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The effects of high altitude on the reproductive cycle and pregnancy in the hamster.

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The Effects of High Altitude on the Reproductive
Cycle and Pregnancy in the Hamster
'
J
~
RICHARD H . PRINTZ
Department of Anatomy, University of Cincinnati College of Medicine,
Cincinnati, Ohio 45219
ABSTRACT
Mature female golden hamsters, which had demonstrated regular reproductive cycles, when exposed to 23,000 feet simulated altitude for eight
or more days became acyclic. Their ovaries, which were polyfollicular, suggested
that LH release or synthesis by the hypophysis had been blocked. Human chorionic gonadotrophin (which has LH activity) caused similarly exposed animals
to ovulate. When animals which were exposed to high altitude for nine days
were returned to control altitude, they ovulated five days later. Starvation for
nine days, which has no significant effect on adrenal weight but does cause increased LH dependent ovarian interstitial development at control altitude, failed
to do so at 23,000 feet. It is hypothesized that high altitude selectively blocks
LH secretions by the hypophysis.
High altitude also interrupted pregnancy when treatment lasted four or more
days and was begun before day 12. Since follicular development of pregnancy
continued normally but corpora lutea regressed and both FSH and prolactin are
needed to maintain the hamster corpus luteum, this study suggests the possibiIity
that prolactin secretion is blocked in the pregnant animal at high altitude.
Interest in the effects of high altitude
upon reproduction originated with early
reports from South America. It was noted
as early as 1535 that fertility was reduced
in women and livestock not acclimatized
to high altitude in Peru; the capitol was
moved from Janja (11,500 ft.) to Lima
(sea level) because of reduced reproductive levels at the high altitude (Monge,
'42; Monge, '43). A modern report that
approximately 25% of airline stewardesses
experience menstrual difficulties during
their first year of jet flight has also stimulated interest in the phenomenon (Cameron, '69).
The effects of both actual and simulated
high altitude on reproduction have been
studied in several species at altitudes up to
18,000 feet (Donayre, '69; FernandezCano, '58; Altand, '47; Moore and Price,
'47; Gordon, Tornetta, D'Angelo and
Charipper, '43; Nelson and Burrill, '44;
Moore and Price, '48; Monge, San Martin,
Atkins and Castanon, '45; San Martin,
Atkins, and Castanon, '45; Morales, '67).
ANAT. REC., 173: 157-172.
In most of these studies the end points
related to cyclicity, number of offspring,
and changes in organ weight. Little attempt was made to elucidate the mechanisms involved in the noted changes. Because there may be a neuroendocrine
mechanism regulating reproduction at high
altitude which is different than occurs at
lower altitude, we undertook the following
project on the effects of simulated high
altitude on the reproductive cycle and pregnancy in the golden hamster. The hamster
was used because it has a regular four day
estrous cycle with day 1, metestrus, indicated by a conspicuous postovulatory
vaginal discharge.
MATERIALS AND METHODS
A simulated altitude of 23,000 feet was
obtained by placing the animals in a hypoReceived Sept. 13, '71. Accepted Dec. 13, '71.
1The research was supported by grant HD04969
from the National Institute of Child Health and Human Development.
zThe author is deeDlv indebted to MIS. Carol
Pehoushek for assistance with all phases of this study.
Technical assistance was also provided by Mrs. Ilona
Ormsby, Mr. Albert Lamperti, and Miss Nancy Adams.
157
158
RICHARD H. PRINTZ
Restriction o f food. Five of the initial
baric chamber. The chamber is cyclindrical with a capacity of 250 1, it was 25 animals lost up to 13% of their body
evacuated so that the rate of air flow weight. In order to determine if this was
through the chamber was 32-34 l/minute. a factor in the high altitude study, a conUnless otherwise noted, animals were trolled feeding experiment was carried out
caged individually and exposures were con- at normal altitude. By restricting the quantinuous except for a daily 15 minute period tity of their food, five animals were caused
when cages were changed and food and to lose 13% of their body weight by day
water replenished ( 5 minutes descent time, 1 of the third cycle. All animals fed the
5 minutes changing time, 5 minutes ascent restricted diet had a vaginal discharge and
time). Except where noted, the animals, had ovaries characteristic of metestrus;
which were 90-120 gm adult female they had fresh corpora lutea indicating
golden hamsters (mesocricetus auratus) ovulation had occurred normally. It was
purchased from the Con Olson Company concluded that up to a 13% loss in body
in Madison, Wisconsin, had access to food weight was not a factor causing a constant
(Teklab hamster diet) and water ad libi- estrus-like blockade of the cycle at high
tum. Body weights were recorded at the altitude.
beginning and end of the experiment.
Gonadotrophin activity in the blockade
Room temperature and a 13 hour light - of the cycle at high altitude. The preced11 hour dark photoperiod were maintained ing experiments suggested that FSH secrefor animals in the chamber, and for con- tion was not affected by high altitude but
trol animals. Control animals were main- that LH secretion was blocked. In order
tained at 650 feet above sea level (altitude to test this hypothesis, ten animals were
of Cincinnati). Daily checks for postovula- maintained in the chamber until such time
tory vaginal discharge were made when as the control animals had reached day
the experiment involved cyclic animals. 4 of the second cycle. Upon removal from
After sacrifice, ovaries, adrenals, uteri, and the chamber, the animals were injected
pituitaries were weighed on a precision subcutaneously with either saline or 10
balance. Ovaries and uteri were preserved I.U. of human chorionic gonadotrophin
in Bouin's fixative and later prepared by which has LH activity. They were then reroutine methods for hematoxylyn and turned to high altitude. Twenty-four hours
eosin staining. Because the results of each later the saline treated animals had polyexperiment suggested the ensuing experi- follicular ovaries (constant estrus-like)
ment, the procedure followed in each ex- while the animals which received HCG
periment is included in the following sec- had ovaries with fresh corpora lutea.
tion of this report.
The question of whether LH synthesis
or LH release was blocked by high altitude
PROCEDURES AND RESULTS
was not directly studied. However, the folBlockade o f the cycle. Beginning on lowing experiment may be pertinent to this
day 1 of the cycle, 25 animals were caged question. After nine days in the chamber,
individually and maintained in the cham- five animals were removed to the control
ber continuously, in minimum groups of environment. Five days after removal from
five, for periods comparable to one to four the chamber (after one 4 day cycle in concycles in control animals. All animals were trols) the animals had a postovulatory dissacrificed on what was day 1 of the cycle charge and had ovaries containing fresh
in the controls, i.e., day 1 of the second, corpora lutea.
third, and fourth cycles during the treatFurther investigation of LH activity in
ment period.
the cyclic animal at high altitude was done
By day 1 of the third cycle, the experi- by studying the combined effects of starvamental animals had become acyclic with tion and high altitude on the cycle. Five
ovarian histology characteristic of constant animals were placed in the chamber and
estrus; there were numerous large unovu- completely deprived of food for a period
lated antral follicles, no fresh corpora of nine days. The animals lost more than
lutea, and the interstitiurn was atrophied 30% of their body weight. Histologically,
(figs. 1, 2).
the ovaries of these animals had no large
159
ALTITUDE AND CYCLIC AND PREGNANT HAMSTERS
follicles. This was comparable to animals
which, for nine days, were starved only
(fig. 3 ) . However, instead of the LH dependent interstitial hypertrophy seen in
nine day starvation studies at low altitude,
ovaries of animals starved at high altitude
displayed an atrophied interstitium (fig.
4). Ovarian weight was markedly less in
starved animals at high altitude than in
starved animals at control altitude (14.4 -C
1.3 mg vs. 24.1 -t 1.9 mg). (Table 1 . )
Uterine weight at high altitude. As an
indication of estrogenic activity, uterine
weights were compared with control animals. Unless the animals were starved,
uterine weights were not affected by high
altitude (table 1).
E f f e c t s of high altitude o n elements of
t h e blood. Hematocrit and hemoglobin
values and reticulocyte counts were obtained for five cyclic animals exposed to
23,000 feet altitude for nine days. The
three blood values were elevated when
compared with control values (table 3).
Effects of high altitude o n pregnancy.
A series of experiments was done to test
the effect of high altitude on pregnancy.
Pregnant animals were exposed to 23,000
feet for various periods of time up to day
12 of the 16 day gestation period. The end
points for this study were maintenance of
pregnancy and changes in ovarian histology. Exposure for four or more days at
any time up to day 12 of pregnancy caused
the death of all fetuses and resorption.
Gross examination of the uteri revealed
comparable numbers of implantation sites
in control and treated animals but in the
treated animals, the fetal swellings were
greatly reduced in size. Histologically the
fetuses of treated animals appeared degenerative. There were numerous leukocytes.
This is demonstrated by comparison of
uterine weights (with fetus in situ) of experimental and control animals (table 2).
When animals were placed in the chamber
on day 12 and removed on the day of gestation, they delivered normal young.
Depending on the length of exposure,
the ovaries displayed varying degrees of
luteal regression; f ollicular development,
characteristic of hamster pregnancy, continued normally (figs. 5-13).
DISCUSSION
In animals maintained at 23,000 feet
simulated high altitude on a normal diet
until day 1 of the third control cycle, follicular development and estrogen secretion
were apparently normal but the absence
of fresh corpora lutea demonstrated that
ovulation was blocked. The ovary resembled the polyfollicular ovary of the
constant-estrus rat (Singh and Greenwald,
'67). Because this histological appearance
is consistent with blockade of LH release
or synthesis by the pituitary, HCG was
given cyclic animals which had been at
high altitude for eight days; unlike saline
it caused the animals to ovulate the next
day (day 1 of the third control cycle). The
effect of high altitude on ovulation was not
permanent; animals maintained at high
altitude for a period of two cycles in control animals were removed to the control
environment. After five days they ovulated
(day 1 of the fourth control cycle).
The previous experiments suggested that
high altitude blocks LH secretion or synthesis but does not affect FSH. As we
TABLE 1
Ovarian and uterine weights of cyclic hamsters at 23,000 feet simulated altitude
Treatment
1
Control
Chamber control 2
High altitude
High altitude
High altitude
Starved control
Starved+ high
altitude
Day of
treatment
Expected cycle day
at sacrifice
Ovarian weight
mg +- S.E.
(no. of animals)
Uterine weight
mg -t S.E.
-
Day 1
Day I, 3rd cycle
Day 1,2nd cycle
Day 1,3rd cycle
Day 1,4th cycle
24.6k1.4 ( 5 )
28.423.2 (4)
21.2-t.1.3 ( 5 )
24.821.9 (5)
24.2-CO.7 ( 5 )
410.0228.2
375.0230.1
352.02 27.6
4OO.O-C-32.1
380.0 4 16.3
Day 1,3rd cycle
Day 1,3rd cycle
24.121.9 ( 8 )
14.421.3 ( 5 )
202.3 2 12.3
200.1 C 13.6
9
5
9
13
9
9
1 Treatment began on day 1 of cycle.
2 In chamber at atmospheric pressure.
160
RICHARD H. PRINT2
'i
TABLE 2
Uterine weights ( w i t h fetuses) o f pregnant hamsters at 23,000 feet simulated altitude
Day of pregnancy
placed in high
altitude
Treatment
Uterine weight
( p m ? S,E.);
No. of animals
Day of pregnancy
sacrificed
Control
High altitude
High altitude
High altitude
-
3
1
14
14
25.401k5.80 (4)
1.7650.04 (5)
0.43 f0.09 (5)
0.48k 0.03 (4)
Control
High altitude
High altitude
High altitude
-
11
11
11
11
7.33e0.70 (5)
3.31'0.12
(5)
0.97f0.08 (5)
0.44 -C 0.03 (5)
1
9
9
2.8720.10 (4)
1.12e0.02 (5)
-
7
3
1
7
7
1.43t0.24 (5)
0.88f 0.10 (6)
0.55k0.07 (5)
5
5
0.85e0.14 (4)
0.47-C-0.08 (5)
14
14
7
7
3
1
-
Control
High altitude
Control
High altitude
High altitude
-
Control
High altitude
1
.
TABLE 3
Blood values of cyclic h m s t e r s at 23,000 feet simulated altitude
Treatment
1
Control 2
High altitude
1
2
Days of
treatment
Expected cycle day
at sacrifice
Hematocrit
( % 2 S.E.)
Hemoglobin
(gm/lOO cm3
2 S.E.)
Reticulocytes
( % -I: S,E. );
No. of ammals
9
Day 1,3rdcycle
Day 1, 3rdcycle
46.8t1.6
65.2e1.9
16.2t0.6
20.6t0.5
1.5e0.1(4)
9.9IkO.1(5)
9
Treatment began on day 1 of cycle.
In chamber at atmospheric pressure.
demonstrated earlier (Printz and Green- hamster. Further evidence for this hypowald, ' 7 0 ) , at control altitude starvation thesis is being sought by measuring plasma
blocks FSH dependent follicular develop- levels of gonadotrophins with radioimment but enhances LH dependent inter- munoassay after similar treatments.
Exposure of pregnant animals to high
stitial growth; because of the interstitial
hypertrophy the absence of follicular de- altitude for four days or more interrupted
velopment does not reduce ovarian weight. pregnancy when exposure was begun on
However, in starved animals maintained days 1-12. Not only did fetal death occur
at high altitude until day 1 of the third but there was extensive luteal regression
control cycle, ovaries displayed an absence in the ovary. Follicular development, charof follicular development and an atrophy acteristic of hamster pregnancy (Greenof the interstitium. This was demonstrated wald, '64), continued normally. In 1967
histologically and by a significant reduc- Greenwald described the minimal comtion in ovarian weight when compared plex of gonadotrophins necessary for mainwith ovarian weights of animals starved tenance of functional corpora lutea of
for a comparable period at control altitude, pregnancy in the hamster; his data demor when compared with ovarian weights onstrate that it consists of FSH and proof control animals.
lactin. That follicular development conBecause of the initial findings, the ex- tinued normally at high altitude, unless
periments with HCG, and results of the the animals were also starved, indicates
studies of starved cyclic animals at high that FSH secretion is not disturbed. Failure
altitude, it is hypothesized that high alti- of luteal maintenance may therefore be
tude selectively blocks LH secretion or due to an inhibition of hypophyseal prosynthesis by the pituitary in the cyclic lactin release. This is further suggested by
z
I
ALTITUDE AND CYCLIC AND PREGNANT HAMSTERS
161
spheric pressures on the activity of the thyroid,
the fact that after day 12, when the
reproductive system and anterior lobe of the
placenta apparently secretes prolactin
pituitary i n the rat. Endocrinology, 33: 366-383.
(Greenwald, '67), pregnancy was main- Greenwald, G. S. 1964 Ovarian follicular detained. Another possibility is that high alvelopment in the pregnant hamster. Anat. Rec.,
148: 605-609.
titude causes the release of a uterine luteo1967 Luteotropic complex of the hamlytic agent which is capable of acting only
ster. Endocrinology, 80: 118-130.
until day 12. Whether prolactin is blocked Monge,
C. 1942 Life i n the Andes and chronic
is presently being studied by transplants
mountain sickness. Science, 95: 79-84.
of pituitaries under the kidney capsule and
1943 Chronic mountain sickness. Physiol.
Reviews, 23: 166-184.
by injections of exogenous prolactin and
Monge, C., M. San Martin, J. Atkins and
progesterone.
J. Castanon 1945 Aclimatacion del ganado
The stimulus for the effects of high alovino en 10s altiplanos andinos. Fertilidad e
titude on the cycle and pregnancy was not
infertilidad reversible durante l a fase adaptativa. Am. Fac. Med. Univ. S. Marcos., 28: 15-31.
identified. Since the animals had elevated
hemoglobin and hematocrit values, several Moore, C. R., and D. Price 1947 Reproduction
a t high altitudes. Anat. Rec., 99: (suppl.), 32.
possibilities are suggested. There could be
1948 A study at high altitude of rea neuroendocrine mechanism involving
production, growth, sexual maturity and organ
weights. J. Exp. Zool., 108: 171-216.
hypothalamic receptors for increased erythropoietin levels, for increased erythrocyte Morales, R. S. 1967 Algunos aspectos de la
fertilidad y fecundidad en la altura. Ginec.
number, or for a reduced oxygen tension.
Obstet. Mex., 22: 1527-1536.
LITERATURE CITED
Atland, P. D. 1947 Effects of discontinuous exposure to 18,000 ft. simulated altitude on the
body weight and breeding behavior of the
albino rat. Anat. Rec., 99: (suppl.), 32.
Cameron, R. G. 1969 Effects of flying on the
menstrual functions of air hostesses. Aerospace Med., 40: 1020-1023.
Donayre, J. 1969 The oestrus cycle of rats at
high altitude. J. Reprod. Fert., 18: 29-32.
Fernandez-Cano, L. 1958 The effects of increase or decrease of body temperature or of
hypoxia on ovulation and pregnancy i n the rat.
Fertil. Steril., 9: 455-459.
Gordon, A. S., F. J. Tornetta, S. A. DAngelo and
H. A. Charipper 1943 Effects of low atmo-
Nelson, D., and M. W. Burrill 1944 Repeated
exposures to simulated high altitude: estrus
cycles and fertility of the white rat. Federation
Proc., 3: 34-35.
Printz, R. H., and G. S. Greenwald 1970
Effects of starvation on follicular development
i n the cyclic hamster. Endocrinology, 86:
290-295.
San Martin, M., M. Atkins and J. Castanon 1945
Aspectos de la fisiologia experimental de la
reproduction en la altura. Am. Fac. Med. Univ.
S. M~ICOS.,
28: 32.
Singh, K. B., and G. S. Greenwald 1967 Effects
of continuous light on the reproductive cycle
of the female rat: induction of ovulation and
pituitary gonadotrophins during persistent
oestrus. J. Endocr., 38: 389-394.
PLATE 1
2B Interstitial tissue from ovary shown in figure 2A. Note the atrophic
appearance with pyknotic clumped nuclei and scanty cytoplasm.
x 445.
2A Ovary of animal maintained a t 23,000 feet altitude until day 1 of the
third control cycle. Note the large unovulated antral follicles (F)
and that there are no fresh corpora lutea; the structure labeled C.A.
resembled a corpus albicans. x 28.
figure 1A. Note the abundant cytoplasm and evenly spaced nuclei.
x 445.
1B High magnification of interstitial tissue in control ovary shown in
1A Ovary of a control cyclic day 1 (metestrus) animal. Note fresh
corpora lutea (C.L.) x 28.
EXPLANATION OF FIGURES
8
Y
Richard H. Printz
ALTITUDE AND CYCLIC AND PREGNANT HAMSTERS
PLATE 1
4B Interstitium of ovary shown in figure 4A. Note the atrophy; there is
clumping of nuclei, pyknosis, and scanty cytoplasm. x 445.
4A Ovary of animal maintained at high altitude (23,000 feet) starved
until day 1 of the third cycle of controls. Note the lack of follicular
development and absence of corpora lutea. The predominant tissue
is also interstitium. X 28.
matin in nuclei, abundant cytoplasm, and lack of pyknosis. A comparison of this photomicrograph with that from control (fig. 1 B )
demonstrates interstitial hypertrophy in the starved animal. X 445.
3B Interstitium of ovary shown i n figure 3A. Note evenly dispersed chro-
3A Ovary of animal at control altitude starved until what would be day 1
of the third cycle. Note the absence of mature follicles or fresh corpora
lutea and predominance of interstitial tissue. X 28.
EXPLANATION OF FIGURES
PLATE 2
1 ce
PLATE 3
EXPLANATION O F FIGURES
5A Ovary of day 7 pregnant control animal. Note the large healthy
corpora lutea. x 21.
5B High magnification of luteal cells from ovary shown i n figure 5A. Note
the regularly shaped cells with abundant cytoplasm.
x 335.
6A Ovary of animal maintained at high altitude during days 3-7 of pregnancy. X 21.
6B Note the early signs of luteolysis. Cytoplasm is reduced, leukocytes
are present, and nuclei are pyknotic and beginning to clump together.
x 335.
7A Ovary from animal maintained a t high altitude during days 1-7 of
pregnancy. Note that follicular development has continued ( f ) but
that the largest corpus luteum (CL) in the ovary is quite small compared to those in the control day 7 ovary (fig. 5A). x 21.
7B Note signs of luteolysis in corpus luteum shown in figure 7A. Cytoplasm is reduced, leukocytes are present, and nuclei are pyknotic.
x 335.
166
ALTITUDE AND CYCLIC AND PREGNANT HAMSTERS
Richard H. Printz
PLATE 3
167
PLATE 4
EXPLANATION OF FIGURES
8A Ovary of control pregnant day 11 animal. X 21.
8B Note the healthy luteal cells. X 335.
9A Ovary of animal exposed to 23,000 feet altitude during days 3-11 of
pregnancy. Note the follicular developnent but corpora lutea reduced
in size. x 21.
9B Signs of luteolysis in corpus luteum labeled in figure 9A are apparent.
x 335.
10A Ovary of animal maintained a t high altitude during days 1-11 of
pregnancy. The largest corpus luteum i n the ovary is very atrophic.
x 21.
10B Details of luteal regression shown in figure 10A. X 335.
168
ALTITUDE AND CYCLIC A N D PREGNANT HAMSTERS
Richard H. Printz
PLATE 4
169
PLATE 5
E X P L A N A T I O N O F FIGURES
11A Ovary of control animal on day 4 of pregnancy.
x 21.
11B High magnification of corpus luteum labeled in figure 11A. X 335.
12A Ovary of animal maintained at high altitude during days 3-14 of
pregnancy. Note reduced size of corpora lutea. X 21.
12B Signs of luteolysis include pyknosis, reduction of cytoplasm, and
leukocytic infiltration. X 335.
13A Ovary of animal maintained at 23,000 feet during days 1-14 of pregnancy. X 21.
13B Note extreme signs of luteolysis in the corpus luteum labeled in figure
13A. Follicular development has continued apparently normally.
x 335.
170
ALTITUDE AND CYCLIC AND PREGNANT HAMSTERS
Richard H. Print2
PLATE 5
171
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