Treatment of Pituitary Adenomas First European Workshop on Treatment of Pituitary Adenomas at Rottach-Egern Edited by Rudolf Fahlbusch and Klaus v. Werder With a Foreword by Frank Marguth With contributions by H.-P. Althoff E. Flückiger U. Krause G. C. Nicola M. V. Sofroniew A. Aulich P. H. Forsham H. L. Krüskemper H. Nowakowski H. G. Solbach F. Bahner T. R. Fraser A. Kuwayama T. Okada N. Stahnke F. Banks U. Fricke S. W. J. Lamberts L. Oliver H. Steinhoff J. Bansemer T. Fukaya R. Landgraf G. Oppizzi A. Stevenaert D. Barwich S. M. Gaini A. M. Landolt A. E. Panerai K. Sugita M. Bäsch M. Giovanelli S. Lange A. Paracchi L. Tagliabue X. Baur R. Göser W. Lanksch F. Peillon M. Takanohashi J. M. Bayer A. Griner J. H. Lawrence E. F. Pfeiffer G. Teasdale P. Beck-Peccoz K. W. M. Grossart S. Levin C. R. Pickardt L. Tharandt G. Benker Th. Grumme M. L'Hermite H. J. Quabbe C. A. Tobias J. Beyer G. Guiot J. A. Linfoot J. Racadot G. Tomei J. C. Birkenhäger K. Hackenberg A. Liuzzi G. Ranft G. P. Tonnarelli W. J. Bock W. Hadam V. Locatelli D. Reinwein T. Torresani B. Böttger J. Happ Ch. Lucke J. Resetic H. Traut J. L. Born D. Heesen D. Lüdecke H. J. Reulen Y. Tsujita H. J. Breustedt J. Herrmann J. Lyman H. K. Rjosk B. Tyrell P. De Camilli K. Hirakawa M. Madler C. Robyn C. Uhlig A. Caufriez H. Huber S. Manaka R. Rothe E. Vila-Porcile D. F. Child R. Illig E. Manougian V. Rothenbühler E. Virasoro P. G. Chiodini A. Jadresic F. Marguth K. H. Rudorff K. H. Voigt C. Chong A. Jefferson W. Meese H. Ruf H. A. D. Walder H. E. Clar F. H. de Jong E. Meijer W. Saeger A. Weindl D. Cocchi G. F. Joplin A. Melo M. Samii S. Wende G. Colussi N. Kageyama R. Mies K. Sano K. von Werder G. Copinschi A. Karduck J. D. Miller U. Scherer W. Wiegelmann U. Cordes R. Kautzky W. Mitschke A. E. Schindler O. Wilcke L. Diamant E. Kazner H. R. Montz K. Schöffling K. von Wild F. H. Doyle E. Keller E. D. F. Motti D. Schräder W. Winkelmann W. Entzian J. Kinnman D. Moussy W. Schuhmacher T. Yoshida G. U. Exner G. S. Kistler A. von zur Mühlen K. Schürmann W. Zäh G. Faglia H. Kley E. E. Müller G. Schwinn R. Fahlbusch J. Köbberling O. A. Müller P. C. Scriba H. L. Fehm D. Kondo A. Nagamune G. Sell C. Ferrari M. H. Koocheck M. Neubauer R. J. Seymour 336 Figures, 85 Tables

Georg Thieme Publishers Stuttgart 1978

CIP-Kurztitelaufnahme der Deutschen Bibliothek Treatment of pituitary adenomas / 1. Europ. Workshop on Treatment of Pituitary adenomas at Rottach-Egern, October 1976. Ed. by Rudolf Fahlbusch and Klaus v. Werder. With contribu­tions by H.-P. Althoff ... - 1. Aufl. - Stuttgart : Thieme; Massachusetts : PSG Publishing Com­pany, 1978.

ISBN 3-13-55 3801-X (Thieme) ISBN 0-88416-236-2 (PSG)

NE: Fahlbusch, Rudolf [Hrsg.]; Althoff, H.-P. [Mitarb.]; European Workshop on Treatment of Pituitary Adenomas < 0 1 , 1976, Rottach-Egern>

mi D S

Some of the product names, patents and registered designs referred to are in fact registered trade­marks or proprietary names even though specific reference to this fact is not always made in the text. Therefore, the appearance of a name without designation as proprietary is not to be con­strued as a representation by the publisher that it is in the public domain. All rights, including the rights of publication, distribution and sales, as well as the right to trans­lation, are reserved. No part of this work covered by the copyrights hereon may be reproduced or copied in any form or by any means - graphic, electronic or mechanical including photo­copying, recording, taping, or information and retrieval systems - without written permission of the publisher. © 1978 Georg Thieme Verlag, Herdweg 63, P.O.B. 732, D-7000 Stuttgart 1 - Printed in Germ by Karl Grammlich, Pliezhausen Thieme: ISBN 3-13-553801-X PSG: ISBN 0-88416-236-2 PSG: LCCCN 77-99148

VII

Contents

In t roduc to ry remarks by the edi tors I l l List of con t r ibu to r s IV Introduction to the workshop: F . Marguth

Foreword 1 ENDOCRINE AND MORPHOLOGICAL ASPECTS - PART I P.C. Scriba, C R . Pickardt , K. v. Werder:

Physiology of the hypo tha lamo-Pi tu i t a ry uni t 3 A. Weindl, M.V. Sofroniew:

Morphology of the hypo tha lamo-Pi tu i t a ry unit 10 H.G. Solbach, W. Wiegelmann, H. Kley, K.H. Rudorff, H.L. Krüskemper:

Endocr ine evaluation of p i tu i ta ry insufficiency 38 H.J. Quabbe :

Endocr inology of g rowth h o r m o n e producing tumors 47 M. L 'Hermi te , A. Caufriez, E. Virasoro, A. Stevenaert , G. Copinschi , C. R o b y n :

Endocr inology of prolac t in-producing tumors 60 H. L. F e h m , K.H. Voigt, E .F . Pfeiffer:

Endocr inology of ACTH producing p i tu i ta ry t umors 77 Short contributions W. Winkelmann, U. Fr icke , W. Hadam, D. Heesen, R. Mies:

Evaluation of dopaminergic and serotonergic regulat ion of growth h o r m o n e and prolact in in acromegaly 87

G. Faglia, A. Paracchi , P. Beck-Peccoz, C. Ferrari : Assessment of the results of t ranssphenoidal h y p o p h y s e c t o m y in acromegaly by means of T R H and L-Dopa tests 91

J. Beyer, J. Happ , U. Cordes , G. Sell, U. Krause, M. Samii, K. Schürmann: Pitui tary funct ion after surgical t r ea tmen t of p i tu i tary adenomas 94

K.H. Rudorff, W. Wiegelmann, J. Her rmann , H.K. Kley, H.G. Solbach, H. L. Krüskemper:

Hypotha lamo-pi tu i ta ry dysfunct ion in eosinophilic granuloma 98 ENDOCRINE AND MORPHOLOGICAL ASPECTS - PART II E. Kazner, R. Fahlbusch , W. Lanksch, R. Ro the , U. Scherer, H. Steinhoff, Th. G r u m m e , S. Lange, W. Meese, A. Aulich, S. Wende:

Computer ized tomography in diagnosis and follow-up examina t ion of pi tui tary adenomas 101

F. Peülon, J. Racadot , D. Moussy, E. Vila-Porcüe, L. Oliver, O. Racadot : Prolactin-secreting adenomas . A correlative s tudy of morphological and clinical data 114

VI I I Contents

W. Saeger: Morphology of ACTH-producing p i tu i ta ry tumors 122

J. Kinnman: Morphology of adenomas in acromegaly 130

A.M. Landol t , V. Rothenbühler, G.S. Kistler: Morphology of the c h r o m o p h o b e a d e n o m a 154

Short contributions P. De Camilli, L. Tagliabue, A. Paracchi , G. Faglia, P. Beck-Peccoz, M. Giovanelli:

In vitro s tudy on the release of GH by fragments of GH-producing h u m a n pi tui tary adenomas . Effect of T R H and DB cAMP 172

D. K o n d o , S. Manaka, A. Nagamune , Y. Tsujita, K. Hirakawa, K. Sano: Electrophysiological s tudy on p i tu i ta ry adenoma cells in tissue cul ture 179

N. Kageyama, A. Kuwayama, T. Yoshida , T. Okada , T. Fukaya , M. Takanohash i , K. Sugita:

Results of t ranssphenoidal opera t ion and tissue cul ture studies in GH secreting p i tu i tary adenomas 182

K. v. Wild, H. Ruf, M. Neubauer , H.-P. Althoff, K. Schöffling: Perioperative h o r m o n e measu remen t s in pa t ients wi th pi tui tary adenomas and h o r m o n e rep lacement therapy 186

R. Illig, T. Torresani , G.U. Exner : Plasma prolact in before and after T R H in 24 chi ldren with craniopharyngioma 193

G. Benker , K. Hackenberg, L. T h a r a n d t , W. Zäh, H.E. Clar, W.J. Bock, D. Reinwein:

T rea tmen t of hypotha lamic-p i tu i ta ry tumors : Endocr ine aspects wi th special regard to acromegaly 196

OPERATIVE TREATMENT G. Guio t :

Considerat ions on the surgical t r e a t m e n t of p i tu i tary adenomas 202 R. Kau tzky , D. Lüdecke, H. Nowakowsk i , D. Schräder, N. S tahnke , Ch. Lücke, H.G. Solbach, W. Wiegelmann:

Transsphenoidal opera t ion in acromegaly 219 R. Fahlbusch , H.K. Rjosk, K. v. Werder:

Operat ive t rea tment of pro lac t in-producing adenomas 225 A. Jefferson:

The t rea tment of c h r o m o p h o b e p i tu i t a ry adenomas by means of t ransfrontal surgery, radia t ion the rapy and support ive h o r m o n e the rapy 237

R.J. Seymour , S. Levin, B. Tyrel l , P.H. Forsham: Long-term results of c r y o h y p o p h y s e c t o m y for the t r ea tmen t of acromegaly 253

G.F. Jopl in , L. Banks, D.F. Child, L. Diamant , F.H. Doyle , T.R. Fraser, A. Jadresic , M.H. Koochek:

T rea tmen t of acromegaly by p i tu i t a ry implan ta t ion of 90y 261

Contents IX

J.H. Lawrence , C A . Tobias , C. Chong , J. L y m a n , J .L. Born, J.A. Linfoot , E. Manougian:

The t r ea tmen t of p i tu i tary neoplasms with heavy particles 266 Short contributions M. Giovanelli , S.M. Gaini , G. T o m e i , E .D.F . Mot t i , P. Beck-Peccoz, A. Paracchi, P. de Camilli:

Transsphenoidal microsurgery of hypersecre t ing pi tu i tary t umors 272 G. Teasdale, K.W.M. Grossart , J .D . Miller:

Compar i son of cryosurgery and microsurgery in the management of acromegaly 280

O. Wilcke, D. Heesen, W. Winkelmann: Experiences in 78 ^ Y t t r i u m implan ta t ions in acromegaly 284

G. C. Nicola, G.P. Tonnarel l i , A. Greiner: Transsphenoidal surgery for secreting p i tu i t a ry adenomas 287

W. Entz ian , A. Melo: Transnasal- t ranssphenoidal approach to p i tu i ta ry adenoma-ext i rpa t ion : effects on visual funct ions 293

A. Karduck, W.J. Bock: Transmaxi l lar- t ranssphenoidal h y p o p h y s e c t o m y : Approach and rhinological follow-up 299

H. E. Clar, K. Hackenberg , D. Reinwein , W. Schuhmacher , G. Ranft : Comparat ive results in cases of t umors of the sellar region after opera t ion by t ranssphenoidal and transcranial approach 304

M. Samii, K. Schürmann: Operative t r ea tmen t in re la t ion to locat ion and extens ion of p i tu i ta ry adenomas : Results 3 1 0

K. Schürmann, H.J. Reulen, J. Beyer: A dramat ic bleeding during t ranssphenoida l opera t ion on an apparent p i tu i tary adenoma caused by an intrasellar aneurysm 316

H.A.D. Walder, E. Meijer: Some considerat ions on the differential the rapy of p i tu i tary adenomas . . . 323

CUSHING'S SYNDROME D. Barwich, F. Bahner:

Pi tui tary tumors in adrena lec tomized pa t i en t s with Cushing's disease 326 H. Nowakowski , H.J. Breus tedt , W. Mitschke, H.R. Montz :

Anter ior p i tu i tary funct ion in hypo tha l amic Cushing's syndrome with and wi thout ACTH-producing a d e n o m a s 3 3 0

D.K. Lüdecke, R. Kau tzky , J. Bansemer, J. Resetic, H. Montz: ACTH secretion and neurosurgical managemen t of Cushing's disease 333

S.W.J. Lamber t s , F .H. de Jong, J .C. Birkenhäger: Trea tmen t of Cushing's disease by unilateral adrena lec tomy followed by external p i tu i ta ry irradiat ion 339

O.A. Müller, X. Baur, R. Fahlbusch , M. Madler, F. Marguth, C. Uhlig, P.C. Scriba, J.M. Bayer:

Diagnosis and t r ea tmen t of ACTH-produc ing pi tui tary t u m o r s 343

X Contents

MEDICAL THERAPY E. Flückiger:

Pharmacology of prolact in secretion 351 E.E. Müller, P.G. Chiodini , D. Cocchi , A.E. Panerai, G. Oppizzi , G. Colussi, V. Locatell i , A. Liuzzi:

Neuro t ransmi t te r cont ro l of growth h o r m o n e secretion 360 K. v. Werder, R. Fahlbusch, R. Landgraf, C R . Pickardt , H.K. Rjosk, P.C. Scriba:

Medical t rea tment of hyperpro lac t inemea associated with pi tui tary t umor 377

Short contributions A.E. Schindler, R. Göser, H. Trau t , E. Keller:

Ovulat ion induct ion with b romoergocryp t ine and pregnancy in pat ients with p i tu i tary tumors 390

H. K. Rjosk, R. Fahlbusch , H. Huber , K. v. Werder: Growth of prolact in-producing pi tui tary adenomas during pregnancy 395

MEDICAL THERAPY OF ACROMEGALY J. Köbberling, G. Schwinn:

Medical t r ea tmen t of acromegaly 4 0 0 Short contributions C. Lucke , A. von zur Mühlen:

Evaluation of b romocr ip t ine (CB 154) in the t rea tment of active acromegaly 411

P.H. Althoff, M. Neubauer , M. Bäsch, B. Böttger, K. v. Wild, K. Schöffling:

Acromegaly and bromocr ip t ine - results of long-term t rea tment 415 DISCUSSION (Except short cont r ibut ions) 421 INDEX OF AUTHORS 438 SUBJECT INDEX 440

3

Physiology of the Hypothalamo-Pituitary Unit P.C. Scriba, C R . Pickardt and K. von Werder, Munich , F R G

Biogenic amines and hypophys io t rop i c h o r m o n e s from the h y p o t h a l a m u s regulate the secretion of the anter ior p i tu i tary h o r m o n e s . These , in tu rn , control the target glands (adrenals , thyro id , gonads) as far as the g landotropic ho rmones (ACTH, TSH and gonado t rop ins ) are concerned . This system is subject to negative and, in some cases, positive feedback control th rough the free fractions of the circulating peripheral ho rmones (Cor t i so l , thyroid h o r m o n e s , sexual s t e r o i d s ) . Some anter ior p i tu i tary h o r ­mones (growth h o r m o n e , prolact in) and the neu roho rmones from the poster ior pitui­tary (ant id iure t ic h o r m o n e , oxy toc in ) exer t their effect directly on the peripheral tissues and organs. A comple te evaluat ion of this system would probably fill a t ex tbook [ 2 1 ] , this review will therefore be l imited to some selected aspects .

The Traditional Interest of Neurosurgeons in Endocrinology

The clinical course of p i tu i tary t umors may be beneficially influenced by a close observation of endocr ine signs and s y m p t o m s , permi t t ing an early diagnosis of hormo-nally active or inactive tumors . In the case of inactive tumors , earlier observat ions (19) revealed that half of the pa t ients showed hypogonad i sm as a first s y m p t o m in their histories; on the o ther hand in 32 of 4 2 pa t ien ts the neglecting of this sign resulted in delay of the diagnosis until de te r io ra t ion of the visual fields set in. Today , in cases of p ro lac t inoma [27 ] . the female pa t i en t s (N = 43 ) wi th a lower prolact in level tend to o u t n u m b e r the males (N = 22) . This is presumably due to an earlier diagnosis in the case of the females, because amenor rhea and galactorrhea are obviously more impressive endocr ine signs than loss of l ibido and p o t e n c e . There is yet another case for endocr inology which should be b rought up in this con­text . Table 1 shows the sites of action and the range of hormona l diagnostic procedures [20. 2 1 ] . With reference to the paper of Solbach et al. [ 2 2 ] , we should like to empha­size briefly the principle of diagnostic floors - in German "Etagen-Diagnos t ik , \ In general, insulin hypoglycemia will s t imulate at the hypo tha lamic level, whereas relea­sing h o r m o n e s may indicate an insufficiency of the anter ior p i tu i tary and TSH-stimu-lation, for instance, will test the responsiveness of the target, thyroid gland. The site of act ion is generally less clear if suppression tests have to be used for the differential diagnosis of h o r m o n e overproduct ion states (Table 1).

Laboratory Methods

Most of the diagnostic ho rmone de te rmina t ions are nowadays per formed by radio­immunoassay. Radio immunoassay procedures have, in fact, con t r ibu ted enormously to the knowledge we have today of the pa thophys io logy of the hypotha lamo-p i tu i t a ry unit . And yet by far not all methodological quest ions have been solved statisfactorily in this field. Studies by Leidenberger et al. [10] showed tha t the LH-values differed considerably in pos tmenopausa l w o m e n when de te rmined by rad io immunoassay or radioreceptor-assay. The ratio of the radioreceptorassay result over rad io immunoassay result was

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higher than ten in some sera. Since the radiore­ceptor levels agreed with a sensitive in-vitro bio-assay, it may be conclud­ed that the r a d i o i m m u n o ­assay of LH in se rum re­tains unsolved p rob lems of accuracy at least in terms of the biological significance of wha t is measured. The in te r labora tory com­parison of r a d i o i m m u n o ­assays for TSH per formed by the German Thyro id Association may be re­garded as ano the r example for methodologica l p rob­lems [ l l j . The value for one sample varied widely around a mean of 2 2 . 9 j u U with an in te r labora tory coefficient of variat ion of 6 4 % . The results of the group were improved to a more accura te mean of 17.3 /iU (coefficient of variation = 2 2 % ) , when s tandards in hormone-free serum were used as a ref­erence for all par t ic ipants . Figure 1 provides further informat ion abou t the accuracy for the radio­immunoassay for TSH [1] . Regular-size TSH pre­parat ions and various big TSH prepara t ions from human pi tui tar ies show corresponding values when analyzed by r ad io immuno­assay and by cy tochemica l bioassay, i.e. n o major descrepancies have been observed so far between radio immunoassay and bioassay for the deter­minat ion of TSH. How­ever, certain aspects of

Phys io logy o f t h e H y p o t h a l a m o - P i t u i t a r y U n i t 5

h-TSH pU/ml

TSH treated with void volume

6 M guanidine (sephadex G200)

the m e t h o d s for the quant i ta t ive determinate con t inued a t t en t ion .

Fig. 1 Comparison of immunological and biological thyrotropin activity in prepara­tions of regular TSH and "big"-TSH (from Erhardt and Doehler [1 ])

of p i tu i tary h o r m o n e s obviously require

The Radioimmunoassay for TRH

With regard to the de te rmina t ion of hypo tha l amic releasing ho rmones , 1 should like t o refer to the recent work of Mitsuma et al. [ 12 ] . These au thors have apparent ly develop­ed a rad io immunoassay procedure which permi ts the analysis of T R H in peripheral se­rum. It is interest ing to note that TRH levels appear to be low in hyper thy ro id i sm. This would favor the early concept of a negativ feedback regulat ion of T R H secretion by thyro id h o r m o n e s , a concept challenged by the studies of Reichlin et al. [18] and Oliver et al. [15] . This TRH assay [12] might even be useful for the differentiat ion bet­ween hypo tha l amic and pi tui tary forms of secondary hypo thy ro id i sm.

TRH Stimulation Tests

In recent years releasing hormones have been applied widely for diagnostic s t imula t ion tests. The normal specificity of TRH, for instance, in s t imulat ing TSH and prolac t in se­cret ion has been repeatedly documented . This specificity may be altered in cases of pi tu i tary adenomas which produce growth h o r m o n e or prolact in ; T R H may now st imu­late g rowth h o r m o n e secretion. On the o the r hand, the s t imula tory effect of T R H on the l ac to t roph may be lost in cases of a d e n o m a [26] . The concep t of " recep to r degenera­t i o n " in p i tu i ta ry adenomas will be dealt with in greater detail later on . The TRH-st imulat ion test may even provide insight into localization and extens ion of tumors in the hypotha lamo-pi tu i ta ry region. As repor ted previously [17 ] , nine pa t ien t s with secondary hypo thyro id i sm and suprasellar disease showed a normal or exaggerated TSH response to T R H st imulat ion. However, a normal or exaggerated TSH response was also found in all pat ients bu t one with secondary hypo thy ro id i sm due to a hormona l ly inactive p i tu i ta ry adenoma. It was concluded from this surprising observat ion, tha t the hypo thy ro id i sm in these cases was a result of suprasellar extens ion of the p i tu i ta ry adenoma , leading to portal vessel occlusion or to direct interference with hypo tha l amic TRH-produc t ion [17] . A suprasellar extens ion may thus be ant ic ipated in pa t ien ts wi th a p i tu i ta ry t umor , secondary hypothyro id i sm and TRH-responsive TSH secretion. Fah lbusch and Pickardt [2] cont inued the work along these lines. Table 2 compares the TSH increase after intravenous and intraventr icular T R H appl icat ion, respectively, du-

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S E R U M - T S H

i i » 1 1 1 i \ -10 0 10 20 30 40 50 60 mm F i 9 - 2 I n h i b i t i o n o f T R H t r a n s p o r t

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o o TRH intravenously a d e n o m a (cf. t e x t ; f r o m F a h l b u s c h

• • TRH intraventricularly and P i c k a r d t 12))

ring a diagnostic punc tu re of the lateral ventricle. The far right co lumn represents the control TSH response to intraventr icular T R H . In cont ras t , the pat ient referred to in Fig. 2 did not respond to intraventr icular T R H , but showed a perfect ly normal TSH in­crement after in t ravenous T R H . These findings suppor t the assumpt ion that it may well be the interference with the T R H t ranspor t from the third ventricle [16 , 17] or, re­spectively, from the hypo tha l amus to the anter ior p i tu i ta ry which causes secondary hy­po thyro id i sm in pa t ien ts wi th suprasellar extens ion of p i tu i ta ry adenomas .

Table 2 Increase in S e r u m T S H C o n c e n t r a t i o n ( j uU /m l ) a f te r I n t r a v e n o u s a n d I n t r a v e n t r i c u l a r

A d m i n i s t r a t i o n o f 50jug of T R H ( f r o m Fah lbusch and P i c k a r d t [2 ] )

i n t ravenous i n t r a v e n t r i c u l a r i. venous i. v e n t r i c u l a r m i n — 0' 30 ' 0 ' 5' 10' 20 ' 30 ' 40 ' 60 ' A T S H at 30'

R.D. 2.4 12.5 4.1 3.1 3.2 5.0 6.1 6.1 6.0 10.1 2.0 M.M. 2.6 16.2 1.3 1.3 1.7 2.7 4.5 6.3 13.6 3.2 E.J. 1.1 6.4 1.8 2.0 2.6 3.8 6.8 9.3 11.1 5.3 5.0 R.F. 1.8 19.9 2.5 3.1 5.8 9.8 13.8 17.5 18.1 7.3 W.P. 4.3 20.8 3.2 4.5 10.0 13.2 12.8 16.5 10.0

On the Regulation of TSH Secretion

Fig. 3 gives the last example of T R H pa thophys io logy I should like to discuss. In this study of Horn et al. [8 ] , the effect of repeated oral adminis t ra t ion of 4 0 m g T R H to a cont ro l group is shown. The first oral T R H adminis t ra t ion resulted in the expec ted in­crease in TSH and prolact in . At the same t ime, the T 4 and T 3 levels were slightly rais­ed towards the upper limit of normal , and T 4 remained on the border l ine , in accord-

Phys io logy o f t h e H y p o t h a l a m o - P i t u i t a r y U n i t 7

TSH° pU/ml

Fig. 3 Diminishing response of TSH and PRL secretion to repeated oral TRH administration {40mg, arrows, cf. text , f rom Horn et al. | 7 , 8 ] )

ance wi th its long half-life. Subsequen t oral T R H appl ica t ions led to much less pro­nounced increments in TSH. After four weeks of such a regimen (Table 3 ) , the T 4 and T 3 levels remained practically normal , whereas the TSH response was b lun ted [ 8 ] . Apart from the physiological in format ion ob ta ined regarding the regulation of TSH se­cret ion by thyroid ho rmones and T R H , respectively, this result provides a s t rong argu­ment against any form of hypo tha lamic hype r thy ro id i sm and against the "Schreck-Basedow" [ 7 , 8 ] .

Table 3 Effect of Oral TRH Application in Healthy Subjects (N = 1 2, 40mg per day over a period of 4 weeks; f rom Horn et al. (8|)

Serum TSH ( M U / m l )

Serum T4 (jug/IOOml)

Serum 7~3 (ng/100ml)

* significance p < 0.005

basal A TSH3Qmin

before TRH

2.0 ± 0.8

8.1 ± 3.0

6.2 ± 1.9

112 ± 22

after TRH

1.0 : 3.0 :

0.5* 1.9*

6.5 ± 1.8

109 ± 32

Somatostatin

I am now turning briefly to the inhib i tory h y p o t h a l a m i c h o r m o n e s . Prolact in secret ion appears to be the only example for a p r e d o m i n c a n c e of the inhibi tory factor, P I F . So­matos ta t in , originally discovered as the inhibi t ing factor of g rowth ho rmone secret ion, apparent ly plays a most interesting role as local inh ib i to ry factor for many secre tory processes and may have addit ional funct ions as a neu ro t r ansmi t t e r [ 6 ] . Three selected

8 Phys io logy o f the H y p o t h a l a m o - P i t u i t a r y U n i t

250jjg i v SOMATOSTATIN # Infusion of 500pg

ng/ml

ZOr

Patient M . 6 . , 37years

Metastasizing medullary

thyro id carcinoma with

ectopic ACTH production

30 60 90 120 150 180 min

Fig. 4 Somatostatin inhibits ectopic ACTH secretion in a patient w i th calcitonin-pro-ducing medullary carcinoma of the thyro id and ectopic ACTH syndrome (from Müller et al. I13p

examples will be men t ioned : first, the inhibi t ion of ACTH secre t ion in Nelson ' s syn­drome [ 2 4 ] ; second, the same inhibi t ion in 3 pa t ien t s with Add i son ' s disease [ 3 ] ; and thi rd , a pat ient , s tudied by Müller et al. [ 1 3 ] , wi th a ca lc i ton in-produc ing medul la ry carc inoma of the thyro id and an ectopic ACTH syndrome , where the ACTH levels could also be lowered by somatos ta t in (Fig. 4 ) .

Unidentified pituitary Hormones?

Are there still u n k n o w n anter ior p i tu i tary hormones? This ques t ion arose dur ing elec-t ronmicroscopic studies of Hachmeis ter [5] on pi tu i tary a d e n o m a s o p e r a t e d on by Dr. Marguth and colleagues. In a number of hormonal ly inactive a d e n o m a s , i.e. from pat ients showing no hormonal excess according to the cur ren t ly available r a d i o i m m u n o ­assays, secretory granules were observed which did suggest some un iden t i f i ed ho rmona l activity. Lipotropins might be a poss ib i l i ty ; unfor tuna te ly this ques t ion is far from be­ing solved, since Dr. S c h w a n d f s pept ide B turned out to conta in n e u r o p h y s i n , which it­self is not l ipolytic [ 14]. An interesting observat ion came from Boston recently. In a t h o r o u g h s t u d y carried out on 6 0 pat ients with p i tu i tary adenomas , Kourides et al. [9] observed 5 pa t i en t s w h o showed anexcess p roduc t ion of alpha-subuni ts , not explained by an excess of t h y r o t r o ­pin or gonado t rop in . The field of unidentif ied secretory p r o d u c t s of p i tu i ta ry adeno­mas is obviously still open for new insights; these would be highly we l come in order to facilitate the handl ing of pi tu i tary adenomas by moni tor ing t h r o u g h h o r m o n e determia-tions.

Antidiuretic Hormone

It is obvious that the discussion of neu rohormones , of diabetes insipidus and of dis­orders of ADH secretion and thirst [20 , 23] had to be excluded by the conveners . Just in order to remind the audience of the existence of these factors, 1 should like to ment ion the exper iments of G o t t s m a n n et al. [4 , 25 ] . Here ADH secre t ion was a sensi­tive indicator of stress, as shown for 15 min kinetosis [25 ] . The increase and the peak in serum ADH were already observed at modera te severity of k ine tos is [4] (Fig. 5) . With respect to the impending Bavarian evening, it may be n o t e w o r t h y tha t k inetosis is a more po ten t s t imulus for ADH secretion than thirst.

Phys io logy o f the H y p o t h a l a m o - P i t u i t a r y U n i t 9

hGH ° a (ng/ml)

hPRLA A

• i i i i 1 0 32 65 98 130 162 176 bowings of the head

0 30 min

Fig. 5 Increase of serum ADH concentration as well as of other "stress hormones" during Coriolis stimulation. The hatched area represents the serverity of kinetosis, up to vomiting (from Gotts-mann et al. [4])

A c k n o w l e d g m e n t s

This invest igat ion was suppor ted by the Deutsche Forschungsgemeinschaft (SFB 51)

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