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numbers of CLs or ova/embryos recovered can give misleading ideas
of success if the ova/embryos are either not recovered or not
developing properly, the important endpoint is number of
transferrable embryos. Hence, it is important to look at success
in terms of transferrable embryos, rather than numbers of
ovulations. The success of superovulation depends partially on
when the embryos are collected. It was found that collection of
embryos on Day 6-8 after estrus is optimal, since they can be
recovered non-surgically, and in good condition, from the uterus
at that time (Hasler et al., 1983, 1987; Seidel, 1981)
The major point that should be made about the success of
superovulation in cattle is that it is highly variable. While it
may be very successful, yielding many good embryos from one
donor, it may fad] miserably with others. A number of recent
reviews on superovulation in cattle have emphasized this lack of
consistency as a major problem (Bindon et al., 1986; Foote and
Ellington, 1988; Monniaux et al., 1983; Moor et al., 1984; Murphy
et al., lg84; Seidel, 1981). There is variability both among
animals and also within the same animal from one treatment cycle
to the next. The variability that one finds in surveying the
literature has a number of sources. Season, breed, gonadotropin
preparation, number of previous superovulations, and dose and
timing of gonadotropin preparations may all contribute to
variability of response. The literature on these sources of
variation will be reviewed briefly.
It has been reported that different breeds of cattle treated
with the superovulatory regimens respond differently (Betteridge,
1977; Saumande, et at., 1978). There are conflicting reports on
effects of season of the year on the superovulatory response,
with some authors finding differences with season (Hasler et al.,
1983) and others reporting no difference (Critser et al., 1980;
Hasler et al., 1987; see Betteridge, 1977 for review of earlier
literature). The potential existence of variation due to breed
and/or season makes comparisons among studies much more
difficult.
Since the goal of bovine superovulation is to reproduce a
valuable female as many times as possible, a critical question is
the number of times a female can be successfully superovulated
and whether repeated superovulation leads to refractoriness or a
lowered response. It seems possible that animals treated
repeatedly with heterologous gonadotropins could develop
antibodies towards them that would lessen or prevent the
response. Hasler et al. (1983) have reported that ovulation rate
remained the same over the course of ten superovulations, but the
number of fertilized eggs declined. Donaldson and Perry (1983)
also found that transferrable embryos decreased with repeated
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superovulations. In contrast a decline in the number of viable
embryos was not observed in studies in which animals were
superovulated fewer times (Moor et al., 1984; Lubbadeh et al.,
1980).
Since the timing of injections of gonadotropins, relative to
luteolysis and relative to changes in follicular populations, may
be critical to the success of superovulation, several
investigators have examined the effects of injecting
gonadotropins at different times during the cycle. Donaldson
(1984) reported that there was no difference in the nether of
embryos or transferrable embryos when FSH-P was administered on
Day 9, 10, 11, 12, or 13 of the cycle (with PGF2a given on the
third day of treatment). Using a similar protocol, Hasler et al.
(1983) reported similar responses to treatment begun on Days 8-
13, except that the responses of infertile cows were lower on
Days 8 and 13. However, Lerner et al.~1986) observed that
greater numbers of embryos plus ova were recovered when treatment
began on Day 10 or 11, as compared with Day 7-9 or Day 12-14.
The effects of varying the dose of gonadotropin on the
success of superovulation have been examined. With older donors
increasing doses of FSH-P were associated with increases in the
recovery of ova plus embryos, whereas increasing doses of FSH had
the opposite effect on younger donors (Lerner et al., 1986~.
Variability among gonadotropin preparations, even from the
same supplier, may explain part of the variability observed in
different superovulation trials. Murphy et al (1984) reported
that the amount of AH vs. FSH immuno- or big-activity varies
considerably among different preparations of PMSG and FSH-P.
They found that preparations with lower ratios of FSH/LH are less
successful in producing ovulations. Donaldson et al. (1986)
removed most of the contaminating LH from FSH-P and found that
their FSH preparation, which had no detectable AH activity, did
not increase the total number of embryos, but did increase the
number and percent transferrable embryos. A subsequent field
study further confirmed the efficacy of the purified FSH
preparation (Donaldson and Ward, 1986~.
Even when the factors mentioned above are controlled for -
i.e. when animals of the same breed are given the same dose of
the same gonadotropin preparation at the same time of the cycle
and the same time of year, and number of previous superovulations
is controlled for, there is still tremendous variability in the
response among, and within, animals. Although part of this
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variability may be explained by the treatment of donors
inadvertently at inappropriate times of the cycle (Britt and
Holt, 1988), it also seems clear that there is much unexplained
variability. It seems logical to conclude that this unexplained
variability comes from individual genetic differences among
animals that determine how they respond to supra-physiological
doses of gonadotropins. The next section addresses the question
of what is currently being done to try to increase the uniformity
of the response.
c. Current strategies to improve the success of
superovulation. One goal is to determine an optimal gonadotropin
treatment. This has not been easy because of the variability of
the preparations that have been marketed. Several investigators
have concluded that preparations with low ratios of FSH to LH
give poorer superovulatory responses. Several investigators have
tested this idea by using highly purified FSH and adding known
amounts of AH to it in attempts to determine the optimum FSH/LH
ratio (Chupin et al., 1987; Donaldson and Ward, 1986; Murphy et
al., 1984~. Another recent suggestion is that it may be helpful
to prime the animals with injections of FSH early in the cycle to
recruit more small follicles to grow prior to the superovulatory
treatment in mid-cycle (Rajamahendran et al., 1987; Ware et al.,
1988~. PMSG is attractive as a superovulatory gonadotropin
because it need only be injected once, as opposed to 8 injections
of FSH-P. Therefore, several groups have tried to improve the
response to PMSG by injecting an antiserum to PMSG around the
time of ovulation to effectively shorten its biologically active
life in the animals and to limit the effects of PMSG on the ovary
to the follicular phase (Dieleman et al., 1987; Saumande et al.,
1984; Wang et al., 1987~.
Some investigators have attempted to analyze what may be
going wrong when superovulation fails by comparing endocrine
profiles and follicular characteristics of superovulated cattle
with normal cattle. As would be expected, estradiol is higher
prior to ovulation and progesterone is higher following ovulation
in superovulated cattle as compared with controls (Henricks et
al., 1973~. Plasma levels of estradiol before ovulation and
progesterone after ovulation are positively correlated with the
number of ovulations (Saumande, 1980; Saumande and Batra, 1985~.
Very high levels of estradiol after superovulation with PMSG are
probably caused by the presence of large, unovulated follicles
(Booth et al., 1975) e Although the magnitude of the AH and FSH
surges appears to be normal in superovulated animals, in some
cases their timing is abnormal and they may not be coincident
(Saumande, 1980; Donaldson, 1985~. Further evidence of lack of
normal coordination of endocrine events in superovulated animals
comes from studies of individual follicles. Profiles of steroids
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in the follicular fluid varied from those seen in control animals
at the same time relative to LH surge and there was considerable
variability among superovulated animals (Fortune and Hansel,
198S). Callesen et al. (1986) found that in superovulated
animals relatively no ~ al plasma levels of progesterone and LR
were associated with normal follicular steroid levels, but that
animals with deviating patterns of AH and progesterone during the
pre- and pert-ovulatory periods had abnormal progesterone:
estradiol ratios in follicular fluid and prematurely activated or
meiotically arrested oocytes. Moor et al. (1984) concluded that
premature activation of oocytes during superovulation protocols
causes significant loss of potential embryos.
d. Summary of superovulation in cattle. Superovulation of
cattle using a combination of gonadotropin treatment and PGF2a is
~ multi-million dollar industry in the United States. Yet it is
clear that the variability of the ovarian response in terms of
numbers of ovulations, but more importantly in terms of numbers
of good embryos, is a definite limitation to its successful use.
There are no obvious solutions to this problem and the approaches
being taken now represent a fine-tuning of the system that may
lead to only slight improvements, rather than more radical
approaches that might lead to more substantive improvements.
Recommendations for research that might provide new insight into
this problem are discussed in the last section of this paper.
Superovulation of Sheep and Goats
Sheep and goats have also been successfully superovulated
for embryo transfer. Induction of multiple pregnancies with
gonadotropin treatment was reported as early as 1944 (Casida et
al., 1944~. A number of studies since that time have
demonstrated that ewes can be synchronized by treatment with
progestagens, and multiple ovulations readily induced by a single
injection of PMSG given one day before the end of progestagen
treatment or by multiple injections of pituitary extracts (see
Wright et al., 1981 for references). Australian scientists have
been especially active in this area of research (see Shelton et
al., 1982 for reviews). Since most breeds of sheep are seasonal
breeders, the induction of ovulation during the anestrous season
is of interest. The use of exogenous gonadotropins for this
purpose has been explored, beginning with the successful
induction of ovulation by Cole and Miller (1933~.
An interesting aspect of research on superovulation in sheep
is that some approaches have bypassed gonadotropin treatment
entirely, using more indirect means to raise endogenous
gonadotropin levels and thereby recruit excess follicles. It is
believed that inhibin made by the ovulatory follicle suppresses
basal levels of FSH in the blood during the follicular phase and
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OCR for page 137
thereby helps ensure the dominance of the dominant (ovulatory)
follicle. It is known that one of the prolific sheep breeds, the
Booroola, which typically ovulate about five oocytes, has lower
levels of inhibin than less prolific breeds of sheep (Bindon et
al, 1986~. Injections of antibodies against inhibin have the
potential of increasing FSH levels and recruiting additional
follicles to ovulate (Bindon et al., 1986~. Another approach to
increasing ovulation rate is immunization against steroids.
Scaramuzzi et al. (1977) first reported an increase in ovulation
rate from I.1 to 2.1 in sheep immunized against androstenedione.
Induction of superovulation with gonadotropin preparations
has been particularly successful in goats (Armstrong and Evans,
1983~. The ability to reproduce genetically superior animals is
especially important for valuable breeds, such as Angora goats.
A purebred Angora female is very expensive, but through
superovulation and embryo transfer, she can potentially produce
many embryos that can be transferred to non-Angora recipients.
Results of experiments performed in Australia and Canada by
Armstrong et al. (1983a,b) showed that injection of porcine FSH
in decreasing doses from day 12-15 of the estrous cycle resulted
in a higher mean ovulation rate (17.6 ~ 5.5/ewe) than injection
of PMSG on day 12 (10.1 + 3.0) of the cycle in feral goats
(Armstrong et al., 1983a). Application of these two gonadotropin
treatments to Angora females in a second study gave almost
identical results (Armstrong et al., 1983b). In the second study
transfer of the embryos to recipients resulted in equal rates of
survival for embryos from FSH vs. PMSG-treated females. However,
these authors found that survival was better when recipients had
2 or 3 corpora lutea (CL) as compared with 1 CL (63 and 75% vs.
52%) and that transfer of two embryos to recipients increased
their chances of survival (65%) as compared with transfers of
single embryos (65% vs. 48% survival).
Effects of Exogenous Gonadotropins on Horses
There have also been attempts to superovulate mares, with a
view towards embryo transfer. Horses are seasonally polyestrus;
their estrous cycles average 21-22 days in length and consist of
a period of diestrus for about 15 days following ovulation,
followed by an estrous period that averages about 7 days
(Ginther, 1979~. The mare is unique among the domestic animals
in having an estrous period that is long and variable in length,
lasting 2-12 days (Ginther, 1979~. AH rises progressively during
the estrous period, but does not peak until after ovulation. In
contrast, FSH is low during most of the estrous period, but there
appears to be a surge of FSH coincident with the LH peak
following ovulation and a second rise in FSH at about Day 10 of
the cycle (reviewed by Irvine, 19811.
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In contrast to cattle, where the effect of exogenous
gonadotropins is to dramatically increase the number of ovulatory
follicles, injections of gonadotropins have not produced large
numbers of synchronous ovulations in mares. PMSG, even in large
doses, is not effective in inducing multiple ovulations (Ginther,
1979~. Its lack of effectiveness in horses, contrary to the
marked response observed when cattle are injected with PMSG, is
probably due to the fact that PMSG is an DH-like hormone in
horses. It binds with only about 4% the affinity of AH to equine
LEI receptors and binds not at all to equine FSH receptors
(Stewart and Allen, 1979~. This is in contrast to the actions of
PMSG in other species, in which it binds to both AH and FSH
receptors. It appears that its lack of FSH action in mares makes
PMSG ineffective and unsuitable for inducing multiple ovulation
in this species.
Treatment of mares with other gonadotropic preparations has
been effective in inducing ovulation in seasonally anestrus mares
and in increasing the ovulation rate in mares treated during the
breeding season. In these studies pony mares or horse mares have
been treated with either a crude extract of equine pituitary
glands, an acetone extract of equine pituitary glands, or a
commercially available preparation of porcine FSH (FSH-P, which
probably also contains some LH). In some studies hCG has been
injected at or towards the end of the treatment with ESH. Such
treatments have been effective in inducing a high percentage of
treated mares to ovulate outside the breeding season (>90%) and a
number of these mares had multiple ovulations (overall average
for mares ovulating = 2.1; Douglas et al., 1974; Lapin and
Ginther, 1977; Woods et al., 1982~. Treatment with these
gonadotropin preparations for 5 to 7 days during the breeding
season has also induced multiple ovulations. Treatment with FSH-
P in two studies resulted in ovulation rates of 1.6 and 1.7
ovulations per mare (Irvine, 1981; Squires et al., 1986), whereas
ovulation rates of 2-3 ovulations per mare were observed when
equine pituitary extract was injected (Lapin and Ginther, 1977;
Douglas, 1979; Woods and Ginther, 1983a; Squires et al., 1986~.
Ovulation rates for controls were always one, or very close to
one, per mare. The inclusion of an injection of hCG near the end
of treatment with FSH produced of rations that were more
synchronous and treatments that began on Day 11-15 produced more
ovulations than treatments beginning on Day 19 (Woods and
Ginther, 1983a).
In summary, the use of gonadotropins to stimulate ovulation
in mares has progressed much less than with cattle and sheep and
there is currently no commercially available preparation for
superovulating horses. There appear to be several reasons for
lack of progress with this species. First, the ovaries of mares
seem much more resistant than ovine and bovine ovaries to
superovulatory treatments. There may be tighter intrinsic
control over ovulation rate in horses than in species like
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cattle, sheep, and humans. Although natural double ovulations
are not uncommon (Woods and Ginther, 1983b), the birth of twins
is rare in horses, indicating that there are mechanisms for
preventing the development of twins when two follicles ovulate
(Ginther et al., 1982; Woods and Ginther, 1983b; Ginther 1984~.
Second, the variable length of estrus makes embryo transfer
logistically more difficult than in other species, since it is
harder to synchronize the donor and recipients. Finally, many
purebred organizations are conservative and stud-book regulations
prohibit most artificial techniques for reproduction. However,
there is a need to understand better the regulation of follicular
development in mares in order to develop better treatments for
infertility and because the development of methods for
superovulating mares could be of particular benefit in preserving
and increasing numbers of individuals in endangered equine
species, through transfer of embryos to recipients of similar but
non-endangered species.
Ovulation Induction in Pigs
The commercial applications of superovulation and embryo
transfer techniques are more limited for swine than for the other
domestic species discussed above. Since sows give birth to
litters and have a relatively short gestation period (about 110
days) , each fertile female is naturally capable of producing
numerous progeny. However, superovulation and embryo transfer
could still be used, theoretically, to increase the rate of
reproduction of genetically superior animals. In the 1960's
several research groups successfully ovulated or superovulated
pigs with exogenous gonadotropins (Day et al., 1967; Pope et al.,
1968; Bazer et al., 1969~. James and Reeser (1979) showed that
ovulation could be induced and embryos collected (surgically)
repeatedly in the same sows. In their study follicular
development was ensured by the injection of PMSG on Day 16 of the
estrous cycle, at 15-20 days of lactation, or at weaning 21 to 35
days post-partum. Ovulation was timed by injecting hCG 72-96 h
after PMSG injection. This treatment was applied and embryos were
recovered an average of 4.S times per donor with an average
recovery rate of 15.6 transferable embryos per surgery. It
should be noted that the gonadotropin treatments were used more
to time follicle development and ovulation, than to
~superovulate~ the animals, since pigs would be expected normally
to ovulate around 15 oocytes. However, these results were
encouraging because they showed that embryos could be surgically
collected repeatedly at 3 to 6 week intervals without the
formation of extensive adhesions or any other apparent
impairments of reproductive function. Other studies have shown
that females can be superovulated with a single dose of PMSG on
Day 15 or 16 of the cycle. Doses of 500, 750, 1000, 1250, and
1500 i.~. resulted in mean numbers of CLs of 15, 25, 26, 25, and
38, respectively (Hunter, 1980~. Despite these positive results,
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gonadotropin treatments and embryo transfer are not much used to
increase the genetic potential of superior female gilts or sows.
In 1981 only 8 of 13,000 purebred seedstock producers in the U.S.
used embryo transfer primarily to exploit genetically superior
females (Martin, 1983~. One reason for this is the difficulty of
identifying superior sows. Therefore, the use of superovulation
and/or embryo transfer for genetic improvement is not a high
priority in the swine industry.
embryo transfer in swine has advantages other than potential
improvement of the gene pool. Disease is a major concern in the
swine industry. Herds have increased in size and they are
frequently confined to environmentally controlled buildings.
Both these conditions encourage the spread of disease and some
herds that are disease-free try to maintain that condition by
becoming ~closed" (i.e. not allowing new animals to be added to
the herd). Embryo transfer offers a means by which new genetic
material can be introduced into closed herds, without the risk of
also introducing disease vectors (Martin, 1983~. Embryo transfer
also provides a means of repopulating diseased herds and of
exporting animals to other countries. Finally, embryo transfer
has proven to be a useful tool in research on pigs, especially in
studies of maternal-fetal interactions (e.g., Pope et al., 1972;
Rampacek et al., 1975~.
In summary, embryo transfer in swine has not been exploited
to increase the reproductive potential of superior females, as it
has in cattle, sheep, and goats. The applications of this
technique to swine center more on prevention of the spread of
disease and on research applications. Although gonadotropin
treatments have been used to ensure and time follicular
development and ovulation, they have not been used to
significantly enhance the already high ovulation rate of pigs.
Recommendations For Future Directions In Research
It is clear that while superovulation of domestic animals,
especially cattle, has produced some spectacular successes, the
current techniques have the important limitation of variable and
unpredictable response. Superovulation is currently the weak
link in the reproduction of genetically superior animals through
superovulation and embryo transfer. Techniques for non-surgical
collection and transfer of embryos have been well developed and
major advances have been made in the cryopreservation, splitting,
and sexing of embryos. However, in the last decade there has
been little improvement in the success of superovulation in
cattle. What kinds of research might lead to substantive
improvements in the regulation of female reproduction in cattle?
~ believe that several approaches should be supported
simultaneously.
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OCR for page 144
twinning in cattle or superfecundity in other domestic species
(Bindon et al.,1986~.
SCARY
The use of commercially available gonadotropin preparations,
coupled with the use of PGF2a to control the time of regression
of the corpus luteum, has resulted in the ability to produce
excess ovulations in cattle, sheep, pigs, and mares. These
techniques have been most widely and successfully used with
cattle and are key to the success of the wider dissemination of
genes of valuable bovine females through embryo transfer.
However, the variability in the response to exogenous
gonadotropins is a major stumbling block to improvements in the
success of superovulation in cattle and other domestic species.
~ have suggested a number of approaches to solving this problem.
These include: 1) basic research on follicular dynamics and the
roles of pituitary gonadotropins in the regulation of follicular
growth and differentiation, 2) basic research on the role of
inhibin in ovarian regulation in cattle and other species, 3)
continued research on other mechanisms by which follicles may
exert dominance, 4) the adaptation of techniques for growing
mouse oocytes to meiotic competence in vitro to domestic species,
5) continuation of studies on genetic selection for multiple
ovulation. I believe that we need a broad range of approaches
for several reasons. First, this field is at a stalemate right
now and it is hard to predict where the next big breakthrough
might come. Second, it seems desirable to think in terms of
different approaches for different types of animals - meiotic
maturation and in vitro fertilization of thousands of oocytes
from the most valuable cows, better or more reliable techniques
for using gonadotropins to superovulate valuable cows, and
endocrine or genetic methods for producing twins in less valuable
animals. The cattle industry would benefit from having more
available options. Also, a wider range of options increases the
chance that some of them would also be useful in developing
countries, where farmers may be unable to benefit from some
techniques that work well for American producers. It seems well
to remember that a high percentage of the worId's domestic
animals live in developing countries and that increases in their
reproduction are very crucial to health and nutrition worId-
wide. Finally, cattle are an excellent model for humans and a
wide variety of approaches to studying the regulation of follicle
development in cattle could well generate new ideas and
approaches f or regulating f ertility in women.
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TABLE 1. Superovulation An Cattle: Results fro Too Co crcial
Ego Transfer Program:
Hasler et al., 1983a
Donaldson, 1984b
# Animals 984 1,263
Mean Ova/Donor S.9 10.1
<0-70)
He an Embryos/Donor . 5.1 . --
(0-38)
Good Embryos/Donor 4.6 4.5
(0-37)
No Embryos (' Donors) 36% 15%
(32.4% - no
good embryos)
Reported in Theriogenology 19: 83-99
sported in Theriogenology 21: 517-524
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.
TABLE 2. Di~;~u=~m of pre~:tes frog tar ems. Prey
cold by palpation though he rectal ·811 between day'; 90
Id 100 of ~eseation. (Seidel, Science 211: 354, !981.)
Donors
Pregnancies from
S - exhalation (no.
-
Age
(years) Breed First Second Third
1 Submental 4 7 ~
1 Simmental S ~ 0 9
4 Cousin 0 0 1
2 Hereford S l 4
2 Pinzgauer 6 1 0
2 Pinzgauer 4 8 20
13 Angus . 4 2 8
lo Hereford 2 0 5
9 Hereford 9 3 7
1 Simmen"1 7 O O
1 Submental 2 1 0
4 Charolais 7 9 0
7 Brangus 2 0 1
2 S1mmen"l 5 11 4
6 Hereford 1 11 S
8 Hereford 2 0 ~
14 Hereford 12 0 1
12 Hereford 0 3 2
2 Hereford 3 1 4
4 Angus - 3 0 2
7 Hereford 4 7 2
5 Angus 4 2 0
5 Angus 4 3 0
5 Angus 4 9 0
4 Submental ~ ]. 0
5 Angus 0 7 2
4 Hereford 0 4 ~
10 Angus 0 6 0
1 Si~enta1 0 2 O
5 Angus 3 6 O
3 Simmental 3 4 14
Average 3 4 3 5 3 4
- ~ 5 3
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17
15
_%
E 33-
_ .
Il..! ~ 1
:E
C)
w
_ .
.,
o
S3
-7
-6
-5 0
-4 ~
;D
O
Z
-3
/
/
1
/
N; I ~ - *
l
/
~ - \ f
` \ /
, rim
Am_'
~ ~ \ ~ \ /
1~.
m\\
17 19 0 1 ~ 5 ~ 9 11 13 15 17 19 0 2
DAY OF CYCLE
- 2
1
O
Figure I. Pattern of growth and regression of follicles (solid
lines) during a complete cstrous cycle. T.ne asterisk
indicates the last day on - ich the ovulatory follicle
was observed and the dashes line shows progesterone
concentrations arotmd the the of luteolysis.
- 154
-
Representative terms from entire chapter:
domestic animals
