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THE RESPONSE OF ADULT DOGS

AND ENGLISH BULL DOG PUPPIES
TO THYROID STEMULATION

Thais for the Degree cf M. S.
IAICHIGAN STATE COLLEGE

Robert Frederic Bergman
1949

 

   

_—__‘ _ “

This is to certify that the

thesis entitled

"The Response of Adult Dogs
and English Bulldog Puppies
to Thyroidal Stimulation."

presented by
Robert F. Bergman

has been accepted towards fulfillment
of the requirements for

M.S. degree in Physiology

 

 

Major professor

[hm May 251 1949

 

0-169

 

 

 

 

 

IH E.

 

 

THE RESPONSE OF ADULT DOGS AND ENGLISH BULL DOG PUPPIES
TO THYROID STIMULATION

By
ROBERT FREDERIC §QRGMAN

A THESIS
Submitted to the School of Graduate Studies of Michigan
State College of Agriculture and Applied Science
in partial fulfillment of the requirements
for the degree of

MASTER OF SCIENCE

Department of Physiology and Pharmacology
1949

THE

l

13

ACKNOWLEDGMENTS

The author wishes to express his sincere gratitude to
Professor E. P. Reineke of the Department of Physiology and
Pharmacology, for the valuable and kindly advice and assist-
ance rendered both during the experimental work, and during
the preparation of this manuscript; to Professor B. V.
Alfredson for the use of the facilities of the department;
and to Associate Professor L. F. Wolterink and Assistant Pro-
fessor J. Meites for the helpful suggestions for the experi-
mental work. A debt of gratitude is owed to Associate Pro-
fessor J. F. Smithcors of the Department of Anatomy for the
dogs used in the experiment. The work performed by Mr. D.
P. Wallach on the asSay of the thyroid preparations is ap-
preciated.

Sincere thanks are also due to the Research Council
of the American Veterinary Medical Association for the fel-
lowship granted for this research. The Ciba Pharmaceutical
Company of Summit, New Jersey, and The Cerophyl Laboratories
of Kansas City, Missouri, supplied funds incidental to this
project without which this work. could not have been comp
pleted and grateful thanks are due. Thanks are also due to
the Parke Davis Company of Detroit, Michigan, for the samples
of desiccated thyroid and to the Kellogg Company, Battle

Creek, Michigan, for part of the dog food used in this work.

216868

TABLE OF CONTENTS

INTRODUC‘PIONOOOOOO00............OOOOOOOOOOOI0.0.0.0...

1

PART I EFFECTS OF THYROID HORMONE ON METABOLISM OF DOGS

REVIEW OF LITERATURE ......OOOOOOOOOOOOOOOOO00.0.00...
Physiology of the Thyroid Gland .................
Thyroidectomy_of Adult Dogs .....................

Studies with Radioactive Iodine..................

 

Canine Metabolism Determinations.................
EXPERIMENTAL PROCEDURE AND EFFECTS ...................
General Procedure for Metabolism Determinations..

Body Temperature............................

PulseOOOOCCOOOOOOOOOOO.......OOOOOOOOOOOOOOO

BOdy ‘uveiglltSOOOOOOOOO O. C. O. ... O O. O O O I. O O O O. .
Basal Metabolic Rate........................
FOOd-OOOOOOCOOOOOOOOOOOO...O.........OOOOOOOO

Trials with Protamone on Intact Dogg.............

 

ProcedurGOOOOOOOOOOOOOO......OOOOOOOOOOOOOOO
EffectSOOOOOOOOO0.00.0.0.........OOOOOOOOOCO

Trials with Desiccated Thygoid on Intact Dogs....

 

Proced‘llreOOCOO......OOOOOOOOOOOO0.00.0000...

EffGCtSOOOOOO.......OOOOOQOOIOOOOOO0.0.0....

Lonngime Trial with Protamone on Intact English

B‘lll Dog BitCheSOOOOOOOOO....OOOOOOOOOOOOOOCOOOOC

 

Procedureooooo00000000000000000..0000000000.
EffeCtSOooooo00000000000000000000000000.0000

Theri-dectorny'OOOOOO......OOOOOOOCOO...0.0.0.0....

 

ProcedureOOOOOOOOO0............OOOOOOOOOO...

3

5
14
16
17
21
21
21
21
21
21
25
24

24
50
50
30

52
52
35
35

55

Thyroid weights..............................36
Individual Surgery Reports and Aftercare.....37
Tetany Effects...............................4O
Effects of Thyroidectomy.....................4l
. IfilSl Determinations on.Thyroidectomized Dogs.....45
Procedure....................................45
Results of 1*131 Injection on a Normal Dog...45
Results of 1*131 Injection on Thyroidectomized
Dogs.........................................46
Autopsy of Dogs with Indications of Thyroid
Functions....................................47

1*151 Determinations on Intact Dogs...............48

 

Procedure....................................48
Results of 1*151 Injection on Intact English
Bull Dog Bitches.............................48
Results of 1*131 Injection of Intact Dogs
Receiving Desiccated Thyroid.................49
Results of 1*151 Injection on Intact English
Bull Dog Puppies.............................49
Trials with Protamone and Desiccated Thyroid gg

Thyroidectomized Dogg.............................51

 

Procedureooooooto00000000000000.000000000000051
EffGCtSooooooooooooooooo00000000000000.00000052
COMPARISON OF POTENCY OF PROTAMONE AND DESICCATED

THYROIDOOOOOOOOOOOOOOOO0.0.............0...............57

DISCUSSION-0.0.0....0.......0...O.......OOOOOOOOOOOOOCOOSQ

fi-rnrm'fi') "
DUl'fllVLnLXY-oooooo.0000000000000...000000000000.coco-0000.... 08

CONCLUSIONS............................................. 70
LITERATURE CITED........................................ 96
APPENDIX................................................10'7
PART II’EFFECT OF THYROID HORMONE ON GROWTH IN DOGS
REVIEJ OF LITERATURE ON THE RELATION OF THE THYROID
GLAND AND GROWTH........................................ '71

Historical-3:00...000......00.0.00.........OOOOOOOOOOC r7]-

 

Relation.with Anterior Pituitary Growth Hormone.... 72

 

hieCh-anism Of Acti-QBOOOOO00......OOOOOOOOOOOOOOOIOOO '73

 

SPGCieS Results...ooo.ooo..o.oo.................... 75
EXPERIMENTAL PKOCEDURE AND EFFECTSooooooooo00.000.00.000 80

Trials with Protamone on Intact English Bull Dog

 

Puppies............................................ 80
Procedure..................................... 80
Effects....................................... 82

DISCUSSION.............................................. 90
SUMMARY................................................. 94
CONCLUSIONS............................................. 95
LITERATURE CITED........................................ 96

APPElq-DIXOOCO.........OOOOOOOOOOOOO0.00.00...0.00.00.00.00107

INTRODUCTION

The prime object of this research was to form a more
perfect foundation for the use of thyroid products upon the
dog. In the past, the dog has been used for a research
animal from.which to base studies upon other species. Al-
though these past studies throw some light upon the status
of the thyroid in the dog, they leave many questions unanswer-
ed.

With the increasing prosperity of the country and the
consequent increase of the dog population, it becomes of in-
creasing importance to perfect its medical therapy. The vet-
erinary profession is complimented by the fact that more dqgs
are living beyond the stage of distemper and other puppyhood
diseases. With this deve10pment, comes the problem of
geriatrics, for the longer the period of residence of man's
best friend, the greater his master's attachment becomes.
There is good evidence that in.man and animal, endocrines
will lengthen life and prolong useful existence.‘ With the
senile decline of metabolism, come many of the "old age
ilkfl'such as loss of activity and reproductiOn. Accordingly,
this is an attempt to form a basis for thyroid therapy in.the
dog.

Another phase of the work was to determine the effect of
exogenous thyroid upon the growth rate of puppies. If this
technic can be perfected, not only will growth be more effi-
cient, but the pup will be sturdy at a time when he needs his

strength to fight off the scourges of puppyhood. The period

in which he would be susceptible to puppy diseases would be
shortened.

The practicability of thyroid medication is increasing
with the advent of standadized products. Desiccated thyroti
U. S. P. XII is prepared from animals edible to man and stan-
darized to the iodine content by chemical assay. The iodine
content must be from..17 to .25% (U. S. P. Convention 1942).
A less expensive preparation, Protamone (commercial name of
the product supplied by Cerophyl Laboratories), is a syn-
thetic iodinated protein. It is prepared by a controlled
process whereby casein is iodinated in a buffered medium
at a set temperature for a set period of time. The resulting
compound is purified and dried (Reineke 1942). The advantages
of this compound, other than its low cost, are that a greater
standaEUZation of the actual thyroxine content is to be had
because of the controlled manufacture. The thyroxine content
of natural therid materials depends somewhat upon the physflr-
logical state of the animal, and the iodine content is butai
relative figure. The potency of Protamone has been shown

to be several times that of desiccated thyroid.

PART I
REVIEJ OF THE LITERATURE

Physiology of the Thyroid Gland

Under normal physiological conditions, the thyroid gland
is the only organ.having the endocrine action attributed to
thyroxine. Recently it has been demonstrated by the use of
thyroidectomized rats that injections of elemental iodine
will produce a result similar to thyroxine injections, Ele-
mental iodine has the power to form a thyroactive compound
in the organism.(Dvoskin 1947). Whether iodides share this
ability is questionable but studies with radioactive iodine
in thyroidectomized rats were believed to indicate thyroxine
and diiodotyrosine formation in the liver and intestines
(Morton, et a1. 1945). Thyroidectomized rats are noted to
grow better if given an iodine supplement which fact supports
the theory of the extrathyroidal formation of thyroactive
compounds (Chapman 1941). The thyroid gland surpasses all
other tissues in its ability to fix circulating iodides.
This ability is regulated to a large extent by the concentra-
tion of thyrotropic hormone (Hamilton and Soley 1940; Leblond
and Sue 1941). The evidence is that the iodine is first
united with tyrosine to form diiodotyrosine and this in turn
forms thyroxine. This reaction probably takes place in the
colloid space (Mann, et a1. 1942). These rmctions probably
take place while the amino acid is still attached to the pro-
tein molecule, and the resulting molecule is termed thyro-

globulin (Salter 1944). There has been some question as to

4

the relative activities of 1- and d—thyroxine. It is gen-
erally conceded that d-thyroxine has little or no activity
while l-thyroxine accounts for practically all of the thyrohi
action. The thyroid gland normally produces 1-thyroxine
(Reineke 1945). Very little effect has been reported for
diiodotyrosine except for one worker who used the question-
able criterion of its maintaining the health of thyroidecto-
mized dogs (Condorelli 1937).

Since the molecule of thyroglobulin has a molecular
weight of about 700,000, it seems questionable that this
entire molecule is able to enter the blood stream and then
permeate the cells of the organism. The logical conclusion
is that it is broken down at least to smaller fragments be-
fore making its physiologic circuit (Salter 1944). Attempts
to identify thyroglobulin in circulating blood by highly
effective precipitation methods have been negative (Stellar
and Olken 1940).

By the use of studies with radioactive iodine, it was
found that protein-bound iodine followed the pattern one
might expect from.the thyroid gland secretion. That is, the
plasma protein bound iodine rose upon injections of thyro-
tropin and fell upon hypophysectomy (Chaikoff,et a1. 1947).
Chemical analysis of the circulating plasma iodine indicates
that it is thyroxine (Taurog and Chaikoff 1947). The blood
iodine content of dogs is very low, 0 to 8 micrograms percent,
and is but little affected by enviromental temperature (Riggs

1942). In the human, the protein-bound plasma iodine is a

definite indication of the basal heat production. The basal
heat production is said to equal 52.5 log. (I)-0.8 calories/
sq. meter/hour. The ratio is valid even after lugolization
and thyroidectomy (Lowenstein,et a1. 1944). It has been
demonstrated that the thyroid hormone is able to permeate
all the cells of the body and is even able to pass through
the placenta and affect the fetus (Cunningham 1941).

Both thyroxine and thyroglobulin.have effects orally
and when given parenterally, but it has been noted that
thyrotropin will produce a more rapid rise in metabolism
than if thyroxine were given. This would indicate that the
hormone of the thyroid possesses the calorigenic activity and
that the thyroxine must undergo some alteration before become
ing active. It was noted‘in'gitgg, that thyroxine was in-
active upon tissues in saline solutions but exerted its influ-
ence part of the time in serum.media. This may indicate that
the thyroxine needs to form a protein linkage to become ef-
fective (Canzanelli, et a1. 1939).

The thyroid hormone is generally classed as a catylyst
rather than an enzyme because of the absence of effect upon
dead or moribund cells. The hormone increases the metabolism
of the cell by increasing its oxidative processes. Metabolism
is able to take place in the complete absence of the thyroid
hormone but at a rate of 10 to 50% below normal, depending
upon the species in question. The presence of excessive
amounts of thyroid hormone can only raise the metabolic rate

to a physiological limit of 50 to 100% above normal (Canzanelli,

6

et a1. 1939). In lower species not possessing a thyroid
gland, the effects of thyroid extracts are somewhat erratic.
Usually the action is of a catabolic nature. It is of in-
terest to note that the higher types of plants and animals
show more of a beneficial response whereas in the lower types,
the response is of an untoward and varied nature (Schneider
1939).

The thyroid hormone increases the activity of cell enzymes
which are usually of the oxidative type. In young dogs fed
.6 gm. of desiccated thyroid/kg. body weight/day for 3 to 6
weeks, the respiration was increased. The reSpiration of
the liver, heart, and nerves was increased an average of 25%
while the respiration of the thyroid gland was decreased 30%
(Gerard and McIntyre 1932). Hyperthyroid animals' brain
tissue was observed to oxidize glycogen, glucose, fructose,
glycerolphosphate, lactate, and succinate at four times the
normal rate; the rate of oxidation of glycine, methyl glyoxal,
and pyruvate was unchanged. This would indicate that the
thyroid hormone increases the activity of the specific de-
hydrogenases concerned with the oxidation of glucose and
its metabolic relatives (Cohen and Gerard 1937) . Hyperthy-
roidism.hastened the oxidation of d-amino acids of cells of
rat liver and kidneys. The enzyme, d-amino acid oxidase was
increased (Klein 1939). The oxygen consumption of hyperthy-

roid rats' liver, kidney, diaphram, and heart was reported.to

be increased. These workers reported no increase in the
respiration of the spleen, brain, and testes (Gordon and
Heming 1944). Thyroid-treated dogs have the ability to

synthesize amino acids from pyruvic acid and ammonia in

zitgg faster than control (Zitowskaya 1939).

Inasmuch as vitamins form a part of many tissue enzymes,
one might expect that the vitamin requirements are increased
in hyperthyrokism. The cocarboxylase content is lower in
hyperthyroid animals and falls more rapidly. Extra amounts
of thiamine have been shown to protect hyperthyroid rats
from weight losses (Peters and Rossiter 1939). Hyperthyroid
dogs on a yeast free diet develOped anorexia in 17 days
while anorexia develops in 32 days in normal dogs. Both
thiamine and riboflavin had to be added to the diet of
hyperthyroid dogs to prevent anorexia and a fall in weight
(Drill and Shaffer 1942). In further studies on dogs
rendered hyperthroid by .4 gm. to .6 gm of desiccated thyroid
per kg. of body weight the pulse rose to 150 to 160 beats/
minute. When yeast was removed from these dogs' diet while
they were still receiving thyroid, their pulse drOpped to
below 100 beats/minute in 30 to 60 days. The rectal temper-
ature of these dogs rose .5 degree while removal of yeast in
the diet caused to drop back to normal. The yeast in the
diet protected these dogs from.a loss in weight (Drill and
Hays 1942). More studies of hyperthyroid dogs revealed a
blood cholesterol varying within normal limits while the serum

phosphatase rose above normal. This rise could be inhibited

by a high yeast diet. The serum phosphatase rose after brom-
sulphalein was retained indicating that the excess thyroid
hormone caused liver damage.(Drill and Shaffer 1943). The
requirements for vitamins A, B complex, and C are shown to

be increased in hyperthyroidism. Vitamin D requirements are
probably increased while vitamin E requirements are not af-
fected in hyperthyroidism (Drill 1943).

The thyroid hormone plays an integral part in protein,
carbohydrate, fat, vitamin, and mineral metabolism, By heavy
feeding of fresh thyroid to dogs, it has been demonstrated
that there is an increased protein breakdown and a fall in
body weight (Schdndorff 1897). Thyroxine injection results
in glyconeogenesisirmnpmxrha in rats (Soskin 1941). In
hypophysectomized dogs, thyroxine injections maintained a
normal blood sugar during fasting (Soskin, et a1. 1939).
Thyroid hormone will also deplete the glycogen stores by ghrxme
oxidation (Althausen 1940). In thyroidectomized dogs, the
blood cholesterol,both free and esterified, phospholipids,
and total fatty acids rose after thyroidectomy. The cholesterol
was 27 to 380% of normal within a short period of time
(Chaikoff,et al. 1941). Later work demonstrated that the
rise of blood lipids depended upon the nutritional state of
the dog. The high blood lipids could be reduced by reducing
the caloric intake (Entenman, et a1. 1942). The high blood
cholesterol resulting from thyroidectomy in dogs could also
be prevented by hypophyseotomy (Thompson and Long 1941).

Both thyroidectomy and hypophysectomy in dogs resulted in

9

fatty livers, while thyroidectomy alone did not (Chaikoff, et
a1. 1943).

The minerals most affected by the thyroid hormone are
calcium and phosphorus. Prolonged hyperthyroidism in humans
results in osteoporosis and an increased calcium and phosphorus
excretion through the kidney and the feces. The extent of
mineral excretion was not correlated with the rise in metabo-
lism. Myxedema in humans results in subnormal excretion of
calcium and phosphorus (Aub, et a1. 1929). Further studies
revealed a negative calcium and phosphorus balance in humans
(Hansman 1938). In dogs, 1 gm./kg. body weight/day of de-
siccated thyroid induced hyperthyroidism within three days
and excretion of calcium began in the urine (Logan, et a1.
1942). Small doses of desiccated thyroid in thyroidectomized
dogs lowered calcium excretion and caused an increased intake
of calcium. In these studies, small doses of desiccated
thyroid restored a positive calcium and phosphorus balance,
which effect lasted for some time after the discontinuance of
dosage (Breitbarth 1940).

The thyroid hormone increases the activity of the kidney,
generally to lower its threshold. Thyroxine treatment in
normal dogs resulted in increased clearance of creatinine,
glucose, and diodrast. This result was theorized to be due
to a combination of the following, 1. Opening of previously
inactive nephrons, 2. Increased functional activity of tubular

tissue, 3. Hypertrophy of existing tubules and 4. Possibhy

10

an influence on the rate of transfer by effects on the actifiry
or the concentration of adenosinetriphosphate (Eiler, et a1.
1944). Thyroid feeding to normal dogs and dogs having diabetes
insipidus resulted in increased glomerular filtration. Urea
clearance was also raised (Hare,iet a1. 1944). Hyperthyroid
dogs have been shown to excrete calcium through the kidney
(LOgan, et a1 1942).

The absorptive powers of the intestine are increaseiby
the thyroid hormone. The increased absorption of carbohydrfies
is theorized to be due chiefly to a stimulation of phosphory-
lation (Althauser 1940). Although thyroidectomy in the dog
did not decrease jejunal secretion while the metabolism
drOpped to 85% of normal,thyroxine doses of 1 to 1% mg/kg.
body weight/day to normal dogs resulted in increases of
metabolism of 1:5 to 16% and 27 to 51% respectively with in-
creases of jejunal secretion on both dosages. The increased
secretion remained some time after the armation of the
dosage (Fink 1944).

The metabolism of nerve cells is increased.with result-
ing speeding of reaction time and cerebration (Salter 1940).
Studies by the Warburg technic indicate the respiration of
hyperthyroid brain cells to be 30% above normal (Cohen and
Gerard 1937). The administration of .4 gm. of desiccated
thyroid/kg. body weight/day for one week to normal dogs,
reduced the shock time of intestinal manipulation from.nega-
tive results even on long periods of manipulation, to 15 to

20 minutes when the intestines were handled (Schachter and

11

Huntington 1940).

The thyroid hormone results in increased function of the
circulatory system such as increasing blood volume, and in-
creasing the rate and strength of heart contractions. Ac—
coring to McIntyre (1931) a dose of .3 gm. dried thyroid/kg.
body weight/day given to dogs for 7 to 8 weeks reSulted in
weight loss and tachycardia. Denervating the heart protected
the dogs from heart flutter and death. The animals lost
weight on this dosage. A dose of .6 gm./kg body weight/day
in the dogs with denervated hearts resulted in weight losses,
tachycardia, and temperature elevation. The pulse rate was
proportional to the metabolism.in 2 dogs. The results are

as follows.

Calories/24 hours Pulse Rate
400 70
450 60
600-800 ‘100
500-700 100-110

Electrocardiogram studies in sheep showed a diminished heart
rate and amplitude of the t wave when the sheep were thyroi-
dectomized (Mullick, et a1. 1948). Human studies revealed a
relationship of metabolism to pulse in children but this re-
lationship was lost as the person aged (Sutliff and Holt 1925).
A drop from 140 - 150 to 90 was reported in a number of human
cases treated for hyperthyroidism.when the metabolism.dropped
back to normal (Starr, et a1. 1924). In human.medical practice,

this correlation is not of too great value because of the great

variability of the pulse ani the lack of a complete correla-
tion (Means and Aub 1925).

The sexual apparatus is affected to some extent by the
thyroid hormone. There are other functions of the thyroid
hormone than in the develepment of the gonads. A male Jersey
was thyroidectomized at 4 months of age and developed myxedema
symptoms in 60 days. There was an absence of sex libido but
semen extracted by ampulla manipulation produced pregnancy.

A dose of 25 gms. desiccated thyroid restored him to normal
behavior and sex libido (Peterson, et a1, 1941). Similar
results were obtained from thyroidectomized cows. Thyroidectomy
resulted in abortion in some cases. Ovulation occurred without
estrus symptoms and pregnancy was produced by artificial
insemination. Thyrotherapy increased milk secretion and
produced normal estrus (Spielman, at al. 1945).

The rate of thyroid secretion depends on several factors.
Seasonal rhythm has been demonstrated in chicks (Reineke and
Turner 1945). The thyroid secretion rate has been shown to
be lessened by high environmental temperature in mice
(Butt 1949). Hybrid chicks have a higher thyroid secretion
rate than pure bred (Mixner and Upp 1947).

The secretion rate is regulated internally by reciprocal
relations between the thyroid gland and anterior pituitary,
and action of iodine containing compounds upon the thyroid
gland itself. Lack of thyroid hormone will result in increased
production of thyrotropin by the anterior pituitary while
excess thyroid hormone will decrease the thyroid hormone

(Leblond and Mann 1942). The oxygen consumption of the

13

thyroid gland is increased by thyrotropin while this effect
is nullified ig.zitgg by the addition of thyroglobulin.
Thus an excess of thyroid hormone would inhibit the thyroid
by direct action (Galli-Mainini 1941). Inorganic iodides
also inhibit the thyroid gland (Morton, et a1. 1944).

The action of the thyroid hormone may be regulated in
other ways than by regulation of its production and the
physiological limits of the tissue. In guinea pigs, the
response to thyroproteins varied as the logarithm of the
dosage (Reineke and Turner 1942). Repeated injections of
thyroglobulin into rabbits failed to cause a rise in metabo-
lism upon subsequent injections. The worker postulated that
antibodies may have been formed to the thyroglobulin
(Lerman 1942). Dogs given thyroid preparations, by injection
and orally, were stated to form substances in the isobutyl
alcohol and acetone extracts of the urine which prevented.the
action of the thyroid hormone in rats so as to lower the
metabolism of the rat (Keeser 1938). In a study made on the
various organs of the pig, ox, and man, it was found that the
paraxanthine content of the tissue was proportional to its
iodine content. Paraxanthine was demonstrated to inhibit
the action of thyroxine on the frog heart. The thyroid gland
was found to be the highest in antithyroid activity by the
paraxanthine determination. The thyroids from.humans with
toxic goiters were found to be somewhat lower than normal
(Carter and Jenkins 1944). This hypothesis is borne out in

studies with myxedematous and euthyroid humans. The eutlyloid

14

individuals were able to tolerate several times their own
thyroid secretion rate of desiccated thyroid without showing
a rise in metabolic rate while myxedematous persons gave a
marked response in metabolic rate to much smaller amounts of
desiccated thyroid (Winkler, et a1. 1942). . Blood
iodine levels and metabolism studies on normal, thyroidec-
tomized and thiourea or‘dfiouracil-treated degs indicate that
the thyroxine destroying properties are not concentrated in
the thyroid gland in the dog but are shared by other tisSues.
Doses of .38 gm. of desiccated thyroid per day caused a small
increase in the metabolic rate and a slight increase of the
blood iodine. A dose of .77 gm. of desiccated thyroid per
day caused similar results with a small loss of body weight.
In three to four weeks the blood iodine and.metabolism fell
back to normal. There was no difference in blood iodine
levels in the normal, thyroidectomized and goitrogen-treated
dogs. In nonaof the dogs could the metabolism be raised
much above normal. Intravenous injections of 2 mg. of thy-
roxine for 13 to 27 days produced similar results to oral
feeding of desiccated thyroid (Danowski, et a1. 1946).
Radioactive tracer studies in the rat indicate that large
doses of thyroxine are detoxified in the liver and secreted
in the bile (Leblond 1949).
Thyroidectomy_of Adult Dogg

The early workers were unaware of the parathyroid function,

and thus the thyroidectomy symptoms they recorded were mostly

15
those of hypoparathyroidism. Even so, one of the earliest
workers noticed that part of the thyroidectomy symptoms in
dogs could be overcome by transplanting thyroid glands into
them (Schiff 1884). Further attempts at thyroid replacement
therapy to thyroidectomized dogs were also clouded by the
parathyroid syndrome,_ Oral administration of fresh thyroid,
various thyroid extracts, and an iodinated casein of doubtful
potency yielded negative results because the dogs died of
tetany. Death usually occurred too early for any myxedematous
symptoms to occur. The description is accurate enough to
show that the thyroid preparations used, probably aggravated
the tetany symptoms (Wormser 1897).

The muscle fiber metabolism of thyroidectomized puppies
was 24.2 to 24.8% below normal. Additions of 2 to 4 mg. of
thyroxine caused the metabolism to be increased to a ceiling
of 50% above normal in some after a period of 8 to 12 days
on dosage. The increase was not uniform (Dye 1933). Another
author reports that thyroidectomy resulted in a drOp of .03
to .5 degrees C or an average of .3 degrees C in body temper-
ature, some decrease in metabolic rate, a decrease in heart
weight and heart rate, and an increase in body weight due
to fat storage (Binswanger 1936). ‘When female dogs were
thyroidectomized, the blood iodine was reported to be relatively
unaffected because the iodine concentrated in the ovaries
(Perkin and Brown 1938). Thyroidectomy was reported not to
decrease the jejunal secretion of adult dogs (Fink 1944).

The dog may normally depend upon the thyroid to a lesser de-

16

gree because the metabolism does not fall to the same extent
as in man, and the severe myxedema syndrome was reported to
be absent (Danowski 1946).
Studies with Radioactive Iodine

Radioactive iodine studies have revealed that the thy-
roid gland picks up iodides from the blood stream at a much
greater rate than any other tissue. When large enough
quantities of iodides were injected, they were found to a
great extent in the urine (Hertz, et a1. 1938). In previously
untreated humans, 50% of the injected iodide is regularily
bound (Chapman and Evans 1946). After thyroidectomy, the
iodine content of the body normally drOps, especially in
organs such as the pituitary, adrenals, and ovaries which
are otherwise high in iodine (Sturm and Buchholtz 1928). The
concentrating action of the thyroid gland may be made use
of to test the completeness of thyroidectomy when one uses
radioactive iodine and a Geiger-Mflller counter (Reinhardt
1942). Dogs! thyroids which had been perfused with iodides
one to two weeks previously were prone to assimilate more
(Sturm 1930). In humans, the lowest tracer dose of radio-
active iodide will yield the greatest percent uptake (Hertz,
et a1. 1942). The thyroid shows the greatest ability to fix
iodides when there is lack of iodine in the diet (Leblond
and Mann 1942).

A study using five dogs from 8 to 10 kg. body weight
showed a turnover rate of 50 to 100 micrograms of protein-

bound iodine in 24 hours. The turnover time was judged to

17
be 4 to 7.5 hours. These studies would indicate that the
dog normally secretes 24 to 240 micrograms of thyroxine
per day (Taurog, et a1. 1947).

Canine Metabolism Determinatiogg

 

In an early experiment, the dOg was used to determine
the caloric value of different foods. In this work, Rubner
(1894) was able to get close correlation of the cal ric in-
take and the direct and indirect metabolism determinations.
Measurements by an indirect method, revealed a marked increase
in the metabolic rate upon exposure to cold in dogs (Morgulis
1924). Adrenaline has been demonstrated to raise the basal
metabolic rate of dogs. The determinations were made by
an indirect method (Boothby and Sandiford 1923). Later
work, by the use of a mask type respirometer, gave a host
of normal basal values. The metabolism of dogs was
demonstrated to be affected by fasting, mange or other skin
irritations, and respiratory infections (Kunde 1922;

Kunde and Steinhaus 1926). A review of much of the pre-
vious results of metabolism determinations on dogs has been
compiled and graphed by Brody and Proctor (1932). A wealth
of data has been recently obtained on the normal m tabolic
rate of dogs under light anesthesia. A mask type respiro-
meter was used (Galvao 1946).

The use of anesthetics to produce quiosence in dogs prior
to basal metabolism determinations does not vary the result
to a great degree. Barbiturates in general produce prompt,

dreamless sleep. Anesthetic dosages produce little diSUlrbance

18
ofibnction. The body temperature is slightly lowered while
the pulse is quickened (Sollman 1943). Hypnotic doses of
Amytal, Barbital Sodium, Dril, Ipral, Neonal, and Phenobar-
bital produce a 4 to 10% decrease in the metabolic rate of
humans (Anderson, et a1. 1930). Intravenous anesthesia of
humans with.Amyta1 produces only a slight fall in metabolism
(Zerfas, et al. 1929). Light anethesia with amytal permits
normal labor and uterine contractions in humans (Robbins 1929).

Intraperitoneal injections of 50 to 60 mg./kg. body weight
of amytal in the dog to produce deep narcosis, resulted in
little change of the respiratory quotient and calories pro-

. duced. The metabolism.usually decreased less than 10% even
when the body temperature fell as much as 2 to 3 degreea(Deue1,
et a1. 1926).

The metabolism remains within normal variability.
Anethesia in goats with Pentobarbital Sodium produces no
disturbance of milk secretion (Reineke 1941). The same
drug in calves lowered the metabolic rate about 10% (Mukerji
1948). The use of-Dial (Ciba Pharmaceutical Co.) at the rate
of 0.30 to 0.40 cc. intraperitonealy after previous injection
of 10.mg. morphine subcutaneously, resulted in no significant
change of metabolic rate in trained dogs‘which.were also
run without anesthesia (Galvao 1946).. A small drOp, approxi-
mating 10%, is found in dogs under light anesthesia with
Pentobarbital Sodium.(Schirmer 1948).

The expression of the metabolic rate of dogs in the past

has been varied and problematical. An accurate means of

19

expressing it in terms of surface area would be satisfactory
if there were a reliable means of surface area determination
in the dog. Meeh's formula for surface area has been much
revised especially in humans. Some time ago, the surface
area of humans was determined quite accurately by paper molds
and a formula devised for calculating it from the individual's
height and weight (DuBois and DuBois 1914; 1916). No such
formulation has been devised for the dog which is valid for
all breeds. Paper mold determinations have lead to a formula
using weight, length, and state of nutrition (Cowgill and
Drabkin 1927).

Since the formulations vary somewhat from each other
on the same dog, a power of the body weight would seem to be
the ideal method of expression of metabolism. Meeh's formula
involves a constant multiplied by the 2/3 power of the body
weight. Lusk reports the 0.60 power of the body weight to
give fairly constant values when related to caloric output
in young dogs (Lusk 1928). Galva>derived a formula of
Calories per hour equal 2.00 wo'go, when the weight is given
in kg. for metabolism valueaobtained on dogs under trOpical
conditions. He discusses the possibility of the warmer
climate making the metabolic rate less dependent upon the
surface area. Brody, compiling records on all species,
arrived at the constant figure of 70.5 calories/24 hours/kg.
body weight to the .73 power. This,he also expressed as the
.734 power (Brody 1945). In the light of his exhaustive survey,

the specific metabolism expressed by Brody, that is the caloric

20

output expressed as a function of the body weight in kg. to
the 0.73 power, seems the best way to express metabolic re-

sults in this type of research.

21

EXPERIMENTAL PROCEDURE AND EFFECTS
‘GQneral Procedure for Metabolism Determinations
Temperature: A certified clinical thermometer was used in
all cases to ascertain body temperature, and inserted approxi-
mately 3 inches in theIBCUny and.allowed to remain at least
two minutes. The thermometer was shaken down immediately
after reading. The temperature was taken before anesthesia,
and before the animal became excited. Occasional readings
taken after the metabolism determination did not show any
depression of temperature during the time involved.
23933; An accurate watch was used for 30 seconds, or longer
if the pulse tended to be irregular. It was taken from the
'median artery.

Body Weights: The weight of the Operator, holding the dog,

 

was taken on a Toledo non spring scales, and then the weight
of the operator alone was subtracted. Weights were taken
preceding metabolism runs, and after the animal had been.with-
out food for at least 12 hours, thus tending to show a more
correct weight.

Basal Metabolic Rate: The dogs were fasted for 12 hours be-
fore the tests were made, but were given free access to water.
Weights were always taken at the same time of night. After
ascertaining pulse, body temperature, and time, Sodium.
Pentobarbital solution was dministered intravenously until a
light anesthesia was produced. The Sodium.Pentobarbital so-
lution consisted of an aqueous solution of 10% pure ethyl
alcohol by volume containing 3% Sodium pentobarbital. The

22

degree of anesthesia was that point at which the pupil of fix:
eye barely contracted and the dog did not resist pressure
around the nose. This would indicate whether he would tol-
erate the fixation of a mask. At this point of anesthesia,
the dogs still powessed digital reflexes and reacted to noise
and handling. The dog was then allowed to rest for 20 to

30 minutes in order to assure a level rate of metabolism.

In order to correct for atmospheric pressure, a Central
Scientific Company mercury barometer was used. The temperature
was taken from the water in the metabolism apparatus by a
centigrade thermometer for at least five minutes. The
caloric factor per liter of oxygen consumed for a dog on a
mixed diet is known to be approximately 4.825 by comparison
with direct calorimetry (Lusk 1928). The aqueous vapor
saturation was assumed to be constant at 80%. As a further
check on barometric pressure, another reading was taken
after the last dog had been run.

The respirometer was of the Benedict-Roth type and used
Wilson's soda lime to absorb the 002. This was changed about
every 90 runs. A smaller bell was used on dogs to get a
greater slope. The ratio was a 1 'mm. rise for every 12.6
cc.of 02 used. The machine was tested before each run by
placing a 30 gm. weight on the bell and it was observed if
the bell fell over a period of 5 minutes. This was repeated
with the mask clamped off, and the valve to it Open.

The oxygen used was thus calculated as calories per hour
when the degs were run for at least 6 minutes, or as long as

was needed to get a steady slope for a six-minute period.

25

To convert to a constant figure somewhat in relation
to surface area, the specific metabolism was computed as
cal./hr./kg.'73 (Brody 1945).

‘Eggd: Throughout the experiment, the food used.was
Dickinson's Dog Food given 3g libitum., manufactured by
Albert Dickinson Company, Chicago, Illinois.

Analysis:

Crude protein, not less than 25.0%

Crude fat, not less than 4.0%
Crude Fibre not over 3.5%
Carbohydrate ) not less

) than 44.0%
Nitrogen Free extract )

This diet was fed ad libitum throughout the experiments
except for 12 hours previous to the metabolisms determina-

tions, at which time the dogs were kept off feed.

24

Trials with Protamone on Intact Dogs

Procedugg: After normal valuGShad been ascertained by at
least three consecutive metabolism determinations, the dogs
were divided into three groups and placed on Protamone.
Group I was grien a dosage of 2 mg./kg. for 30 days and then
given 12 mg./kg. for 19 additional days. Group II was given
a dosage of 4 mg./kg. for 30 days and then given 20 mg./kg.
for 19 additional days. Group III was given a dosage of

8 mg./kg.for 30 days and then given 28 mg./kg. for 19
additional days. The dosage of exogenous thyroid was given
in capsule form daily.

Effects: Group I included dogs 1, 2, 5A, and 28, Group II
included dogs 3, 4, and 27, and Group III included dogs 25,
26, SB, and 24. These dogs were of several breeds, both
sexes, and adults. (table I)

On the lower dosages administered for the first 30
days to all the groups, no apparent symptoms were observed.
Although.it was impossible to keep food records, the amount
consumed may be said to have risen.

As to general appearance, only two dogs appeared to be
effected. Dog 5A in group I showed increased vigor and a more
luxuriant hair coat than he had previously. Previous to the
trial, this dog was somewhat lethargic and had a ragged coat
Dog 26 in group III became overexcitable and had an intermit-
tent diarrhoea. His movements may be described as lacking

the intelligence normally expected.

25

On the higher dosages administered for 19 additional
days, symptoms of hyperthyroidism began to appear. Food con-
sumption was increased. Differences were not evident by groups,
but more by breeds. Dogs 1, 3, 24, and 25, all Cocker-
Pointer crosses, were more tense and exhibited a strained
expression about the face. Dogs 5B and 27, both Cockers,
showed no evident effect. Dog 5A showed no effect on lower
dosage. In the Collies, dog 28 showed no effects, dogs 2 and
4 showed some hyperexcitability, and dog 26 became more
excitable, with a persistant diarrhoea. Alopecia and a rough
coat developed on dog 26. This was due in part to his
rubbing against the cage. His facial features assumed thoea
of an older dog.

The values such as Cal./hr/kg.°75, body weight, pulse
rate, and body temperature did not come to equilibrium dur-
ing the trial.

Group I, on the lower dosage of Protamone, 2 mg./kg./dmy,
showed a drop of metabolism to 75.8% of normal on the 8th
day and then rose to 111.5% of normal on the 17th day. At
the end of 30 days it was practically normal again. (tables
II and V) The body weight rose to about 110% of normal by
the 11th day and remained there (table VIII). The pulse rate
rose with the metabolism but remained somewhat higher. It
did not show a depression such as the metabolic rate had (tank:
XI). The body temperature remained slightly, but probably
not significantly, above normal (table XIV).

Group I, on the higher dosage of Protamone, 12 mgekg.fl$w

26
showed a rise of metabolism to 131.4% of normal on the 19th
day after the start of the higher dosage (tables II and V).
The body weight showed an irregular rise (table VIII). The
pulse rate and body temperature rose but not to the extent
of the metabolic rate (tables VIII and XI). The average
metabolism of this is compared with that of two other groups
in Fig. 1.

Group II, on the lower dosage of Protamone, 4mg./kg./day,
also showed a preliminary drop in metabolism. The metabolism
fell to 74.0% of normal on the 8th day, and then rose to
112.9% of normal on the 17th day. At the end of 50 days, it
was practically normal again (tables III and VI). The body
weight rose to about 106% of normal by the 8th day and
remained there (table IX). The pulse rate showed irregular
rises above normal (table XII). The body temperature was
from 100.1 to 100.8% of normal (table XV).

Group II, on the higher dosage of Protamone, 20mg./kg./
day showed little change in metabolism. It fell to 91.4%
of normal on the 12th day after the start of the dosage
but was about normal on the 19th day (tables II and VI).

The body weight rose to 111.5% of normal by the 19th day
after the start of the dosage (table IX). The pulse rate

was markedly increased 125.2 to 124.7% of normal (table XII).
The body temperature was also high, 100.5 to 101.2% of
normal (table XV).

Group III, on the lower dosage of Protamone, 8mg./kg./day
showed the preliminary drop in metabolism which occurred
on the 5th day, when it was 85.2% of normal. The drop was

partially repaired by the 8th day. The maximum rise was on
the 17th day when the metabolism was 114.3% of normal. After

27

that it dropped back toward normal (tables IV and VII).
The body weight rose to about 110% of normal by the 11th
day and remained there (table X). The pulse rate Was ir-
regular but always above normal (table XIII). The body
temperature was 100.0 to 101.3% of normal (table XVI).

Group III, on the higher dosage of Protamone,
28mg./kg./day, showed little change in energy metabolismi
(tables IV and VII). The body weight rose to 116% of nor-
mal (table X). The pulse rate was 120.4 to 119.1% of
normal (table XIII). The body temperature was 100.6 to
100.8% of normal (table XVI).

The metabolic response of the intact dogs depended to
a large extent upon the breed. The breeds were distri-
buted fairly evenly throughout the groups. The Cocker-
Pointer crosses, dogs 1, 3A, 24, 25, showed the least re-
aponse except that they all showed the characteristic drop
in metabolism on the 8th day following the initiation of
dosage. They never rose a great deal above normal on any
dosage (tables II to VII).

The Collies, dogs 2, 4, and 26 showed a greater reSponse
than the Cocker-pointers.. Dog 28 was a Collie but of another
litter. The Collies showed the drop in metabolism on the
8th day and by the 17th day it rose to its maximum, All
were headed downward by the 30th day but 2 and 26 were still
about 120% of normal. On the higher dosage, dog 2 rose

markedly while the others were relatively unaffected (tables

II to VII) 0

28

0f the rest, the response was variable. Dogs 28, a
Collie; and 27 and 5B Cookers showed the drop about the
8th day but failed to show a marked.rise in metabolism.on
any dosage. Dog 5A, an old dog of doubtful ancestry,
failed to show a drop in the metabolic rate and was 102.8
to 132.4% above normal on 2mg./kg./day of Protamone and
125.6 to 132.6% of normal on l2mg./kg./day of Protamone

(tables II to VII).

29

 

 

 

 

 

 

 

 

 

MO a . 4 3f . j
PERIOD. OF LOWE'R DOSAGE PERIOD OF HIGHER DOSAGE
d «I. anew/ml 60.1.20me
(Q ‘P ” l OAK/K6 3:, GRI’I’l 28.0116 “’Rfi
. '30T’ cry/”Joanna“ .4
g /A/ 7:407 0063“” ON PROTAMONE
$20 -
gflo camp I. . '
g . Xi“ /”".
2/00 ’-
K \ ROI/P III. /
090 \" 4
If: new II.
he .
$80 .
Lg] l L 1 L 1 1 1
A 7% /0 20 30 4o 50
3 DAYS 0N TR/AL
Figure 1
The effects of Protamone on the metabolic rate of
three groups of intact dogs.
lst 30 days last 19 days
Group I 2.0 mg./kg. day 12.0 mg./kg./<hy
Group II 4.0 mg./kg. day 20.0 mg./kg./day
Group III 8.0 mg./kg. day 28.0 mg./kg./day

30

_Trials with Desiccated Thyroid_g§ Intact Dogg

 

 

Procedure: Two mature dogs were used in this study, Number 6
was an aged.mongrel weighing about 9 kg. and about 7 years
of age. The muzzle hairs were graying. Number 29 was a 5
year old,male,Scotch Terrier weighing about 8 kg. Number 6
was given 4 mg. per kg. of body weight and number 29 was
given 2 mg. per kg. of body weight. The trial was continued
28 days.

Effects: There were no visible effects upon the dogs'
behavior or appetite in any stage of the trial. The
metabolism followed the same trend as that observed with

the intact dogs given Protamone. The values obtained at

the seventh day after the start of the trial were 67 to
70% of previous normal. The following values were close

to previous normal and did not go much above or below nor-
mal (tables XVII and XVIII). The body temperature did not
deviate much from normal and may have risen very slightly
above normal (table XXI). The body weight of the dogs de-
clined slightly on experiment (table XIX). The pulse of the
dogs showed a rise some 20 to 30% above normal (table XX).

The above effects are summarized in Fig. 2.

31

 

/40 V I I I I
IN 7:467 0065 ON DES/66A r50 THI’ROID
2 AND 4 MGJKGJDAI’ x PULSf

 

 

 

 

AVE. PERCENT OF NORMAL WLLES

J l l

20 30

 

A9
DAYS 0N mm.

*5 ' - -“ ‘ — ——._,_’.£.V.:r...-.—-a.- “v— “—’t‘-

Figure 2

The effect upon metabolism, body weight, pulse rate,
and body temperature of intact dogs receiving Desiccated
Thyroid at the rate of 2 to 4 mg. /kg./day for 28 days.

52

Lonngime Trial with Protamone on Intact English Bull Dqg
Bi tches
Pgocedure: Three adult English Bull Dog bitches were included
in the trial. Number 1 was 3% years old and had.whelped a
litter of 4, 2 of which had survived. She whelped 58 days
previous to trial and weaned the pups 7 days previous to the
beginning of trial. At the start of trial, she was gaunt,
especially in the flanks, and shedding excessively. Number 2
was 2 years old and had whelped a litter of 8, 5 of which
survived. She whelped 45 days previous to trial and was
on trial the last 5 days before weaning. Number 3 was 1
year old and a maiden.
Ibgs number 1 and 3 were put on 2 grams of Protamone
per 100 lbs. of dry matter and number 2 was allowed to re-
main as a control.
The diet was fed once daily in the following propor-
tions:
6 oz. Condensed Milk (75% water)
8 oz. Canned dog food (74% water)
8 oz. Dry meal
The meal was ground "Gropup" and supplied by the Kellogg
00., of Battle Creek, Michigan. Its guaranteed analysis was

as follows:

Protein (Minimum) 22.5%
Fat (Minimum) 3.5%
Fiber (Maximum) 4.0%

Moisture (Maximum 8.0%

33

Nitrogen Free Extract (Minimum) 50.0%

Ash (Maximum) 9.0%

Potassium iodide was in the

meal at , .00057%
The canned dog food was "Pard", marketed by Swift &

Co. of Chicago, Illinois. Its guaranteed analysis was as
follows:

Protein (Minimum) 10.5%

Fat (Minimum) 2.5%

Nitrogen Free Extract (Minimum) 9.0%

Fibre (Maximum) 1.0%
Ash (Maximum) 5 .0%
Moisture (Maximum) 74.0%
Calcium.(Maximum) .65%
(ninimum) .45%
Phosphorus (Minimum) .30%
Salt (Maximum) .75%

.50% iodized salt

The diet was deemed adequate and the Protamone mixed
in the meal in a proportion so that there was 2 grams of
Protamone per 100 lbs. of dry matter fed. The amount fed,
was the amount the dogs*would clean up in 20 minutes.

The weights of the dogs were taken in the afternoon
and the dogs were fed in the morning.
Effects: No evidences of changes were seen in Dog 2, the
control, and dog 3 on Protamone. Dog 1 recovered from her

poor condition by filling in at the flanks in the first three

34

weeks. Her hair coat assumed a sheen and the shedding stopped
during this period. The weight records of all the dogs re-
vealed no marked difference between the control and the
treated dogs (table XII).

For the first 48 days of the trial, the treated dogs
received an average of 36.0 mg./day of Protamone. This would
be about 2.0 mg./kg./day. For the last 100 days of the
trial, the treated dogs received an average of 32.6 mg./day
of Protamone. This would be about 1.7 mg./kg./day.

The radioactive iodine studies showed no definite de-
pression of the thyroid gland activity (pg. 48).

The dogs all came into estrus normally while on trial.

55

Thyroidectomy

 

Procedure: The object was the complete removal of all the
thyroid tissue, leaving as much parathyroid tissue as possible.
In all cases, the two lateral parathyroids were left.

The Operative procedure was done under sodium pento-
barbital anesthesia and performed aseptically. A midline
incision was made from the region of the thyroid carilage
for about two inches posteriorly. The ribbon muscles ventral
to the trachea were separated by blunt dissection. The
thyroid was found on either side as an almond-shaped,
reddish-brown gland, near th; angle of the jaw and adjacent
to the carotid sheath. The carotid artery could be palpated
in this area, thus aiding in location. The vessels inferior
to the g1and.were ligated with catgut and the gland dis-
sected out, leaving vessel attachments. The lateral para-
thyroid was located as a pink, oval structure on the lateral
surface of the thyroid. By use of a sharp, pointed scissors
and small hemostat this was dissected free from the thyroid
and its blood supply also was dissected free from the thyroid
until it was possible to ligate the superior thyroid vessels
without including those of the parathyroid. The superior
vessels were ligated and the thyroid removed. This was re-
posted with the other thyroid. In some instances the para-
thyroid was high on the thyroid and it was impossible to re-
move it and its blood supply without including some thyroid
tissue. In this event, the parathyroid.was dissected free

and inserted into the muscular tissue.

36

The ribbon muscles were sutured with catgut and, after
sulfa-urea application, the skin was sutured with nylon. The
dermal sutures were removed on the fifth day. The procedure
of surgery is outlined by Markowitz (1937). Anatomy of the
region is outlined by Sisson (1938).

No symptoms indicative of injury to the recurrent
laryngxd.nerves were observed.

Thyroid Weights:

 

Thyroid wt.
Wt. left Wt. rt. as Per Cent
Dog No. Gland Gland of Body Wt. Remarks
1 .6249 .4470 .00812 Grou I: Protamone
2mg. g. 10/19-11/19
2 .4447 .5245 .00740 12mg/kg.1l/20-12/16
5A .4170 .4955 .01049
28 .4446 .4751 .00578
3 .2105 .2943 .00407 Grou II: Protamone
4mg. g. 10/19-11/19
4 .2485 .2440 .00291 20mg./kg.ll/20—12/16
27 .2000 .5684 .00458
25 .3227 .3900 .00532 Grou III: Protamone
8mg. g. 10/19-11/19
26 .6604 .5567 .00665 28mg./kg. 11/20-12/16
58 .5117 .5549 .00580
24 .5988 .4552 .00527

The only evident difference seen here is that the dogs
in Groups II and III had smaller thyroids, indicating that the
Protamone had more depressing effects upon thyroid activities

in higher dosages. There was no control group of the same

57

breeds, so a further comparison would be of little value.
Groups II and III had thyroids of almost the same size.

Individual Surgery Reports and Aftercare: The Calcium

 

Gluconate used was a 10% aqueous solution with 10% dextrose
and given intravenously and intraperitoneally (McClean 1942).
The Parathyroid Extract (description of dogs, table 1; )

was U. S. P.31 cc. equaling 100 units (Albright 1942).

Group I V

Number 1 was thyroidectomized 12/8/48 with a rather
difficult dissection of the parathyroids. However, b0th.were
left intact. Three days later some tetany developed, alleviated
by calcium gluconate. Moderate tetany developed for two
days afterwards and was treated as before with the addition
of .1 cc parathyroid extract intramuscularly and calcium
chloride in the drinking water. There was no recurrence of
tetany and recovery followed.

Number 2 was thyroidectomized 12/9/48 with an easy dis-
section of the parathyroids leaving both of them intact. On
the third day there was some twitching which ceased upon cal-
cium gluconate injection. The procedure was repeated on the
fourth day. Calcium.chloride was included in the drinking
water. 0n the 14th and 15th.day, tetany occurred andvvas
treated by calcium gluconate injection. However, the dog died
in coma on the 15th day.

Number 5A was thyroidectomized 12/9/48 with a difficult
dissection of the parathyroids. Both the parathyroids were
dissected free and replaced in muscle. There1were no symptoms

of tetany following the surgery.

58

Number 28 was thyroidectomized 12/9/48 with an easy
dissection of the parathyroids leaving both of them intact.
There were no symptoms of tetany following the surgery.

Group II

Number 5 was thyroidectomized 12/8/48 with a difficult »
dissection of the parathyroids. Both parathyroids were dis-
sected free and replaced in.muscle. Tetany occurred 3 days
afterwards and was treated with calcium.gluconate. Less
severe tetany occurred the 4th and 5th day and was treated
with calcium gluconate and .1 cc injections of parathyroid
extract. Calcium chloride was put in the drinking water.
Tetany occurred intermittently under treatment until the 18th
day when the dog died in coma.

Number 4 was thyroidectomized 12/9/49 with a rather
difficult dissection of the parathyroids. One gland was
left intact while the other was dissected out and replaced
and inserted into muscle. Tetany occurred on the 3rd day,
was worse on the 4th and.the dog died on the 5th day despite
treatment with calcium gluconate and .1 cc parathyroid extract.

Number 27 was thyroidectomized 12/9/48 with an easy dis-
section of the parathyroids leaving both glands intact. There
were no symptoms of tetany following the surgery.

Group III

Number 24 was thyroidectomized l2/8/48 with a difficult
dissection of the parathyroids. However, both were left in-
tact. Violent tetany occurred on the 3rd day. Calcium
gluconate injections alleviated the convulsions but they re-

occurred on the 5th day and were followed by death.

59

Number 25 was thyroidectomized 12/8/48 with a difficult
dissection of the parathyroids. However, both were left in-
tact. Severe convulsions occurred on the 3rd,4th, and 5th
days but were alleviited by injection of calcium gluconate
and .lcc parathyroid extract. Severe tetany recurred on the
7th day, followed by coma and death despite calcium.gluconate
injections.

Number 26 was thyroidectomized l2/9/48 with a fairly
difficult dissection of the parathyroids. One gland was
left intact while the other was dissected free and reinserted
into the muscle. Twitching occurred on the 2nd day and
continued through the 5th under treatment with calcium gluconate
and .lcc parathyroid extract. Intermittant periods of twitch-
ing occurred for 18 days and were treated with calcium gluconate
injections and calcium chloride in the drinking water. Re-
covery followed.

Number 5B was thyroidectomized 12/9/49 with an easy
dissection of the parathyroids leaving both glands intact.
Slight twitching occurred on the 3rd and 4th days which was
alleviated by calcium.gluconate injections. 0n the 6th day,
sudden tetany occurred, however, followed by coma and death.
Dogs Previously Untreated: All of these dogs were used in
the Studies with Protamone and Desiccated Thyroid in Thyroidec-

tomized Dogs together with dogs 1 and 27 from the Studhas of

Protamone on Intact Dogs (Described in table XXXII).

40

Number 2 was thyroidectomized 12/13/48 with a difficult
dissection of the parathyroids. One gland was left intact
and the other dissected free and reinserted into the muscle.
There were no symptoms of tetany following the surgery.

Number 5 was thyroidectomized 12/15/48 with an easy
dissection of the parathyroids leaving both glands intact.
There were no symptoms of tetany following the surgery..

Number 4 was thyroidectomized 12/5/48 with a rather
difficult dissection of the parathyroids. One gland was
left intact and the other dissected free and reinserted int:
the muscle. There were no symptoms of tetany following the
surgery.

Number 24 was thyroidectomized 12/13/48 with aneeasy
dissection of the parathyroids leaving both glands intact.
There were no symptoms of'tetany following the surgery.

Number 25 was thyroidectomized 12/13/48 with an easy
dissection of the parathyroids. Both glands were left intact.
There were no symptoms of tetany following the surgery.
Tetany Effects:

Previously

Group I Group II Group III Untreated
Number of dogs in

the group 4 3 4 5
Number of dogs de-
veloping tetany 2 2 4 0

Average days for
tetany to develop 3 3 2.8 -

Number'which
succumbed l 2 3 0

Number which
survived 3 l l . 5

41

Group I received 2 mg. Protamone/kg./day for 30 days followed.
by 12 mg. Protamone/kg./day for 19 days.

Group II received 4 mg. Protamone/kg./day for 30 days followed
by 20 mg. Protamone/kg./day for 19 days.

Group III received 8 mg. Protamone/kg./day for 30 days folhawed
by 28 mg. Protamone/kg./day for 19 days.

The previously untreated group had no previous dosage of

exogenous thyroid.

The effects of the surgery were to remove two of the four
parathyroid glands and injure, or c0mp1etely sever in some
cases, the blood supply to the two remaining. The surgery
was all performed by the author and thus differences in technic
would be negligible. The extent of damage to the parathyroid's
blood supply was not the determining factor in the development
of tetany from.hypoparathyroidism. For example, dog number 5A
had his parathyroids reinserted and developed no tetany. The
greater the previous dosage of Protamone, the quicker the
develOpment of tetany, the greater the fatality, the less
survival, and the greater the number developing tetany. None
of the dogs previously untreated developed tetany while all
of the dogs on the highest dosage of Protamone develOped.tetany.
Effects of Thyroidectomy; Normal values were obtained.from
only those dogs which had been on previous Protamone studies
and thus the comparisons with the normal runs were complicated
by the effects of the protamone. Values were obtained from

dogs number I, 5, 26, 27 and 28. These dogs were formerly on

42

Protamone (tables II to XVI). In the case of dogs number 5
and 28 no drop could be seen in calories per hour per body
weight, pulse rate, and body temperature. The body weight
of both dogs was seen to change but little (tables XXIII to
XXVII).ID1bfih of these dogs, radkmctivity tests showed a re-
taining power for the 1* and thus may be assumed to have had
some thyroid function left (pg. 45). They also showed no
other symptoms of thyroidectomy. For these reasons they were
omitted from this phase of the study.
TABLE OF THYROIDECTOMY EFFECTS
(Compiled from tables XIII to XVII) Dogs 1, 26 and 27

Average after
Normal Thyroidectomy % of Normal

0a1./hr./kg.°73 4.714 5.402 72.2
«Body weight (kg.) 13.0 15.2 117.0
Pulse rate/min. 86.8 72.6 83.8
Body temperature 100.0 99.5 99.5

(degrees F.)
*The body weight was 113.1% of normal at the time of
thyroidectomy.

Dogs number 1, 26 and 27 were seen to react within 35

to 40 days after'the thyroidectomy by a marked fall in specific
metabolism of nearly 30% while the body weight rose slightly.
The pulse made a less sizable drop than the specific metabolism.
The body temperature dropped an.average of 0.5 degrees F.

Other effects of thyroidectomy on the above dogs were a

general lethargy, and loss of appetite. They showed little

45

inclination to play or romp as had been their previous

custom. There was a slight but perceptible edema of the lower
portions of the body such as the brisket and legs. One

Cooker (#27) showed edema of the face. Less pentobarbital

was needed to produce light anesthesia. Other dogs for which
no pre-thyroidectomy determinations had been made showed

similar symptoms of edema and lethargy. The progressive
decline in metabolism.and pulse rate with increasing time

after thyroidectomy is shown clearly in Fig. 3

 

 

 

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weight, pulse rate, and body temperature.

DAY OF
7107701056 70w

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Figure 3

The effects of thyroidectomy on the metabolism, body

The first values

obtained were gotten on the last day that they received Pro-

tamone.

The normal values were obtained previous to the

Protamone trial.

45

1*131 Determinations on Thyroidectomized Dogs

Procedure: The procedure was essentially that of Reinhardt
to determine the completeness of the thyroidectomy and de-
termine if there was any remaining thyroid tissue (Reinhardt
1942) (dogs described tables I and XXXII).

Five cc.of a solution of 1*131 (1000 counts per minute
per cc.) was injected into the dogs' radial veins. Counts
over this area 2 minutes after injection revealed no foci
of activity, thus verifying completeness of injection. Counts
were obtained by a Geiger-Muller counter, over the regions
of the kidney, extremities, body, heart, and thyroid. Besides
the thyroidectomized dogs, a new dog from the pound was included
as a control.

Results of 1*131 Injection on a Normal Dog: Counts after

 

injection of 1* in a normal dog. Figures are in counts per

minute on the Geiger-Muller counter. The dog's weight was

10.5kg.

Time Extremities Thyroid Kidney Heart
5 min. '23-)!- --- ’23-):- —-— 550 '35-)? -...
10 min. ** --- 250 300 250
20 min. ** --- 250 300 250
1%— hr. H- --- 500 500 200
3% hr. 50 250 200 100
8 hr. 25 350 100 50
24 hrs. 50 900 100 ** ---
6 days 50-60 800—900 50-60 50-60
13 days 15-20 350-450 0 0
19 days 0-5 150 O 0

we no determination made

46

Results of 1*131 Injection on Thygoidectomized Dogs:

Counts after injection of 1* into thyroidectomized dogs.
Figures are in counts per minute on the Geiger-Muller counumu
The dogs are described in table XXXI. Ext. - extremities;
Thy. - thyroid region; K. - kidney region; H. - heart region.
*Body weight in kg.

24 hrs. 53 hrs.

Dog
No. Wt.* Ext. Thy. K. H. Ext. Thy. K. H.

1 12.3 5-10 5-10 25 5-10 0-5 0-5 O-5 0-5

2 9.6 55 55 50 60 0-5 0-5 25 10
5 9.7 50-55 55 260 100 0-25 5-15 5 15
4 8.7 20-55 15-25 160 55 15 15 25 20
5 8.9 40 90a 120 120 25 50480a 80 50

24 19.3 30 20-25 160 25 5-10 0-10 25 10-15
25 12.9 35 35-40 310 35 15 5-15 15 15-20
26 18.7 25-30 25-30 50 20-25 10-20 10 3O 2O
27 13.8 40 30-35 60 35 10 10 10 10
28 15.5 25 25-30 110 30 5-15 5-15 100 15
a- mostly in the thymus region

The rapid disappearance of the 1*131 from the thyroi-
dectomized dogs was in.marked contrast to the normal. In
none of the dogs except number 5 was there any high incidence
of count over the thyroid region in relation to the extremities
and in this individual it was in the region of the thymus.
The high initial count over the heart and kidneys would in-
dicate circulating iodide rather than thyroxine. However,

number 28 retained a high count especially over the kidney region.

47

Autopsy of Dogs with Indications of Thyroid Function: Inas-
much as both 5 and 28 had retaining powers for the 1*131, it
would indicate that they had some thyroid function left.
Their metabolic rate had not dropped from the normal rate,
(table XIV). Accordingly, they were sacrificed and autopsied
65 hours after injection of I*l3l.

Autgpsy of Number_§

 

No thyroid tissue was found in the region of the remowmi
thyroid. Both parathyroids were found functioning. The

counts were as follows on the Geiger-Muller counter:

Body and extremities 20

Thymus ' 40-50

Liver 80

Kidney 20

Spleen 8O

Aorta region 20-80 (80 where the aorta

passes through the
diaphram.)

Autopsy of Number 28
N0 thyroid tissue was found in the region of the removed
thyroid. Both parathyroids were found functioning. The counts

were as follows on the Geiger-Muller counter:

Body and Extremities 10
Thymus 15
Liver 2O
Kidney 20
Spleen 20
Aorta region 15-20

Adrenal 60

48
The retention of iodine would indicate some thyroid
activity.

I*l3l Determinations on Intact Dogs

 

Procedure: It was the objective to determine the effect of
feeding exogenous thyroid materials on the function of the
thyroid gland.

The dogs used were the English Bull Dog bitches on the
long time trial on Protamone, dogs I, II, and III (pg 32);
the intact dogs on desiccated thyroid, dogs 6 and 29 (pg 30);
and the English Bull Dog Puppies on the growth experiment
with Protamone (pg.80).

A solution of 1*131 was injected into the radial vein
and.counts were taken over the area two minutes later to
determine the completeness of injection. The solution used
contained other iodides than the 1*131. The English Bull Dog
puppies and dogs 6 and 29 were injected with 2 cc of a so-
lution of 1*131 (lOOO counts per minute per cc.) while the
English Bull Dog bitches were injected with 4 coeof the same
solution. Counts were obtained over the thyroid region and
the extremities. t values were calculated after the thyroid
gland had picked up its maximum.count (1 hr.) by the following

formula: t equals counts_per minutelbody weight
counts per minute injected

 

Results of I*l3l Injection on Intact English Bull Dog Bitches:
The amount of iodine picked up by the thyroid gland of dog II
(control) was slightly lower than in dogs I and III. The re-
gression of the logs. of the t values was y equals .OO9l77x

-2.9249 for dogs I and III and y equals .OO5139x - 3.1035 for

49
dog I. This would indicate a greater thyroid turnover of
iodine in the treated dogs. The greater pickup of 1* would
indicate greater thyroid gkind activity in the treated dogs.
Results of 1*131 Injection on Intact Dogs Receiving Desiccated
Thyroid: Both dogs were receiving desiccated thyroid for 28
days previous to the I*131 injection; number 6 at the rate
of 4 mg./kg./day and number 29 at the rate of 2 mg./kg./day
(described pg. 50). The counts picked up by the thyroid
gland were low in relation to the extremity counts. The
regression equation of the logs. of the t values was y equals
.OO7252x-2.6295, indicating a low thyroid turnover of iodine
(table XXIX) in these dogs. The small pickup of iodine by
the thyroid would indicate low thyroid activity.

figsults of 1*131 Injection on Intact English Bull Dog Puppies:

 

These dogs were in two groups, the control group consisting

of dogs number 1, 3, 5, and 6, and the group receiving Protamone
at the rate or 4 gm./lOO lbs. dry matter for 48 days consisting
of dogs number 2, 4, and 7 (descrfloed pg. 80). The uptake of
iodine by the thyroid gland was Slightly greater in the con-
trol group. However, the regression equation of the logs.

of the t values was y equals .OlOO3x-2.6488 for the control
group and y equals .01131x-2.8194 for the group receiving
Protamone. This would indicate the thyroid turnover rate of
iodine was similar in both groups (tables XXX and XXXI).

There was a lowered pickup of iodine by the thyroid glands

of the Protamone group. Results of all 1* determinations are

summarized in Fig. 4.

L06. 0F 7' VALUES 0F /"/3/ COUNTS

'T

‘__.

 

  
 

 

 

 

 

 

— 24 I I I I I I I I I
X
.. / /3/ MUEC T/O/VS
— 26 -:
-2 08 h
‘0
Jmalt/6647150 film/o
_. 3.0 - r = .007252x- 2. 62.95
. ‘ A '
. . . caw‘ROL PURS
_ 3,2 . V3.0/003X‘36’488
. . ° Aco/v TROL Bl my
r VAL UE EOUALS: rams/wrap”
_ 3.4 - COUNTS PER MIN. OVER THE/VOID \ 1. mo 74 AlO/VE 3/ 701755
KG. soar WE/GH 7 V '7 00-9/7 7 X19249
:
COUNTS FER MIN. INJEC TED ° PROMMONE PUPS
_ .36- r-‘ .0/13/ x-é'. 81.94
_ '3. 8 1 1 1 1 I 1 1 1
. O /O 20 30 4 0 50 60 70

HOURS AFTER /" /3/ /NJECT/ON

' ' V'—r"’m— ——-— —__‘.-_ ___

 

Figure 4

The log. of the t values of the thyroid counts at
various times after the I*13l injection. The regression
lines were calculated by the method of least squares.

51

 

 

Trials with Protamone and Desiccated Thyroid on Thyroideg-

tomized Dogg

 

.Procedurg: The general procedure for obtaining the metabolism,

 

pulse rate, body weight, body temperature and the feeding
schedules was identical with that described previously (pgzi).
The dosage of exogenous thyroid was given in capsule form

once daily. Aftertwo runS'were completed at the thyroidectomy
level, dosage was initiated for for the Protamone group at

0.5 mg./kg. and continued for 14 days; on the 15th day it

was increased to 1.0 mg./kg.l The dosage was then increased

to 2 mg./kg and continued for 14 days. The desiccated thyroid
group received desiccated thyroid containing 0.3% Iodine and
supplied by Parke, Davis & Co. of Detroit, Michigan. The
initial dosage of 2 mg./kg. was continued for 14 days. The
dosage was then 4 mg./kg. for 22 days, and finally increased
to 8 mg./kg. for the last 14 days.

Effects: The Protamone group included dogs 1, 3 and 4. The
desiccated thyroid group included dogs 2, 24, 25 and 27. These
dogs were adults of both sexes (tablexmfl).

At the beginning of the trial, all of the above dogs
showed the thyroidectomy symptoms of lethargy, poor appetite,
and edema. On the sixth day following the initiation of
dosage, there was a lessening in the extent of edema in
numbers 1, 3, 4, and 24. These dogs appeared to be more lively
although the difference was still not clear-cut. By the
thirteenth day after the start of dosage, the evidence of edema
was gone in all the dogs. At this time, numbers 1, 2, 3, and

4 appeared lively while numbers 24, 25,and 27 were still

52

sluggish. By the 20th day after the onset of the low dosage
or after the dogs had been on the medium dosage for 6 days,
all were lively and no differentiation.was possible. No
further changes in behavior were evident in the dogs through-
out the remainder of the experiment.

0n the 11th day, dog number 2 came into estrus. Symptoms
of this were observed four days prior to this. She remained
in estrus for five days.
Lower Dosage of Protamone and Desiccated Thyroid on Thyroi-

_d§ctomized Dogs. (Compiled from tables XXXII to XLII)

 

Dogs 1, 3, and 4 on Protamone O.5mg./kg./day
Dogs 2, 24, 25 and 27 on Desiccated Thyroid 2mg./kg./day

Average % of

Average % of Thyroidectomy
Thyroidectomy Level on Dosage
Level on Dosage of Desiccated
of Protamone Thyroid
.73

0a1./hr./kg. 107.7 105.0

Body Weight 105.1 '105.2

Pulse Rate 99.8 106.7

Body Temperature 99.9 100.3

hedium.Dosage of Protamone and Desiccated Thyroid on Thyroi-

 

_dectomized Dogs,(Compiled from tables XXXII to XLII).

 

Dogs 1, 3, and 4 on Protamone 1.0 mg./kg./day
Dogs 2, 24, 25, and 27 on Desiccated Thyroid 4 mg./kg./day

Average % of Average % of
Thyroidectomy Thyroidectomy
Level on Dosage Level on Dosage of
73 of Protamone Desiccated Thyroid
Cal./hr./kg. 140.8 122.2
Body Weight 106.1 105.6
Pulse Rate 95.3 109.4

Body Temperature 100.0 100.4

55

Higher Dosage of Protamone and Desiccated Thyroid on Thyroi-

 

dectomized DogsJ(Compiled from tables XXXII to XLII).

 

Dogs 1, 3, and 4 on Protamone 2.0 mg./kg./day
Dogs 2, 24, 25, and 27 on.desiccated thyroid 8 mg./kg./day

Average % of

Average % of Thyroidectomy
Thyroidectomy Level on Dosage
Level on Dosage of Desiccated
of Protamone Thyroid
0a1./hr./kg.'75 152.2 151.5
Body Weight 109.0 107.1
Pulse Rate 104.2 115.0
Body Temperature 100.0 100.7

The lower dosages of Protamone (0.5 mg./kg./day) and
desiccated thyroid (2.0 mg./kg./day) resulted in small,
approximately equal rise in metabolism.and body weight in
both groups. The pulse rate and body temperature were little
if any affected except that the pulse rate in the desiccated
thyroid group was raised moderately.(Figs. 5, 6, and 7).

The medium.dosages of Protamone (1.0 mg./kg./day) and
desiccated thyroid (4.0 mg./kg./day) resulted in a marked
rise in metabolism in both groups with.the Protamone group
higher and probably up to the normal rate. The weight rise
in both groups was equal. Pulse and temperature were slightly
higher in the desiccated thyroid group.

The higher dosages of Protamone (2.0 mg./kg./day) and
desiccated thyroid (8.0 mg./kg./day) resulted in a slight
decline of metabolism in the Protamone group and a rise of

this value in the desiccated thyroid group up to the value

54
of the Protamone group. The rise in body weights was
nearly equal between groups. The pulse and body temper-
ature were slightly higher in the desiccated thyroid

group.

55

’—

._‘_. 1 l... -

 

 

 

 

 

 

 

 

 

/ (0.3.53.0? I I Emu/kiln” I I T maxi/m r
[50 WW/Dfirm/ZED 0065 ON DES/C04 TED THVRO/D
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Figure 5

The effects on dogs": metabolism, body weight, pulse
rate, and body temperature of Desiccated Thyroid (50% stronger
than U. S. P.). The dosage was as follows:

lst 14 days 2 mg./kg./day
next 22 days 4 mg./kg./day
next 14 days 8 mg./kg./day

Figure 6

The effects on dogs"3 metabolism, body weight, pulse
rate and body temperature of Protamone. The dosage was as

follows:
1st 14 days 0.5 mg./kg./day
next 22 days 1.0 mg./kg./day
next 14 days 2.0 mg./kg./day

van-1‘.

. 7.]

AVE. PERCENT OF (”MO/DEC row CAL ./HR. l/m.

ogenous thyroid had time to become effective.

56

 

I50 I T I I ' '
THYRO/DEC mM/ZED DOGS 0N PmTAMO/IE AND
.QEQCCAEED 7WWWUW7
I40 P . /o \ d
\
/ \ \

/ \9

I30 - flmHWNE «

[20

//0

 

[00

 

asuahmflur

ONE Lo
«4452
mm

Figure 7

    
 

 

The effects on metabolism of dogs when given Protamone
and Desiccated Thyroid in various dosages after the ex-

005’ 100,

and 2.0 mg./kg./day of Protamone was given while 2.0, 4.0,
and 8.0 mg./kg./day of Desiccated Thyroid.was given.

57

COMPARISONS OF POTENCY 0F PROTAMJNE AND DESICCATED THYROID

The Protamone was of lot P. A. 2-011 supplied by Cerophyl
Laboratories. Isotope dilution values of the preparation
gave 0.578% thyroxine while the butanol extraction of thyroxine-
1ike compounds gave a value of 3.5% (Reineke, et a1. 1949).

The desiccated thyroid was 50% stronger than U. S. P.,
containing 0.3% iodine, supplied by Parke Davis Co. Assume
ing that 25% of the iodine was thyroxine iodine, this would
yield a value of 0.1147% thyroxine.

Thus, the Protamone by chemical methods of analysis would
appear to be 5.04 times as potent as the desiccated thyroid.

The trials with Protamone and desiccated thyroid on the
thyroidectomized dogs yielded a more accurate comparison of
the two. The last two runs may be taken, when the dosage of
both preparations was highest, the metabolism of the Protamone
group was 132.2% of the thyroidectomy level while the metabo-
lism of the desiccated thyroid group was 131.3% of the
thyroidectomy level. Inasmuch as the dosage of Protamone
was 2mg./kg./day while the dosage of desiccated thyroid was
8mg./kg./day, the Protamone would appear to be 4 times the
strength of the desiccated thyroid. If, however, the 1 mg./
kg./day of Protamone whichlraised the metabolism to 140.8%
of thyroidectomy level, is compared with the 8 mg./kg./day
dosage of Desiccated Thyroid which raised the metabolism.to
131.3% of the thyroidectomy level, the Protamone would appear
to be 8 times the strength of the desiccated thyroid.

Another method of comparison.makes use of the .73 power

of the body weight in kg. When the percentage rise above the

58

thyroidectomy level of the Oa1./hr./kg.'75

.73

is divided by
the body weight in kg. a constant figtneis obtained for
all the thyroidectomized dogs on all dosages. This was
averaged for each dosage for eachggroup. Then these averages
were added for each group and compared. By this comparison,
the Protamone appeared 5.131 times as potent as the desic-
cated thyroid. This result agrees very closely with the
ratio of 5.04 estimated from the thyroxine content of the
Protamone, as estimated by the highly specific isotOpe
dilution method, and the probable thyroxine content of the

desiccated thyroid.

59

DISCUSSION

The normal metabolic rates of the dog as determined in
this study were within the range reported in Brody's compila-
tions ‘ (1952) and the work of Galvao (1946) . a comparison of
the caloric output in relation to the body weight is impos-
sible from this number of dogs, but the body weight to the
0.73 power gave a figure which was in general agreement be-
tween weight ranges. The largest deviations from the aver-
age were seen in the smaller, more energetic breeds. The

73

average cal./hr./kg.' was generallytibove the figure of

2.937 given by Brody (1945) as universal for all species.
The body weight trends were generally in agreement with
other workers. Evidently the vitamin B complex was in high
enough concentration in the diet because the dogs did not
lose weight when given exogenous thyroid. Weight loss has
been reported in dogs rendered hyperthyroid only when the
diet was yeast free (Drill and Hays 1942; Drill and Shaffer
1942) and in rats (Peters and Rossiter 1939). A transient
fall in body weight for 3 to 4 weeks after which the normal
weight was regained was reported in dogs receiving 2 mg.
thyroxine daily and .77 gm. desiccated thyroid U. S. P.
daily (Danowski et a1. 1946). This was in the vicinity of
the largest dosage of exogenous thyroid used here. The two
oldest dogs, on 2 and 4 mg./kg./day desiccated thyroid,
showed a slight weight loss which may be attributable to
their age. Heavy dosage of thyroid caused weight losses in
dogs by nitrogen breakdown (SchBrndorff 1897). A dose of

.3 to .6gm./kg./day of desiccated thyroid in dogs caused a

60

marked fall in body weight dllrlJlg 7 to 8 weeks in an
experiment of another worker (McIntyre 1931).

Dott (1923) reports a similar weight fall on .07 mg./
kg./day of desiccated thyroid. Ten gm. of fresh horse thyroid
per day per dog caused severe losses in body weight (Moussu
1899). Undoubtedly, the caloric intake is a factor in the
maintaince of body weight during hyperthyroidism.

The weight gain seen after thyroidectomy agrees with
the general consensus of Opinion.which attributes the increase
to more body fat and fluid, (Dott 1923).

The pulse rate could not be correlated to the metabolic
rate. Perhaps the enzyme system of the heart did not have
time to build up to the point where the thyroid hormone could
act upon it to increase the rate of beat. The thiamine
status of the dog has been reported to affect his pulse rate
under hyperthyroidisms Dosage of .4 to .6 gm./kg./day of
desiccated thyroid caused a rise in the pulse to 150 to 160
beats per minute within 6 to 8 days. When they were still
receiving the exogenous thyroid and the yeast was removed from
their diet, their pulse dropped to below 100 beats per minute
(Drill and Hays 1942). In the present experiments, the pulse
did not usually rise this high, probably because of the lower
dosage used.

On the intact dogs receiving Protamone the pulse rose to
a greater extent than the metabolic rate. The intact dogs

on desiccated thyroid showed little if any rise above normal

61

in the metabolic rate while the pulse rate rose considerably
above normal. In the thyroidectomized dogs, the pulse rate
of the group on Protamone did not rise appreciably while the
metabolic rate rose to normal, and the pulse rate of the
group on desiccated thyroid showed somewhat of a rise when
the metabolism rose to normal. The lack of rise in the
thyroidectomized groups may be attributed to the low calorie
intake before the administration of exogenous thyroid began.
The thyroidectomy pulse rate in this experiment ranged between
64 and 94 which is below normal for dogs. In the diagnosis
of hypothyroidism, the pulse probably is not of paramount
importance because of its large variability (Means and Aub
1925).

The difference between the response of the intact and
thyroidectomized dogs to Protamone and desiccated thyroid is
parallel to the findings of other workers working on thyroi-
dectomized rats. In their work, iodinated protein raised the
metabolism of the rats to normal without appreciably affecting
the pulse rate while desiccated thyroid raised both the me-
tabolic rate and the pulse rate. They attributed this to a
cardiotropic factor in the natural thyroid gland (Meyer and
Danow 1940). They reported the amount of the cardiotrOpic
factor in the thyroid gland as being variable and dependent
upon the physiological status of the gland and the amount of
preiodination in the living animal before extraction of the
desiccated thyroid (Meyer and Danow 1941; Meyer and Thompson

1940).

62

The body temperature followed the general trend expected
of intact dogs on exogenous thyroid. The increase in body
temperature of O to 1 degree F. is in.agreement with the rise
of .5 degree F. reported by Dott (1923) and Drill and Hays
(1942). In the later work,the temperature rise could be pre-
vented by removing yeast from the diet. The drop from.normal
of .5 degree F. after thyroidectomy is verified.by other work
(Dott 1923, Binswanger 1936). Exogenous thyroid did not raise
the temperature back to normal in this experiment as reported
by Dott (1923).

The behavior of the dogs was generally in agreement with
the metabolic rate. Exogenous thyroid, in the dosages used
upon intact dogs, caused little effect upon behavior in the
lower range. Appetite was increased, confirming previous
work (Moussu 1899). Hyperthyroid symptoms when the dogs were
on the highest dosage are those generally described for other
species. Hypothyroid symptoms of thyroidectomy were similar
to those reported by several other workers (Dott 1923; Bins-
wanger 1936). On the other hand, little effect on behavior

   
  
    

was seen after thyroidectomy and goitrogenic drug : : :477tion
of dogs ty Danowski (1946) and Mayer (1947) 'flg’. ‘
reported.here, is not generally reported fo .oogs. However,
thyroidectomy in dogs has been reported to cause high blood
concentrations of cholesterol, phospholipids, and fatty acids
which are associated.with myxedema in humans (Chaikoff, et.a1.

1941; Entenman, et a1. 1942; Thompson and Long 1941).

63

‘

Replacement therapy corrected the hypothyroid symptoms as
reported‘in most species. Early trials with iodocasein in
dogs resulted in failure of the replacement because of the
removal of the parathyroids and the doubtful potency of the
compound (Wormser 1897). Recently,more potent iodocasein
preparations have resulted in replacement therapy in several
species (Brody and Frankenbach 1942; Reineke and Turner 1941).
The percent drop in metabolism is greater than that reported
by several other workers (Fink 1944; Danowski 1946).
Thyroidectomy and removal of part of the parathyroids
resulted in tetany with resultant disturbance of ;he calcium
metabolism. At the time of thyroidectomy, the dogs were not
markedly above the normal level of metabolism. However, in
hyperthyroid humans, it has been demonstrated that the degree
of calcium excretion is much greater than the rise in the
metabolic rate. In these persons, if the condition has existed
long enough, osteoporosis occurs due to excessive secretion
of calcium.and phosphorus (Aub, et al. 1929). Similar results
have been obtained in the dog (Logan, et a1. 1942). Since
the dogs in this experiment were thyroidectomized 2 to 3 days
after Protamone was stopped, it is a logical assumption that
some of the effects of excess thyroxine were still in force.
Due to the removal of 2 of the parathyroid glands and trauma
to the blood supply to the 2 remaining in the surgery, the
dogs are consequently hypoparathyroid while there is excessive

excretion of calcium under the influence of the excess thyroid

65a

hormone. Thus, under such conditions, one would expect the
number of dogs undergoing tetany and death to be greater
when the previous dosage of exogenous thyroid was greatest.
Such was the case in this work, while none of the previously
untreated dogs showeitetany effects.

The drop of metabolism on the 7th to 8th day of deter-
minations with its rise back to or above normal on the 11th
to 15th day in euthyroid dogs receiving exogenous thyroid is
puzzling. It occurred in dosages of 2 mg./kg./day of desiccated
thyroid to 8 mg./kg./day of Protamone representing 0.002294
to 0.04624 mg./kg./day of thyroxine, respectively. Such a
drOp has been reported in hyperthyroid humans given 2 grains
of desiccated thyroid per day (Cavett et al. 1934). There
has been some question as to whether the thyroXine is
active alone or needs a particular protein linkage to exert
its calorigenic effect (Canzanelli, et a1. 1939). The thyroid
hormone inhibits the anterior pituitary gland from.secreting
thyrotrOpin thus decreasing stimulation of the thyroid
gland (Leblond and Mann 1942). Thyroglobulin will nullify
the effect of thyrotrOpin on the thyroid gland itself (Galli-
Mainini 1941). Inorganiciodides will inhibit the thyroid
gland (Morton, et al. 1944), and will lower the metabolism
in hyperthyroidism (Starr, et a1. 1924). It seems conceivable
that the exogenous thyroid temporarily upset the normal thyroid-
anterior pituitary balance and was not able to act immediately
itself because it lacked the proper linkage. It may also have

inhibited the thyroid gland and thus had the same effect.

64

There is also evidence that the dog produces antimetabolites
to thyroidal materials (Keeser 1938) and thus there might have
been a temporary imbalance between the antimetabolite production
and the action of the exogenous thyroid.

It is also known that iodinated protein in Protamone
andébsiccated thyroid is not entirely thyroxine, but compounds
similar structurally to thyroxine are present also. Some of
these compounds have been shown to have little thyroxine
inhibiting action (Barker et a1. 1949), but they may have fin
ability to depress the thyroid gland secretion through the
anterior pituitary gland or act on the thyroid gland itself.
There may be some that inhibit the thyroid hormone in the
tissues. The destruction of the excess thyroid hormone may
have taken place in the liver (Leblond 1949) out of balance
with the normal rate of thyroxine destruction, because of
the added impetus of the extra thyroid and thus destroyed
all the animal's own thyroid hormone in addition to that
given, thus causing the metabolic rate to be temporarily
lowered.

The above described drop in metabolism did not occur
in an intact dog with a low metabolic rate, 5A, and the
thyroidectomized dogs, even though the dose of exogenous
thyroid given was similar to those showing a drOp. Work on
euthyroid and myedematous humans has shown that the myedema-
tous persons are more sensitive to exogenous thyroid, and that
the metabolic rate of euthyroid humans was little affected
by exogenous thyroid (Winkler, et a1. 1942). The concentra-

tion of paraxanthine, an alleged thyroxine inhibiting substance,

65

is highest in the thyroid gland (Carter and Jenkins 1944).

It may be that the thyroid gland destroys the excess thyroid
hormone and thus in the euthyroid, the excess thyroid hormone
increases the thyroxine destroying action of the thyroid gland
so that it destroys all of the normal secretion and the

excess also for a short period of time.

The failure of the metabolism to increase as the logarithm
of the dosage, and remain greatly above normal for a long
period of time is of interest. The metabolism and blood iodine
levels in thyroidectomized and euthyroid dogs given large doses
of exogenous thyroid could not be raised much above normal,
or for prolonged periods, in the work of Danowski (1946).
Euthyroid humans are able to metabolize several times their
own thyroid secretion rate without showing a rise in metabo-
1ism.(Wink1er, et a1. 1942). Probably there were no anti-
bodies produced, since the thyroid preparations were not given
parenterally (Lerman 1942). The production of an antimet-
abolite by the dog (Keeser 1948) is a theory to be given some
credence. The production of paraxanthine by the tissues of
the dog to inhibit the action of the excess thyroid hormone
may be the key to the situation (Carter and Jenkins, 1944).
Probably the liver is able to metabolise excess thyroxine
(Leblond 1949) after the dog's liver becomes adjusted to
the situation. This is done in a delicate enough balance
to center upon a level near the normal even under higher
dosages of exogenous thyroid. The rise was in.agreement with
the rise on these dosages of exogenous thyroid reported by

Fink (1944).

66

The therapeutic range of dosage of thyroid preparations
may be termed as the amount which.will replace the animal's
own thyroid secretion rate. This amount of Protamone was 1
to 2 mg./kg./day and for desiccated thyroid was 4 to 8 mg./kg./
day. Since the thyroidectomy resulted in a 27.8% fall in
metabolism from the normal rate, the metabolism would have to
rise to 138.5% of the thyroidectomy level to be back to normal.
Inasmuch as the amount of the exogenous thyroid which was
absorbed is not known, the thyroid secretion rate of the
dog cannot be definitely determined from these data. However,
it required 5.78 micrograms of thyroxine/kg./day, given orally
in Protamone to replace the secretion rate and 4.588 to 9.176
micrograms/kg./day of thyroxine orally in desiccated thyroid
tor‘eplace the thyroid secretion rate. This is within the
range of the thyroid secretion rate of 24 to 240 micrograms
thyroxine per day for the dog given by another worker on
the basis of radioactive studies (Taurog,et a1. 1947).

The differences in breed responses to exogenous thyroid
in the intact animal may reflect differences in the ability
of different breeds to metabolize excess thyroxine and also
may be some indication of the animal's thyroid secretion rate.
If cross breeding increases thyroid secretion rate of dogs,
as it does in chicks (Mixner and Upp 1947), it might be
theorized that the dog would have a higher metabolic rate,
be closer to the threshold of response, and thus be more active
in destroying the excess hormone. It may be seen in this work

that the Cocker-pointer crossbreds were able to metabolise

67

all the exogenous thyroid without showing an appreciable
rise in metabolism. The Cookers were similar in response to
these and it would seem that the Cocker is normally a re-
latively hyperthyroid individual.

The radioactivity studies with 1*131 on the thyroidec-
tomized dog succeeded in locating those dogs which had some
thyroid function left. The determinations on the intact
English Bull Dog bitches revealed no depression of the thyroid
iodine turnover rate by the Protamone. Such results are not
borne out by other work which paints to depression of the
thyroid secretion rate by exogenous thyroid. Indeed, even
in this experiment the dogs receiving high dosages of Pro-
tamone exhibited small thyroid glands. It may be that the
1*131 was retained in the ovaries (Perkin and Brown 1938)
and thus disrupted the test. Small thyroid glands have been
shown to pick up a higher concentration of iodine and thus
perhaps size of the gland is not a determining factor

(Hertz and Roberts 1941).

68

SUMMARY
1. The amount of Protamone needed to raise the cal./hr./kg..75
back to the normal level in thyroidectomized dogs was
1 mg./kg./day.
2. The amount of desiccated thyroid (containing 0.3% iodine)
needed to raise the cal./hr./kg.°75 back to the normal level
in thyroidectomized dogs was 4 to 8 mg./kg./day.
3. Dosages well above the therapeutic dosage of Protamone
were well tolerated by intact dogs, with no disturbances of.
behavior and little permanent rise in the metabolism, pulse,
and body temperature. 2 mg./kg./day stronger desiccated
thyroid resulted in no rise in metabolism above normal in
2 intact dogs.
4. Protamone caused an increase in body weight due to increased
caloric intake.
5. Protamone caused no ill effects in a long time trial
with intact English Bull Dog bitches when fed at the rate
of 2 grams per 100 lbs. dry matter for a period of 148 days.
It improved the condition of one of the dogs.
6. Metabolism.determinations at the 7th to 8th day in intact
dogs on 2 to 8 mg./kg./day of Protamone and 2 mg./kg./day
of desiccated thyroid resulted in a drop to 67.2% and lesser
amounts of the normal metabolism, This drop was repaired
to or above normal in 10 to 15 days. The drop was not ob-
served in thyroidectomized dogs given exogenous thyroid.
7. The thyroid secretion rate of the dog was‘roughly computed

as 5.78 to 9.176 micrograms thyroxine/kg./day assuming that

69

the exogenous thyroxine was mosdyassimilated.

8. By chemical analysis the strength of the Protamone was
5.04 times the potency of the desiccated thyroid, while by
assay on thyroidectomized dogs, the Protamonelvas 4 to 8
'times the potency of the stronger desiccated thyroid.

The most logical ratioshowsProtamone to be 5.13 times as
potent as stronger desiccated thyroid.

9. 1*131 injections located thyroid functions in thyroidec-
tomized dogs.

10. I*l31 injections failed tocietect depression of thyroid
iodine turnover rate in intact English Bull Dog Bitches

fed Protamone at the rate of 2 mg. per 100 lbs. of dry

matter for 87 days previous to the injection.

11. High dosages of Protamone given intact dogs for a period
of time reduced the size of the thyroid glands.

12. The Protamone antagonized the action of the parathyroid
gland, causing tetany in dogs thyroidectomized while still
under the influence of the Protamone. The incidence of
tetany was prOportional to the previous dosage of Protamone.
l3. Thyroidectomy resulted in a 27.8% drop in.metabolism,

a dr0p in the pulse to below 100, and a small drop in body
temperature. Lethargy and slight edema resulted also.

14. Replacement with Protamone or desiccated thyroid alleviatei
the symptoms of thyroidectomy.

15. Desiccated thyroid caused greater responses on pulse
rate than Protamone in both intact and thyroidectomized dogs.
16. Using the body weight to the .73 power as a base for comp

puting the metabolism gave a fairly constant figure for comparison.

70
CONCLUSIONS

1. Both Protamone and desiccated thyroid can be used thera-
peutically in the following dosages, Protamone l to 2 mg./
kg./day, Stronger Desiccated Thyroid (50% stronger than

U. S. P.) 4 to 8 mg./kg./day and Desiccated Thyroid U. S. P.
6 to 12 mg./kg./day.

2. These dosages will produce no untoward effects even when
used over-prolonged periods of time.

3. The dog is able to metabolize large. amounts of exogenous
thyroid without dire effects upon hisbehavior, metabolism,
veight, pulse,and.body temperature.

4. Dogs receiving exogenous thyroid in moderate dosages win.
usually gain weight because they eat more.

5. Radioactive iodine determinations are of use in deter-
mining the completeness of thyroidectomy in the dog.

6. Thyroidectomy will result in symptoms of lethargy, fall
in metabolism, lowering of pulse and body temperature, and
decrease in body temperature.

7. There is a transient fall in the metabolic rate on the
7th to 8th day when a euthyroid dog is given exogenous thy-
roid, in small to medium dosages.

8. Excess exogenous thyroid will aggravate hypoparathyroidism

in the dog and result in tetany if given in sufficient dosage.

71

REVIEW OF THE LITERATURE ON THE RELATIONSHIP
OF THE THYROID GLAND AND GROWTH

The m a n y aspects of the thyroid gland's role
in growth and maturation have been studied in several ways.
The first, and most natural method, was the removal of the
gland in the infant animal and observation of the resulting
syndrome. Replacement of the gland by feeding of thyroidal
materials was the next logical step. The last, and.mon3
promising step, was the feeding of thyroid to intact animals
to augment the normal growth and maturation processes.

Historicgl

 

The dog was one of the earliest animals to be used.
An early French worker removed the thyroid of young dogs
and noted tetany and death. Part of this syndrome can
be attributed to the removal of the parathyroids. The
observed myxedema could be somewhat alleviated by trans-
plantation of thyroid glands into the operated dogs
(Schiff 1884). Another French.worker noted a cessation
of growth when he thyroidectomized puppies. Using fresh
horse thyroids, he fed litter mate puppies varying amounts
and noted that on the lower dosage levels, the dogs ma-
.tured.more quickly but did not become any larger than
their controls finally became. He claimed the dogs grew
faster in weight, height, and length. When he fed higher
dosages -- 10 gms. of fresh horse thyroid per kg. of body
weight -- the dogs lost weight and died (Moussu 1899).

Exogenous thyroid also stimulates growth in other

animals. The fllyrozld is the only endocrine which was shown

72

to augment growth when fed orally to white rats (Schafer
1912). In thyroidectomized rabbits, the cretinism symptoms
of small size, coarse coat, and lethargy could be partly
overcome by feeding desiccated thyroid (Basinger 1915).
(figlation'with Anterior Pituitary Growth_Hormone

Thyroxine has been shown to stimulate development of
fibroblasts, periosteum, heart, lulg, and other tissues
(Schneider 1939). This stimulating action of the thyroid
has no effect in the absence of the growth hormone of
the anterior pituitary. This has been demonstrated in
rats which were thyroidectomized and hypophysectomized.
Growth hormone and thyroid gave the greatest growth response
when administered together, while in the absence of the
thyroid, the growth hormone only produced half as much
growth; the rats administered thyroid alone showed no
gain over the untreated, operated rats (Evans, et al.1939).
By observations on the development of osteoid tissue of
guinea pigs, thyroidectomy produced a lessening of develop-
ment which is not as great as that produced by both thy-
roidectomy and hypophysectomy (Silberberg and Silberberg
1936). Hypophysectomized rats gave the optimum growth
response when given both growth hormone and thyrotrophic
hormone (Marx, et a1. 1942). In rats, Which'were thy-
roidectomized on the day of birth, the body weight and
skeletal growth were markedly increased over the untreated
controls by the administration of growth hormone. The

secondary ossification centers of the bone were not affected

73

and the response did not depend on the time of starting
the injections. The response was greatest in those rats
which possessed thyroid fragments (Scow and Marx 1945).
The above findings were not borne out by other work on
rats thyroidectomized at birth in which no skeletal growth
was noted in completely thyroidectomized animals given
growth hormone (Salmon 1941). In humans, hypothyroidisn
resembles the picture of hypophysectomy inasmuch as ra-
dioactivity studies show that there is little iodine
metabolism.of the thyroid (Hamilton, et a1. 1943).

_M§chanism.of Action

 

The general concept at the present time is that the
thyroid hormone augments the action of the growth hormone.
The growth hormone is mainly responsible for the prolifer-
ation of cells while the thyroid hormone increases the
size of the cells.(Evans, et a1. 1939; Salter 1940).

The first requirement for increased growth.is that
of nutrition. In ruminants, it has been demonstrated
that raising the metabolism by thyroprotein administration
causes an increase in appetite (Blaxter 1949). The
jejunal secretion rate and peristalsis was increased in
the dog by the administration of large amounts of desic-
cated thyroid (Fink 1944). This effect lasted for some
time after the thyroid administration was terminated.
Increased absorption of carbohydrates has been demonstrated
in the hyperthyroid rat, chiefly due to an increase in

phosphorylation (Althausen 1940). Thyroid-treated dogs'

74

liver in vitro had the ability to synthesize amino acids
from pyruvic acid and ammonia faster than normal (Zitowskaya
1939). Increase of d-amino oxidase in the rat liver has
been observed under hyperthyroid conditions (Klein 1939).

In growing animals, thyroid administration causes increased
retention of nitrogen and anabolic protein activity.

Excess thyroid will result in catabolic protein metabolism
(Soskin 1941).

Bone metabolism has been used as a more concrete
example of thyroid effects. By the use of radioactive
phosphorus it has been shown that the greatest turnover
of phosphorus occurs in the early growth stage when the
thyroid secretion rate is the highest. In mice, it was
impossible to demonstrate a significant increase of
phosphorus turnover as a result of thyroxine administra-
tion (Falkenheim.1942). In.dogs, the calcium-phosphorus
balance was shown to be disturbed by thyroidectomy. This
could be corrected by thyroid administration. The calcium
excretion was lowered at the same time as the uptake of
calcium was increased (Breitbarth 1940). Large amounts
of thyroid hormone in the guinea pig, at first, caused
slight hyperplasia, hypertrophy, and accelerated differen-
tiation of the euhyaline cartilage of the epiphyseal line,
ribs, joints, and vertebrae. Later, the replacement of
the hypertrophied cartilage by bone was retarded and
increased bone absorption by the osteoclast cells lead
to osteOporosis and arthropathic rarefication of the

cartilagenous covering of the joints (Silberberg and

75

Silberberg 1938). In mice, the growth and development

of the epiphyseal cartilage is inhibited by castration.
This effect may be counteracted by thyroxine. Thyroxine
was demonstrated to cause ageing of the epiphseal cartilage
and epiphyseo-diaphyseal union earlier (Silberberg and
Silberberg 1947). In hypothyroid children, thyroid therapy
was shown by radiographic studies to increase bone density
and hasten epiphyseal union besides increasing the growth
rate and mental alertness.(Einkler, et a1. 1944). In
newborn rats, the eruption of teeth was shown to be
hastened by severe hyperthyroidism (Karnofsky and

Cronkite 1939).

Species Results

All species of mammals studied have been demonstrated to
need the thyroid gland for normal growth and maturation.
Some species show a further increase in growth upon the
administration of exogenous thyroid to the normal animal
while other species do not. The amount of thyroid ad-
ministered is thought by some to be necessarily above
the animal's own secretion rate to produce results
(Hurst and Turner 1947).

Mice, in general,show an increased growth rate when
exogenous thyroid is given. Desiccated thyroid, at the
rate of 1 mg. per day per mouse, increased the rate of
growth but not the final weight attained (Robertson 1928).
Similar results were obtained on white mice when .015 a:

.04 mg. of crystalline thyroxine was injected per day.

76

The treated mice showed a greater retention of nitrogen
(Roger, et a1. 1942). Later, similar effects were obtained
by thyroprotein feeding at .15% to .60% of the ration,
although the heavier dosages tended to depress growth
(Koger, et a1. 1943).

In guinea pigs and rabbits, therprotein in the ration
had no effect upon growth in low dosages and depressed
growth in higher dosages. In rats, there was little
response (Koger and Turner 1943).

In chicks, a thyroprotein level of .l% to .2% in
the ration, resulted in better gains on less feed per
unit gain. The chicks showed a more mature type of
feathering than the control (Parker 1943). Other workers
reported similar findings in chicks fed low dosages of
thyroprotein while higher dosages in the ration (113 gms
per 100 lbs. of feed) resulted in depressed growth and
a high mortality rate (Irwin, et a1. 1943).

In humans,cretinism has been the main point of
study. There is some evidence that this malady is heredi-
tary (Lewis 1937). For dwarfism, thyroid therapy has
been a valuable tool even in cases where there was no
clearcut evidence of thyroid insufficiency (Webster 1939).
There is some evidence from studies of thyrotoxic girls,
that the excess thyroid.will result in an unusually tall
individual (Hertz and Galli-Mainini 1941).

In ruminants, thyroidectomy has resulted in premature
cessation of growth when done on a young heifer (Brody

and Frankenbach 1942) and in fattening when done on steers

77

(Andrews and Bullard 1940). In goats, a lethargic, un-
developed, dishfaced individual resulted from thyroidectomy.
.5 to 1 gm. of thyroprotein daily served as replacement

to produce normal growth (Reineke and Turner 1941).

There is somewhat of a breed difference in swine
in the response to feeding of exogenous thyroid. The
dosage of therprotein used ranged from 1.4 to 5.6 grars
in 100 lbs. of feed. 0n the higher dosages, some ill
effects were observed. The Optimum.dose seemed to be
about 2.8 gms./100 lbs. of feed. Berkshires, Yorkshires,
and Duroc Jerseys were noted to make greater and more
economic gains, while Chester Whites showed no beneficial
effects (Reineke, et a1. 1948).

There is also some variation in the data reported
from.the dog. After the work previously cited for the
dog, further studies were carried on under improved
methods of surgery. Thyroidectomy resulted in a cessation
of growth, subnormal temperature, adiposity, a scaley
and course hair coat, and a reduction of 81% in femoral-
epiphyseal activity. In normal mongrel dogs administered
0.07 gm. of desiccated thyroid per kg. of body weight,
there was a slight elevation of body temperature, loss
of body fat, and an increase of 28% in epiphyseal activity.
No unnatural activity was reported. The gonads grew ane

quickly and the dogs matured at an earlier age but at a

78

subnormal size (Dott 1923). Other workers (Dye and
Maugham 1929) removed the thyroid glands of mongrel puppies
at 5 to 6 weeks of age and reported dwarfing of most of

the pups. The absolute diameter of the epiphyses of the
bones was little if any diminished. The skull, mandibles,
scapulae, vertebrae, and coxae were disprOportioned. The
cranial cavity was of less volume and the growth of bone
from cartilage was greatly diminished. Subperiosteal

or membrane bone was unaffected. The weight was also

much reduced. Further work on mongrel dogs showed a
somewhat less striking reduction of the growth impulse
which may be due to a different strain. Mest of the dogs
thyroidectomized.were dwarfed (Binswanger 1936). A
goitrogenic drug, propylthiouracil, was used at the dose

of 30 mg./kg. body weight per day and given in capsule
form once per day to growing Beagle puppies (Mayer 1947).
This was started at 33-40 days of age and continued through
6 to 8%-months. There was no difference reported in the
growth rate behavior, and only slight differences in the
hematology. On autopsy, no differences were found in

any of the endocrines except an enlargement of the thyroid.
There was no difference in the degree of ossification or
the appearance of the red bone marrow. There is some
question as to whether goitrogenic drugs administered in
the above manner will completely suppress the thyroid

secretion. In Collies, the growth rate and efficiency of

79

gain was increased by thyroprotein in the feed at the
rate of 2 gms. and 4 gms. per 100 lbs. of dry feed
(Brown and Smithcors 1948). The greatest growth and
efficiency of gain was reported on 4 gms. per 100 lbs.
of dry feed. In a similar experiment using Cocker:
pointer cross-breds, and dosages of 2, 4, and 8 gms.

of thyroprotein per 100 lbs of feed, no effect upon the
growth rate and efficiency of gain was observed. Both
the above types of dogs showed no difference in the
rate of ossification of the epiphyseal cartilages of

the humeral-radial-ulnar joint and carpal joints when

demonstrated by X-ray plates.

80

EXPERITENTAL PROCEDURE AND EFFECTS

fig

Frames.
Procedure: Seven English Bull Dog puppies were put on the

‘_

 

 

 

 

 

Trials with Protgmgne on Intactggnglish Bull D_

trial at weaning. The control group consisted of four dogs,
1, 3, 5, and 6 while the protamone group consisted of three
dogs, 2, 4, and 7. Dogs 1, 2, 3, and 4 were males and 5, 6,
and 7 were females. Dogs 1 and 2 were littermates from.a
litter born 64 days previous to the start of the trial
and weaned 15 days previous to the start of the trial.
Dogs‘gg 3, 4, 5, and 6Xwere littermates and were born 53
days previous to the start of the trial and.weaned 2 days
previous to the start of the trial. Dog §\was placed on the
same bitch as 1 and 2 and thus received more nourishment than
his littermates and thus grew faster. All of the dogs were
in good condition at the start of the trial. Their ancestry
indicates that they were of a small type of English Bull Dog.
The diet throughout the e periment consisted of condensed
milk, canned dog food, and dry meal. The milk contained 25%
dry matter. The canned dog food was "Pard" marketed by
Swift & Co. of Chicago, Illinois. Its guaranteed analysis
was as follows:

Protein (Minimum) 10 .575

Fat (Minimum) 2 .5751

Nitrogen Free Extract
(Minimum) 9.0%

Fibre (Maximum. 1.0%

Ash (Maximum) 3.0%

Moisture (Maximum) 74.0%

81

Calcium (Maximum) .65%
(Minimum) .45%

Phosphorus (Minimum) .50%
Salt (Maximum) .75% - 50% iodized salt
The meal was ground "Gropup" supplied by the Kellogg Co.

of Battle Creek, Michigan. Its guaranteed analysis was as

follows:
Protein (Minimum) 22 .5%
Fat (Minimum) :5 .57»
Fiber (Maximum) 4.0%
Moisture (Maximum) 8.0%

Nitrogen Free Extract (Minimum)50.0%
Ash (Maximum) 9.0%

Potassium iodide was in the
meal at .00037%

'For the first 5 days on experiment the diet was given
in the following ratio:
910 gm. canned dog food
740 gm. milk
400 gm. meal
For the next 28 days on experiment the diet was given
in the following ratio:
1135 gm. canned dog food
1092 gm. milk
500 gm. meal
For the next 54 days on eXperiment the diet was given

in the following ratio:

1135 gm. canned dog food

82
728 gmi milk
1800 gm. meal
For the remaining period of experiment the diet was
in the following ratio:
1362 gm. canned dog food
2800 gm. meal
In the Protamone group, the Protamone was mixed with
the meal so that it comprised 4 gm. per 100 lbs. of dry
matter fed. The pups were fed three times daily for the first
three months of experiment and then.were fed twice daily
for the remainder. They were given the amount which they
would clean up in 30 minutes at a feeding. Each pup was
also given 1/2 teaspoon of cod liver oil and 7 1/2 gms. di-
calcium phosphate three times weekly throughout the trial.
All pups were permanently innoculated for distemper between
the 14th to the 24th day of trial by intradermal injectrans
of distemper vaccine without any ill effects. The pups were
treated, with no ill effects, for ascarids and hookworms
with Oil of Chenopodium.when they had been on experiment
for 2 1/2 months. The infestation was mild.
Effects: The behavior of the Protamone group became more
aggressive than that of the controls by the 2nd week on
experiment although the difference was not marked until the
2nd month. By the second month of experiment, the Protamone
group became more active than the controls and also showed
some features that indicated greater mental alertness. For

,A
instance, pups naturally resent being weight, measured,zand

85

having their teeth examined; but the Control group continuei
to come to the side of the pen after the first pup had gone
through the above procedure, While the Protamone pups observed
the process taking place in the control group and retreated
to a farther corner when motions were made in their direction.
The Protamone pups were more aggressive in their play as de-
termined by scratches on the author's knuckles. Toward the
end of the experiment, the Protamone group succeeded in dis-
locating the partition between them.and the controls, thus
gaining entrance to the Control's pen, after which the Control
group was thoroughly beaten and diapersed.with several teeth
puncture wounds. By the 2nd month of the experiment, the
Protamone group was cleaning up its food at a markedly
greater rate than the 'Control group.

Throughout the experiment, the hair coat of all the dogs
was in good shape. The hair coat may have been slightly
more shiny in the Protamone lot, but the effect was not
marked. However, after the first month on experiment, the
hair coat of the Protamone group was a great deal darker than
that of the Controls although the dogs were all of the same
shade at the start. This effect was present throughout the
remainder of the experiment.

The general appearance of all the dogs at the beginning
of the experiment was a lack of uniformity, as expected inlnor-
mal puppies at their age. By the second month on trial, the
Protamone group began to become more uniform.than the Controls
and began to assume a more mature appearance than the Controls.

These effects became more pronounced during the remainder of

84

the experiment. The Protamone group, by the 5rd month on
trial, had more protruding lower jaws, more wrinkled faces,
were wflier chested and narrower in the flanks although the
flanks were full, and generally showed the more rugged appear-
ance of the adult English Bull Dog. By the 5th month of the
trial, the Protamone group appeared to be about a month older
than the Control group.(Figs. 8 and 9).

The rate of dentition did not appear to be appreciably
affected by the administration of Protamone.

The body measurements showed a trend toward a more
mature type of dog in the Protamone group. The measurements
of the males of the Control group showed a greater flank
girth than heart girth up until measurements taken on the amt
day after the start of trial (table XLV). The heart girth
of the males of the Protamone group was greater than the
flank girth on the 53rd day after the start of trial when
the first measurements were taken (table XLVI). Toward
the end of the trial, the ratio of the heart girth to flank
girth became similar in the Control and Protamone groups.
This ratio was not quite as pronounced in the females. In
the Control females, the heart girth did not become greater
than the flank girth until a period between measurements taken
on the Blst to the 109th day after the start of the trial
(table XLV). The female in the Protamone group evidenced a
larger heart girth than flank girth.when the first measure-
ments were taken on the 53rd day after the start of the trial

(table XLVI). Toward the end of the experiment, the heart

85

girth to flank girth ratio was still greater in the Protamone
group female, and the measurements were also greater.

Of the other body measurements, there was little dif-
ference in body lengths except that the female in the Pro-
tamone group was longer than the females in the control group
by 5 inches (tables XLV and XLVI). The height appeared to
be little affected except that the female in the Protamone
group was generally 1 to 2 inches taller than the females
in the control group (tables XLV and XLVI).

As to the body weight, the Protamone group finished
the experiment heavier than the Control group. The Protamone
males after 158 days on trial were 1.442 kg. heavier or
8.52% heavier than the males in the control group and the
female in the Protamone group was 5.785 kg. heavier or 50.20%
heavier than the females in the control group after 158 days
on trial (tables XLIII and XLIV). The Protamone males did
not become heavier than the controls until about the 60th
day of trial. The Protamone female gradually became heavier
than the controls after the start of trial, was about 1 1/2 kg.
heavier than the controls after 40 days on trial, and by the
70th day on trial was 2 1/2 kg. heavier than the controls(Fig. 10).

.The paired littermate males, #1 and #2, were least af-
fected by exogenous thyroid, since their weights did not
vary much during the course of the experiment. Dog #5, a

male, had a head start in growth because of his being placed

With another bitch and thus had better nourishment. His

paired littermate on Protamone overtook his early lead by
the 66th day on trial andfinished 2800 kg. heavier.

Soon after the trial started the weights on the Protamone
group became more uniform than those of the Control group.

The food consumption and.amounts of Protamone received

and efficiency of gain are as follows:

Amount of Protamone
received by Protamone
Group
Efficiency of gain (Based on average
(kg.dry feed/kg. of weight at begin-

Amount of dry
Months matter consumed

on (lbs.) gain in body wt.) ning and end of the
Trial Controls Protamone Controls Protamone monfii
lst 107.415 90.501 4.076 4.075 8.061 mg./kg./day
2nd 84.708 87.814 5.029 4.061 4.669 mg./kg./day
5rd 105.700 112.108 6.079 5.418 4.551 mg./kg./day
4th 124.459 112.108 7.508 6.700 5.476 mg./kg./day
5th 157.892 100.897 11.419 8.059 2.710 mg./kg./day
last

8 50.850 50.269 *negative 24.971 2.868 mg./kg./day
days
Gain T46.l48 45.117
(kgo)
Total
time 588.985 555.697

21.548 gms. of Protamone were consumed in all.
After the first month, the efficiency of gain was greater
in the control group, but by the third month, it was consis-

tantly greater in the Protamone group. The efficiency of

% Weight lost during this period.

87

gain coincided with the rapid growth period and was

naturally greater in the Protamone group.

88

 

Figure 8

Upper photo:

Control Group of English Bull Dog Puppies. Picture
taken at the end of trial. Left to right are dogs 5(female),
1(male), 6(female), and 5(male).

' Figure 9

Lower photo:

Protamone Group of English Bull Dog Puppies picture
taken at the end of trial. Left to right are dogs 2(male),
4(male) , and '7(female) .

Notice the greater uniformity, the wider chested and more
robust individual, the more adult type face, and the greater size.

89

 

20 r T v .
I
1 ["81- _
RQOTAWAE MALE H15?
/6- ~
avma
/;4_ PUPSQ‘) .
i F
Q's/2. / I/"_\ d
g: I
“OTWE
é/O‘ / FIJI IL! 1
003 .
1 . 8~ CCWTRCV. FEMALE F'UPS (2)
1 e

ENGL/SH ECU. DOG PUPPIES

53mm 0F ‘

”VA“; GROW TH TP/AL W/ TH P70 7A MOE
4 - /‘ ‘ my MA was FED T
2/ J

46M/00Pa/A05
1 LI I_ l L l l l l
20 40 60 80 IOO /20 EU I60 /80
‘ DAVS

 

 

 

Figure 10

Growth curves of male and female Bull Dog Puppies in
control and Protamone fed groups. Notice the marked difference
between the females when Protamone was given.

90

DISCUSSION

The effects of exogenous thyroid on the behavior are
what one would expect if the species in question inclined to
be hypothyroid. Such was indicated by the similarity of thy-
:mfld histology of the English Bull Dog to that of a breed of
swine which responded well in growth to exogenous thyroid
(Reineke, et a1. 1948). Since cretinism is believe to be
hereditary in humans (Lewis 1957), it is conceivable that such
is the case in various breeds of dogs inasmuch as their
origin is a history of inbreeding. Since the hypothyroid
symptoms in humans include' slow cerebration and dullness
of the sensorium (Thompson 1942), it is logical that the use
of exogenous thyroid would increase the mental alertness as
seen here. The English Bull Dog, by appearance, suggests
a hypothyroid individual.

Increased hair growth is to be expected in the hypothy-
roid individual upon the administration of exogenous thyroid.
Such has been demonstrated in the mouse (Koger, et al. 1942).
The darker hair coat in the Protamone group may be explained
as the type of hair coat of a more mature individual. Such
has been demonstrated in feather growth of chicks on exogenous
thyroid (Parker 1945).

The more mature appearance of the Protamone group is
similar to the results on chicks (Parker 1945; Irwin, et a1.
1945) in dogs (Moussu 1899; Dott 1925), in humans (Webster
1959), in swine (Reineke, et al. 1948) and in goats (Reineke

and Turner 1941).

91

The rate of dentition was not noticeably different
between the groups because the dosage was probably not as
great as in mice wherethe rate of dentition was increased
(Karnofsky and Cronkite 1959).

I The more mature type of appearance was also reflected
in the body measurements inasmuch as in mature animals, the
heart girth becomes greater than the flank girth. The in-
creases of height and length were not as marked as Moussu
(1899) reported on his dogs of a mongrel type. Perhaps the
difference lies in the breed of dog used. Since the dosage
was not unduly great, it did not cause a premature cessation
of growth at a small size as reported by Dott (1925).

The weight records followed the expected trend of a
species which benefits by exogenous thyroid in the growth
period. The reason for the wider difference in gain in the
females is a matter for speculation. The difference in
response between the litters may reflect a strain difference
comparable to the hereditary hypothyroidism reported in
humans by Lewis (1957). The weight increase was generally
of the nature of that reported in Collies on Protamone
(Brown and Smithcors 1948) and in swine (Reineke, et a1. 1948).
It would be interesting to note if the final weight attained
by the dogs in both groups would be ecual as indicated by
work on.mice (Robertson 1928), and dogs (Moussu 1899); or
if the final weight would be greater than the controls such
as is reported in thyrotoxic girls (Hertz and Galli-Mainini

1941). If the English Bull Dog were a hereditary cretin, one

92

would expect a larger than usual individual to be produced
by exogenous thyroid as has been shown in humans (webster 1959).
The increased efficiency of gain found in the Protamone
group is what one would expect from previous work. Similar
findings were reported by Brown and Smithcors (1948) in
Collies and by Roger, et al. (1945) in mice. The faster
gain in the Protamone group is probably the reason for the
increased efficiency. Similar findings in swine have been
reported (Reineke, et a1. 1948).
Radioactivity studies with the pups on their 48th day
of trial, indicated a lessened pickup of iodine by the thyroid
glands of the Protamone group. The turnover rate of iodine
in the thyroid was indicated to be similar in both groups.
This is not in entire agreement with the opinion of Hurst
and Turner (1947) that the amount of thyroid administered
must be greater than the animal's own thyroid secretion rate
to produce an effect. Such radioactive results would not
be the case if the thyroid gland were completely suppressed.
The lessening of the pickup of iodine may be explained (Galli-
Mainini 1941) by a suppression of thyroid function by the

exogenous thyroid.

94

SUMMARY
1. Protamone, at the dosage of 4 gm./100 lbs. of dry
matter consumed resulted in increased growth and hastened
maturity in Intact English Bull Dog Puppies started on
trial at weaning. The effect was more marked in the
females.
2. The hastened growth and maturity were judged by
more mature appearance, measurements, and weight.
5. The disposition of the Protamone group was more
alert and aggressive.
4.‘ The efficiency of gains was generally greater in
the Protamone group.
5. Radioactivity studies indicated a decreased pickup
of iodine by the thyroids of the Protamone group; the
turnover rate of iodine by the thyroid was similar in

both groups.

95

CONCLUSIONS
English Bull Dog Puppies respond to exogenous thyroid

by increased growth rate and greater alertness.

96

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Meyer, A. E. and Thompson, M. M. 1940. Difference in Action
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104

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Salter, W. T. 1944. Euthyroidism and Thyroid Dysfunction.2h1
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Schackter, R. J. and Huntington, J. 1940. Use of Orally
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105

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107

APPENDIX

Table I
DESCRIPTION OF THE INTACT mGS 0N PROMO“
Grog I
O Dog 1 was a female. 9 months old. Cocker-Pointer weighing 10.7 kg.
u m; 2 was a mic. 9 months old, Collie reigning 11.6 kg.
Dc; fit m a. female. 5 years old. mongrel resembling a Scottish Terrier

weighing 8.0 1:5.
mg 28 was a male. 3 year old. Collie weighing 15.11» kg.
Grog II
'- Dog 3 m a. femle. 9 months old. Cocker-Pointer weighing 10.6 kg.
in Ibg ’4 m a male. 9 months old. Collie weighing 15.3 kg.
Dog 27 was a female. 3 years old. Cocker weighing 11.9 kg.
Gregg III
0 Dog 2‘!- was a male. 9 months old. Cocker-Pointer voigiing 12.3 kg.
9 Dog 25 was a tonic, 9 months old. Cocker-Pointer weighing 11.14 kg.
at 1b; 26 was a male. 9 months old. Collie weighing 16.7 kg.
Inc 53 was a female. 5 year- old. Cocker weighing 10.9 kg.

It Cocker-Pointer litter mt”

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Table III I

*BOIJY WEIGHT BEGOBN IN A LONG TIME TRIAL WITH PROMMONE 0N
IN‘ELCT ENGLISH BULL mo DIME

. mks.

fl Dog II 13 the control

ht. mg 1 "Dog 11 Dog 111
11/25 15.100 -- 13.000
11/29 15.778 16.977 13.119
12/2 16.170 18.h10 13.190
12/9 16.519 18.11% 13.1126
12/18 16.810 19.090 1h. 318
1/1 17.080 19.553 111.055
1/11 16.615 19.759 111.950
1/21; 15.1100 18.».30 13.820
2/7 17.115 20.010 H.900
8/21 16.290 19.525 13.710
3]? 16.730 19.680 114.550
3/21 15.960 19.160 13.965
u/u 16.020 18.680 111.300
h/18 15.780 18.935 111.5145

lbs: I and II were fed Pmtauono at the rate 01’ 2 gum/100 lbs. dry

latter in the food. Dog 11 was the control.

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Table mu!
BEETS OF 1*131 INJECTIONS OF INTACT ENGLISH BULL BITCHES
0N PROTAMJNII
figures are in counts per mimte
I. II. III were injected with l+000 Ot./m1n.
kt. - Extremitiea my. a Thyroid. region

control

nae Dead-17.1 kg. Dog-II-ao.o kg. pagan-1M9 kg.

Ext. Thy. 311;. My. m. m.
7.5 m. 25 1:5 3o ho #5 60
15 m. ' 30 so 20 35 35 50
30 mo 35 85 30 70 30 35
1 hr. 55 loo 25 55 no 85
2 hip. 145 so no 60 35 55
.11 hr. 30 75 no 60 20 7o
8 hr. ho 60 so 60 1&5 65
16 hr. 30 no 35 55 35 60
32 hr. 20 25 15 1&5 25 50
6h hr. 15 15 10 30 10 25

Table mu: (cont.)

t values 01' the above and logs of same

rm t 103 t t 103 o: ave.
1 hr. .000687 4.16301; .001h62 .001176 I 833.;71376
2 hr. .000750 4.12191; .001169 .000922 -2.9sol+7
u hr. .000750 4.12191; .001096 .00117u -2.9l+500
8 hr. .000750 4.12% .000876 .001090 -3.oo7ll5
16 hr. .000687 4.15301; .000595 .001006 4.09909
32 hr. .000562 -3. 25026 .0003145 .000838 -3.22768
6h hr. .000375 -3. M2597 .000219 .oooluu 4.50031

Dog! I and III were on 2 gm. of Protamone per 100 lbs. dry matter. which
amounted to 2.0 to 1.7 mg./1:g./deyo

Dog II nae untreated.

be t value was calculated after the thyroid gland had pickedup ite

mum count (1 hr.) by the_'folloving for-.11”

t- counts 1e1- minutejbodl weight
. counts per m‘mte injected.

m regression equation of the loge of the t veluee was obtained for
use I and III as y :- .009177 3 52.92% and. for do; II as y I- .005139 2
3.1035 '

. H e
e h 0
O ""' O
Q ““ I
. _ C
e “‘ O
t 0
e O

Table XIII

RESULTS 03‘ F131 INJECTIONS
01' DITACT mGS ON HESICCATED THEOID

:11 dogs were injected with 2000 cte./min. Figures in counts/min.
#6 was receiving ’4 mgn. /1:g. [day for 28 days before teete

#29 was receiving 2 mgn./kg./day for 28 days before teete
Inn-extremities. Thy.- thyroid region

Mme Cte. Dog #6 - 8.8kg. Cta. Dog #29 - 7.61:3.
7.5 min. 20 35 30 30
15min. 15 15 25 25
30 min. 20 55 15 25
1 hr. 20 50 30 1I5
2 m. 1:0 1'5 No 115
11 hr. 15 35 15 no
8 hr. 30 3o 30 1"5
16 hr. 20 25 20 25
32 hr. 15 25 5 25
6h hr. 5 10 10 20

t values of the above and logs of same

Tine t t log. of average
1 hr. .00281l-1 .002860 4.514516
2 hr. .002056 .002860 4.619112
14 hr. .001888 .002631 -2.611589
8 hr. .0017011 .002860 4.611168
16 hr. .001h20 .00161114 4.921171;
32 hr. .001h20 .0016»; 4.921171;
6h hr. .000568 .001315 4.02595

The t value was calculated after the thyroid gland had picked up its
mum count (1 hr.) by the following formula.

t a mtejer minutejbodi weight
, counte per nimte injected

m regression equation of the logs. of the t values was obtained for the
above dose and was y n .007252: a 2.6295.

{cable In

news or 1.131 mmcmons
on 11111102 ENGLISH BULL Doe PUPPIES ON snowman

m injected with 2000 cts./min. Figures in counts/min.
Ihis group had been fed ll» gram/100 lbs. dry matter for ’4 months previous
to the test. Ext. - extremities. Thy. - thyroid region

Time Ots. Dog 2 - 12.8kg. Ote. Dog 1} -l3.5kg. Gts. Dog 7 - 12.2kg.
7-5 min 35 lIO 55 55 30 55
15 min. ho ‘40 55 50 30 no
30 min. 75 75 7o 80 no 145
1 hr. 25 ’45 30 35 ‘40 1"'5
2 hr. 25 25 5o 55 20 25
n hr. 30 30 35 35 ‘40 35
8 hr. '45 No 30 55 30 ‘45
16 hr. 15. 20 20 3o 20 25
32 hr. 5 15 o 15 5 10
611 hr. 0 5 0 lo 5 10
t values of the above and logs of same

log. of
{fine t t t average
1 hr. .001753 .001296 .0013m+ -2.83uh6
2 hr. .000938 .002037 .0010211 -2.87517
11 hr. .001172 .001296 .001h3h -2.88572
8 hr. .001562' .002037 .oo13uu -2.783oh
16 hr. .000781 .001111 .00102h 4.01233
32 hr. .000586 , .000555 .oooluo 4.28651
6h hr. .000180 .000370 .oooulo 4.1491485

Ihs t value was calculated after the thyroid gland had pidced up its
madman count (1 hr.) by the following formula.

t :- counts per minuteL

? weigt

, counts per mimteTn ecte

The regression equation of the logs. of the t values was determined to

by y a .01131: - 2. 819“.

mamas or 1.131 mmcnons

Table m

ON NWT. UNTREATED. ENGLISH HILL DOG PUPPIES

‘11 injected. with 2000 cts./min.

Ext. - extremities. Thy. «- thyroid region

Time

705 mm.

15 min.
30 min.
1 hr.
2 hr.
1} hr.
8 hr.
16 hr.

32 hr.
611 hr.

Ext.

30
no
60

3°
25
30
no
20
5

10

no
50
70
no
55
1+5
55
30
15
10

15
30

25
no

35
no
30
20
10

t values of the above and logs

i'ime

1 hr.
2 hr.
’4 hr.
3 hr.
16 hr.

32 hr.
611 hr.

t

.00175h
.002n12
.001973
.0021112
.001315
.000658
. 0001138

1'.

.002372
.002007
.002372
.0 011159
.001277
.000912
. 000729

M.
35
no
55
65
55
65
no
35
25
20

of some

15

.002083
.003125
.002083
.002083
.001302
.000781
.000521

Ext.

no
no
#5
2o
35
35
25
15
5

5

50

55
60

no
60
no
no
25

15
10

t

.00286h
.0028614
.001562
.00286h
.001562
.oomlu
.000781

Ext.
35
no
55

20
3O
3O
35
20

10
15

CtSemgl-‘llelkge Ctsemg}13.7kg. 01:8.Dog5-9e6kg. Ct8.Dog6-9.6kge
Me Me

W.

* 55
1*5
55
55
55

3O
55
30
20
15

log of
average

-2.61IJ436
-2.581469
~2-709llo
.2.65679
-2.865i9
4.07160
~3-20971

the t value was calculated after the thyroid gland had picked up its

maximum count (1 hr.) by the following formula.

t :- counts per minute/body wei
, counts per mifmteTnJecte

1:

Elle regression equation of the logs. of the t values was determined to
be I . .OlOOpx '- 2.61.880

Table MI
MSGRIPTION 03‘ m EEHYBOIDEC'IDMIZED IDGS
ON PROIAMQIE AND DESICCATED THYRO ID

Protamone Group
Dog 1 was a female. L-yean-old. Cocker-Pointer weighing 12.6 kg.

and was dog 1 in the intact dogs on Protamone
Dog 3 was a male. lpyean-old. Smooth Haired Fox Terrier weighing 9.9 kg.
Dog 34 was a female, l-yearbold, short haired. mongrel weiéfmg 9.7 kg.

Desiccated {thyroid Group

Dog 2 was a female. 2pyear-old. Smooth Haired Fox Terrier weighing 9.5 kg.
mg 214 was a male. 1 1/2—yean-old. Gordon Setter weighing 19.5 kg.
nag 25 was male. l-year-old. long haired mongrel weighing 13.3 kg.

Ibg 27 was a female. 2—year-old. Cocker weighing 13.9 kg. and was dog 27

in the intact cbgs on Protamone.

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Table XLIII

RECORDS OF *BODY WEIGHTS OF ENGLISH BULL DOG PUPPIES

* body weight in kg.

CONTROL GROUP

Dogs 1 and 5 are males, dogs 5 and 6 are females.
Protamone Group started on trial 12/3/48

Date
11/1/48
11/15/48
11/20/48
12/2/48
12/9/48
12/18/48
12/25/48
1/1/49
1/8/49
1/15/49
1/24/49
1/51/49
2/7/49
2/14/49
2/21/49
2/28/49
5/7/49
5/14/49
5/21/49
5/28/49

4/4/49
4/11/49

4/18/49
4/25/49
572/49
5/9/49

Dog #1

1.984
5.252
2.800
2.980
5.884
4.100
4.850
5.840

6.985
7.560

8.820

10.050.
. 10.995

10.985
11.450
11.815
12.005
12.580
12.940

14.590

15.220
15.550

16.200
16.850
16.550
16.010

Dog #5

1.505
2.555

5.900
4.475
5.527
6.170
6.792
8.580
9.102
9.170

10.265
11.460
12.065
12.860
15.698
15.565

14.570
14.055

14.755

15.550

16.600
17.040

17.515
18.100
18.170
17.850

Dog #5

1.154
1.845
2.440
2.757
2.915
5.572
4.270
5.200
5.475
6.100

7.150

8.100
8.285
sumo
9.845
9.415
9.845
10.170
11.045

11.595

12.500
12.145

12.955
15.415
15.185
15.100

D0846
1.049
1.845
2.200
2.570
5.115
5.800
4.740
5.500
5.750
8.140

6.965

7.800
8.560
8.855
9.658
9.775
9.710
10.405
10.880

11.450

11.970
11.620

11.950
12.105
12.520
11.970

Table XLIV

RECORDS OF *BODY HEIGHTS OF ENGLISH BULL DOG PUPPIES
0N PROTAMONE
*body weight in kg.
Dogs 2 and 4 are males, dog 7 is a female.
Started on Protamone 4gm./lOO lbs. of dry matter consuned

12/5/48

Date Dog #2 Dog #4 Dog #7
11/1/48 1.899 1.108 1.581
11/15/48 5.280 2.288 2.410
11/20/48 4.100 2.440 2.450
12/2/48 4.855 2.275 2.800
12/9/48 5.247 2.950 5.424
12/18/48 5.780 5.800 4.200
12/25/48 6.585 4.550 4.980
1/1/49 7.520 8.580 8.150
1/8/49 8.255 7.800 7.145
1/15/49 8.850 '7.845 7.585
1/24/49 9.850 9.255 8.440
1/51/49 10.290 10.510 9.220
2/7/49 12.015 12.555 10.875
2/14/49 11.755 12.740 11.280
2/21/49 12.800 15.485 12.185
2/28/49 15.050 14.100 12.290
5/7/49 12.820 15.940 12.455
5/14/49 15.510 14.505 12.805
5/21/49 15.810 15.275 15.550
5/28/49 15.140 18.541 14.545
4/4/49 15.570 17.550 14.875
4/11/49 15.855 18.555 15.405
4/18/49 18.205 19.285 15.585
4/25/49 16.060 19.480 18.540
5/2/49 18.475 20.080 15.940
5/9/49 18.095 20.850 18.520

Table XLV

RECORDS OF *BODY MEASUREMENTS OF ENGLISH BULL DOG
PUPPIES, 0 ONTROL GROUP

*Body measurements are in inches.

Dogs 1 and 3 are males, dogs 5 and 6 are females.
Protamone group started on trial 12/5/48

Hkheart girth, F-flank girth, L-1ength from tailhead
to nose, Ht-height at withers

Dog #1
Date H F L

Dog #5 Dog #5 Dog #6

Ht H F L Ht H F L Ht H F L Ht

1/27/49 19 20 21 12 21 21 25 15 18 17 21 12 18 17 22 11

2/7/49 20 21 24 15 21 21 25.15517 19 25 15 18 17 22 12

2/21/49 20 18

20518

22 2O

24 15 22 20 26 15 18 24 15 18 18 24 12

28 1%19518526 1%
27 15 20 19 27515

18

5/7/49 25 15522 19

2552815519
5/21/49 27 14 25 21 50 145 20 19

4/4/49 22 21 51 14 25 25528 20 27514520520527 155

4/18/49 25 22 50 14525 24 29 2o 29 14 20518 28 14

5/2/49 25 20 29 14524 21 50 19 29 14521 19 29 14'
RECORDS OF *BODY MEASUREMENTS OF ENGLISH BULL DOG
PUPPIES 0N PROTAMONE
*Body measurements are in inches.
Dogs 2 and 4 are males, dog 7 is a female.
Started on Protamone 4 gm./100 lbs. of dry matter con-

sumed 12/5/48

Date

1/27/49
2/7/49
2/21/49
5/7/49
5/21/49
4/4/49
4/18/49
5/2/49

Dog

#2

H F L

19
19
20
21
21
22

25
22

17
17
19
18
17
19

2O
20

24
25
25
26
27

28
29
29

Dog #4
Ht H ‘F L
15 19 18 22
15 21 20 25
15 21 19528
15522 19 28
14 22 20 50
1%252251
15 25 22 55
11525 25 55

Dog #7
Ht H F L
15 18 17 25
14 19519 25
15 20 20 25
14521 20 25
1%211E28
14522 19 28

15 25 19 29
15525 20 29

Ht
15
14
14
14
14
15
15
15

 

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Roam USE 0:47
Feb 27 ’501. f
Mar 13 '50
FE 21. '55
Oct 29 '57.

 

 

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