FEMALE BOVINE INFERTILITY 0749-0720/93 $0.00 + .

20

FEMALE REPRODUCTIVE
PHYSIOLOGY AND
ENDOCRINOLOGY OF CATTLE
H. Allen Garverick, PhD, and Michael F. Smith, PhD

Maximizing reproductive efficiency is of major economic impor-

tance to dairy and beef producers. The development of new and
improved methods of increasing reproductive performance depends on
our understanding of the physiologic and endocrinologic mechanisms
controlling the reproductive process. This article reviews the mecha-
nisms associated with puberty, estrous cycles, pregnancy, parturition,
and postpartum return to estrus. Due to the large volume of published
information in the preceding areas, the reader will be referred to reviews
for further information whenever possible.

PUBERTY

Increasing reproductive efficiency in beef herds depends, in part,

on maximizing the proportion of females that calve early in the calving
season. Achieving this goal necessitates selecting replacement heifers
that conceive early in the breeding season and therefore calve early. It
is necessary that heifers reach puberty prior to the breeding season.
For reviews on factors regulating the onset of puberty in heifers see
references 79, 80, and 99.
Puberty has been defined as the onset of the first ovulatory estrus
that is followed by a normal duration luteal phase. 99 Prepuberal heifers
frequently display an anovulatory estrus, and this phenomenon has
been called nonpuberaZ estrus. lOS, 127 The incidence of nonpuberal estrus
may be affected by age, breed, and photoperiod or season of the year. lOS

From the Department of Animal Sciences, University of Missouri, Columbia, Missouri

VETERINARY CLINICS OF NORTH AMERICA: FOOD ANIMAL PRACTICE

VOLUME 9 • NUMBER 2 • JULY 1993 223

224 GARVERICK & SMITH

Factors Affecting Age At Puberty

Age at puberty is affected by a variety of factors, including geno-

type, body weight, nutrition, social environment, and season. A brief
discussion of the effects of these factors on age at puberty follows.

Genotype
The genetic makeup of a heifer can have an important effect on
age at puberty. Differences in age at puberty have been reported among
breeds of cattle. 40, 85, 87, 88, 115 In general, European cattle breeds attain
puberty at younger ages than Zebu breeds. Although there is variation
among breeds, the variation in age at puberty among females within a
breed is also substantial. 75 Breed of sire and dam are reported to affect
age at puberty in cattle 163 and crossbreeding can reduce age at puberty
in heifers. 163
Although puberty is affected by environmental factors (nutrition
level, social environment, and season, as discussed subsequently), age
at puberty can be influenced by selection. Heritability estimates for age
at puberty have been reported as 0.4187 and 0.64.42 Furthermore, Brinks
et aP8 reported that heifers sired by bulls with large scrotal circumfer-
ence reach puberty at younger ages than heifers sired by bulls with
small scrotal circumference. Mating heifers that reach puberty early to
bulls with large scrotal circumference provides producers with a means
of decreasing age at puberty in subsequent generations.

Body Weight and Nutrition Level

Within a breed, age and weight have an important influence on
the onset of puberty in heifers. Heifers do not reach puberty at a fixed
age or weight, but these factors interact to regulate the timing of the
first ovulatory estrus. Level of nutrition obviously has an important
influence on body weight. Age at puberty in heifers on a high plane of
nutrition can be advanced; on a low level, delayed. 146, 164 Both prewean-
ing and postweaning weight gains have been shown to affect age at
puberty in heifers. 163

Social Environment
In wild populations of certain mammals, the presence of a male
decreases age at puberty in females. Several studies have been con-
ducted to determine the effect of bull exposure on age at puberty in
heifers. In some studies, exposure of heifers to a bull for a short14,94 or
long125 period of time did not reduce age at puberty. Kinder et aI, 80
however, reported that bull exposure decreased age at puberty in
heifers. The inconsistency among studies may be attributable to differ-
ences in growth rate of the heifers; response to bull exposure was
influenced by the growth rate of the heifers. 80
 FEMALE REPRODUCTIVE PHYSIOLOGY AND ENDOCRINOLOGY OF CATILE 225

Season
Although cattle are seasonally polyestrous animals, there is evi-
dence that season or photoperiod may affect age at puberty in heifers.
Schillo et aP35 reported that autumn (September) born heifers reached
puberty earlier than spring (March) born heifers. Because autumn born
heifers would reach puberty and calve earlier than spring born heifers,
both would tend to calve in the spring or summer regardless of their
own birth date.

Endocrine Mechanisms Associated With Puberty

The precise mechanisms controlling the onset of puberty are not

known in cattle. The hypothalamus, pituitary, and ovaries are func-
tional in the prepuberal heifer; however, the appropriate feedback
relationships among these endocrine glands have not been established.
Several months prior to the onset of puberty, the hypothalamus is very
sensitive to the negative feedback of ovarian follicular estradiol and,
therefore, concentrations of luteinizing hormone (LH) are low. 79 In-
creased sensitivity to estradiol may be attributed partly to an increased
number of estradiol receptors within the hypothalamus. 79 As a heifer
approaches puberty, the concentration of hypothalamic estradiol recep-
tors decreases and the frequency of LH pulses increases. 79 Conse-
quently, ovarian follicular growth and estradiol secretion increase as
the negative feedback of estradiol on the hypothalamic "pulse genera-
tor" decreases. Eventually, estradiol acts on the hypothalamo-pituitary
axis to cause estrous behavior and an ovulatory release of LH.79
Before the first ovulatory estrus in heifers, two transient increases
in progesterone occur. 54 The ovary has been shown to be the source of
progesterone in prepuberal heifers;13 however, the physiologic role of
increased concentrations of progesterone during the prepuberal period
is not known. Increased concentrations of progesterone may be in-
volved in preparation of the uterus for the possibility of pregnancy or
in the establishment of patterns of gonadotropin secretion characteristic
of postpuberal females. Short-term exposure of prepuberal heifers to a
progestin (norgestomet) has been an effective method of inducing a
fertile estrus, as discussed subsequently.

Induction of Puberty

Because many heifers do not reach puberty by the start of the

breeding season, hormonal and nonhormonal methods of decreasing
age at puberty have been developed.

Hormonal Methods
The 5yncro-Mate B (5anofi Animal Health Inc, Overland Park, KS
[5MB]) treatment consists of an ear implant containing 6 mg norgesto-
226 GARVERICK & SMITH

met placed in the back of the ear for 9 days and an intramuscular
injection containing 3 mg norgestomet and 5 mg estradiol valerate
administered at the time of implant placement. The 5MB treatment has
been shown to induce and synchronize a fertile estrus in prepuberal
heifers.lO, 143, 147 The effectiveness of the 5MB treatment depends on the
heifers having adequate body weight at the time of treatment,
however. 20, 143

Nonhormonal Methods
The effect of bull exposure on decreasing the age at puberty has
already been discussed. Another method of decreasing age at puberty
involves feeding an ionophore to prepuberal heifers. When heifers were
fed monensin (coccidiostat), age at puberty was decreased. lOI , 102 Mo-
nensin is known to increase feed efficiency, but the mechanism by
which puberty is advanced is unclear.

Management of Replacement Heifers

Increasing the number of heifers detected in estrus at the beginning

of the breeding season is essential for maximizing reproductive effi-
ciency. Heifers that conceive early in the breeding season calve early
in the calving season and consequently wean heavier calves. 89 Further-
more, heifers that calve early with their first calf tend to calve early
during subsequent calving seasons. Another advantage of having heif-
ers reach puberty prior to breeding is that fertility may be increased.
Pregnancy rates at first service were increased following the third
compared with the first puberal estrus. 22
A management program designed to increase the number of
replacement heifers that calve early in the calving season has been
proposed. 15 At the time of weaning, only the oldest and heaviest of the
structurally sound heifers are selected as potential replacement heifers.
In addition, approximately 30% to 40% more heifers are selected at
weaning than will be needed as replacement heifers. From weaning to
breeding, the heifers are fed to attain a target weight at breeding.
Target weight is defined as the body weight that a heifer must have at
13 to 16 months of age for a designated percentage (50%, 70%, or 90% )
of the heifers to have reached puberty. A list of the target weights for
several breeds is included in Table 1. The desired target weight at
breeding normally is approximately 65% of mature weight. Once a
target weight is selected, the average daily gain each heifer needs to
attain the target weight is calculated. For each heifer to reach the target
weight by the start of breeding, heifers should be subdivided into at
least two groups and fed to attain the necessary average daily gain.
The breeding season for heifers should begin 2 to 3 weeks before
the older cows and should not exceed 60 days. A restricted breeding
season ensures that some heifers will calve early and therefore have
extra time to return to estrus postpartum as well as wean a heavier
 FEMALE REPRODUCTIVE PHYSIOLOGY AND ENDOCRINOLOGY OF CATTLE 227

Table 1. ESTIMATES FOR HEIFERS REACHING PUBERTY AT 13 TO 16 MONTHS AT

DIFFERENT TARGET WEIGHTS*
Percentage of Heifers Which Have Attained
Puberty at Selected Target Weightst
50% 70% 90%+
Straightbred heifers
Angus 550 600 650
Brahman 700 750 800
Brangus 600 650 700
Charolais 700 750 775
Chianina 700 750 800
Hereford 600 650 700
Limousin 650 700 750
Santa Gertrudis 700 750 800
Shorthorn 500 550 600
Crossbred heifers
Brahman x British 675 725 750
British x British 575 625 675
Charolais x British 675 725 775
Jersey x British 500 550 600
Limousin x British 650 700 775
Simmental x British 625 675 750
S. Devon x British 600 650 725
Brown Swiss cross 600 650 700
Maine Anjou cross 650 700 750
*Courtesyof Dr. John Spitzer, Clemson University.
tThe target weights are based on published data approximately 12 years old. As a result of
increases in frame sizes among some breeds, the target weights may need to be increased.

calf. In addition, heifers should be bred to bulls with a record of calving

ease because dystocia is known to delay postpartum estrus in cattle.
After the breeding season, heifers should be diagnosed for pregnancy
and only those that conceive during the first 45 days of breeding are
retained as replacements.

ESTROUS CYCLE

In this section, the important endocrinologic and physiologic mech-

anisms regulating the estrous cycle are discussed. Numerous reviews
discuss the regulation of the estrous cycle;57, 149 emphasis therefore is
given to specific physiologic and endocrinologic mechanisms involved.

Characteristics of the Estrous Cycle

Cattle are seasonally polyestrous animals that have an estrous cycle

varying from 18 to 24 days in length. In general, the duration of estrus
lasts from 12 to 18 hours and ovulation occurs approximately 30 hours
after the onset of estrus. Unlike other livestock species, cattle ovulate
several hours after the end of estrus. Although characteristics of the
228 GARVERICK & SMITH

estrous cycle are similar among most breeds, important differences

have been reported between Bas Taurus and Bas Indicus breeds. 46, 69
Specifically, Bas Indicus females are reported to have a shorter duration
of behavioral estrus,17, 116 decreased interval from onset of estrus to
ovulation,119 decreased magnitude of the preovulatory LH surge, 119
smaller corpora lutea,71 and lower luteal phase concentrations of
progesterone3 than Bas Taurus females.

Hormonal Patterns During the Estrous Cycle

In general, the estrous cycle is regulated by hormones secreted by

the hypothalamus and pituitary glands, ovary, and uterus. Changes in
ovarian structures (follicles and corpora lutea), patterns of hormone
secretion, and changes in ovarian blood flow during the estrous cycle
are depicted in Figure 1.
The estrous cycle has been divided into three stages-follicular
phase (maturation of preovulatory follicle), estrus, and luteal phase.

~
W

o Progesterone
CD ,.~._'_I_'_'_'-.~.,
C
o ,." ".
E
... .,' ",
o
:t: '-_.-..............................................................................
.,., Estradiol .:)-

~ Luteal Ovary
o
u:
"oo
iii
Estrus
FolI/cular Luteal Follicular
Phase Phase Phase
Phase of Estrous Cycle

Figure 1. Changes in ovarian structures (preovulatory follicle and corpus luteum), hormones
(luteinizing hormone, estradiol, and progesterone) and ovarian blood flow (ovary containing
[luteal ovary] or not containing [non luteal ovary] a corpus luteum) during the three phases
of the estrous cycle (follicular, estrus, and luteal phase).
 FEMALE REPRODUCTIVE PHYSIOLOGY AND ENDOCRINOLOGY OF CATTLE 229

The follicular phase begins at the time of corpus luteum regression in

the nonpregnant female. As plasma concentrations of progesterone
decrease, the pulsatile secretion of LH increases (probably because of
reduced negative feedback of progesterone). Coincident with the in-
crease in LH, plasma concentrations of estradiol also increase, which
results in estrous behavior (estrus) and induction of the preovulatory
gonadotropin surge. The preovulatory surge of LH initiates a cascade
of intrafollicular events, resulting in follicular rupture and luteinization.
The luteal phase begins following ovulation and ends with luteo-
lysis. During the luteal phase, concentrations of progesterone are
positively correlated with changes in luteal weight. The pattern of LH
secretion changes during the luteal phase. During luteal formation or
regression, when plasma progesterone concentrations are low, the
pattern of LH secretion has been characterized as pulses of high
frequency and low amplitude; during the mid-luteal phase (high pro-
gesterone), however, the pulsatile pattern of LH secretion is character-
ized by low frequency and high amplitude. u8 In cattle, uterine secretion
of prostaglandin F2cx (PGF2cx) increases during the late luteal phase to
cause corpus luteum regression.
Some of the important endocrinologic and physiologic events
regulating the estrous cycle are described· in more detail below.

Neuroendocrinology

Neuroendocrinal mechanisms regulating gonadotropin secretion

have been the focus of numerous studies. 37, 41 The hypothalamus
integrates information from internal (positive and negative endocrine
feedback, nutritional status, and so on) and external (photoperiod,
presence of a male) cues and subsequently regulates pituitary gonado-
tropin secretion. Gonadotropin-releasing hormone (GnRH) is synthe-
sized within the cell bodies of neuroendocrine cells located within the
arcuate, suprachiasmatic, and preoptic nuclei and transported down
the axons that terminate in the median eminence. In response to the
appropriate physiologic cues, GnRH is secreted in a pulsatile manner
into surrounding capillaries that drain into the hypothalamo-hypophy-
seal portal vessels that transport GnRH to the anterior pituitary gland.
Gonadotropins are secreted in a pulsatile manner in response to the
pattern of secretion of GnRH,98 as previously presented. The pulsatile
pattern of LH secretion varies during the estrous cycle and the pattern
is related to circulating concentrations of progesterone. U8

Folliculogenesis

Folliculogenesis is an important process, involving the develop-

ment of a primordial follicle (oocyte surrounded by a single layer of
pregranulosa cells) into a preovulatory follicle. The majority of ovarian
 -
230 GARVERICK & SMITH

follicles do not complete this process but, instead, undergo atresia

(follicular degeneration). The process of folliculogenesis has been di-
vided into three stages-recruitment, selection, and dominance. 55 Re-
cruitment occurs when follicles first become responsive to and depen-
dent upon gonadotropin stimulation. Following recruitment, several of
the "recruited" follicles are selected to escape atresia and to continue
toward ovulation. At some time after the selection process a follicle
becomes dominant and thereby avoids becoming atretic. If the dominant
follicle does not ovulate, atresia occurs several days later.
The use of real-time ultrasonography has enabled investigators to
determine that ovarian follicular growth in cattle occurs in waves. 131, 140
There normally are three follicular waves during the bovine estrous
cycle, but some cows have two or four waves. 14O A transient increase
in follicle-stimulating hormone (FSH) occurs before each follicular wave
in cattle and may serve as the initiator of follicular waves. 1 Understand-
ing the mechanisms regulating follicular waves may result in the
development of more effective methods of superovulation and estrous
synchronization.
During the follicular phase, preovulatory follicular maturation re-
sults from the coordinated actions of LH and FSH on theca and
granulosa cells, respectively. 44, 45 Luteinizing hormone binds to mem-
brane receptors on the surface of theca interna cells and stimulates
androgen synthesis, which subsequently diffuses through the basement
membrane and into granulosa cells. Follicle-stimulating hormone binds
to membrane receptors on granulosa cells and increases aromatase
activity, which converts androgens to estradiol. Increased circulating
concentrations of estradiol result in estrous behavior and induction of
the preovulatory gonadotropin surge. In addition, estradiol can act
within granulosa cells to increase LH receptor concentration and thereby
prepare the preovulatory follicle to respond to the gonadotropin
surge. 124

Ovulation

The preovulatory gonadotropin surge coordinates several impor-

tant events during the preovulatory period, including resumption of
meiosis within the oocyte, events associated with follicular rupture,
and luteinization of follicular cells. Although LH generally is believed
to be the primary gonadotropin that initiates the just-mentioned events,
FSH also has been shown to cause ovulation. 47 The precise rationale
for a preovulatory release of both gonadotropins is not clear.
Follicular rupture is the result of a complex cascade of events
leading to the activation of proteolytic enzymes that digest the follicular
wall (stigma). This process has been likened to mechanisms associated
with inflammation. For additional information on ovulatory mecha-
nisms, see reference 91 for review.
 FEMALE REPRODUCTIVE PHYSIOLOGY AND ENDOCRINOLOGY OF CATTLE 231

Corpus Luteum Function

Corpora lutea are a continuation of follicular maturation and are

reported to develop from both theca and granulosa cells in cattle5 and
sheep.Il3, 155 The corpus luteum has an important regulatory role in that
it secretes progesterone, which determines estrous cycle duration and
the time of parturition. Regulation of luteal lifespan or administration
of synthetic progestins have important practical implications for con-
trolling the time of ovulation (estrous synchronization).
The preovulatory gonadotropin surge initiates luteinization of fol-
licular cells even prior to follicular rupture. Because the corpus luteum
is transient and capable of secreting large quantities of progesterone
within a few days following ovulation, rapid recruitment of a capillary
network by the avascular granulosa cells is essential. Corpora lutea
receive the majority of the ovarian blood flow (see Fig. 1) and the blood
flow to the luteal ovary and progesterone secretion are highly corre-
lated. 112 Around the time of ovulation, the basement membrane within
the bovine preovulatory follicle breaks down and new capillaries from
the theca interna penetrate into the granulosa layer. Although new
blood vessels have entered the granulosa layer within hours after
ovulation, the luteal vascular system is not complete until about day 9
of the bovine estrous cycle. 82, 104 Bovine granulosa cells secrete an
angiogenic factor that most likely has an important regulatory role in
the development of the luteal vascular system. 72, 82
A primary function of the corpus luteum is the secretion of
progesterone, which is regulated by secretions from the anterior pitui-
tary, uterus, ovary, and embryo. III The regulation of progesterone
secretion probably is regulated by a balance of luteotropic and luteolytic
stimuli, given that both types of stimuli are secreted concurrently
during the estrous cycle. In cattle, LH is considered to be the primary
luteotropic hormone.
The corpus luteum consists of a heterogeneous population of cells,
including luteal (small and large) cells, fibroblasts, endothelial cells,
and various other cell types. 38, 58 Small and large luteal cells have
different morphologic, endocrinologic, and biochemical character-
istics,43, 59 and these two cell types may interact in ways that are yet to
be discovered.
It is well known that PGF2a is the naturally occurring uterine
luteolysin in cattle and PGF2a is commonly used to synchronize estrus
in cattle. Late in the luteal phase of domestic ruminants, the uterine
concentration of PGF2a increases in the endometrium and PGF2a is
secreted into the uterine veins. 70 Prostaglandin F2a is transported from
the utero-ovarian vein into the ovarian artery via a counter-current
transfer mechanism66, 97 and is transported to the corpus luteum, where
it causes luteolysis. Prostaglandin F2a is secreted from the uterus in
pulses and the frequency of pulses has been reported to be important
in the initiation of luteolysis. 78 , 114, 139
The mechanisms associated with luteolysis are not completely
232 GARVERICK & SMITH

understood; however, PGF2<x probably has both an indirect and direct

action on the corpus luteum. Prostaglandin F2<X is known to be a potent
vasoconstrictor and may reduce luteal blood flow. 111 In addition, luteal
cells are known to have PGF2<x receptors on the plasma membrane and
direct inhibitory effects of PGF2<x on luteal progesterone secretion have
been demonstrated. 111

PREGNANCY
Hormone Patterns

As previously described, follicular cells luteinize following ovula-

tion and the corpus luteum develops and secretes progesterone. In
pregnant cows, the corpus luteum secretes progesterone throughout
pregnancy before regressing approximately 2 days prior to parturition.
Circulating concentrations of progesterone remain relatively high and
constant throughout gestation,121 although a slight gradual decline is
observed the last 2 to 4 weeks of gestation. 68 The main source of
progesterone during pregnancy in cattle is the corpus luteum, although
there is some contribution from the placenta later in gestation. Preg-
nancy is maintained in cows ovariectomized after 200 days of preg-
nancy, and progesterone concentrations remain elevated, but are con-
siderably lower after ovariectomy. 36 Although pregnancy is maintained
in these cows, parturition is advanced approximately 2 weeks and
parturition is characterized by dystocia and retained placenta.
Secretion of estrogen during pregnancy is primarily associated with
the development of the fetal/placental unit. Circulating estradiol during
the early stages of pregnancy is similar between pregnant and non-
pregnant animals and the major source likely is ovarian follicles. Waves
of follicular growth continue during early pregnancy (0-35 days).31, 151
There is decreased follicular development on the ovary ipsilateral to
the corpus luteum/conceptus, however. In addition, Schallenberger et
aP33 reported decreased secretion of estradiol in pregnant versus non-
pregnant animals during early gestation. Thereafter, circulating concen-
trations and urinary excretion of estrogens increase as pregnancy
progresses. Rapid increases in secretion of estrogens occur near the
end of pregnancy, when circulating concentrations and urinary excre-
tion rates are several hundred-fold those observed at estrus. 64 , 68, 121, 145
Secretions of estrogens decline markedly following parturition.
Circulating concentrations of gonadotropins are similar between
pregnant and nonpregnant animals during early gestation, and secre-
tory patterns have not been well defined during later stages of preg-
nancy. Luteinizing hormone is secreted in a episodic pattern during
gestation and the pulse frequency and amplitude decrease during later
gestation. 92 At or following parturition, concentrations of FSH are in
the normal range, but mean concentration and pulsatile secretion of
LH are markedly lower53,103 (see discussion in postpartum section).
 FEMALE REPRODUCTIVE PHYSIOLOGY AND ENDOCRINOLOGY OF CAITLE 233

Fertilization, Early Embryonic Development, and

Maternal Recognition of Pregnancy

Following ovulation, fertilization usually occurs in the ampullar

portion of the oviduct. Sperm must reside in the female reproductive
tract for a period of time before becoming capable of attaching to or
penetrating the oocyte (capacitation). The major site of capacitation
appears to be the isthmic region of the oviduct (for review, see reference
9).
The embryo migrates to the uterus 72 to 96 hours after fertilization.
Embryos are in the morula stage at this time and progress to the
blastocyst stage over the next 2 to 3 days. Embryos become oblong or
tubular by days 12 to 13, and become filamentous and occupy two-
thirds of the gravid horn by days 17 to 18 (for review, see reference 8).
Placentation begins within a few days and is complete by day 36. 29
Unless pregnancy is established, uterine secretion of PGF2a results
in luteal regression and initiation of another ovulatory follicular phase.
In pregnant cows, the ability to release PGF2a around the time of
expected luteal regression is attenuated. 152 A signal for pregnancy
recognition therefore must be transmitted to the dam prior to the time
of luteal regression, which also precedes the attachment of embryonic
tissue to the uterine epithelia (placentation). This is thought to occur
between day 16 and 19 in cattle. 152 The term maternal recognition of
pregnancy has been used to describe the biochemical and physiologic
changes that permit the dam to recognize and adjust to the presence
of an embryo in her reproductive tract. 126
The bovine conceptus produces a number of low molecular weight
acidic proteins that, when introduced into the uterine lumen, extend
the lifespan of the corpus luteum (for review, see reference 152). A low
molecular weight acidic protein secreted by the ovine conceptus from
day 13 to 21 of pregnancy was first reported by Godkin et al. 52 The
protein, termed ovine trophoblast protein-l (oTP-1), also extends the
estrous cycle in nonpregnant ewes. A similar protein that interacts
immunologically with oTP-1 and is secreted by the bovine conceptus
(bovine trophoblast protein-I; bTP-1) from days 16 to 25 of pregnancy
has been purified more recently. 63 Intrauterine infusion of bTP-1 extends
the luteal phase in cattle. 152 Sequencing of the N-terminus of the purified
polypeptides and molecular cloning of the cDNA for oTP-1 and bTP-1
have shown that both trophoblast proteins are structurally related to
the a-interferon family of proteins (for review, see reference 125).
Trophoblast proteins may exert their effect by attenuating secretion of
PGF2a 152 or inducing synthesis of an intracellular inhibitor of PGF2a
synthesis. 62
The identification of bTP-1 as an interferon and its association with
maternal recognition of pregnancy suggest that recombinant bovine
interferon all (rboIFNa 11) may be used to increase pregnancy rates in
cattle. Injection of rboIFN all increases pregnancy rates in sheep. 96, 110, 134
Administration of rboIFNa 11 to cattle does not increase pregnancy
234 GARVERICK & SMITH

rates, however, and, in fact, tends to depress conception rates. 7 One

cause may be the hyperthermia observed after injection of rboIFNa11.
More work is necessary to define the mechanisms involved.
Following fertilization, the most dynamic and developmental proc-
ess in biology proceeds over the next 280 to 285 days, and culminates
in the birth of a live calf. The zygote weighs approximately 1 ng and
grows to an average of 38.5 kg at birth, about a 38-trillion-fold increase
in weight. 67 The fetus reaches a size of approximately 100 g by day 80
of gestation. 35, 117 Thereafter, growth rate (weight accumulation) com-
mences at an exponential rate, with the most rapid rate of weight
increase occurring from 150 to 240 days of gestation. The rate of growth
then slows from day 240 of gestation to parturition. 6, 35, 117 The peak
average gain by fetal calves occurs around day 230 of gestation. 6
Depression in growth rate as term approaches may be attributed to the
fetus exceeding the capabilities of the placenta and maternal unit to
maintain a high rate of growth. 35
There are high correlations among fetal weight, fetal fluid weight,
and placental weight. 117 Increases in fetal weight may lag behind those
of fluid volume and fetal membranes, however.35 A prerequisite for
fetal growth is a plentiful supply of nutrients. Expansion of fetal
membranes and increases in fetal fluid increase the capacity for nutrient
exchange, and fetal growth then accelerates.
After elongation, growth initially is due to hyperplasia. As devel-
opment continues, growth is due to both hyperplasia and hypertrophy,
and later to hypertrophy. 165 The chances for retardation of fetal growth
therefore are higher during early than later fetal development. 117 In
fact, limitation of dams' dietary intake in later gestation did not have a
significant effect on birth weight or dystocia. 6, 117 Factors affecting birth
weight were reviewed recently. 67

Pregnancy Diagnosis

Early diagnosis of pregnancy or identification of the nonpregnant

female playa major role in maintaining optimum reproductive efficiency
and economic competitiveness of livestock producers. Fifteen to 25
percent of cows and heifers bred that have not returned to estrus and
therefore are assumed to be pregnant, are actually nonpregnant. 168 The
percentage often is higher in poorly managed herds. Presently, preg-
nancy in cattle usually is diagnosed via palpation per rectum at least
35 days after insemination. Diagnosis is based on an increase in the
size of the horn of the uterus associated with the pregnancy, accumu-
lation of fetal fluids, the "fetal membrane slip," the amnionic vesicle,
and cotyledons. 168 Ultrasonic detection of pregnancy has been used
with varying degrees of success, depending on the type of instrument
used. Real-time ultrasonic scanning uses a number of crystals within
the transducer head that result in a moving two-dimensional image
that can be displayed on a video monitor. Several different research
 FEMALE REPRODUCTIVE PHYSIOLOGY AND ENDOCRINOLOGY OF CATTLE 235

trials have shown that pregnancy can be detected with this technique
by 20 days after breeding (for review, see references 10 and 56). The
use of real-time scanning in farm situations is limited by the cost of the
instrument, but it is likely that less expensive equipment will become
available in the future.
On-farm tests for progesterone in milk have been developed for
pregnancy diagnosis. It should be recognized, however, that the pres-
ence of progesterone in milk is not a diagnosis of pregnancy, but an
indication of pregnancy. As previously described, demise of the corpus
luteum occurs around day 18 following estrus and circulating proges-
terone declines in nonpregnant cows. In pregnant cows, the corpus
luteum remains functional and secretion of progesterone continues.
Thus, progesterone in milk would be expected to be high in pregnant
cows and low in nonpregnant cows 21 to 22 days following estrus. If
the progesterone concentration in milk is low, nearly all cows are
nonpregnant. If the concentration of progesterone is high, the accuracy
of a positive pregnancy diagnosis is about 75%.167 Embryonic deaths,
breeding cows at the wrong time, and cystic ovaries may lead to an
erroneous estimation of pregnancy. Progesterone tests should be con-
firmed by rectal palpation at a later time.
Biochemical detection of pregnancy relies on detection of sub-
stances in the maternal system that are produced by the conceptus.
Pregnancy-specific proteins have been identified in cattle, but most,
although found in uterine flushings, are not detectable in the circula-
tion-i.e., oTP-1. 134 In cattle, there has not been an easily identifiable
pregnancy marker such as chorionic gonadotropin in primates or equine
chorionic gonadotropin in horses. A pregnancy-specific protein (preg-
nancy-specific protein B; PSPB) recently was identified in the blood of
cows and is detectable by 24 days after breeding (for review, see
reference 129). Pregnancy-specific protein B is a glycoprotein produced
by the binucleate cells of the placenta in cattle and has been used as a
pregnancy test. The half-life of PSPB is long (7.3 days) and care must
be taken when evaluating animals in the early postpartum period for a
new pregnancy. 129

PARTURITION

There is a precipitous drop in progesterone about 2 days prior to

parturition. 48 There may even be a period of quiescence of myometrial
contractions following the decline in progesterone before rhythmic
uterine contractions begin and parturition is initiated. l50 In addition,
there is a softening and dilation of the cervix and preparation of the
soft tissues of the birth canal during late gestation under the influence
of relaxin or estrogens, even in the absence of uterine contractions.
There is little production of prostaglandins by placental cells during
early pregnancy, but a marked increase in synthesis in vitro of both
PGF2 Cl and PGE2 is observed after 100 days of gestation. 153
236 GARVERICK & SMITH

The fetal adrenal gland plays a major role in initiating parturition

(for review, see reference 153). Liggins et al90 suggested the hypotha-
lamic-pituitary-axis was involved in parturition initiation following
experiments in which destruction of the fetal pituitary gland in sheep
resulted in lack of initiation of parturition at term. If adrenal cortico-
trophic hormone (ACTH) was administered to the fetus, parturition
occurred. If adrenalectomy was performed prior to injection of ACTH,
parturition was delayed. Similarly, extension of gestation duration in
sheep with continued growth of the fetus has been observed following
complete bilateral removal of the fetal adrenal glands. 32 Prolonged
administration of glucocorticoids, but not ACTH, to adrenalectomized
fetal lambs of 88 to 129 days gestation resulted in premature initiation
of parturition. Abnormally long gestations also have been directly
related to fetal adrenal abnormalities in cattle. 25, 76 In the preceding
reports, the fetal pituitary gland was subfunctional or absent, and
adrenal cortices were hypoplastic. Secretion of glucocorticoids from the
fetal adrenal glands therefore is necessary for initiation of parturition.
The mechanism(s) whereby the fetal adrenal gland initiates partu-
rition is not completely understood. In cattle, production of progeste-
rone by the corpus luteum is terminated before parturition occurs (for
review, see reference 8). There also is a dramatic increase in plasma
concentrations of estrogens near the end of gestation. In addition,
secretion of fetal cortisol increases as parturition approaches. 42 It has
been proposed that the increased secretion of cortisol from the fetus
increases release of PGF 2a, which induces luteolysis and, subsequently,
parturition. Also, concentration of oxytocin receptors increases as term
approaches, the uterus becomes more sensitive to the PGF 2a-induced
release of oxytocin, and parturition is initiated. 8

Induction of Parturition

Calf loss at birth because of dystocia is a major factor associated

with reduced calf crops. Calf losses may run as high as 15% and losses
among first-calf heifers are usually higher than in mature cows. Most
calves that die at birth are probably normal and could be saved if
assistance were available. Procedures have been developed that allow
timing of delivery before the expected calving date, based on under-
standing of the previously described mechanisms associated with ini-
tiation of parturition. Birth can occur when personnel are available for
assistance.
Because secretion of cortisol by the fetal adrenal gland has been
associated with initiation of parturition, synthetic glucocorticoids have
been used to successfully induce parturition prior to the expected time. 2,
48, 73 In addition, PGF 2 a or its analogs have been used to induced
parturition. 65, 74 Induction of parturition has been successful (live calves
and full milk production) when induction occurs within 10 days of the
expected date of parturition. Following injection of the glucocorticoids,
circulating concentrations of progesterone drop precipitously and par-
 FEMALE REPRODUCTIVE PHYSIOLOGY AND ENDOCRINOLOGY OF CATILE 237

turition usually occurs within 40 to 50 hours, with 85% to 95% of the

cows responding to treatment (for review, see reference 48). Response
to treatment has been defined as occurrence of parturition within 72
hours of treatment. 2 If parturition has not occurred within 72 hours,
gestation usually goes to full term.
A high incidence of retained placenta occurs following birth of
calves after injection of either glucocorticoids or prostaglandins. 2, 65, 73, 74
Because secretion of estrogens by the conceptus is lower at premature
induction of parturition, exogenous treatment of estradiol-1713 with
dexamethasone was used to reduce the incidence of retained placentas.
Occurrence of retained placenta was reduced in some48 but not other
studies. H , 16, 136 More recently, relaxin has been used alone or in
combination with synthetic glucocorticoids to induce premature partu-
rition in cattle. The rationale was that relaxin may assist in softening
tissues of the birth canal and ,facilitate parturition. Results of studies
are not consistent when relaxin was given alone to induce parturition:
Relaxin given alone was effective in inducing parturition in one study l06
but not another. 23 In the former study, parturition was not induced
until day 278 of gestation; in the latter, day 272. When given in
combination with dexamethasone, parturition was prematurely induced
and the occurrence of retained placentas was reduced.107 More work is
necessary to further define the effects of relaxin when used to induce
premature parturition.

POSTPARTUM ANESTRUS

The period of time from parturition until the first postpartum estrus
accompanied by ovulation is the postpartum interval. 33 The interval
may be as short as 15 days or longer than 100 days. Associated with
this time frame is the preparation of the cow to prepare for another
pregnancy. Following parturition, involution of the uterus and resump-
tion of ovarian cycles must occur before pregnancy can be re-estab-
lished. These processes are highly variable and are influenced by
numerous factors.

Uterine Involution

The process of uterine involution has been reviewed. 81 Processes

associated with the return of the postpartum uterus to a state capable
of initiating and supporting another pregnancy are complex and the
interrelationship between the uterus and the ovaries is not fully under-
stood. 81 Preparation for re-establishment of pregnancy likely involves
three overlapping processes: (1) reduction in size, (2) loss of tissue, and
(3) tissue repair. 51 At calving, the uterus of cows weighs approximately
9 kg and it decreases to approximately 3 kg by 10 days postpartum, 1
kg by 20 to 30 days postpartum, and 750 g by 50 days postpartum. 51
238 GARVERICK & SMITH

The early reduction in uterine size results from vasoconstriction

and peristaltic contractions that persist for several days (for review, see
reference 81). There is a considerable amount of fluid in the uterus just
after calving, and the lochia normally clears over the next 2 to 3 weeks.
The early reduction in size appears to be caused primarily by loss of
tissue fluids via sloughing of tissues and regenerative changes. 154
Degenerative processes usually are complete by day 15 postpartum and
regenerative changes occur for at least 10 more days following the end
of degenerative changes. 51 Involution of the uterus is considered to be
complete by 40 to 60 days postpartum, when caruncles have regressed
to a smooth, oblong, epithelium-covered, avascular knob. 51 Peripartu-
rient diseases and abnormal occurrences affecting the uterus, such as
retained fetal membranes and infections, delay uterine involution.
Uterine involution, factors effecting uterine involution, and the role of
the uterus in regulating postpartum intervals have been reviewed. 81

Ovarian Activity

In addition to involution of the uterus, ovarian cyclicity must be

re-established before pregnancy can be established again. At parturi-
tion, cows have been acyclic for 280 days, and a period of time ensues
before ovarian cyclicity is restored. The first ovulation in dairy cows
after parturition occurs by 3 weeks postpartum,19 and is delayed 1 to 2
months in suckled beef COWS. 157 Fertility in dairy cows increases with
earlier resumption of ovarian cycles postpartum. It therefore is impor-
tant that ovarian cycles are initiated soon after parturition and, certainly,
that all cows are exhibiting estrous cycles by 60 days postpartum.
Early studies24, 95, 100 reported that ovarian follicles in dairy cows
were detected in most cases via palpation per rectum by 10 days
postpartum. More recently, real-time ultrasonography has been used
to monitor ovarian follicular growth in cattle. Using ultrasonography, 130
follicular development was observed within 7 to 10 days in postpartum
dairy cows. Similarly, the average interval to detection of the first
dominant follicle in suckled beef cows was 10 days.105 In dairy cows,
the first dominant follicle detected ovulated by 27 days postpartum in
most cases. Conversely, the first ovulatory follicle was not the first
dominant follicle in most cases in suckled beef COWS.105 In the latter
study, follicular growth was characterized by the growth and regression
of a variable number (range, 1-6) of nonovulatory follicles.

Hormonal Changes

Following parturition, circulating concentrations of progesterone

are low and circulating concentrations and urinary excretion rates of
estrogen decline rapidly. 64, 68 Fluctuations in concentration of estradiol-
17~ and progesterone observed following parturition respectively are
 FEMALE REPRODUCTIVE PHYSIOLOGY AND ENDOCRINOLOGY OF CATTLE 239

associated with waves of follicular growth and corpus luteum devel-

opment following first ovulation.
Resumption of ovarian follicular growth following parturition likely
depends largely on stimulation by the gonadotropins, FSH, and LH.
During pregnancy, the prolonged secretion of steroids and, particularly,
the high concentrations of estrogen observed near term, are associated
with suppression of the hypothalamic-hypophysial axis.109 Pituitary LH
content and plasma LH concentrations are low shortly after calving and
generally increase during the postpartum period. 77, 83,103,128 Furthermore,
short-term episodic surges of LH increase as time postpartum
increases26,53, 148,156 and LH responsiveness to GnRH is low at parturition
and increases as time postpartum increases. 39, 77 The frequency of the
pulsatile LH secretory pattern increases just prior to the first ovulatory
surge of LH.26
Data in the literature concerning pituitary concentrations of FSH
during the postpartum interval are less clear. Pituitary concentrations
of FSH have been reported to decrease83, 128, 154 or not change27 during
the postpartum interval in beef and dairy cows. Pulsatile release of
FSH and plasma concentrations of FSH were suppressed during the
first 2 weeks postpartum, but increased with time after parturition. 30, 84,
132, 161 These results support the concept that follicular development after
calving may be initiated by FSH secretion, whereas the time of first
ovulation is related to secretion of LH.
Inhibition of gonadotropin secretion near the end of pregnancy
likely occurs through the inhibitory effects of estradiol on expression
of the messenger RNA's (mRNA) coding for the subunits of the common
(l subunit and specific ~ subunits of FSH and LH.I09 Expression of

mRNA for the subunits is low at parturition and generally increases

thereafter.

Factors Affecting Postpartum Anestrus

A variety of factors have been shown to affect the period of anestrus

following parturition in cattle. These factors include suckling, lactation,
level of nutrition, body condition, season, breed, age or parity, bull
exposure, dystocia, and chronic debilitating disease. The major factors
that prolong anestrus postpartum are suckling and nutritionlbody
condition. 139
Major factors: As mentioned, suckling prolongs the anestrus period
in postpartum COWS 162 (for review, see reference 159). The duration of
postpartum anestrus is shortened if calves are weaned at birth138 or
suckling is limited. 122, 143 The effect of suckling likely is mediated through
depression of pulsatile LH release. 26, 84, 161 Pituitary content of LHI03 and
pituitary responsiveness to GnRH160 are not depressed in suckled cows,
however. The decreased pulsatile release of LH may result in inadequate
stimulation of the thecal cells and, thus, reduce androgen precursor
available for conversion to estradiol by granulosal cells. 93 The decreased
240 GARVERICK & SMITH

production of estradiol-17r3 may result in decreased sensitivity of the

pituitary to GnRH. The result could be the suckling-induced inhibition
of the preovulatory surge of LH. The role of FSH is less clear. Some
authors have reported no difference in suckled versus nonsuckled cows
and others have reported depression of FSH secretion (for review, see
reference 160).
The second major factor associated with postpartum anestrus is
nutrition and related body condition (for review, see reference 120). A
decreasing negative energy balance postpartum21 and good body con-
dition prepartum158 are both associated with early resumption of ovarian
cycles postpartum. Several reviews (references 33, 34, and 120) con-
cluded that prepartum nutrition and body condition are more important
than postpartum nutrition. Cows calving in poor body condition have
extended periods of anestrus postpartum, and reproductive perform-
ance is lower in cows that experience higher negative charges in body
condition during the postpartum period. 21 Thus, nutrition and body
condition both pre- and postpartum are important.
Minor factors: Season has been linked to anestrus. Cows calving
from late fall to early spring have a longer period of postpartum
anestrus than cows calving in late spring to early fall. 12, 141 Although
seasonal effects may be modified by other factors such as suckling,
nutrition, and genotype,60 it has been shown that truly seasonal effects
related to light occur. 61 Breed and genotype also may affect postpartum
anestrus. Differences between breeds may be affected by amount of
milk produced, dietary intake, and other factors (for review, see
reference 139). First-calf (2-year old) cows have a longer postpartum
interval than older cows. 139 The difference is attributable at least partially
to the added nutritional requirement for growth by the younger cows.
Two other factors, dystocia 12, 86 and chronic debilitating or infectious
disorders,28 have been shown to prolong postpartum anestrus. In
general, any abnormal occurrence that alters the well-being, overall
health, and nutritional status may be associated with prolonged post-
partum anestrus.
Exposing postpartum, anestrous cows to bulls decreases the period
of anestrus. 4, 166 Presence of a bull with postpartum, anestrous cows
has been suggested as a management technique to reduce the postpar-
tum interval. Other management procedures for reducing the postpar-
tum interval include having cows in good body condition at calving, a
positive energy balance diet during the postpartum period, and judi-
cious use of early weaning or limited suckling of cows during the
postpartum period (for reviews, see references 33, 139, and 157). Several
hormone treatments given postpartum have also been used to induce
ovulation. These include injection of GnRH at 2 to 3 weeks postpartum
(for review, see reference 50) and use of the 5MB treatment regimen. 144
Injection of GnRH at 2 to 3 weeks postpartum can induce ovulation in
anestrous cows; however, progesterone secretion and luteal lifespan
usually are reduced unless preceded by progestogen pretreatment. 123
An important prerequisite for GnRH induction of ovulation and corpus
luteum formation is adequate follicular growth. Follicles less than 10
 FEMALE REPRODUCTIVE PHYSIOLOGY AND ENDOCRINOLOGY OF CATTLE 241

mm in diameter reportedly do not ovulate in response to a GnRH-

induced LH release. 49 There is very little information on fertility follow-
ing GnRH-induced ovulation in postpartum cows. Use of the 5MB
treatment after day 40 postpartum has been shown to induce and
synchronize an ovulatory estrus, especially when combined with 48-
hour calf removal at the time of implant removal. l44

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