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The effect of Steroids on mitosis and maintenance of pregnancy in spayed rats.

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The Effect of Steroids on Mitosis and Maintenance
of Pregnancy in Spayed Rats '
Department of Obstetrics and Gynecology, and Department of Biology,
Western Reserve University, Cleveland, Ohio
Rats were ovariectomized on the eighth day of pregnancy and either
10 or 20 mg of progesterone, 10 mg of progesterone with 1pg estradiol benzoate or
1 pg estradiol benzoate alone were administered between the eighth and twelfth day.
On the twelfth day tritiated thymidine was injected to study mitoses in the junctional
zone cells of the placenta by autoradiography, and tracings of spontaneous uterine
contractions were made. Twenty milligrams of progesterone daily sustained pregnancy
to the twelfth day in spayed rats as effectively as it was sustained in the untreated
normal rats; 10 mg progesterone daily was less effective and 10 mg progesterone with
1pg estradiol benzoate did not maintain normal pregnancy. Progesterone produced
normal rates of mitosis in the placental trophoblast cells of spayed rats. No correlation was found between the maintenance of pregnancy and decreased contractions
of the myometrium in this study. The injection of 2 0 m g progesterone produced patterns of contraction similar to the normal contraction patterns and differing from
those found in spayed rats and in rats injected with 10 mg progesterone, progesterone
and estradiol benzoate or estradiol benzoate alone. It is concluded that a sufficient
supply of progesterone maintains both normal mitotic activity in the trophoblastic
cells and normal patterns of contraction by the muscle of the uterus.
Ovariectomy of pregnant rats leads to
abortion and resorption of the fetuses. Administration of progesterone aids in the
maintenance of pregnancy but the combination of progesterone and estrogen has
been reported to lead to better maintenance (Zarrow, '61). Bridgman ('48) observed that the twelfth through fifteenth
day of pregnancy is a period of active
mitosis in the placenta and a period of
further development of structures already
present. Jolly ('64) reported that nuclei
of the junctional zone trophoblast cells
incorporated 3H-thymidine between the
twelfth and eighteenth days of gestation.
The purpose of the present study was to
determine the correlation between the mitotic rate of the junctional trophoblast cells
as measured by the uptake of 3H-thymidine and the maintenance of early pregnancy by ovarian steroid hormones in
spayed rats. As additional measures of
steroid effects, records of contraction of
the pregnant uteri and histological studies
of placental and uterine morphology were
also made.
Three line-bred strains of rats, each isolated since 1956, ranging in weight from
200 to 350 gm were used. Female rats
ANAT. REC.,160: 37-46.
from breeding cages were examined for
vaginal plugs twice daily at 9 :30 A.M. and
4: 30 P.M. On the day the vaginal plug
was detected, the rat was removed from
the breeding cage to a cage with other
pregnant females and that day was
counted the first day. On the eighth day,
implantation sites were observed by lightly
anesthetizing the rats and ovariectomy
was also performed. The rats were divided
into six groups (see table 1) and steroid
hormones in peanut oil administered subcutaneously starting on the day of operation as follows: group I - control rats,
no ovariectomy and no hormones given;
group I1 - ovariectomy and 20 mg progesterone daily for four days; group IIIovariectomy and 10 mg progesterone daily
for four days; group IV - ovariectomy
and 10 mg progesterone with 1 p g estradiol benzoate4 daily for four days; group
V - ovariectomy and 1 pg estradiol daily
1 This work was supported by grants TI HD 24 and
A-3061 from the National Institutes of Health, U S .
Public Health Service.
2 Post-doctoral Research Fellow at Department of
Obstetrics and Gynecol?gy, School of Medicine,
Western Reserve University. Present address : Coney
Island HosDital. Brooklvn. New York.
3 Progesterone was obtained through the courtesy
of the Upjohn Company, Kalamazoo, Michigan.
4 Estradiol benzoate solution in oil (PROGYNON)
was obtained through the courtesy of Scherlng Company, Bloomfield, New Jersey.
Effect of steroid hormones o n the maintenance of embryos in the pregnant ruts
between eighth and t w e l f t h days o f gestation
No. of histologically examined embryos
No. of
Total no.
implantation sites
No. of
_ _ _ ~
Bilateral spayed
Prog. 20 mg daily
Bilateral spayed f
Prog. 10 mg daily
Bilateral spayed
Prog. 10 m g
Est. 1 pg daily
No. of
or degenerating
Bilateral spayed
Est. 1 pg daily
for four days; and group VI - ovariectomy
with no supplemental hormones. On the
twelfth day of pregnancy, each rat except
those in group VI was injected intravenously with 3H-thymidine in physiological
saline solution diluted 1: 1. Seventy-five
microcuries of 3H-thymidine were injected
into animals weighing between 200 and
250 gm, 100 UCin those weighing between
251 and 300 gm and 150 UC in those weighing between 300 and 350 gm respectively.
Four hours after the injection of the 3Hthymidine the rats were anesthetized with
ether. The depth of anesthesia was controlled by maintaining the respiration rate
at 100 per minute and tracings of spontaneous uterine contractions were obtained
from all animals using a Cushny smoke
writing myocardiograph. Deeper anesthesia decreased the rate of contractions but
did not change the patterns obtained until
the rat became severely anoxic. The spontaneous uterine contractions were recorded
by attaching the middle portion of the
right uterine horn to the levers of the
myocardiograph so that an implantation
site of the uterus was placed between the
two levers. The uterus was replaced in
the abdomen and the opened abdominal
wall loosely sutured to preserve the body
temperature but not disturb the movement of the instrument. Each recording
was carried out for 15 minutes.
The uterus was removed and fixed in
toto in Bouin’s solution for 24 hours. After
24 hours of fixation, odd numbers of implantation sites, counting from the ovarian end of the left uterine horn, were
taken for specimens. The uterus, embryo
and placenta were bisected parallel to the
long axis of the uterus and fked in Bouin’s
solution for another 24 hours. Specimens
were cut serially at 7 u in a plane parallel
to the long axis of the uterus. Mounted
sections were deparaffinized, dipped in
Kodak NTB-3 photoemulsion in the darkroom and exposed for four weeks before
development. Slides were developed in
Kodak D-19 developer and stained with
Harris’ hematoxglin and eosin. Normal
embryos were in stage 25 on the twelfth
day (Griffith and Farris, ’42).
Gross and microscopic examination of
specimens showed that pregnancy was
well maintained in both normal control
rats and in those ovariectomized and given
20 mg progesterone. Fewer surviving embryos were found in group I11 and most
embryos in group IV were resorbed or degenerating. All implantation sites were
resorbed in group V (table 1). These latter groups were, therefore, very different
in the maintenance of pregnancy from
5 Ha-thymidine was purchased from Nuclear Chicago, Des Plaines, Illinois.
Mean Hs-thymidine index of placental junctional
trophoblast cells with normal embryos in the
pregnant rats o f groups I, I1 and Ill
Normal control
Bilateral oophorecProg.
20 mg daily
Bilateral oophorectomy
I0 mg daily
std. error)
49.362 10.34
55.47k 12.37
55.33 k 13.22
groups I, 11 and 111. Two rats were used
in group VI for uterine contraction studies
only and these had resorbed all implantation sites. Histological specimens for the
study of junctional zone trophoblast cells
were unnecessary in this group. Histological examination of groups I, 11, 111, IV
and V showed that, regardless of the
treatment of the animals, normal implantation sites were not present if the embryo was degenerating or absent.
The percentage of nuclei incorporating
3H-thymidinein 100 junctional zone trophoblast cells (giant cells excluded) was
determined from each normal placenta
with a normal embryo (table 2 , fig. 2).
This was defined as the 3H-thymidine index of the placental junctional trophoblast
cells. Groups IV and V did not maintain
enough embryos to allow comparisons of
their 3H-thymidine indices with those of
other groups. An analysis of variance
showed no significant difference among
the three groups analyzed. The grains per
nucleus in ten junctional zone trophoblast
cells from each normal placenta in these
groups were also determined. An analysis
of variance showed no significant difference in the mean number of grains per
nucleus among the groups. The rate of
uptake of 3H-thymidine by those nuclei
synthesizing nucleic acids was the same
in all groups in the time period studied.
The major difference appears to be in the
number of nuclei in this stage, rats of
groups I, I1 and I11 had numerous cells
while few trophoblast cells were found in
rats of the other groups. Thus, the mitotic
rates of junctional zone trophoblast cells
were stimulated by both doses of progesterone used in this study and were the
same as those of the normal untreated
control rats.
The records of contraction obtained using the Cushny myocardiograph showed
Fig. 1 Tracings of spontaneous uterus contractions with a Cushny myocardiograph on
six different groups of pregnant rats, each tracing is traced for a total of five minutes (1
minute shown on figure). ( a ) Normal control across normal implantation site ( b ) Bilateral
ovariectomy and progesterone 20 mg across normal implantation site ( c ) Bilateral ovariectomy and progesterone 10 mg across normal implantation site ( d ) Bilateral ovariectomy and
progesterone 10 mg and estrogen 1 +g across abnormal implantation site ( e ) Bilateral
ovariectomy and estrogen 1 pg across implantation scar ( f ) Bilateral ovariectomy and no
hormone supplement with no implantation, (Horizontal contractions of the uterus are
magnified 7 x to the vertical tracings on the record. Contraction height is indicated by the
2 cm scales on the record.)
variability among rats in each group in is shown by the fact that the lower dose
both rate and amplitude of the contrac- of progesterone produced both lower rate
tions. However, records from all groups and amplitude of contractions than the
could, without difficulty, be separated into normal control or the higher dose of prothe injection groups on the basis of their gesterone.
contraction pattern alone. The records preThe mean height of surface epithelial
sented were chosen because they were cells of the uterus was determined by
considered to be typical representatives of measuring the height of ten cells in the
those obtained in each group (fig. 1 ) . The antimesometrial area of each uterus to
spontaneous uterine contraction pattern of aid in evaluating the biological actions of
groups I and I1 (fig. la,b) were similar
but group 111 showed both lower ampli- the steroid hormones used (table 3). Group
tudes and frequencies of the contractions V showed markedly higher cells when com(fig. l c ) . Groups IV and V had similar pared with the other four groups (fig. 3).
amplitudes and durations of contractions The differences among all groups were
but in group V the contractions were more statistically significant (table 4). Since
frequent than in group IV (fig. Id, e). the difference is an expected one, rats
Group VI showed the most frequent con- injected with progesterone and estrogen,
tractions of the uterus among the six progesterone alone and normal rats were
groups studied but the amplitude was very also analyzed (table 5). This analysis
small in this respect, similar to group I11 showed that group I had higher surface
(fig. l f ) . Thus, progesterone did not in- cells and that there was a significant difhibit uterine contractions but rather im- ference between the groups. It is interestposed a pattern which was neither that of ing that the surface cells of group IV
the untreated ovariectomized animal nor (fig. 4) were not as high as those of either
that of the estrogen treated animal. This the normal controls or those of group V.
Mean height of surface epithelial cells of the uterus i n groups I , 11, I l l , IV and V
Height ( a )
of uterine
epithelial cells
(Mean and
std. error)
Normal control
20.802 0.77
Bilateral oophorectomy and Prog.
20 mg daily
19.41zk 0.48
Bilateral oophorectomy and Prog.
10 mg daily
18.862 0.43
Bilateral oophorectomy and Prog.
10 mg and Est. 1 pg daily
Bilateral oophorectomy and Est.
1 pg daily
Analysis o f variance o f the height of surface epithelial cells of the uterus
among groups I, 11, I l l , IV and V
Sum of
Between groups
Degrees of
Within groups
P < 0.01
Analysis of variance o f the height of uterine surface epithelial cells
among groups I, 11, I11 and IV
Degrees of
Sum of
Between groups
Within groups
In normal embryos all tissues of the
embryo proper incorporated 3H-thymidine.
Incorporation was especially notable in the
ependymal layer of the nerve cord of the
embryo. However, if the embryo was degenerating, the incorporation of 3H-thymidine by its tissues was poor although some
cells still incorporated it. Similar findings
were observed in the yolk sac and fetal
placenta. The fetal placenta, syncytial
cells in the labyrinth, junctional zone cells
and giant cells in the area between the
junctional zone and decidua were well labelled regardless of group differences as
long as the embryo and placenta were normal. Giant cells located in the area of the
antimesometrial and lateral uterine lumen,
and decidual cells were not labelled in
any of the rats studied. Endothelial cells
lining the maternal blood vessels, uterine
epithelial cells and myometrial cells incorporated 3H-thymidine regardless of the
presence or absence of the embryo and
Embryonal tissue was resorbed first then
the placenta itself. In the placenta, the
labyrinthine area showed degeneration
first and was resorbed, followed by the
junctional zone, giant cells and finally the
decidua. It was particularly noticeable
that in placentae of group IV syncytial
cells broke through the layer of giant cells
and penetrated directly into the decidua
to a distance of 512 CI from the layer of
giant cells (fig. 5). Some placentae of
groups I, I1 and 111, whether intact or degenerated, showed a break-through penetration of syncytial cells. In these groups,
the syncytial cells were present along the
walls of the maternal blood vessels in the
decidua, adjacent to the layer of giant
cells, formed around large sinuses and
never penetrated into the decidua farther
than 300 (most of them less than 100 v)
< 0.025
from the layer of giant cells. In group IV,
syncytial cells were invading the decidua
independently of maternal blood vessels
and were not found in the walls of the
sinuses. These forerunning syncytial cells
were not labeled with 3H-thymidine. In
all four groups, it was observed that the
walls of some of the maternal blood vessels in the decidua were lined with syncytial cells, some of which were hyperplastic and, sometimes, occluded the
lumen of the vessel completely, forming
islands of syncytial cells. This phenomenon seemed to be more prominent in
groups I and IV. In all cases, the penetration of syncytial cells into the uterus was
confined to the decidual area and, in no
instance was there penetration into the
other layers of the uterus.
Daily treatment of the pregnant rats
spayed on the eighth day with 20 mg progesterone maintained normal pregnancy,
but the incidence of resorption was higher
when the daily dose was 1 0 m g progesterone. Lerner et al. ('62) reported that the
combination of 10 mg progesterone with
1 vg estrone sustained 100% gestation to
the twentieth day in rats ovariectomized
on the eighth day but microscopical observations of either embryos or placentae
were not included. Yochim and Zarrow
('61) noted that optimal fetal maintenance in the rat (90% survival at least)
could be attained at estrogen: progesterone ratios of 1:5000 - 1:50,000. However, this optimal maintenance in these
dose ratios was dependent on the species
studied, the dosage schedule as well as
the total dose, and the estrogen and progesterone esterification products used. In
our study, only five out of 20 embryos and
placentae were normally maintained in
rats spayed the eighth day and treated
with estradiol benzoate and progesterone
in a dose ratio of 1:10,000. Interactions
between estrogen and progesterone also
vary markedly with the organs studied
(Courrier, ’50). Thus, an estrogen : progesterone ratio of 1:1000 may be synergistic at low doses but antagonistic at
higher doses because part of the progesterone may not affect the tissue and, therefore, the ratio is not effectively reached.
Yochim and Zarrow (’61) suggested that
suboptimal maintenance may be the result
of the following : hormone deficiency (decreased absolute levels), progesterone deficiency (estrogen antagonism), estrogen
deficiency (suboptimal synergism) or hormone excess (increased absolute levels).
In this study, suboptimal maintenance in
group IV may be attributed to any of these
reasons as well as animal differences since
one rat in four under this treatment maintained pregnancy with normal implantation sites.
The mitotic cycle of a multiplying cell
population can be divided into growth
(GI), synthesis ( S ) , second growth (Gz)
and mitotic phases. Deoxyribonucleic acid
synthesis is restricted to the S-phase and
the synthesis rate is sometimes equated
with the mitotic index of dividing cells.
When cells are exposed to 3H-thymidine
all cells in the S-phase should take up the
isotope into DNA which is then being
synthesized in their nuclei (DeRobertis
et al., ’65). There was n o difference in
the uptake of 3H-thymidine and, presumably, the mitotic rates of placental junctional zone trophoblast cells between normal control rats and spayed rats injected
with either 10 or 20 mg progesterone. Progesterone appeared to maintain the normal mitotic rates but did not increase
these rates above the normal level. The
increased placental weight found in
spayed pregnant rats maintained on progesterone (Alloiteau and Acker, ’62)
appears to be due to hypertrophy of cells,
increased extracellular fluid and, in the
placenta, increased blood rather than to
hyperplasia of the trophoblastic cells.
Thus, in this study, a sufficient supply of
progesterone prevented degeneration and
resorption of the embryo and placenta in
rats spayed in early pregnancy and this
was due, in part, at least, to the maintenance of normal mitotic rates in the placenta.
Distortion of the fetus has been reported
following ovariectomy in the rat (Haterius, ’36) and it has been suggested that the
operation resulted in compression which
caused death, Frazer (’55) reported that
when pregnant rats were spayed on the
fifteenth day and at the same time certain
conceptuses, with amnia intact, were freed
from the uterine tension by incisions of
the uterus, twice as many freed fetuses
survived in both spayed and normal
mothers as in the intact uteri of spayed
mothers. The death of the freed fetuses in
both spayed and normal mothers were
associated with hydramnios. Among living
freed fetuses a greater increase in amniotic fluid was found in spayed than in
normal mothers possibly caused by an inadequate transfer of fluid across the
placenta as a result of adhesions and the
increased tone of the uterine circular
muscle. Csapo (’56) reported a series of
experiments showing the action of estrogen
and progesterone on uterine myometrium.
He proposed the concept of the “progesterone block.” In later work, on single muscle
fibers from rabbit uteri (’65), he has
suggested that progesterone suppresses
electrical activity of the muscle fibers and
restricts it to the point of origin. Weakening of the “progesterone block causes
moderate electrical activity with very
limited spread. However, Kao and Siegman (’63) found that myometrial strips
isolated from rats injected with progesterone had an earlier appearance of active
transport phenomena than strips from
estrogen treated rats which had a large
passive redistribution of both sodium and
potassium ions before the active phase took
effect. Marshall (’59, ’62) observed that
single fibers from the esterogen-dominated
uterus had membrane potentials near the
threshold for spontaneous discharge. These
uteri also had well synchronized action
potentials which led to regular thythmic
contractions. In contrast, the progesteronedominated uteri had weak irregular spontaneous contractions which could occur
without action potentials preceding them.
Some fibers did not become active at all,
others became active only when some ten- in animals injected with both estrogen
sion was developed. Pacemakers were pres- and progesterone. On the other hand, the
ent in both types of muscle but were more activity of the uterine muscle showed the
labile in fibers from progesterone uteri and estrogen effect. Thus, there is a differential
in these uteri well synchronized electrical sensitivity of various tissues in the uterus
discharges conducted over long distances to both steroid hormones and to the interwere not present. Pacemakers of the estro- action of the hormones at the cellular level.
gen-dominated uteri were localized to Apparently the interaction of the hormones
either the ovarian end or the cervical end. prevented hypertrophy of the epithelial
Our data on intact uteri and those of cells while inducing elements of an estroothers (Hendricks et al., '61; Henry and gen contraction pattern in the muscle cells.
Browne, '43; Kao and Nishiyama, '64; Whether the break-through penetration of
Pose and Fielitz, '59) do not support the syncytial cells described for the estrogenconcept of a "progesterone block as pro- progesterone group (IV) is a phenomenon
posed by Csapo. Groups I, 11, and I11 show of the interaction of these hormones at the
well developed myometrial contractions cellular level or a common process of
although each recording was taken across placental degeneration is a problem which
an implantation site. Group VI shows less must be further explored.
well organized activity but all embryos
were resorbed. Our results also show that
The senior author wishes to express his
progesterone given to spayed rats in
higher doses seems to increase the activity sincere gratitude to Professor Kenneth J.
of the myometrium toward that shown by Ryan, Department of Obstetrics and Gynenormal uteri during pregnancy. Haterius cology, Western Reserve University, whose
('36) suggested that the pattern of con- support made this study possible. Thanks
traction of the pregnant uterus is necessary are also due Drs. G. W. Bartelmez, M. X.
to aid proper circulation through the Zarrow and Eugene Spaziani for their
maternal blood sinuses. The differences criticism of the manuscript.
observed above in contraction patterns of
uteri treated with different steroids are
and G. Acker 1962 Le Controle
probably due to differences in permeability
du poids placentaire par les hormones ovarienof the muscle membrane and, therefore, to
nes chez la Ratte. Compt. Rend. Acad. des
the electrical activity produced by estrogen
Sci., 254: 3901-3903.
and progesterone. Since transmembrane Bridgman, J. 1948 A morphological study of
the development of the placenta of the rat. J.
resting potentials are a measure of the
Morph., 83: 195-215.
permeability to potassium ion, it is inter- Courier,
R. 1950 Interactions between estroesting that records obtained from myogens and progesterones. Vitamins and Hormetrial fibers from spayed rats had the
mones, 8: 179-214.
lowest potentials, those from estrogen- Csapo, A. I. 1956 The mechanism of effect
of the ovarian steroids. Recent Progr. Hortreated rats higher potentials, while those
mones Res., 12: 405431.
from progesterone-treated rats had the Csapo, A. I., and H. Takeda 1965 Effect of
highest (Kao and Siegman, ' 6 3 ) . None of
progestrone on the electric activity and intrauterine pressure of pregnant and parturient
these experiments shows suppression of
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electrical activity as reported by Csapo for
E. D. P., W. W. Nowinski and F. A.
fibers from rabbits injected with progester- DeRobertis,
Saez 1965 Cell Biology. 4th Ed. p. 291.
one. This may be a species specific effect
W. B. Saunders Co., Philadelphia.
but the literature indicates that it is not Frazer, J. F. T. 1955 The mechanism of fetal
loss after pregnant rats are spayed. J. Physiol.,
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130: 253-256.
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induced in both normal pregnancy and in
i n Laboratory Investigation, p. 57, 61. J. B.
spayed animals injected with progesterLippincott, Philadelphia.
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The measurement of height of uterine
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Kao, C. Y., and A. Nishiyama 1964 Ovarian
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Pose, S. V., and C. Fielitz 1959 Proceedings of
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Editor. Williams and Wilkins Co., Baltimore.
A portion of the junctional zone of a normal placenta. Nuclei of the
trophoblast cells showing incorporation of 3H-thymidine. x 800.
Uterine epithelium of a group V female (ovariectomy and estradiol
benzoate 1 pg). X 320.
Uterine epithelium of a group IV female (ovariectomy and progesterone 10 mg and estradiol benzoate 1 pg). x 320.
A portion of the decidua of a group IV female with a degenerating
embryo. Syncytial cells with dark stained cytoplasm (left middle)
have invaded the decidua independently of blood vessels. x 320.
Yong Jim Kim and Darhl Foreman
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pregnancy, steroid, effect, mitosis, maintenance, spayed, rats
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