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Species differences in egg transport in response to exogenous estrogen.

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Species Differences in Egg Transport in
Response to Exogenous Estrogen
GILBERT S . GREENWALD
Departments of Obstetrics and Gynecology and Anatomy,
University of Kansas Medical CenteT, Kansas City, Kansas
The effect of exogenous estrogen on tubal transport of ova was deABSTRACT
termined in the guinea pig, hamster, mouse, rabbit and rat. T h e animals were given a
single injection of estradiol cyclopentylpropionate ( E C P ) shortly after mating. The
dose of ECP required to interrupt pregnancy in 80% or more of the animals was as
follows: guinea pig (10 fig); hamster (25 p g ) ; mouse (1 fig); rabbit ( 5 0 pg); rat
(10 pg). Acceleration of egg transport through the oviduct occurred after the following doses of ECP: guinea pig (50-100 pg); hamster (100 pg); mouse (1 pg and
above); rabbit (25 pg); rat (10 pg and above). Hence, the amount of estrogen which
accelerates egg transport in the guinea pig and hamster is considerably higher than
the dose which interrupts pregnancy.
Retention of ova for longer than the normal period of tubal passage (tube-locking)
resulted from the following doses of ECP: guinea pig (250 pg); hamster (250 pg);
mouse (1pg); rabbit (100 pg); rat (no dose). In the species i n which ova were tubelocked, the majority of eggs were located a t the ampullary-isthmic junction rather
than the utero-tuba1 region of the oviduct.
Tube-lockjng of ova was never observed in the rat; ECP always caused premature
entry of eggs into the uterus and eventual expulsion per uaginam. For example, eggs
passed through the cervix by 12 hours after the administration of 250 fig ECP at day 1
of pregnancy.
The effectiveness of estrogens in interrupting pregnancy in the mouse and rat
was first shown by Parkes and Bellerby
('26) and Smith ('26). A fruitful period
of research occurred during the next decade, culminating in the work of Burdick
and associates (Burdick and Pincus, '35;
Whitney and Burdick, '36, '38; Pincus and
Kirsch, '36). These investigations were
mainly concerned with the effect of exogenous estrogen on egg transport in the
mouse and rabbit. The major findings were
that moderate doses of estrogen retained
eggs in the oviduct for longer than the
usual period of tubal passage (henceforth
referred to as tube-locking) : however,
large doses of estrogen accelerated transport so that ova were prematurely expelled
from the oviduct into the uterus.
There has recently been renewed interest in the effect of estrogen on pregnancy
in rodents. Most of these studies have used
as an endpoint the number of young delivered at term or the number of embryos
present at 8-10 days past coitum. In view
of the numerous pre-implantation events
affected by estrogen, such studies quite
ANAT. REC., 157: 163-172.
obviously shed little light on the mechanisms responsible for embryonic mortality. Several studies from this laboratory
have considered the effect of exogenous
estrogen on egg transport in the rabbit and
rat. Contrary to the initial reports, small
doses of estrogen in the rabbit expelled ova
from the reproductive tract and large doses
caused tube-locking (Greenwald, '57,'59,
'63). It is of interest that the block to egg
transport was located at the level of the
ampullary-isthmic junction rather than the
utero-tuba1 junction (Greenwald, '61a). In
the rat, effective doses of estrogen always
caused premature entry of eggs into the
uterus; no dose was found which retarded
egg transport through the oviduct (Greenwald, '61b). Several authors have postulated that in the rat tube-locking is responsible for the embryonic mortality that
follows estrogen treatment. However, the
concept of tube-locking is based on the
mouse and there is no evidence to substantiate its existence in the rat. The guinea
pig is the only other species in which the
effect of estrogen on tubal transport has
been determined (Deanesly, '61 ) Over the
.
163
164
GILBERT S. GREENWALD
dosages utilized, estrogen induced premature entry of guinea pig eggs into the
uterus; higher doses which might have
been expected to cause tube-locking were
not tested.
The present report was designed to compare the effects of estrogen on egg transport in five species: guinea pig, hamster,
mouse, rabbit and rat. It was felt that the
uniformity resulting from the use of a
single estrogenic preparation, administered over the same dosage range to all
five species, combined with a standard
method to recover ova from the reproductive tracts would considerably enhance the
value of such a study. The specific objectives of this investigation were to ( 1 ) determine the dose of estradiol cyclopentylpropionate (ECP) required to interrupt
pregnancy, when given as a single injection shortly after mating; ( 2 ) to ascertain
whether the embryonic mortality following
estrogen treatment was attributable to acceleration of egg transport and/or tubelocking of ova, and ( 3 ) to localize the site
in the oviduct at which ova are trapped if
tube-locking does occur.
MATERIALS AND METHODS
Positive smear or vaginal plug) with different doses of ECP; ova were flushed
from the reproductive tract during the
next 2 to 5 days. Sixty-one guinea pigs of
a mixed strain were placed with fertile
males on the night of full vaginal cornification. Mating was either observed or confirmed by the presence of sperm in the
vagina by the next morning (day 1 of
pregnancy). Animals were then injected
subcutaneously with 1 to 250 ug ECP. In
contrast to the other species in which ova
were recovered by flushing via the ostium
tubae abdominale, eggs were recovered
from the guinea pig by inserting the 30
gauge needle into the oviduct via the uterotubal junction.
Tube-locking of ova was observed in the
guinea pig, hamster, mouse and rabbit. To
determine the region in the fallopian tube
at which ova were blocked, the oviduct was
divided into three segments : ampullaryisthmic region, isthmus and utero-tuba1
junction. Each segment was then flushed
with 0.9% physiologic saline. The ampullary-isthmic region consisted of the ampulla and the contiguous first loop of isthmus; the utero-tuba1 junction contained
the tip of the uterus and the adjacent segment of isthmus.
All doses of estradiol cyclopentylpropionate were injected in 0.1 ml cottonseed
oil. Additional experiments are described
in appropriate sections of the text.
A total of 45 New Zealand giant white
rabbits were used in the experiments. The
does were mated twice to males of proven
fertility and immediately post coiturn given
a single intramuscular injection of 25 to
250 wg estradiol cyclopentylpropionate
RESULTS
(ECP). During the next five days, rabbits
Guinea pigs were given a single injecwere killed by intravenous injection of
5 ml sodium pentobarbitone. The location tion of cottonseed oil or ECP on the mornof tubal ova was determined by a previ- ing of sperm-positive vaginal smears. At
ously described method (Greenwald, '61a). laparotomy, 12 to 15 days later, only half
Sprague-Dawley rats of the Holtzman of the animals treated with 1 vg ECP were
strain (66 animals) were caged with males pregnant whereas five of six pregnancies
and on the morning that sperm were found were terminated by 10 vg of the hormone
in the vaginal smear (designated as day 1 (table 1). However, regressing avascular
of pregnancy) the females were injected corpora lutea were observed in the ovaries
subcutaneously with 1 to 500 vg of ECP. of a number of the ECP-treated animals
The animals were killed at various inter- SO that it appeared likely that the interrupvals during the preimplantation period by tion of pregnancy was due to a luteolytic
an overdose of ether. The oviducts and action of ECP rather than to its effects on
cornua were flushed separately with physi- egg transport.
The former explanation was apparently
ologic saline by a 30 gauge needle attached to a 0.5 ml tuberculin syringe. confirmed when the location of ova was
Similarly, 69 golden hamsters and 70 determined following ECP treatment. In
white swiss mice were mated and injected control animals (injected with cottonseed
subcutaneously on day 1 (day of sperm oil) ova were present in the oviduct on
165
ESTROGEN AND EGG TRANSPORT
TABLE 1
Effect of ECP on pregnancy in the guinea pig
Mean no.
embryos
(+- SE)
Trealment
at day 1
No. of
animals
0.1 ml cottonseed oil
7
6
3.5 f0.86
-
1 p g ECP
8
4
3.0f0.58
3 animals with regressing
corporalutea (C.L.)
10 p g ECP
6
1
3.0
4 animals with
regressing C.L.
1 Laparotomy
No.
pregnant
1
Remarks
at 12 to 15 days P.C.
TABLE 2
Effect of ECP
Time
examined
(days p.c.1
OR
ova distribution in the guinea pig
No. of
Location
of ova
3
4
3
5
oviduct ( 3 )
oviduct (3)[
uterus ( 2 ) J
2-4 celled ova; x’ no. eggs = 2.7
3
1
4
1
oviduct
uterus
-
3
4
2
1
oviduct
uterus
.-
50 pg ECP
3
4
3
2
oviduct
missing
E no. eggs = 2.0
100 p g ECP
3
4
1
7
oviduct
missing
-
250 pg ECP
4
7
oviduct ( 5 )
missing (2)
-
oviduct ( 3 )
missing ( 1 )
-
Treatment
at day 1
Controls
1 pg ECP
10 p g ECP
5
1
4
Remarks
12-16 celled ova
no eggs in tract
no eggs in tract
._
-
No. in parentheses = no. of animals in thls category.
day 3 p.c. (table 2). By the morning of
day 4, eggs began to enter the uterus
although in some animals they were still
present in the oviduct. Following the injection of 1 to 50 Vg ECP ova were still
located in the oviduct by day 3. However,
with 50 or 100 vg ECP, ova were absent
from both the uterine tubes and horns by
day 4. These doses presumably accelerated
egg transport to the extent that ova were
expelled from the reproductive tract. Tubelocking of guinea pig ova occurred after
the injection of 250 vg ECP at day 1, although in a few instances no eggs were
found in any portion of the tract (table 2).
The oviduct was sectioned at day 5 in
three animals which received 250 pg ECP.
Normal morulae were recovered from all
animals ( 2 , 3 , 3 eggs) from the ampullaryisthmic region of the tube, which lies approximately 4 cm above the utero-tuba1
junction.
Effectsof ECP on pregnancy in
the hamster
The hamster was much more resistant
to the deleterious effects of ECP than the
other species that were investigated.
Neither 1 nor 10 pg ECP interrupted pregnancy (table 3) but 25 to 100 pg of the
hormone terminated pregnancy in every
animal. Treatment with 25 vg or more of
ECP led to the regression of the corpora
lutea of pregnancy; they were represented
166
GILBERT S. GREENWALD
TABLE 3
Effect of ECP on pregnancy in the hamster
Treatment
at d a y 1
No. of
No.
animals pregnant
1
Mean no.
embryos
Remarks
(._
+ SE)
~~I
1pg ECP
10 Fg ECP
25 pg ECP
50 p.g ECP
100 gg ECP
4
4
4
4
0
4
4
0
0
4
1 Hamsters killed
10.0-+0.71
11.0* 1.08
-0-0-
-0-
-
2/4 with corpora albicantia (CA)
4/4 with CA
4/4 with CA
at eight days p.c.
TABLE 4
Effect of ECP on ova distTibution in the hamster
Treatment
at day 1
Controls
Time
examined
No. of
(days P.c.)
Location
of ova
Remarks
2
3
4
3
3
3
oviduct ( 3 )
oviduct ( 3 )
uterus ( 3 )
2 celled eggs
4-8 celled eggs
beginning of nidation
25 gg ECP
5
3
oviduct and uterus ( 3 )
4-8 celled eggs
50 pg ECP
3
3
4
3
oviduct and uterus (3)(
no eggs recovered
J
14 eggs - oviduct
116 eggs - uterus
100 pg ECP
2
3
3
oviduct ( 3 )
no eggs in tract (3)
j ; no. eggs
250 fig ECP
2
2
3
4
38
4
3
5
oviduct (2 )
oviduct (3)
missing ( 1)
oviduct ( 3 )
oviduct (4)
missing ( 1)
3
-
= 10.7
- eggs = 10.0
-xx no.
no. eggs = 2.3;
4celledeggs
--xx no.
no. eggs = 9.3
eggs = 3.3;
blastocysts and degenerating
ova
5
3
oviduct ( 3 )
NO.in parentheses = no. of animals inthis category.
Cornua ligated at day 1.
-
;no. eggs = 3.3; ova
degenerating
in the ovary on day 8 by small, avascular locking of ova. However, from day 3
on very few ova were retained in the falcorpora albicantia.
The normal rate of egg transport was lopian tubes and it seemed plausible that
determined in a series of uninjected ham- the missing ova had already entered the
sters. Ova were present in the oviduct on uterus before being expelled from the tract.
day 2 and the morning of day 3, but they To test this possibility, the oviducts of
entered the uterus by the afternoon of three ECP-treated animals were ligated at
day 3 (table 4). Blastocysts could no the utero-tuba1 junction on day 1. When
longer be flushed from the uterus by day 4 killed two days later, the normal compleindicating that nidation had begun. A ment of ova were found in the ligated
single injection of 50 vg of ECP accel- tubes (table 4).
The specific site at which hamster ova
erated the rate of transport; healthy blastocysts in normal numbers were present in were retained was determined by sectionthe uterus on day 3. Following treatment ing the oviduct into three segments (table
with 100 pg ECP, two-celled eggs were in 5 ) . The results indicate that the majority
the oviduct on day 2 but ova were missing of eggs were trapped at the ampullaryfrom the tract by day 3. A single injection isthmic junction and not in the proximity
of 250 pg of the hormone caused tube- of the utero-tuba1 junction. By day 4, some
167
ESTROGEN AND EGG TRANSPORT
of the tube-locked ova were still normal
but all eggs had degenerated by the next
day.
TABLE 5
Site of tube-locking of ova i n hamster'
Day
oviduct
sectioned:
Day4
Day5
No. of hamsters:
4
4
No. with tube-lockedova:
4
4
122
4
2
0
0
Location of ova:
1. Ampullary-isthmicjunction
(MS)
2. Isthmus
3. Utero-tubal junction
( UTJ 1
1
a
92
Hamsters injected with 250 pg ECP at day 1.
No. of ova recovered from each segment.
Effect of ECP on mouse pregnancy
A single injection at day 1 of 0.1 pg
ECP had no more effect on pregnancy in
the mouse than the injection of cottonseed
oil; the percentage of pregnant animals
and mean number of embryos did not
differ between the two groups (table 6).
Pregnancy was interrupted in every instance on increasing the dose of ECP to
1 wg.
In control mice, ova were present in the
oviduct on the morning of day 3 but all
o n pregnancy i n the mouse
eggs migrated into the uterus by the next
morning (table 7). After the injection of
Mean no.
No. of
No.
0.1 vg ECP, ova were retained in the ovianimals pregnant 1
Tybg~ duct
at day 4 in over half the animals
(table 7) and an average of 5.6 normal
6
4
9.3& 0.85 appearing blastocysts were recovered.
6
4
11.0f0.41 Treatment with 1 pg ECP resulted in tubal
retention of ova in five mice, with an aver6
0
age of five blastocysts per animal. However, in four additional animals, no eggs
days p.c.
TABLE 6
Effect of ECP
Treatment
at day 1
~~
0.1 ml cottonseed oil
0.1 pg ECP
1 pg ECP
1 Mice
killed 9-12
TABLE 7
Effect of ECP on ova distribution in mice
Treatment
at day 1
Cottonseedoil
0.1 fig ECP
1 pg ECP
Time
examined
(days P.c.)
N?.
Location
of ova
Of
3
4
5
2
3
4
1
7
3
2
4
10
Remarks
oviduct ( 2 )
uterus ( 3 ) l
uterus (2)J
4-8-celled eggs
blastocysts
uterus
oviduct ( 4 )
uterus (2)
no eggs (1)
oviduct (5)
uterus (1)
missing ( 4 )
-
-
-
-
-
no eggs in tract
10 pg ECP
4
5
missing ( 5 )
no eggs in tract
100 fig ECP
4
4
missing ( 4 )
no eggs in tract
1
No. of animals in this category.
TABLE 8
Location of tubal ova in mice at day 4 after ECP treatment
Dose of ECP
at day 1
No: of
mice
No. with
tubal ova
Tuba1 ova/
animal
Location of tubal ova 1
AIJ
Isthmus
UTJ
0.1 fig
5
2
1.5
0
0
3
1.0fig
16
11
4.2
27
10
9
Actual number of eggs recovered from each segment.
168
GILBERT S. GREENWALD
were recovered from either the oviduct or
uterus. With 10 or 100 vg ECP, no ova
were found in the reproductive tracts by
day 4.
Attention was next directed to the specific site in the oviduct at which ova were
tube-locked on day 4 p.c. (table 8). The
results indicate that a single injection of
0.1 clg ECP at day 1 was relatively ineffective in retaining ova in the tubes; the few
ova present were clustered at the uterotubal junction. However, following the administration of 1 ug ECP, considerably
more ova were tube-locked, with the majority recovered at the ampullary-isthmic
junction. For the 1 ug ECP group, the
average number of eggs found on sectioning the oviduct into three portions was
similar to the number recovered following
flushing of the tube in toto. On the other
hand, there was a discrepancy between the
number of eggs collected by the two methods in mice receiving only 0.1 vg ECP. The
fewer ova recovered from these mice could
be attributed either to the small number
of animals sampled or to possible loss of
ova at the time that the oviduct was divided. Vigorous contractions of the muscular isthmic and utero-tuba1 areas might
expel ova from the divided oviduct. This
phenomenon apparently also occurs in the
rabbit since there is a discrepancy in the
number of ova recovered from the lower
isthmus when eggs are flushed from the
intact or divided tube (Greenwald, '61a).
TABLE 9
Effect of ECP on pregnancy in the rabbit'
Dose
1Pg
10 ag
25 /a
50 ag
100 Pg
250 pg
No.
No. of
animals
pregnant
6
6
6
6
6
6
6
3
3
1
0
0
Mean no. of
embryos
I + SE',
8.332 1.02
3.17% 1.45
1.50-tO.80
0.33t0.33
0.0
0.0
Modified from Greenwald ('63).
mating, resulted in a marked disparity between the number of corpora lutea and
embryos by eight days post coitum (table
9). Of 18 rabbits given from 50 to 250 vg
of ECP, only one animal remained pregnant; 25 clg was almost as effective in interrupting pregnancy.
The oviduct was flushed during the first
five days after ovulation to ascertain
whether disturbances in the rate of egg
transport could account for the embryonic
loss. Ova normally remain in the oviduct
for 72-75 hours p.c. before entering the
uterus (Boving, '56). By 48 hours after
mating, most of the eggs passed through
the oviducts of rabbits given 25 ug of ECP
(table 10). On the other hand, treatment
with 100 or 250 vg of the hormone leads
to retention of ova in the fallopian tube,
primarily at the ampullary-isthmic region
of the tube. All eggs had degenerated by
day 5 .
Effect of ECP on pregnancy in
the rat
Effect of ECP on pregnancy in
the rabbit
The effect of a single injection of ECP
A single intramuscular injection of 10 on rat pregnancy is summarized in table
ug ECP, administered immediately after 11. The administration at day 1 p.c. of 5
TABLE 10
Location of ova in the rabbit after ECP treatment
Location
of ova in
oviduct
62
12
AIJ (9)
Isthmus ( 3 )
4
31
23
AIJ (21)
Isthmus (2)
4
37
28
AIJ (20)
Isthmus (8)
Day
killed
No. of
animals
25 fig
3
7
100 Pg
5
250 cLg
5
1 Day
1 = day of mating.
Total
no. of
Total
no. eggs
recovered
Dose of EqP
at day 1
* No. of ova recovered from each segment.
lutea
169
ESTROGEN AND EGG TRANSPORT
uterine eggs were recovered from only one
of five rats. With higher doses of ECP, ova
were missing from both the oviducts and
No.
cornua at day 5. Thus, ECP in the doses
Treatment
~ o . o f pregnant
ys:g
at day 1
animals
(9-11
utilized, never produced tube-locking of
days P.c.)
(*SE)
ova.
0.1 ml cottonThe results suggested that, if anything,
4
4
10.5 k2.9
seed oil
exogenous estrogen in the rat caused pre4
4
11.3 42.8
1 pg ECP
mature entry of ova into the uterus and
thence their expulsion per vaginum. To
4
3.9
C
1.7
8
5 fig ECP
test this possibility, rats given a single in1
0.4 f0.37
8
10 p g ECP
jection of 250 pg ECP were killed at progressively earlier times and the reproduc1 Modified from Greenwald (’61).
tive tract examined for ova. The results
TABLE 12
(table 13) indicate that ova disappeared
Location of ova in the rat after ECP treatment
by day 2 P.c.; i.e. 24 hours after the injecTime
No. of
tion of 250 pg ECP. Ova still embedded in
Treatment examined No’ Of animals
(days P.c.)
with ova
granulosa cells were recovered from the
oviduct, five hours after the administration
Controls
2
1
1
oviduct
of
ECP but by 12 hours, most of the eggs
4
3
3
oviduct
were no longer in the tract. An additional
5
6
6
uterus
5
0.1pgECP
5
5
uterus
group of three mated rats were injected
5
5
1pgECP
4
uterus
with 250 pg ECP and the cornua then
10mECP
5
5
1
uterus
ligated at the cervical end (table 13).
When killed 12 hours later, eggs were recovered from the uterus, a site normally
not reached until days 4 to 5 p.c. The obor 10 pg ECP interrupted pregnancy in al- vious conclusion is that egg transport in
most every animal. The rats were pseudo- the rat is extremely sensitive to estrogen
pregnant on the basis of persistent vaginal with considerable acceleration in the rate
diestrus.
of migration of ova.
The location of ova in the reproductive
DISCUSSION
tract is recorded in table 12. In normal
pregnant rats, ova were still present in the
A comparison of the effects of a single
oviduct on the morning of day 4 but mi- injection of ECP on egg transport in the
grated into the uterus by the next day. five species amply justifies the inclusion
Following the injection of 0.1 or 1.0 crg of the phrase “species-differences” in the
ECP, normal blastocysts were found in the title of this paper. In the mouse, a relauterus on day 5 but with 10 pg ECP, tively small dose of ECP caused tubeTABLE 11
Effect of ECP on pregnancy i n th.e rat
Lzfc:toa’].
TABLE 13
Effect of 250 pg ECP on e g g transport in the rat
Time
examined
Day 5
Location
and no.
of ova
5
0/5
-
Day 3
2
0/2
-
Day 2
2
0/2
-
Dayl-
1
animals
NO. of
animals
with ova
No. of
5hours
2
2/2
oviduct (13,13)
Day 1 - 12 hours
2
1/2
oviduct ( 5 )
Day 1 - 12 hours
3
3/3
oviduct (O,O,2)
uterus ( 6 , 9 , 4 )
Uterus ligated immediately after ECP injection.
170
GILBERT S. GREENWALD
locking of ova; larger doses accelerated
the rate of transport through the oviduct.
These results confirm the findings of Burdick and Pincus ('35) which to my knowledge have never been repeated since the
original observations.
ECP in a dose range of 1 to 500 pg failed
to induce tube-locking of ova in the rat.
On the contrary, estrogen treatment above
the 1 clg dose consistently accelerated egg
transport. Following the injection of 250
vg of ECP, ova were normally expelled
from the reproductive tract within 12
hours. The acceleratory effects of estrogen
on egg transport in the rat confirm preliminary observations (Greenwald, '61b)
and the work of Banik and Pincus ('64).
The latter authors found that doses of 20
clg or higher of estrone caused a premature
expulsion of eggs into the uterus in about
20-24 hours.
The marked sensitivity to estrogen of
the reproductive tract of the female rat is
of interest for two reasons. Firstly, a number of authors have postulated that tubelocking of rat ova accounts for the
preimplantation mortality that follows
estrogen administration. This represents
an unfounded extrapolation from the
effects of estrogen in the mouse. Secondly,
the rat has been used extensively to determine the mode of action of various nonsteroidal compounds which interrupt pregnancy (for references, see Walpole, '65).
The failure to recover ova from rats
treated with these compounds has been
interpreted as indicating that they exert
a direct anti-zygotic action, leading to
rapid degeneration of ova. However, these
compounds have estrogenic as well as antiestrogenic activity and the disappearance
of ova could result from acceleration of
egg transport rather than the dissolution
of ova in utero. This has already been
shown to be the case with a diphenylindene
derivative-U-11 lOOA (Greenwald, '65a).
The simple procedure of ligating the cornua at the cervical end would permit a
distinction between the direct or indirect
effect on ova of these non-steroidal agents.
With the exception of the mouse and
rat, increasing doses of ECP first accelerated egg transport and then at still
higher levels caused retention of eggs in
the oviduct. The results in the rabbit are
consistent with previous investigations
from this laboratory (Greenwald, '61a,
'63). My findings contradict the previous
studies of Pincus and Kirsch ('35) who reported that low doses of estrogen induced
tube-locking of ova in the rabbit whereas
high doses invariably accelerated egg
transport. No explanation can be offered
for the different results.
In both the hamster and guinea pig the
dose of ECP which disrupted egg transport
was considerably higher than the minimal
amount required to terminate pregnancy.
Hence, other mechanisms sensitive to estrogen are responsible for the interruption
of pregnancy by the hormone. It has already been well established for the hamster
that estrogen has a luteolytic action on the
corpora lutea of pregnancy (Greenwald,
'65b). This is accomplished by a single
injection of 25 ug ECP compared to the
100 pg dose necessary to expel ova from
the reproductive tract. The hamster was
by far the most resistant species to ECP,
requiring a minimum of 25 clg of the hormone to interrupt pregnancy. This may
account for the fact that massive amounts
of U-11100A are unable to interfere with
pregnancy in the hamster (Duncan et al.,
'63) unlike the situation in the rat.
The effective dose of ECP which interrupted pregnancy in the guinea pig was
also less than the amount required to alter
tuba1 transport. The lower dose level appears to also act on the maintenance of
the corpus Iuteum since regressing corpora
albicanita were observed in a number of
guinea pigs killed 12 to 14 days post
coitum. However, it is possible that other
preimplantation phenomena are affected
by the hormone. Deanesly ('61) found
that treatment with less than 10 clg of
estradiol benzoate did not accelerate oviducal transport of eggs in the guinea pig
and there was no evidence that tube-locking of ova occurred at any dose tested. In
the present study ova were tube-locked at
day 5 after a single injection of 250 clg
ECP, a dose considerably higher than any
that were used by Deanesly.
In the current investigation, the specific
site at which ova were tube-locked was of
considerable interest. It has previously
been shown that ova are retained in the
oviduct of the rabbit at the ampullary-
ESTROGEN AND EGG TRANSPORT
171
isthmic junction (Greenwald, ’61a). The BGgli, B. 1959 Das tuba-uterine ventil beim
goldhamster. Rev. Suisse de Zool., 66: 14-227.
present experiments demonstrate that the BGving,
B. G. 1956 Rabbit blastocyst distribuprincipal blocking mechanism for egg
tion. Am. J. Anat., 98: 403-434.
transport also exists at this site in the Burdick, H. O., and G. Pincus 1935 The effect
of oestrin injections upon the developing ova
mouse, hamster and guinea pig. Burdick,
of mice and rabbits. Am. J. Physiol., 111: 201Emerson and Whitney (’40) noted that in
208.
the androgen-treated mouse more ova were Burdick,
H. O., B. E. Emerson and R. Whitney
recovered from the “ovarian” third of the
1940 Effects of testosterone propionate on
fallopian tube than the remaining portion.
pregnancy and on passage of ova through the
The utero-tuba1 junction (UTJ) has long
oviducts of mice. Endocrinology, 26: 10811086.
been thought to be the major barrier to
egg transport and its anatomy has been Deanesly, R. 1961 The effects of oestrogen on
tubal transport and ovo-implantation in the
the subject of several papers (Lee, ’28;
guinea-pig. Proc. IVth Inter. Cong. on Animal
Kelly, ’28; Anderson, ’28; Bogli, ’59). It
Reprod., 371-374.
appears that the ampullary-isthmic junc- Duncan, G. S., S. C. Lyster, J. J. Clark and D.
Lednicer 1963 Antifertility activities of two
tion (AIJ) may be of greater significance
diphenyl-dihydronaphthalene derivatives. Proc.
in egg transport than the UTJ. The nature
Soc. Exp. Biol. & Med., 112: 43-42.
of the blocking mechanism at the AIJ has Greenwald,
G. S. 1957 Interruption of pregnot been definitely determined. However,
nancy in the rabbit by the administration of
estrogen. J. Exp. Zool., 135: 461-481.
the AIJ represents the junction between
1959 The comparative effectiveness of
the thick muscular isthmus and the less
estrogens in interrupting pregnancy in the
muscular ampulla. Hence, a sphincteric
rabbit. Fertil. & Steril., 10: 155-161.
block at the AIJ appears to be a strong
1961a A study of the transport of ova
possibility for the tube-locking activity of
through the rabbit oviduct. Fertil. & Steril.
12: 80-95.
estrogen.
1961b The anti-fertility effects in pregAlthough tube-locking of ova occurred
n a n t rats of a single injection of estradiol
in all species examined (except for the
cyclopentylpropionate. E n d o c r i n o l o g y , 69:
rat), massive amounts of estrogen were
1068-1 073.
required in the hamster, guinea pig and
1963 Interruption of early pregnancy
in the rabbit by a single injection of oestrarabbit. These doses certainly represent
diol cyclopentylpropionate. J. Endocrin., 26:
pharmacologic amounts, rarely, if ever,
133-138.
duplicated by endogenous hormone levels.
1965a Effects of a dihydronaphthalene
The usual effect of smaller quantities of
derivative (U-11100A) on pregnancy in the
rat. Fertil. & Steril., 16: 185-194.
exogenous estrogen is acceleration of egg
196513 Luteolytic effect of estrogen on
transport through the oviduct and eventual
the corpora lutea of pregnancy of the hamexpulsion of ova per vaginam. Hence, egg
ster. Endocrinology, 76: 1213-1219.
transport is a very vulnerable stage in the Kelly, G. L. 1928 The utero-tuba1 junction in
the guinea pig. Am. J. Anat., 40: 373-318.
reproductive cycle and one, which for several reasons, would be suitable for various Lee, F. L. 1928 The tubo-uterine junction in
various mammals. John Hopkins Hosp. Bull.,
methods of fertility control.
42: 335-357.
ACKNOWLEDGMENTS
This is a contribution from the Research
Professorship In Human Reproduction.
The research was supported by grant HD00596-04 from the NIH-U.S.P.1I.S. and by
the Ford Foundation.
LITERATURE CITED
Andersen, D. H. 1928 Comparative anatomy
of the tubo-uterine junction. Histology and
physiology in the sow. Am. J. Anat., 42: 255305.
Banik, U. K., and G. Pincus 1964 Estrogens
and transport of ova in the rat. Proc. Soc. Exp.
Biol. & Med., 116: 1032-1034.
Parkes, A. S., and C. W. Bellerby 1926 Studies
o n the internal secretions of the ovary. 2.The
effects of injection of the oestrus producing
hormone during pregnancy. J. Physio., 62:
145- 155.
Pincus, G., and R. Kirsch 1936 The sterility in
rabbits produced by injections of oestrone and
related compounds. Am. J. Physio., 115: 219228.
Smith, M. G. 1926 On the interruption of pregnancy in the rat by the injection of ovarian
follicular extract. Bull. Johns Hopkins Hosp.,
39: 203-214.
Walpole, A. L. 1965 Non-steroidal agents inhibiting pituitary gonadotrophic function. In:
Agents Affecting Fertility. Ed. by C. R. Austin
and J. S. Perry, Little, Brown & Co., Boston,
Mass., pp. 159-179.
172
GILBERT S. GREENWALD
Whitney, R., and H. 0. Burdick 1936 Tubelocking of ova by oestrogenic substances. Endocrinology, 20: 643-647.
- 1938
Acceleration of the rate of passage of fertilized ova through the fallopian
tubes of rabbits by massive injections of Progynon B. Endocrinology, 22; 639-642.
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