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THE RELATION BETWEEN THERMAL ENVIRONMENT AND THE THYROID-ADRENAL CORTICAL APPARATUS

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University Microfilms
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hi
jrt M o d
.G7
Bernstein, Joseph G
(*/ I l|»A >
1940
The relation between thermal environ.B4
ment and the thyroid-adrenal cortical
apparatus...
New York, 1940.
2p.1.,110,c6a typewritten leaves,
tables,diagrs. 29cm.
Thesis (Ph.D.) - Hew York university,
Graduate school, 1940.
•'Literature cited’1: p.90-110.
A54462
r
Xerox University Microfilms,
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T H IS D IS S E R T A T IO N H A S B E E N M IC R O F IL M E D E X A C T L Y A S R E C E IV E D .
J..'ti]<A K Y
N. Y. U niv .
’
THS HALATION B3T-.73SN THBRIiAL ^NTI'iOIJMiHT
AND THU THYROID-ADRENAL CORTICAL APPARATUS
Joseph G, Bernstein
Submitted in partial fulfillment of the
requirements for the degree of doctor of
philosophy at New York University
June 1940
PLEASE NOTE:
Some pages may have
ind isti nct print.
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University Microfilms, A Xerox Education Company
CONTENTS
PAGE
INTRODUCTION
1-4
LITERATURE
4-43
1. The development of body temperature regulat­
ion with age
i
*
2. The physiology andanatomy of
1. Nervouscontrol over the
heatregulation
4-28
physiology of
heet regulation
4-13
A, Central nervous control
4-9
B. Autonomic nervous oontrol
9-12
C* Relation between the hypothalamus
and the autonomic nervous system
in maintaining body tempereture
12-13
2. Endocrine control over the physiology of
heat regulation
13-28
1. Hypophysis
15-24
A, The relation between the hypo­
thalamus and hypophysis
15-19
B, The hypophysis and body temper­
ature
19-20
C, The relation between the hypoph­
ysis and thyroid in heat regulat­
\ H 0 ^ S'
ion
2* Thyroid
20-24
24-25
3, Adrenal
25-28
1* Medulla
2* Cortex
25-26
26-28
3. The affect of thermal environment on
the morphology of the endoorines
1. Thyroid
A* Season
B. Experimentally altered environ­
mental temperatures
2. Adrenal cortex
A. Season
B. Experimentally altered environ­
mental temperatures
MAT1SHIALS AMD METHODS
OBSERVATIONS
1. Gross observations
2. Histological observations
DISCUSSION
3UM&IARY AND CONCLUSIONS
BIBLIOGRAPHY
ILLUSTRATIONS
INTRODUCTION
The ability of the higher mammals to maintain a oonstant
body temperature is one of the more striking physiological prop­
erties of suoh organisms. The constancy of the thermal equilibtium of these homeotherms is generally conceded to be depend­
ent on the maintenance of a balance between those factors which
cause heat production and those which activate heat loss. The
changes in heat production which occur in temperature regulation
might generically be termed chemloal control and depend on the
metabolic activity of the tissues; on the other hand, alterations
which are concerned with heat loss might be considered as phy­
sical control and include both physiological and physical factors.
The physiological variable in heat loss is the flow of heat
from the Internal tissues to the surface of the skin; beyond
that point, purely physical Hectors are involved. In recent
years investigations in temperature regulation have emphasized
the importance and illustrated the separation of the physiolog­
ical and physical factors.
The essential central controlling mechanisms for body
temperature regulatory activity have, by virtue of long and
carefully planned investigations, been shown to consist of cert­
ain well defined neuro-anatomical structures. It Is now almost
universally reoognized as well substantiated that a physiolog­
ical "center ' situated in the tuber cinerama of the hypothalamic
region of the brain stem is essential for the normal thermo­
regulatory activity of the organism, lioreover, the fact that
2.
the autonomic nervous system as a whole has definite anatomical
representation in certain of the hypothalamic nuclei lends fur­
ther credence to the belief that this region is important in
this raspeot, since it has been demonstrated by numerous re­
searches that the autonomic system exercises profound effects
on both the production and the loss of body heat.
The primacy of the neural mechanisms in controlling and
integrating body heat seems firmly established. Liore recent
developments, however, have tended to alter the conception of
the importance of these structures in this respect. The exist­
ence of other subsidiary or accessory mechanisms which play a
role In the complete picture of thermo-regulation has slowly
come to be recognized. Control of metabolism, in turn affecting
heat production, may possibly take place through the medium of
metabolic products of the tissues themselves. Moreover, evid­
ence that several of the ductloBS glands, viz: the hypophysis,
thyroid, adrehal medulla and cortex are involved in aiding the
maintenance of thermal equilibrium has been forthcoming from
several sources. In point of fact, the thyroid gland by virtue
of Its control over the metabolic rate, and the adrenal gland
(both portions) have been linked together to constitute the most
important non-neural accessory thermal mechanism.
Hecently a new Interest has been taken in those slow ad­
aptations of the organism to external tomperature which are
known to take place between different seasons of the year,
EHPERil*ENT6
Because of these adaptations,*Aperformed in the summer may pro-
3.
duce
results that differ significantly from those of winter
experiments. Thera apparently is no doubt that endocrine fact­
ors are involved in these slow adaptations to the thermal
environment, and the physiological differences between the
winter and the summer animal may indicate the importance of
such factors in heat regulation.
The importance of the neural structures has been ad­
mirably and adequately illustrated. Most investigations on
temperature regulation, indeed, lay emphasis on them. Less
stress, has, it seems, been placed on the accessory endocrine
mechanisms with the result that no complete information is
available about them. Notwithstanding the fact that the phy­
siological aspects of temperature regulation mediated through
the endocrines have been studied for some time, there ere
still lacking detailed, correlated morphological data on the
effect of the thermal environment, which includes both normal
seasonal and controlled variations, upon those organs.
It is with this in mind that the present series of exp­
eriments has been undertaken in order to determine the hist­
ological effects of different types of variation in the therm­
al environment on certain of the endocrines, specifically the
thyroid and the rdrunal cortex; and to suggest the possible
OP
signifioanoeAthese morphological changes in maintaining the
normal and experimental thermal economy of the warm blooded
animal.
4
The author wishes to acknowledge the kind assistance of
Prof. M.hL Hoskins in collaboration with whom this study was
undertaken. Further thanks are due to the Research Laborator­
ies of the General Electric Company for the gracious provision
of certain of the technical equipment utilized in the invest­
igation.
LITERATURE
1. The development of body temperature regulation with ago
The capacity for body thermo-regulation may or may not
be
present at birth; and it Is well known that in the human
infant it remains ill-developed for sdme time (Kleitmanet al,
*37.) In the hedgehog full development of thermo-regulation
is apparent at 31 days (Eisentraut, *35.)
In the albino
rat, Gullck (*37) has demonstrated that full thermoregulatory
powers are present at 20 days of «ge.
2. The physiology and anatomy of heat regulation
1. Nervous control over the physiology of heat
regulation
A, Central nervous control
studies on animals in which the spinal cord has been
transected show quite conclusively that the heat regulating
mechanism of the central nervous system hes a supra-spinal
localization. Sherrington (*24) has demonstrated that trans­
ection of the 3pinal cord In tho cervical region causes a
precipitous drop in the body temperature of dogs and primates
5.
unless it is artificially maintained. Moreover, even if the
spinal animal is kept alive for several weeks it displays no
effective thermoregulatory responses,i.e.,it remains essentially poikilothermio.
The literature on the subject of central neural control
of body temperature before 1912 apparently concerned itself
primarily with the importance of the corpora striata in this
respect. Barbour (*12) applied localized thermal stimuli to
these structures which induced marked bodily thermal responses.
However, in the light of subsequent careful work, it seems
probable that Barbour’s results were due to alterations in
the temperature of the hypothalamus which lies in close anat­
omical relation to the corpora striata.
Although the first suggestion that the hypothalamus was
the essential eentral neural mechanism concerned with thermo­
regulation was made by Ott as early as 1087,(quoted in MacLeod)
this Investigator’s findings apparently had no great influence
on other contemporary workers, end it was not until 1912
that Isensohmld and Krehl first offered definite evidence
that the diencephalic region of the brain of the rabbit was
important in this respect. Still other experiments performed
by Isenschmid and dohnitzler (12) indicated a more circum­
scribed area of the diencephalon, the tuber oinereum, as
the essential structure. Much later, Keller and Hare (*32),
Keller (’33) and Bazett, Alpers and Erb (*33) clearly demon­
strated that the hypothalamus was the primary central nouro-
anatomical factor involved in body temperature regulation.
Earlier references to central nervous control are cited by
Bazett ( »3^ .
Recent work has consisted of a further delimitation of
specific nuclear masses in the hypothalamus as being most
vitally concerned. Hanson and Ingram ('35) have found that
bilateral destruction of the lateral nuclear masses and
caudal hypothalamus in the otherwise intact monkey
through
lesions induced by means of the Horsely-Clorke apparatus causes
hypothermia. Ranson et «1 (*37) have indicated, in the cat and
monkey, that there is an anatomical separation of nuclear
centers controlling, individually, heat loss and heat prod­
uction.
More exact localization of the center has been made by
Frazier et al (*36j These investigators have placed it in the
mesial hypotholamio nucleus of the oat and in the substantia
gri3ea centrali3 in man, close to the floor of the third vent­
ricle. Magoun et al (*38) utilizing localized thermal stimuli
inducea by low voltage high frequency currents applied by means
of the stereotactic instrument mentioned above, were led to
believe that the effective heat loss region la concentrated
in the medial portion of the caudal part of the ventral tel­
encephalon. A significant investigation undertaken by Morgan
(*38) throws light upon the localization from a morphological
point of view. Observations of retrograde changes In the nouroncs
of the hypothalamic nuclei after fever induced by typhoid and
7.
bronohi-septicus infeotion revealed specific chromolytic
variations in the nucleus tuber-raammillarlB. It should be
remembered that such results may be caused by the result­
ant generalized bacteremia*
Krieg {*35) has shown that in the albino rat poikIlotharmy is associated with experimentally produced irrit­
ations of a region at the junction of the hypothalamus and
the mid-brain. He admits, however, the possibility that
the effective Injury may be to fibers with a more rostral
origin. In every case of poikilothermy ("cold puncture")
the posterior fibers of the periventricular tract were in­
jured.
.available evidence at the present time points to the
anterior hypothalamus as the region concerned with the mech­
anism of heat loss, although it is not yet possible to make
assignments to specific nuclei (Fulton, '3QJ The medial nuc­
lei as a group appear to be more significant for regulation
both against heat and cold, while heat production, which
Includes the phenomena of shivering, mobilization of carbo­
hydrate reserve, vasoconstriction, elevation of heart rate
and metabolic activity generally, seems to be mediated
through the nuclear groups in the posterior hypothalamus.
For clarification of these points it might be well
briefly to review the general morphology of the hypothalamio a
groups. The constituent nuclei may be divided into three
groups, viz;
1. /interior—
including the paraventricular and
8.
supraoptio nuclei.
2. Kiddle-— including the tuber, lateral, dorsomedial
and ventro-medial hypothalamic nuclei.
3. Posterior—
including the posterior hypothalamic
nucleus and the mammillary bodies.
Pervading the entire area around these nuclei are illdefined neurones, grouped under the general heading of
substantia griaea centralis. Further details may be found
in FultonTs excellent volume on the physiology of the nerv­
ous system (*38.)
The
hypothalamic nuclei may be responsive to temp­
erature variations both through the thermal receptors in
the skin and through direct thermal action on the nuclei
concerned through the medium of the circulating blood.
The latter fact has a firm raorphological basis as shown
by the work of Wi3locki and King (*3fi) and Wisloeki (*37),
who have demonstrated that the hypothalamic area is one of
the most richly vascularized regio§ft of the entire brain.
Further, Kagoun et al (^38) have recently produced evidence
which does not directly demonstrate the former fact but
indicates that the interior nuclei are definitely responsive
to changes in temperature per se, ind honco, presumably
to the te i.perature of the blood which passes through them.
Further, "organ's findings previously mentioned also may
lend support to the importance of direct thermal stimulation.
In summary, it may be sai4 that it has been almost
universally established that a physiological "cehter"
9.
situated In the hypothalamus is essential for the reg­
ulation of body temperature. Recent opposition to such a
view has been afforded by Thauer (’35) and Thauer and
Peters (*37) who employed rabbits as experimental animals.
However, it is a matter of common knowledge that in this
species the major role of physical heat regulation is
plnyed by the large ears which in this case may not have
been denervated. This fact, therefore, leaves this work
somewhat open to question. Furthermore, disturbances in
heat regulation in pothol&gical conditions like chronic
encephalitis and dementia praecox (Finkelmsn and dtevens,
*36) have been attributed to lesions of the hypothalamus.
B.
Autonomic nervous control
A consideration of the reactions which occur when the
body temperature tonds to rise or fall shows that (with
the exception of shivering), alterations in respiratory
movements and other responses in the skeletal muscles and
cutaneous areas, all are mediated through activity of the
autonomic nervous system. Regional stimulation of the hypo­
thalamus, moreover, indicates that the vegetative nervous
system is extensively represented in this area of the brain.
Thi3 has been demonstrated by Bronk, Lewy and Larrabee ('36.)
It is the contention of these investigators that the hypo­
thalamus Initiates nerve impulses which ere discharged
through the sympathetic nerves. This fact indicates the
strong possibility of a close functional inter-relationship
between these two nervous mechanisms in thermo-regulation
as well as other visceral functions.
10*
Relatively few of the thermal responses of the organ­
ism ere mediated through the parasympathetic or cranio­
sacral division of the autonomic nervous system. Local
vasodilatation in glands and to a small degree in the cut­
aneous regions upon exposure to heat,Is due to activity of
this constituent of the autonomic system. The greater part
of the generalized temperature responses is due to sympath­
etic or thoraco-lurabar control. For example, when environ­
mental cold tends to lower the body temperature, sympathetic
activity leads to constriction of peripheral vessels, erect­
ion of hairs and liberation of adrenin. This latter point is
of especial significance since it is known that adrenin has
a calorigenic effect in the normal organism; the breakdown
of muscle glycogen by the action of adrenin to lactic acid
is an exothermic reaction. Still more important, however, i3
the fact that thi3 ;orves to focus attention on the function
of the endocrines in thermo-regulation. Bodily responses to
external heat are sweating (in animals with sudoriferous glands),
generalized cutaneous vasodilatation and hyperpnea.
The importance of the sympathetic system in the thermo­
regulatory process has been conclusively 3hown by the exper­
imental utilization of successful preparations of totally
sympatheotomized animals. Probably among the first to accom­
plish this were Cannon et al (*29.) These investigators dem­
onstrated that such animals exhibited certc-in defects when
confronted with the problem of maintaining normal body temp-
IX.
eratures in tho face of altered cnvironiTiental heat and cold.
When placed in a cold room synpetheeternized cats exhibited
a deeper depression of rectal temperature than normal animals
and, moreover, a much greater frequency and vigoroue-neae of
shivering. Further studies investigating the effects of high
and low environmental temperatures on sympatheatomized cats
were c^rri ;d out by Sawyer and Schlossberg (*33) also in
Cannon's laboratory. These animals likewise showed definite
defeots in thermo-regulatory ability. Such facts, along with
certain others, have led Cannon (*35) to a teory of the role
of the sympathetic nervous system in the important physiolog­
ical concept of"homeostasis"; viz: the normal organism is so
Integrated anatomically and physiologically as to exert a
tendency to remain in
'
q
state of physiological status quo
in the face of a threatening environment. This concept was
antedated by Claude Bernard's earlier, somewhat restricted,
elucidation of "milieu interieur” (*51, *52, *58.)
That the adrenal medulla constitutes nn integral part
of the sympathetic nervous system has been known for some
time. This
basod both upon embryological and physiological
findings. In point of fact, Cannon (*35) has linked the ad­
renal medulla and the thoreco-lumbar division into a "sympethoadrenel” system and has offered experimental physiological
evidence that both tend to go into action os an integrated
whole in times of physiological stress. With respeot to
OF ADftENiN
body temperature regulation, the caloric effect^has already
been mentioned. In addition, it might be noted that adronin,
by virtue of its capacity to increase tissue oxidations.
12
may aid in heat production also. The role of the mcdulliadrenal secretion in the chemical control of body temp­
erature has been amply demonstrated by Gannon, Queiido,
Britton and Bright (*27.) as a result of their experiments
it was concluded that an increased discharge of adrenin occurs
under circumstances which tend to lower the body temperature
of cats.
G. Relation between tho hypothalamus and the
autonomic nervous system in maintaining body
temperature
On tho basis of available physiological information,
the autonomic centers in the hypothalamus have been regard­
ed as being superimposed on the lower autonomic mechanisms,
over which they exert a regulatory influence (Kuntz, *34.)
Such a contention apparently is in accord with Jackson*8 (*98)
classical and Papez* (*37) more recent postulation of the
existunca of "functional levels’* in tho nervous system.
Regulatory control of autonomic functions probably is of
much greater importance m
those animals whose existence de­
pends on their capacity to maintain a constant body temper­
ature in the face of the external environment, i.e., birds
ana msmiaala (Kuntz.)
The conclusions of Bronk and his collaborators prev­
iously mentioned,as well as the work of Meyer^(quoted in
Kuntz) indicates a close interrelation between hypothalamic
and autonomic control of body temperature. The latter in­
vestigator offers evidence indicating that the hypothalamic
13.
center for thermo-regulation inoludes an aggregation of
oells, stimulation of whioh influences thornco-lumbar
outflov; (sympathetic) and couses a rise in temper*ture;
and another distinct group, stimulation of whioh influences
tho cranio-sacral outflow (parasympathetic) causing a fall
in body temperature. This contention is somewhat similar to
the evidence offered by Hanson and his co-worker3 already
mentioned.
The end organs through which tho nervous regulation
of body temoerature is effected are mainly the blood vessels,
sudoriferous glands and internal organs whose metabolic
activity tends to increase or inhibit heat production (Kuntz.)
Further, the glands of internal secretion also play an im­
portant role in bodily thermo-regulation, although diroct
autonomic stimulation of certain of the ductless glands
(thyroid) involved has recently been denied by Uotlla (*39.)
This fact notwithstanding, the endocrine glands, through thoir
secretory activity may exert a direct influence on the metabolic
processes through which heat is generated, as already indic­
ated. Further^ Kuntz believes that the temperature regulating
centers may be activated directly by endocrine products in
tho blood stream. That endocrine activity influences body
temperature directly or indirectly can no longer be denied.
2. Endocrine oontrol over the physiology of heat
regulation
Tho profound effect of adrenin, an endocrine secretion,
14*
on the thermal equilibrium has already been mentioned.
The recognition of thi3 fact has served to focus attention
on the endocrine system as a whole in the maintenance of
body temperature. ;/!ore specifically, the hypophysis and
the thyroid and adrenal glands, the latter two being link­
ed together as a distinct apparatus, have been considered
as important accessory mechanisms in this regard (Cramer
*2Q and Borchardt f29.)
Extirpation of the adrenals is followed by a drop in
body temperature (Burton *39.) Disorders of the endocrines
generally result in abnormal body temperatures. Experimental
lesions inflicted upon the endocrine system of dogs cause
disturbances in heat regulation {(Jal'perina *30.) Hypofunction of the thyroid as manifested in myxedema tends
to depress body temperature whereas hyperfunction (exopthalmas), is not uncommonly accompanied by a ri3e in temperature
(Best and Taylor *37.) Abnormally low body temperatures in
Addison's disease doubtless must be duo to destruction of
adrenal tissue (Burton), although Gal'nerina believes that
experimentally induced adrenal insufficiency causes height­
ened body temperatures.
Cawadias 1*20) indic£:tes that certain long continued
fevers not caused by intoxication or infection are the re­
sult of endocrine disorders. Additional early references
pertaining to endocrine factors in thermo-rogulation nro
listed by Barbour (*21.)
An interesting and significant view has been advanced
15.
by Morgan (*30) which strongly indicates that the cell
groups in the tuber cinereum represent secretory centers
for certain of the endocrines, particularly tho thyroid
and the adrenals. If this is so, it may safoly be assum­
ed that the influence of the hypothalamus on visceral
function may, in part at least, be exerted indirectly
through the activity of the endocrine glands. This hypo­
thesis differs somewhat from Uotila's more recant one.
v;hst it does serve to bring out however, is the relation
between certain of the endocrines and heat regulation.
1. Hypophysis
A. The relation between the hypothalamus and
hypophysis
Interrelation both from the point of view of physiol­
ogy as well as morphology between the hypothalamus and the
hypophysis has been demonstrated by several investigators.
The excellent monograph by Fisher, Ingram and Hanson (*38)
as well as their earlier work (’35 and f36) gives ample
evidence for this.
The study of the nervous innervation of the hypoph­
ysis is one of the more recent morphological attacks on
the mode of function of the gland. It is largely through
the efiorts of the three investigators mentioned above and
Hasmussen (*3S), that a definite anatomical relationship
could be demonstrated between the supraoptic nuclei, and
to some extent the paraventricular nuclei of the hypothal­
amus, and the hypophysis. It is now generally agreed that
16.
those nuclei are the sources of origin of the supraopticohypophyseal tract which converges in the tuber cinereum
in the infundibulum, through which it enters the pars
nervosa. Here it forms an exceedingly complex plexus of
non-myelinated nerve fibers which ramify to all parts of
this lobe.
Older evidence relative to a supposed sympathetic
innervation of the hypophysis was offered as early as
1845 by Bourgery. Dandy (*13) also described nerve bundles
from the sympathetic carotid plexus which passed along
the hypophyseal vessels to the hypophysis where most of
them became related to the anterior lobe.
Experimental evidence for the anatomical connection
between the supraoptic nuclei and tho hypophysis in the cat
was offered by tiasmu3sen (*37.) In this study,nearly all
the neurones of tho supraoptic nuclei had disappeared through
retrograde degeneration by 6 months after hypophysoctomy.
Evidence for the relation between these structures had
been previously offered by Ingram, fisher and Hanson (*36.)
furthermo re, a second tract was described, vi".: a small
bundle of fibers which deconds in the dorsal wall of the
infundibular 3talk. This arises from the cells situated
more posteriorly In the tuber cinereum and is called the
tuber-hypophyseal tract.
The findings of Mahoney end Sheehan (*36) describing
the sparesness of neural fibers passing along the infund­
ibular stem of the monkey apparently cannot be reconciled
with Rasmussen’s (*38) estimation of at least 40,000 fibers
coursing in the macaque infundibular stalk.
Nerve fibers have been traced into the pars inter­
media in humans (llamon y Cajal, *94; also Pines, '25; and,
in cats, Hair, *38.) Bodian, employing a special neuro­
logical staining technique, has more recently (*37) ob­
served frdrly numerous nerve fibers in limited regions of
the pars intermedia in the cat and monkey; but could only
rarely demonstrate definite nerve endings about epithelial
colls. Rasmussen (*38) Is of the opinion that neural fibers
merely pass through the intermedia coming into physical
contact with the Herring bodies.
The innervation of the anterior lobe of the hypophysi
is 3 till a question of considerable controversy, although
the prevailing view for c. long period of time was that this
portion of the gland was supplied by fibers from the int­
ernal carotid sympathetic plexus. Herr Inf; (*08), Graving
(*26) and Bucy (*32) could demonstrate no fibers in the
pars dlstalls; while Tello (*12) and Croll (*28) report
only a few in a very limited region (usually peripherally
located.) On the other hand, Pines (*25) and Hair (*38)
contend that nerve fibers are plentiful In the anterior
lobe. Recently Brooks and Gersh (*38) claim to have ob­
served a terminal net enclosing most of the surface of
the chromophil colls of the rat hypophysis.
Van Dyke (*36) is not impressed with tho importance
of secretory fibers to the anterior lobe; whereas Roussy
and Mossinger (*36) stress the role effected by tho
10.
sympathetic .system in the neural regulation of the
hypophysis.
In lower forms there is considerable uncertainty
about the nerve supply to the glandular portion of the
hypophysis. Burr (*28) and Weinberg (*33) found some
nerve fibers passing from the pars nervosa into the
pars intermedia in fish and amphibians. In amblystoma
Herrick (*33 end *34) observed that some fibers also
reached the pars disteli3.
Rasmussen (*3G) however, strongly indicates the
possibility that the cells of the hypophysis may be in­
fluenced through a humoral mechanism rather than by
direct activation of the secretory cells by the nerve
fibers of the supraontico-hypophyseal tract. Such a
postulation is reasonable when examined in the light of
the humoral doctrine of nervous exditatlon as described
by Loewi (*22), Dale and Feldbarg (*34) and Cannon and
Rosenblueth (*37.) V/hat is important to note here, how­
ever, is
get the hypothalamico-hypophyseal tracts actually
do regulate the secretory acti/ity of the nervosa, :Ibeit
tile exact mechanism is still obscure, experimental evidence
for this is offered by the previujosly mentioned work of
I’isher et al. This latter paper, contains n complete list
of references reporting the presence of the hypothalamicohypophyseal system in cyclo3tomes, fish, amphibia, reptiles,
birds, rat, cat, dog, monkey, cow, mouse and sperm whale.
Rasmussen’s contention that a humoral mechanism exerts
secretory influence upon the Uypophysool cells is borne out
19
by the work of Friedgood {*37), who asserts that the
adrenal cortex probably produces a hormone which helps
stimulate the anterior hypophysis in association with
effective nervous impulses. The view is further strengthened
by Rasmussen's morphological findings which show that a
large proportion of the anterior lobe colls appear to be
devoid of nerve fibers. The fibers which are found are
probebly vasomotor in function.
B. The hypophysis and body temperature
Earlier evidence that the hypophysis i3 concerned
with the maintenance of body temperature has been supplied
by Graving (*23), who donionstrotod thnt ablation of the
gland is followed by a fall in body temperature which
persists despite the naministration of pyrogonic '.gents.
No mention of the exact mechanism is nude here.
Further, Biddle et al (*38) fo»nd that the basal
metabolic rate (BUR) of pigeons is reduced after hypophy­
ses tomy (-33# at 3G°C or -17# at 20OC.) If 10-23# of the
gland is removed, there is a definite but less pronounced
fall, moreover, it has been demonstrated by Wolf and Greep
(*37) that the hypophysectoml’
/.ed rat adapts itself poorly
to a cold environment. It3 body temperoture is abnormally
low (34-35.5°C) after 29 days in an environment of 2-4.5°C.
It was also observed that the thyroids of such animals exh­
ibited colloid absorption at the peri hery; the cuntral
part of the gland is
trophic owing to withdrawal of the
20.
hypophyseal tlirotropic principle.
C.
The relation between the ayponhysi
thyroid in heat regulation
One of the most impressive effects of hypophysectomy
in mammals is a marked fall in the rate in which body heat
is produced. This change is due principally to Inadequate
function of the thyroid gland (as 3toted by Wolf and Greep),
To
notAhypophysectomy per se, and c m be correlated with morph­
ological changes in the thyroid. After hypophysectomy a low
coefficient of thyroid activity is indicated nior ho logically
by the atrophy of the thyroid follicles and the distension
of the latter with dense non-vacuolatod colloid. Such
changes were reported by Howlands (’35) v/ho hypophysactoraizod
fowls m d several species of mammals (ferret, guinea pig and
hedgehog.) It is Interesting to note that .
‘itdrm and ilchoning
(*35) believed that ovarian or medullary edrenal extracts
may act like true thyrotropic hormone in this respect.
Repetition of this work with ovarian hormones, however,
yielded no confirmation (Bsilliff and Gherscovici *36,
I'cGinty and ..oCullough *36 and Emerson *37. )
The most significant action of thyrotropic hormone
appears to be to facilitate or promote the discharge of the
thyroid hormone from the thyroid gland. Increased thyro­
tropic stimulation causes vacuolization of the colloid,
a diminution of follicle size and a hypertrophy of tho
epithelial cells (Van Dyke *39.) Kippen and Loeb (*35)
reported that injections of anterior pituitary extracts in
guinea pigs resulted in an average of 190,000 mitotic fig­
ures in immature thyroid glands compared to the average of
approximately 150 mitotic figures In the normal gland.
Further confirmation and elucidation of the specific
hypoThyaeal principles involved is offered by the work of
Riddle et al (*36.) These investigators tested the cslorigonic action of prolactin, thyrotropic, and follicle stim­
ulating fractions from 17 different anterior pituitary prep­
arations. They are led to believe that the anterior pituit­
ary possesses two hormones which affect the rato of oxygen
consumption vi.,; 1) prolactin which has a n/rkod celori renic
effect acting independently of the thyroid and 2) the thyro­
tropic principle. The prolans, furthermore, have no oalorigonic action. 'The luteinizing fraction possesses this cap­
acity only by virtue of the amounts of thgfrotropic prin­
ciple and, prolactin in it. This contention is supported
by Loeb et al (*36.) Tests of an ndronotropic preparation
revealed some thermogenic action, /in interesting finding
was that simultaneous injections of proLen and the thyro­
tropic principle produced a synergistic action on oxygen
consumption. This is similar to the well known "augmentetlon” phenomenon which occurs upon simultaneous injections
of the gonadotropic px*inciples(Fevold *39.) Growth princ­
iples contain ;:iore or less of both of the cnlorigenic factors
and hence these fractious give r .ther high cnlorigenic activity.
22
.
Van Dyke (*39) states that injections of thyrotropic
principles cause^ a rise in basal metabolic rate at first;
but later this returns to normal, after which however, re­
crudescences of an elevated rate may appear, earlier evid^thnt injection of thyrotropic hormone results in an increased
metabolic rate in intact animals was offered by Jiebert and
omith (*3Q), Verzar and 77ahl (*31), Diefenbach (*33), /mderson
and Collip (*34) and Zajic (*35.) In addition, .Anderson and
/.It £*37) have shown that thyrotropic hormone increases the
oxygen consumption of dog thyroid in vitro. Similar results
have been obtained by Ganzonelli and Rapport on guinea pig
material (*3Q.)
Still further evidence that the hypophysis has only
an indirect effect on thermogeneais has been offered recent­
ly by Uotila (*39a), who reviews the literature relative to
a direct secretory autonomic innervation to the thyroid
gland from the cervical sympathetlcs, and is led to the
conclusion that no satisfactory proof has as yet been off­
ered of such a relation. This is borno out by the independent
experimental work of Manley and Marine (*15), Crawford and
Hartley (*25), Smith and Molay (*30) and Raid and Holman (»36.)
Uotila*s experimented, findings indicate that the ant­
erior pituitary through the thyrotropic principle is the
chief activator of the thyroid gland. Hypophysectomy in rats
is followed by thyroid atrophy which cannot be compensated
by sympathetic stimulation (exposure to cold.) The cervical
sympatnetlcs ore apparently unnecessary for continued hist­
33
ologically normal thyroid function. It has boen suggested,
however, (Nonidez,*35) that the thyroid gland receives
vasomotor fibers from the sympathetic system. Control of
circulation here may possibly exert an indirect effect on
secretion rate.
Eitel*s (*36) observations are in accord with older
views in that he concludes the action of thyrotropic horm­
one doos not depend upon peripheral somatic nerves.
Uhlenhuth's work (*37) gives some indication that nervous
control may play a part in the secretory function of th.i
gland; although he is not certain that this is due to act­
ion by peripheral fibers of the autonomic nervous system.
Kusohinsky {*35} reports that if rats are kept at
4°C their hypophyses contain about the some amount of thyro­
tropic hormone in association with histologic signs of
diminished (at first) or increased (later) thyroid function.
However, he further shows that thyrotropic hormone might
almost disappear from the pituitary of animals with Inactive
thyroids induced by exposure to environmental temperatures
of 38-40°C.
It seems definitely e3tcbli3hed, therefore, that the
hypophysis has its effect on heat production indirectly
through the elaboration of the thyrotropic principle which
in turn -.'ctlvetes the thyroid. (Loeb and Hessett, Lee, Teel
enu Gagnon, Siebort and Smith, Gaebler and earlier work of
Uhlenhuth, Smith, and diddle. All quoted in Riddle et al
J36.)
The problem of the inter-relntIon3hips between the
.
24
various structures involved in thermogenic control by the
hypothalamic-hypophy3oal-thyroid system is apparently
admirably explained by the recent work of Uotila (*39b.)
Pituitary stalk section, followed by exposure to cold,
prevents the increased secretion of thyrotropic hormone
and thyroid hypertrophy ’;uich normally occurs in intact
animals upon exposure to cold. Prom this it soem3 clear,
in animals exposed to cold et least, that the hypothalamus
stimulates the secretion of thyrotropic hormone by impulses
transmitted through the nerve tracts running through the
pituitary stalk. The role of the stalk in this regulation
is thus more important that that that of the cervical sympf-thetios. Moreover, Uotila also considers the adrahals
in this regard. This investigator concludes that the anterior
pituitary appears to have a basic secretory rhythm which
Is independent of the stalk under normal conditions and is
largely under humeral influences. This upholds Hasmussen’s
M earlier contention. However, the hypothalamus and pituit­
ary stalk participate in the regulation of anterior pit­
uitary secretion in specific adjustments to certain environ­
mental situations such as temperature v a r iations, which
apparently impose some physiological stress upon the organ­
ism.
2. Thyroid
As early as 1895 M^nus-Levy (cuoted in MacLeod) rec­
ognized that clinical hypothyroidism was characterized by
25.
a lowering of the heat production (BUR)—
in some instances
as much as 4C$. This depression exists during the life of
the individual and is only mitigated by thyroid medication.
Numerous other researches since then have borne thi3 out.
In rats, adaptation to cold climates is accompanied by
evidence of the role of the thyroid in temperature regulation.
After a sojourn in the cold, the Bi'/IR of these animals is
markedly increased (Schwabe et al, *37 and *38.) A similar
observation has been made in fish by Gcherobokov {*57.)
The changes are attributed to the thyroid gland, activity
of which seems to be increased at low temperatures, (Woitkowitsch, f38) and which is more active in winter than in
summer (l3sekutz ot al, f37 and Alwall et al, *37 and *38.)
In evaluating experimental variations, seasonal changes
must, therefore, bo token into account (Mills and Ogle, ’38.)
Sarlior evidence of a seasonal variation in the thyroid
gland of cats was offered by Lowe (*30.) Ruff (T36) likewise
demonstrated a seasonal variation in thyroxin content in these
animals. Thyroid activity in frizzle fowls was also correl­
ated to environmental temperatures by Lrndauer and Davis {'54.)
3. Adrenal
1. Medulla
That the adrenal medulla is concerned in the process of
body heat regulation has already been indicated by the prev­
iously mentioned investigations of Cannon and his co-vjorker3.
Creaer (*28) likewise
entious the importance of the modulli-
adronal secretion in this regard. More recently, Griffith ot al
26.
{*40} have demonstrated that injections of odrenln into
chloralose anesthetized oats caused on increase in oxygen
consumption. Host of tho earlier physiological investigat­
ions in thi3 respect havo stressed the importance of
adrenln, so that it can no longer be questioned that this
hormone plays an important role in the endocrine thermo­
regulatory process.
2. Cortex
It is only within comparatively recent times that tho
function of the adrenal cortex has come to be understood.
Its importance in the salt and water economy of the normal
organism ha3 been indicated by the researches of Swingle {*33*37} end others. Still other vital functions ore attributed
to the cortical hormone, enumeration of v.-hioh, however, would
not lie within the province of this paper. It has been sug­
gested by the work of Cramer (*28), Borchardt {*28}, Hartman
et al {*31}, '?yman and Turn Suden (*?32) and others, that it
performs some function in tho xuaintenanoe of tho normal
thermal equilibrium.
The relation of the
drenal cortex to hoot production
has recently been studied by Horvath et al {*38.} It was found
that basal heat production was unchanged after unilateral
adrenalectomy; but, if these rats had been exposed to a temp­
erature of 4°C for a time, the heat production measured at
29°C was not altered as much as that of normal animals.
The unilaterally odronalectomizt d animal showed only a 7,f>
27
inorease in heat production as compared with 22/S in tho
normal controls.
Horvath (*38), moreover, deraonstrated that bilaterally
Gdrenaloctomized x’ata exhibited an actual decrease of 10yS
in Heat production under the oerae experimental conditions.
However, King's findings (*30) apparently refute such evid­
ence. lie found that removing part of tho adrenal cortex
doos not decrease the stimulating effect of cold. His con­
clusions Indicate that complete adrenalectomy depresses
many living processes, oxidation being only secondarily
affected, and that the adrenal cortex per se has nothing to
do with tho ''master" reaction for oxidation, at least at
the temperature studied. Such an hypothesis is similar to
the one expressed by Martin and Marosh (’33) somewhat earlier.
It is interesting to note, however, that Selye and Schwenlcer
(*38) have devised a bloassay for cortical hormone based on
the maintenance of lifo of adrenaloctomized rats exposed to
low temperatures.
The exact mechanism of the adronul cortical hormone
In thermo-regulation, is tnen, apparently still obscure.
That it is concerned, directly or indirectly in the process
can, hraever, be 3 rifely assumed.
To bo borne in mind, moreover, is tho lnter-relatiohship betv.'een the adrenal gland and the hypophysis. Although no
reference to a specific linkage with regard to thermo-reg­
ulation could be found in the literature, ample evidence
for physiological inter-function between the two endocrines
has been forthcoming in other respects.
28.
It io well-known that the cortex of the adrenal gland
undergoes a marked atrophy after hypophysectomy, whereas
the medulla Is effected scercely at all (Van Dyke, *39.)
Anterior pituitary extracts readily evoke an enlargement
of the adrenals of normal or hypophysoctonized animals,
chiefly by bringing about cortical hypertrophy, Thi3 has
been shown by Bierring (*35), Friedgood (f36) and Latyszewski (*37) who used rats, guinea pig3 and rabbits,
L'oon (*37) reported that in rats the cells of the glomerular
and fascicular zones underwent both hypertrophy and hyperplasia
after injection of anterior pituitary extract. Latyszewski
working on the guinea pig and rabbit,described the principal
effects as taking place in the fascicular zone. These consisted
of a loss of lipoids and a cellular hypertrophy affecting
both the cytoplus ■ and the nucleus.
On the other hand, Rei33 et al (*30) and f.oon found that
after hypophysectomy, tho outer part of tho fascicular zone
rapidly loses ita lipoids, which are specifically restored
by injections of pituitary extracts containing adrenal cort­
ical stimulating hormone. Davidson (*37) also produced a
marked hypertrophy of the adrenals as a result of anterior
pituitary injections into hypophysoctomised rats. Cortical
enlargement, he demonstrated, was due to cellular hyper­
trophy, not hyperplasia.
3. The effect of thermal environment on the morphology
of the endoorines
29
I, Thyroid
A. Season
A seasonal varlutlon in the activity of the thyroid
inland has been suggested by several previously mentioned
investigators. In addition, SpOttal (?29) has demonstrated
that thyroid weight is lowest in Juno, July and August and
greatei? in November, December and January. He considers
tho epithelial height as playing tho most significant role
here. The seasonal change is attributed to variations in
temperature and light.
On the other hand, Lowe (*30a) ha3 reported that
thyroids of yearling male sheep and wethers (castrated males)
were in the colloid condition (inhibited activity) from Oct­
ober to January, add actively secreting from May to August.
a sex difference is apparently exhibited hore,since the thyroids
of yearling females were actively secreting from October to
January. From May to August the glands of all lambs and year­
lings, both male and female, were in the colloid condition.
However, in glands of older animals (3 years
nd older) the
colloid condition was the rule and did not appear to respond
to sex or seasonal Influences.
In another study undertaken on cats (f30b), this in­
vestigator demonstrated that the sex difference was apparent
only in the period of October-Docoraber when the glands of
males contained far more colloid than those of females.
During the rest of the year seasonal changes affected both
sexes equally* Increased activity (resorption of colloid)
30.
tool: place In January and February with a fall in J-arch.
From Juno to August tho glands wore again actively socrotory.
Glands of pregnant females were more actively secreting
than those of non-pregnant females but vnritid in accord­
ance with tho seasonal variations recorded for normal males
and females.
IlcCarrlson ('30) has reported on a series of rats 20150 days old brod in Coonoor, Jouth India, where the temp­
erature is very high during most of the year. The thyroids
of 107 albino rats reared there exhibited an average weight
50^ below the figures obtained from animals of similar age
and condition raised in the United States. This geographical
variation^ can no doubt^ be referred back to the extreme
differences in environmental temperature.
Kenyon (T33) has also noted a seasonal variation in
the thyroids of rats* This is likewise ’•ttributed to temp.rature differences.
Lore recently, A'atzka (*36) has d monetrnted In the pig,
squirrel,sparrow and goose that severe cold causes tho colloid
to di3eppear. The epithelial cells show signs of hypertrophy
and reversed polarity, ",'ith warm weather colloid is again re­
stored.
Lieber*s studies (*36) on the cold blooded teleost also
indicated histological evidence of seasonal changes as re­
flected in the condition of the epithelial elements and
colloid. In this form, however, during the cold months from
October to March, thyroid activity is decreased. The animals
31.
at these times are in their winter rest period. In April
the thyroid increases in functional activity, here the fish
are again taking food. In June activity drops again despite
intake of food. This, according to Lieber, is related to
reproductive aotivity since at this time the fiah contain
ripe eggs =nd sperm. There is no sex difference in this spoc-i-es.
decently, filler (f39) has reported on seasonal variat­
ions of tho thyroid of the sparrow. Thyroids of birds coll­
ected during the winter months when tho metabolic rate is
elevated, present a histologic 1 picture indicn-cing height­
ened activity,i.e. epithelial cell height increased, nuclei
a-pe. largo and round with prominent nucleoli, and some eoilolu
resorption. Summer birdsT thyroids (low metabolic rate) had
low cuboidel epithelium and no apparent colloid resorption.
This investigator, moreover, indicates that sexual aotivity
has no effect on the histology of the gland. iSxperimental
exposures to low temperatures cause stimulation of the thy­
roid concomitant with a rise in metabolic rate. A similar
response in rats exposed to low temperatures has been re­
ported by several workers. See Bnilliff (f37) for review.
Seasonal variations in the bird thyroid have also
been considered by several other investigators viz:
diddle and Fisher, *25 (pigeon), Haocker, *26 (crow and
sparrow), and Ktiohler, *35 (robin, field sparrow and house
sparrow ). There is some divergence of opinion but on tho
whole, it is agreed that greatest activity is seen iri tho
32
winter thyroid, as indicated by small follicles, high epithiura and los3 of colloid.
DogtLotti and Huti l*o5) have shown that there is a
decrease in amount of colloid and an hypertrophy of the
apitn H u m with increasing age in man* This is regarded as
Indicative of increased activity to.offset the normal senilo
decline in metabolism. However, Coudry (*36) illustrates
the thyroid of a woman aged 111 years which appears to be
normal in histological appearance.
D. Experimentally altered environmental temperatures
The deraonstrat ion of the participation of the thyroid
in heat regulation of necessity demands the utilisation of a
means of modifying the gland*3 morphology by easily manipulated
experimental conditions that can safely be ragardad as demand­
ing ougraanted or inhibited secretion. ISxternnlly applied heat
or cold ore effective in this respect.
In a serie3 of articles beginning in 1916 and ending in
1928, Cramer and Ludford recorded the following observations
in rats and mice exposed to cold; increased vascularity of the
thyroid -land, cellular hypertrophy with enl rgement of mito­
chondria and Golgi apparatus, altered staining properties
of the intrn-alveoler colloid, followed by a diminution in its
amount, and, eventually, necrobiosis of the glandular epith­
elium. This was interpreted as indicative of increased secretory
activity of the gland induced by an added metabolic strain.
Conversely, at warm temperatures, the colloid increased in am­
ount and the epithelial cell3 became flattened.
33
In Cromerfa reports, however, experimental details are
given rather sketchily so that it is often difficult to ob­
tain an exact picture of the thermal environment and of tho
degree of histological change. Ho attempt was made
to determine a quantitative index of thyroid function.
Uills (*18) is more exact in his experimental data,
fhis investigator reported an increase in epithelial cell
height, vacuolization of colloid and a decline in its amount
in 16 rabbits and 4 guinea pigs exposed in a cold room or
outdoors at -5° to plu3 10°C for from 3 to 30 days. In 28
rabbits, 2 cats and 3 guinea pig3 exposed in a well ventil­
ated hot box ot 27 to 37°C, all but 4 animals showed a de­
crease in thyroid cell height and an increase in amount of
non-vacuolated colloid.
Hart (*22) reported findings in the grey house mouse
subjected to exposures of 32-40°C and exposures of 4-7°C
for periods not stated. At the high temporature,epithelial
cells were ouboidnl, colloid was reduced in amount and the
follicles wore empty ;nd folded. At low temperatures,cells
wore cuboidal and colloid was abundant. These results differ
from others with respect to col.Loid content. Ho ttempt was
mad i to explain the diocre* ancy.
Hergefeld (*30) demonstroted that tho thyroid of male
ana female rats kept in a dark and cold cellar at about
0° 0
for 4-6 weeks, exhibited cellular hypertrophy and colloid loss,
while those kept in a cellar illuminated by day-li*ht were
34.
normal, kmong animals living for 0 weeks in thermostats at
29°C, 3 kopt in darkness exhibited hypertrophy of celliilsr
epithelium, while three kept in the light showed no suoh
affect. This investigator concludes, in view of these find­
ings, that darkening nets without reference to temperature
to cause changes that indicate an increased function and
that temperature alone is without influence. Those findings,
therefore, introduce another factor which may play a pnrt
in the function of the thyroid glar.u, namely ultra-violet
light.
Confirmation of this view was offered by Hosenkranz
(*31) in rabbits and Turner ('30; in chickens and Turner and
Benedict (*32) also in chickens.
Bergefeld (f31) later adduced better substantiating evid­
ence tfcat the thyroids deprived of ultra-violet light for
21-63 d-ys were hypertrophied and poor in colloid (in rats.)
However, neither Qergefeld nor Turner and his co-worker
could detect any rise in basal metabolism of tne animals de­
prived of ultra-violet light, so that the reason for the
hypertrophy remains obscure.
In seeming direct refutation of the
bovo findings
concerning tho import Mice of ultra-violet light, were the
results obtained by Kenyon ('33.) It was found,in tho albino
rat, that darkness alone, within a period of 25 days, does
not produce striking hyper trophy and colloid loss. This fuct
is emphasized by Kenyon to shov that the effects of cold
cannot be attributed to the exclusion of light.
He demonstrates, further, in a series of 72 rats ex-
posed to temperatures of 0-4°C for 10-25 days that there
woe no drop in rental temperature, a grin in gross weight
of the entire thyroid gland over the normal figure, hyper­
trophy of tho epithelial cells, loss of colloid and increas­
ed vascularity. Further, on increased number of mitotic fig­
ures were noted. Cellular hypertrophy nnd colloid loss were
most extreme in the centra] portions of the gland whereas
the peripheral alveoli were not so profoundly affected.
Desquamation of epithelial colls, as described by Cramer,
w"s not noted.
Furthermore, age, 3ex and stage of estrus cycle had
no apparent influence on tho structure of tho gland.
In general, it appears then, that the earlier con­
tentions of Cramer and hills are largely borne out by
Kenyon’s work, at least under conditions in which the metabol­
ism of tlic animal is greatly heightened (exposure to cold.)
According to Benedict and I'acLeod (*29) such conditions
cause a rise of approximately 150/i in the HIiH of the albino
rot. Unfortunately, Kenyon did not extend his observations
to a converse situation, i.o. an inhibition of the gland by
application of heat.
Duch an investigation was undertaken later by Bailliff
(’37.)
Ho likewise demonstrated that the thyroids of rats
exposed to temperatures of -4°C for periods of n few hours
to 8 days, showed a murked loos of colloid, reduction of
folliole size, increased epithelial cell height and an in­
creased interfollicular vascularity. These changes occurred
36
ohiofly In tho central portions of the gland,whereas the
peripheral ports apparently showed no response to the cold
stimulus; in these respects the work of Kenyon is confirmed.
In apparent confirmation of framer's findings and in
refutation of those of Kenyon, however, Bailliff believes
that if the stimulus for secretion is severe or long con­
tinued, desquamation of border cells may occur, in this
manner destroying portions of the follicular walls. This
point is of certain significance in the light of Br.illiff's
further findings with respect to tho function of the socnlled interfollioulor cells. These, he believes, become
transformed into new alveoli almost as soon as exposure to
cold begins, /echal (*32 and '33) believes these groups of
colls are embryonic rests. Nonidez ('32a and *32b) has also
described these elements in the inbrfollicular spaces.
In rata kept in a constant temperature cabinet at
34-3800 Bailliff reports a marked respiratory embarrassment
and n 3tate of flaccid suoclc. The rnt is apparently able
to withstand heat for relatively short periods of time.
Thyroids of such animals exhibit a marked accumulation of
follicular colloid which distends the follicle, thereby
stretching the epithelial cells into a low cuboidal form.
L'oreovor, secretory precursors (mitochondria, Golgi app­
aratus) almost disappear from tho cell cytoplasm. The morph­
ology of the intorfollicular cell is not greatly altered
by exposure to heat. These elements retain their large size,
light nucleus and highly vacuolated cytoplasm.
37
decently, Schmidt and Jchmidt (*38) hove dernonstrated
flattened epithelium and retracted colloid In the thyroids
of guinea pigs exposed to temperatures of 3£OC; however,
after 0 weeks of oxposure the morphology reverted to normal
in some animals. This muy indicate a process of acclimatizat­
ion. Horeovor, thyroxin treatments caused a flattened epith­
elium, distension of the alveoli with colloid and patent
capillaries,Indicative of inhibition of function.
harlior evidence on heat depression was offered by
Fischborn (*35) who demonstrated that follicular volume in
such thyroids was far greater than normal. Such follicles
contain u hom^ogeneous, highly staining colloid which is
characteristically free from cither central or marginal
vacuoles.
Periodic applications of high frequency radio fever
were administered to n series of 0 rabbits by Jorns (T32.)
It was found that basal metabolism was retarded to the came
extent as that following surgical thyroid removal. Histolog­
ical examination of the gland revealed general hyperemia,
decreasod colloid and no effect on the epithelial cell3. There
was no ovluence of cell injury, such as tissue necrosis or
v-ssel changes.
In general, then, it may be said that exposure to cold
instigates increased activity on the port of the thyroid which
is reflected morphologically by a heightened cellular epith­
elium, resorption of intra-ulveolar colloid and an increased
38
vnucularity. Conversely, exposure to high temperatures
inhibits thyroid ictivlty which is indicated, along with
other changes, by a lower epithe;liaL cell height and
intre-alveolar accumulation of colloid.
2. adrenal cortex
A. Season
The histological appearance of the adrenal cortical
lipoids has received the special attention of rteis3 (f36)
and of iuoon 1*37.) In normal rats there exists a narrow
bcna
of tissue between tho fasciculate and tho glomerulosa,
(also shown by Bernstein ,'40} which histologic"lly appears
to contain little or no lipoid. Deposition of lipoids in
the cells of this zone is one of the earliest signs of a
cortical stimulating effect (libon.) This has also been shown
by B’lexner and Grollman (*39.)
There is apparently no reference made in the/ cogent / *, j
o
V
•
literature to a direct effect of season on the morphology
-
'V
' v
1
t
of thd adrenal cortex, dalesky (*34), however, demonstrates
V v '.n £.1
that adrenal cortical weight Is a function of the sexual
cycle in the 13 lined ground squirrel (Gitellus Trideeomllne^tus), which in turn is dependent upon the season of the
year. This investigator reports that, in the spring,(which
coincides with the onset of breeding activity) the cortex
becomes hyporemic while
the zonn reticularis widens and
differentiates into 2 sub-zones both having relatively low
lipoid content. Those two factors account in part, for the
increase in the volume of the cortex.
v
r-
39.
Further ovidence for e gon«d-adronal cortical relat­
ionship h:-s bean demonstrated by Kolmar (*12) in the guinea
pig, Tamura (*26), Vesui end Tcmura (*26) and iloward-killer
(*27) in the mouse. G-aunt and Parkins (*33) as well as others
have also demonstr.: ted a linkage in this connection. The
recent work of Beall ana tteichntein (*G8), moreover, indicates
that the ossontinl principles elaborated in the gonads and the
adrenal cortex have a striking chemical similarity.
Variations in the amount of cortical lipoid with resp­
ect to sex and age have been indicated by V/hitehead (*33) in
the mouse, in the guinea pig (*34), and in the rabbit (*36.)
The cortex of tho adult fomalc possesses a slighter but
"7
demonstrably greater amount of lipoid.
^ilthough casual references to the presence of cortical
lipoia
in the rat adrenrl have boen made, no attempt to det­
ermine Quantitatively the normal vari? t '
of this substance
an i to correlate this figure v/lth age, sex and season, has
apparently been undo.
Uoiinidt and Sohiaidt (*38), however, report, in adrenals
of normal guinea pigs kept Ft 20°C,that the lipoid cont -i riing
portion of the fascicular zone occ .pied the ’'outer ono~half
or more" of the cortex. Although gencr lly similar, the lip­
oid containing zone was more variable in size in females.
vVhiteher.d (*34) cites the figure .8-.9 for the ratio
between lipoid and lipoid-free zones in this species. This
is the normal maximum extent of lipoid at 14 days of age;
thereafter, there is e progressive fall in amount, so that
40
at 168 days of
ge the figure Is .4-.6.
Morphological variations in human adrenal cortices
have been noted by hwemor (*14G J but these variations have
not been correlated with differences v?44rh soason or thermal
environment.
Deanesly (*31) has shown that in mice, the outer iiono
of tho cortex (comparatively rich in deeply staining fats
and lipoids) occupies more than half of the depth of tho
cortex, although tho extent and density may vary. In this
work, also, no explanation of the variations is offered.
None has, however, attempted to study such a variation
in tho albino rat with reference to season, although an
indication of its existence has been suggested by Hoskins
and Bernstein (*39.)
B. Experimentally altered environmental temperatures
There r.re fro mont references to experimental enlarge­
ment or hypertrophy of the
drenal cortex in the literature,
some of which appear to be based on inadequate data. See
Jaffa {* 27.)
Cramer (*28) believes that high ten- cratures Induce,
among other changes, a more oxtonsivo deposition of cortical
lipoid In the adrenal of the mouse.
Deanesly (*31) has indicated that injoctiorxG of dead
Goortner's bacillus, morphine ^estate, and thyroxin cause an
enlargement of the cortex which sho\v3 either a decrease or
increase in its stainoblo fat. Cortical enlargement is always
41
initiated by an increase in size of the cortical cells
followed by thoir mitotic division. Administration of
thyroxin usually csukoo n disappearance of lipoid first
from the zona "asoiculnta with a tendency to accumulate in
the zonn reticularis. do ad JJ.Gaertnar suspension cruses a
dis-pperrn.nes of lipoid and a marked congestion of blood
capillaries and sinusoids, Tho medullary cells are apparently
not ;ffocted. Continued mile doses of bacilli or thyroxin,
however, cruse cortical onu rgament with an inoraase in
fats and linoids in proportion to the size, instead of
diminution. This v;as M.I3 0 observed by dwemer (*36.) After
toxic injections r.re discontinued, bonneoly aiiovroii that the
adrenals gradually revert to norm;.l size and histological
opp-j ranee.
adrenal cortical enlargement at ordinary temperatures
induced by thyroxin injection has been noted earlier by t-R.
Hoskins (*1G), Hewitt {*18), Herring (*30) and .Jquier and
Grebfield (*22.)
ochmidt and hchmidt {*50) have demonstrated in guinea
pigs, that in both males and fern* las kept at 32oC for 2-4
weeks, the lipoid containing zone was narrowed, occupying
not more than the "outer third" of the cortox. hfter 6 weeks
at this temperature some glfinds were still like those at
4 weeks, vihereas others had reverted to the control condition.
No effects were noted in the medulla.
Flexner and Grollman (f39), utilizing a nev/ technical
method (reduction of osmlc acid) to demonstrate the presence
of lipoid have shov/n that heat, cold and drugs stimulate
adronnl cortical activity in rats. Short exposures to
mild cold (10°G) caused an increased reduction of osmic
acid. This indicated tho presence of more lipoid, particul­
arly in tho peripheral, clear, fascicular and reticular
zonos. 7/ith longer exp°suro3
to cold there was a marked loss
A
of reducing substance, only the peripheral zone retaining
lipoid.Short exposures to heat (37-38°G) caused an increase
in reducing substances in all zones, with a most marked effect
in tiis peripheral and clear zone3. Upon longer exposures,
however, there is a complete loss of lijjoid from ;11 portions
of the cortex except the peripheral and inner fascicular ..ones.
These investigators, moreover, demonstrated that, in the
guinea pig, injecti ms of thyrotropic hormone Increased the
amount of reducing sub3 t nees in the cortex. This apparently
bears out previous findings, Iftnery and ktwell (*33.)
However, the results of Dalton ot al (*40) indicate that
the 'drenol cortex is richest in lipoids when it is ut rest
or inhibited, and poorest when it is most active.
It is Cramer’s contention, on the other hand, that an
active adrenal cortex ia characterized m o r p h o lo g ic a lly by a
congestion of the sinusoids of the sons reticularis, but more
striking is the ohange in distribution of tile cortical lip­
oids, It ha3 been demonstrated that tho cortical lix>oid app­
ears to bo swept from the periphery o f the c o r t e x toward tho
center (i.o.
towards the medulla). Under these conditions,
there ere fo u n d large g lo b u lo 3 of l i p o i d in the zon a ret-
43.
ioulari3, which in the normal resting gland is free from
lipoid. However, that this is not so in tho rat in every
ease has been demonstrated by Hoskins and Bernstein ('39.)
Confirmation of Cr-:mor♦s^v/ith respect to the effect
of heightened environmental ti-mperatura on the spread of
coriiical lipoid has been offered
(Bernstein, *30 and *40.)
Continued, mill elevations of body temperature induced an
increased deposit of sudanophil substance whereas single
lethGl doses had no apparent effect.
In genor'-l, it can be said that continued, mild exp­
osures to cir-nges in the thermal environment cause nu in­
crease.! deposit of cortical lipoid; v-neroas, profound,
prolon ged ch'iiges oonversloy, a use a loss, (exhaustion)
tixIrenes of temperature stimulate activity of the adrenal
cortex and this is shov/n by (1) a hypertrophy of the ''lend
following sub lection of an ■nimal to these conditions; (2)
the additional cortical hormone required to maintain animals
following edrsmaloc tomy and {3) the short survival period of
adren Ineternized animals ruintnined at abnormal temperatures
(Grollraan,*36.) A possible species difference with respect
to cortical lipoid is suggested by Gersh. and Grollman (*39}
In this regard.
k
44.
MATERIALS AMD METHODS
Over a period of two years, during which time this study
was in progress, a total of 270 animals was employed. These
were albino rats, 60 days of age (sexually immature} except
where otherwise noted, and of mixed sex. The majority were from
the same colony (Carworth Farms) while a small group of exper­
imental animals came from another colony (Rockland Farms.)
Only rats in apparent good health were utilized. Upon
coming into the laboratory, all animals were segregated acc­
ording to sex and placed in cages to which adequate light and
air had access. A short period (3-6 days) of acclimatization
to the new laboratory conditions then ensued during which
period the animals were adequately supplied with Purina chow
(standard iodine content) and water.
In all, 150 animals v/ere utilized as a basic control
series, while 120 were divided into groups for various ex­
perimental thermal procedures.
iinviromnental temperatures were recorded by means of a
recording thermograph and, in those experiments which altered
body temperature, rectal temperatures were obtained by raeqns
of a clinical thermometer.
During all seasonal tests as well os experimental proced­
ures the animals had free access to food and water.
At the end of the test period, the animals were killed
by ether anesthesia, and the left adrenal was immediately
removed and fixed in a 10# formol solution; the right adrenal,
gonad, thyroid, thymus and 3pleen v/ere then removed and fixed
45.
in "Susa*—
Haidcnhain's modification. Particular care was
exercised in handling the adrenals, to avoid the effect of
bruising them with forceps; and in the case of the thyroids,
the trachea, esophagus and surrounding muscles at the level
of the gland were dissected out and fixed as one piece so
that the thyroid should not be damaged.
Formol fixed adrenals were sectioned in the longitud­
inal plane by means of the freezing microtome at 10u, and
sections which passed approximately through the center of
the gland were stained with Sudan III (specific for fats and
lip>oids) and counterstained with Harris* hematoxylin.
Susa fixed thyroids were prepared by routine paraffin
methods, sectioned serially at lOu, and stained with triosin
(Galigher) and Harris* hematoxylin.
Paper reconstructions of several sections of each ad­
renal were made by means of micro-projection at uniform en­
largements. In order to determine the extent of the corticnl
lipoid, the boundaries of the projected sections on the paper
were outlined and cut out, and the different portions were
weighed on a chemical balance. The weight ratio. lipoid laden cortex
whole cortex
was thus determined, and an index for cortical lipoid, here­
inafter referred to as the adrenal Index, obtained. Since the
weights vary directly with the areas of the drawings of the fig­
ures, the figure so obtained may also be considered the area
ratio, iidrenal index, however, does not take into account
lipdid density and the best means for detecting differences
46
.
in this factor is to compare sections directly under the
microscope. In adrenals of normal rats, stained with uniform
procedures, however, the differences in lipoid density in tho
lipoid laden portion of the cortex are very slight.
The above outlined method is a modification of the means
employed by Deanesly to determine adrenal cortical and medullary
volume. Whitehead also utilized such means for a study of the
area occupied by cortical lipoid. Hammer, {*14) furthermore,
contends that weighed paper reconstructions of endocrines are
a reliable means for determining their volume. In the present
paper the term lipoid with respect to the adrenal cortex is
restricted to the substances stainable by the histological
method used (Sudan III. }
Similar procedures were followed in obtaining figures
for the thyroid gland. Sections passing through the approximate
center of the gland were projected and a minimum of 14 alveoli
were outlined. Alveoli which appeared abnormal or which were
peripherally located were disregarded, T.7eigilts were obtained of
cut-outs of the epithelial cell lining as well as the entire
alveolus. The weight ratio, epithelial cell height
whole alveolus
thus
obtained offers an epithelial cell height index, hereinafter
referred to as the thyroid index. hithough references in the
literature to such a method are few, it is felt that it affords
a more or less accurate mean,3 for determining the index of act­
ivity of the thyroid.
The method outlined above is quite laborious and timeconsuming, to be Bure. However, it is believed that such means
are quite justified inasmuch as they afford a relatively
47.
quantitative means for measuring morphological criteria of
activity and, further, almost entirely eliminate the person­
al element iir evaluating histological details.
Animal groupings
1. Normal series (N)
In order to ascertain the effects of season on the thy­
roid and adrenal cortioal glands, the series of normal control
animals was divided into six groups, each of which was autopsiad
in a different month of the year.(See Table 1.) All of these
groups were maintained under normal laboratory conditions for a
10 day period, during which time laboratory temperatures were
recorded on a thermograph. At the end of the period the animals
were autopsled and the glands removed.
2. Experimental series (E)
To determine the effects oi a x uered thermal environment
on the two glandular components, the experimental series was
divided into seven groups, each of which was subjected to a
specific change in environmental temperature.(See Table 2.)
Temperatures in each case were recorded on the thermograph.
TABLE 1
Normal series (N)
GROUP
N 1
N 2
ANIMALS
MONTH
January, '39
March
AVERAGE LABORATORY TEMP.
(10 days proceeding
autopsy)
23 males
24 females
65° F (constant)
25 males
(90 days of age)
65° F (rising)*
N 3
May
19 males
65° F (rising)**
N 4
June
19 malos
(90 days of .
’-go)
70° F (falling)***
12 males
12 females
65° F (constant)
N 5
N 6
November
3 males
2 females
(Rockland Farms)
(60-90 days of ago)
January, *40
65° F (constant)
3 males
4 females
(Carworth Farms)
(90 days of age)
* From 36° to 49° F mean outdoor temperature
*
"
52° to 61° F
*
"
75° to 68° F
"
"
"
”
"
( Temperature (outdoor) data obtained from U.:5. .'.'oatiior Bureau)
49.
TABLE 2
Experimental series (E)
JROUP
.ANIMALS
EXPTAL. PROCEDURE
BODY TEMP.
Experimental heat
E 1*
8 males
8 females
Intermittent doses of
ultra-high frequency
artificial fever (10
minutes per day for 10
successive days)
102° F at each
exposure
Normal at autop
sy**
E 2
5 males
5 females
Intermittent exposures
to ventilated,thermoregulated oven (107.6°?)
(same prooedure as in
S 1 for a comparison
between radio and oven
fever)
102° F at each
exposure
Prolonged oven fever
(oven at 91.4°? for
10 days)
Continuous
103°?
E 3
5 males
5 females
Normal at
autopsy***
Normal at
autopsy****
Experimental cold
E 4
5 males
5 females
Prolonged mild cold
(53°? for 10 days)
near open window
Normal at
autopsy
E 5
13 males
2 females
Extreme cold
(23.5°F for 2 days)
in sheltered box
on roof
Normal at
autopsy
E 6
13 males
2 females
Prolonged extreme cold
(32°F for 5 days)
in ahitered outside
window box
Normal at
autopsy
E 7
13 males
2 females
Extreme cold
(32°F for 3 days)
and back to laboratory
warmth (70°F for 2 days)
Normal at
autopsy
50
*
In this group (E 1) 5 males and 5 females were also
subjected to lethal doses of ultra-high froquency radio
fever (body temperature over 107° F) and 5 mules and
5 females were used as laboratory controls. This phase
of the experiment has already been reported, Bernstein,
(’40.)
** Rectal temperature returned to normal 90 minutes after
last exposure.(E 1)
*** Rectal temperature returned to normal 20 minutes after
last exposure. (E 2)
**** Rectal temperature returned to normal GO minutes after
last exposure, i.e. after being removed from oven on tenth
day. (3 3)
51
OBSERVATIONS
X. Gross observations
1.
Normal (N) series
The IJ series animals apparently led a normal existence dur­
ing the laboratory teats. There were no untoward occurrences in
any of the groups. All animals exhibited a normal weight gain.
The viscerafupon examination at autopsy, appeared quite normal
except for the appearance, in two animals, of small, rather welloircurascribed, greyish-white cysts in the liver. These were, in all
probability, parasitic liver flukes. There were no marked variations
in body temperature among the different groups.
S. Experimental (E) series
1.
E 1 (intermittent radio fever)
Experimental heat
Cyanosis, respiratory distress,
oral salivation, dehydration and loss of weight
were apparent in this group. (Other details have
been reported elsewhere.)
E 2 (intermittent oven fever)
At the end of the ton minute
exposure period the animals were more or less
quiescent and breathing rapidly. Cyanosis and
respiratory distress, howover, were not app­
arent. Oral salivation and tissue dehydration
likewise were absent. In these respects this
group differs from E 1. Upon being placed into
the oven, the body temperature of the animals
rose rapidly so that at the end of the exposure
period the average recLai temperature for the
group was 102°
subsidence to normal here
52
took plaoe in 20 minutes compared, to 90
minutes for the high frequency treated group.
(See fig* 1*) At autopsy, a slight amount of hyper­
emia was noticeable in the viscera. Weight
gain was normal.(See fig. 2*)
E 3 (prolonged oven fever)
At the end of two hours in the
oven, some of the animals began to exhibit
signs of acute distress. All were lethargic
while sorne appeared moribund. Oral salivation
was very evident. The rats made no effort to
take food. During the first night of exposure,
two animals died. The condition of the others
become progressively more distressed and dur­
ing the night of the 7th day of exposure, another
animal died. The remainder by this time appeared
to be in a state of flaccid shock and were
stretched out on the floor of the cage. However,
they survived until the end of the tenth day of
exposure when they were autopsied. The body
temperature during the experiment averaged about
103° F with only a slight degree of fluctuation.
Subsidence of body temperature took plaoe in
60 minutes after removal from the oven,(fig. 1.)
Such a procedure was adopted to obviate any
"short time” effects. The gain in body weight
was far below normal during the exposure period,
(fig.2.)A marked hyperemia and congestion were
obvloua in tlie viscera.
53 ♦
3* Experimental cold
E 4 (prolonged mild cold)
Upon being placed near
the open window, the animals became very
active. During the night when the temper­
ature fell they tended to huddle together.
No shivering was apparent. During the early
part of the exposure period, several were
sniffling and sneezing but this eventually
of
passed av/ay, so that ^autopsy none exhibited
respiratory discomfort, Body temper -tures
were normal,as was weight gain. No untoward
manifestations were evident at autopsy.
E 5 (extreme cold)
Like those in 2 4, those animals
upon being placed in the cold, became very
active and later tended to huddle together,
m i d shivering was apparent in some of the
animals. The coats in all cases were shaggy.
Body temperature was approximately normal
and the animals exhibited a normal weight
gain. At autopsy the adrenals, which norm­
ally appear dark tan in color, were dull red
and markedly enlarged. The roar extremities
in some animals were slightly edematous and
cyanotic. During the first night of exposure
(lowest temperature recorded 34°F) 2 animals
expired.
H 6 (prolonged extreme cold)
Essentially the same cond­
itions apply here as for E 5. During the
54.
first night of exposure when the recorded
temperature fell as low as 10° F , three
animals died. Weight gain in this group
was not normal,(fig. 2.)Edema and cyanosis
were more marked.
j!
»7
(cold to warm)
Similar conditions were likewise
observed in this group upon exposure to
cold. However, after a short stay in the
laboratory after being token in from the
cold, edema and cyanosis disappeared,
ikt autopsy no naked eye abnormality could
be discerned in the adrenals. Two animals
died during the first night of exposure
when the temper -ture dripped to 22° F»
2. Histological observations
1. Thyroid
The normal thyroid glend consists of numerous follicles
or elveoli which are bounded by a simple epithelial layer of
cells. These alveoli are generally rounded, but sometimes arc
elongated, and occasionally may communicate with one another.
The lining cellB are cuboidal or low columnar. They do not rost
upon a conspicuous basement membrane but rather aeem to be
placed upon fine strands of v/hat appear to be reticular fibers,
which mnke up the 3troma of the gland. The alveoli vary in size,
being larger at the periphery of the gland than in the central
portions.
Situated between the alveoli are fine collections of fibers
and small capillaries, some of which contain erythrocytes; small
patent vessels with no contained cellular elements are also
present. These may be lymphatics. Small and large lymphocytes
as well as polymorphonuclear leucocytes are
also seen. It is
difficult to discern nerve fibers with routine staining procedures.
In the interfolllcular spaces are clumps oi relatively large
eosinophilic cells with rather dense hyperchromatic nuclei.
These calls ore irregularly arranged with no indication of a
lumen. It is probable that these elements represent the "Interfollicular" colls Mentioned by previous investigators.
7'ithin the follicles, constituting perhaps the most
characteristic histological feature of the gland, 13 a homogeneous,
hyaline, nccllular material which stains intensely v;lth triosln
(acidophilic stain.) This is the tayroid colloid. In most Instances
it does not fill the follicle completely and mry appear to have
retracted slightly from the lining epithelial colls; in other
instances, small and large clear vacuoles appear to separate it
from tho epithelial colls. These are generally thought to be
fixation artifacts (i'aximow.) Occasionally, detached epithelial
colls and what appear to be leucocytes may appear in tho colloid.
Around the periphery of the gland is a connective tissue
capsule composed primorily of eosinophilic collagenous fibers,
in the interstices of vvhioh may bo discornod fibroblasts, leuco­
cytes and lymphocytes. The capsule sends occasional fine trab­
eculae into the substance of the gland end is continuous with
the cervical fascia through a lryer of loose connective tissue.
56.
X. Normal (N) sories (fig. 8)
Generally speaking, the description outlined above coincides
with the picture presented by the thyroids of all the groups of
animals in the N series. Only under high magnification could
slight but significant differences be discerned. The epithelial
cells in groups N 3,4 and 5 (3umner) were of the cuboidal type;
whereas in groups M 1,2 and 6 (winter) the cells were distinct­
ly of tho columnar variety. Extensive retraction of colloid from
the epithelial cells could not be clearly discerned although
peripheral colloid vacuoles were almost universal. These wore
most conspicuous in the peripheral alveoli. Groups N 1 and 6
exhibited the greatest number of vacuoles which wore, in these
instances, of considerable size. In groups H ;■> and 4 colloid re­
traction was reduced to a minimum giving the alveolus a plump,
well-filled appearance. In only a few casos could desquamated
epithelial cells be seen in the alveoli (N 2.)
There was no marked variation in tho vascularity of the
gland although there was an indication of a slight increase in
groups N 1 and 6. Similarly, there was no apparent variation
in tho distribution of the interfollicular cells.
2. Experimental (E) series (fig. 8)
1.
Effect of heat
Although there were minor differences, in th3 main the
histological picture here was the same in each of the various
heat treated groups, i*e. (2 1,2,3.)
In group E 1 (intermittent radio fever) however, the
nuclei of the low cuboidal lining epithelial cells have lost
their normal regularity; a great number of them are no longer
57
round
or
spherical tmt appear to be flattened slightly. Cell
boundaries are more or less indistinct. This, however, is not
a universal condition. .Although .eripheral vacuoles are present
in the deeply eosinophilic colloid, there is no noticeable
retraction of the latter. Tho intorfollicular capillaries are
markedly congested with erythrocytes. A similar condition was
coincidentally noted in tho sinusoids of the embedded para­
thyroid gland. Intorfollicular cells v/ere present.
The glands of the animals of group £ 2 (intermittent oven
fever), exhibited essentially the same morxdiological features
except for a slightly less marked hyperemia.
i'ho gland3 of animals of group 1 3 (prolonged oven fever)
ejcnlbite
considerable variation from the normal condition.
Here theepithelial cells wore definitely
flattened and the
alveoli markedly distended with deeply eosinophilic colloid.
Peripheral colloid vacuoles were not apparent in some of the
alveoli but in those of other animals in the group, vacuolization
is very marked.
2. affect of cold
Changes in the thyroids of groups ii4,5 and 6 were aruong
the most striking to be observed. In group £ 4 the epithelial
cells has assumed a low columnar form and their coll boundaries
were ruito distinct. The nuclei wore hyperchromatic end largo.
The alveoli v/ere more irregularly shaped and somewhat smeller
in si.:o than in the normal condition. There was marked peripheral
vacuolization. No retraction of colloid was evident, however.
Group g 5 thyroids exhibited a low columnar epithelial
58
lining around the alveoli, which were very irregular in shape
and smaller in size. There v/aa no marked vacuolization but
some of the central alveoli presented evidence of colloid
resorption.
Group t£ 6 thyroids demonstrated a definite columnar
epithelium with a marked irregularity in alveolar shape and
size (especially the central alveoli.) evidence of colloid
resorption and vacuolization was common. Interfollicular vas­
cularity was apparently increased.
In all of the groups exposed to cold, the eosinophilic
ixitensity of the colloid was noticeably diminished.
Group d 7 thyroids (cold to warm) however, presented for
examination a more or less normal cuboidal epithelial lining
with slig itly larger and more regularly shaped alveoli.
In both the heated and cooled animals interfollicular cells
were present, and no striking difference in distribution could
be noted among the various groups. Occasional desrmamated cells
ana leucocytes could also be discerned in the intra-alveolar
colloid of some of the acini.
It becomes obvious at once that the great variation
in e; ithelial cell height and various other subjective factors,
make it necessary to resort to reconstructions if a quantitative
index of thyroid activity ia to be determined.
Calculated thyroid index (epithelial cell height) figures
for both normal (N) and experimental (E) series are listed in
Table 3. The average fi ;uro for each group Is given a3 well as
the range in each particular group. The results are graphically
represented in figures 3 and 4, respectively.
59
TABLE 3
THYROID INDEX (fa)
GROUP
AVERAGE
RANGE
*50.6
57.0-41.0
N series
N 1
(Jan. *39)
N 2
(March)
47.0
52.0-43.6
N 3
(May)
44.6
55.0-38.2
N 4
(Juno)
42.0
50.0-34.0
N 5
(Nov.)
**46.6
53.0-42.0
K 6
(Jan. *40)
52.4
58.0-49.0
E series
E1
(radio fever)
38.5
44.0-31.0
4 2
(oven fever)
38.1
44.0-34.0
E 3
(prol. oven fever)
42.3
45.0-41.0
a4
(mild cold)
53.0
57.0-51.2
a 5
(extreme cold)
56.1
GO.0-51.0
2 6
(prol. ext. cold)
60.7
66.0-56.0
a 7
(cold then warm)
52.4
58.0-49.0
;*Dividing H 1 and 5 according
N 1
males
females
50.6
50.6
57.0-41.0
55.0-42.0
K 5
males
females
47.0
47.5
53.0-43.0
50.0-42.0
.
60
It is apparent, thus, that no significant sex difference
is manifest with regard to thyroid index, at least at this age
(60 days.) This fact, then, demonstrates that the figures obtained
for either one of the sexes may safely be indicative of tho
condition in the other. The results are represented graphically
in figure 5.
2. Adrenal
1. Medulla
No marked variations could be discerned in the histological
structure of the medulla in either the normal (II) or the experi­
mental (E) series. It is composed of blue staining groups of cells
usually arranged in an acinar fashion around a lumen. However, there
was aw apparent normal variation in each of the groups in each
sorios with respect to tho diameter of the medullary blood vessels.
This was net consistent in the normal groups and could not be
correlated with season or sex. Extremes of temperatures, however,
caused a dilatation of the medullary sinusoids,(fig. C.jA similar
lack of correlation applied for the occasional orange-red staining
cortical islands or peninsulas which projeoted into the medulla
from the cortex.
2. Cortex (fig. 6,8)
The normal adrenal cortex section stained with Sudan III
and Harris* hematoxylin is best studied under the 16 mm. object­
ive. High power work is exceedingly difficult owing to the re­
fractive nature of the sudanophil material in the cortical cells.
Around the periphery is a blue staining connective tissue
capsule composed of collagenous fibers and fibroblasts,which
sends fins trabeculae into the substance of the gland.
61
.
Beneath tho capsule is o relatively wide, orange red stain­
ing zone, cellular in character, and rich in sudenophll globules
which mask cellular detail. The nuclei, however, can be discerned
as pale blue staining ovals or spheres. This is the outer portion
of tho zona glomerulosa.
Next, proceeding toward the center of the gland, is a rather
narroy/ blue staining cellular band apparently devoid of sudanophil
globules. TI1I3 may be of variable width but is always present in
sections of normal glands and may represent the inner portion of the
zona gl.;.ierulosa.
Under this is a comparatively light orange staining zone
wnich is relatively narrow. Deeper to this is a darker staining
area. The orange staining capacity here is due to the presence of
sudanophil substance. The cells of these two layers are arranged
in long, irregular strands which extend almost all the way to
the medulla. This is the zona fasciculata and is of varying depth.
The cells comprising the outer portion of the fascicular zone
have been called ’'spongiocytes" because of their vesicular char­
acter. The innermost border of this zone has a serrated appearance.
This is due to the projection of blue strands of cells from the
innermost layer of tne cortex, the zona reticularis.
This is an irregularly outlined blue staining zone with
cell groups connected to one another anastometically. It lies
immediately adjacent to the medulla and has very little or no
sudanophil substance. If lipoid is present, it appears as irreg­
ularly scattered small groups of globules. This zone is relatively
rich in Sinusoids. Duch vessels are also present in the other
62.
layers of the cortex in a lesser degree. .Although this zone
is generally said to contain no lipoid, it has been found
(Hoskins and Bernstein, *39) that in a small percentage of
normal cortices, sudanophil substance may be present here in
considerable quantities.
Occasionally, cellular strands of the innermost cortical
zone project into the medulla and appear as the islands or
peninsulas mentioned above. Sudanophil subGtance may or may
not be present in these cellular aggregates. Further details
concerning the normal morphology of the Sudan III stained ad­
renal cortex may be obtained by consulting Bernstein (*40.)
1. Normal (IN) series (figs, 6,8)
In the main, adrenals of all the groups in this series
presented a similar picture as indicated above for the normal
gland. A most noticeable divergence, howover, was the marked
variation in the extent of distribution of the cortical lipoid
in the various groups, and moreover, between the individuals
within the several groups.
The adrenal index for group N 1 averaged 86.0$, with a
range of 100-71$. 4 males (9,13,17,19) and 3 females (36,42)
exhibited an index of 100$. Average for all males was 85.75a;
forall females, 84.4$.
Adrenal
(fig. 5)
index for group H 2 averaged
93.0$, with a range
of 100-69$. 11 animals in this group demonstrated a figure of
100$ here.
Adrenal
of 100-79.5$.
index for group N 3 averaged
98.6$, with a range
All animals in this group exhibited figures of
100$ except one (83) which had a figure of 79.5$.
63
Adrenal index for croup N 4 was 87$, with a range of 10073.0$. 6 animals in this croup had figures of 100$.
Group N 5 as a whole exhibited an adrenal index of 81.0$,
with a range of 100-67$. 2 males (9,10) and 3 females (13,15,16)
revealed an index of 100$. Average for all males was 82.0$;
for females, 80.2$. (fig.5)
Mrenal index for group N 6 was 63.6$, with a range of
78-53$.
All figures here are averages. The results are tabulated
in Table 4 and represented graphically in figure 3.
No significant variation in cortical vascularity could
be detected in any of the groups of the N series.
2. Experimental (2) series (figs. 6,8)
1. Effeot of heat
Upon examination of adrenalsAwhose body temperatures
had been elevated by experimental means, marked variations
from the normal condition were immediately discernible. There
were slight histological differences between the adrenals of
animals in groups E 1,2,3, but almost all demonstrated an in­
creased extension of the cortical sudanophil substance toward
the medulla in such a manner as to mask the normally lipoid
free zona reticularis. This situation applies only if tho
temperature is relatively high and, most important, maintained
over a relatively long period of time. It has been shown
(Bernstein, *38 and *40) that single lethal doses of induced
artificial fever have little or no effect on the distribution
of cortical lipoid. The only effeot here is a marked dilatation
of the medullary and cortical blood vessels, (fig. 6)
64.
TABLE 4
ADRENAL INDEX (#)
GROUP
AVERAGE
RANGE
N series
* 86.0
100-71.0
N 2 (March)
93.0
100-69.0
N 3 (May)
98.6
100-79.5
N 4 (June)
87.0
100-73.0
N 5 (Nov.)
**Q1.0
100-67.0
N 1 (Jan- *39)
N 6 (Jan. f40)
63.6
78.0-55.0
E series
3 1 (radio fever)
100
3 2 (oven fever)
90.1
E 3 (prol. oven fever)
100
3 4 (mild cold)
69.8
72.0-61.0
a 5 (extreme cold)
36.6
57.0-10.0
E 6 (prol. ext. cold)
67.7
100-52.0
E 7 (cold then warm)
63.5
75.0-55.0
100- 68.0
♦^Dividing N 1 and 5 according to. sex
*N 1 males
females
85.7
84.4
100-71.0
100-73.0
**N 5 males
females
82.0
80.2
100-67.0
10C-67.0
65.
The cortical sinusoids of adrenals in group E 1 are
noticeably dilated and filled v;lth numerous erythrocytes.
{fig.6} The normally lipoid free
inner glomerular zone has
disappeared from view,to be replaced by a refractive band of
sudanophilic substance. The spongiocyte cell3 in the fascicular
zone appear more vesicular and swollen or enlarged. In all
cases, both male and female, without exception, the cortical
lipoid had swept dovm to tho medulla so that adrenal index was
100$. These are the essential manifestations brought about by
rises in body temperature. Further minor details have already
been reported. {*40)
Although
in
the
a
slight
adrenals of
group
increase
3
2,
in
this
vascularity
was
was
discerned
by no means as
marked
as
°F
in the adrenals of group E 1* Adrenal index -fre the group averaged
90.1#, with a range of 100-68.0#. The mules exhibited an average
of 91.0$; females, 90*4#* 6 moles were 100,1 while 7 females
were 100#.
Vascularity in the adrenals of group 3 3 was similar to
the pattern exhibited by those of group E 1 viz: marked dilat­
ation and engorgement of the sinusoidal vessels. Other details
were essentially the same. Adrenal index in all cases here was
#.
100
2.
Effeot of cold
All cold treated groups revealed a slight Increase in vas­
cularity.
as
in the heated groups, variations in cortical lipoid
ware the most marked effects. Moreover, projected sections of
animals exposed to cold, especially those of groups E 5 and 6,
66
.
were noticeably larger than normal ones. Tho enlargement had
no effect on the adrenal index, however, since measurement was
on a relative basis.
The adrenal index for group E 4 was 36.6$, with a range of
57.0-10.0;5. This group exhibited the greatest variation in dis­
position of sudanophil substance among individual animals.
Moreover, animal 5 (male) exhibited an apparently reversed lipoid
distribution i.e. there was no sudanophil substance in the outer
cortex but instead the lipoid hod assumed the nature of a narrow
band located in the inner reticular /.one (which is normally free
from lipoid.) This band encircled the medulla. Adrenal index in
this particular instance vros 20;5. A similar situation was noted
in f female (9) in tho same group; in this instance the index
was 10;6.
Adrenal index for group E 6 was 67.7-;$, with a range of 10052.0,5. One animal (1-male) exhibited an index of 100?S.
The adrenal index for group E 7 was 63.5$, with a range of
75.0-55.0°,$.
Calculated adrenal Index figures for both normal (N)
and experimental (E) series are listed in Table 4. The average,
as well ss the range, for each group is indicated. The results
for the normal series are represented graphically in figure
3, whereas those for the experimental series are represented in
figure 4.
It is obvious, here, as in the case of thyroid index, that
no significant sex differences exist with respect to the dist­
ribution of adrenal cortical lipoid, at least, for sexually im­
mature rats. 3ex adrenal indices are graphically illustrated in
figure 5.
G?.
Thyroid, as well as adrenal indices for both the normal
(N) end the experimental (E) series are tabulated in Table
5,along with the temperature conditions pertaining to each
group.
r
63.
TABLE 5
GROUP
THY.INDEX (j£)
ADR.INDEX (#)
N aeries
TEMPERATURE
N 1 tJon. ’39)
50.6
86.0
(average 10 days
pre-autopsy period)
65° j? (constant)
IJ 2 (J.arch)
47.0
93.0
65° F (rising)
N S { lia y )
44.6
98.6
65o F
N 4 (June)
42.0
87.0
70° F (falling)
N 5 (Nov.)
46.6
81.0
65° F (constant)
N 6 (Jan. *40)
52.4
63.6
65° F (constant)
1
38.5
100
E 2
38.1
90.1
E 3
42.3
100
4
53.0
69.8
530 F (10 days)
E 5
56.1
36.6
23.5° F (2 days)
E 6
60.7
67.7
320 f (5 days)
E 7
52.4
63.5
32° F (3 days)and
70° F (2 days)
(ri3ing)
E series
ilcat
Body temp. normal at
autopsy
Cold
r. 1
E 2 —
intermittent doses of radio fever 10 minutes each day
for 10 successive days; body temperature 102° F at each
exposure.
intermittent doses of oven fever (oven at 107.6° F) 10
each day for 10 3 U o c o s s i v e days; b o d y temperature
102° F at e a c h exposure.
minutes
E 3, — - prolonged oven fever (oven at 91.4° F) for 10 successive
day3 ; body temperature 103° F continuously.
All body temperatures normal at autopsy
69
DISCU3SI0N
From the evidence presented in these experiments, it
is apparent that environmental temperatures exert an influence
upon the morphology of the thyroid and adrenal cortical
glandsj and, further, that these consituents of the endocrine
system may, in some manner, be concerned with bodily thermo­
regulation.
In the main, morphological changes observed in the
thyroid coincide essentially with those reported by others.
-i seasonal morphological variation has been adequately dem­
onstrated (Kenyon, gills, Lowe and other previous investigators)
and here such findings are readily confirmed. Thyroids of
animals autopsied during the winter months demonstrate, among
other variations, a heightened alveolar epithelial lining
and on absorption of colloid. Summer thyroids, on the other
hand, exhibit a flattened epithelium and a marked accumulation
of intra-alveolar colloid which is more eosinophilic than
that of the winter groups. No marked seasonal variation in
in the amount and distribution of the interfollicular cells
could be discerned. These conditions are represented in figure
.
8
In the present investigation, however, evidence indicates
that retraction of colloid in the thyroid is not a reliable in­
dication of seasonal activity, as has been claimed by others,
inasmuch as no consistent variation in this respeot could be
noted in either seasonal or experimental series. It is entirely
possible that colloid retraction is merely a fixation artifact,
70.
as I.laximow suggests. Experimental error in this respect in
the present investigation has been minimized by the use of
a rapidly penetrating fixing fluid that causes little or no
tissue distortion ( Susa.) V7ith this in mind, it is suggested
that resorption of colloid alone cannot safely be utilized
as a criterion for thyroid activity. Variations in the epith­
elial lining of the follicles are a more accurate indication
of glandular activity.
In seeking the aetiological factor for the observed
seasonal morphological variation, it may seem, at first glance,
that temperature variation is the causative cgent involved.
That such a view, however, cannot
be maintained i3 evident
upon careful examination of the average laboratory temperatures
to which the normal (IT) series of animals had been exposed.
Beference to Table 1 will show that average laboratory temp­
eratures during the various months were approximately the
same in all instances. ?or example, during the winter months
the laboratory temperature was 65° F; this is not much lower
than the recorded summer temperature at the time of autopsy,
(70° F). Although the temperatures were almost identical, the
thyroid index exhibited a difference between these two season­
al groups; viz: an average of 425a for the June group and 51.5,£
for the winter groups. Statistical treatment of the figures
shows this difference to be mathematically significant.
It appears, therefore, that normal seasonal temperatures
play no significant role In altering thyroid morphology. In
this respect, there is a divergence from the view expressed
by .,!iller, Aanyon and others, who believed that seasonal
71
iaorphological variations were directly related to differences
in environmental temperatures. In the present Investigation
the results indicate that under normal temperature conditions
there exist3 a seasonal variation in the gland which bears
no apparent direct relation to laboratory temperature. Howevor, abnormal temperature variations, as demonstrated in
the experimental (E) series, do produce a distinct effect on
thyroid morphology.
It is significant to note, then, that while thyroid
morphology varies with extremes in temperature, (E series)
it apparently varies also with season per se, irrespective of
the temperature. The factor of ultra-violet light may be ruled
out here, since at no time were the animals exposed directly
to sunlignt; moreover, all the light which entered the labor­
atory was filtered through ordinary glass windows.
To test the role of extremes in temperature in bringing
about alterations in morphology, the E series of experiments
was planned and carried out. Reference to figure 4 makes it
evident at once that under these conditions an inverse re­
lation exists between temperature end thyroid index, i.e.
when environmental temperatures drop, the index is high; when
the temperature is high, the index is low. Moreover, it app­
ears that the two factors are related in a somewhat quantit­
ative fashion. Increasing intensity and duration of exposures
to abnormal cold result in an almost step-like increase in
thyroid index. By reference to figure 4, it can be seen that
group E 6 thyroids(exposed to freezing temperature for 5 days)
exhibit the greatest increase in epithelial cell height
(GO.7,o) while group E 5 thyroida(exposed to the some degree
72.
of cold for two days) have an index of 56.1$. Those exposed
to mild cold (S 4) had an index of 515.0$. The control figure
for winter animals kept at normal laboratory temperatures (65°F)
is 58.4$ for group N 6.
Similar conditions can be noted with extremes in heat.
Intermittent doses of high frequency fever (gtoup E 1)
induced
the relatively low thyroid index of 38.5$, which is signifi­
cantly lower than the lowest seasonal index (42$ in group
N 4.J The Intensity of the treatment in this experiment may
be noted by reference to figure 1, which indicates that the
raised body temperature of animals treated In this manner,
persisted for a longer period of tirao then oven induced fever.
It a pears then, that changes In environmental temp­
erature play an important part in altering thyroid morph­
ology. The effects of abrupt changes of temperature and of
the duration of exposures ore illustrated by groups E 5*G»
and 7 and their control, II 6. «11 these animals were from
tho same colony find were autopsied in the same month (Jan*
*40.) Group E 6 was expossd to a constant outdoor freezing
temperature (32° F) for 5 days, E 5 was placed outdoors for
two days (23.5° F), and the animals in E 7 were kept outdoors
for 3 days (32° F) and not autopsied until they had boon in
a warm room (70° F) for two days after the exposure. The
thyroid Indices of the three groups were, respectively,
60.7$, 56.1$ and 52.4$, while that of the control group
(N 6) was 52.4$. '.Vhen the variations of temjjerature and thyroiu index in these four groups are plotted, as in figure 7,
73
a clear-cut result is obtained which may bo accepted as
evidence of the reversibility of the morphological variation
in the thyroid brought about by extremes in environmental
temperatures. This is true, however, only if no damage has
been inflicted upon the glandular tissue, Kore significant,
however, is the fact that prolonged extremes of temperature
in either direction cause a progressive, constant effect
on the thyroid, ivhich appears auditive in nature. Short
exposures cause similar variations in a given direction,
but not to such a marked degree. It seems, then, that thy­
roid morphology variations are inversely related to absolute
experimental temperatures, and, moreover, that these variations
are in direct relation to the intonsity and the duration of
the thermal stimulus.
N
Reference to figure 5 will idicnte that in 60 day old
rats sex has no apparent influence on the thyroid index (in
either spring or winter) since the differences exhibited by
the two sexes of corresponding groups of animals are relat­
ively insignificant. In this respect, these results confirm
the findings of Kenyon and I>iiller.
As to the exact physiological mechanism of the cor­
relation between extremes in environmental temperatures and
thyroid index, little can safely be said from this study.
Exposure to cold for relatively long periods of time app­
arently causes on Increased general metabolic rate. 7,'hether
thyroid activity is the result or the cause could not be
determined here. However, it i3 evident that abnormal sit-
74
nations which tend to lower the body temperature cause a
compensatory hyperactivity of the thyroid as revealed by
the morphological picture. The process of change, moreover,
is a cumulative one end rather closely follows the absolute
environmental temperature in an inverse direction* It is,
furthermore, a reversible one, provided necrosis of the
glandular tissue has not token place.
Fxposuro to experimental heat, a procedure which tends
to raise the body temperature, on the other hand, Induces
a reverse morphological picture. Flattened epithelium (low
thyroid index) and concomitant accumulation of intra-alveolar
colloid may indicate a state of inactivity of the gland.
The relation of morphology to activity becomes more difficult
to interpret, since expression of glandular activity here
may be only relative. It is entirely possible that the epith­
elial cells are actively secreting into the alveolar lumina
while none of the active principle is leaving the gland,(i.e.
a storage phase) Increased body temperatures may cause a
diminution of the need for thyroid hormone by the tissues,
and, as a result the gland stores its secretion in the form
of colloid. Continued accumulation of this material would
cause increased pressure upon the lining cells, which, as a
result, y/ould assume a slightly flattened shape. Thus,
flattened epithelium and colloid distension may still re­
present a very "active" gland with respect to the epithelial
cell. The goneral consensus of opinion, however, seems to
be that heightened epithelium indicates hyperactivity while
a flattened epithelium indicates a hypoactive state, (Kenyon,
75.
Cramer, Mills, Turner and others.)
Epithelial oell height, however, in heat treated an­
imals may still be safely utilized as a criterion of thy­
roid function, albeit an indirect one, since in the last
analysis, the amount of the active principle leaving the
gland as a whole is the determining factor with respect to
glandular activity. V/hatever the situation may be, it can
safely be assumed that thyroid index follows experimentally
altered environmental temperatures in an Inverse direction
and may reflect an attempt on the part of the normally
thermo-regulating organism to maintain a normal thermal
equilibrium.
It is to be understood,of course, that no claim is
being made for a direct and isolated action in this respect.
The role of the other heat-regulating mechanisms, especially
the hypothalamioo-hypophyseal system, may also be involved.
It is entirely possible that the thermal effect is an indirect
one acting primarily through the hypothalamus or the anterior
hypophysis. The morphological variations observod may be due
to an indirect effect on the thyroid through the thyrotropic
principle. In a similar manner, the adrenal cortex, also may
be affected by corticotropic hormone elaborated from the ant­
erior pituitary. In any event, no matter what the exact mech­
anism, direct or indirect, extremes in the thermal environ­
ment do exert an effect on the morphology of the gland.
From the observations made here, no definite signifi­
cance could be assigned to the interfollioular cells. It has
been claimed (Bailliff) that these elements greatly increase
76.
in number and eventually give rise to new follicles if the
need for thyroid principle is increased (e.g. upon exposure
to cold.J Although cell counts were not made in the present
study, no marked variation in the number and distribution
of these cell groups could be discerned in the vcrious
groups.
The results of this investigation also indicate that
the effect of generalized fever induced by ultra-high freq­
uency radio emanations is apparently no different from fever
caused by externally applied heat, as far as thyroid morph­
ology Is concerned. Flattened epithelium and colloid distension
are brought about by application of the two totally different
thermal stimuli, although in the case of the radio induced
fever, the heat effeflt is apparently more intense and per­
sists over a longer period of time (fig.l.) This is in acc­
ordance with
previously reported observations. There is app­
arently no specific tissue effect caused by ultra-high freq­
uency emanations.
The relatively increased vascularity in radio treated
animals may be said to be caused by the differential character
in heating rates end intensity. This is in accord with the
beliefs of Kchler, Chalkoly and Voegtlin (*32) and Bevelander
and Bernstein (*40.) It is apparent then, that no specific
effects other than those induced by a generalized rise in
body temperature can be ascribed to radio fever. Any local
effects must necessarily be referred back to this condition.
The present findings with regard to the effects of radio
fever on thyroid morphology are not in accord with those re-
77
ported by Jorns. However, due consideration must be paid to
a possible species difference in this respect. It is more
likely, however, that this Investigator’s exposures wore not
carried out over a long enough period of time
effectively T°
activate morpiiological variations in the gland.
The adrenal cortex, In contradistinction to the thyroid,
is an extremely sensitive organ, the morj)hology of which may
be altered considerably by a wide variety of stimuli. The most
striking feature of the cortex is the marked variation, under
both normal and experimental conditions, of the distribution
of the cortical sudanophilic substance. The situation is such
that it is quite difficult to cite a"normal" index for cort­
ical lipoid. The results of the normal (N) series,(a3 can be
seen in Table 4,)with regard to this factor, indicate an ex­
tremely wide divergence between, as well as within,the various
groups.
That the cortical index may vary with season (Hoskins
and Bernstein *39) is readily confirmed here. However, the
most obvious fact to be noted as a result of these experiments,
is that, unliko the thyroid index, the cortical lipoid vjrie3
with changes in temperature which may be considered normal.
This tends to skew the seasonal curve (fig. 3) out of lino.
For example, the outdoor temperature for the 10 day pre-autopsy
period yjss, in the llarch group (N 2), a rising one viz: from
36° to 49° F; adrenal index here was 93.0';S. In the (lay group
(IT 3), the temperature likewise was a rising one, but,on a
higher level (56°-61° F); adrenal index here apparently
78*
followed the increasing temperature since the figure was found
to be 98.6;‘S. However, in the June group (N 4), although the
average temperature was on a higher absolute level (70° F),
there was a progressive fall in outdoor temperature which
was reflected in the laboratory temperature (75° to 68° F)
during the pre-autopsy period; the adrenal index here dropped
to 87.0,j. Significantly enough,the thyroid index exhibited no
such variation; this ?\irther serves to enhance the view that
thyroid index is not greatly affected by normal variations
in temperature. The discrepancy in adrenal values in the two
January groups IT 1 (81;«) and IT 6 (65.6;*), may be partly due
to the fact that the group3 were unavoidably obtained from
different colonies. The seasonal adrenal indices are listed
in Table 4 and graphically represented in figure 5.
-in explanation offered by come authors for seasonal
variation in the adrenal cortex, is the relation of season
to breeding periods. If animals are seasonal breeders, the
gonad-adrenal cortical relationship must necessarily be borne
in mind in considering seasonal variations in the latter organ.
This was demonstrated by 5alesky in the ground squirrel.
However, this source of error is not injected into the present
experiments inasmuch as the albino rat is not a seasonal
brooder. Sex dlfferercos with respect to adrenal index, in
rats of this age, are relatively insignificant.(See figure 5.)
As in the thyroid, no explanation for the seasonal variation
in adrenal cortical lipoid in the white rat can at present be
offered, although it is more probable that in the adrenal
79.
normal temperature variations may play a part in the process.
It becomes apparent at once that the adrenal cortex,
while it follov/s the seasonal curve, is quite unlike the
thyroid in that it is disturbed by a reaction to tho normal
temperature changes which immediately proceeded autopsy.
Furthermore, again unlike tho thyroid, adrenal index is
directly related to a normal changing thermal environment
and varies directly with it in any given direction.
It appears that the adrenal cortex is more acutely
sensitive to absolute changes in thermal environment than
is the thyroid. Corroboration for this hypothesis is obtain­
ed fron the results of the experimental (ii) series .
Reference to figure 4 shows that application of any form
of heat which tends to raise the body temperature ( groups
E 1,2,3) causes an increased deposition of sudonophil sub­
stance (increased adrenal index) to 100/2 in almost all cases,
whereas exposures to extreme conditions which tend to lower
tho body temperature, cause a marked decrease in the distrib­
ution of this material (lowered adrenal index.)
Tho situation with regard to cold is s little more com­
plicated than in exposures to hoat. It will be noted (Table
5 and figure 4) that prolonged mild cold (10 days at 53° F)
induced an index of 6 9 . 8 in group
4. Exposure to severe
cold (23.5° F) for a shorter period (2 days) caused a prec­
ipitous drop of the index to 36.G;o in group E 5; while
prolonged exposure to extreme cold (32° F for 5 days) in
group K 6, brought the index back up again to G7.7ya. It is
CO.
interesting to note that the last-mentioned treatment
actually caused tie index to exceed the figure for the
control of this group (II 6) which was 63.6/a. This apparent iuconsistency in the group exposed to cold for n long time
may very well be explained on the basis of a compensatory
action on the part of the adrenal cortex. The longhtened
period of exposure in this instance affords time for the
cortex to become r.ccustomed to the excessive strain being
placed upon its secretory activity, and allows it to renew
its 3tore of sudanophilic substance. This fact further tends
to emphasize the greater variability in the cortical response
to the thermal environment.
Still further indication of the sensitivity of the
cortex in its thermal response is illustrated by the fact that
the index (65.5;j) in group 3 7 (3 days of cold followed by
2 day3 of warmth) reverted to a value almost identical with
thu/6ontrol figure, which was 63.6‘S. It may be noted from
figure 7 that tho thyroid index in 2 7 has not yet returned
to tile.- n jrnal figure. This is additional evidence of the more
rnpia response of tho udronal cortex to thermal stimuli.
Furthermore, this is :;lso indicative of the reversibility
of the phenomenon.
It becoraos obvious, then, that relatively short exp­
osures to extremes in environmental temperatures may pro­
foundly affect the distribution of sudenophil substance. In
this respect confirmation is afforded for the contentions
81.
of Jlaxner and Grollman with regard to oamlc acid reducing
substance3 . The results nl3o show that the cortex responds
very rapidly to alterations in environmental temperatures,
and are in accordance with Cramer^ contention of the
"explosive" nature of the cortical response. The apparent
inconsistency in K 6 has already been explained on a basis
of compensation dependent on a time factor. These experiments,
then, amply support tho premise that the adrenal cortex is
readily affected by changes in absolute environmental temp­
eratures as well as by rates of change. In this respect, more­
over, it is more sensitive than the thyroid since greater
variation is apparent in adrenal than in thyroid indices.
The functional significance of the morphological app­
earance of the adrenal cortex with regard to distribution of
sudanophil substance at any particular time, is susceptible
to various Interpretations. This is a common situation in
morphological endocrine studies in general, and may be part­
icularly so in the case of the adrenal cortex. The differences
of opinion with reference to the significance of this distribut­
ion of tho cortical lipoid have previously been pointed out.
It seems that the ideal situation would bo to substantiate or
correlate morphological findings with concurrent physiological
experimental results.
/Whether Increased deposition of sudanophil substance ,
observed after exposure of animals to temperatures which tended
to raise the body temperature, indicates an increased secretion
82.
phase or merely an increased storage phase (inactive) analogous
to that found in the thyroid, cannot safely be stated. Although
Cramer’s contention that spread of cortical lipoid indicates
hyperactivity of the cortex seom3 quite probable, tho poss­
ibility that the condition indicates a storage phase (Dalton
et al) should not be ignored.
At any rate, it is demonstrated that exposures to con­
tinued mild elevations of body temperature cause n deposition
of sudanophilic substance in regions which normally contain
little, if any of this material. This may be the result of
either one of two factors; viz: 1) in response to a heightened,
thermal environment, the need for cortical lipoid (and its
contained cortical hormone) is decreased. This condition
would be be manifest in a storage of this substance in all
layers of the cortex; or 2) the need for cortical hormone by
the tissues is increased. In such an eventuality, the normally
lipoid-free zona reticularis may take over the function of
elaborating and secreting the essential principle. Credence
to the view that the zona reticularis can elaborate lipoid is
lent, perhaps, by the occasional occurrence of small amounts of
intracellular lipoid globules in this area under normal cond­
itions.
The presence of considerable amounts of lipoid in the
reticularis of a small number of normal winter animals ia, in
all probability, a reflection of the normal variation which,
as has been pointed out, may be considerable. Its appearance
in the reversed position in animals exposed to extreme cold
83
,
(group E 4), is, however, of quite a
different nature, the
significance of which will be discussed later. It is interest­
ing to note, in this regard, that a relatively small number
of normal winter adrenal3 had lipoid in the zona reticularis,
while the incidence 6f this condition in the summer and exp­
erimental heat groups was markedly higher. The significance
of considerable quantities of sudanophilic substance in the
normal winter adrenal i3 not clearly understood.
The low index in the experimental cold groups, is prob­
ably an indication of cortical hyperactivity rather than of
storage or rest. The time element i3 important in evaluating
results here. Had the animals
been autopsied after a shorter
exposure to cold, the adrenals might hove been found to be
laden with sudanophil substonce throughout their entire extent.
Such a condition has been indicated by Floxner ana Grollman
through the agency of osmic acid reducing substances. Continued
exposure to cold causes a progressively increasing drain on
the cortex with no uttempt made at compensation; this would
naturally tend to lower the adrenal index. Further continued
exposure allows time for a compensatory mechanism to be brought
into play and the cortical index would then tend to come back
to normal. This has already been illustrated.
xinother indication of extreme hyperactivity due to cold
is the condition exhibited by the adrenals of some of the an­
imals exposed to 3hort intervals of extreme cold (E o.) The
severe naturo of such a treatment is indicated by the fact that
2 animals succumbed to the effects of the Intense cold. Here,
84
.
the only site of sudanophil deposition is a thin band in
the juxta-medullary reticularis. This may be indicative of
a cortex on the way to exhaustion. In no instance, however,
was any gif’nd completely devoid of sudanophil material.
Before such a condition is reached, tho adrenal cortex enters
upon a compensatory phase and the adrenal index starts on
its way baok to the normal condition.
V/hatever the situation may be concerning the physiological
aspects of cortical activity, the fact remains that heightened
environmental temperatures affect the adrenal index in one direct­
ion, while lowered temperatures produce an opposite effect. It
is of interest to note, moreover, that variations in cortical
lipoid in a given direction oocur no matter what the inducing
thermal agent may be. Hiaes in
body temperature to a comparable
level, i.e. those Induced by intermittent doses of radio fever
(3 1), intermittent doses of oven induced fever (E 2) and pro­
longed oven induced fever (E 3), bring about a similar condition
in the distribution of cortical lipoid. This fact further bears
out the contention that the adrenal index is affected by a gen­
eralised temperature effect and not through a specific action
by any of these thermogenic agents.
What is significant, therefore, in both the case of the
thyroid and the adrenal cortex, is the fact that the morphology
of both of these structures varies, presumeably as the result
of experimental temperature variations. Whether or not tissue
metabolism Is the Important causative e.gent cannot be st'id with
c jrtainty.
85
Objection may be made, in view of 3elyefs (T35) findings
in connection with the condition of the adrenal cortex in the
so-called "alarm-r©action", to the results obtained in the
heat treated groups of animals. It is the contention of this
investigator that, among other changes, the adrenal cortex
responds by hypertrophy to any non-specific alarming stimulus.
No claim is being mad© in the present investigation that extremes
in temperature, which must of necessity fall into the category
of alarming stimuli, specifioally effect the cortex. In point
of fact, the -generalized effect of radio induced artificial fever
has already been emphasized. Moreover, if extension of cortical
lipoid is due to an "alarm reaction", on what grounds can the
adrenal index figures revealed by the normal summer adrenals
(almost 100^ in all groups) be explained? Here, normal summer
temperatures, albeit relatively high, can hardly be construed
as an ',alarming"sti?:iulus. It seems, rather, that the 3tote of
the cortex represents a normal adaptation to a sub-critical en­
vironmental temperature.
ns to the underlying causative physiological mechanism for
tho experimental variations in adrenal index, relatively little
can be said with safety. One possibility is that altered tissue
metabolism is brought about by thermal changes. These metabolic
changes may then make their effects manifest upon the morphology
of the gland.
.Another possibility is a disturbance in salt and water
metabolism as a result of extreme changes in tho environmental
temperature. It is well known that the adrenal cortex is vitally
concerned with salt and water metabolism (Swingle, *33-'57 and
others.) Experimentally induced fever In the animal may
86
cause an upset in the normal water equilibrium that exists
In the two great water compartments of the organism. Con­
tributing factors to such a situation would be the observed
dehydration, oral salivation, possibly tho subnormal gain in
body weight (although this may have been due to the refusal to
take food) of the animals treated with prolonged doses of oven
heat, and the edema in the extreme cold treated animals. A
tendency to disturb the normal water relations in the intraand intercellular compartments, as well as the absolute loss
of water, induce an increased activity on the part of the
adrenal cortex to maintain equilibrium water conditions. This
may be reflected in the morphological variations which ensue.
Furthermore, a similar situation may apply with respect to
plasma ionic equilibrium since it is known (iiacLeod) that
urinary excretion of NaCl is diminished during fever but that
it increases suddenly and greatly at crises.
It may be postulated, then, that the thyroid and the ad­
renal cortex are vitally concerned in the thermo-regulet ory
process of the normal organism, and that they go into action
as a unit in response to extreme variations in tho thermal
environment which tend to niter the normal body temperature.
Exposure to cold induces increased epithelial cell height in
the thyroid (increased activity) whereas in the cortex the
amount of sudanophil substance is diminished (increased act­
ivity.) Exposure to heat results in the reversed sfcte of
affairs. Epithelial cell height is diminished (decreased act­
ivity) and the sudanophil substance is increased in its
87
distribution (which may be indicative of either hypo- or hyper­
activity.) It seems then, that
justification is afforded for
referring to these two endocrines in the thermo-regulatory
process as an '’apparatus". This bears out the contentions
that the two organs are functionally related made by Cramer,
K.R. Hoskins and others.
Although the exact physiological mechanism for the action
of this system is obscure, it is of value to note that morph­
ological alterations in the component parts occur in specific
directions upon exposure of the organism to an environment
which tends to disturb the body temperature.
If diminution of sudanophil substanoe may be accepted
as an indication of hyperactivity of the adrenal cortex, a
relation between thermal environment and the thyroid-adrenal
cortical apparatus may be postulated as follows: extremes In
environmental temperature which tend to lower body temperatures,
induce increased activity on the part of both the thyroid and
the adrenal cortex. These changes may be brought about by
altered tissue metabolism and may be an indication of a com­
pensatory endocrine attempt to maintain normal thermal equil­
ibrium. In this respect, tho thyroid-adrenal mechanism may be
considered as a functional unit which operates in conjunction
with the nervous elements in the maintenance of a constant, normal
body temperature.
08.
SUMMARY M D CONCLUSIONS
1. Evidence is presented to indicate a normal seasonal
variation in epithelial cell height of the thyroid and in the
distribution of the adrenal cortical sudanophilic substance.
S. In the sexually immature albino rat, these seasonal
variations cannot be correlated with environmental temperature.
3. There is no significant sex difference In either the
thyroid or adrenal cortex at this age.
4. VJhile the thyroid index follows a seasonal curve, the
adrenal index is more likely to vary with changes in the therm­
al environment which may be considered normal.
5. Extremes in environmental temperature which tend to
alter body temperature are causative factors in producing morph­
ological variations in these two organs. This has been verified
by the exposure of groups of animals to several types of exp­
erimentally produced variations in the thermal environment.
6. Epithelial coll height is Inversely related to exper­
imentally altered environmental temperatures; whereas distribution
of cortical sudanophil substance is directly related.
7. Evidence is adduced to illustrate that the morphological
effect, as far as the thyroid and the adrenal cortex are con­
cerned, produced by ultra-high frequency induced artificial fever
differs in no great respect from that Induced by externally app­
lied oven heat.
8* Morphological variations in the thyroid and the adrenal
cortex Induced by experimentally altered thermal environments are
69
,
reversible providing no tissue Injury has been sustained.
9. The possibility of the thyroid-adrenal apparatus being
concerned in general tissue and 3alt ana water metabolism is
suggested.
10. The thyroid-adrenal cortical apparatus is, in some
manner, concerned with the maintenance of a constant body
temperature and may operate in conjunction with the nervous
thermo-regulatory mechanisms.
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Ober den .-influes des Gehirns
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13.:.17
Li. AND 17. SCHKITALER
191-1
Beitrag zur Loacalization
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1937
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.Ved., vol.
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The nature
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KELLER, A.D.
1933
Observations on the localization in the
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1932
Heat regulation in medullary
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:.T.
1933
The histological changes in the tayrcid
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KLEI iL’juN,
TIT"C3AUI/, 3. ATD H. HOEEPAJI
1937
ablishment of the diurn'1 temperature cycle,
The est­
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KlfTEN, A. .A. 4J-J0 L. LOEB
1935
The relr. tion between the
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e o .,e e r ,
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funktion.
KRIEG, 17.J.L.
Beziehungon von Mebenniere und GoschlectsPflug. Arch., vol. 144, p. 361.
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An experimental study of the function of
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KUCilLER,, IV.
1935
Ph.D. Dissertation, II.Y.U.
Jnhrcszylclische VorfindGrungon im hi3tolog-
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KUNT3, -A.
1934
KU -CHIN;4.Y, G.
The Autonomic Nervous Jystem. Lea and Eeblger Co.
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(Iber don einfluss verschiednor Tempernturon
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LANDAU'SR, 7/. AND L.T. DAVID
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Thyroid activity and
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Tests morphologiques da la reaction
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Dor Jahraszyldus der Bchilddruse von
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The relation­
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Oher humorale Obertragbarkeit der Herznerven'1
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.
1930 a
Variations in the histological condition
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--- IBID 1930 b
Seasonal and 3©xual variation in the thyroid
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The mechanism of secretion in the
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Activation of heat loss mechanisras by local
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The pi tuitary-hypo thalamic
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Studios in thyroid trans­
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The effect of gonadectomy
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1936
Thyrotropic horm­
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1939
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MILLS, Cm A, AND G. 0GL3
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Delation of 103s of body
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Preparation and biological assay of
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-- IBID
1938
Cell changes in some of the hypothalamic
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The origin of the "parafollicular' cell,
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IBID
1932 b
component of the thyroid gland of
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Further observations on the parafollicular
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— —
IBID
1935
Innervation of the thyroid gland. III. Dist­
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PAP3A, J.V.
Am. J. Anat., vol. 57, p. 135.
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The brain considered us an organ: neural
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PinS3t J.F.
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Algunas contribucioneo al con-
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Hypothalamic
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HANSON,:}. 7., AND ’/‘.H. INCH*ALS
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1935
Hypothalamus and control
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1937
Reaction of the supraoptic nucleus
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IBID
193B
Innervation of the hypophysis.
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HI3ID, N.H. AID G. HOLD AN
1936
Effect of removal of Stella to
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REI83, 0.
1936
Eur morphogenetischon Virlcung und biolog-
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RIDDLE, 0. AID ’
//. ;. FISHER
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thyroid size in pigeons.
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Deasonal variations of
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105
RIDDLE,(X, SMITH,G.C. AND C.S. MORAN
1938
Effects of
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Proo. Soc. Exp. Biol, and
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RIDDLE, 0., SMITH, G.C. , BATES, R.W., MORAN, C.S. AND S.L.
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1936
Action of anterior pituitary hormones
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Endocrinology, vol. 20, p. 1.
RING, G.C.
1938
Metabolism and body temperature of normal
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ROGENKHANZ, G.
1931
Einfluss des ultravioletten Gonnen
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ROUP Y, G. AND H. M0SINGEH
195G
La regulation nerveuse
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1935
Changes in the thyroid gland of
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1936
Thyroxine in thyroids in various seasons.
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1933
Studies Of
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106.
SCHERBAKOV, A.P.
1937
Respiration and temperature adapt­
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Bull. Biol. Med.
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SCHMIDT, I.G. AND L.H. JCiL'iIDT
1938
Variations in the
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Endocrinology, vol. 23, p. 559.
SCHTa BH, E.k, AND F..:. ElJHiY
1937
Dome effects of pro­
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1938
The effect of prolonged exposure to low temper­
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1935
Studies on adaptation.
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1938
A rapid and sensitive
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SHERRINGTON,
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1924
Notes on temperature after spinal
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31 EBERT, V.’.J. AND U.S. SiAITH
1930
The effect of various
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107
thyroidoctoraized guinea pigs.
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1930
The effect of nervo stim­
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1929
Die Abhnngigkeit der Schilddrusenausbilduung
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Ztschr. Anat. u. jlntvricklungsgesch., vol. 89, p. 606.
SOJIER, T.L. Alio G.P. GHABFIELD
1932
Adrenal enlargement
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STURM, A. AND V/. SCHONING
1935
Haohweis des Thyreotropon
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SWINGLE, fl.W.
1937
Experimental studies on the function
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TAliURii.,
Y.
1926
Structural changes in the suprarenal
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TELLO, F.
1912
Brit. J. Exp. Biol., vol. 4, p. 81.
Algunas observationes sobre la histologia
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THAU3R, H.
1935
'V&rmaregulation und Fieberfahigkeit nach
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Arch. f.d. gcs. Physiol., vol. 236, p. 102.
THAUER, R. AND G. PETERS
1937
Warmeregulation nach operativen
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Ausschaltung des wWar^lezent^ums.,,
Arch. f.d. gos.
Physiol., vol. 239, p. 483,
IBID
1937
Warmeregulation ohno Hypothalamus.
Verhandl. deut. Ges. inn. Mod., vol. 49, p. 188.
TURNER, K.3.
1930
Thyroid hyperplasia produced in
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Proc.
3oc, Exp. Biol, and Bod., vol. 28, p. 204.
TURNER, K.13. AND K.M. BENEDICT
1932
Thyroid hyperplasia
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J* Glin, Investigation, vol. 11, p. 761.
UOTILA, U.
1939
The role of the cervical ayrapauhetics
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Endocrinology, vol. 25, p. 63.
— — IBID
1939
On the role of the pituitary stalk in
the regulation of the anterior pituitary, with special
reference to the thyrotropic hormone.
Endocrinology,
vol. 25, p. 605.
UHLENHUTH, S.
1937
The thyroactivator hormone: its isol­
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Ann.
int. Med., vol. 10, p. 1459.
VAN DYKE, H.B.
1936
the Pituitary Body.
IBID
1939
Ibid
V IRZAR, F. AND V. WAHL
The Physiology end Pharniocology of
U. of Chi. Press.
Vol. II.
1931
V/irkung des Hypophysenvorder-
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Biochem. Ztschr., vol. 240, p. 37.
109.
7JATZKA, M.
1936
LIchtbilder projektion iibor physiologische
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Verhandl. Anat. Gesell*,
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TJEINBERG, E.
1933
Uber die Baziehung der Nervenfoserver-
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intermedia der Hypophyse.
VJHITEHEAD, li.
1933
Anat. Anz., vol. 76, p. 155.
Variations in cortical lipoid of the
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J. Anat., vol. 67,
p. 393.
-—
IBID
1934
Variations in cortical lipoid of the guinea
pig suprarenal
'ith sex ana age.
J. Ariat., vol. 69,
p. 72.
— — IBID
1936
Variations in cortical lipoid of the rabbit
suprarenal with sox and age.
WISLOCKI, G.B.
1937
J. Anat., vol. 70, p. 380.
The vascular supply of tho hypophysis
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Anat. Rec., vol. 69, p. 361.
TI3L0CKI, G.h. AND L.3. KING
1936
The permeability of the
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vascular supply.
N0ITE7/ICH, A*
1936
Am. J. Anat., vol. 50, p. 421.
Structure and biological activity of the
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Bull. Biol.
Med. Sxptl. U.3.3.R., vol. 1, p. 350.
fOLF, 0. AND H. GRE3P
1937
Histological study of the thyroid
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Proc. Boo. hbcp. Biol, and tfod., vol. 36, p. 056.
S/YUAN, L.0.
1932
regulation.
61.
Th3 suprarenal cortex and temperature
Broc. Boo. Biol, and mad., vol. 30, p.
110
WYtflAN, L.C. AND C. TTJM 3UDSK
1932
cortical tissue in the rat.
Growth of transplanted
Am. J. Physiol., vol.
101, p. 662.
ZALESKZ, M.
1934
A study of tho seasonal changes in the
adrenal gland of the 13 lined ground squirrel (Citellus
Tridecemlineatus) with particular reference to its
sexual cycle.
ZAJIC, F.
1935
Anat. Rec., vol. 60, p. 291.
Grunduiasatz und das fhyreotrope Ilormon de3
Hypophyoenvorderlappens.
Arch. f.d. ges. Physiol.,
vol. 235, p. 575.
ZKCHSL.G.
1932
Cellular studies on the thyroid gland.
Jurg. Cynoc. and Obstet., vol. 54, p. 1.
— — IBID
1933
Observations on the follicular cycle und on
the presence of 'hnacrothymocytes'* In the human thyroid.
Anat. dec., vol. 56, p. 119.
Z'.VISKER, H.L.
1936
A study of adrenal cortex morphology.
Am. J* Path., vol. 12, p. 107.
ILLUa?RA'riOIItJ
Figure 1 —
the chart illustrates the lengthened persist­
ence of artificially induced radio fever in
group 15 1 {solid black line}. This nay bo ind­
icative of a more intense
thermal effect of
artificial fever (radio induced) than that brought
about by application of external oven heat.
-J
Figure 2 -- demonstrates the effect of variations in thermal
environment on the body v/eight gain of several
experimental groups of animals compared with normal
Vistar rats of the same age. note that although the
initial weights of the experimental -.ninals in groups
E 1 and 2 ere higher than the Vistar figures, the gain
ever the ten day period approximates the 7/istar curve,
note also that prolonged oven fever-(15 3) treatment
results in an abnormal gain curve. Prolonged extreme
(
cold (E 6), however, results in a more or loss normal
•'u>. -»V
gain, (the curve here was interpolated -dotted linoafter tho fifth day which was the autopsy tirao for the
group.)
SUBSIDENCE OF B ODY T E M P E R A T U R E
toi &-o-
A FTE R FEVER.
-o«.
‘o.
* \
P ro lo n g e d o o c n f e v e r ( E 3)
101
DEGREES
1 FAM.
I n t e r m i t t e n t r ud tu f e v e ^ f E f )
lHi,+r*i;(t€nf
>o
Qtrfr. f s v e r . f Z '
20
SO
40
>
»-
5C
bO
■
10
80
90
■
100
TIME
MINUTES
R E M O V A L P R O M PYROGENIC INFLUENCE.
FIG. 1
EFFECT OF T H E R M A L E N V IR O N M E N T
I
P ro lo n g e d c x t r e r w
ON
BODY
W E IG H T .
co/d .tE b)
f Prolonged overt fe v e r (E I)
t_ I
M c r / m t t c n i h t q h f r e q u e n c y f e v e r , £ t)
[ I n t e r m t t t c r f o v e n f e v e r ■£
W i s t r t r re i ls
1
6j
AGE
lW bS
IN
66
DAYS.
FIG* 2
67
70
Figure 3
—
the chart illustrates the effect of season
on thyroid and adrenal indices in a graphic
I
maimer. Note that while adrenal index varies
v/ith normal rises in temperature ( W 2 and 3)
and with normal falls ( N 4), thyroid index
does not. In tho winter months thyroid index
is high while adrenal index is low; whereas, in
the summer months the situation is reversed.
Koto also that ordinate units are not comparable
in both instances. Thyroid index was plotted over
wider intervals than adronal index because of the
s
i
relatively slight variations in tho former. The
i*-
wider spacing was employed to bring out more clearly
thyroid index variutions.
Figure 4
—
this ohart graphically represents the inverse relation
which exists* between thyroid and adrenal Indices upon
subjection of animals to experimental variations
in thermal environment, hote that while increasing
intensity and duration of cold results in cumulative
effect on the thyroid index, adrenal index, as a
result of prolonged exposure to cold tends to rovert
to normal (E 6). This may be a compensation or res­
istance phase. Furthermore, the greater sensitivity
of the adrenal cortex to thermal stimuli, particularly
cold, is illustrated.
SEASONAL VARIATIONS IN THYROID INDEXfEPlTHEl.lAL CELL HEIGHT)
A N D ADRENAL INDEX (ADRENAL CORTICAL LIPOID).
T U Y R O ID
IN D E X
fo
■10
N 1
MAU.
JA N .J9
N J
N 4
N5
M AY
JE.
NO V
No
JAN. 4 0
FIG. 3
E F F E C T OF E X P E R IM E N T A L L Y A L T E R E D E N V IR O N M E N T A L
T E M P E R A T U R E S ON T H Y R O ID AND A D R E N A L IN D IC E S .
COLD
MEAT
ADRENAL <*>
INDEX
40
40
E2
E4
E5
E ! : Interm ittent hiqh frequency feoer E 4 : Prolonged m ild cold.
E 2 : Interm ittent 0 0 en feuen'
ES: Extreme cold.
£ J Prolonged otren feiren
Efi : f
FIG. 4
E6
Figure 5 —
this figure graphically reprooer.ts the sex diff­
erences in two groups of normal animals. TTote
that thyroid end adrenal index differences are
relatively insignificant.
Figure 6 —
drawings of Huden III and'Harris* hematoxylin stain­
ed adrenal sections (frozen) cut at lOu, to illust­
rate the effect of artificial radio fover on the
distribution of cortical sudanophil substance. !Tote
that single lethal doses (over 108° F) result in
no great marked variation in this material from the
normal. However, cortical (reticular) as well as
medullary sinusoids are greatly enlarged and congest­
ed. .Repeated, sublethal doses (102° F) result in a
wider distribution of sudanophil substance as well as
a marked vascular effect.
X 18.
E F F E C T
OF
SEX.
THYROID INDEX
ADRENAL
INDEX
INDEX
%
FIG. 5
m m m
n m m
MEO.
NORMAL
S IN 6L E LETH A L
FIG. 6
lO SUB L E T H A L
Figure 7 —
this chart illustrates the effoots of changes in
thermal environment on the thyroid-adrenal app­
aratus. noreover,
7 demonstrates tne revers­
ibility of the thermal effect on the two endocrines.
N
6
may
be coiisidered as the normal group for this
series. Temperature conditions are indicated below •
E F F E C T OF V A R I A T I O N I N T E M P E R A T U R E
ON T H Y R O ID - A D R E N A L A P P A R A T U S .
W arm to Cold
P r o lo n g e d E x t r e m e Cold
E6
T H Y R O ID ,
INDEX
4 0 .7 %
ADRENAL,
INDEX
TEM R
ES
IJ*0%
TWYR.IND I
ADR. IND. I
IF F
il'F
41‘Ak
TEMR
-Jddi/i
adrenal
,
THYRIND I
1*14%
INDEX
iS'F
45*1
TE M P
£7
I S14 %
I
t_
■Sdayt'
iii.iV
Cold to W a r m
P r o lo n g e d W a r m t h
Nb
! TUVROID
■n d e x
M-IdWi-
I T 4 .6 %
I«*.*■%
ADR.IND
TEM R
-A
-,1 0 'F
u*x
4« V r
-Jdjyj--**—Id«L-
FIG. 7
Figure 8 —
this is n semi-diagrammatic composite drawing
illustrating the offset of (1) season and (2}
experimentally altered environmental temperatures
on the morphology of the thyroid end adronal
oortical glands. Tho figures indicate average
indices in each case.
Note the flattened epithelium, light colloid and
indistinct cell boundaries in the sunnier thyroid;
and extensive distribution of cortical sudanophil
substance. Winter thyroids show heightened epithel­
ium, large, hyperchromatic nuclei, distinct cell
boundaries and large peripheral colloid vacuoles;
adrenals here show a distinct lipoid-free zone in
the reticularis.
In experimental heat thyroids the epithelium Is
still more flattened, and colloid is deeply eosin­
ophilic, while tho adrenal cortex exhibits an ext­
ensive deposition of sucunophil substance and
markedly dilated cortical and medullary sinusoids.
In experimental cold thyroids the epithelium i3
hoigthened, colloid is faintly eosinophilic with
large peripheral vacuoles and the entire alveolus
is irregular in shape. Blood capillaries here as
well os in the experimental heat groups are en­
gorged with blood cells, hdrenals here show a
marked diminution of cortical suaanophil substance
and increased vascularity.
EFFECT OF (I)SEASON AND (tt EXPERIMENTALLY ALTERED TEMPERATURES
ON TMC THYROID - ADRENAL APPARATUS.
THYROID
THYROID
InierfollicuU
*
it.
L a r g e v a c u o le s
L ig h t
ADRENAL
Large tsacuolei
Light to iin "
S m a l l s c a t t e r e d tra c u o fa s
'Deep eostn
}6.5%
5314%
fig.
e
Library '
Y- Umy.-
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