648
Morphological Changes in the Growing R a t Skull Following Administration
of Cortisone Acetate.* (21905)
MELVINL. 3loss.t
From the Department of Anatomy, Coliirizbia University, College of Physicians and Surgeons,
New York City.
Retardation of skeletal maturation in the
growing rat follows the administration of
cortisone, Parmer et al. ( 1) ; Follis ( 2 ) . Sev-
eral visceral components of the rat skull ex-
hibit diverse behavior under similar esperi-
mental conditions: the growth and differen-
tiation of teeth and alveolar bone are stimu-
lated, Goldsmith et al. (3,4), while that of the
brain is partially suppressed, Field ( 5 ) .
The osseous facial and neural components
of the skull, largely reflecting the morphology
of the protected or supported cranial viscera
Starck ( 6 ) . have no necessary morphological
correlation with each other, Hofer ( 7 ) . As
the cranial bones and viscera exhibit a dif-
ferential response following cortisone therapy,
it should be possible to display experimentally
the morphogenic role of these cranial viscera.
This paper presents the data of such a dem-
onstration.
Methods. Thirty Long-Evans rats were
subcutaneously injected with 50 y,/g body
weight of cortisone acetate on the day of birth
(first day), and on the second, fourth and
sixth days. These rats and 35 controls were
sacrificed on the fifteenth day. Intact skulls
were prepared by boiling in water and bleach-
ing in 37& H202.
The skull vault dimensions measured were:
the length of the internasal, metopic, sagittal,
coronal, anterior lambdoid and tempero-
parietal sutures, the total skull length and the
greatest skull width. The detailed technic
was reported by JIoss(8). The occlusal
length of the mandibular molar arcade and
the height of the ramus (coronoidangular
processes) were also measured. The greatest
length and width of the cerebrum were meas-
ured, in situ, by the technic of Sugita(9),
following removal of the calvaria.
*Cortisone acetate supplied by Merck and Co.
Inc., Rahway, N. J.
t Work done under the tenure of a Lederle Medical
Faculty Award.
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(Introduced by G. K. Smelser.)
FIG. 1. Fifteen-day rat skulls, normal at left, cor-
tisone-treated at right, showing gross size differen-
tial. Xote especially lack of interdigitation of treated
rats sagittal suture and hypodevelopment of lambdoid
region in this animal.
Results. The effect of the preparation on
vault dimensions was tested and proved to be
negligible (Table 111). All experimental
bone dimensions were significantly smaller
than controls (p<.Ol) (Table I, Fig. 1 ) .
The dimensional reduction of the skull vault
as a whole was not proportional. The facial
vault exhibited greater reduction than the
neural vault. In terms of percentage, the or-
der of magnitude of the reduction of facial
skull vault length (dimension S ) , height of
ramus (dimension 9) and body weight (di-
mension 13) were similar; and as a group,
greater than those of the neural skull vault.
In addition to this regional disproportional-
ity, within the neural vault itself the reduc-
tion of the cerebral and skull vault dimen-
sions were also disproportionate, producing a
paralleled “brachycephaly” (Table 11, index
# 1 ) . Calculation of cephalic indices further
demonstrated the relatively greater reduction
of the visceral skull dimensions (Table 11, in-
dex # 2 ) .
The mandibular molar teeth were unaf-
fected by the drug. They exhibited a nor-
mal occlusal length (dimension 10) and
crown pattern, and were well embedded in
 CHANGES RAT SKULL
IN GROWING 649

TABLE I. Dimensional Values of 15-day-old Rats Following Administration of Cortisone Acetate.

Description Exper. mean (mm) N
___.___
Control (mm) N "/o reduction
Coronal suture 5.7 -I- .lo* 19 6.2 -C- .07 16 8
Sagittal 4.8 & .07 19 5.9 2 .ll 16 18
77

Ant. Iambdoid suture

Tempero-parietal suture
5.6 2 .ll
9.0 k .20
19
19
6.2 *
10.3 k .18
.16 16
16
9
13
Internasal suture
Lambda-anterior nasal point
6.3 * .11
19.6 2 .15
19
19
8.4 2 .23
2 3 . 4 k .26
16
16
25
16
Metopic suture
Squamosal width
8.2 * .10
12.2 2 .08
19
19
9.2 f .14
13.6k 26
16
16
11
10
Coronoid-angular processes S.7 .-L .07 6.9 f .04 10 17
Length of molar arcade 6.6 2 .04 10
lo 6.6 -I .03 10 0
Parasagittal length of cerebrum 11.4 2 2 3 11 12.3 2 .15 19 7
Greatest width of cerebrum 12.7 * .16
18.8 & .58
11
11
13.1 2 .09
23.5 .98
19
19
3
20
Body wt (g)
* Standard error of mean calculated for small samples.
TABLE 11. Cephalic Indices of Normal and Experimental Rats.
Index No. Dimensions ( X 100) Exp . Contr ol
1 Squamosal width ( 8 )
93.8 90.0
Metopic suture (7) 4- sagittal suture ( 2 )
2 Squamosal width (8)
62.2 54.7
Lambda-anterior nasal point (6)
3 Cerebra1 length (11)
90.0 94.0
Cerebral width (12)
_ _ _ _ ~ - .____-

TABLE 111. Effect of Preparation on Skeletal Vault
Dimensions.
Mean shrinkage in mm
(Exp.) (Control)
Dimension N=6 N=8
Squamosal width (8) .2
Internasal suture .O
length (5)
Lambda-anterior nasal .6
point (6)
alveolar bone, confirming and extending the
findings of Goldsmith et al. (3,4). The molar
arcade, as a whole, was more posteriorly situ-
ated relative to the mandibular foramen. The
areas of muscle attachment, coronoid and an-
gular processes (dimension 9), were signifi-
cantly reduced (p<.Ol).
Histological sections of the vault revealed
deficient growth of cortical plates, diploe and
sutural areas, as compared with the controls
(Moss, 8). The sutural tissues were under-
developed, relatively acellular, avascular and
more fibrous. At sacrifice, the vault bones
were freely movable in the treated rats, but
not in the controls. This mobility was ap-
parently related to the immature state of the
bone edges at the sutural areas, i.e., their lack
of interdigitation.
Discussion. The administration of corti-
sone to neonatal rats is followed by dispro-
portionate morphological changes in the grow-
.S ing membranous skull bones. No evidence
.1
presently available indicates intrinsically dif-
.9 ferent responses to such therapy in adjacent
skull vault bones. The relatively greater re-.
tardation of the facial skull vault compared
with the neural vault implies that, under
these experimental conditions, brain size and
shape are competent morphogenic agents.
The growing cerebrum, experimentally re-
tarded to a lesser degree, is capable of over-
coming a greater degree of osseous retarda-
tion. It causes the formation of a sufficient
area of vault to provide for its own protection.
This is not accomplished by merely separat-
ing smaller bones and increasing the width
of the sutures. In some manner osteogenesis
is stimulated, although only immature bone
is produced in the experimental rats. The
parallel brachycephalization of cerebrum and
skull vault supports this statement. Dispro-
portionate cerebral dimensions apparently

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650 CHANGES
IN GROWING
evoke similar osseous disproportions. Exam-
ination of the data of Moss(8) and of Sugita
( 9 ) clearly shows that the absolute dimen-
sions and relative proportions of the experi-
mental rats are not those of younger rats.
There is no normal developmental stage at
which all of these osseous and neural dimen-
sions occur simultaneously, absolutely or rela-
tively.
The hypothesis that the morphology of
skull components are directly related to the
size and function of their related viscera(van
der Klaauw, 10) is further supported by the
mandibular data. The dimensionally normal
molar dentition of the experimental rats is
provided with adequate alveolar bone, despite
the generalized reduction of the basal mandi-
bular bone.
Decreased facial vault length implies a
growth retardation ( 2 5 % ) of the respiratory
components of the facial skull approximating
that experienced by the body as a whole
(20%). The retardation of nasal bone length
cannot be attributed to the effect on the
cartilage found a t the anterior nasal margin.
I t has been shown that the chief growth site.
in length, of the facial vault is at the fronto-
nasal sutural area (Massler and Schour, 1 1 ) .
The percent of nasal bone length retardation
is identical with that reported by hlortimer
( 12 ) (25 a/c ) , following hypophysectomy of
young adult rats.
The retardation of body weight and linear
dimensional values may be due to either a
general inanition response to the drug, or to
a specific effect of cortisone. In this experi-
ment, cortisone was used only as a tool. The
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RATSKULL
results obtained are, in this sense, independent
of the mechanisms of their production.
Summary. 1. Disproportionate changes in
skull and brain morphology followed the sub-
cutaneous administration of 50 y / g of corti-
sone to neonatal rats. 2. The visceral skull
vault showed greater retardation than the
neural skull vault. 3. The cerebrum and
neural skull vault also showed disproportion-
ate dimensional changes leading to increasing
brachycephalization. 4. The growing rat
brain and molar teeth are competent morpho-
genic agents. Under these experimental con-
ditions, they are capable of overcoming the
relatively greater retardation of related bone,
and of thus providing for their own functional
protection and support.
1. Parmer, L. G., Katonah, F., and Angrist, A. A.,
BIOL.AND MD., 1951, ~ 7 7 215.
PROC. S O C . EXP. ,
2. Follis, R. H., ibid., 1951, v76, 722.
3 . Goldsmith, E. I)., and Stahl, S. S., J. Dent.
Res., 1953, v32, 699.
4 . Goldsmith, E. D., and Ross, L., ibid., 1955, v32,
699.
5. Field, E. J., Nature, 1954, v174, 182.
6 . Starck, D., 2. f. wissemch. Zool., 1953, vl.57,
169.
7. Hofer, H., Anat. A m . , 1952, v99, 1012.
8. Moss, M. L., Am. J . Anut., 1954, v94, 333.
9. Sugita, N., J. Comp. Neurol., 1917, v28, 495.
10. van der Klaaw, C. J., Arch. N e e d . d . Zool., 1946,
v7, 16.
11. Massler, M., and Schour, I., Anat. Rec., 1951,
v110, 83.
12. Mortimer, H., Radiology, 1937, v28, 5.
Received June 10, 1955. P.S.E.B.M., 1955, v89-