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Roentgen cephalometric studies on skull development in rats. III. Gigantism versus acromegalyAge differences in response to prolonged growth hormone administration

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THE ANATOMICAL RECORD 19619-21 (1980)
Roentgen Cephalometric Studies
on Skull Development in Rats
I l l . Gigantism versus Acromegaly: Age Differences
in Response to Prolonged
Growth Hormone Administration
IRENE SAVOSTIN-ASLING, ROY NAKAIYE, AND C. WILLET ASLING
Uniuersity of California, San Francisco, California, 94143
ABSTRACT
Experimental conditions simulating the induction of clinical
pituitary gigantism and acromegaly were established by prolonged administration
of growth hormone in high dosage to adult male rats starting a t two different ages:
6 months (growth still active) and 14%months (growth virtually arrested). Treatment continued for 14%months, controls receiving saline injections. Each group
numbered eight at onset. Standardized x-rays of skull were made in ventro-dorsal
and lateral planes, at onset, mid-period, and end of the study. Representative
dimensions of cranial and facial segments were measured, including lengths,
widths, palate dimensions, gnathic and interzygomatic angles, and incisor
curvature. Some related indices were calculated. Means and standard errors were
computed, usually on five to eight rats (oldest controls: three only). The response
pattern of overall skull length was most illustrative. Younger adult controls grew
actively until 14 months of age (5%) while injected rats grew still faster (8%);
thereafter, controls grew negligibly (1%)
and injected rats only slightly (2%).Older
controls showed negligible skull elongation from 14%t o 29 months of age, and
growth hormone stimulated no gain. In the younger group, skull length gains were
almost entirely in the facial region; cranium gained no length and widened only
slightly. Cranial index increased slightly with the hormone. Facial (bizygomatic)
width increased in both injected groups-proportionately in younger rats (to gigantism) and disproportionately in older rats. Palatal and dental growth followed
facial patterns in both groups. Cranial vault bones thickened and, in older rats,
developed surface irregularities, giving them a more massive, acromegaloid structure.
The increasing availability of growth hormone for human therapeutic use brings with it
the need for more detailed knowledge of the
effects of its prolonged administration. Questions have arisen as to why skeletal responsiveness to the hormone may decline in time, or
may even be absent (Trygstadt, '69; Prader et
al., '67). Issues of resistance due to the subject's
age, or to antibody development, have been
raised. The degree of proportionality maintained in the skeletal response is a closely related topic, for it implies that within the same
subject the various growth centers may differ
markedly in responsiveness, even to the point
of risk of deformity (Dymlingand Willner, '78).
In studying these issues in the laboratory,
rats offer a number of advantages. Their small
size permits economy in use of a hormone of
limited availability. Because of their relatively
short life-span, several months of hormone injections represents "prolonged administration". Their responsiveness to growth hormone
over extended periods was one of the first facts
established (Evans et al., '33). The skeletal, and
especially the post-cranial, effects of chronic
growth hormonal deficiency and excess have
been evaluated in a variety of circumstancesintact rats (Evans et al., '48, Asling et al., '551,
Received April 19, 1979; accepted July 18, 1979
0003-276X/80/19601-0009$02.60 0 1980 Alan R. Liss, Inc.
10
IRENE SAVOSTIN-ASLING. ROY NAKAIYE. AND C. WILLET ASLING
hypophysectomized rats (Becks et al., '49),and
thyroidectomized rats (Asling et al., '65).
Appendicular long bones (e.g., femur, tibia,
metacarpal) or axial bones (vertebrae, ribs)
have been preferred for osteogenetic studies,
both endochondral and periosteal. For the
study of proportionality in growth the skull
offers some advantages. It is reasonably proportional to body length; skull length is about
15%of the total body length in very young rats
and 1Wo in adults, the slight early predominance being linked with precocious brain
growth (Asling and Frank, '63). The growth of
its two major components-cranium (neurocranium, brain-case) and face (viscero-craniu m b m a y be compared. Separately, each may
be evaluated for changes in length, width,
height and angular dimensions in judging proportionality. The growth hormone-associated
clinical facies of nanism, gigantism, and acromegaly are available to aid in the comparison
(Labhard, '74).Finally, roentgen cephalometry
allows standardized repositioning of the living
subject's head to obtain bony growth data from
the same individuals during the observation
period (Bevis et al., '77; Galabert et al., '77).
Earlier reports on roentgen cephalometry in
rats compared normal growth patterns in
males and females over the age range of four to
40 weeks, and described the effects of hypophysectomy on growth retardation and changes in
proportions (Asling and Frank, '63; Wright et
al., '66). Hughes et al. ('78) reported closely
comparable findings on normal skull growth,
and showed examples of strain differences in
proportions. By starting their studies in the
perinatal period, previously undetected growth
spurts in some dimensions were demonstrated.
Miura et al. ('69) reported that short-term
growth hormone treatment altered the dentofacial complex of young intact rats.
The present report examines the effects of
prolonged administration (14% months) of
growth hormone on skull development of intact
male rats. Two different age groups were studied. In the younger adults, skeletal growth was
still active when the hormonal injections
began, while in the older adults, virtually all
growth had ceased. The two ages were overlapped to provide an intermediate seven-month
period when growth comparisons could be
made. The circumstances were intended to
simulate those of clinical pituitary gigantism
and acromegaly. In human beings, the bones
respond by overgrowth when the onset of
growth hormone excess occurs during active
normal growth, but if growth has ceased, the
bones become more massive under the excess
hormonal stimulus. In such acromegalics,
biopsy of the iliac crest shows accelerated bone
turnover in cancellous bone (Roelfsema et al.,
'701, and radiologic measurements showed
thickening in cortical bone due to periosteal
hyperactivity (Dequeker, '71). By giving
growth hormone to adult dogs, Harris et al.
('72) demonstrated that the net gain was due to
more rapid periosteal apposition than endosteal resorption, although both were stimulated. In the present studies, therefore, both
quantitative gains in skull dimensions and
qualitative changes in the roentgenographic
appearance of bony surfaces were sought.
MATERIALS AND METHODS
Male rats of the Long-Evans strain were selected for study of their response to prolonged
growth hormone administration starting a t
ages of 6 and 14% months.' Eight animals in
each group were to receive the hormone, with
another eight of each serving as controls. The
experimental groups received intraperitoneal
injections of growth hormone' in saline solution, six days weekly. Initially the dose was 0.5
mgiday, increasing with body weight increase
to 3.0 mgiday in the younger, and 3.5 mgiday in
the older rats. Controls received only the saline
vehicle. Injections were continued for 14%
months.
All rats in good health were lightly anesthetized and head x-rays were made at three
times during the experiment: onset, approximately mid-way (eight months), and at the
time of autopsy. As described previously in detail (Asling and Frank, '631, a craniostat held
the head lightly at three points: posteriorly at
the two external auditory meatuses, and anteriorly between the pair of maxillary incisors
a t their gingival margin. The head (and wellsupported body) could be rotated through 90" on
the midline of this triangular plane, yielding
'The roentgenograms on which this report is ha.sed were made on
rats forminx part of a study on neoplasms induced by growth hormone.
Only suprarenal medullary pheochrornocytomas could be attributed to
this treatment (Moon et al., '56). Ages and injection periods have been
rounded to months. At onset the actual age of the young adults was 181
days, and the old adults, 444 ? 18 days. Rats were x-rayed at the onset,
after 250 days, and at autopsy after 448 days of injections.
"The bovine pituitary growth hormone was prepared by the method
of Li et al. ('46). The very large amount required for the experiment
(over 15 gms) was obtained by pooling several lots. In potency it comesponded to the international standard (1I.U. = 1 mg) as determined by
the standard 4-day tibia1 bioassay (Greenspanet al., '49). Bioassay for
contaminants at the 1 mg dose level in hypophysectomized immature
female rats revealed traces of thyrotropic and interstitial-cell-stimulating hormone, but no adrenocorticotropic or follicle-stimulating
hormone.
RAT CEPHALOMETRY: GIGANTISM VS. ACROMEGALY
11
x-ray views in standardized ventro-dorsal and C’); Palatal length (H to I) and Palatal width
lateral projections. The plane used is shown by (H’ to H ) . Two angles were also measured;
the line of dashes in figure lB, and examples of their construction and significance follow. The
the x-ray pictures are seen in Plate 1.Shadows “interzygomatic angle” was constructed by exof the craniostat were used to align the x-ray tending the lines of the two zygomatic arches
images of skulls on a transilluminated grid. (dashes in figure 1A) to their intersection far
The fine grain of the film (Eastman Industrial anterior to the rostra1 tip of the skull. This
Type A) allowed measurements to be made angle reflects differential growth in cranial and
with vernier calipers to 0.1 mm, with a var- facial width, the posterior end of the arch being
iability of less than two parts in 100. (For anchored on the cranium (squamosal bone) and
example, skull lengths were in the 50 mm the anterior on the maxilla. When facial width
range, and measurements were repeated by the increases more rapidly than cranial width,
same observer or replicated by two observers these lines intersect progressively more anwith differences of less than one mm.)
teriorly, with diminution in the angle. The
Figure 1 illustrates tracings of roentgeno- “gnathic angle” was an approximation of the
grams of the rat skull and shows the landmarks angle which, in anthropometry, indicates
used in measurement. The dimensions meas- changes in facial height. The dimension nasion
ured were as follows: Skull length (A to B) and to prosthion is “upper facial height” (as in
its two components;Cranial length (A to D) and Gray’s Anatomy, ’731, and the angle is at the
Facial length (D to B); Cranial width (E to E’) intersection of the nasion-basion and
and Bi-zygomatic width, or Facial width (C to prosthion-basion lines. It was simulated in rats
(Fig. 1B).
by the dotted lines diverging from “0”
Differential growth in other parts of the skull
was also investigated by computing ratios between pairs of widths and lengths (cranial
index, palatal index, and the ratio of facial
length to bizygomatic width). Finally, the
curvature of the maxillary incisor tooth arc C‘r”
in Fig. 1B) was measured by projecting the
shadow of the x-ray at four-fold magnification
and fitting templates of known radii of curvature to the midline of the tooth shadow.“
Means and standard errors were computed
for all dimensions and ratios, using “Student’s”
correction for small samples. These means are
shown in the graphs of results (Fig. 8-11). The
“T-test” was used to analyze differences between groups, and over a time period within
groups. In presenting the interpretation of findings, “P’values above 0.02 are regarded as
indicating no significant difference. The actual
means, standard errors, and numbers of rats at
each point graphed are seen in Table 1. Although each group contained eight rats initially, occasional deficiencies in x-ray quality
or, more commonly, attrition from sickness and
even death a t the more advanced ages resulted
in ever smaller samples. Fortunately, in the
Fig. 1. Tracings of representative x-rays of rat skulls, in
(A)ventrodorsal and (B) lateral projections; landmarks used
only instance where the number dropped to
in measurements are as follows: A. External occipital prothree, the data were needed only to complement
tuberance; B. Tip of nasal bone; C, C’.Most lateral extent of
a prior conclusion showing that growth had
zygomatic arch; D. Rostra1 extent of cranial cavity; E, E’.
long been in abeyance in senescent normal rats.
Most lateral extent of squamosal bone, between zygomatic
and post-tympanic processes; H. Most caudal extent of palatal margin of third molar tooth, I. Palatal margin of maxillary incisor tooth (used in place of “Prosthion”);0. Midpoint
of anterior margin of foramen magnum (“Basion”);r. Radius
of curve following axis of maxillary incisor tooth; .1In B, site
of fronto-nasal suture (the equivalent of “Nasion”).
.‘In growth, the rat incisor actually follows a logarithmic curve
(Herzbergand Schour, ’41)but the deviation of a half-turn of this curve
from a semicircle is so small as to fall within the error of measurement;
hence, radii have been used, for greater simphcity of comparison.
12
IRENE SAVOSTIN-ASLING,ROY NAKAIYE, AND C. WILLET ASLING
the first half of the experimental period was
8%, the growth hormone-injected group gained
Figures 2-7 illustrate representative x-rays almost 1290, but subsequent gains were not
obtained during the study, the two vertical sets significantly different. By the end of the injecrepresenting the younger (left) and older adult tions, the facial structure of treated rats was 6%
series, respectively. Pairs of views (ventro- longer than controls. In the older adults, with
dorsal and lateral) are provided, the examples negligible normal growth potential, the horbeing selected for their correspondence to the mone stimulated no added growth.
mean skull length of the group represented.
The cranium did not contribute to the skull’s
Furthermore, in each column, the upper two growth in length in any group, even though it
pairs are of the same animal-at the beginning normally represented almost half of the overall
of the experiment, and after 14% months of length when injections began.
growth hormone injections. The bottom pairs
Growth in bizygomatic width in the younger
illustrate untreated controls of the same ter- adults was like that in facial length (Fig. 9).
minal age as the injected rats. (It is also worth The controls increased 7% during the early
noting that the untreated rats form a normal period, while injected rats gained 16%;thereafseries covering the adult age period of 6 to 29 ter, during the time when normal gains became
months, in the order of Fig. 2, 5 , 4,and 7.)
insignificant, the hormone stimulated no furAlthough dimensional changes are better ther growth. Ultimately, the injected rats’
shown by graphs, these pictures illustrate some skulls were 11% wider than normal. In the
of the qualitative changes observed. In particu- older rats, growth hormone stimulated some
lar, the ventro-dorsal view of the older treated skull widening (9%) in the early part of the
rat (Fig. 6) shows surface irregularities of the experiment, but this growth was not mainsquamosal and occipital bones not seen in the tained latterly.
younger treated rat (Fig. 3); both show bony
Growth in cranial width was a barely detectthickening in the frontal, nasal, and zygomatic able 4% in younger adult controls during the
regions. Differences in proportions mentioned first part of the period (p<0.05) and ceased
hereafter can also be recognized in the pic- thereafter. The injected rats gained 8% during
ture~.~
the early period, and insignificantly thereafter.
Among quantitative changes, skull length At the end of the experiment they exceeded
measurements yielded the clearest pattern of controls by 6.5%.Among older adults, the conresponse (Fig. 8).Controls of the younger group trols made no cranial width gains; the injected
(represented by open circles)were still growing rats gained very slowly, requiring the entire
actively at six months of age, the beginning of 14%months to reach a barely significant 5%
the experiment. They increased by 5% between above controls.
6 and 14 months of age, but slowed to an insigThe palate of all younger adults grew in
nificant 1%thereafter. Administration of length, somewhat more actively during the eargrowth hormone (closed circles) accelerated lier part of the experiment; however, the final
growth in skull length to 8% during the early gain of 11%made by injected rats was not signiperiod, but continued treatment resulted in ficantly greater than the 8% gained by their
negligible further gain (2%). In contrast, in the controls, Palate length was unchanged in all of
older group of rats, where the rate of skull the older rats. Growth in palate width was
length increase was normally already negligi- slightly more active, but the 15% gain in the
ble by the onset of treatment (open squares), younger injected rats was not significantly
rats receiving the hormone showed no significant further gain (closed squares).
‘The antero-displacement of the mandible in older, larger rats is an
Figure 8 also shows that the face accounted artefact and does not represent the mandibular prognathism of acThe blunt conical plastic ear-plugs of the craniostat tended
for almost all of the foregoing growth. In the romegaly
to press the larger mandibles forward under the relaxation induced by
younger adults, when the normal increase in the anaesthetic
RESULTS
X-rays of skulls of anesthetized rats in ventrodorsal and lateral projections, at natural size. Pointed black
shadow represents a part of the craniostat lying in axis of rotation for the two views.
Fig. 2. Rat six months of age, at onset of the experiment.
Fig. 3. Same rat as in figure 2, a t 20% months of age after 14% months of growth hormone treatment.
Fig. 4. Untreated control, 20% months of age.
Fig. 5. Rat 14% months of age, a t onset of the experiment.
Fig. 6. Same rat as in figure 5, at 29 months of age after 14% months of growth hormone treatment.
Fig. 7. Untreated control, 29 months of age.
RAT CEPHALOMETRY GIGANTISM VS. ACROMEGALY
13
14
IRENE SAVOSTIN-ASLING, ROY NAKAIYE, AND C. WILLET ASLING
26t
Cranial Length
1 -
6
I
I
18
12
LU
24
30
A G E IN M O N T H S
Fig. 8. Graphs showing means of stated dimensions of rat skulls a t ages of 6 to 29 months. Symbols: closed
circles and squares indicate growth hormone-injected rats; open circles and squares indicate corresponding
controls.
greater than the 11%control gain. In contrast
to the pattern for length, the older adults
showed a slow gain (6%-lO%)in palate width,
but without appreciable hormone effect.
Figure 10 presents three indices computed
from the foregoing measurements, in a search
for disproportions induced by the growth hormone in the cranium, face, and palate. Although some differences appeared in these indices, the individual variations were so large as
to make their significance questionable; the
variability in absolute dimensions was compounded when the ratios between pairs of these
dimensions were calculated. The facial
length-width ratio was stable over the entire
age-span in controls but dropped during the
first part of the injection period in both younger
and older adults. This change indicated a
growth rate in facial (bi-zygomatic) width
greater than that in facial length, as had appeared in the actual dimensions. The greater
difference from controls was in the older animals (7%), but the amount was of doubtful significance (p<0.05). Likewise, palatal index in
the older animals indicated somewhat more active widening than lengthening under growth
hormone, the significance being questionable
(p<0.05). The cranial index was stable in all
controls; it increased with growth hormone
treatment (probably reflecting bony thickening) but the change was not statistically significant.
15
RAT CEPHALOMETRY GIGANTISM VS. ACROMEGALY
2ot
C r a n i a l Width
16
/
\
/
I
6
I
I
I
12
I
18
I
I
24
A G E IN MONTHS
I
1
30
Fig. 9. Graphs showing means of stated dimensions of adult rat skulls. Symbols: closed circles and squares
indicate growth hormone-injectedrats; open circles and squares indicate corresponding controls.
Figure 11 shows that the gnathic angle, a
facial height indicator, increased in the
younger adults. The increase in injected rats
(13%) did not differ significantly from that iri
controls (%). The gnathic angle remained unchanged in older rats, with or without the hormone.
The interzygomatic angle decreased
abruptly in the young adults, but in this study,
the measurement was insensitive t o possible
differences caused by growth hormone treatment. The zygomatic arch became appreciably
rounded, especially in the treated groups, making construction of the angle inaccurate. This
curvature of the arch was possibly related to
development of the masticatory musculature.
The radius of curvature of the maxillary incisors increased in younger adults, more rapidly in those receiving growth hormone than
in controls. It remained virtually unchanged in
older adults. This response pattern resembled
that of growth in facial length. It suggests that
during the continued eruption of this tooth it
continually adapted to the dimensions of its
bony enclosure.
DISCUSSION
The growth response of the skulls of adult
male rats to chronic injection with pituitary
growth hormone was related to the age a t
which the treatment began. Skulls of younger
adults became gigantic in most dimensions.
16
IRENE SAVOSTIN-ASLING, ROY NAKAIYE, AND C. WILLET ASLING
110-
104
Fa c ia I " L e ng t h
Bizygom W i d t h
"
102
CC'
6
1
I
I
12
I
I
18
I
24
1
1
30
AGEIN MONTHS
Fig. 10. Graphs showing means of ratios between stated dimensions of adult r a t skulls. Symbols: closed circles
and squares indicate growth hormone-injected rats; open circles and squares indicate corresponding controls.
Most of the overgrowth was in the first part of
the injection period, between 6 and 14 months
of age; overgrowth was much reduced in the
remaining 6% months. In contrast, when the
onset of hormone treatment was delayed until
14% months of age, most of t h e principal
growth centers were unresponsive, with only
localized bony overgrowths resulting.
The chief difference between the two groups
of rats was in the normal growth expectancy
during the age-periods spanned. Some overall
skull growth is expected in males beyond six
months of age (Wright et al., '66). Most of this is
in the face; cranial growth is normally complete
before this time, in accord with the precocious
attainment of full brain size. (Prolongation of
the facial growth period well into adulthood
indicates the importance of sturdy facial structure to gnawing rodents, and especially to the
more combative males.) Growth hormoneinduced skull overgrowth followed this pattern.
Cranial growth was not stimulated; a t least two
important growth centers (the synchondroses
associated with basioccipital and basisphenoid
bones) were unresponsive to the hormone. In
contrast, facial growth in length, width, and
height was at times as much as 1% above
normal.
Skull growth was in abeyance in older normal rats when hormone injections began at
14% months of age. No growth in length resulted from the treatment. Facial and palatal
widths increased somewhat, and i n t h e
cranium bony thickening and irregularity re-
17
RAT CEPHALOMETRY: GIGANTISM VS. ACROMEGALY
22 8
8 -Gnathic
~ n a t h i cAngle,
Angle, D
D ee g
g rr ee ee s?
IOk
lnterrygomatic Angle, Degrees
_I
olM a x i l l a r y Incisor T e e t h
I
6
12
18
24
30
AGE I N M O N T H S
Fig. 11. Graphs showing means of stated dimensions of adult rat skulls. Symbols: closed circles and squares
indicate growth hormone-injected rats; open circles and squares indicate corresponding controls.
sulted in modest cranial widening. The resulting massive structure represented acromegaly
in these rats.
Other roentgen cephalometric studies have
noted the selective response of the facial bones
t o growth hormone and the age-linked nature
of this trait. Miura et al. ('69) found that skulls
of 21-day-oldrats responded more actively than
those of 51-day-old rats to 10 days of growth
hormone treatment, with dentofacial development predominating. Bevis et al. ('77) followed
the progress of hypopituitary children, of prepuberal to late adolescent ages, in response to
human growth hormone therapy. Whereas
most cranial sutural growth centers were inactive, those of the cranial base bordering the
face, and of the facial bones as well, were activated by the hormone. (Baume, '68, has emphasized the importance of the presphenoid and
nasal cartilage as well as the sutures in human
facial growth; comparable growth regions exist
in rats.) The distinctive facies of human acromegaly have also been confirmedby roentgen
cephalometry (Galabert et al., '77).
Growth hormone-induced bony overgrowths
have been noted repeatedly. Rat skulls showed
thickening of the cranial diploe and exostoses
a t the attachment of the temporalis muscles
18
IRENE SAVOSTIN-ASLING, ROY NAKAIYE, AND C. WILLET ASLING
and on vertebral bodies (Asling et al., '55);the
thickening of the tibia1 diaphysis was uneven
on different surfaces of the bone, rather than
showing a "tree-ring" pattern in cross-section
(Asling et al., '65). Identical bone pathology is
seen in acromegalics (Kellgren, et al., '52). Exostoses are conspicuous in John Hunter's preparation of an acromegalic giant skeleton (the
"Irish Giant" Byrne), and become grotesque
in the acromegalic giant of Shiraz (Ghorban, '66).More recently, the selective sensitivity of the periosteum has been described. In
balance studies on cortical bone of adult dogs
(using tetracycline flourescence and microradiography a s indicators), three months
of growth hormone stimulated increased
periosteal formation at a rate greater than the
increase in endosteal resorption, with a net increase in bone mass (Harris et al., '72). Measurements of cortical bone in x-rays of the hand
of acromegalics confirmed t h e marked
periosteal apposition, with variable findings on
endosteal resorption (Dequeker, '71). The efficacy of growth hormone in promoting healing of
fractures and bone defects (human subjects,
Koskinen et al., '77; animals, Simpson et al.,
'53, Herold et al., '71) is also pertinent because
of the periosteal role in bone repair. Other bony
components are also responsive. Osteones, and
even single lamellae, were double normal size
in the Shiraz giant (Ghorban, '66). Trabecular
bone in iliac crest biopsies in acromegalics had
accelerated turnover with net gain (Roelfsema
et al., '70). Localized differences in osteogenetic
response to growth hormone may result in severe deformities; the stature of a hypopituitary
patient increased under hormone treatment,
but a previously mild scoliosis was markedly
accentuated in spite of efforts to control the
posture with a brace (Dymling and Willner,
'78).
Progressive diminution in responsiveness to
growth hormone underlies the differences observed between the younger and older adult
rats in this experiment, and even between early
and late parts of the treatment period in the
younger group. One of the more commonly
postulated factors is the formation of specific
antibodies to this protein hormone. Of 149 children whom Chalkley and Tanner ('71) studied,
one-third had non-specific antibodies to human
growth hormone; specific antibodies developed
in only 4 of the 42 under continuing growth
hormone therapy. Trygstad ('69) found little
development of resistance in 26 children
treated with growth hormone; antibody formation was thought most likely to result when the
hormonal preparation had an appreciable content of denatured molecules. During longcontinued treatment of a pituitary dwarf with
human growth hormone (Li), Escamilla and
Forsham ('7 1)detected no antibodies even after
seven years; gain in stature was virtually
linear for eight years, and the advance in bone
age was almost so. There is indirect but strong
evidence that antibody effects were negligible
in the present experiment. Older rats showed
measurable gains i n some dimensions i n response to growth hormone; rats whose treatment had started at a younger age showed
parallel gains i n spite of having received the
hormone for t h e preceding eight months.
Weight gain was accelerated in each treated
group for almost a year, declining only terminally (Moon et al., '56). Still more striking evidence for negligible antibody effect was seen in
a study where growth hormone was given to
thyroidectomized adult rats for eight months
without appreciable growth; subsequently,
when hormonal injections were augmented by
a small daily dose of thyroxine, skeletal growth
was resumed at a rate exceeding normal and
maintained for two months (Asling e t al., '65).
An age-dependency in skeletal response to
growth hormone was shown by Thorngren et al.
('73). The bones of rats hypophysectomized a t
40 days of age grew more actively under therapy than those hypophysectomized 20 days
later, even when dosage was adjusted to body
weight differences." The extent of maturity
rather than the ageper se may be the important
factor. Chronological age was a less suitable
predictor t h a n bone age in projecting the
skeletal growth response of human dwarfs
(Trygstad, '69). Patients responded well to the
hormone even in their late 20's if their skeletons were immature; both stature and bone age
advanced under treatment, but the response
slowed after a "catch-up" phase. In rats, the
remarkably extended growth period was noted
by early workers (Donaldson, '19;Dawson, '25)
and led Washburn ('46)to suggest its primitive
nature, reminiscent of the reptilian pattern of
indeterminate growth. These observations
were based chiefly on the vertebrae and long
bones, where lapsed union results in persistence of numerous epiphyseal cartilage plates
'Age-related effects of growth hormone are not limited to the skeleton. For example, in muscle metabolism studies, the isolated diaphragms of young normal rats display age-dependent enzyme systems
(Alhertson-Wikland and Isaksson, '76). The erythrocytes of elderly
human males became resistant to growth hormonal mediation of some
enzyme-related functions, such as inhibition of glucose consumption,
although other enzyme systems retained responsiveness (Root and
Osk, '69).
RAT CEPHALOMETRY: GIGANTISM VS. ACROMEGALY
into senescence. Age, size, epiphyseal status,
and responsiveness to growth hormone are very
closely linked (Asling and Evans, ’56). Vertebrae have two epiphyses, each showing lapsed
union; growth hormone reactivates them even
in adulthood, length of body and tail is increased, and gigantism may ensue. Most appendicular long bones show persistent epiphyseal patency a t one end and an early-fusing
epiphysis a t the other. Growth hormone maintains or reactivates growth at the former, even
to gigantism, while epiphyseal fusion takes
place concurrently at the latter. In bones with a
single, early-fusing epiphysis (e.g., those of the
paws) the fusion occurs a t the normal age in
intact, growth hormone-treated animals, and
a t the normal length when treatment follows
hypophysectomy; the hormone does not effect
overgrowth. In any of these circumstances,
periosteal osteogenesis may be stimulated.
The rat skull possesses a composite of endochondral, sutural, and periosteal growth centers whose capacity for activity may range as
broadly as those just summarized for the postcranial skeleton. Loeb’sgeneralized concepts of
tissue development were applied to the skeleton by Silberberg and Silberberg (’43) as a
“skeletal time curve”. It was proposed that each
of the bony growth centers has a genetically
determined pattern of growth and maturation;
hormones can modify this pattern, but only
within limits which were partially determined
by the progress along the “time curve” which
had been achieved when the hormonal intervention was attempted. The findings on skull
growth in this study are compatible with this
concept.
ACKNOWLEDGMENTS
A part of this work was carried out under a
Summer Student Research Fellowship provided by the School of Dentistry, U.C.S.F.
LITERATURE CITED
Albertson-Wikland, K., and 0.Isaksson (1976) Development
of responsiveness of young normal rats to growth hormone.
Metabolism, 25t747-759.
Asling, C.W., and H.M. Evans (1956)Anterior pituitary regulation of skeletal development. In: The Biochemistry and
Physiology ofBone. G.H. Bourne, ed. Academic Press, New
York, Chap. XXI, pp, 671-703.
Asling, C.W., and H.R. Frank (1963) Roentgen cephalometric studies on skull development in rats. I. Normal and
hypophysectomized females. Am. J . Phys. Anthrop.,
21t527-543.
19
Asling, C.W., M.E. Simpson, and H.M. Evans (1965) Gigantism: its induction by growth hormone in the skeleton of
intact and hypophysectomized rats, and its failure following thyroidectomy. Rev. Suisse de Zool., 72:l-37.
Asling, C.W., M.E. Simpson, H.D. Moon, C.H. Li, and H.M.
Evans (1955) Growth hormone induced bone and joint
changes in the adult rat. In: The Hypophyseal Growth
Hormone, Nature and Actions. R.W. Smith, Jr., O.H. Gaebler, and C.N.H. Long, eds. The Blakiston Division,
McGraw-Hill Book Co., New York, Chap. 9, pp. 154-177.
Baume, L.J. (1968) Patterns of cephalofacial growth and
development. Int. Dent. J., 18r489-513.
Becks, H., C.W. Asling, M.E. Simpson, C.H. Li, and H.M.
Evans (1949) The growth of hypophysectomized female
rats following chronic treatment with pure pituitary
growth hormone. 111. Skeletal changes: tibia, metacarpal,
costochondral junction and caudal vertebrae. Growth,
13t175-189.
Bevis, R.R., A.B. Hayles, R.J. Isaacson, and A.H. Sather
(1977) Facial growth response to human growth hormone
in hypopituitary dwarfs. Angle Orthod., 47.193-205.
Chalkley, S.R., and J.M. Tanner (1971) Incidence and effects
on growth of antibodies to human growth hormone. Arch.
Dis. Child., 46.160- 166.
Dawson, A.B. (1925)The age order of epiphyseal union in the
long bones of the albino rat. Anat. Rec., 31:l-17.
Dequeker, J. (1971)Periosteal and endosteal surface remodelling in pathological conditions. Invest. Radiol., 6.260265.
Donaldson, H.H., and S.B. Conroe (1919) Quantitative
studies on the growth of the skeleton of the albino rat. Am.
J. Anat., 26:237-314.
Dymling, J.-F., and S. Willner (1978) Progression of a structural scoliosis during treatment with growth hormone.
Acta Orthop. Scand., 49:264-268.
Escamilla, R.F., and P.H. Forsham (1971) Treatment with
human growth hormone (Li)for over eight years-Effects
of long-term therapy in a pituitary dwarf. Calif. Med.,
115 161.72-76,
Evans,H.M., H. Becks, C.W. Asling, M.E. Simpson, and C.H.
Li (1948)The gigantism produced in normal rats by injection of t h e pituitary growth hormone. IV. Skeletal
changes: tibia, costochondral junction and caudal vertebrae. Growth, 12t43-54.
Evans, H.M., K. Meyer, and M.E. Simpson (1933) The
Growth and Gonadstimulating Hormones of the Anterior
Hypophysis. Memoirs of the University of California, Vol.
11. University of California Press, Berkeley.
Galabert, J.,J. Oliver, A. Bourdoncle, and G. Gregoire (1977)
Analyse cephalometrique de 17 sujets acromegales. Deductions. Bull. Group. Int. Rech. Sci. Stomatol. Odontol.,
2Ot61-71.
Ghorban, Z. (1966) Observations on a giant skeleton. Acta
Anat., 65.157-164.
Gray’s Anatomy (1973) 35th British Edition, R. Warwick
and P.L. Williams, eds. W.B. Saunders Company, Philadelphia, p. 313.
Greenspan, F.S., C.H. Li, M.E. Simpson, and H.M. Evans
(1949) Bioassay of hypophyseal growth hormone. The tibia
test. Endocrinology, 45t455- 463.
Harris, W.H., R.P. Heaney, J. Jowsey, J. Cockin, C. Akins, J.
Graham, and E.H. Weinberg (1972) Growth hormone: the
effect on skeletal renewal in the adult dog. I. Morphometric studies. Calcif. Tissue Res., IOtl-13.
Herold, H.Z., A. Hurvitz, and A. Tadmor (1971)The effect of
growth hormone on the healing of experimental bone defects. Acta Orthop. Scand., 42377-384.
Herzberg, F., and I. Schour (1941) The pattern of appositional growth in the incisor of the rat. Anat. Rec., 80:497506.
20
IRENE SAVOSTIN-ASLING, ROY NAKAIYE, AND C. WILLET ASLING
Hughes, P.C.R., J.M. Tanner, and J.P.G. Williams (1978) A
longitudinal radiographic study of the growth of the rat
skull. J. Anat., 127t83-91.
Kellgren, J.H., J. Ball, and C.K. Tutton (1952) The articular
and other limh changes i n acromegaly. Quart. J. Med.,
21.405- 424.
Koskinen, E.V.S., R.A. Nieminen, R.V. Lindholm, J. Puranen, and U. Attila (1977)Human growth hormone in bone
regeneration of non-healing fractures. Calcif. Tissue Res.,
22 Suppl.:521- 523.
Labhart, A. (1974) Clinical Endocrinology-Theory and
Practice. Springer Verlag, New York, Heidelberg, Berlin,
pp. 106 et seq.
Li, C.H., H.M. Evans, and M.E. Simpson (1945) Isolation and
properties of the anterior hypophyseal growth hormone. J.
Biol. Chem., 159t353-366.
Miura, F., E. Nunota, K. Hanada, K. Ohyama, and K .
Noguchi (1969) Effect of growth hormone on growth and
development of the dentofacial complex in the young rat; a
study by means of longitudinal roentgenographic
cephalometrics. Bull. Tokyo Med. Dent. Univ., 16: 109122.
Moon, H.D., A.A. Koneff, C.H. Li, and M.E. Simpson (1956)
Pheochromocytomas of adrenals in male rats chronically
injected with pituitary growth hormone. Proc. Soc. Exper.
Biol. and Med., 93t74-77.
Prader, A,, M. Zachmann, J.R. Poley, R. Illig, and J. Szeky
(1967)Long-term treatment with human growth hormone
(Raben) in small doses. Helv. paediat. Acta, 22:423-438.
Roelfsema, F.,J. Van der Sluys, and D. Smeenk (1970)Quantitation of bone and bone turnover in biopsy specimens
from the iliac crest in acromegaly. J. Endocrinol., 48:lxi.
Root, A.W., and F.A. Osk (1969) Effects of human growth
hormone in elderly males. J. Gerontol., 24t97-104.
Silberberg, M., and R. Silberberg (1943) Influence of the
endocrine glands on growth and aging of the skeleton.
Arch. Path., 36:512-534.
Simpson, M.E., D.C. Van Dyke, C.W. Asling, and H.M.
Evans (1953) Regeneration of the calvarium in young
normal and growth hormone-treated hypophysectomized
rats. Anat. Rec., 115r615-625.
Thorngren, K.-G., L.I. Hansson, K. Menander-Sellman, and
A. Stenstrom (1973) Effect of dose and administration
period of p o w t h hormone on longitudinal bone growth in
the hypophysectomized rat. Acta Endocrinol., 74: 1- 23.
Trygstad, 0. (1969) H u m a n growth hormone and
hypopituitary growth retardation. Acta Paediatr. Scan.,
58:407- 419.
Washburn, S.L. (1946) The sequence of epiphyseal union in
the opossum. Anat. Rec., 95t353-363.
Wright, H.V., Inger Kjaer, and C.W. Asling (1966)Roentgen
cephalometric studies on skull development i n rats. 11.
Normal and hypophysectomized males; sex differences.
Am. J. Phys. Anthrop., 25t103-118.
23.0
20.22
16.1
k0.22
27.1
k0.53
22.1
kO.10
6.2
k0.07
Length of
cranium, mm
Width of
cranium, mm
Length of
“face”,mm
Length of
palate, mm
Width of
palate, mm
~
8.4
r0.80
6.3
k0.14
Interzyg.
angle, Deg.
Radius of
incisor, mm
6.7
20.21
k 1.08
4.8
25.8
~0.53
7
20.7
=
width. L
7.2
20.19
0.4
+0.37
26.6
20.45
to.19
29.4
2 1.08
71.6
~1.28
109.7
7.0
20.10
23.9
10.31
29.9
20.42
16.8
t0.23
23.6
20.15
27.3
20.34
53.5
20.37
‘Means and standard errors.
‘Abbreviations (see Fig. 1):
Bizygomat. = bizygomatic; Interzyg. = interzygomatic; W
24.4
k0.48
29.1
~0.39
28.2
50.31
71.3
21.38
70.0
k 1.02
108.3
6.8
k0.08
23.5
k0.24
29.2
k0.44
16.8
k0.18
23.6
20.25
26.9
k0.33
52.8
50.40
14.2
8
Controls
21.72
-.1.97
Gnathic
angle, Deg.
x loo
Palatal L
_ _ _ ~
Palatal W
x loo
Cranial L
Cranial W
x 100
Bizygom. W
_ 108.3
25.1
50.29
Bizygomat.
width, m
_
50.1
20.38
Paramete?
Length of
skull, mm
“Facial” L
6
5
Age, months
Number
Group
6
6
=
20.10
7.3
23.8
k0.15
30.6
-.0.43
17.4
k0.15
23.8
20.34
29.3
50.49
=
degrees.
7.2
20.23
4.9
20.51
26.6
20.22
20.57
30.6
21.33
73.2
21.36
104.5
length, Deg.
6.3
t0.12
10.0
50.45
24.3
20.25
~0.49
29.7
20.98
70.3
t 1.48
108.8
6.5
20.14
22.0
20.14
27.4
20.42
16.1
20.13
22.9
t0.30
25.2
10.18
54.4
20.38
14.2
7
Growth hormone
50.3
k0.25
Young adults
7.7
kO.0
2.1
20.37
27.5
50.46
10.68
30.4
k1.90
75.6
22.15
105.2
7.5
20.16
24.5
20.15
31.8
50.47
17.9
k0.20
23.8
20.45
30.3
?0.53
55.6
10.63
20.7
7
20.0
6.4
4.8
20.90
25.5
20.60
?0.27
30.6
6.7
20.26
3.7
k0.46
26.4
20.58
t0.40
30.4
69.7
2 1.59
70.2
k 1.98
109.1
7.2
50.11
23.8
k0.24
29.4
20.42
16.4
k0.25
23.6
20.22
27.0
20.15
53.0
20.27
22.8
5
2 1.60
20.76
109.3
7.1
20.06
23.1
20.12
29.0
20.37
16.5
k0.22
23.4
20.32
26.5
20.21
52.4
50.45
14.7
5
Controls
6.8
20.43
3.2
k0.44
26.4
20.90
50.64
31.7
2 1.13
71.9
51.50
110.2
7.5
20.12
23.7
k0.44
30.0
k0.60
16.7
50.20
23.3
k0.14
27.1
20.18
53.1
20.49
29.3
3
Old adults
TABLE 1 , Skull dimensions and proportions of male rats inJected chronically with growth hormone.’
6.4
20.0
4.0
20.26
26.3
~0.48
6.6
20.22
3.3
20.67
26.3
20.40
31.9
20.90
31.0
6.7
20.32
2 1.08
3.0
26.9
20.55
+0.01
33.4
75.1
2 1.24
73.8
22.20
103.0
7.8
tO.10
23.3
20.48
30.3
20.61
17.6
20.23
23.4
20.15
29.4
t0.58
53.7
20.60
29.3
4
~0.96
+ 1.06
103.0
7.6
k0.17
23.7
20.25
29.8
20.38
17.4
20.21
23.5
50.25
29.0
20.43
53.3
20.38
22.8
6
20.41
50.84
72.5
r1.14
105.6
7.1
k0.05
22.9
20.20
29.1
k0.31
16.8
20.11
23.2
k0.16
27.5
50.27
52.3
20.35
14.7
6
Growth hormone
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