S H secretion. Again, T S H suppression and, even more, the failure of T R H to induce a T S H response is widely aeeepted as a very sensitive tool for the diagnosis of endogenous or exogenous excess of thyroid hormones. Notedly, the sensitivity of this feedback Inhibition carries the general diagnostic disadvantage, that T S H suppression may persist for prolonged intervals after e. g. sufficient and successful treatment of hyperthyro-idism. The latter Observation has been described by V O N Z U R M Ü H L E N in 1971 (103)
and was confirmed repeatedly (11 , 3 2 , 84 , 104). Selecting the endemic goiter patients again for this consideration, I should like to
draw the attention to what was called the "functional cycle of the autonomous adenoma" by P I C K A R D T et al. (76 , 85) . This coneept was derived from observations of nume-rous patients at different stages of the disease, extending the work of M I L L E R et al. (59) . Fig. 3 describes schematically the development of an adenoma, its poorly understood acquisition of autonomy, the gradual addition of toxicity with the concomitant in-
Anterior Pituitary and T S H 43
Stadium
Szintigramm
Thyroid hormone level u \ -
Adenoma Autonomy Toxicity Remission Iodine Lack of Iodine application degeneration
- - 3 a " \ 1 2-^-3a, 3b 4 5 6
TSH increment M A after TRH Stimulation N f '
Fig. 3 F n n c t i o n a l c y c l e o f t h e a u t o n o m o u s a d e n o m a . After P I C K A R D T , C . R. et al., Dtsch. med. Wschr. 9 8 : 152 (1973).
crease of thyroid hormones and decrease of the T S H secretion and response to T R H , and finally the possible spontaneous remission. One has of course only rarely the occa-sion to follow this cycle throughout all stages in one single patient. However, spontaneous transitions have been observed in between all stages depicted. The most fre-quently observed transition is certainly from stage 2 , which is an autonomous nodule with normal T 4 and T 3 and positive T S H response to T R H Stimulation - usually called compensated autonomous adenoma - to stages 3 or 4 with normal or elevated T 4 and T 3
and suppressed T S H , which is commonly called decompensated autonomous adenoma. The latter transition has been regularily observed in a somewhat courageous study of M A H L S T E D T and J O S E P H (55) , when practically all compensated autonomous adenoma ta in patients were converted to "decompensated" ones by contrast media used for cholecystography. T R H Stimulation tests show easily in the patients with decompensated autonomous adenoma, that the T S H secretion is in fact suppressed, as it was correctly predicted by the earlier indirect methods of nuclear medicine. The existence of suppressed paranodular thyroid tissue around the hot nodule can be documented by simple palpation or by 9 9 m T c scintigraphy with increased sentitivity (35 , 101) , avoi-ding the disadvantages of a T S H Stimulation test, which may be only justified if con-comitant cold nodules have to be depicted. The hazards of the exogenous T S H Stimulation test consist mainly in the sometimes dangerous elevation of the thyroid hormones (34) by Stimulation of the paranodular tissue and of the hot nodule itself (43) , which is thus not "autonomous" in this respect.
In conclusion, I should like to express my hope, that it was not against the intentions of the convenors, that the emphasis of this presentation was put on clinical aspects.
44 P. C . Scriba, F. Erhardt, H . G . Heinze, K. H o r n , 1. Marschner, G . R. Pickardt
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46 Discussion
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Discussion
S C H L E U S N E R raised the question of the binding of the T S H /3-subunit to thyrocyte membrane preparations. W O L F F pointed out that bovine /3-subunit binds to bovine
Discussion 47
membranes at about 8 % of the T S H potency (Bethesda). The more complicated the stimulated cell funetion, the more intact the tissue is, the less active is theß-subunit.
V O N Z U R M Ü H L E N suggested to study the question of the biological acticity of the "big T S H " originating from human pituitaries. Reference was made by R A L L to the studies of W E I N T R A U B and R O S E N , in which they looked at tumors, bronchogenic Carcinoma, mostly, that produced ectopic T S H . They could isolate different clones of cells from these tumors, and some of the clones would produce normal T S H , the al-pha-beta material, some would produce just the alpha and some would produce just the beta. A n d this gets back to the fundamental question as to whether they are synthe-sized as separate Polypeptide chains and combined then in an entirely physical way? The mentioned data tended to suggest the latter, which makes then the "big T S H " a difficult protein to swallow.
However, work from R Y A N ' S group suggested, that large molecular weight gonado-tropins might consist of one/3-subunit and several a-subunits. Further workis needed to clarify these important questions.
C R O O K S reported a study of pregnancy goiter and of normal controls from Iceland and Scotland, respectively, where the controls had the same frequency of thyroid antibodies. The Icelandic normal population has twice the level of plasma inorganic iodine of the controls of Scotland. The normal T S H levels in Iceland are lower, with a narrow ränge normal distribution, as compared to Scotland, where the normal ränge of T S H is spread widely yet still normally distributed.
This raised the question what actually regulates T S H at different levels in these two populations? A rather general ans wer would be, that the sum of interactions of anterior pituitary reeeptors for T 3 , T 4 and possibly triac with the intracellular concentra-tions of these hormones at the site of the (nuclear) reeeptor should be the relevant event. There is a modulation by the TRH-thyrotroph System, but thyroid hormones are probably the most important factor.
Rare cases of evident hyperthyroidism with positive T S H response to T R H Stimulation were reported from L o o s , U l m and S T A U B , Basel, the incidence being probably very low and the mechanism still obscure.
P I N C H E R A commented a study from Pisa. Patients with a completed course of anti-thyroid treatment showed an inverse relationship between the T S H response to T R H and the serum T 3 and T 4 , respectively, whereas there was no correlation to the suppression test. However, the T R H Stimulation test was of no predictive value for the question of relapse of hyperthyroidism. This was supported only in part from Dr . E M R I C H , Göttingen, where in most but not in all patients treated for hyperthyroidism
48 D i s c u s s i o n
follow up studies showed coincidence of negative suppression tests and negative T R H Stimulation tests and vice versa. The persistance of negative T R H Stimulation tests in the presence of low T 4 and T 3 after antithyroid treatment might also be a funetion of the duration of the preexisting thyrotoxicosis.
P I N C H E R A raised the question of the T 4 and T 3 response to T R H Stimulation in goiter patients. L E M A R C H A N D - B E R A U D gave comments to this question. In Switzerland (Lausanne), endemic goiter is aecompanied by normal responses of T 4 and T 3 levels to T R H . In addition, the T S H response is usually normal and sometimes decreased. These findings are of interest in view of the installed iodine Prophylaxis in Switzerland. As supported from K O U T R A S Athens, the T S H levels or responses are apparently the higher, the more severe the iodine deficiency is. In addition, high proportions of goiter patients with positive thyroid antibody titers tend to cause supranormal T S H levels (Helsinki, Brüssels). From Brüssels, further cases were reported with latent thyroidi-tis, with hypersecretive thyrotrophs and with high biological, but normal immunolo-gical T S H activity. A l l discussors agreed to treat patients with elevated T S H levels by administration of thyroid hormones.
W O L F F raised the question of the T R H test in patients under lithium therapy. L A M -BERG commented on this. In a systematic study from Helsinki no changes were observed, neither in the T S H response to T R H nor in thyroid hormone levels. Studies from Athens and Freiburg however tend to show, that under lithium therapy some patients go through initially low T 4 and T 3 levels and that patients with lithium goiter are usually "hypothyroid" .
O P P E N H E I M E R questioned the role of T R H in the practice of medicine in terms of diagnostic use and socioeconomical implications. The author of the above paper repeated the view, that T R H Stimulation tests are at present the most sensitive tool for dia-gnosis of lack or excess of thyroid hormones, even with the drawback of persisting suppression after thyrotoxicosis, that they allow to choose a dose of thyroid hormone, which will suppress the T S H response for instance in the treatment of non-toxic goiter, or which alternatively normalizes the T S H response in substitutive therapy for myxedema. In addition, the facilitation of the diagnosis of an autonomous (toxic) adenoma was stressed. Finally, the T R H test is economical in terms of patients and doc-tors timeif compared with repeated radioiodine uptake tests or suppression tests e. g., and that the actual costs for the radioimmunoassays of T S H can be lowered by auto-mation. This view was challenged from G R E E R , and supported from H Ö F E R . I n sum, the T R H test is used for practical diagnostic purposes in some places, and it is conside-red a research procedure in others.