Pharmacologic Manipulation of Fertility: Applied Pharmacology and Therapeutics

Applied Pharmacology and Therapeutics II 0749-0720/92 $0.00 + .
20
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 concentra-
tions, and responses to exogenous hormones has arisen associated with the
availability of sensitive assay procedures, pure hormone preparations, and in-
creasing 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 gonado-
tropin-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 57
58 PATRICK J. WRIGHT AND JAKOB MALMO
II
luteolysis
Preovulatory surge
of LH (and FSH)
"0
o
o
:0
.~
C/)
Q)
"
C
o Estradiol
E
o
I LH
Luteal phase window Follicular phase window
Estradiol
--------------,----' Progesterone
Progesterone
/ \
LH
/
Estradiol
,,-/
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 fre-
quency 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 communi-
cation 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 fre-
quency of LH pulses increases (20-30/24 h), causing maturation of the preo-
vulatory follicle, which in turn produces increased secretion of estrogens and
inhibin. Estrogens act on the progesterone-primed brain to elicit estrous be-
havior and on the hypothalamic-pituitary unit to stimulate (estrogen positive
feedback) the surge release ofLH (preovulatory surge). This LH surge, occur-
ring around the start of estrus and lasting 8 to 10 hours, results in ovulation
PHARMACOLOGIC MANIPULATION OF FERTILITY 59
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 se-
creted 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 ac-
tion on the uterus is required for the production of prostaglandin F2a. Estro-
gens 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 clock-
the 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 secre-
tion 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 (domi-
nance phase), and further increases in size; the other recruited (subordinate)
follicles become atretic. If the dominant follicle is exposed to proestrous fre-
quencies 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 associa-
tion 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 preg-
nancy). 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
the antiluteolytic effect of the embryo results from bTP-1 causing increased
activity of an endometrium prostaglandin synthetase inhibitor, leading to re-
duced secretion of prostaglandin F2a. 61 ,208,210 Other changes in endocrine func-
tion that probably are not related to trophoblast protein-1 have been described
in early pregnancy in ewes and cows. Pregnant animals had higher concentra-
tions of plasma progesterone and lower concentrations of plasma estradiol,
uterine oxytocin receptors, and luteal oxytocin than nonpregnant ani-
mals. 43 ,60,85,187
Pregnancy
Progesterone is required throughout pregnancy (duration of 280 days-
range of270-292 days). The main source of progesterone is the ovary; second-
ary sources are the placenta and adrenal gland. In the second and third trimes-
ters, 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 hypo-
thalamic-pituitary-adrenal axis, leading to increased concentrations of cortico-
steroids 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 se-
creted from the posterior pituitary in response to the fetus entering the birth
canal. Uterine contractility is stimulated by prostaglandins and oxytocin. Pros-
taglandin 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-par-
tum 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
response to increasing concentrations of estradiol acting on the hypothalamic-
pituitary axis (estrogen positive feedback). Inadequate secretion of LH early
post partum (10-20 days) initially reflects reduced function of the hypotha-
lamic-pituitary axis and subsequently reflects increased sensitivity of the hypo-
thalamic-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 devel-
opment of ovarian follicles, which, in turn, secrete estradiol and inhibin. Estra-
diol stimulates the production of estradiol receptors in the pituitary and hypo-
thalamus, 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 approxi-
mately 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 pro-
gesterone 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 tech-
nique, 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 partu-
rition to first ovulation or estrus. The complexity of the relationship between
nutrient status and reproductive function has been outlined and re-
viewed. 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 hypotha-
lamic-pituitary axis to the inhibitory effects of estradiol (as also described in the
ewe 226) (estrogen negative feedback) and an ovarian steroid-independent re-
duction in secretion of LH by the hypothalamic-pituitary axis. 65 Blood glucose
concentrations are suggested to be the factor linking nutrient status with re-
productive function at the level of the hypothalamus. 195
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 secre-
tion,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 pep-
tide 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 concentra-
tions 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 differ-
ences in photoperiod and not to seasonal differences in nutrition. Photoperiod
also influences plasma LH concentrations in ovariectomized heifers: concentra-
tions 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 ovariecto-
mized 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 simi-
lar lack of temporal coincidence between mechanisms affecting plasma LH
concentrations in entire and in ovariectomized animals would explain the para-
dox 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 se-
cretion 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
the responsiveness of animals to measures to induce ovulation or ovarian cycli-
city. 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 affect-
ing 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 con-
centrations, 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-pitui-
tary axis, which alters estrogen-independent or estrogen-dependent secretion
HEIGHT OF ESTRUS
UPLIFTING FACTORS + T DEPRESSING FACTORS ,
OVARIAN CYCLICITY
TIME POST PARTUM EARLY POST PARTUM
NUTRIENT DEFICIENCY
NUTRIENT SUPPLEMENTATION
SUCKLING
BULL INTRODUCTION PHOTOPERIOD

increasing (INHIBITORy)
PHOTOPERIOD (STIMULATORy)
! responsiveness to
treatments to induce
ovulation /estrus
decreasing
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.
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 asso-
ciated with ovarian cyclicity. An explanation for the seasonal difference ob-
served 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 re-
sponsiveness to treatments to induce ovulation, such as correcting nutrient
deficiency, reduces responsiveness to GnRH195 and to weaning,222 and in-
hibits the "bull effect. "207 Responsiveness to pregnant mare serum gonadotro-
pin (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 hypothala-
mus 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, 100-
250 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 in-
duced ovulation of mature follicles requires pretreatment with progester-
one. 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 luteopro-
tective 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 superovula-
tion. 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 antibod-
ies against the exogenous gonadotropin. N ormalluteal function subsequent to
gonadotropin-induced follicular maturation and ovulation requires pretreat-
ment 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
revealed relatively rapidly (40 - 50 h) and slowly (118 -123 h) cleared compo-
nents. 12,188 The slow clearance rate permits less frequent treatment but may
contribute to excessive ovarian response. The action ofPMSG involves a reduc-
tion in follicular atresia and selection of increased numbers of dominant
follicles. 130
FSH preparations (such as FSH-P, Burns-Biotec, Omaha, NE) are of pitui-
tary 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 preg-
nant 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 hor-
mone 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 pro-
gesterone 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 pre-
ovulatory 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 concentra-
tions resulting from intravaginal devices are higher for a longer time in prepu-
bertal 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 synchro-
nize 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 progesterone-
releasing 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
induce similar patterns of plasma progesterone. For 7 days, luteal phase con-
centrations (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 es-
trone. 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 luteoly-
tic89,137,223 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 cor-
tex in response to adrenocorticotrophic hormone (ACTH) released from the
pituitary. Corticosteroids are involved with carbohydrate and protein metabo-
lism 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 parturi-
tion 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 flu-
methasone 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 mymetrial-
stimulatory 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, fenpros-
talene (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 sys-
tems 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
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 Proce-
dures to induce estrus in acyclic cows post partum involve the reduction of the
depth of anestrus (improved nutrient status; weaning-early, partial, or tem-
porary; bull introduction) and hormonal treatments. Generally, hormone treat-
ments involve treatment with progestagen and hormones that stimulate follicu-
lar 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 mat-
uration 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 treat-
ment 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 fixed-
time 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
follicle (> 10 mm) is present. 90 Progesterone pretreatment is required for nor-

mal luteal function. 2oo Low-dose pulsatile treatments may cause follicular de-
velopment leading to plasma LH surges, but normal luteal function is uncom-
mon. 39,70,150,168,213,216 Continuous low-dose treatments are similarly in-
effective. 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 concen-
trations 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 demon-
strated that cows receiving treatment for 20 days had higher plasma LH con-
centrations 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 ovula-
tion 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 re-
flects 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 in-
semination according to observed estrus.
The end of the progestational phase can be synchronized using prostaglan-
din 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
Table 1. Hormone Preparations Used for the Pharmacologic
Manipulation of Fertility
PREPARATION RELEVANT ACTION APPLICATION
Gonadotropin-releasing large doses

hormone (via induce ovulation in Treatment of cystic follicles
induced LH mature follicles Reduction in embryo loss
secretion) luteoprotective (through
induction of atresia or
luteinization of immature
follicles)
small doses Estrus induction
induce follicle maturation (under investigation)
PMSG, FSH, HMG reduction of follicular Estrus induction
atresia, selection of Superovulation
numbers of dominant
follicles, stimulation of
follicular maturation
HCG induction of ovulation in Treatment of cystic follicles
mature follicles
luteoprotective (through Reduction of embryo loss
induction of atresia or
luteinization of immature
follicles)
Progestagens suppression of LH secretion Estrus synchronization
sensitization of brain to Estrus induction
estrus-inducing effects of
estrogens
required before follicle
maturation and ovulation
to ensure normal function
of corpus luteum
Estrogens luteolysis Estrus synchronization
Prostaglandins luteolysis Estrus synchronization
myometrial contractility Abortion induction
Parturition induction
Improvement of fertility at
prostaglandin-induced
estrus
Corticosteroids activation of enzymes Abortion induction
systems in the placenta Parturition induction
facilitating conversion of
progestagens to estrogens
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 With-
drawal of progesterone treatment in these situations results in a good
synchrony of estrus owing to ovulation of these aged follicles. However, low-
ered 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 lessen-
ing the depth of anestrus (such as weaning) may improve the response to
treatment.
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 follicu-
lar 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 dur-
ing 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 re-

flecting 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) 0 20 45 20 5 10
1 treatment on day 7 (100) 0 0 72 9 6 13
1 treatment on day 12 (100) 0 0 23 37 30 10
1 treatment on day 16 (100) 0 0 79 10 6 5
treatments on days 7 -16 (100) 0 0 51 22 13 14
Heifers 1 treatment (100) (data set 1) 0 0 61 10 7.5 21.4
(data set 2) 0 0 47.1 39.7 7.0 6.2
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 inade-
quate 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 prostaglan-
din treatment can be given the day before or at the end of progestagen treat-
ment. 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 treat-
ment. 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. Short-
term treatments (7 - 9 days) commencing in the second half of the cycle re-
sulted 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
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 treat-
ment. 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 regres-
sion 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 reHect-
ing 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 concep-
tion 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 ob-
servation 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 fertil-
ity at the prostaglandin-synchronized estrus is exploited. The progestagen
treatment ensures all animals are in luteal phase and responsive to prostaglan-
din treatment.
SUPEROVULATION
Basic Aspects
Much remains to be learned concerning the mechanisms controlling the
waves of follicular growth, follicular recruitment, selection of the dominant
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 re-
viewed. 57,117 The hormones commonly used to induce superovulation are FSH
of pituitary origin or PMSG. Preparations derived from the urine of meno-
pausal 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 re-
ductions 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 mid-
diestrus (days 8 - 14 of the cycle) and the administration 2 days later of prosta-
glandin 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 TREATMENT 1 TREATMENT 2 TREATMENT 3 RECIPIENTS
1 AM PMSG FSH (5 mg) FSH (5 mg)

PM (2500IU) FSH (5 mg) FSH (5 mg)
2AM FSH (4 mg) FSH (5 mg) prostaglandin
PM FSH (4 mg) FSH (5 mg)
3AM prostaglandin FSH (3 mg) FSH (5 mg)
prostaglandin prostaglandin
4AM FSH (2 mg) FSH (5 mg)
5AM
PM AI AI AI
6AM AI AI AI
PM AI AI AI
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 propor-
tional, 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 recom-
mended. 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 re-
sponse 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 PMSG-
treated 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 gonado-
tropin 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 prepara-
tion 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 sug-
gested 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-
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 estra-
diol 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 occur-
ring 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 Pros-
taglandin treatment of luteal cysts results in luteolysis and fertile estrus in 90%
of cases. Treatment of cows with prostaglandin 7 days after induced luteiniza-
tion 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 prefera-
ble 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 proges-
terone, 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.
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 fre-
quency 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 im-
proved 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 concen-
tration of endogenous prostaglandin metabolite (from the uterus) in the
blood. 94 ,95,115 In other studies of larger numbers of cows, however, no benefi-
cial 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 appli-
cation 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 ma-
ternal 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 lute-
01ysis. 106,108,210
A beneficial effect on pregnancy rates (22.7% vs 15.6%) was obtained
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-in-
duced 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 proges-
terone 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 proges-

terone 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 preg-
nancy, 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 de-
clines 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 proges-
terone secretion and increasing estrogen production, which leads to prosta-
glandin 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 nonfunc-
tional placenta such as fetal mummification, prostaglandin treatment is
indicated. 212
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 preg-
nancy, and late-to-calve cows in seasonal pasture-based dairy areas. Late calv-
ing 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, prostaglan-
din 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 mum-
mification. 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. Placen-
tal retention is commonly associated with premature parturition, and its inci-
dence 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 prostaglan-
dins. 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 corticoste-
roids, 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 parturi-
tion occurring 24 to 72 hours after treatment. We have found butterfat produc-
tion 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
and the formation of a normal corpus luteum, and then treatment with exoge-
nous 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 progesta-
gens with or without luteolytic agents. Procedures to synchronize follicular
waves need to be established.
The induction of superovulation can be achieved readily using gonadotro-
pins prior to estrus synchronization using prostaglandin F2a. The responses to
standard treatments in terms of ovulation rates and yield of transferable em-
bryos are highly variable. The development of procedures to reduce this varia-
bility 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 mem-
branes associated with treatment.
ACKNOWLEDGMENT
The contribution of Carolynne Chisholm in the preparation of the figures is gratefully

acknowledged.
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Address reprint requests to
Patrick J. Wright, BVSc, MVSc, PhD

University of Melbourne
School of Veterinary Science
Veterinary Clinical Centre
Princes Highway
Werribee, Victoria 3030
Australia

Pharmacologic Manipulation of Fertility: Applied Pharmacology and Therapeutics

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Applied Pharmacology and Therapeutics II 0749-0720/92 $0.00 + .

Patrick J. Wright, BVSc, MVSc, PhD, *

In this article, basic aspects of reproductive endocrinology and physiology

Over the past 20 years, a large body of literature describing naturally

·Senior Lecturer, Department of Veterinary Science, University of Melbourne School of

Luteal phase window Follicular phase window

Figure 1. Schematic outline (not to scale) of plasma hormone concentrations during

Suckling. Suckling (> 2 - 3 times/day) increases the duration of ovarian

UPLIFTING FACTORS + T DEPRESSING FACTORS ,

BULL INTRODUCTION PHOTOPERIOD

of LH. Depth of anestrus therefore may be reflected as variations in plasma LH

The hormone preparations used for the pharmacologic manipulation of

In this section, the induction of estrus in post-partum cows with no uterine

follicle (> 10 mm) is present. 90 Progesterone pretreatment is required for nor-

Gonadotropin-releasing large doses

result in an extended lifespan for the dominant follicle and a suppression of

The achievement of a degree of synchrony of estrus resulting in optimal

Prostaglandin Treatment Strategies. A number of treatment protocols re-

Table 2. Proportions (0/0) of Cows in Estrus on Days after Prostaglandin

to the absence of a corpus luteum, resulting in an aged follicle. PRIDs and

Table 3. Schedule of Treatments to Induce Superovulation (Day 1 is the First

1 AM PMSG FSH (5 mg) FSH (5 mg)

CYSTIC OVARIAN DISEASE

Cystic ovarian disease is a condition characterized by cystic structures on

IMPROVEMENT OF CONCEPTION RATE OR EMBRYO SURVIVAL

Based on a survey of the literature,202 the embryonic loss rate in cattle is

GnRH During the Post-partum Period

INDUCTION OF ABORTION AND PARTURITION

Pregnancy maintenance is dependent on progesterone. Sources of proges-

The professional application of agents to the manipulation of fertility of

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

6. Anderson GA, Malmo I: Pregnancy rate of cows given synthetic gonadotrophin-re-

Patrick J. Wright, BVSc, MVSc, PhD

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