Pharmacologic Manipulation of Fertility

Applied Pharmacology and Therapeutics II

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Pharmacologic Manipulation of Fertility Patrick J. Wright, BVSc, MVSc, PhD, * and Jakob Malmo, BVSc, FACVSct

In this article, basic aspects of reproductive endocrinology and physiology are outlined, pharmacologic agents described, and the application of these agents to the manipulation of fertility discussed. We have not attempted to cover the ground in terms of the experimental detail contained in several recent block-busting literature reviews, which are referred to in the relevant sections. The authors have partaken of a small degree of self-indulgence in some areas of particular interest to them. BASIC PHYSIOLOGY/ENDOCRINOLOGY Over the past 20 years, a large body of literature describing naturally occurring blood hormone concentrations, tissue hormone receptor concentrations, and responses to exogenous hormones has arisen associated with the availability of sensitive assay procedures, pure hormone preparations, and increasing numbers of research staff. Studies of the endocrinology of puberty, estrous cycles, pregnancy, and parturition in cattle have been reported and reviewed.9,22,42,44,59,81,82,157 Ovarian Cyclicity The estrous cycle is approximately 21 days for cows and 20 days for heifers (range 17 -25 days). Estrus lasts 18 hours (12-22h), and ovulation occurs after the end of estrus (soon after hour 12).170 The blood hormone concentrations during the estrous cycle are presented schematically in Figure 1. The final stage of maturation of the ovarian follicle is stimulated by luteinizing hormone (LH). LH is secreted in pulses from the pituitary gland in response to gonadotropin-releasing hormone (GnRH), which is secreted in a pulsatile mode by the hypothalamic neurons into the hypophyseal portal system. During the luteal

·Senior Lecturer, Department of Veterinary Science, University of Melbourne School of Veterinary Science, Werribee, Victoria, Australia tSenior Academic Associate, University of Melbourne School of Veterinary Science, Werribee; and MaH'ra Veterinary Centre, MaH'ra, Victoria, Australia Veterinary Clinics o/North America: Food Animal Practice-Vol. 8, No.1, March 1992

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PATRICK J. WRIGHT AND JAKOB MALMO

II

luteolysis Preovulatory surge of LH (and FSH)

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Figure 1. Schematic outline (not to scale) of plasma hormone concentrations during the estrous cycle of the cow. During the luteal phase, a low frequency of LH pulses is maintained by negative feedback of estradiol and progesterone. After luteolysis, the absence of progesterone results in a greatly diminished negative feedback, so the frequency of LH pulses increases and drives the follicle(s) through the final stages of maturation. The concentrations of estradiol increase until a threshold is reached, above which estradiol induces the pre-ovulatory surge of LH (positive feedback) and estrous behavior. Increases in plasma estradiol concentration during luteal phase reHect waves of follicular growth and atresia. (Adapted from Martin GB, Thomas GB: Roles of communication between the hypothalamus, pituitary gland, and ovary in the breeding of ewes. In Oldham CM, Martin GB, Purvis IW (eds): Reproductive Physiology of Merino Sheep: Concepts and Consequences. Perth, Australia, The University of Western Australia School of Agriculture Animal Science, 1990, p 23; with permission.)

stage of the cycle, the frequency of LH pulses is low (6-8 pulses/24 h), reflecting the inhibitory effect of ovarian steroids, particularly progesterone, on the hypothalamic-pituitary axis. Commencing at luteal regression, the frequency of LH pulses increases (20-30/24 h), causing maturation of the preovulatory follicle, which in turn produces increased secretion of estrogens and inhibin. Estrogens act on the progesterone-primed brain to elicit estrous behavior and on the hypothalamic-pituitary unit to stimulate (estrogen positive feedback) the surge release ofLH (preovulatory surge). This LH surge, occurring around the start of estrus and lasting 8 to 10 hours, results in ovulation

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some 24 to 30 hours later, leading to the formation of the corpus luteum. The corpus luteum secretes progesterone. On day 3 (day 0 = day of estrus), plasma progesterone concentrations are low (around 1 ng/mL), rise to 6 to 10 ng/mL from day 7 to 18, and then at luteolysis decrease over 24 to 36 hours. Plasma follicle-stimulating hormone (FSH) concentrations fall during proestrus as a result of increasing concentrations of estrogen and inhibin secreted by the maturing follicle. Inhibin is a glycoprotein hormone, secreted by the follicle (granulosa cells), that acts at the pituitary to inhibit the secretion of FSH. FSH is first released in a surge mode associated with the LH surge and again in a smaller surge approximately 24 hours later. Prostaglandin F2a secreted by the uterus results in the regression of the corpus luteum (luteolysis) over 24 to 36 hours. The secretion of prostaglandin F2a from the uterus involves the interaction of estradiol from ovarian follicles and progesterone and oxytocin from the corpus luteum. 44,82 Progesterone action on the uterus is required for the production of prostaglandin F2a. Estrogens stimulate the formation of uterine receptors for estradiol and oxytocin. Oxytocin from the ovary stimulates release of prostaglandin F2a, which in turn stimulates further secretion of ovarian oxytocin. However, the time clockthe mechanism(s) timing the duration of the cycle through timing the initiation of luteolysis - has not been defined. Recent longitudinal studies of the growth and development of ovarian follicles using ultrasound techniques,52,53.83.153,183,184,198 have extended earlier findings based on postmortem examination of ovaries 201 and on estradiol secretion by the ovary.68 During the estrous cycle and into early pregnancy, there are waves of follicular growth. A number of follicles are "recruited" and increase in size over a few days. One is selected, becomes dominant (dominance phase), and further increases in size; the other recruited (subordinate) follicles become atretic. If the dominant follicle is exposed to proestrous frequencies of plasma LH pulses, it matures and ovulates. Dominant nonovulatory follicles become atretic. The number of follicular waves per cycle ranges from one to four and is most commonly two or three. The duration of growth of the dominant follicle is roughly 4 to 6 days. In heifers with two follicular waves per cycle, the waves commenced at day 0 (day of ovulation) and on day 9. For the first (nonovulatory) dominant follicle, the growth phase was 6 days, followed by a static phase of 6 days, and then a regressing phase. 52,74 In heifers with three follicular waves, dominant follicles of each wave reached a maximum size around days 6, 16, and 21 of the cycle; in cows, maximum size was reached around days 8, 18, and 24, reflecting a slower rate of follicular growth in COWS. 183 ,184 Cycle lengths are influenced by the age of the cow and the number of follicular waves. Cycles are longer in cows than in heifers, and three-wave cycles are longer than two-wave cycles. Thus, cycle lengths for cows with two and three waves and for heifers with two or three waves were 22.2, 24, 20.5, and 20.5 days, respectivelyl83,184 The waves of follicular growth and atresia continue up to day 70 of pregnancy.54,183 Studies at later stages have not been reported. Plasma estradiol concentrations increase during diestrus in association with maturing of the dominant follicles. 68 After conception the maintenance of pregnancy requires progesterone from the corpus luteum; therefore, a suppression of luteolysis and continuing estrous cycles is necessary. Thus, if conception occurs, pregnancy maintenance requires the cow to recognize she is pregnant (maternal recognition of pregnancy). The maternal recognition of pregnancy involves the suppression of secretion of prostaglandin from the uterus. Maternal recognition of pregnancy occurs 15 to 17 days after ovulation, and embryo-produced proteins such as bovine trophoblast protein 1 (bTP-l) are involved. Recent studies indicate that

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PATRICK J. WRIGHT AND JAKOB MALMO

the antiluteolytic effect of the embryo results from bTP-1 causing increased activity of an endometrium prostaglandin synthetase inhibitor, leading to reduced secretion of prostaglandin F2a. 61 ,208,210 Other changes in endocrine function that probably are not related to trophoblast protein-1 have been described in early pregnancy in ewes and cows. Pregnant animals had higher concentrations of plasma progesterone and lower concentrations of plasma estradiol, uterine oxytocin receptors, and luteal oxytocin than nonpregnant animals. 43 ,60,85,187 Pregnancy Progesterone is required throughout pregnancy (duration of 280 daysrange of270-292 days). The main source of progesterone is the ovary; secondary sources are the placenta and adrenal gland. In the second and third trimesters, the placenta secretes increasing amounts of estrogens. The high continuous concentrations of progesterone (and estrogens) from the ovary during pregnancy results in pituitary depletion of LH, probably reflecting inhibition of secretion of GnRH. GnRH is required for both synthesis and secretion of pituitary gonadotropins. Parturition The initiation of parturition involves increased activity of the fetal hypothalamic-pituitary-adrenal axis, leading to increased concentrations of corticosteroids in the fetal blood. Fetal corticosteroids act at the placenta to activate enzyme systems, resulting in conversion of progestagens to androgens, and androgens to estrogens. Estrogens stimulate the production of the uterine prostaglandin F2a and increase the number of uterine oxytocin receptors. The secretion of prostaglandin F2a is also stimulated by oxytocin. Oxytocin is secreted from the posterior pituitary in response to the fetus entering the birth canal. Uterine contractility is stimulated by prostaglandins and oxytocin. Prostaglandin F2a also causes the luteolysis of the corpus luteum of pregnancy. Softening of the cervix and relaxation of the sacrosciatic ligaments and the birth canal involve progesterone withdrawal, estrogens, and prostaglandins. The role of relaxin from the ovary is unclear. 71 Anestrus A period of anestrus, reflecting ovarian acyclicity, occurs in cows post partum. Reported intervals from parturition to first estrus are 30 to 76 days for dairy cattle and 40 to 48 days for beef cattle. First ovulations commonly occur in dairy cattle by around 2 to 4 weeks post partum. 102,132,170 The first ovulation post partum may not be accompanied by estrus, and this seems more common in dairy cattle, which ovulate sooner post partum, than do beef cattle. 182,196 The lack of estrus probably reflects a lack of progesterone sensitization of the brain to the estrous-inducing effects of estradiol. 127 The first ovulation often results in a short-lived corpus luteum, leading to a short interestrous or interovulatory interval of around 8 to 10 days.50,116,144,162,183,189 These short cycles are noted as a cause of infertility in beef and dairy cows owing to regression of the corpus luteum before maternal recognition of pregnancy. 114,144 The basic mechanisms associated with ovarian acyclicity in the post-partum period have been reviewed,141,196 and studies of growth of ovarian follicles using an ultrasound technique have been reported. 159,182 The major factors limiting the onset of ovarian cyclicity post partum are (1) an inadequate frequency of the pulsatile secretion of LH necessary for the final stages of follicular development and maturation (similar to secretion during proestrus), and (2) an inadequate surge release of LH (preovulatory surge) in

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response to increasing concentrations of estradiol acting on the hypothalamicpituitary axis (estrogen positive feedback). Inadequate secretion of LH early post partum (10-20 days) initially reflects reduced function of the hypothalamic-pituitary axis and subsequently reflects increased sensitivity of the hypothalamic-pituitary axis to the inhibitory effects of estradiol on LH secretion (estrogen negative feedback).196 Plasma FSH concentrations are not limiting, because they are at normal levels shortly after parturition. 86,196 Early (up to 2-5 weeks) in the post-partum period, CnRH is secreted at low frequency (3-6 pulses/24 h) and is sufficient to replenish pituitary LH stores depleted during pregnancy. Subsequently, the frequency of CnRH pulses and, consequently, of plasma LH pulses increases, resulting in the development of ovarian follicles, which, in turn, secrete estradiol and inhibin. Estradiol stimulates the production of estradiol receptors in the pituitary and hypothalamus, which is necessary for estrogen-positive feedback. Finally, a further increase in plasma LH pulse frequency (similar to that in proestrus) stimulates follicular maturation and increased estradiol production, which in turn induces a plasma LH surge and ovulation. Studies using ultrasonographic technique in lactating dairy cows show that early in the post-partum period, there is growth and regression of small «4 mm) and medium-sized (5 - 9 mm) follicles. This is associated with a frequency of plasma LH pulses of 8 to 12 per 24 hours. Subsequently, a dominant follicle (> 10 mm) is detected associated with a plasma LH pulse frequency of 20 to 28 per 24 hours.) This follicle usually ovulates (without estrus) after approximately 3 to 5 days or becomes cystic and persists. The ovulatory cycles commencing early post partum « 10 days) are of either normal or long duration (18-24, > 24 days), but those commencing later (> 20 days post partum) are of short duration (9 -13 days). Between 10 and 20 days post partum, long, normal, and short cycles are observed. 183 The basis for short cycles is unclear but may reflect a need for progesterone priming of ovarian follicles for subsequent normal luteal function. Pretreatment with progesterone results in normal luteal function in early post-partum cycles in beef COWS. 67 ,160,196,200 In the studies cited previously using an ultrasonographic technique, it is suggested that the normal length of cycles occurring early post partum reflect a priming effect of progesterone of pregnancy, whereas for cycles commencing later post partum, there is no such priming effect and therefore the cycles are of short duration. 183 Factors Affecting the Duration of Ovarian Acyclicity Post Partum Factors affecting the duration of ovarian acyclicity post partum include nutrient status, suckling, season, presence of bulls, and genotype. 148,161,196 Nutrient Status. Reduced nutrient status increases the interval from parturition to first ovulation or estrus. The complexity of the relationship between nutrient status and reproductive function has been outlined and reviewed. 161 ,195 Nutrient status or balance reflects nutrient reserves and intake and the requirements for basic metabolism, growth, lactation, and activity. Reduced nutrient status is associated with lower plasma concentrations of LH and estradiol, delayed follicular development, and a delay in the occurrence of or decrease in the magnitude of the estradiol-induced plasma LH surge. The low plasma LH concentrations reflect an increased sensitivity of the hypothalamic-pituitary axis to the inhibitory effects of estradiol (as also described in the ewe 226) (estrogen negative feedback) and an ovarian steroid-independent reduction in secretion of LH by the hypothalamic-pituitary axis. 65 Blood glucose concentrations are suggested to be the factor linking nutrient status with reproductive function at the level of the hypothalamus. 195

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Suckling. Suckling (> 2 - 3 times/day) increases the duration of ovarian acyclicity, lowers plasma LH concentrations, increases the sensitivity of the hypothalamic pituitary axis to the inhibitory effects of estradiol on LH secretion,I,114,194,196,215,222 and inhibits the secretion of GnRH in the absence of estradiol. 233 The effect on LH secretion involves the endogenous opioid peptide system in the brain. Weaning (complete, partial [reducing the number of suckling episodes] or temporary [that is, for around 48-72 h associated with treatments to syncronize estrus)) can result in increased plasma LH concentrations and a hastening of the onset of ovulation and ovarian cyclicity. Season. Marked seasonal effects on the duration of post-partum acyclicity have been reported. Cows calving from late spring to early autumn have shorter periods of post-partum anestrus than cows calving from late autumn to early spring. 84 ,196 Cows calving in spring have shorter periods of post-partum anestrus than cows calving in winter. 131 ,148,151 Differences of 10 to 35 days are reported. The mean interval from calving to formation of the first dominant follicle is shorter in cows in autumn than in spring (difference of 13.2 days [6.8 vs 20 days)).182 These effects are considered to be related to seasonal differences in photoperiod and not to seasonal differences in nutrition. Photoperiod also influences plasma LH concentrations in ovariectomized heifers: concentrations are highest in winter and lowest in summer. 24 A similar effect of season on plasma LH pulse frequencies in ovariectomized ewes has been noted. 172 It may seem hard to explain the shorter post-partum interval in ovary-intact cows occurring around the time of lowest plasma LH concentrations in ovariectomized heifers (summer). In ewes, the onset of the ovulatory season is marked by a sudden decrease in the sensitivity of hypothalamic-pituitary axis to the inhibitory effect of estradiol on LH secretion. This change occurs just after the summer solstice (when plasma LH pulse frequency is lowest).172 Thus, the period of low degree of estrogen negative feedback and the period of high LH pulse frequency in ovariectomized animals are not coincident. In cows, a similar lack of temporal coincidence between mechanisms affecting plasma LH concentrations in entire and in ovariectomized animals would explain the paradox of low concentrations of plasma LH in ovariectomized heifers temporally related to the time of shortest duration of post-partum anestrus. Other studies in ewes have shown that the onset of the ovulatory season in ewes (owing to a sudden reduction in estrogen negative feedback) is due to refractoriness to inhibitory photoperiod (lengthening photoperiod-spring/early summer)173 and the onset of the anovulatory season is due to refractoriness to stimulatory photoperiod (shortening photoperiod-late autumn/early winter).I71 In the cow, it is probable that photoperiod also affects ovarian cyclicity through modulation of the degree of estrogen negative feedback. The nature and timing of mechanisms linking changes in photoperiod to changes in estrogen feedback remain to be defined. Presence of Bulls. The introduction of bulls to cows previously isolated from bulls can shorten the period of post-partum ovarian acyclicity196 by 12 to 20 days.2,25,51,190,232 The basic mechanisms involved have not been determined. Rams have a similar influence on acyclic post-partum ewes,144 and the effect is probably mediated through increased plasma LH concentrations as a result of reduced estrogen negative feedback and of increased steroid-independent secretion of LH by the hypothalamic-pituitary axiS. 118 These mechanisms may also be involved with the "bull effect." Depth of Anestrus The "depth of anestrus" is a concept (not infrequently mentioned, often not defined, nevertheless intuitively understood) that can be used to describe

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the responsiveness of animals to measures to induce ovulation or ovarian cyclicity. Animals in deep anestrus are unresponsive, whereas animals in shallow anestrus are responsive. Furthermore, animals in deep anestrus take longer to commence ovarian cycles than animals in shallow anestrus. This concept can be applied to individual animals or to groups of animals. The concept assists in understanding the interactions of factors affecting acyclicity and the efficiency of treatments and procedures used singly or in combination to induce ovarian cyclicity, or to synchronize ovulation in groups containing both cyclic and acyclic animals. Data for the cow (and ewe) indicate that factors contributing to the duration of anestrus also contribute to the depth of anestrus. These factors are season, breed, nutritional status, suckling status, stage post partum, and bull presence. Thus, animals can be considered to be at a point on a depth of anestrus scale, reflecting the effects of these factors (Fig. 2). There is some evidence that above the threshold on the scale for the commencement of ovarian cyclicity, alterations in the basic mechanisms affecting depth of anestrus, (more properly at this point, the "heights of estrus"), may also be manifest. Thus, season, which affects the depth of anestrus in acyclic cows, also has an effect on ovarian function in cyclic COWS. 124 Cyclic cows in early winter have larger estrogen-secreting dominant follicles with more granulosa cells, heavier corpora lutea, higher plasma progesterone concentrations, and lower luteal phase plasma LH pulse frequencies than do cows in spring. Basic Mechanisms. There is evidence that all factors increasing depth of anestrus suppress plasma LH pulse frequency by effects on hypothalamic-pituitary axis, which alters estrogen-independent or estrogen-dependent secretion

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DEPTH OF ANESTRUS Figure 2. Factors affecting the depth of anestrus in cows (individual or groups). The depth of anestrus is a concept to describe the responsiveness of animals to measures to induce ovarian cyclicity. Animals in shallow anestrus are more responsive than animals in deep anestrus. The basic mechanisms involved with the depth of anestrus in acyclic animals may also vary in cyclic animals, resulting in the heights of estrus.

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PATRICK J. WRIGHT AND JAKOB MALMO

of LH. Depth of anestrus therefore may be reflected as variations in plasma LH pulse frequency or in the degree of difficulty necessary to alter LH pulse frequency settings from those associated with ovarian acyclicity to those associated with ovarian cyclicity. An explanation for the seasonal difference observed in cyclic cows is that the larger follicles (observed in early winter) reflect a higher plasma LH concentration/pulse frequency during proestrus than occurs in spring. These larger follicles result in heavier corpora lutea and higher plasma progesterone concentrations than do the smaller follicles. The lower plasma LH pulse frequencies during luteal phase therefore reflect the higher plasma progesterone concentration. There is evidence that factors affecting the depth of anestrus affect responsiveness to treatments to induce ovulation, such as correcting nutrient deficiency, reduces responsiveness to GnRH195 and to weaning,222 and inhibits the "bull effect. "207 Responsiveness to pregnant mare serum gonadotropin (PMSG) in anestrous cows is affected by season, suckling, and nutrient status. 102,110,134,136 PHARMACOLOGIC AGENTS The hormone preparations used for the pharmacologic manipulation of fertility are listed in Table 1. Gonadotropin-releasing Hormone GnRH is a decapeptide which is synthesized by neurons in the hypothalamus and secreted into and taken to the pituitary by blood vessels of the hypophyseal portal system. 15 GnRH is rapidly cleared from the circulation (half-life of 4-7 minutes in rats).163 More potent analogs with slower clearance rates and increased binding affinities to pituitary GnRH receptors have been developed. 97 ,147,206 These include deslorelin ([D-Trp6]-GoRH) and buserelin ([D-Ser(tBu)6, Pr09 NEt])-GnRH. GoRH (2.5 p,g IV) elicits plasma LH pulses similar to naturally occurring pulses. 70 Higher dose rates (for example, 100250 p,g [even 0.5 -1.5 mg]) elicit surge release of LH that can cause ovulation of mature follicles. 64 ,75 In acyclic cows, such follicles are 10 mm in diameter or greater. 49 The response of immature follicles to the surge release of LH is luteinization or atresia. 1l3,210 The formation of normal corpora lutea after induced ovulation of mature follicles requires pretreatment with progesterone. 50 ,200 GnRH is used at higher dose rates to elicit a surge release of LH to induce ovulation of mature follicles, to treat cystic follicles, and, by a luteoprotective action, to reduce embryo loss. To date, studies of the administration of GoRH at low dose rates to stimulate follicular development and maturation have not devised an effective and reliable treatment for the induction of fertile estrus in acyclic cows. Such treatments are effective in ewes 122,225 and mares. 63 Gonadotropins The gonadotropins with follicle-stimulating activity (pregnant mare serum gonadotropin, FSH) are used in programs for estrus induction and superovulation. Human chorionic gonadotropin (with LH-type activity) is used to induce ovulation of mature follicles. Because these are foreign proteins, there is always the possibility that repeated treatments will induce the production of antibodies against the exogenous gonadotropin. N ormalluteal function subsequent to gonadotropin-induced follicular maturation and ovulation requires pretreatment with progestagen. 156,193 PMSG is derived from the blood of pregnant mares. It is a glycoprotein that exhibits both FSH and LH activity in the cow. 4 Studies of the half-life of PMSG

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revealed relatively rapidly (40 - 50 h) and slowly (118 -123 h) cleared components. 12,188 The slow clearance rate permits less frequent treatment but may contribute to excessive ovarian response. The action ofPMSG involves a reduction in follicular atresia and selection of increased numbers of dominant follicles. 130 FSH preparations (such as FSH-P, Burns-Biotec, Omaha, NE) are of pituitary origin, have a shorter half-life than PMSG, and usually contain significant amounts of LH. The half-life of an FSH preparation (NIH-FSH-S8) in the cow was approximately 5 hours.88 Preparations with mainly luteinizing hormone activity are derived from pituitary glands (for example, P-LH Burns-Biotec) and from the urine of pregnant women-human choronic gonadotropin (HCG). HCG is a glycoprotein secreted by the placenta of pregnant women and is excreted in the urine. In women, HCG is involved with the maternal recognition of pregnancy and maintenance of the corpus luteum. LH preparations have effects on ovarian follicles similar to those described for LH surges elicited by large doses of GnRH. Progestagens The main naturally occurring progestagen is progesterone, a steroid hormone produced by the corpus luteum. Free and protein-bound forms occur in the blood. Half-life studies reveal fast (2-3 min), slower (10-28 min), and slower still (54 min) cleared components. 66,217 Progesterone is metabolized in the liver, and metabolites are excreted in the bile. Some progesterone also is metabolized in the uterus and mammary gland and in the blood. 55 Blood progesterone concentrations resulting from treatment are affected by clearance rate, dose rate, method of delivery, sexual maturity, and prior exposure of the animal to estrogen and progestagen. Progesterone primes the brain to permit estrogens to elicit estrous behavior, suppresses secretion of GnRH, and is necessary for the maintenance of pregnancy. Progesterone pretreatment is necessary for normal luteal function subsequent to the induction of follicular maturation and ovulation in response to gonadotropins or GnRH. Progesterone pretreatment is necessary for adequate development of LH receptors in preovulatory follicles,62,67 and this may be necessary for subsequent normal luteal function. Studies in ewes showed that one injection of progesterone in oil (20 mg) is sufficient for normal luteal function, and that treatment for several days is necessary for estrous behavior. 197 Clinically useful synthetic progestagens have a longer half-life than progesterone and may be active when administered orally. Progesterone in oil administered intramuscularly results in detectable blood progesterone concentrations for 18 hours. Longer durations (9 to > 14 days) of detectable plasma progesterone can be achieved using implants or intravaginal progesterone-releasing devices. Plasma progesterone concentrations resulting from intravaginal devices are higher for a longer time in prepubertal heifers than in mature ovariectomized heifers, and concentrations are increased for the first 2 to 3 days after insertion by pretreatment with estradiol and progesterone. 138 Progestagens are used in programs to induce or synchronize estrus and ovulation. Progestagens may be administered orally, such as melengestrol acetate (MGA), 6 methyl-17 acetoxy-progesterone (MAP), and 6 chloro-g-dehydro-17 acetoxy progesterone (CAP); as subcutaneous implants, such as those containing norgestomet (Syncromate-B, Ceva Laboratories, Overland Park, KS); from devices placed in the vagina, such as progesteronereleasing intravaginal devices (PRIDS, Ceva, Australia); or from controlled internal drug-releasing devices developed in New Zealand (Eazibreed CIDR-B, CHH Plastic Moulding Co, Hamilton, New Zealand). 110 Both PRIDs and CIDRs

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PATRICK J. WRIGHT AND JAKOB MALMO

induce similar patterns of plasma progesterone. For 7 days, luteal phase concentrations (6 - 8 ng/mL) are achieved; concentrations then decline to 2 to 4 ng/mL or less at 12 to 14 days. 110,133,138,175,199 Estrogens The main naturally occurring estrogens in the cow are estradiol and estrone. Estrogens are steroid hormones. The main sources of estrogen are the granulosa cells of mature follicles and the placenta in late pregnancy. Free and protein-bound forms occur in the blood. The half-life is short « 5 min27). Estrogens are metabolized in the liver (and to a lesser extent, in many other tissues), and metabolites are excreted in urine and feces. Synthetic estrogens are metabolized more slowly by the liver, resulting in a duration of action longer than that of estradiol. The duration of effect is also influenced by the rate of absorption from the site of administration. Estrogens are luteolytic89,137,223 and are given at the start of progestagen treatment in programs to synchronize estrus. Luteolysis generally occurs 5 to 7 days after administration. Estrogens given to cows in late diestrus may induce cystic follicles associated with a premature LH surge. 164 There is some evidence that estrogens cause follicular atresia,41 and they may provide a method of controlling follicular waves to improve estrous synchrony after luteolysis. Corticosteroids Corticosteroids (cortisol, corticosterone) are produced by the adrenal cortex in response to adrenocorticotrophic hormone (ACTH) released from the pituitary. Corticosteroids are involved with carbohydrate and protein metabolism and have anti-inflammatory effects. Free and protein-bound forms occur in the blood. Corticosteroids are metabolized in the liver, and metabolites are excreted in the urine and feces. Fetal corticosteroids are involved with parturition through an effect on placental enzymes. The pharmacologic activity of synthetic corticosteroids is affected by their rate of absorption from the site of injection and their rate of clearance from the circulation. For the induction of parturition, short-acting (flumethasone, dexamethasone) and long-acting (dexamethasone trimethyl acetate, triamcinolone acetonide, suspensions of flumethasone or betamethasone) forms of corticosteroids are used. Prostaglandins Prostaglandins are 20-carbon unsaturated fatty acids, originate in many tissues, and have a variety of functions. 14,38,203 Prostaglandin F2a from the uterus is the luteolysin in the cow. Prostaglandins are cleared rapidly from the circulation and are metabolized particularly rapidly by the lung. 38,204 Stable analogs are used for their luteolytic action or for their mymetrialstimulatory effect in programs for the synchronization of estrus and ovulation, and for the induction of abortion or parturition. Available preparations and their luteolytic dose rates are dinoprost (Lutalyse, Upjohn, Kalamazoo, MI)25 mg, cloprostenol (Estrumate, ICI, Mobay, Shawnee, KS) - 500 j1.g, fenprostalene (Bovilene, Syntex, West Des Moines, IA) -1 mg, alphaprostol (Alfavet, Hoffman-La Roche, Nutley, NJ)-5 mg. INDUCTION OF ESTRUS In this section, the induction of estrus in post-partum cows with no uterine pathology is considered. The common economic objective in production systems is for cows to produce one calf each 365 days. In seasonally producing pasture-based dairy production, the time of calving should allow lactation to coincide with the period of optimal pasture growth. To achieve a calf each 365

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days, the cow must conceive by around 85 days post partum (depending on duration of gestation for the breed). Ovarian cycles should commence well before this period, because insemination at a number of heat periods may be required to achieve pregnancy and because fertility is higher in cows that have cycled prior to the inseminated-estrus than in cows that have not. 76,103 Procedures to induce estrus in acyclic cows post partum involve the reduction of the depth of anestrus (improved nutrient status; weaning-early, partial, or temporary; bull introduction) and hormonal treatments. Generally, hormone treatments involve treatment with progestagen and hormones that stimulate follicular development and maturation. Progestagen treatment (1) primes the brain so that subsequent increased concentrations of estradiol elicit estrous behavior, and (2) ensures normal luteal function after ovulation. 50,67,156,193 Follicular maturation is stimulated directly by the action of exogenous gonadotropins (PMSG, FSH), or by endogenous LH secretion stimulated by exogenous GnRH. In the field, some animals in the herd may have commenced ovarian cycles and some may be acyclic. This leads to variability in responsiveness to treatment with gonadotropins and GnRH. Some of the acyclic animals become potentially cyclic during a period of progestagen treatment. Hence, at the end of progestagen treatment, some animals enter proestrus and some are still acyclic. A dose rate of gonadotropin suitable for acyclic cows may be excessive for cyclic cows and result in multiple ovulations. Similarly, a dose regimen of GnRH suitable for acyclic cows may be excessive for cyclic cows. Such a dose may induce a premature LH surge by acting on a pituitary sensitized by estradiol from a maturing follicle. This may result in ovulation without estrous behavior. 125 Progesterone Progesterone treatment for approximately 7 days (e.g., CIDR-B, PRID) can hasten the onset of estrus post partum. 11 ,36,143 The main actions of progesterone are to delay any follicle maturation that may have commenced during the period of progesterone treatment and to ensure estrous behavior and normal luteal function associated with follicles maturing and ovulating over the days after treatment. It is unclear whether progesterone treatment per se can hasten the onset of ovarian cyclicity, but it may do so in cows in shallow anestrus. Calf removal at treatment withdrawal can improve the estrous response. 143 Progesterone/PMSG The use of progesterone treatments (7 -14 days) followed by PMSG has produced variable results. Anestrus in dairy cows in New Zealand102,110,111 is treated with CIDR-B for 7 days, followed by 400 to 600 IU PMSG. Of 850 cows studied, 85% ovulated within 2 to 3 days, but 22% of these did not exhibit estrous behavior. Factors affecting the response to treatment included herd, age, season, and nutrition. In another study73 this treatment synchronized but did not induce ovulation. Syncromate-B treatment followed by PMSG (400 IU) was beneficial in first-calf dairy heifers but not in older COWS. 47 Wide-ranging, difficult-to-understand studies 134,136 in beef and dairy cows indicated treatment with progesterone (PRID for 14 days), and PMSG on the day before PRID removal (375 IU for suckling anestrous or cycling animals, 500 IU or 750 IU for heifers and cows with nutritional anestrus) improved pregnancy rates to fixedtime insemination at 54 to 58 hours and 70 to 74 hours after PRID removal. Pregnancy rates were approximately 38% to 48%. Progesterone/GnRH No reliable method for the induction of fertile estrus using GnRH has yet been developed. Bolus injections of GnRH may cause ovulation if a large

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follicle (> 10 mm) is present. 90 Progesterone pretreatment is required for normal luteal function. 2oo Low-dose pulsatile treatments may cause follicular development leading to plasma LH surges, but normal luteal function is uncommon. 39,70,150,168,213,216 Continuous low-dose treatments are similarly ineffective. 7o ,169 Long-term (28 days) continuous low-dose treatment induced a short-term corpus luteum, but a subsequent normal corpus luteum did not eventuate as hoped even though plasma LH concentrations remained higher in treated cows than in control cows for 20 days.26 Continuous low-dose GnRH treatment after pretreatment with progesterone (PRID for 7 days) resulted in most animals developing normal luteal function, but the occurrence of estrus and fertility were not assessed. 26 These results and those from other studies in ewes 122,225 and COWS 177,200,211 show that progesterone pretreatment is essential for formation of normal corpora lutea. Continuous low-dose GnRH treatments may be less effective in anestrous cows than in ewes, reflecting a longer duration of increased plasma LH concentrations required for follicular maturation in the cow and the development of refractoriness of the pituitary to GnRH stimulation. The period of development of the first dominant follicle in acyclic post-partum cows was 3 to 5 days.182 In some studies,70,87 the pituitary became refractory to GnRH administered in continuous low doses after 24 to 48 hours, however, another study28 demonstrated that cows receiving treatment for 20 days had higher plasma LH concentrations than control cows. Another factor limiting the success of treatment early post partum may be inadequate estrogen positive feedback in response to estrogen from follicles induced to mature. SYNCHRONIZATION OF ESTRUS The main indications for the synchronization of estrus (and ovulation) are to facilitate artificial insemination in cows that are not handled intensively (beef cows, dairy heifers), to maximize the number of cows inseminated close to mating start date in seasonally producing dairy herds, to limit periods of close observation and insemination to discrete periods in nonseasonal dairy herds, and to facilitate embryo transfer programs. Theoretical and practical aspects of estrous synchronization have been reviewed recently.57,79,143,166,176 Procedures to synchronize estrus and ovulation in cyclic animals are based on synchronizing the end of the progestational phase and therefore the start of proestrus (estrogenic or follicular phase). Variability in the time required for follicular maturation and ovulation can result in a spread of estrus and ovulation over 5 to 6 days. This variability reflects the stage of the follicular wave at the onset of proestrus. Heifers may enter estrus sooner (average-12 h) than cows,18,143,166 which probably reflects that a shorter time is needed for follicles to mature,183,184 although this effect was not seen in heifers receiving one treatment of prostaglandin (Table 2). Fixed-time insemination results in somewhat lower fertility rates than insemination according to observed estrus. The end of the progestational phase can be synchronized using prostaglandin or progestagen treatment. Prostaglandin F2a or analogs terminate the progestational phase by causing luteal regression, which occurs over 24 hours.105 Progestagens administered over time permit the natural occurrence of luteal regression, and the progestational phase is terminated by cessation of treatment. Progestagen treatment suppresses the frequency of plasma LH pulses so that final follicular maturation and ovulation do not occur. Luteal phase concentrations of plasma progesterone permit follicular waves to occur.199 Plasma progesterone concentrations lower than those of luteal phase

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Table 1. Hormone Preparations Used for the Pharmacologic Manipulation of Fertility PREPARATION

RELEVANT ACTION

Gonadotropin-releasing hormone (via induced LH secretion)

large doses induce ovulation in mature follicles luteoprotective (through induction of atresia or luteinization of immature follicles) small doses induce follicle maturation reduction of follicular atresia, selection of numbers of dominant follicles, stimulation of follicular maturation induction of ovulation in mature follicles luteoprotective (through induction of atresia or luteinization of immature follicles) suppression of LH secretion sensitization of brain to estrus-inducing effects of estrogens required before follicle maturation and ovulation to ensure normal function of corpus luteum luteolysis luteolysis myometrial contractility

PMSG, FSH, HMG

HCG

Progestagens

Estrogens Prostaglandins

Corticosteroids

activation of enzymes systems in the placenta facilitating conversion of progestagens to estrogens

APPLICATION

Treatment of cystic follicles Reduction in embryo loss

Estrus induction (under investigation) Estrus induction Superovulation

Treatment of cystic follicles Reduction of embryo loss

Estrus synchronization Estrus induction

Estrus synchronization Estrus synchronization Abortion induction Parturition induction Improvement of fertility at prostaglandin-induced estrus Abortion induction Parturition induction

PMSG = pregnant mare serum gonadotropin; FSH = follicle stimulating hormone; HMG = human menopausal gonadotropin; HCG = human chorionic gonadotropin.

result in an extended lifespan for the dominant follicle and a suppression of follicular recruitment, resulting in a cessation of follicular waves. 99 ,199 Withdrawal of progesterone treatment in these situations results in a good synchrony of estrus owing to ovulation of these aged follicles. However, lowered fertility will probably result from an increased incidence of abnormal embryos caused by aged ova. 102,199,224 The onset of estrus is earlier with progestagen than with prostaglandin treatment, reHecting the more prompt withdrawal of progesterone. In treating groups in which some cows are cyclic and some acyclic, other measures lessening the depth of anestrus (such as weaning) may improve the response to treatment.

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The achievement of a degree of synchrony of estrus resulting in optimal fertility at fixed-time insemination requires control over both the onset of luteolysis and the timing of waves of follicular growth. Some control over both follicular waves and luteal function that results in some improvement in estrous synchrony over that obtained with prostaglandin treatment alone is obtained by the administration of a GnRH analog (Receptal 6 f.lg) and prostaglandin administered 7 days later. 21o The GnRH analog gains some control over follicular waves by inducing ovulation, luteinization, or atresia of follicles (according to their maturity), and the prostaglandin controls luteal function by inducing luteolysis. The degree of synchrony is still inadequate for optimal fertility to a fixed-time insemination. Some preliminary evidence suggests that the use of estrogens at the start of progestagen treatment (for example, Sycromate B221) may improve estrous synchronization by synchronizing follicular waves as a result of causing follicular atresia. 41 Prostaglandin Important features of the application of prostaglandin F2a or analogs are: 1. Luteolysis can only be induced in mature corpora lutea (days 5 -1 7, or, more reliably, days 7 -17 of the cycle). 2. Failure of complete luteal regression may occur early in the cycle «day 10). 3. The sensitivity of the corpus luteum to luteolytic effects increases during the cycle. 4. Estrus occurs in most cows over a period of 2 to 5 days after treatment. The distribution of stages of onset of estrus varies with the time in the cycle that animals are treated: the spread is greater for cows treated between days 8 and 14. Of cows treated early and later in the cycle, more show estrus on day 2 and 3: for cows treated in mid-cycle, more show estrus on days 3 to 4 (Table 2).69,80,100,109 The use of estrogen or GnRH98 treatments after prostaglandin treatment has not provided methods of practical significance for the reduction of the spread of estrus. For most cows, estrus occurs within a 5-day period. Fertility may be higher (by 10%) in prostaglandin-treated cows inseminated at estrus than in cows inseminated at naturally occurring estrus. 100,104

Prostaglandin Treatment Strategies. A number of treatment protocols reflecting the pharmacologic action of the drug and management, economic objectives, and technical resources have been described. 79,143,165 Technical resources include availability of people and facilities to handle cattle, detect estrus, identify corpora lute a by rectal examination, and inseminate (natural or Table 2. Proportions (0/0) of Cows in Estrus on Days after Prostaglandin Treatment (Day 0) DAY OF ESTRUS TREATMENT

1

2

3

4

5

6

2 treatments 12 days apart (heifers) (80) 1 treatment on day 7 (100) 1 treatment on day 12 (100) 1 treatment on day 16 (100) treatments on days 7 -16 (100) Heifers 1 treatment (100) (data set 1) (data set 2)

0 0 0 0 0 0 0

20 0 0 0 0 0 0

45 72 23 79 51 61 47.1

20 9 37 10 22 10 39.7

5 6 30 6 13 7.5 7.0

10 13 10 5 14 21.4 6.2

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artificial). Management aspects include the urgency to get cows pregnant and the desirability of a short calving period. Recommended times for fixed-time inseminations are 72 to 80 hours or 72 and 96 hours after treatment; perhaps 12 hours earlier for heifers. The protocols include (1) administration of prostaglandins twice to all cows 11 to 12 days apart, and insemination only after second treatment. Synchrony is better than with one injection, because most cows are at a similar stage of diestrus (days 6 - 9) at the second treatment, but there may be some failure of luteal regression. (2) Administration of two treatments: insemination of cows responding to the first, treatment of the others any time after day 6 to 12, and insemination when in estrus. (3) Insemination of all cows at naturally occurring estrus over 6 days, treatment of the rest on day 6, and insemination when in estrus. This permits assessment of the degree of cyclicity in the herd and of the accuracy of estrous detection before major costs are incurred. Within the first 5 days, 20% to 25% of cows should show estrus. (4) Give one treatment only: 70% to 75% randomly cycling animals should be in estrus within 5 days. (5) The objective of the "Why Wait" system is to inseminate as many cows as possible in a 10-day period, commencing at mating start date (MSD) (day 0) in a seasonally producing dairy herd. Heat detection starts 11 days before MSD. Cows in heat on days -11 to -6 are given prostaglandin on MSD. Cows in heat on days -6 to 1 are given prostaglandin on day 6. Cows are inseminated at observed estrus. Progestagen Treatment Important points relating to progestagen treatment are

1. Long-term treatment (14-20 days) results in lower fertility at the first synchronized estrus than for control animals. Suggested reasons include inadequate sperm transport, disordered hormone secretion or patterns of follicular development, and retarded embryo development. 143 2. Treatment for periods shorter than an estrous cycle length (e.g., 14-21 days) are effective because animals treated during proestrus and estrus do not ovulate or form a corpus luteum, and animals treated in metestrus have early luteal regression. 3. Treatment periods of 14 days or less (to 7 days) require the use of a luteolytic agent to ensure no functional corpora lutea at the end of treatment. An estradiol ester may be administered at the start of treatment, or prostaglandin treatment can be given the day before or at the end of progestagen treatment. Better synchrony occurs if prostaglandin is given the day before so that endogenous progesterone does not extend the progestational phase for some cows past the time of withdrawal of exogenous progestagen. Prostaglandin treatment may be more reliable than estrogen treatment to ensure luteal regression. 4. It is suggested that for optimal fertility, high (luteal phase) plasma progesterone concentrations should be maintained for the duration of treatment. 175,176 Failure so to do may result in persistence of a dominant follicle and suppression of a follicular wave. 99,199 This follicle undergoes final maturation promptly at progestagen withdrawal, resulting in early and good synchrony of estrus but reduced fertility due to aged ova, resulting in embryo loss. Shortterm treatments (7 - 9 days) commencing in the second half of the cycle resulted in lower pregnancy rates than treatment commencing early in the cycle. These treatments involved feeding MGA for 7 days and prostaglandin injection on the last day of feeding,10,145 or Syncromate-B treatment,17 The reduced fertility could have reflected lower plasma progesterone concentrations owing

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to the absence of a corpus luteum, resulting in an aged follicle. PRIDs and CIDRs were found to maintain luteal phase progesterone concentrations for 7 to 8 d ays 110,133,138,175 Short-term Progesterone Treatment 1. Syncromate-B is a commercially available short-term progestagen treatment. Practical aspects of its use have been discussed79,166 and the results of its use reviewed. 143 Treatment involves a subcutaneous implant containing 6 mg norgestomet and an injection of 3 mg norgestomet and 5 mg estradiol valerate at the time of implant placement. The implant is removed after 9 days, and most cows are in estrus 36 to 60 hours later. A somewhat better synchrony is obtained than with prostaglandin treatments, and fixed-time insemination is recommended 48 to 54 hours (or at 48 and 72 h) after implant removal. N orgestomet from the implant suppresses LH secretion and blocks proestrus. The injected norgestomet blocks estrus and ovulation in cows treated from day 1 7 until ovulation and shortens the life-span of the corpus luteum in cows treated early after ovulation. Estradiol valerate is given to induce luteal regression in animals with corpora lutea at the time of implant placement. A review of a large number of studies shows that the proportion of cows in estrus after treatment is 77% to 100%; the first service conception rate is 33% to 68%.143 Factors associated with reduced conception rates include a low proportion of cows in the herd cycling before treatment; luteal dysfunction, perhaps reHecting inadequate secretion of LH after implant removal; poor body condition; and delayed occurrence of estrus and ovulation. 128 Coincident implant and calf removal (until insemination) may improve conception rates. Administration of CnRH (250 p,g) 30 hours after implant removal is reported to improve conception rates to a 48-hour, timed insemination, but continuous low-dose infusion suppressed the occurrence of estrus. 125 Significant concentrations of plasma progesterone have been detected in some cows at implant removal, suggesting inadequate luteal regression. 125,149,191 Better results may be obtained using prostaglandin treatment to induce luteolysis on the day before implant removal. 221 2. CIDR-B/prostaglandin. Treatment with CIDR-B for varying times (7, 14, 21 days) and prostaglandin at CIDR removal resulted in estrus in 93% to 100% cows within 96 hours. Fertility was best for the short-term treatment (for example, by 16% for 7 vs 14 day CIDR). 102,110 3. PRID/prostaglandin. A treatment regimen that limited periods of observation and insemination to 6 days out of each 3 weeks has been validated. 45 Cows received either (1) a PRID for 7 days (days 1-7), with a prostaglandin injection on day 6, or (2) prostaglandin, then 13 days later, a PRID for 9 days. Cows were inseminated when in estrus, and a PRID was inserted 12 days after insemination and removed 9 days later to synchronize returns to insemination. 4. Other strategies giving good fertility involve synchronization of estrus using long-term progestagen treatment,18,23,77 and a prostaglandin injection 16 to 18 days after the end of treatment with progestagen. The reduction in fertility at the progestagen synchronized estrus is avoided, and the good fertility at the prostaglandin-synchronized estrus is exploited. The progestagen treatment ensures all animals are in luteal phase and responsive to prostaglandin treatment. SUPEROVULATION Basic Aspects Much remains to be learned concerning the mechanisms controlling the waves of follicular growth, follicular recruitment, selection of the dominant

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follicle, and follicular atresia that occur during the estrous cycle and early pregnancy. Currently, it is believed that FSH is required to stimulate growth and development of small follicles and that the effects of FSH are modulated in the ovary by autocrine and paracrine factors (for example, inhibin, insulin-like growth factor, follicle regulatory protein, transforming growth factor) that control ovarian growth, atresia, and selection of the dominant follicle. 68 ,186 The induction of superovulation using exogenous gonadotrophins (FSH, PMSG) overrides these intraovarian controlling mechanisms, resulting in reductions in both follicular atresia and the selection of increased numbers of dominant follicles. 123,130 Practical Aspects Practical aspects of the induction of superovulation have been reviewed. 57,117 The hormones commonly used to induce superovulation are FSH of pituitary origin or PMSG. Preparations derived from the urine of menopausal women (human menopausal gonadotropin [HMG]) have also been used3,121 and had effects similar to FSH of pituitary origin. Comparisons of results for FSH and PMSG treatments show equivocal results, with the effects of the two preparations being similar, 29,129 or better responses being obtained with FSH5,40 or with PMSG.228 A feature of all treatments is the variability in ovarian responsiveness. Some variability can be associated with nutrient status, breed, and strain; however, much variability occurs within similar groups of animals. Major reductions in this variability will require new approaches to treatment based on understanding of the mechanisms controlling follicular growth and atresia, and the selection of dominant follicles. Over a number of studies using various gonadotropin preparations, the range of mean responses (each with a large standard error) were 6 to 33 corpora lutea; 3 to 27 ova/embryos recovered; and 2.5 to 11 transferable embryos.29,34,56,96,121,180,181 Treatment involves the administration of FSH or PMSG commencing middiestrus (days 8 - 14 of the cycle) and the administration 2 days later of prostaglandin to cause luteolysis and the start of proestrus. Treatment early or later in the cycle results in poorer responses. 58,185 A single injection of PMSG (long half-life) or twice-daily injections of FSH (shorter half-life) on successive days are required (Table 3). FSH given twice daily at a constant dose (5 mg) yielded

Table 3. Schedule of Treatments to Induce Superovulation (Day 1 is the First Day of Treatment Between Days 8 -14 of the Cycle) DAY

1 AM PM 2AM PM 3AM PM 4AM PM 5AM PM 6AM PM

TREATMENT

1

TREATMENT

2

TREATMENT

3

prostaglandin

FSH (5 mg) FSH (5 mg) FSH (4 mg) FSH (4 mg) FSH (3 mg) prostaglandin FSH (3 mg) FSH (2 mg) FSH (2 mg)

FSH (5 mg) FSH (5 mg) FSH (5 mg) FSH (5 mg) FSH (5 mg) prostaglandin FSH (5 mg) FSH (5 mg) FSH (5 mg)

AI AI AI

AI AI AI

AI AI AI

PMSG (2500IU)

RECIPIENTS

prostaglandin

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WRIGHT AND JAKOB MALMO

similar results to the reducing dose rate regimen. 32 The induced luteolysis is followed by patterns of hormone secretion similar to those in a normal cycle, but estrus and the LH surge occur sooner after prostaglandin (around 48 h) than for a normal cycle (around 72 h).12.20 Plasma estrogen concentrations and the time to the onset of the LH surge are proportional and inversely proportional, respectively, to the numbers of follicles that develop. 12 Treatments with gonadotropins cease at estrus, and because ovulation occurs over 24 hours, twice daily inseminations commencing 12 hours after estrus onset are recommended. Cows coming into estrus early usually have good superovulatory response and embryo recovery, those with late estrus have poor responses. Recipients receive prostaglandin 24 hours before the donor cows (on day 2). Nonsurgical embryo collection is performed on days 6 to 8 after the onset of estrus. In terms of ovulation rate and numbers of transferable embryos, the response to PMSG treatment can be improved by treatment with anti-PMSG serum at estrus or after the preovulatory LH surge. 28 ,29,180 This treatment results in suppression of formation of a second wave of follicles. There are fewer follicular cysts, and the period of ovulation is shorter than for PMSGtreated cows not receiving antiserum. OfPMSG-treated cows, 10% to 15% fail to show an LH surge.1 2,29,178 The response to treatment with FSH is affected by the amount of LH in the preparation. Reduction of LH content results in better responses in terms of fertilization rate and proportion of transferable embryos.19..34,35 It is considered that LH in the FSH preparation interferes with normal follicle and oocyte development. 19,33,34 The LH activity in PMSG preparations can vary widely, 139 but it is not clear whether this variation can affect results. Batches of PMSG examined by others showed no significant variability in LH activity, 4 and there was no batch effect on responses. The reduced efficacy of high doses of gonadotropin preparations may reSect increasing LH activity. High doses of PMSG are associated with reduced ovulation rates. 179 High doses of FSH-P and HMG are associated with reduced fertilization rates. 121 ,146 High doses of an FSH preparation of low LH content (Folltropin) showed no reduction in efficacy.56 The administration of GnRH or HCG applied generally at the time of estrus does not produce a consistent improvement in response 46 ,155,181,214,227 but may be helpful if delayed ovulation is suspected. Recent studies have shown that ovulatory response was not improved by giving a small dose of FSH-P early (day 2) in the cycle before the main treatments,167 and it was suggested that the improvement reported in another study158 may have been associated with the poor ovulatory responses in that group of animals.

CYSTIC OVARIAN DISEASE Cystic ovarian disease is a condition characterized by cystic structures on the ovaries reSecting ovulatory failure and alterations to the normal ovarian cycle (for reviews see references 75, 170, 231). Cystic structures can be identified as those that are greater than 2.5 cm in diameter that persist for longer than 10 days. Follicular cysts are thin-walled with little, if any, luteal tissue. Luteal cysts are thicker walled with luteal tissue. Follicular cysts may be single or multiple and may be present in one or both ovaries. Luteal cysts commonly occur as single structures in one ovary. Follicular cysts are more common than luteal cysts. The incidence is suggested to be on the order of 30% of post-partum cows; many cysts occur early in post-partum period and probably resolve spontaneously before being diag-

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nosed. Factors suggested to be associated with the occurrence of cystic ovaries are high level of production, reduced nutrient status, season (higher incidence in autumn/winter), uterine infections,16 age, and peripartal stress. Failure or inadequate LH secretion in response to increasing plasma estradiol concentrations (due to attenuated estrogen positive feedback) is probably an etiologic factor, especially early post partum, in the development of luteal and follicular cysts. Cows with cystic follicles fail to show an LH surge in response to exogenous estrogen. 165 Estradiol administered late in the cycle can result in a premature LH surge and the development of ovarian cysts (both follicular and luteal). 164 Treatment of cyclic cows with ACTH suppressed the LH surge resulting in ovulatory failure and follicular cystS. 164 ACTH may be involved in the occurrence of stress-related cystS. 16 The cause of cysts occurring in cows after a period of ovarian cyclicity is unclear. Ovarian cysts in most (62-85%) cows are associated with anestrus; the remainder exhibit persistent, intermittent, or, sometimes, extreme estrous behavior. Cysts occurring early post partum are more likely to be associated with anestrus. Treatment and control of cystic ovarian disease have been reviewed,64 financial aspects of treatment strategies involving GnRH and HCG analyzed,142 and recent studies of treatment reported. 3o,140 The aim of treatment is to stimulate the resumption of ovarian cyclicity. Hence, follicular cysts should be treated with HCG or GnRH to induce luteinization of follicular cells. A survey of published results64 showed that GnRH treatment resulted in ovarian cyclicity in 62% to 97% of cases with conception rates of 37% to 57% within 28 to 30 days of treatment. Luteal cysts should be treated with prostaglandin to cause luteolysis. 91 ,140 Prostaglandin treatment of luteal cysts results in luteolysis and fertile estrus in 90% of cases. Treatment of cows with prostaglandin 7 days after induced luteinization of follicular cysts may result in luteolysis followed by a recurrence of cysts. Treatment with prostaglandin 15 days after GnRH is considered preferable. The efficacy of GnRH and HCG are similar. 64 Treatment with GnRH is preferable because of the risk of development of antibodies to the foreign protein (HCG). Differentiation between follicular cysts and luteal cysts may require detection of plasma progesterone in the milk or blood. Treatment of cows with luteal cysts with GnRH and prostaglandin simultaneously did not impair the luteolytic function of prostaglandin. 30 Recommended dose rates for HCG are 2500 to 5000 IV; dose rates for GnRH are 100 to 250 J1g. Other, less effective treatments include administration of FSH/PMSG, corticosteroids, and progesterone, alone or in combination with HCG. The administration of GnRH (100-200 J1g) on days 12 to 14 post partum reduced the incidence of ovarian cysts,64,75 probably by causing ovulation of potentially cystic follicles. This preventative measure would be most useful in situations of a high incidence of follicular cysts, as may occur during autumn. 170,182

IMPROVEMENT OF CONCEPTION RATE OR EMBRYO SURVIVAL Based on a survey of the literature,202 the embryonic loss rate in cattle is 38%. This reflects a fertilization rate for normal cows and heifers of 88% to 90%, and a calving rate to a single service of 55%. The highest incidence of embryo loss occurs about days 15 to 18 after estrus. This is the time of maternal recognition of pregnancy. An improvement in pregnancy rates would reduce labor and insemination costs, and in seasonal areas, would ensure the cow conceived (and calved) at the most appropriate time for optimal production.

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GnRH During the Post-partum Period The results of many studies of the effects of GnRH administered during the post-partum period on reproductive efficiency have been reviewed. 90 Overall, the findings are equivocal. Significant effects have been detected in some studies but not in others. Significant effects reported include a reduced frequency of cows with cystic ovaries, shortened calving to conception intervals, and a reduction in the number of services/conception. Treatment is expected to be of benefit in situations of a high incidence of cows with cystic follicles. Prostaglandin During the Post-partum Period Prostaglandin administered once between 18 to 28 days post partum improved conception rates (62% vs 48%)229,230 or reduced the number of services per conception 120 in dairy cows. The effect did not involve luteolysis as it occurred in cows with plasma progesterone concentrations less than 0.5 ng/mL, but it may have involved an effect on uterine involution. The rate of uterine involution in normal cows is proportional to the duration and concentration of endogenous prostaglandin metabolite (from the uterus) in the blood. 94 ,95,115 In other studies of larger numbers of cows, however, no beneficial effect of prostaglandin treatment was detected. 107 The reasons for the variable responses are unclear. GnRH (or HCG) at the Time of Insemination The administration of GnRH around the time of insemination at observed estrus of normal or repeat breeder cows has been recorded to increase (by up to 45%) pregnancy rates or to have no effect. 6,21,126,152,205 Beneficial effects may be more likely when untreated cows have low fertility. On the basis of a comprehensive survey of the literature and original studies, it was concluded that beneficial effects were found in only 25% of trials and that general application of the treatment with GnRH or with HCG could not be recommended. 93 Fertility at Prostaglandin-induced Estrus Fertility at prostaglandin-induced estrus was 9% higher than at naturally occurring estrus,100,104 and a similar effect (7% improvement in pregnancy rates) has been observed in other studies. 101 ,192 The reason for this effect is not known, but it may be associated with overall better quality of ova associated with a period of luteolysis shorter than that which occurs naturally. 100 GnRH at Mid-diestrus The administration of GnRH analog buserelin (Receptal, Hoechst A.G., Somerville, NJ) 10 f.Lg once on days 11, 12, or 13 postinsemination increased pregnancy rates by 11 %, and in cows returning to service improved conception rates by 15.6% in one trial 112 but had no effect in another.72 The reason for the variability in results is not known. GnRH treatment was considered to act through delaying luteal regression, thereby increasing the time in which maternal recognition of pregnancy could occur. Treatment resulted in fewer short cycles « 21 days) in cows returning to estrus than in control cows. 106,112 The nature of the luteoprotective mechanism in response to induced LH secretion could result from (1) a direct effect ofLH on the corpus luteum or (2) LH-induced atresia or luteinization of small follicles. An effect on the small follicles would lead to alterations in the patterns of secretion of estradiol necessary for prostaglandin secretion from the uterus leading to lute01ysis. 106,108,210 A beneficial effect on pregnancy rates (22.7% vs 15.6%) was obtained

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using HCG (3300 IU intravenously on day 15) in heat-stressed cows with presumed retarded embryo development,209 but no effect was seen in normal COWS. 93 The mechanism was probably similar to that obtained with GnRH-induced LH secretion. 210 The situations in which mid-diestrous treatment with GnRH (or HCG) is beneficial to fertility need to be better defined before the routine application of this treatment can be recommended. Progesterone Administered after Insemination plasma progesterone concentrations were noted to be higher in pregnant cows than in nonpregnant cows by day 10 after insemination,86 but the nature of any cause - effect relationship has not been determined. Treatment of cows with progestagens after insemination has not consistently improved fertility. 31 In a herd of low fertility (cause not diagnosed), treatment with PRIDS from days 5 to 12 or days 10 to 1 7 after insemination improved pregnancy rate by 30%.174 In cows of normal fertility, treatment with CIDRs for 6 to 12 days commencing 6 to 8 days after insemination improved pregnancy rates by 9% to 19%,102 although similar use of used CIDRs in PMSG-treated cows had no beneficial effect.135 This lack of effect may have reSected that plasma progesterone concentrations from used CIDRs were lower than from fresh CIDRs, or an absence of effect of supplementary progesterone in animals with higher progesterone concentrations than normal resulting from PMSG treatment. Any improvement in pregnancy rate may result from improved embryo growth maximizing the occurrence of maternal recognition of pregnancy. Such an effect on embryo growth mediated through a stimulation of endometrial secretory function was observed in cows treated with progesterone on days 1 to 4 after insemination. 48

INDUCTION OF ABORTION AND PARTURITION Pregnancy maintenance is dependent on progesterone. Sources of progesterone that can contribute to the maintenance of pregnancy in the cow are the corpus luteum, placenta, and adrenal glands. 154 For the first 150 days of pregnancy, the corpus luteum is the mandatory source of progesterone. From 150 to 250 days of pregnancy, progesterone from extra-ovarian sources (placental54 and adrenal gland220 ) may be sufficient to maintain pregnancy if corpus luteum function is terminated. From 250 days of gestation, the corpus luteum is again necessary for pregnancy maintenance. Placental progesterone production declines are associated with increased fetal corticosteroid activity, resulting in increased placental synthesis of estrogens. 154 Prostaglandin F2a can reliably induce pregnancy failure through its luteolytic action up to 90 days and after 250 days of gestation. Corticosteroids act at the placenta, suppressing progesterone secretion and increasing estrogen production, which leads to prostaglandin release by the uterus. In our experience, corticosteroids can reliably induce parturition from day 180 of gestation. Pregnancy termination from day 150 to 180 requires both prostaglandin and corticosteroid treatment. The prostaglandins cause luteolysis, and the corticosteroids suppress progesterone production by the placenta and adrenal gland. The efficacy of corticosteroid treatment clearly requires a functional placenta. In situations with a nonfunctional placenta such as fetal mummification, prostaglandin treatment is indicated. 212

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Applied Aspects The clinical aspects of the induction of abortion and parturition have been well reviewed. 7,8,218,219 Indications for the induction of abortion and parturition include animals entering feedlots, inappropriate matings, pathologic pregnancy, and late-to-calve cows in seasonal pasture-based dairy areas. Late calving cows at mating start date are less likely to have commenced estrous cycles and are likely to have lower conception rates than early calving cows. The aim is for calving to have occurred by 40 days before the mating start date. Induction of Abortion. Up to 3 months of gestation, a luteolytic dose of prostaglandin F2a or analog causes abortion in most animals within 5 to 10 days. Prostaglandin given between 3 and 5 months causes abortion in most animals but is somewhat less reliable. After 5 months of gestation, prostaglandin plus corticosteroid (25 mg dexamethasone) reliably causes abortion (2-10 days after treatment) in most animals. In animals more than 6 months pregnant, a single injection of long-acting corticosteroid causes abortion in most animals. In cows more than 4 months pregnant, placentae usually are retained. Abortion failure may be associated with failure of luteal regression and with fetal mummification. Estrogens administered in large doses, repeated if necessary, are less reliable. Induction of Parturition. Calves born up to 2 weeks before term have good viability; those born more than 3 weeks before term have low viability. Placental retention is commonly associated with premature parturition, and its incidence reHects the degree of prematurity. Short-acting corticosteroids result in parturition in 24 to 72 hours in 80% to 90% of cows treated within 2 weeks of their expected calving date. Retained placentae are common, and calf viability is excellent. The incidence of retained placentae is not reduced by the administration of estrogens 13 or prostaglandins. 37,92 Treatments involving both corticosteroids and prostaglandins may result in increased responsiveness and a shorter time (36 h) to delivery.92 Long-acting corticosteroids may be administered up to 3 months prior to the expected calving date and result in parturition 2 to 3 weeks after treatment. The time of calving is much more variable than with short-acting corticosteroids, and the incidence of retained fetal membranes lower and calf mortality is higher. Calf mortality increases as the degree of prematurity of the induced calf increases. Calf mortality is associated with premature placental detachment. Short-acting corticosteroids or prostaglandins administered 7 to 12 days after a long-acting corticosteroid result in calving 2 to 3 days later. Prostaglandin treatment gives a similar response to short-acting corticosteroids, with parturition occurring 24 to 72 hours after treatment. We have found butterfat production in cows induced with long-acting corticosteroids at longer than 6 months of gestation to be around 96% that of control cows calving naturally. In our seasonally producing area, failure to induce calving in potentially late calving cows results in a loss in production as a result of a shorter lactation period in late calving cows than in cows calving at the normal time. All cows in the herd are dried off at the same time (mid-winter). SUMMARY The professional application of agents to the manipulation of fertility of cows requires basic and applied knowledge of the physiologic mechanisms that are affected and of the pharmacologic agents that are used. In all areas of the pharmacologic manipulation of fertility, the achievement is less than the ideal, and further research is required to improve the efficiency of treatments. The induction of estrus in acyclic animals can involve a reduction in the depth of anestrus, pretreatment with progestagen to ensure estrous behavior

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and the formation of a normal corpus luteum, and then treatment with exogenous gonadotropin. Responsiveness to treatment can be variable and reflects the depth of anestrus of the animals. Improved treatment regimens require a knowledge of the basic mechanisms involved with the depth of anestrus, a means of assessing the depth of anestrus, and an understanding of the hormonal requirements of ovarian follicles for development and maturation in animals at different depths of anestrus. The optimal precision in the synchronization of estrus (and ovulation) in cyclic animals requires the synchronization of both follicular waves and the end of progestational phase. The end of progestational phase can be synchronized effectively using prostaglandin F2a (or analogs), or by treatment with progestagens with or without luteolytic agents. Procedures to synchronize follicular waves need to be established. The induction of superovulation can be achieved readily using gonadotropins prior to estrus synchronization using prostaglandin F2a. The responses to standard treatments in terms of ovulation rates and yield of transferable embryos are highly variable. The development of procedures to reduce this variability requires an understanding of the intra-ovarian mechanisms involved in recruitment of follicles for a wave of follicular growth, in the selection of dominant follicles for further development, and in the mechanisms controlling follicular atresia. Cystic ovarian disease can be treated effectively using HCG or GnRH (follicular cysts) or prostaglandin F2a (luteal cysts). The basic mechanisms resulting in failure of estrogen positive feedback on LH secretion (that results in cystic follicles) remain to be determined. Small but significant increases in pregnancy rates can be achieved treating cows with prostaglandin during the post-partum period, with prostaglandin to induce estrus for insemination, with GnRH or HCG at estrus, and with GnRH or progestagen treatment during diestrus. Beneficial effects of treatment have been shown in some trials but not in others. Studies are required to understand the basic mechanisms involved so as to determine appropriate situations or animals in which these treatments will be effective. The induction of abortion or parturition can be achieved readily using prostaglandin or corticosteroid treatment as is appropriate for the stage of gestation. Studies are required to understand the reasons for treatment failure, to improve fetal viability, and to reduce the incidence of retained fetal membranes associated with treatment. ACKNOWLEDGMENT

The contribution of Carolynne Chisholm in the preparation of the figures is gratefully acknowledged.

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