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HEALTH SCIENCES STANDARD
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These three lectures were delivered before
the students of the Medico-Chirurgical College.
Owing to the many requests for several parts
of our various publications of the work done
in the laboratory I have thought it best to
incorporate the results in a general review of
the internal secretions. While many state-
ments are contradictory, yet I have included
them, as the whole subject is in a stage of flux
and reflux. "Dire n'est rien; faire est tout" â€”
Renan. Isaac Ott.
Sept. 28, igio.
in the laboratory of our college. It was the
genial Franco-American physiologist, Brown-
Sequard, who in 1856 first stated that the adrenals
when removed caused the death of the animal.
This was the commencement of the discoveries
about glands with an internal secretion.
I was the first to state, in the Medical Bulletin,
1897, that "the adrenals enlarged the lumen
of the intestine at the moment of the injection
of the filtrate. When the arterial tension is
mounting the intestine is relaxing."
This property of the adrenal is of value in
intestinal hemorrhage of typhoid fever in
slowing the peristalsis. In the same paper I
showed that the spleen had a most marked
effect in exciting peristaltic movements. I have
also shown in the laboratory that iodothyrin
excites peristalsis and explains the diarrhea
in exophthalmic goitre, where we usually have
a hyperthyroidism. We also found that the
mammary, prostate and spermin were power-
ful excitants of uterine contraction.
The parathyroids were first discovered by
Sandstroem, a Swedish anatomist, in 1880.
They are often called by the Germans, epithelial
Parathyroids, Position of. â€” In the cat the
parathyroids are very regularly four in number,
two on each lobe; an external one more or less
free ui!)on the external surface of the thyroid,
and an internal one embedded in the substance
of the lobe nearer to the internal than the ex-
ternal surface of the thyroid, and always smaller
than the external. From their anatomical posi-
tion the cat is the most suitable animal for
parathyroidectomy. In color and size they,
resemble in the cat miliary tubercles.
The rabbit has two thyroid lobes connected
by an isthmus. In each lobe is embedded a
parathyroid. Two additional parathyroids, one
on each side, lie distinct from the thyroid,
usually at some distance from it. He has four
In the dog there are four parathyroids, but
the external pair are usually embedded in the
thyroid. The internal parathyroids are rarely
seen exposed upon the internal surface of the
Guinea Pig. â€” The thyroids usually consist of
two separate and distinct lobes, with occasion-
ally an isthmus uniting the lower ends of the
lobes. The number and position of the para-
thyroids is variable, more so than in any other
animal. Each lobe of the thyroid contains a
parathyroid embedded more or less in its tissue;
besides these, two additional parathyroids on
each side separated from the thyroid and varia-
ble in position in the levels of the thyroids.
He has four parathyroids.
Rats. â€” The thyroid consists of two lobes
united by an isthmus, one parathyroid to each
lobe, lying on the external surface. It is easily
accessible and can be readily cauterized.
In the monkey there are four parathyroids,
always embedded in the substance of the thyroid,
two in each lobe.
In man, the parathyroids are three or four
in number, two on each side in front of the
vertebral column just behind the rear margins
of the lateral lobes of the thyroid gland. The
inferior thyroid artery is in close relation with
them. A small grain of Indian corn repre-
sents their size and shape. Their color is red-
dish yellow or reddish brown (Fig. i).
Fig. 1. â€” The Four Parathyroids in Man â€” Posterior View
Gilbride, in man, found that the most common
site of the parathyroids is in the region of the
inferior poles of the thyroid gland; the superior
or external glands are behind and close to the
inferior border of the lateral lobes and in close
proximity to the inferior thyroid artery, the
inferior or internal glands lying posterior and
below the superior glands, nearer the median
line or below the thyroid and resting on the
anterior and lateral surface of the trachea.
W. Berkeley, in 125 autopsies, occasionally
found as many as five or six, often only two or
three, but always one, parathyroid.
Proportion of Parathyroid to That of the Thy-
roid. â€” Thyroid tablets of commerce are chiefly
from the glands of the lamb. The fresh thyroids
of six mature lambs weighed 24.7 grams (dried
8.4 grams), while twelve external parathyroids,
fresh, weighed 0.23 gram (dried 0.09 gram).
In feeding with thyroid tablets the parathyroids
play an exceedingly small part in the medica-
Histology. â€” These glands are rich in cellular
elements and enclosed by a delicate capsule
of connective tissue. In the parathyroid, trabec-
ulae run from the deep surface of the enveloping
capsule, branch and unite to divide the interior
of the gland into polygonal compartments.
The cells are small, with a large round nucleus.
The amount of protoplasm in the cell is small.
The cells of the parathyroid are in structure
very different from those of the thyroid. The
cells are of two types, the chief and oxyphile,
which are considered by Forsythe to repre-
sent two stages in the activity of one kind of
cell. In repose, the clear protoplasm of the
chief cells are filled with oxyphile granules
which are subsequently extruded, and run to-
gether to form drops of colloid material which
enters the blood via the lymphatics.
In the parathyroids the masses of polyhedral
cells are in varying stages of active secretion;
often, however, a drop of the colloid secretion
forces the cells apart. The formation of vesicles
in the isolated parathyroid is quite common
in the glands of man.
Morphology. â€” Three diverticula form the thy-
roid, a median one growing from the second
visceral arch and which moves to a pretracheal
position, where it is connected with the lateral
thyroid buds which develop from the dorsal
wall of the fourth inner pharyngeal cleft.
Parathyroids are thickenings of the epithelium
on the dorsal aspect of the third and fourth
visceral clefts. The thymus arises as a pair
of outgrowths from the epithelium of the third
Chemistry of the Parathyroids. â€” The colloid
material secreted by the parathyroid is now
conceded not to contain iodine. Glycogen is
found in abundance.
Blood Supply. â€” The parathyroids receive their
blood supply usually from the inferior thyroid
artery. Nate Ginsburg has shown that one of
the superior parathyroids derives its blood
supply from the superior parathyroid artery
instead of from the inferior thyroid artery.
Ginsburg also found that there is an anastomosis
between the parathyroid arteries on one side
with those of the other, so if one of the inferior
or superior thyroid arteries is intact the blood
supply not only of the parathyroid bodies of
one side, but those on the other, are preserved.
Parathyroids in Thymus. â€” Erdheim found small
accessory parathyroid glandules in the thymus.
This has also been seen by Pepere in rabbits
and in man. Harvier and MoreP found in half
of the cases a group of parathyroids in the cat,
chiefly in the cervical lobes. They found that
tetany did not ensue unless these thymic para-
thyroids were also removed. Dr. Scott and I
have frequently noted and removed the thymic
Changes in Parathyroids after Removal of
Thyroids. â€” When the thyroids were removed
it was found, by Vincent and Jolly, that the
parathyroid tissue approximates in appearance
to ordinary thyroid tissue. There is, however,
no hypertrophy of the tissues of the parathyroids.
Walter Edmunds^ has shown by experiments
upon dogs that the parathyroids even when left
in animals with great thyroid insuflEiciency do
not change into thyroid proper.
What is Tetany? â€” This name "tetanie" was
first used by Lucien Vavirsort in 1852. It is
not a distinct disease, but a symptom-complex.
It consists of spontaneous intermittent muscular
contractions, attended with decreasing strength
1 Comptes Rendus de la Biologic, May, 1909, p. 837.
2 Journal of Pathology and Bacteriology, 1910, p. 288.
until death ensues. There is also a spastic,
tottering gait, tachycardia, dyspnea, rapid
emaciation and psychical depression. It is as-
sociated with hypoparathyroidism.
When all the parathyroids are removed there
is partial paralysis, especially of the extensors;
trembling in all the muscles, followed by a series
of convulsive attacks, with loss of appetite;
there is often vomiting and dyspnea, which
is replaced by polypnea during the convul-
sive attack. The temperature rises during the
convulsions, which fact we have often observed.
This tetany begins in twenty-four to forty -
eight hours after the operation in the dog and
cat. The dog generally dies from the second
to the fifth day in convulsions. Robert Quest,
in 1905, analyzed the brains of three infants
dead by tetany and found the amount of cal-
cium to be small. There was also a change
in the proportion between the amount of sodium
to that of calcium.
Oddo and Sarles found the urine in the tetany
of infants to have an exaggerated amount of
calcium phosphates. They explained the cause
of tetany to be due to loss of calcium salts.
Silvestri (1906) held that tetany and eclampsia
could be explained by a diminution of the cal-
cium in the organism.
Netter cured three cases of tetany in infants
with calcium chloride by the mouth. Mac-
Callum and Voegtlin confirmed the results of
Quest as to the lessened amount of calcium in
the brain. They also confirmed the results
of Oddo and Sarles that there was an increased
excretion of calcium in the urine. MacCallum
and Voegtlin also found the calcium content
in the muscles and blood to be one-half the usual
amount. Halstead has cured tetany in man,
due to the removal of the parathyroids in opera-
tions on the thyroid, by calcium.
MacCallum and Voegtlin arrested tetany for
twenty-fours hours in dogs when seven grains
of calcium lactate were given by the vein. Beebe
has shown that injection of parathyroid ex-
tract causes the symptoms of tetany to vanish
for a time, but death finally ensued, just as it
did in animals after the use of calcium lactate.
Quantity of Calcium. â€” Parhon, Dumitresco
and Nissipesco^ found that in proportion to
weight, animals, cats chiefly and dogs, the
proportion of calcium in the nerve centers was
greater after thyroparathyroidectomy than in
normal animals. They do not confirm Silvestri
and MacCallum's results.
Leopold and V. Reuss^ in rats after removal
of the parathyroids found rather an increase
of calcium in the body when compared with
noirmal animals. These experiments would
rather support the theory of Stoelzner, that
there is a hypercalcification which causes tetany.
Quest made some experiments upon dogs
1 Compies Rendus de la Societe de Biologie, 1909. May, p. 792.
- Wiener Klin. Wochenschrift, No. 35, 1908, p. 1243.
by subcutaneous injection of calcium chloride
solution to produce an excess of calcium in
the body. He never observed an elevation of
the electric excitability of the nerves. The
faradic current showed a prompt depression
of irritability.^ These experiments tend to prove
that Stoltzner's idea that an excess of calcium
causes tetany is not correct.
Musser and Goodman^ studied the metab-
olism of a case of surgical or post-operative
tetany. They found no "diabetes calcareus,"
but a marked diminution of the calcium in
the urine. They found no relation between
the amount of calcium and the severity of the
symptoms. They pertinently ask: If tetany
is due to a withdrawal of calcium, why should
the symptoms persist when the organism is
in the perpetual condition of calcium store?
Leopold and Von Reuss suggest that the poison
which normally is paralyzed by the parathyroids
is able to precipitate calcium and leads to the
deprivation of the organism of active calcium
in a physiological sense. This might explain
that with normal or increased total calcium
there could be a poverty in ' active calcium.
Musser and Goodman found a high percentage
of ammonia in the urine, it never falling below
5 per cent. This coefficient of ammonia bore
a distinct relation to tetany. They practically
found that . when rigidity or some distress ref-
' Berliner Klinische W ochenschrifi, 1910, p. 1074.
- University of Penna. Medical Bulletin, p. 90, May, 1909.
erable to the tetany was complained of, the
ammonia percentage was raised. They are
of the opinion that an acidosis may be the under-
lying feature of surgical tetany.
MacCallum and Voegtlin have discovered
in parathyroidectomized animals: (i) a marked
reduction in the calcium content of the tissues,
especially of the blood and brain; (2) an in-
creased output of calcium in the urine and feces
on the development of tetany; (3) an increased
output of nitrogen in the urine; (4) an increased
output of ammonia in the urine, with an in-
creased ammonia ratio in the urine; and (5)
an increased amount of ammonia in the blood.
Jean V. Cooke^ found in dogs dying from
parathyroid tetany a slightly greater amount
of calcium in the brain than in the brain of
normal dogs, which indicates that a decreased
calcium content of the brain is not constant
in tetany. After removal of the parathyroids,
with the animal fasting, the elimination in urine
of magnesium is greatly increased, while that
of calcium remains unchanged. The augmenta-
tion of magnesium begins before tetany is ob-
served. It is suggested that tetany represents
a condition of altered salt equilibrium in the
nerve cells brought about by a disturbance in
the catalytic processes of the body which in-
creases the acid factors.
Walter Edmunds^ found in animals, if a large
' Proceedings of Society for Experimental Biology and Medicine,
1909. p. 13.
^ Journal of Pathology and Bacteriology, 1910, p. 290.
amount of calcium was given or mainly fed on
milk previous to the operation, that after a total
thyroidectomy which includes the parathyroids
the symptoms ensuing are removed or tem-
porarily mitigated. The calcium and milk was
continued after the operation.
Poison in the Blood of Animals in Tetany. â€”
Pfeififer and Mayer found in the sera of six out
of seventeen dogs, which had tetany after re-
moval of the parathyroids, a toxic principle.
This was shown by experiments upon mice.
Berkeley and Beebe regard tetany to be due
to a metabolic poison: (i) the symptoms have
a central origin; (2) the symptoms are shown
best in young animals and are more severe if
the animal is kept on a meat diet; (3) the symp-
toms have a close relation to certain chemical
conditions which are accompanied by severe
nutritional disturbances; (4) gastric tetany is
accompanied by severe metabolic disturbances,
it has similar symptoms and is promptly re-
lieved by intravenous injection of calcium and
by parathyroid and nucleoproteid ; (5) bleed-
ing followed by intravenous infusion relieves
the animal, a procedure well suited to free the
body from a circulating poison; (6) symptoms
are promptly relieved by the injection of fresh
parathyroid nucleoproteid; (7) injections of
known simple poisons, such as ammonia and
xanthin, produce symptoms which can be
promptly relieved by injections of calcium or
strontium salts similar to the relief obtained
by the same means in tetany; (8) parathyroid
tetany has a deranged metabolism accompanied
by a large increase in the excretion of ammonia.
Meljnikow/ in tetany of rabbits after re-
moval of parathyroids, found that injections
of calcium acetate quickly improved the ani-
mals, but it was quite temporary. He states
that the parathyroids have a specific histo-
logical structure which is not converted into
thyroid tissue. Goitre degeneration of the thy-
roid has but little effect upon the parathyroids.
There is some regressive change, probably due
to mechanical pressure from the enlarged thy-
roid, and not to any physiological connection
with the thyroid.
Beebe found that strontium acted equally
well as calcium in relieving tetany. Barium
also relieves tetany. These facts indicate that
calcium loss is only a part of the factors in the
course of tetany.
Bleeding cures tetany, but it can not do it
by loss of calcium, as this operation diminishes
this element more. It is not likely in forty-
eight hours after the operation that in the onset
of tetany the hypocalcification is so great as
to cause the disease, for plenty of calcium can
come from the store-house in the bones.
Magnesium also relieves tetany, according
to MacCallum and Beebe. Neither barium
nor magnesium should be used, as they are
toxic to the heart. Beebe found parathyroid
1 Wiener Klinische Wochensckrifi, 1910, p. 410.
nucleoproteid to relieve tetany. The globulin
in parathyroids has no effect on tetany. The
nucleoproteid will relieve tetany if given by
the mouth, but is much more quickly and cer-
tainly effective when given subcutaneously or
Berkeley and Beebe are inclined to believe
that the parathyroids are chiefly concerned in
furnishing enzymes, which are of prime im-
portance in the intermediary metabolism of
nitrogen. They do not believe that the ab-
normal secretion of calcium is the cause of
tetany, but a deranged metabolism giving rise
to an active poison.
Clara Jacobson finds in the blood of para-
thyroidectomized animals an increase of am-
monia and she believes it is directly responsible
for the tetany, as the concentration of ammonia
in the blood of the parathyroidectomized cats
and dogs is sufficient to cause tetany, tremors,
and depression in the normal animal. Nor-
mally in cats it is 1.57 milligrams per 100 cc,
but in parathyroidectomized animals it is
on an average of 6 animals 2.53.^
Our experiments were made upon sixty cats
and two dogs. One hundred and thirty- three
observations were made on these sixty-two
animals. The cats were first etherized, then
the parathyroids removed under antiseptic pre-
cautions. The thymus was always examined
1 Proceedings of Society for Experimental Biology and Medi-
cim. Vol. VIII, No. 4. p. 124.
for parathyroids. The cat has usually four
parathyroids, but more may exist. In young
cats the parathyroids have a looser anatomical
relation to the thyroid than later in life. In
many cases some of the thyroid was removed
in the desire to obtain all the parathyroids,
but enough thyroid was left to maintain its
functions. When removal in part of the para-
thyroids was ineffectual to produce a tetany,
then the thyroid was also removed, and we
always found it contained a parathyroid larger
than the normal. In cats, when all the para-
thyroids were removed symptoms of tetany
came on in about forty-eight hours as a rule.
The first symptoms were a slowness in move-
â€¢ment and a state of apathy. The animals
were disposed to remain in one place. First,
as a rule, was developed a lifting of the pos-
terior extremities and sometimes of the an-
terior, as though the animal had been stepping
in water. The posterior extremities were stiff-
like in movement and spread apart in their
gait. Then trembling ensued in the extrem-
ities, followed by convulsions of the whole
body. In the convulsive state the animal
usually made loud cries before and after the
convulsion. Conjunctivitis was frequently noted
in the tetania parathyreopriva. The sense of
hearing, sight, smell, and taste remained. They
did not respond to petting. They also had the
projecting abdomen noted by Hagenbach.
In some old cats some time after removal
of parathyroids and thyroids and careful ex-
amination of the thymus, no tetany ensued
for two weeks. Now, Bell and Martin have,
shown that pituitary increases the calcium
content of the blood. Hence, it is probable
that the well-developed pituitary of old animals
was sufficient to delay the appearance of tetany,
although the animals were kept on a meat diet,
which favors tetany. We injected subcutane-
ously in animals with tetany about ten to twenty
grains of pituitary extract, rubbed up with dis-
tilled water. Then in about three hours the
vacillating, spastic gait disappeared, the tremor
was replaced by steadiness, and the lifting of
the feet as though wet with water disappeared.
The head, which usually hung down, was ele-
vated, and the whole bearing of the animal
was changed. This continued for about twenty-
four hours, when tetany reappeared. In no
case were we able to prevent death by repeated
injection of the pituitary. We also injected
pituitary by the vein, but the best results were ob-
tained by subcutaneous injections. That neither
calcium nor its combination with other salts
was concerned in the action of the pituitary
was proved by. the fact that incineration of
the pituitary extract and the injection of the
ash was not followed by any curative effect.
The extract was subjected to intense heat in
a capsule for a couple of hours, then the re-
maining salts were dissolved in distilled water
and injected subcutaneously and by the vein.
All our observations show that it is an organic
body in the pituitary which abates the tetany.
We also tried pituitrin, an acidulated extract
of the infundibular part of the pituitary. It
was used subcutaneously in doses of 4 cc. up
to 28 cc. It acts rapidly in the relief of tetany,
but the action is much more fugitive than the
pituitary extract. Pituitary extract by the
jugular is not as effective as subcutaneously.
Adrenalin was given by the jugular, in the
cat, and some improvement was noted. Lowen-
thal and Wiebrecht saw a good effect in human
tetany by adrenal extract.
lodothyrin was also given by the jugular, and
it had a quieting" action upon the tremor.
Mammary gland, thymus, testicle, prostate,
spleen, spinal cord (all rubbed up with distilled
water), and Poehl's spermin had no effect upon
tetany; they were all given subcutaneously.
Pancreas had a quieting effect in seven cases
out of ten.
As to the comparative value of pituitary
extract and calcium lactate, our experiments
did not show any particular difference. The
intravenous injection of calcium lactate passed
off quickly, while the subcutaneous effect of
pituitary came on slower and continued longer.
Pituitrin did not have the permanent effect
that the gland substance did. Evidently in
tetany the gland itself should be used, as there
is something wanting in the pituitrin. The
"Vaporole" Extract of Infundibulum (i cc.)
2o% (Burroughs Wellcome & Co.) may be
the best to use. It is inferable that the in-
fundibular lobe is the active part of the gland
in antagonizing the tetany after the removal
of the parathyroids.
As to the cause of tetany, we have two theories,
one of hypocalcification, held by Silvestri,
Netter, Quest and MacCallum; the other, that
the removal of the parathyroids leaves a poison
in the blood (Pfeiffer and Mayer), or, according
to Berkeley and Beebe, it is a poison generated
in proteid metabolism.
Beebe's experiments showing that strontium
will relieve tetany quite as well as calcium
indicate that hypo-calcification is not the whole
cause of tetany, but only an epiphenomenon.
Our experiments show that:
(i) Removal of the parathyroids alone causes
(2) Pituitary extract will temporarily cure
(3) Between the parathyroids and the pitui-
tary there is a co-operative action.
(4) The infundibular lobe contains the active
(5) Tetany is not due to want of calcium,
but to a poison in the blood.
The nucleoproteid^ (S. P. Beebe's method)^
was used in part of the experiments upon the
intestine, uterus and kidney. The gland itself
1 Thanks to kindness of Dr. W. N. Berkeley, of New York.
^ The Old Dominion Jo%irn<ll of Medicine and Surgery, April,
1909. p. 231.
lines represent drops of urini
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