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RESPONSES TO GONADOTROPINS IN DOMESTIC ANIMALS J.E. Fortune INTRODUCTION Superovulation and embryo transfer in domestic animals and human in vitro fertilization (I9F) programs have in common the use of large doses of gonadotropins to "persuade" additional follicles to grow to preovulatory size and to produce fertilizable oocytes that will develop into normal young. It has been known since the 1940's that both pituitary gonadotropins, LH and FSH, interact with the developing preovulatory follicle and are essential to its growth and differentiation (Fevold, 1941; creep et al., 1942; Fraenkel-Conrat et al., 1943~. Hence, protocols used for superovulation of animals and hyperstimulation of women in IVF programs are based on the idea that abnormally high doses of gonadotropins will overcome the normal restraints imposed by each species on the number of ovulations, and will recruit and select "extra" follicles for ovulation. In the first part of this manuscript I will review the effects of ovarian hyperstimu~ation with exogenous gonadotropins (or "superovulation") in cattle, sheep and goats, horses, and pigs. In the second part I will make suggestions for future directions for research with animal models, directions that may generate new information to improve protocols for superovulation in both domestic animals and women. Superovulation In Domestic Animals Much of the impetus for the use of gonadotropins to stimulate superovulation in domestic animals comes from the desire to exploit the genetic potential of superior females. Artificial insemination, especially in the cattle industry, has made possible a very wide dissemination of the genes of superior males. It is estimated that popular bulls may sire around 50,000 calves per year (Seidel, 1981~. Since the use of frozen semen allows reproduction by males even after death, the genes of a highly desirable male can be disseminated widely through a population. However, the genetic improvement of species or breeds is still limited by the small number of offspring that an individual female can produce in her lifetime. Repeated superovulation of superior females and the collection and transfer of their embryos to less valuable recipients greatly enhances the reproductive potential of these females and makes it 130 -

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possible to disseminate their genes more widely than could be achieved through natural pregnancies and more directly than through ~natural" male offspring. Among the domestic animals, superovulation and embryo transfer have had the greatest impact on the cattle industry. As techniques for ovarian stimulation and for non-surgical embryo collection and transfer were developed and improved this industry has boomed. Therefore, will concentrate the discussion of superovulation in domestic animals primarily on cattle; other domestic species will be discussed more briefly in subsequent sections. Superovulation of cattle ~ How are cattle superovulated? The bovine estrous cycle averages 21 days in length (Day 0 = day of estrus behavior). Ovulation occurs on Day 1 and is followed by a luteal phase of about 18 days and then a follicular phase of 2-4 days. The first experimental induction of superovulation in farm animals was reported by Casida et al. (1943) who used pituitary gonadotropins to superovulate cattle (for a review of the early experimental work see Willet, 1953~. Current superovu~atory protocols involve the injection of exogenous gonadotropin during mid-luteal phase (Day 8-14) to recruit extra follicles near the end of the luteal phase for ovulation following the next follicular phase. Several gonadotropin preparations have been used in commercial superovulation programs. In the 1970's pregnant mare's serum gonadotropin (PMSG, also called equine chorionic gonadotropin or eCG) was widely used for superovulating cattle. This gonado- tropin is produced by the equine conceptus and can be obtained from the blood of pregnant mares. Although it has only LH-like action in horses, PMSG has the interesting feature of binding to both AH and FSH receptors in other mammalian species (Stewart and Allen, 1979) and exhibiting both LH-like and FSH-like activity in bioassays (PapRoff, 1981~. Therefore, its effects as a superovu- lating treatment are probably due to its capacity to mimic the actions of both pituitary gonadotropins. The advantage of PMSG in superovulation of domestic animals is that it can be given as a single injection to produce multiple ovulations several days later. This is because the higher sialic acid content of PMSG confers on it a much longer half-life (the half-life appears to have two components - a shorter one of 40-50 h and a longer of 118-123 h; Schams et al., 1978) than the pituitary gonadotropins. However, the long half-life of PMSG is also a disadvantage, since the gonadotropin continues to stimulate the ovaries over a long period of time and this can lead to asynchronous ovulations and large unovulated follicles on the ovaries after ovulation. Although attempts have been made to attenuate PMSG's long half-life by injecting anti-PMSG just before ovulation (see 131 -

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below), the use of pituitary gonadotropins has gradually displaced PMSG for superovulation of cattle. The most widely used are commercially available preparations of FSH extracted from pig (or other domestic animal) pituitaries, referred to as ~FSH-P". These preparations usually contain high and variable levels of contaminating AH and are typically given as a series of 8 injections of either equal or decreasing strength for 4 days, beginning around Day 10 of the cycle. Superovulation with pituitary gonadotropins was reported to produce more transferrable embryos (Critser et al., 1980) and pregnancies {Elsden et al., 1978) than superovulation with PMSG. In a few studies human menopausal gonadotropin (HMO) has been used successfully to produce multiple ovulations in cattle (Laurie et al., 1982a,b), but it is not used commercially. Early in the history of bovine superovulation, it became apparent that the variable length of the estrous cycle in cattle makes it difficult to control the application of gonadotropins relative to the time of luteolysis. Normal estrous cycles can vary in length from around 18-26 days and, in contrast to the situation in humans, it is the luteal phase that is the most variable. Therefore, current superovulatory regimens with PMSG or pituitary gonadotropins include the injection of prostaglandin F2a (PGF;a) to regress the corpus luteum (CL) and reduce the variability in the interval from gonadotropin injection to estrus (Betteridge, 1977; Elsden et al., 1978; Seidel, 19813. The use of PGF OCR for page 130
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 - 134

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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 - 135 -

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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 - 136 -

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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. 137 -

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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 138 -

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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, - 139

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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. - 140 -

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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. 144 -

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REFERENCES Armstrong, D. T., and G. Evans. 1983. Factors influencing success of embryo transfer in sheep and goats. Theriogenology 19:31-42. Armstrong, D. T., A. P. Pfitzner, G. M. Warnes, M. M. Ralph, and R. F. Seamark. 1983a. Endocrine responses of goats after induction of superovulation with PMSG and FSH. J. Reprod. Fert. 67:395-401. Armstrong, D. T., A. P. Pfitzner, G. M. Warnes, and R. F. Seamark. 1983b. Superovulation treatments and embryo transfer in Angora goats. J. Reprod. Fert. 67:403-4IC . Bazer, F. W., 0. W. Robison, A. J. CIawson, and L. C. Ulberg. 1969. Uterine capacity at two stages of gestation in gilts following embryo superinduction. J. An. Sci. 29:30-38. Betteridge, K. J. 1977. Superovulation. pp. 1-9 in Embryo Transfer in Farm Animals, K. J. Betteridge, ea., Can. Dept. Agric. Res. Branch Monograph #16. Bindon, B. M., L. R. Piper, L. P. Cahill, M. A. Driancourt and T. 0. Shea.1986. Genetic and hormonal factors affecting superovulation. Theriogenology 25:53-70. Booth, W. D., R. Newcomb, H. Strange, L. E. Rowson, and H. B. Sacher. 1975. Vet. Record 97:366-369. Britt, J. H. and L. C. Holt. 1988. Endocrinological screening of embryo donors and embryo transfer recipients: a review of research with cattle. Theriogenology 29:189-202. Callesen, H., T. Greve and P. Hyttel. 1986. Preovulatory endocrinology and oocyte maturation in superovulated cattle. Theriogenology 25:71-86. Casida, L. E., R. K. Meyer, W. H. McShan, and W. Wisnicky. 1943. Effects of pituitary gonadotropin on the ovaries and on the induction of superovulation in cattle. Amer. J. Vet. Res. 4: 76-94. Casida, L. E., E. J. Warwick, and R. X. Myer. 1944. Survival of multiple pregnancies induced in the ewe following treatment with pituitary gonadotropins. J. Anim. Sci. 3:22-28.

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Chupin, D., Y. Cognie, Y. Combarnous, R. Procureur, and J. Saumande. 1987. Effect of purified AH and FSH on of ration in the cow and ewe. pp. 63-71 in Follicular Growth and Ovulation Rate in Farm Animals, J. F. Roche and D. O'Callaghan, eds. Dordrecht: Martinus Nijhoff Publishers. Cole, H. H. and R. F. Miller. 19 33. Artificial induction of ovulation and oestrum in the ewe during anoestrum. Amer. J. Physiol. 104:165. Critser, J. R., R. F. Rowe, M. R. Del Campo and 0. J. Ginther. 1980. Embryo transfer in cattle: factors affecting superovulatory response, number of transferable embryos, and length of post-treatment estrous cycles. Theriogenology 13:397-406. Day, B. N., D. E. Longenecker, S. C. Jaffe, E. W. Gibson, and J. F. Lasley. 1967. Fertility of swine following superovulation. J. An. Sci. 26: 777-''A 786. Dieleman, S. J., M. M. Bevers, and J. Th. Gieleu. 1987. Increase of the number of ovulations in PMSG/PG treated cows by administration of monoclonal anti-PMSG shortly after the endogenous LH peak. Theriogenology 27:222. Donaldson, L. E. 1984. The day of the estrous cycle that FSH is started and supero~ ration in cattle. Theriogenology 22:97- 99. Donaldson, L. E. 1985. AH and FSH profiles at superovulation and embryo production in the cow. Theriogenology 23: 441-447. Donaldson, L. E., and B. Perry. 1983. Embryo production by repeated superovulation of commercial donor cows. Theriogenology 20:163-168. Donaldson, L. E., and D. N. Ward. 1986. Effects of luteinizing hormone on embryo production in superovulated cows. Veterinary Record 119:625-626. Donaldson, L. E., D. N. Ward, and S. D. Glenn. 1986. Use of porcine follicle stimulating hormone after chromatographic purification in superovulation of cattle. Theriogenology 25:747-757. Douglas, R. H. 1979. Review of induction of superovulation and embryo transfer in the equine. Theriogenology 11:33-46. Douglas, R. H., L. Nuti, and 0. J. Ginther. 1974. Induction of ovulation and multiple ovulation in seasonally anovulatory mares with equine pituitary fractions. Theriogenology 2:133- 142. - 146

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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 - 152 8

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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 -