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Response to pituitary growth hormone of rats thyroidectomized on the day of birth.

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RESPONSE TO PITUITARY GROWTH HORMONE O F RATS
THYROIDECTOMIZED ON T H E DAY O F BIRTH'
ROBERT 0. SCOW AND WALTER MARX
Institute of Experimental Biology and the Division of Anatomy, University of California,
Berkeley
FOUR TEST FIQURES AND TWO PLATES (FOUR FIQURES)
It is well established that normal growth is dependent upon the secretions of both the thyroid and the pituitary glands. It has been demonstrated that the pituitary contains a factor which can stimulate growth
in rats in the complete absence of the pituitary or thyroid, or of both
glands (Smith, '27, '30, '33 ; Evans, Simpson and Pencharz, '39). In all
these types of rats the growth response is better if thyroid extract is
given concurrently wit.h the growth hormone (Smith, '33 ; Evans, Simpson and Pencharz, '39). I n these studies and in the earlier work of
Flower and Evans ( '25), in which a response to growth hormone was
reported in thyroidectomized rats, the animals were thyroidectomized
after weaning. Salmon ('38, '41) in repeating this work, removed the
thyroid at birth and was unable to correct the resultant dwarfism by
the administration of either anterior pituitary growth extracts or pituitary implants. Tn view of these contradictory results, Salmon suggested that the important factor involved appeared to be the age of
the animal at the time of the thyroid ablation, that in very early postnatal life animals can not respond to hypophyseal substances without
the thyroid.
The purpose of this study was to repeat Salmon's interesting experiments, to see whether, employing a purified growth hormone preparation of adequate unitage, we could confirm the report of the lack of
growth response of rats thyroidectomized at birth.
EXPERIMENTAL PROCEDURE
Growth hormone preparation. The anterior pituitary growth hormone used was a cysteine treated globulin fraction (Marx, Simpson and
Evans, '42, '43) which was practically free of other known pituitary
'Aided by Grants from the Research Board of the University of California, the National
Research Council, Committee on Medical Research and the Rockefeller Foundation, New Pork
city.
227
228
ROBERT 0. SCOW AND WALTER MARX
hormones.2 The growth hormone was injected daily, intraperitoneally,
in 1mg. doses, dissolved in 0.5 cc. of physiological saline solution. This
daily. dose contained 20 to 30 hypophysectomized rat units. As this
was considered a large dose for such small animals, the initial two injections were of 0.5 mg. each. The average injection period was 23
days. The number of growth hormone units injected daily was less
than one-half that stated to have been injected daily by Salmon.
The method of thyroidectomy, the characteristics of the thyroidectomized animals and method of determining completeness of the operation have been described in the preceding paper (Scow and Simpson,
'45). Only animals with a skeletal age of 15 days, when chronologically
30 days old, were used in these experiments. The rats were divided into
two equal groups, one to be injected with growth hormone and the other
to act as a control group. The injection period began on the thirty-second day of age. (A preliminary report of this study has been given by
Scow, '43 and by Scow and Marx, '44).
BODY WEIGHT
The increase in body weight of injected (11)and uninjected (7) rats
is shown in table 1 and figure 1. The body weight of the injected rats
doubled during the 23-day injection period. Body weights were recorded for 12 days after cessation of injection and no further growth
occurred. This growth during injection represented an increase of 1.1
gm. daily above the rate of growth of controls. It will be noted that the
initial body weight of the injected rats was less because the smaller
rats were placed in the injected group. As can be seen in figure 1, the
growth hormone produced a greater increase in body weight in a
group of three rats which later were shown to have small fragments of
thyroid tissue.
Figure 2 shows the individual growth curves of three completely
thyroidectomized rats, two of which received their first injections on the
fifty-first to fifty-eighth day of life. A marked increase in body weight
was observed during the injection period, with plateauing of the growth
curve occurring after the injection period was terminated. When a
second period of injection was begun in these same animals at 81 to 89
a When injected into hypophysectomized 26-28-day-old rats, 14 days postoperatively, in a
total dose of 2.5 mg. over a 4-day period, the preparation (pH XXXI, l c ) showed no evidence
of gonadotropic or adrenocorticotropic hormones, while the presence of a trace of thyrotropie
hormone was problematical. At a total dose of 5 mg. the presence of thyrotropic hormone was
shown by a slight but definite response, and contamination by a minute amoult of adrenocorticotropic hormone became apparent. Such preparations are always found to have less than 0.5%
lactogenic hormone.
TABLE 1
The effect of growth hormone upon rats thyroidectomized at birth.
Daily injections of 1.0 mg. of growth hormone were made from the 32nd day o f age for 8 3 days.
Effect on body weight
BODY WEIQHT QAIN, QM.
NO.
~
11
35
7
7
During 12 day8
following injection
Per cent of
body Weight
Total
I n jected
Unin jected
I
During injection 1
OF
BATS
Weight
gained
per ds.
weight
Rained
I
-2
0.3
I
SKElrETAL A Q l , DAYS
LENGTH OF TIBIAL DIAPHYSIS, M Y .
$I&
Increase during
injection
period 1
___
I n jected
Uninjected
L I '
I
40
Onset
~
I
45
I
SO
_
I
55
00
12 days after
injection
End
_
_
_
18
18
15
15
0.7
0.7
6.6
4.8
I
During injection
Increase during
next 12 days
-
11
6
0.3
I
NO.
TEEATMENT
- 0.2
I
65
I
70
-
18
18
I
75
Aga in Daya
Fig. 1 Increase in body weight of eleven growth hormone injected and seven uninjected
thyroidectomized rats during a 23-day experimental period beginning a t 32 days of age. The
body weight increase of three injected rats subsequently found to have been incompletely
thyroidectomized is also shown.
230
ROBERT 0. SCOW AND WALTER MARX
days of age, they immediately displayed an increment of body weight,
which again ceased when the injections were no longer given. A third
rat was injected only during the second period, beginning at 89 days
of age, at which time it was able to respond to the growth hormone.
Skeletal development. The roentgenograms showed that the increase
in body weight was not diie to a response of the soft tissue only, but
also to an increase in the skeletal structure of the thyroidectomized rats.
n
E
e
(3
k
U
m"
I
40
I
I
I
I
I
I
50
60
70
80
90
100
I
110
I
120
t
130
I
140
Age in Days
Fig. 2 Increase in body weight of two completely thyroideetomized rats injected with
growth hormone for 18 days beginning on the fifty-first to fifty-eighth day of life, and again
for 12 days beginning at 81 to 89 days of life. A third rat was injected only during the second
period.
The response of the skeletal structures to growth hormone is recorded
in table 1 and figure 3. The length of the diaphysis of the tibia was
used as an index of the growth of the skeletal system. The increment
in the length of the tibias of the injected rats during this period was
37% greater than that of the uninjected animals. During the 14 days
after the injection period, the increase in the length of the tibia was
about the same in both groups. It is noteworthy that though the bones
did increase in dimensions, the shape of the bone was not altered. No
* Roentgenograms were made one before the injection period, one 2-4 days after the injection
period, and one just prior to autopsy.
231
GROWTH HORMONE AFTER THYROIDECTOMY
changes were noted in the number of tarsal and carpal bones, or in the
shape of the ends of the diaphyses, and the epiphyses. This is a most
remarkable effect of the growth hormone upon the skeletal system,
namely, to stimulate the growth in size of the bony structures without
the accompanying appearance of new epiphyseal centers. The skeletal
W
24
g
p
-
-
I
I
I
I
I
I
I
I
I
-
0
.
)
8
0
.o
I0
20:
18
16
c
2
-
22,
14
f
I2
-
;-_----;
-
o
.
lnioctii ooriod
Injootod Thyroidrotomlxo~
-
Uninjortod
c
h'
10
-
I
x,
I
I
40
I
45
I
50
I
I
I
I
L
55
60
65
70
'Is
age of the injected rats was the same as that of the uninjected rats of
the same chronological age. Similar effects upon the skeletal structures were observed in the rats injected at the older ages (fig. 4).
Typical roentgenograms illustrating the effect of growth hormone
upon the skeletal system me shown in figures 5-8. The uninjected
thyroidectomized rat in figure 5 has a chronological age of 89 days, but
a skeletal age of only 18 days, as may be seen by comparison with the
normal 18-day-old rat in figure 7. The slightly greater width of the
ends of the diaphyses in the thyroidectomized rat is the only noticeable
difference. The effect of growth hormone upon the skeletal system of
the thyroidectomized rat is shown in figure 6. The animal is a littermate
of the uninjected rat in figure 5, but was injected with 1 mg. of growth
hormone daily for 22 days, beginning at 30 days of age. Although the
bones have increased in dimensions, the degree of ossification has re-
232
ROBERT 0. SCOW AND WALTER MARX
mained the same as that of the 18-day-old normal rat. For comparison,
a normal rat of the same chronological age, 89 days, is shown in figure 8.
Other obseruatiofls. No aceleration in the opening of the vagina, or
changes in the gonads or adrenals were observed. The peculiar gait
was unaffected by the injection of growth hormone as was also the
transformation from the infantile hair to the adult hair. The weights
of the organs and the ratio of these weights to body weight, as shown
in tables 1and 2 of the preceding paper, were unaffected.
28
26
Ii
E
22
5
I-
2o
*0
18
fK
-I
16
14
I
I
I
I
I
I
1
-
-
-
0
*
0
:
24-
0
I
-
2
a
a0
-.-
I
-
.s
0
I
t
0
fr
-
-
;
Thyroidoctomlrod (W-4)
Thyrotd~c?c~nlrod
Thyroldoctomird
(6-9)
(W-7)
0
-
-
4 I n j e t m brgun
t
Injactim sttopprd
-
I
I
I
I
I
I
I
I
I
I
50
60
70
80
90
00
110
140
130
140
-
GROWTH HORMONE AFTER THYROIDECTOMY
233
stimulation of growth could be initiated in these dwarfs as early as 29
days and as late as 89 days of age.
I n discussing the possible reason for the failure of Salmon to obtain
growth following the administration of growth extract to thyroidectomized rats, the state of the health of these animals must be considered. It was pointed out in the preceding paper that marked differences existed in the characteristics after 23 days of age between the
thyroidectomized rats reared by Salmon and those described here. I n
the former case a growth plateau was reached at 23 days, the rats were
susceptible to intestinal disturbances and infection, and had a maximal
longevity of 60 days. Further, Salmon injected “only those rats which
ceased growing after 23 days” of age. A very slow prolonged growth
is described here as characteristic of the rat considered completely
thyroidectomized by all the criteria used (see preceding paper). It is
possible that the rats reared by Salmon which “ceased growth” at 23
days of age were incapable of growing when stimulated by growth
hormone. This remark has been occasioned by the observation that
animals in the present series which were suffering from mild intestinal
disturbances, such as flatulence, were not able to respond to the growth
hormone and frequently became worse until the injections ceased.
Smith, Evans, and others have shown that the response of animals to
growth hormone is greater when thyroid hormone is present. This was
clearly shown in this experiment, since the response of the animals
shown to have small fragments of thyroid tissue was greater than that
of those which were completely thyroidectomized.
CONCLUSIONS
1. The growth rate of rats completely thyroidectomized at birth was
stimulated by a purified preparation of anterior pituitary growth
hormone. The following points were noted :
a. The body weight was doubled in 22 days.
b. The skeletal size increased at an accelerated rate.
c. No acceleration was observed in the appearance of secondary
ossification centers.
d. The response elicited did not depend upon the age of the animal
at the beginning of the injections of growth hormone.
2. The growth stimulating effect of growth hormone was greater in
thyroidectomized rats which were shown to have a fragment of thyroid
tissue present than in completely thyroidectomized rats.
234
ROBERT 0. SCOW AND WALTER MARX
LITERATURE CITED
1939 Relation between the growth proEVANS,
H. M., M. E. SIMPSONAND R. I. PENCHARZ
moting effects of the pituitary and the thyroid hormone. Endocrinology, vol. 25,
pp. 175-182.
FLOWER,
C. F., AND H. M. EVANS1925 The repair of dwarfism following thyroidectomy by
the administration of anterior hypophyseal fluid. Anat. Rec., vol. 29, p. 383.
MABX,W., M. E. SIMPSON AND H. M. EVANS1942 Bioassay of the growth hormone of the
anterior pituitary. Endocrinology, vol. 30, pp. 1-10.
1942 Purification of the growth hormone of the anterior pituitary. J. Biol.
Chem., vol. 147, pp. 77-89.
T. N. 1938 The effect on the growth rate of thyro-parathyroidectomy in newborn
SALMON,
rats and of the subsequent administration of thyroid, parathyroid and anterior
hypophysis. Endocrinology, vol. 23, pp. 446-457.
1941 Effect of pituitary growth substance on the development of rats thyroidectomized at birth. Endocrinology, vol. 29, pp. 291-296.
Scow, R. 0. 1943 The effect of anterior pituitary growth hormone upon the thyroidectomized
rat. Master 's Thesis, University of California.
Scow, R. O., AND W. MARX 1944 Thyroidectomy in the rat on the first day of life. Anat.
Rec., vol. 88, p. 456.
Scow, R. O., AND M. E. SIMPSON 1945 Thyroidectomy in the newborn rat. Anat. Rec., vol.
91, p. 209.
SMITH,P. E. 1927 The disabilities caused by hypophysectomy and their repair. The tuberal
(hypothalamic) syndrome in the rat. J.A.M.A., vol. 88, pp. 158-161.
1930 Hypophysectomy and a replacement therapy in the rat. Am. J. Anat., vol.
45, pp. 205-273.
1933 Increased skeletal effects in A.P. growth-hormone injections by admbistration of thyroid in hypophysectomized thyro-parathyroidectomizedrats. Proc. Soc.
Exp. Biol. and Med., vol. 30, pp. 1252-1254.
PLATE 1
EXPLANATION O F FIQURES
Roentgenograms of normal and thyroidectomized rats, 3 actual size.
5 Uninjected 89-day-old rat which was thyroidectomized on the first day of life. The
skeletal age of this animal is 18 days, a s may be seen by comparison with the 18-day-old normal
r a t in figure 7. Note the slightly wider ends of the diaphysis in the thyroidectomized rat.
6 Littermate, thyroidectomized on the first day of life, of the rat shown in figure 5; injected with 1mg. of growth hormone daily for 22 days, beginning at 30 days of age. The rat
gained 41 gm. during the injection period. Whereas the bones have increased in length and
breadth, there has been no advance in skeletal age, as may be seen by comparison with the
18-day-old normal r a t in figure 7 and the 89-day-old normal rat in figure 8.
7 Normal 18-day-old rat, with which the skeletal development of the 89-day-old thyroidectomized rats in figures 5 and 6 is to be compared.
GROTYTH H O R N O N E A F T E R TI1TROIJ)RCTOMY
ROBERT 0 SCOW A B D W A I I T I R ?[ARK
PLATE 1
GROWTH HORMONE AFTER THPROIDECTOMY
PLATE 2
ROBERT 0. SCOW AND WALTER X A R S
8 Roentgenogram of a normal 89-day-old rat, g actual size. The skeletal development is f a r
in advance of that attained by thyroidectomized rats of the same chronological age (figs. 5
and 6 ) .
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