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The effects of chronic administration of thyroxin to hypophysectomized rats on their skeletal growth maturation and response to growth hormone.

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T H E EFFECTS O F CHRONIC ADMINISTRL4TION O F
THYROXIN TO HYPOP€IYSECTO1\IIZED RATS
ON THEIR SICELETAL GROWTH, MATURATION AND RESPONSE TO GROWTH
HORMONE
C. W I L L E T ASLING, MIRIAM E. SIMPSON, CHOH H A 0 LI
AND HERBERT M. EVANS
T h e Institute of Experimental Biology and The Departments of A n a t o m y
and Biochemistry, University of California, Berkeley
TEN FIGURES
There have been conflicts in the literature regarding the
ability of thyroid hormone to induce growth in hypophysectomized rats. The Dutch workers, Laqueur and Dingemanse
( '41), also Boer6 and Gaarenstroom ( '43), have reported
that thyroid hormone stimulates skeletal growth in the absence of the pituitary gland. I n contrast, studies at the
Institute of Experimental Biology have repeatedly confirmed
the original observation of Smith, Greenwood and Foster
('27) that thyroid hormone is not a growth factor for hypophysectomized rats. It is true that in some short-term experiments slight but statistically significant gains in body
weight and length have been recorded (Asling et al., '49;
Ray et al., '50). However, it is questionable whether this
is adequate evidence f o r considering the thyroid hormone as
a growth hormone.
It is considered here that three criteria must be met by a
true growth-promoting hormone. The first is that the growth
induced in the hypophysectomized rat should exceed the
growth which can be induced by less specific stimulants. It
is known that slight growth can be induced in hypophysAided by grants from the I T . S. Public Health Services (RG-409 C3 and C4).
101
102
ASLING, SIMPSON, LI A N D EVANS
ectomized rats by several different factors ; beside hormonal
factors such a s thyroxin there are dietary and possibly even
physical factors. The unit of growth, whether assayed by
body weight gain (Evans et al., '33; Marx et al., '42) or by
the tibia1 epiphyseal cartilage test (Evans et al., '43; Greenspan et al., '49) was carefully selected so that its value exceeded the slight growth induced by these nonspecific factors.
The second criterion for a true growth hormone is that growth
must be proportional to dosage over a wide range of dosages
(Evans et al., '33). The pituitary growth hormone is the
only substance which has been found to meet this specification (Marx et al., '44). The third criterion is that administration of the growth-promoting substance over a prolonged
period of time should result in sustained growth in the hypophysectomized rat. Such a demonstration has been made
for purified growth hormone (Simpson et al., ,49). The
present experiment was designed to determine whether thyroxin is able to meet this last and most exacting criterion
by sustaining growth for a prolonged period.
A corollary objective of the experiment was to achieve, if
possible, complete skeletal maturation by thyroxin. The
short-term experiments which demonstrated its efficacy in
repairing the retarded skeletal maturation of hypophysectomized rats have been reported by Becks, Simpson, Evans,
Ray, Li and Asling ( '46). Maturation of bones whose epiphyses normally fuse to the diaphysis early in life (up to 120
days of age) has been repeatedly observed. I n none of the
experiments was epiphyseo-diaphyseal fusion produced at
those epiphyseal cartilage plates (such as that at the proximal
end of the tibia) which normally persist until senescence. I n
fact, such fusion has only been induced in normal rats by high
dosage levels of thyroid hormone, toxic to the majority of the
animals (Smith and McLean, '38). I n the present experiment, therefore, the maximum skeletal maturity attainable
in hypophysectomized rats by the chronic administration of
physiologic levels of thyroxin was sought. Subsequently,
the response of these animals to growth hormone adminis-
THYROXIN AND SKELETAL DEVELOPMENT
103
tration was to be compared with that of hypophysectomized
rats which had not received thyroxin and whose skeletons
therefore would still be immature.
Accordingly, 75 female rats of the Long-Evans strain were
hypophysectomized when 27-28 days of age. Thyroxin injections were started on the day following the operation in
40 of these animals, and the remaining 35 were kept as untreated controls. The initial daily dosage was 2.0 pg; during
the ensuing 12 months the dose was raised three times by 0.5 pg
increments to the maximum dosage given, 3.5 pg. The thyroxin
was injected subcutaneously 6 times weekly. Diet XIV was
available to the rats at all times. I n addition, they were fed
daily a wet mash of a modified McCollum’s diet2; lettuce was
given as a supplement. Thirty thyroxin-treated rats and 22
controls survived the 12-month period. (One of the latter was
rejected for further study on evidence of incomplete hypophysectomy.)
I n addition to the results of this chronic experiment, certain
results of an unpublished experiment (conducted for another
purpose by C. P. Williams in conjunction with the authors)
were instructive, and are being included here. The basic
conditions were the same, save that the thyroxin dosage was
2.5 &day and that treatment was continued for only 40 days.
An additional advantage of the experiment was the use of
two treatment groups, one receiving food ad libitum while the
other was restricted in food intake by pair-feeding with the
hypophysectomized untreated controls.
RESULTS
The body weight increased slightly in the early period of
thyroxin treatment (fig. 1). The difference in average weight
Ground whole wheat 68.5%, casein (technical)
fish meal lO.O%, fish oil 5.0%, sodium chloride
1.5%. Potassium iodide added (analysis approximately l p g iodine per gram of
diet).
Diet I (modified after McCollum) : Ground whole wheat 67.5?6, casein (technical) 15.0%, skim milk powder 7.5%, hydrogenated vegetable oil 6.75%, fish oil
(vitamin A-D concentrate) L O % , sodium chloride 0.7570, calcium carbonate 1.570.
Potassium iodide added (analysis 0.9-1.0 pg per gram of diet).
a
Composition of Diet XIV:
5.ov0, alfalfa leaf meal lO.O%,
10.1
ASLING, SIMPSON, LI AND EVANS
of the injected and control groups after one year was 34gm.
Over half this difference (18gm) was attained by the 40th
day of injections.
Barely detectable growth in length also occurred (fig. 2).
The difference in average body length (2.7 em, p < 0.01)
demonstrable after 40 days of treatment was the same as that
observed after one year of treatment.
+ Tx
+ Tx
2501
2e 2oo-
0
.-C
E(5,
150-
.-
2
100-
=-.
-0
m" 50-
P
I
0
50
100
I50
200
250
300
350
400
450
Age in Days
Fig. 1 Graph comparing the arerage weight of 31 hypophysectomized rats
treated with thyroxin from the day following hypophysectomy with t h a t of 15
untreated hypophysectomized rats. A curve of weights of normal female rats is
given f o r comparison.
The food consumption, both in the experiment of 40 days'
duration and during a 13-day period a t the end of the longterm experiment, averaged 7.0 gm/day/rat in thyroxin-treated
animals and 4.5 gm/day/rat in untreated animals. When
thyroxin-treated rats were restricted to a food intake equal
to that of the untreated rats, their weights and lengths corresponded to those of untreated rats.
The individual bones also developed differences in length.
After 40 days of treatment, the tibias attained an average
length of 30.2 4 0.57 mm, while in untreated rats they averaged 28.2 t 0.33 mm. This 2 mm lead was not exceeded even
105
THYROXIN AND SKELETAL DEVELOPMENT
after 12 months of treatment. The other bones measured
(humerus, third metacarpal, and femur) were also slightly
longer in thyroxin-treated rats.
As ~ 7 a sexpected (on the basis of previous experiments
summarized by Simpson et al., '50) , the skeletal maturation
of the untreated hypophysectomized rats was markedly retarded. However, it has not previously been clear whether
hypophysectomized rats reach absolute stasis in maturation
Nnrmnl
400 -
E
350-
2
C
' -
Hypophysectomized,+ Thyroxin
300-
/;,',,,',
f
0
C
3
x"
m
-*
Hypophysectomized. Untreated
I
250-
200
I5O!J
-
'
;
O
IbO
140
2bO
240
360
340
400
4
b
Age in Days
Fig. 2 Graph comparing the average lengths (measured under anesthesia) of
representative groups of hypopliysectomized rats, treated with thyroxin f o r 14
months ( 6 rats) and untreated f o r the same period ( 5 rats). Data from a shortterm experiment (40 days, 5 rats per group, C. P. Williams, unpublished) are
interpolated, connected with dotted lines. A curve of Iengths of normal female
rats is given for comparison.
or whether the eventual maturation is so slow that any advance is difficult to detect. This question could be resolved
in the present study since x rays of the skeletons of the same
animals were taken at intervals over a long period. Furthermore, additional criteria not previously available f o r judging
skeletal maturation in the period between 50 and 60 days of
age were applied in this study, namely, critical transformations in the region of the hip-joint and fusion of the exoccipital synchondrosis. It was found that while the skelet,al
106
ASLING, SIMPSON, LI AND EVANS
age of untreated hypophysectomized rats was between 45
and 50 days three months after hypophysectomy, it continued
to advance very slowly and attained a skeletal age of 55 days,
a year after hypophysectomy.
I n hypophysectomized rats maintained on physiological
levels of thyroxin skeletal maturation continued at the normal
rate. After three months of treatment, when the hypophysectomized rats were 4 months old, all epiphyses which in the
normal rat fuse to the diaphysis by that age showed fusion.
These included the medial humeral epicondyle, the proximal
radial epiphysis, the metacarpal, metatarsal, and phalangeal
epiphyses, the distal tibial epiphysis, and the tuberosity of
the calcaneus. All remained separate in the untreated animals.
The patency of epiphyses in untreated rats, and the complete
resorption of epiphyseal cartilage plates in treated rats are
seen in the histologic sections illustrated in figures 3 to 8.
The evidence for continuation of skeletal maturation beyond
4 months of age in the thyroxin-treated rats is unsatisfactorily
meager. The long latent period in maturation between the
early-fusing group just listed and the epiphyses whose fusion
is delayed into senescence (such as the proximal humeral
epiphysis, the distal radial and ulnar epiphyses, the distal
femoral epiphysis, and the proximal tibial epiphysis) has
been pointed out by Simpson et al. ('50). There is one
epiphyseal cartilage, however, which fuses in the intervening
period, and which may be of some use. The epiphyseal cartilage in the head of the femur is resorbed between one and
two years of age, though with appreciable individual variation. I n the thyroxin-treated rats (13 months of age at autopsy) this cartilage plate was resorbed in part of the group.
Precocious maturation was not induced by thyroxin treatment. The epiphyseal plates which normally persist until
the senescent period were found intact in the treated rats
when over a year old. For example, the proximal tibial epiphyseal plate was intact, though too narrow to be seen in
roentgenograms. Terminally, both untreated and thyroxintreated hypophysectomized rats showed similar cartilage
THYROXIN AND SEELETAL DEVELOPMENT
107
inactivity, in accord with the growth stasis reached in both
groups (figs. 9 and 10).
To review this part of the experiment, rats which received
thyroxin slightly exceeded their untreated hypophysectomized
controls in weight and length during the first 40 days of
treatment, but thereafter, though injections were continued
for a long period, showed no further growth. Even this
minimal initial growth failed to occur when food intake was
restricted to an amount equalling that of the controls. The
skeletons of the thyroxin-treated rats matured at a rate paralleling normal and attained adult status, while those of their
hypophysectomized controls remained immature.
Response to growth hormone
At the end of the 12-month period, during which time the
rats had remained untreated or had received thyroxin as
described above, growth hormone was injected in order to
determine whether the skeletal maturity attained under the
influence of thyroxin would affect the responsiveness. Also,
thyroxin was e v e n during this terminal two-month period
to some animals which had not previously received it. Suitable onset control and autopsy control groups were reserved.
The division of the animals into essentially similar treatment
groups was made on the basis of weight gain during the
preceding year, and of weight a t the beginning of this acute
experiment. The dosage of growth hormone given during the
two-month period was 0.2 mg daily, intraperitoneally, 6
times ~ e e k l y The
. ~ treatments of these groups and the results
therefrom are shown in figures 1and 2, and in table 1.
All animals which received growth hormone promptly resumed growth in body weight and length. Individual weight
The growth hormone injected showed evidence of slight contamination with
thyrotropic hormone and interstitial cell stimulating hormone, but no evidence
of follicle stimulating or adrenocorticotropie hormone, as tested a t high levels for
4 days in hypophysectomized immature female rats. Rats in these experiments
which were injected for two months with much lower doses showed no endocrine
stimulus other than minimal thyroid and partial ovarian interstitial tissue repair.
+
6
Growth
Iiornioiie
thyroxi II
+
6
Growth
liori~iotie
6
6
Autopsy
colltrols
‘I’hyrosiii
6
4
Growth
hormone
thyroxin
OllSPt
co.1tlols
6
5
Growth
hornioiie
5
Autopsy
controls
OF
RATS
Onset
controls
Next
2 months
NO.
38.8 -c 0.60
6.5
5.2
0.6
37.5 2 0.63
0.7
33.0 C 0.66
7.9
5.7
32.9 -c 0.47
32.3 ? 0.47
38.0 2 0.31
35.8 2 0.34
30.4 2 0.67
0.3
mm
mm
30.1 2 0.30
Increase
Length
~~
1
227 k 16.3
256 tr 19.8
158 2 1.1
169 tr 3.8
189 2 4.4
250 & 20.9
303 % 18.9
181 2 2.7
180 -c 10.8
P
Width
38
67
-31
-20
70
123
1
c
1 nerease
Epiphyseal plates
Proximal
TInIA
Ahsent
Absent
Absent
Absent
Absent
Present *
Present
Present
Present
Distal
7.0 i- 0.07
7.0 & 0.06
7.0 t 0.08
7.1 -t 0.12
7.0 k 0.01
7.8 C 0.09
7.2 k 0.07
6.6 2 0.13
6.6 2 0.07
mm
Length
.
0
0
0
0.1
.
1.2
0.6
0
mm
Increase
31 ZT ACARP A L
Absent
Absent
Absent
Absent
Absent
Present
Present
Present
Present
Epiphyseal
plate
Epiphyseal width nieasuied in hiptological section.
a Exceptions occurring in this group wete: two iiist:mws i l l wliicli the distal tibia1 plnlvs :uid one iu whicli the nietwarpnl plate were absent.
Thyroxin discontinued during this final two-month period.
The adult condition is that typical f o r the r a t betwcen 4 and 20 mouths of age.
Thyroxin
None
First
12 months
TREATMZNT
TABLE 1
Dafferences in t h e g r o c l h arid niatccration of bones of hypophysecfomazed rats reszilfing front lhyroxin and growth hormone
Adult
Adult
Adult
Adult
Adult
95 days
55 days
55 days
55 days
SKELETALAGE
THYROXIN A N D SKELETAL DEVELOPMEKT
109
gains ranged from 1 to 2.5 gm per day ; these were niaintained
over the 60-day injection period. No differences in growth
rate existed between rats which had previously been treated
chronically with thyroxin and those which had not been so
treated. Ra t s wliich received thyroxin siniultaneously with
growth hormone grew more than those receiving growth
liorinone alone, in accord with the familiar augmenting effects
of these two hormones. The administration of thyrosiri to rats
which had previously not received it resulted in somewhat
more rapid growth in response to growth hormone.
Measurements of the tibia (table 1) showed essentially the
same degree of response to difl’erent treatments as did body
length. The superiority of response to growth hornione given
with thyroxin when no preliminary thyroxin treatment had
been given is well shown by the tibia. (Measurements of
femur and humerus led to similar conclusions, and are therefore not presented in the table.) Increase in the tibia1 epipliyseal plate width was greatest in the rats receiving no
thyroxin.
The metacarpal of the r a t s previously treated with thyroxin m7as incapable of responding to growth hornione by an in
crease in length, due to resorption of its epiphyseal cartilage
plate during the thyroxin treatment. That of the previously
untreated hypophysectomized rats increased markedly in
length, showing the capacity of the persistent, atrophic cartilage plate to respond to administered growth hormone.
Advance in maturation (“Skeletal Age”, table I) was
observed in only one group -that which had previously received no thyroxin, but which received thyroxin simultaneously with growth hormone. Growth hormone alone did not
result in maturation. In r a t s which had been treated
chronically with thyroxin no further advance was noted, nor
would it be expected in rats whose skeletons were already
mature.
Some observations worthy of special note were made on
roentgenograms of the skull. In general it can be said that
skull growth paralleled growth of the body. Three of the
110
ASLING, SIMPSON, LI AND EVANS
synchondroses of the basicranium were studied specifically
for evidence of maturation. The pair between the basioccipital and exoccipital bones showed synostosis relatively
early (before 120 days of age) in the thyroxin-treated rats,
as might be expected from the age of closure in the normal
rat which occurs between 50 and 55 days of age. Closure
was delayed at this site in the uninjected hypophysectomized
rats, but after a year the majority showed synostosis. The
synchondrosis between basioccipital and basisphenoid bones
(normally found patent in old rats) was damaged by trephining at hypophysectomy. The wound healed by synostosis,
but fragments of the cartilage remained laterally. The synchondrosis was thus neither reconstituted nor resorbed in
any group. The synchondrosis between basisphenoid and
presphenoid bones, normally persistent in old normal rats,
also persisted in all groups of hypophysectomized rats, both
control and injected. Its response thus resembled epiphyseal
cartilage plates such as that at the proximal end of the tibia.
Changes in dentition, notably in the incisors, were shown
clearly in lateral view roentgenograms of the head. Schour
and Van Dyke ( '32), and subsequently Becks, Collins, Simpson and Evans ('46) have described the development of distorted incisor teeth in hypophysectomized rats, the commonest
lesion being irregular contour and multiple foldings of the
labial surface a t the apical end of the upper incisor teeth.
The latter authors reported the incidence to be 50% approximately one year after hypophysectomy. The incidence of
this lesion in untreated hypophysectomized rats of this series
equalled or exceeded that reported by Becks et al. This
folding did not develop in the hypophysectomized rats
treated from operation with thyroxin. (Two such animals
showed an apical defect-a
small, rounded, dense region
a t the root-but
this in no way resembled the deformity
which has been described.) I n rats which received no treatment f o r a year after hypophysectomy, and to which growth
hormone was then administered, the folding was present but
this part of the tooth had been moved outward from the apex
THYIXOXIX ASD
SKELETAL DEVELOPMENT
111
by reinstatement of normal tooth formatioii at the apex. At
the maximum, this defective p a r t had been moved two-thirds
of the way along the tooth.
The histologic structure of the endocrine target organs
was essentially the same in all groups, showing the atrophy
characteristic of the hypophysectomized rat after a prolonged
postoperative period. There were, however, several findings
worthy of special note.
The ovaries of the hypophysectomized controls, either 12
or 14 months after operation, showed the changes which have
consistently been found to characterize ovaries of hypophysectomized r a t s after such a long interval. Follicles were few
and small, seldom reaching the stage of beginning antrum
formation. Interstitial cells were shrunken and pyknotic. I n
addition, large areas in the stroma had been transformed into
a pale, eosinophilic type of tissue, supposedly of interstitial
cell origin, frequently interspersed with incipient or wellformed tubular structurcs ( a s described by Simpson, T,i and
Evans, '49). Thyroxin given from tlic time of opcration
prevented these ovarian changes wliich a r e characteristic of
long periods after hypophysectomy, while cffkctiiig no repair
of either follicles or interstitial tissue. The ovaries assumed
the appearance typical after shorter postoperative periods
such as two to 4 weeks. Discontinuance of the thyroxin
therapy during the terminal two months of the 14-month
postoperative period, following the 12-month treatment
period, did not result in these advanced clianges in the
stroma of the ovaries. Growth hormone administered alone
between 12 and 14 months postoperative caused some repair
of deficient interstitial tissue, the areas of age transforniation
persisting. TYhen thyroxin had been administered for 12
months previous to administration of growth hormone the
partial repair of interstitial cells was then superimposed on
a n ovary showing no age changes.
The thyroids of the uninjected controls showed compact
colloid, with no evidence of resorption. The epithelium varied
from squamous to low cuboidal in height. Thyroxin injection
112
ASL ISG, SIMPSON, LI AS11 E V A S S
for 1 2 or 14 nionths did not modify this picture. T11 t h e
groups receiving growth hormone thc1i.e was evidence of
partial thyroid repair. An increase in cytoplasniic i i i ~ s sw a s
pi*escnt,the nuclei were lighter stainiiig, and there was sometimes a barely detectable vacaolatioii of tlie colloid. Tliyrosiii,
in tlie doses employed, had n o inhibiting effect o n this riiiiiinlal
stimulation by the growth hormone preparation.
The adrenal coitex in all groups was typical of tlici hypophysectomizcd, regressed condition.
RIT'MMAHY
Thirty feinale r a t s liypopliysectoniised when 2% ( l a y of
age aiid imincdiately ti-cated with thyroxin did iiot slio~vtlic
early growth arrest which characterized t h e 2 1 uiitreal ccl
liypophysectoinized controls. Gain iii weight and lciig tli (~011tiiiued for approsiniately 40 days, though a t a rate far below
normal growth. These gaiiis were not sustained, l i o w ( ~ e i . ,
atid for the rest of the treatment yeiiod (total, oiic ; v e a l . )
weight and length curves were a s flat a s in the conti.01~. By
tlie end of the cxperinient, the thyroxiii-treated rats were
337; heavier and 10% longer than the controls. In aniiiials
similarly injected with thyroxin but restricted to tlic food
intake of tlie untreated controls the body weight and lciigtli
did iiot exceed but oiily equalled those of the controls. Maturation of the skeleton of tliyrosin-treated r a t s coiitinned
and the status of the various epiphyscal plates attained that
of the iiormal adult. I n the untreated l i y p o p l i ~ s e ~ t o ~ i i i z c ~ ~
rats skeletal maturation was very slow, though iiot coniylctely
a i ~ e s t e d .One year after hypopliysectomy these aninials had
imched a skeletal age of 55 days.
After one year, growth hormone was injected into selected
groups for two nionths to determine whether animals wliicli
liad long been under the maturing influence of thyroxiii Tvc1-e
more o r less iwponsive to the influence of growth hormoiie
than hypophysectoniized rats which had not been treated
previously. No differences in this i*esponsewere found wlieii
growth liornioiic was given alone. However, the previously
T H Y C O X l N AND S K E L E T A L DEVELOPMENT
113
uiitreated rats were more susceptible to the angiiieiiting
cftf’ect of thyroxin given concurrently with growtli hornioiie.
L I T E R A T U R E CITED
ASLING, C. W., H. T~ECKS, M. E. H I ~ I P S O N A N D H. BI. EVANS 1949 The effect
of thyrosin iiijectioiis on growth and epipliyseal closure of the third
nietacarpal bone in l i ~ ~ ~ o ~ ~ l i g s e c t ofemale
~ n i z e drats. Anat. Hee., 104 :
255-260.
EECKS,€I., D. A. COLLINS,M. E. SIMPSON
AND H. M. EVANS 1946 Changes
in the central incisors of lippophyscctoniized female rats after different
postoperative periods. Arch. Path., 41 ; 457-476.
R E C K S , H., M. E. SIMPSON,
H. M. EVANS,
R. D. RAY, C. H. LI A N D C. W. ASLIW
1946 Response to pituitary growth hormone and thyroxin of the tibias
of hypopligsectomized rats after long postoperatiye intervals. Anat.
Rec., 9 4 : 631-656.
BOER$, J. M., A N D .I. TI. G A A R E N S T R O O N
1943 Over dell iiivloed V R ~ Igrocxiliormooii
op den skelet.groei. Versl. Xed. Akad. v. Wetensch.,
E V A N S , €I. M.,K. MEYERAND M. E. SIWSON 1933 The gr
stimulating hornlolies of tlie anterior hypophysis. Memoirs of the
TJnir. of Calif., 11: 1-65.
E Y A X S , 1-1. >I., M. .E.8131PSOS, W. MnRs AND E. T<Ii%RI(IK 1943 Bioassay of
the pituitary growth hormone. Width of tlie proximal cpipliysial
cartilage ~f the tiliiii in hypopliyseetomixed rats. Endocrinology, 3? :
13-16.
1’.1s,
F. S.,(1. 11. L r , M. E. SIMPSOS
AND H. M. E V A N S 1949 Bioassay
of hypolhyseal glowth liormoiie : The tibia test,. Endocrinology, 45 ;
455-463.
II.\QUErK,
E., E. ~ ) l S G I C l L 4 X S E A N D J . F R E U D 1941 The influence of anterior
pituitary and of thyroids upon the growth of rats. Acta Erev. Neeriaad.,
2 . 1 : 46-51.
ALIKS, IY., M. E. SIMPSON A N D H. M. EVANS1942 Bioassay of tlic growth
Iiornionc of the anterior pituitary. Endocrinology, 30 ; 1-10,
1944 Specificity of the epipliyseal cartilage test for the pituitary
growtli hormone. Proc. Soc. Exp. Biol. and Med., 55: 250-252.
R A Y , R.. I)., C. W. ASLING,M. E. SIMPSOP\’ AND H. M. EVANS 1950 Effects of
thyroxin injections on growth and differentiation of the skeletoii of
Iiypophyseetoniized feni:ile rats. Anat. Rec., 107 ; 253-264.
SCIIOGR,
I., AND H. R. VANDYKE 1932 Changes in the teeth following Iiypopliysectomy. I. Changes in the incisor of the white rat. Am. J. Anat.,
5 0 ; 397-433.
SnrPsoN, M. E., C. ITr. AFLINCAND H. M. EVANS 1950 Some endocrine influences on ske1et:rl growth and differentiation. Yale J. Riol. and Med.,
23: 1-27.
S I X E 3 O N , 31. E., 11. If. E
AXD C. H. LI 1949 The growth of hypopliysectomized female rats following clironic treatnient witli pure pituitary
growth hormone. I. General growth and organ changes. Grolvth, 13:
151-170.
114
ASLIXG, SIMPSON, LI A X D E V A X S
SMITH,E. E., AND F. C. A ~ c L E A N 1938 The effect of liypertliyroidism up011
growth and chemical composition of Foiie. Endocrinology, 23 : 546-552.
1927 A comparison in nornlal,
SMITH,
P. E., C. F. GREENWOOD
AND G. L. FOSTER
thyroidectomized and hypophysectomized rats of the effects upon metabolism and growth resulting from daily injections of small amounts
of thyroid extract. Am. J. Path., 3: 669-687.
PIATE 1
EXPLANATION OF FIGURES
3 Distal elid of third nietncarpal (and proxiinal eiid of proxiilia1 pliahnx) of
liypophysectoniized untreated fcinale rat, one year after operation. Tlic maturation
of the bones is retarded, as shown by the persisting, atrophic, epiphyseal plates
(normal closure time approximately 100 days of age). (Mid-sagittal section, H
and E stain, X 39.) (Spec. 2902.)
4 Bones corresponding to those i n figure 3, but after one year of thyroxin
treatment. The epipliyseal cartilage plates have been resorbed. (Spec. 2926.)
3 Distal elid of tibia one year after hypopliysectoiiiy. Delay in maturation is
shown by the persistence of the epipliyseal plate, which has not been remol cd
(normal age of cartilage resorption 95 days). (Frontal s v t i o n , H and E,
12.3.)
(Spec. 2901.)
x
6 Distill end of tibia of 1iypopli;vsrctomized r a t treated witli thyroxin for one
year. The epiphyseal cartilage plate lias been fiilly resorlwd. (Spec. 2928.)
PLATE 1
THYROXIN A N D SKELETAL D E V E L O P V E S T
A S L I S G , StMPSON, L I A N D EVAXS
115
10 Proxiiiial t i h i 1 epipliysenl cni t i h g e plate of liypopliyscctoiiiized rat trcntcd with thyroxin for one y w r . Precocious
resorption of the plate has not occurred (normal age of fusion circa three years). (Spec. 2924.)
9 Prosini;il tibinl epipligsenl cartil~igeplate one year after Ii~~)ol’liysectoiiiy.Tlic plate is atrophic. (Mid-sagittal section,
€I :ind E, X 6 2 . 5 . ) (Spec. 2903.)
8 Humerus corresponding t o figure 7 hut after one year of thyroxin trcntmciit. The cpihpysis lins fully matured. (Spec.
2925.)
J Dist:rl ciitl of humerus oiie year after Iiypephysectoiny. The iiiain epipliysc~lplate (iioim:illy resorbed :it 40 days
of age) WIS already partially resolbcd :it the tiiiie of hypophysectoniy (28 days of age) and eoiiipleted its resorption. The
medial eliicoiidylar cartilage plate ( o n left) failed t o be rcTsorbed a t the 1iorin:il agc (120 days). (Frontal section through
olecranori foss:~,I€ aiid E, X 12.5). (Spec. 2903.)
ESPLIX’ATION O F FIGUKES
PLATK 2
117
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skeletal, effect, response, growth, administration, maturation, thyroxine, rats, hypophysectomized, hormone, chronic
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