Table Of ContentENDOCRINE ASPECTS
OF
DISEASE PROCESSES
Proceedings of the Conference held in honor of
HANS SELYE
Mont Tremblant, Quebec
Edited by
GAETAN JASMIN
Département de Pathologie
Faculté de Médecine
Université de Montréal
WILLIAM HEINEMANN MEDICAL BOOKS LTD
Published and Distributed by
WARREN H. GREEN, INC.
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All rights reserved
© 1968 by WARREN H. GREEN, INC.
Library of Congress Catalog Card No. 68-14063
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William Heinemann Medical Books Ltd
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Printed in the United States of America
2-A
Participants
Adamkiewicz, V. W., Département de Microbiologie et Immunologie, Uni-
versité de Montréal
Bajusz, E., Bio-Research Institute, Cambridge, Mass.
Beck, J. C, Department of Medicine, Royal Victoria Hospital, Montreal
Bélanger, L. F., Département d'Histologie et Embryologie, Université d'Ot-
tawa
Bois, P., Département d'Anatomie, Université de Montréal
Cantin, M., Département de Pathologie, Université de Montréal
Carey, N., Hockenden House, Nr. Swanley, Kent, England
Constantinides, P., Department of Pathology, University of British Columbia,
Vancouver
Copp, D. H., Department of Physiology, University of British Columbia,
Vancouver
Dieudonné, J. M., Département de Physiologie, Université de Montréal
Ducommun, P., Faculté de Médecine, Université de Genève
Forder, C, Département de Physiologie, Université Laval, Québec
Gabbiani, G., Institut de Médecine et de Chirurgie expérimentales, Université
de Montréal
Guillemin, R., Department of Physiology, Baylor University, Houston
Hall, C. E., Department of Physiology, University of Texas, Galveston
Halpern, B., Collège de France et Hôpital Broussais, Paris
Hartroft, W. S., Hospital for Sick Children, Research Institute, Toronto
Heilmeyer, L.,* Medizinisch-Naturwissenschaftliche Hochschule Ulm
Heuser, G., Departments of Medicine and Anatomy, University of California,
Los Angeles
Hoene, R., Wentworth Hospital, Dover, New Hampshire
Ingle, D. J., Department of Physiology, University of Chicago
Jasmin, G., Département de Pathologie, Université de Montréal
Jean, P., Département d'Anatomie, Université de Montréal
Laborit, H., Laboratoire d'Eutonologie, Hôpital Boucicaut, Paris
Lemire, Yvette, Institut de Cardiologie de Montréal
Lemonde, P., Institut de Microbiologie et d'Hygiène, Université de Montréal
Li, C. H., Hormone Research Laboratory, University of California, San
Francisco
Macintosh, F. C, Department of Physiology, McGill University, Montreal
Masson, G. M. C, Cleveland Clinic Foundation, Cleveland
McLean, F. C, Department of Histology, College of Dentistry, Chicago
Messier, B., Département d'Anatomie, Université de Montréal
V
vi Participants
Mustard, F., Department of Pathology, McMaster University, Hamilton
Nadasdi, M., Toronto Western Hospital, Toronto
Page, I. H.,* Research Division, Cleveland Clinic, Cleveland
Parrot, J. L., Laboratoire de Physique Pathologique, Hôpital Boucicaut, Paris
Renaud, S., Institut de Cardiologie de Montréal
Richer, Claude-Lise, Département d'Anatomie, Université de Montréal
Riopelle, J. L., Département de Pathologie, Université de Montréal
Robert, Á., Metabolie Diseases Research, The Upjohn Company, Kalamazoo
Rocha e Silva, M., Departamento de Farmacologia, Universidade de Säo Paulo
Rojo-Ortega, J. M., Institut de Diagnostic et de Recherches cliniques, Mon-
tréal
Sacra, P., Département de Microbiologie et Immunologie, Université de
Montréal
Selye, H., Institut de Médecine et de Chirurgie expérimentales, Université de
Montréal
Skelton, F. R., Department of Pathology, State University of New York at
Buffalo
Strebel, R. F., New York Medical College, New York
Timiras, Paola S.,* Department of Physiology-Anatomy, University of Cali-
fornia, Berkeley
Tuchweber, Â., Institut de Médecine et de Chirurgie expérimentales, Uni-
versité de Montréal
Veilleux, R., Département d'Anatomie, Université de Montréal
* Not present at the meeting.
Preface
T
HE Hans Selye Conference was held amidst the picturesque
scenery of our Laurentian Mountains, near Montreal, Quebec.
It was a great moment long anticipated by Selye's colleagues and
former graduates from l'Institut de Mιdecine et de Chirurgie
expιrimentales de l'Universitι de Montrιal, who wished to pay
him a tribute on the occasion of his 60th birthday. Needless to
say, a cordial atmosphere prevailed and all the graduates coming
from different parts of the world were most eager to communicate
their personal feelings and to review their scientific achievements
at this very exceptional gathering.
As has been our custom over the years, both French and En-
glish were used at the reunion; but the proceedings, except for
part of the voluntary discussion, have been edited entirely in
English. They will provide the reader with a good insight into
"the productive ideas" instilled by Selye into his trainees during
the past 25 years. The presentation of the papers follows the same
sequence as was observed during the Conference. Their number
had to be restricted because of time limitations. But original con-
tributions and pertinent illustrations were incorporated within
the discussions, to give us an opportunity to hear from alumni
and colleagues engaged in active research.
Great advances have been made during these past years in the
concept of endocrine factors in disease processes and, in agreement
with the participants, I can only say that this Conference illustrates
the multiple pathways opened by Selye to his disciples as to all
categories of workers in experimental medicine. In many of his
writings, Professor Selye refers to the triad as the starting point
of a series of discoveries on the non-specific reactions in biology.
Similarly, the tripartite theory of disease production that he
postulated proved to be highly productive in the design of experi-
ments for the study and understanding of pathological processes.
The essential components are: 1) the stimulus; 2) the sensitizer;
and 3) the target tissue. Many of the experiments reported here
were planned in accordance with this scheme.
My editorial task was facilitated by the full collaboration of all
vii
viii Preface
the contributors and the invaluable assistance of Mrs. Bridget
Sacra and Miss Francesca Pozzy in the preparation of the manu-
scripts. I also wish to express my thanks to Warren H. Green, Inc.,
who contributed by simplifying our editorial task. The Conference
would not have been possible without the collaboration of the
very efficient members of the Organizing Committee: Drs. Eugène
Robillard, Vice-Dean, M. Cantin, P. Jean and G. Gabbiani from
the Faculty of Medicine, Université de Montréal. As the president
of this Committee I wish to express my gratitude to the Medical
Research Council of Canada, le Conseil de la Recherche Médicale
du Québec, and to all the pharmaceutical firms * who, by their
kind financial assistance, contributed to the success of this reunion.
Université de Montréal Gaétan Jasmin
January 1968
* La Compagnie Ciba Ltée, Cyanamid of Canada Ltd., Eli Lilly and Company
(Canada) Ltd., Fisher Scientific Co. Ltd., Fisons (Canada) Ltd., Charles E. Frosst
& Co., Geigy (Canada) Ltd., Hoechst Pharmaceuticals, Frank W. Horner Ltd.,
Merck Sharp & Dohme, Pfizer Ltd., Poulenc Limitée, Sandoz Pharmaceuticals, and
John Wyeth & Brother (Canada) Ltd.
Hypothalamic Hormones Regulating the Secretions
of the Anterior Pituitary
ROGER GUILLEMIN
T
HE generation to which I belong was taught that the anterior
pituitary was the "master" of all other peripheral endocrine
glands with, admittedly, some debate upon its control of para-
thyroids and the pancreas; also that a subtle and exquisite recip-
rocal equilibrium between concentrations of circulating "periph-
eral" hormones and quantities of the corresponding pituitary
hormones maintained endocrine homeostasis. This feedback or
push-pull theory,, which had been suspected as early as 1931 by
Aron and his collaborators and which was later expanded by
Selye, Hoskins, Evans, and Sayers, satisfactorily explained the
experimental compensatory hypertrophy of peripheral endocrines
following unilateral ablation, the development of goiter, the com-
pensatory atrophy of the contralateral adrenal in the case of a
unilateral adrenal tumor, the atrophy of the adrenal cortex fol-
lowing administration of crude extracts of the adrenals, etc. These
were also the days when the first extensive purification of anterior
pituitary hormones was reported from the laboratories of Collip
and of Evans, from Kamm and Du Vigneaud's laboratory for the
posterior pituitary hormones, reaching in 1952, the isolation,
determination of the molecular structure and total synthesis of
the two principles of the posterior lobe of the pituitary by Du
Vigneaud. Then followed a twilight period in which numerous
aspects of the elegant physiological construction of the previous
fifteen years lost their appealing clarity and heuristic value, as it
was realized that there were circumstances in which the simple
pituitary-target-organ relationship was not exclusively operative.
Thus, the simple feedback theory could not explain the original
observation by J. S. L. Browne and Venning of the prolonged
excretion in the urine of large quantities of corticoids during
3
4 Endocrine Aspects of Disease Processes
prolonged stress or exercise or the hypertrophy of the adrenal
cortex during chronic stress as reported by Selye as early as 1936;
nor could it explain the extreme rapidity of the changes in
ACTH secretion induced by stress, with no evidence of a preceding
fall in plasma concentration of the peripheral corticoids that
could have triggered the feedback system; finally came the demon-
stration by Sayers himself that increased secretion of ACTH upon
exposure to stress could take place in adrenalectomized animals
maintained on constant high levels of corticoids. Meanwhile,
clinicians and experimenters, with Cushing, Roussy and Mos-
singer, Ranson, Magoun, Markee, Benoit, and Harris, had been
reporting more and more evidence that lesions in certain areas of
the base of the brain (in the hypothalamus), which anatomically
did not come in contact with the pituitary, could produce various
syndromes of pituitary dysfunction: inhibition of the stress-
induced release of ACTH, permanent diestrus, permanent estrus
with an ovarian picture reminiscent of that of the Stein-Leventhal
syndrome, testicular atrophy, obesity, etc. Today, we teach our
students that for the most part the center of control of the adeno-
hypophysial functions is to be found in the hypothalamus, that
the feedback relationships between peripheral hormone levels and
adenohypophysial secretions are mainly transhypothalamic, and
that the hypothalamic control over the pituitary functions is ex-
erted through the secretion of hypothalamic substances, the hypo-
thalamic hypophysiotropic hormones or releasing factors^ which
reach the anterior pituitary through the hypothalamo-hypophysial
portal system.
It is interesting that our information about the endocrinology
of the hypothalamus was acquired through the simple intellectual
and experimental processes that have led to all the basic knowl-
edge in endocrinology: the deficiency syndrome produced by the
classical surgical ablation of the suspected endocrine tissue was
achieved here by localized destruction of various parts of the
hypothalamus through stereotaxically placed electro-coagulations
or by subtracting the hypothalamic influence from the pituitary
by isolating the gland in peripheral grafts or by in vitro explanta-
tion or incubation; replacement therapy was achieved by injecting
hypothalamic extracts into the animals with hypothalamic lesions
Hypothalamic Regulation of Pituitary Secretions 5
and studying the function of the adenohypophysis or, more sim-
ply, by adding these extracts to the pituitary isolated in vitro and
studying its release of hormones. A unique feature of this neuro-
endocrinology has been the possibility of electrically stimulating
hypothalamic areas to specifically induce the release of the pitui-
tary hormone as well as recording the electrical activity of hypo-
thalamic nuclei as modified by the levels of circulating hormones
and also of correlating this electrical activity with pituitary secre-
tion. Precise localization of the origin of a given releasing factor
cannot be ascertained in terms of specific hypothalamic nuclei as
they have been described by the neuroanatomists. Rather, the
neuroendocrine areas in the hypothalamus appear to be somewhat
diffuse if we consider the overlapping of hypophysiotropic activi-
ties related to one area or another. This question of the exact
hypothalamic origin of specific releasing factors requires further
investigation. In its present and perhaps final state, the question
is reminiscent of the conclusions reached by the neurophysiolo-
gists not many years ago regarding the absence of specific localiza-
tion in the hypothalamus for sympathetic and parasympathetic
integration, for instance.
With this important restriction in mind we can say, however,
that stimulation of the posterior or ventral hypothalamus is fol-
lowed by secretion of ACTH, whereas stimulation of a more
anterior area will trigger secretion of TSH. Somewhere in be-
tween is an area that upon electric stimulation will produce
ovulation in suitably prepared animals and, hence, may be con-
sidered to be related to secretion of gonadotropins (LH and FSH).
It appears also that this mid-hypothalamus area is under the com-
mand of a somewhat more anterior (supra-chiasmatic) area, the
interplay between the two regulating "basal" secretions of gonado-
tropins and "spurt" secretions as in the triggering of ovulation.
Conversely, minute lesions as made by electro-coagulation of the
same areas of the hypothalamus will reduce or inhibit secretions
of ACTH, TSH, FSH and LH. After lesion of the ventral hypo-
thalamus, particularly of the area known as median eminence,
the acute release of ACTH that usually follows exposure to any
stressful stimulus is completely inhibited. Lesions of the anterior
hypothalamic region can prevent the acute secretion of TSH that
