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The effect of hypoxia on the fetal rat adrenal.

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T H E E F F E C T OF HYPOXIA ON THE FETAL
RAT ADRENAL 1*2
ROBERT C. HOLLAND5
Departments of Anatomy, University of Wisconsin, Madison,
and Unisersity of North Dakota, Grand Forks4
INTRODUCTION
EIQHT FIGURES
The inner zones of the adrenal cortex of many mammalian
species undergo partial involution and reorganization immediately after birth. This is especially striking in the neonatal human wherein an inner fetal zone normally disappears
completely leaving a considerably smaller gland. Lanman
( ' 5 3 ) reviewed the literature on the fetal zone and concluded
the physiology of the fetal zone is unknown.
Although the adrenal gland of the newborn rat does not
possess a well-defined fetal zone such as is found in the
human, the inner portion of the cortex does undergo structural reorganization into an adult reticular zone shortly after
birth (Jackson, '13, '19 ; Howard, '38 ; van Dorp and Deane,
'50). Josimovich, Ladman and Deane ('54) report that a
significant decrease in volume of the rat adrenal cortex occurs
within two days after birth, an actual loss of cortical tissue.
It has been demonstrated that hypoxia causes an increase
in size and function of the adrenal gland of adult animals
(Giragossintz and Xundstroem, '37 ; Armstrong and Heim,
This study is based on a thesis submitted to the Graduate School of the University of Wisconsin in partial fulfillment of the requirements for the degree of Doctor
of Philosophy in Anatomy and Zoology.
* Presented a t the annual meeting of the American Association of Anatomists,
April 4-6, 1956, Milwaukee, Wis.
a Formerly research assistant, Wisconsin Alumni Research Foundation.
'Present address.
177
178
ROBERT C. HOLLAND
'38 ; Tornetta, Gordon, d 'Angel0 and Charipper, '43 ; Dalton,
Jones, Peters and Mitchell, '44). It occurred to the present
investigator that the amount of oxygen supplied the fetus
might influence the development of its adrenal gland. This is
a report of an investigation of the influence of hypoxia,
through reduced atmospheric pressure, on the size of the
adrenal glands of newborn rats.
MATERIALS AND METHODS
Reduced pressure apparatus. Four pyrex vacuum dessicating jars with an inside diameter of 250mm were used as
decompression chambers. A coarse galvanized wire screen
replaced the usual porcelain tray of the jars. At the air intake,
which served all 4 jars, a two-way straight bore stopcock
served as control valve. Rubber pressure tubing conducted
air to the jars, arranged in parallel, permitting each jar to
receive equally fresh air.
Connected to the air line between the jars and the pump
was a U-shaped mercury manometer. The air inlet valve
was set so that the pressure was reduced to 379.4mm Hg
which is equivalent to an altitude of 18,000 feet. At this
altitude the partial pressure of oxygen is 79.7mm H g which
is a reduction of 49.97%. The vacuum pump used displaced
0.35 1 of air per second when operated against an atmospheric
pressure of 379.4mm Hg. Thus theoretically the air in the
chambers was simultaneously renewed 1.33 times each minute.
Eqerirnental animals and basic procedures. Virgin female Sprague-Dawley albino rats weighing approximately
200gm served as mothers for the newborn in this experiment. Throughout the experiment the adult female rats were
given tap water ad libitum and fed Purina Laboratory Chow
with fresh lettuce supplement twice each week. Estrum was
determined by vaginal smears. The females were mated and
gestation age was calculated by counting as day one the day
on which sperm appeared in the vaginal smears. On gestation
day 12 the pregnant rats were randomly assigned to one of 4
groups, each group containing 15 rats. Group 1 served as the
EFFECT OF HYPOXIA ON FETAL ADRENAL
179
control and was sham adrenalectomized. Group 2 was placed
at high altitude and was also sham adrenalectomized. The
pregnant rats of group 3 were subjected to bilateral adrenalectomy only. Group 4 were bilaterally adrenalectomized and
also subjected to reduced atmospheric pressure. The animals
in groups 3 and 4 were adrenalectomized on the morning of
the 12th day of pregnancy. The rats of groups 2 and 4 subjected to reduced atmospheric pressure were placed in the
decompression chambers (one rat per chamber) on the 18th
day of pregnancy and were kept there continuously until the
21st day, except for one “descent” for cleaning the jar and
replenishing the food and water. Therefore, they were at a
simulated altitude of 18,000 feet f o r 72 3 hours. Compression and decompression were conducted at the rate of 2,000
feet per minute.
Only rats of litters born at 21 days of gestation or obtained
by caesarean section on the 21st day of gestation were used
for the study of the adrenal of the newborn. The living
newborn were weighed, killed by decapitation, and bled. The
adrenal glands were removed, placed on filter paper moistened
with normal saline solution, and with the aid of a stereoscopic
microscope were dissected free of surrounding tissues. The
organ was then touched twice t o dry filter paper and quickly
weighed on a Roller-Smith micro-torsion balance having a
sensitivity of 0.2mg. To serve as control and to determine
whether another organ as well as the adrenal gland had a
change in weight due t o experimental treatment, the kidneys
were removed and treated in the same manner as the adrenal
glands. The two kidneys were weighed together as were the
adrenals. All tissues were then fixed in 10% formalin. Tissues
for microscopic examination were stained by the standard
hematoxylin-eosin method.
RESULTS
The means of the body weights, adrenal weights, and kidney
weights for each of the 4 groups are presented in table 1.
It was determined that when the body weights of the newborn
15
15
Group 3
Adrenalectomized
Group 4
High alt.
adrenalectomized
<
15
Group 2
High
altitude
98
105
98
108
NO.
NEWBORN
3.2
4.8
4.6
2.3
2.5
1.4
2.0
mg
gm
5.7
Unadjusted
mean wt.
2.6 a
2.5 *
1.4
1.8
mg
A2ju;t;d
wt.
NEWBORN A D R E N A L S
BODY WT.
MEAN
Groups =
0.483
Within
Among
Means =
-0.161
Correlation
coefficient
(rP)
21.2
38.6
34.2
45.1
mg
Unadjusted
mean wt.
29.2 a
36.9
34.8
38.9
mu
wt.
*$$,""p
NE\'I'DORK KIDNETS
'Formula used: MYX = My-b within ( M x - Gen. Mx), where M = mean, Y = organ weight, X = body weight, b = regression coefficient.
* Indicates P = .01.
15
LITTERS
NO.
Group 1
Control
EXPERIMENTAL
GROUP
Mean body, adrenal and kidney weights of newborn rats after various treatments
TABLE 1
Within
Groups =
0.652
Among
Means =
0.998
Correlation
coefficient
(r)
E F F E C T O F H Y P O X I A O N F E T A L ADRENAL
181
in the experimental groups were compared to the controls,
there was a significant loss of body weight and it was therefore necessary to make an analysis of covariance ’ on the data
to determine whether the variations in the adrenal \veights
and kidney weights were significant and independent of the
body weight variation.
Adrenal weight-body weight analysis. The changes in adrenal weights among the groups were independent of body
weight change ( P = < . O l ) as revealed by the analysis of
covariance. After the adrenal weights were adjusted for
body variation (table 1) it ~ 7 a sfound that the experimental
groups varied significantly (P = < . O l ) from the control
group. On the basis of this analysis it can he concluded that
the newborn of the high altitude group had adrcnals whose
weights were significantly smaller than those of thc controls,
while the adrenals were significantly heavier in the adrenalectomized group (confirming the work of Ingle and Fischw,
’38) and in the high altitude adrenalectomized group. Statistically these changes were found to be independent of body
weight change. Figure 1 presents the distribution of the 4
groups of unadjusted adrenal weights.
K i d n e y zueight-body weinht analysis. The kidney weights
were subjected to a statistical analysis identical to the
adrenal weight analysis in order to check another organ for
the possibility of a gencral alteration in organ weight-body
weight relationship and also to provide a control for the
technique of obtaining organ weights. As expected on a
theoretical basis the kidney weight was found to be a f u n c
tioii of body weight (fig. 2) and therefore a verification of the
The analysis of covariance method outlined in Statisttcs i n Psychology and
Educataon, H. E. Garrett, 1953, Longmans, Green and Co., New York, 288-297,
was followed with the exception of substitution of the revised formula,
from Experimental Designs, W. G . Cochran and G. M. Cox, 1950, John Wiley and
Sons, New York, page 79, f o r Garrett’s “Step 9.”
182
ROBERT C. HOLLAND
0
0
0
0
m
mm
a
m m
0 0Q
Q,
m m
m
mm
m
m
m
3 0-
I
2I
I
w
I
E E
I
I
4
I
5
BODY WEIGHTC GRAMS)
I
3s
Ei
I
I
6
J
ADRENALECTOM Y
e HIGH ALTITUDE
0 MATERNAL ADRENALEGTOMY
a HIGH ALT a MATERNAL
0 CONTW3L
0
Fig. 2 The relationship between the mean kidney weight and mean body weight of litters of newborn rats subjected to various treatments. The kidney weight appears rn a function of body weight in contrast to the grouping of adrenal weights in
figure 1.
lo--
2 0--
WEIGHT
C MGM.3
KIDNEY
4 0-
so
0
0 0
LITTER MEANS OF KIDNEY/BODY WUGHT RELATIONSHIP
O F NEWBORN RATS
w
4
0
184
ROBERT C. HOLLAND
accuracy of the weighing technique was obtained. The analysis
of covariance revealed that after adjustment f o r body weight
variation there was no significant difference of kidney weights
between animals of groups 1, 2, and 3 (table 1). I t must be
noted that in the high altitude adrenalectomized group 4 the
kidney was unaccountably smaller (I)= < .01) than the other
groups (0.67% of the total body weight as compared to 0.77%
for the other groups). However, it is noteworthy that the
adrenals were relatively the heaviest f o r this group.
The coefficientof correlation ( r ) provides further information for comparing the adrenal weight and the kidney weight
data (table 1). There was excellent correlation among the
group means in the kidney weight data ( r = 0.998) as compared to the correlation among group means in the adrenal
weight data ( r = -0.161). There was good correlation within
all groups ( r =0.483, adrenals ; 0.652, kidneys).
Hisfology. The zona glomerulosa of all 4 groups was
similar in histological structure. It was thin, 6 to 8 cells deep,
and lacked the glomerular arrangement typical of the adult.
The cytoplasm of the cell was typically more dense and basopliilic than elsewhere in the cortex. The glomerulosa-fasciculata junction was distinct in all groups.
The zonae fasciculatae of the adrenal cortex of the three
experimental groups presented major histological differences
from the control group. I n the latter group the fasciculata
cells had moderately pale eosinophilic cytoplasm with occasional vacuoles present (fig. 3 ) . I n contrast to the controls
the fasciculata cells of the high altitude group 2 were much
smaller, were more compactly arranged, and had dense, darkly
stained nuclei (fig. 4). The narrow zone of cytoplasm was in
general non-vacuolated and deeply stained. On the other hand,
the cells of the zonae fasciculatae of the adrenalectomized
group 3 animals %'ere hypertrophied, paler and more vacuolated (fig. 5). The high altitude adrenalectomized group 4
had the largest and most vacuolated cells of any group
(fig. 6).
E F F E C T OF HYPOXIA O N F E T A L ADRENAL
185
It has been found, therefore, that a correlation exists
between the weights of these glands and the histological
picture. The small (suggesting inactivity) glands of the high
altitude group had small, compact, non-vacuolated cells and
presented the appearance of ‘ ‘ resting’ ’ glands while the large
glands of the other two experimental groups had hypertrophied vacuolated cells and presented the appearance of
highly active glands. These changes were in the zona fasciculata.
A well-defined zona reticularis was not apparent in the
adrenal of any of the animals of this experiment. There was
an intermingling of cortical and medullary cells not seen in
the adult gland and it is probable that the reticularis was
represented by these cortical cells which had small nuclei,
eosinophilic cytoplasm, and indistinct cell membranes. I n a
separate study it was determined that at one week postpartum a distinct medulla can be seen and no cortical cells
can be observed intermingled with the medullary cells.
The sinusoids of all groups were relatively bloodless. There
were, however, some residual blood cells present and of
particular interest were the orthochromatophilic normoblasts
undergoing karyorrhexis found in the two groups subjected
to high altitude. These large cells were first generation cells
undergoing degeneration in some instances and maturation in
others (fig. 7 ) . Many smaller second generation orthochromatophilic normoblasts with well-defined nuclei are also present (fig. 8). The prominence of these cells in the high altitude
groups suggests that the lowered blood 0, tension of the
fetuses was reflected in accelerated hernatopoiesis.
DISCUSSION
The observation of this investigation that the adrenal glands
of newborn rats made hypoxic by lowering the 0, tension of
the maternal blood during the last three days of gestation
(group a), were smaller than normal, is contrary to results
observed when the adrenal glands of adult animals subjected
to reduced pressures are examined. Giragossinta and Sund-
186
ROBERT C. HOLLAND
stroem ('37) noted adrenal hypertrophy to occur in adult
rats subjected to hypoxia produced by lowering the atmospheric pressure. Dohan ( '42) ; Tornetta, Gordon, D'Angelo
and Charipper ('43) ; Dalton, Jones, Peters and Mitchell
('44); and Edelmann ('45) also reported increased size or
function of adrenals of adult rats exposed to hypoxia as did
Armstrong and Heim ('38) f o r the rabbit. However, the fetal
adrenal has been reported t o decrease in size and function
after subjecting the fetus or mother to other experimental
procedures. Removal of the fetal source of ACTH by hypophysectomy of the fetus (by decapitation) will produce fetal
adrenal atrophy (Wells, '47; Domm and LeRoy, '51; Jost,
'53). Schmidt and Hoffman ('54) reported that ACTH injected in pregnant monkeys resulted in maternal adrenal
hypertrophy and fetal adrenal atrophy. Pellets of cortisone
o r of hydrocortisone implanted in the rat fetus reduced the
volume of the fetal adrenal cortex which presented histochemical signs of reduced functional activity (Yakaitis and
Wells, '56). Decreased function of the fetal adrenal was also
shown by Jones, Lloyd and Wyatt ( '53) who exposed pregnant
rats to cold stress and found maternal cholesterol levels lowered, indicating hyperactivity, and fetal adrenal cholesterol
levels elevated, indicating hypoactivity of the adrenals.
The adrenals of the newborn of adrenalectomized mothers
subjected to hypoxia (group 4) were significantly larger than
the controls. This contrasts with the adrenal atrophy noted
in the newborn of group 2. The maternal adrenal, therefore,
was the factor which helped determine the adrenal's response
in the newborn when hypoxia was introduced as an experimental treatment. The addition of the hypoxic stress in group
4 caused the adrenals to enlarge to the same degree that
maternal adrenalectomy alone produced in group 3. Theoretically the stress which was introduced in group 4 should
have produced adrenals which were larger than those of
group 3 although the failure to find a significant increase of
weight was not entirely unexpected for several reasons. The
72 hours of hypoxic stress may not have been a sufficiently
EFFECT O F HYPOXIA ON FETA L ADRENAL
187
long period of time to permit a significant amount of hypertrophy to develop beyond that which occurred as a result of
maternal adrenalectomy. There is also the possibility that
the pituitary of the fetus did not respond to the stress, as
Jailer ('50) reported that infant rats did not respond to cold
stress with a reduction of adrenal ascorbic acid until the 16th
day postpartum, and by the same criteria showed no response
until the 8th day postpartum when injected with epinephrine.
They did, however, respond to injected ACTH on the 4th
day. The unresponsiveness of the newborn pituitary in Jailer's experiment is not necessarily incongruous with results
reported here because there is the possibility of the existence
of more than one pathway o r mechanism by which a stimulus
from a stress may ultimately reach the anterior pituitary.
Perhaps certain brain stem centers are senstitive to certain
stimuli earlier than others or it may be that later myelinization
of some tracts of the central nervous system delays the time
a response to a given stimulus first appears.
The zonae fasciculatae and reticularis in groups 3 and 4
showed histological signs of increased function. These zones
are thought to produce the carbohydrate regulating hormones
under the direct control of ACTH, while the glomerulosa probably produces DOCA and is largely independent of the pituitary (Jones, '49, '50 ; Deane and Greep, '46 ; Deane, Shaw and
Greep, '48; Miller, '49). I n their review Sayers and Sayers
('48) categorize the size and weight alterations and histochemical response of the adrenal cortex to various influences.
Their Type IV Adrenal Response is characterized by a loss
of sudanophilic substance and ascorbic acid from the adrenal
cortical cells, plus an increase in size, all of which are criteria
presented as showing hyperactivity of this gland. They point
out that a severe stress followed by recovery, such as adaptation to low atmospheric pressure, will cause this reaction.
Injection of Kendall's adrenal cortical extract helps protect
the animal against the stress of high altitude (in rats, Thorn,
Clinton, Davis and Lewis, '45 ; in mice, Kottke, Taylor, Kubicek, Erickson and Evans, '48). The histological changes in
188
ROBERT C. H O L L A N D
groups 3 and 4, therefore, conform with theoretical expectations and it is assumed that the carbohydrate regulating hormones in these groups are being produced at an accelerated
rate.
Any attempt to elucidate the details of the physiology of
fetal endocrine organs must include consideration of any influence that may be exerted by maternal hormones. Work has
been quoted earlier in this discussion wherein certain treatments of the pregnant animal produced smaller inactive fetal
adrenal glands, as was found in the newborn of group 2 of this
report. From these experiments on pregnant animals it may
be presumed that the treatment resulted in high levels of circulating corticoids in the mother and, therefore, elevated levels
of these corticoids crossed the placental barrier to the fetus.
These corticoids may consequently have reduced the output of
ACTH from the fetal pituitary causing fetal adrenal atrophy.
This assumption is made because it has been shown that the
removal of the fetal source of ACTH by hypophysectomy
(decapitation) of the fetus will produce fetal adrenal atrophy
(TTTells, '47, Domm and LeRoy, '51; Jost, '53) which is prevented by intrafetal injected ACTH (Wells, '48). It would
also appear that in spite of the elevated level of circulating
maternal ACTH none or at least no unusual amount, was
crossing because if the fetal levels of ACTH had been increased the fetal adrenals would probably have hypertrophied
and have shown other signs of increased function in spite of
higher titres of circulating corticoids in the fetus. That adrenal atrophy does not occur in the adult rat in the presence of
additional amounts of a cortical hormone if sufficient ACTH
is present was shown by Ingle and Higgens ( '38). Ingle ( '38)
also hypophysectomized rats and then injected cortin and
anterior pituitary extract and found no adrenal atrophy.
Lewis, Rosemberg and Wilkins ( '50) reported that compound
E acetate injected in 8-week-old rats caused adrenal atrophy
(21% smaller) and cholesterol accumulation (40% more)
while injection of compound E in hypophysectomized rats
maintained on ACTH did not alter adrenal cholesterol or
E F F E C T O F H Y P O X I A O N F E T A L ADRENAL
189
adrenal size. The same dosage of DOCA injected in intact
rats had little or no effect. The fact that this experiment was
on 8-week-old rats and not fetuses qualifies the immediately
preceding discussion as to its applicability to the physiology
of the fetus. However, the compensatory hypertrophy of the
remaining adrenal following unilateral adrenalectomy in the
fetus (Kitchell, '50) which is prevented by implanted cortisone but not DOCA (Kitchell and Wells, '52), and the other
adult-like actions that the fetal adrenal exhibits which were
mentioned above would appear t o permit the assumption that
if an increased titre of ACTH of maternal origin were circulating in the fetus, the fetal adrenal would not atrophy in
spite of the increased titre of corticoids circulating in the
fetus. The observation of Angevine ('38) that in human
anencephalic monsters the adrenals were extremely small
suggests that maternal ACTH is not responsible for the large
fetal adrenal. Evidence that extracts of the anterior lobe of
the hypophysis do not cross the rabbit placenta (from fetus to
mother) was reported by Wislocki and Snyder ('32), and
Peterson and Young ('52) reported on the failure of thyrotrophin to cross the placenta to the guinea pig fetus.
While the foregoing discussion indicates that normal levels
of circulating ACTH in the pregnant animal cannot cross the
placental barrier to the fetus, there is reason to believe that
high unphysiological levels can cross this barrier (Jones,
Lloyd and Wyatt, '53). Knobil and Briggs ( '54) report that
high levels of maternal ACTH can cross the placenta although
they later conclude (Knobil and Briggs, '55) that normally
maternal ACTH may not play a role in fetal adrenal control.
On the basis of the work reported here it is not certain that
a relationship exists between the relatively hypoxic environment the fetus is in near term and the adrenal enlargement
present in most animals at birth. However, the evidence would
appear t o reject the idea that maternal ACTH has a role in
the etiology of the enlarged adrenal. Benirschke, Bloch and
Hertig ('56) show good evidence for the production of weak
androgenic steroids by the adrenal cortex of the early human
190
ROBERT C. HOLLA N D
fetus. Bloch, Benirschke and Rosemberg ('56) reported that
the amount of C19-steroids present in the adrenal cortex of
the human fetus has dropped considerably by the 16.5-21 week
of gestation and suggest that they are produced in the fetal
and reticular zones of the adrenal and that the glucocorticoid
and mineralcorticoid hormones are produced in the fascicular
and glomerular zones respectively. This work does not, therefore, rule out the possibility that the relative hypoxia of the
fetus near term may be a stimulus which results in a high rate
of production and release of fetal ACTH which in turn stimulates the adrenal cortex causing hypertrophy, hyperplasia and
hyperfunction of the gland. The advent of efficient air-lung
respiration at birth marks the end of hypoxia, and a partial
involution of the adrenal cortex may be the result.
SUMMARY AND CONCLUSIONS
1. Exposing rats in the 18th day of pregnancy to a simulated altitude of 18,000 feet for 72 hours (group 2) resulted
in a loss of weight of the fetal adrenal gland when compared
with the controls (P= < .01).
2. The newborn of rats adrenalectomized the 12th day of
pregnancy (group 3 ) have adrenal glands whose mciglits are
significantly heavier ( P = < .01) than those of the controls,
confirming previous reports in the literature.
3. Exposure of adrenalectomized pregnant rats to a simulated altitude of 18,000 feet for 72 hours (group 4) resulted in
a significant increase of weight of the fetal adrenal gland when
compared with the controls (P = < .01).
4. Histologically the fetal adrenals present evidence of
cellular alterations in the zona fasciculata which indicates that
it is probably the production of the OI1-steroids that is
changed.
5 . Because it may be assumed that the pregnant rats in
group 2 had increased levels of circulating ACTH due to the
hypoxic stress, it is concluded that the mothers of group 2 had
elevated levels of circulating adrenal corticoids which crossed
the placenta and depressed the fetal pituitary-adrenal axis as
EFFECT O F HYPOXIA O N FETAL ADRENAL
191
evidenced by the fetal adrenal atrophy. Since exogenous Oiladrenal corticoids fail to produce adrenal atrophy in adult
rats in the presence of exogenous ACTH, it is concluded that
the maternal elevated level of circulating ACTH was not
reflected in the fetus and therefore ACTH did not cross the
placental barrier.
6. I t is concluded that fetal adrenal corticoids crossed the
placenta to the adrenalectomized mothers in groups 3 and 4
and the resultant drop of the lcvel of circulating fetal corticoids activated the fetal pituitary which released increased
amounts of ACTH with a resultant hypertrophy of the fetal
adrenals.
7. The possibility of a relative hypoxia of the fetus near
term causing the enlargement of the adrenal cortex is
discussed.
ACKNOWLEDGMENTS
The encouragement and counsel of Dr. Harland W. Mossman of the University of Wisconsin, so generously given during the investigation and preparation of the manuscript, are
acknowledged with deep gratitude. I am also indebted to Dr.
Christopher J. Hamre of the University of North Dakota for
his valuable advice and helpful critical reading of the manuscript.
LITERATURE CITED
ANGEVINE,D. M. 1938 Pathologic anatomy of the hypophysis and adrenals in
anencephaly. Arch. of Path., 86: 507-518.
H. G., AND J. W. HEIM 1938 Effect of repeated daily exposures t o
ARMSTRONG,
anoxemia. J. Aviation Med., 9: 92-96.
BENIRSCHKE,
K., E. BLOCHAND A. T. HERTIG 1956 Concerning the function of
the fetal zone of the human adrenal gland. Endocrinology, 58:
598-625.
BLOCH,E., K. BENIRSCHKEAND E. ROSEMBERG1956 C steroids, 17a-hydroxycorticosterone and a sodium retaining factor in human fetal adrenal
glands. Ibid., 58: 626-633.
DALTON,A. J., B. F. JONES,
V. B. PETERS
AND E. R. MITCHELL 1944 Organ
changes in rats exposed repeatedly to lowered oxygen tension with
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192
ROBERT C. HOLLAND
DEANE,TI. W., AND R. 0. GREEP 1946 A morphological and histochemical study
of the rat’s adrenal cortex a f t e r hypophysectomy, with comments on
the liver. Am. J. Anat., 79: 117-145.
DEANE,H. W., J. H. SHAWAND R. 0.GREW 1948 The effect of altered Sodium
or Potassium intake on the width and cytochemistry of the zona glomerulosa of the rat’s adrenal cortex. Endocrinology, 43 : 133-153.
DOIIAN,F. C. 1942 Effect of low atmospheric pressure on the adrenals, thymus
and testes of rats. Proc. Soc. Exper. Riol. and Med., 4 9 : 404-408.
DONM,L. V., AND P. LERQY 1951 A method for hypophysectomy of the rat
fetus b y decapitation. Anat. Rec., 1 4 9 : 395-396.
EDELNANN,
A. 1945 The significance of changes i n adrenal size after periods
of anoxia in rats. Proc. SOC. Exper. Biol. and Med., 58: 271-272.
GIRAGOSSINTZ,
G., AND E. S. SUNDSTROEM
1937 Corticoadrenal insufficiency in
rats under reduced pressure. Ibid., 3 6 : 4 3 2 4 3 4 .
HOWARD,
E. 1938 The representation of the adrenal X-zone in rats in the light
of observations on X-zone variability in mice. Am. J. Anat., 62:
351-374.
INGLE,D. J. 1938 The effects of administering large amounts of cortin on the
adrenal cortices of normal and hypophysectomized rats. Am. J.
Physiol., 124: 369-371.
INGLE,D. J., AND G. M. HIGGENS1938 Atrophy of the adrenal cortex in the r a t
produced by administration of large amounts of cortin. Anat. Rec., 7 1 :
363-372.
INGLE, D. J., AND G. T. FISCHER1938 Effect of adrenalectomy during gestation
on the size of the adrenal glands of newborn rats. Proc. SOC.Exper.
Biol. and Med., 3 9 : 149-150.
JACKSON, C. M. 1913 Post-natal growth and variability of the body and of
the various organs in the albino rat. Am. J. Anat., 15: 1-68.
1919 Post-natal development of the suprarenal gland and the effects
of inanition upon its growth and structure in the albino rat. Ibid.,
25: 221-290.
JAILER,J. W. 1950 The maturation of the pituitary-adrenal axis in the newborn
rat. Endocrinology, 46 : 420-425.
JONES, I. C. 1949 The relationship of the mouse adrenal cortex t o the pituitary.
Ibid., 4 5 : 514-536.
1950 The effect of hypophysectomy on the adrenal cortex of the
immature mouse. Am. J. Anat., 86: 3 7 1 4 0 3 .
JONES,J. M., C. W. LLOYDAND T. C. WYATT 1953 A study of the interrelationships of the maternal and fetal adrenal glands of rats. Endocrinology,
53: 182-191.
JOSIMOVICH,
J. B., A. J. LADMAN
AND H. W. DEANE 1954 A histochemical study
of the developing adrenal cortex of the rat during fetal and early
postnatal stages. Ibid., 54: 627-639.
JOST, A. 1953 Problems of fetal endocrinology. The gonadal and hypophyseal
hormones. Rec. Prog. in Hormone Res., 8: 379-418.
KITCHELL,
R. L. 1950 Compensatory hypertrophy of the intact adrenal of fetal
rats subjected to unilateral adrenalectomy. Proc. SOC.Exper. Biol. and
Med., 76: 824-827.
EFFECT O F HYPOXIA O N FETAL ADRENAL
193
R . L., AND I>. 7. W E L L S 1952 Rcriproral relatiomhip bctlveen tlic
liypopliysis and adreirals in fetal rats : Effects of unilateral :iilrenalcctomy and of implanted cortisone, DOCA, and sex liorniones. Eiidocriiiology, 50: 83-93.
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-__
1955 Fetal-niaternal rndocrinc iiitrrrrlatioiislii~~s:
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K o w m , F. J., (f. R. TAYLOR,
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1). M. ERICKSON
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1953 The fetal zonr of the adrriial gland. I t s developinental
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idrenal systeni in tlir
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IC IT C H E L L ,
~~
I’LATE 1
EXPLANATION O F I”1GURF:S
Tralisvcrse sections of aclreiials of newborn. G1:illds fixed iu a 70% neiitr:iI
formalin solution, sectionea a t G p, and staiiieil witli Iieinatosylin a n d cosiii.
3
h(1ren:il of a eoiitrol ~ie\vborii (littrr N = 1.5). X 183.
4 Adrcwal of a ~ i e w b o r i i of high :tltitude groul) (litter 21). Note iiici~c~:isc~~
ce1lul:irity and small size of cclls iii zona f:rscic~nnt:r. X 183.
5
Adrenal of n nowborn of niatcrii:il-:idrcii:il(~(~toiiiizc~(l
group (litter 2.5 ,I).
Note the Iiypcrtrophied vacuolated cells of zoiiii f:iscirnl:ita. Scattered elunips
of iiicclullnry cells are visible. x 183.
G
Atlrcwrl of a iiewborii of Iiigli :iltittidc m:itcrii:il-ndreiinlectoniizcd grou1) (litter 117 E ) . The zoiia fasciculata cells :iw markedly Iigpcrtrol)liic~l:in(1
vacuolated. Clumps of iidu1l;iry cells a r c visiblt.. X 183.
7
Zolia f:isciculata of a Iiewbom of liigli :iltitu(lr group. Secoiid gcsiicrntioii
ortlioclirornatopliilic normoblasts ( a r r o w ) a n d karyorrliexis of iiorinoblnsts
(lincd arrow) present evidence of fetal r(xsl)oiise t o ligpxia. x 900.
8 Zolia fascieulntn of a newborn of high altitude ii~atcrri:il-ad~.(~ii:ilectoiiiizecl
group. Cellular hypertrophy coiitrasts with preceding figurc. R(q)olise to
hypoxia same as preceding figure. x 900.
EFFECT OL’ IIYI’OXIA ON FETAL ADRENAL
XOB&RT C . HOLLAND
195
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