Endocrine Causes of Early Embryonic Death: An Overview
Embryonic mortality denotes the death of fertilized ova and embryos upto end of implantation. Early embryonic mortality accounts for majority of reproductive failures with a mortality rate upto 40% of fertilized eggs. PGF2α secreted by endometrial cells by activation of specific receptors by oxytocin of luteal origin causes demise of corpus luteum. In bovines embryonic trophoblast secretes interferonι which constitutes major signals for maternal recognition of pregnancy having antiluteolytic effect and luteoprotective agents like PGE2 around day 8-9. Abnormal luteal function can be due to short luteal phase or abnormal luteal phase. Lack of exposure of the uterus to progesterone and estrogen prior to first postpartum ovulation decreases the concentration of progesterone and up regulation of oxytocin receptors which causes premature secretion of PGF2 α from uterus resulting in short luteal phase in most of cows. Milk, plasma and saliva progesterone concentrations, PAG test and ultrasonography can be used as diagnostic tool to know the embryonic mortality. Various treatment regiemes including use of hCG, GnRH, PMSG, interferon and supplementing Omega-3 fatty acids can be tried.
The success of diary enterprise is dependent on the milk production of dairy
cattle and buffaloes (Bajaj et al., 2006a). Production
is directly related to the reproductive phenomenon. The reproductive efficiency
is affected by very well known factors like fertilization failure and embryonic
mortality the later being more significant (Bajaj et
al., 2006b). Embryonic death/mortality denote the death of fertilized
ova and embryos upto the end of implantation (Jainudeen and
Hafez, 2000). Mortality is more common during the early than the late embryonic
period, i.e., from day 8th to 16th at the hatching of blastocysts and initiation
of elongation and commencement of implantation without affecting cycle lengths.
Early embryonic mortality is a major source of embryonic and economic loss with
mortality rate upto 40% in animal production through repeat breeding and increased
cost of artificial insemination (Sreenan and Diskin, 1986;
Zavy, 1994; Bajaj, 2001), extended
calving intervals and prolonged dry period resulting in reduced life time milk
production (Roche et al., 1981) and reduced net
calf crop (Maurer and Chenault, 1983). Earlier, it was
believed that the bovine conceptus was resrobed, but transrectal ultrasound
examination (Kastelic et al., 1991) had demonstrated
that the conceptus and its breakdown products apparently is eliminated by expulsion
through the cervix, which either goes unnoticed or appears as a vulval discharge
of clear mucus.
When, the interestrus or the interovulatory intervals are extended in bred
animals, it usually indicates embryonic loss that occurred around the period
of Corpus Luteum (CL) maintenance (Van Cleef et al.,
1991; Humblot, 2001). Measurement of progesterone
in blood suggested that embryonic death at the time of CL maintenance delayed
luteolysis and extended interestrus interval (Humblot, 2001).
Therefore, when embryonic death precedes luteolysis, luteal regression is delayed
by at least 3 days after the end of pregnancy (Kastelic
et al., 1991). However, when luteolysis precedes and probably causes
embryonic death, return to estrus are dependent upon the stage of follicle development.
Humblot (2001) suggested that luteolysis and return
to estrus prior to day 24 might be linked with early embryonic death (early
embryonic loss) but if the CL is maintained and returns to estrus are delayed
beyond day 24 and 24-49 (late embryonic loss). Pregnancy losses detected after
day 50 known as fetal losses.
The cost of losses to farmers has been estimated as high as 250 million year-1
in the UK alone (Peters and Ball, 1995) and $1.4 billion
in the USA (Hansela et al., 1976). Although,
it is clearly not possible to extrapolate these figures to the whole world as
national agricultural economics vary so widely, it can be seen that global cost
of embryo mortality in a total cattle population (Bos taurus and Bos
indicus) of approximately 1.28x1012 (FAO, 1994)
is a large amount clearly justifying the relatively modest sums invested in
research into its cause.
EMBRYO AND NORMAL EMBRYONIC DEVELOPMENT
An embryo is a product of fertilization characterized by growth and differentiation leading to the establishment of different organ systems that make up the individual.
Fertilization in the bovines occurs at ampullo-isthamus junction of the fallopian tube (Uterine tube) and the embryonic period can be divided into zygote, cleavage, morula, blastocyst, implantation and postimplantation. The zygote being the first structure formed as a result of successful fertilization cleaves mitotically into 2, 4, 8 and 16 cell stages. The cleaved embryo enters the uterine horn at the morula (mass of cells within the zona pellucida) stage about 4-5 days after fertilization. The morula then develops into blastocyst (having distinct blastocoele, trophoblast and embryonic disc) at days 6-7. The zona pellucida ruptures, resulting in hatching of the embryo after 9-10 days. The hatched blastocyst begins a process of elongation from about day 12-13, which is accompanied by the secretion of embryonic interferons. Early attachment (apposition) of the conceptus to the endometrium takes place from about day 19 and actual adhesion occurs by day 21-22.
Maternal recognition of pregnancy: Short (1969)
firstly coined the term maternal recognition of pregnancy which means that the
luteal function is maintained in early pregnancy and that the normal luteolytic
mechanism is inhibited. In bovines mononuclear cells of trophectoderm secretes
specific proteins (bovine trophoblastic proteins, later recognized as Interferon
tau) (Thatcher et al., 2001) having anti-luteolytic
effect (Danet-Denosyers et al., 1994) and luteal
protective agents like PGE2 around day 8-9 (Bazer
et al., 1994). Interferon-tau (IFNι) mediates its
antiluteolytic effect by inhibiting expression of endometrial oxytocin receptors
and by transduction mechanism after oxytocin-receptor binding on the endometrial
cells thus inhibiting the episodic release of PGF2α (Demmers
et al., 2001). Whenever, development of embryo is compromised or
underdevelopment of trophectoderm, premature luteolysis occurs.
The ovine and bovine IFNι molecules have about 80% amino acid
sequence homology whereas there is about 50% homology between IFN-α and
IFNι (Roberts et al., 1992).
Both ovine and bovine IFNι are secreted by the conceptus coincident
with the blocking of luteolysis (Roberts, 1989).
Hernandez-Ledezma et al. (1992) indicated that
bovine trophoblastic protein-1 (bTP-1/IFNι) production begins
at the expanded blastocyst stage on day 8-9 just prior to the rupture of zona
pellucida and hatching. They also suggested that embryonic mortality between
day 14 and 19 is caused by luteal failure and occurs because certain embryos
develop more slowly than normal and do not produce enough IFNι
to prevent luteolysis and maintain the pregnancy.
Intrauterine infusion of recombinant ovine or bovine IFNι in
on-pregnant cows extended oestrus cycle by abolishing oxytocin induced PGF2α
secretion on day 17 and hence proved to be more effective in preventing embryonic
mortality than IFNα (Meyer et al.,
Martal et al. (1997) have reported many deleterious
cytokines such as TNF-α, IFN-γ IL-2 and beneficial cytokines such
as TGF-β, LIF, CSF-1, GMCSF, IL-1, IL-3, IL-6, IL-10 and IFNι are
involved in embryo survival in ruminants and other species.
Kerbler et al. (1994) reported that an increased
concentration of progesterone in cattle during early luteal phase is associated
with enhanced embryonic production of the anti-luteolytic signal, IFNι.
The CL that is maintained during maternal recognition of pregnancy is capable
to convert PGF2α to its metabolite (PGFM) (Silva
et al., 2000).
According to Spencer and Bazer (2004) establishment
and maintenance of pregnancy results from signaling by the conceptus and requires
progesterone produced by the Corpus Luteum (CL). Trophoblastic hormones in most
of the mammals maintain progesterone production by acting directly or indirectly
to maintain the CL. In domestic animals (ruminants and pigs), trophoblastic
hormones maintain progesterone production by acting on the endometrium to prevent
uterine release of luteolytic PGF2α.
DEATH OF THE EMBRYO AND TIME OF OCCURRENCE
Embryo death before day 13 of gestation results in return to estrus at the normal interestrus period. Death after day 13 extends the interestrus period beyond the generally accepted figure of 18-24 days.
Linares (1981) concluded that Early Embryonic Mortality
(EEM) rather than fertilization failure was the major cause of repeat breeding
in heifers as long as estrus detection and insemination had been properly performed.
EEM is more important than fertilization failure in parous females in their
relative contributions to reduced reproductive efficiency (Maurer
and Chenault, 1983). According to Maurer and Chenault
(1983), the critical period of embryo demise is day 7 of gestation when
the morula develops into a blastocyst.
Markette et al. (1985) studied the incidence
of embryonic loss following embryo transfer during the first week of development
and concluded that between 50 and 75% of the embryos of poor quality are eliminated
during the first 3 weeks.
Sreenan and Diskin (1986) reported that 20-25% of inseminations
fail during the embryonic period, i.e., between day 1 and 42, most of the losses
have occurred before day 25, the most substantial losses occurring between day
8 and 13 (8-9%) and days 14 and (13-15%).
Dunne et al. (2000) carried out studies on
embryo and fetal loss in beef heifers between day 14, 30 of gestation and full
term by measuring embryo survival rates which were 68, 76 and 71.8%, respectively.
This led to the conclusion that most embryo losses in heifers occurs before
day 14 after insemination.
CAUSES OF EARLY EMBRYO DEATH
Survival of embryo is affected by nutrition, temperature and heat stress, time
of insemination, genital infections (Bajaj et al.,
2006c), uterine environment and asynchrony (Bajaj, 2001),
maternal age, genetic factors, immunological and endocrine factors. Endocrine
factors/causes play an important role in embryonic death (Bajaj,
2001). To understand the influence of endocrine causes on embryo survival
and mortality one should be familiar with the structural composition and functioning
of corpus luteum and interaction between different reproductive hormones affecting
Cells of corpus luteum and their function: On the basis of morphology
and biochemical properties corpus luteum is composed of two distinct steroidogenic
cell types (Hoyer and Niswender, 1985):
||Small luteal cells (follicular origin): These cells
derived from theca interna of preovulatory follicles (Priedkalns
et al., 1968)
||Large luteal cells (granulosa cell): These cells derive
from granulosa cells (Oshea, 1987). Small luteal
cells are able to differentiate into large luteal cells as the cycle progresses
(Hansel and Dowd, 1986). Farin
et al. (1988) postulated that conversion of small luteal cells
to large luteal cells occurs only during the early part of oestrus cycle
||Stem cells of corpus luteum: These different cell types
contribute to circulating progesterone (P4) in different manner.
Luteinizing Hormone (LH) is the major luteotropin in domestic ruminants
(Niswender et al., 1985) and cattle and there
is marked difference in the response to LH by large and small luteal cells
Harrison et al. (1987) reported that small luteal
cells possess higher number of LH receptors than large luteal cells. Niswender
et al. (1985) found that 20% of the progesterone (P4)
in the ovarian vein in mid-cycle is secreted by small luteal cells while nearly
80% of P4 is secreted by large luteal cells which have only few functional
receptors for LH. Oshea (1987) indicated that
on per cell basis large luteal cells produce more progesterone than small cells.
Luteal function during early pregnancy: Plasma and milk progesterone concentration rise similarly in early luteal phase in pregnant and non-pregnant animals but the higher concentrations are maintained in pregnant cows for duration of pregnancy which are essential for mantainence of pregnancy. Anti-luteolytic substances secreted by embryo around day 13 are probably responsible for differences in progesterone patterns between pregnant and nonpregnant animals.
|| Conversion of luteal cells
Lamming et al. (1989) found that milk progesterone
concentrations in pregnant and nonthpregnant cows rise indifferently until day
9, which later on diverged and the concentrations in pregnant cows remained
higher. They also reported a significant dip in progesterone concentrations
in pregnant animals on day 11, followed by a rise which reflects a rescue effect
of the corpus luteum by the embryo.
Shelton et al. (1990) reported that the rate
of rise in progesterone concentration was lower in the postovulatory period
in cows identified for sub-fertility than in pregnant and nonpregnant heifers.
Role of oxytocin, oxytocin receptors (OTR) in luteal function: Wathes
and Lamming (1995) have reported that during luteal regression, pulses of
oxytocin stimulate synthesis and pulsatile release of PGF2α
following an increase in endometrial oxytocin receptors (OTR). Oxytocin receptor
synthesis and PGF2α release are inhibited by interferon production
by the conceptus during early pregnancy. They also reported that OTRs are present
during anoestrus, oestrus and late luteal phase and during most of pregnancy
while the plasma oxytocin concentration causes parallel changes in plasma progesterone.
These concentrations are basal at oestrus and rise from about day 2 of the cycle
peaking around day 9 and falling from about day 12-13 before the onset of luteolysis
(Wathes et al., 1993). The pattern is similar
in the pregnant animal and plasma concentrations fall from 12-13 days after
Plasma concentrations of PGF2α are generally low for most of
the cycle but pulsatile release starts at day 13 and the pulse frequency increases
until luteolysis (day 17). In nonpregnant ewes most oxytocin pulses occur in
association with PGF2α whereas, in pregnancy most pulses are
not associated with PGF2α (Hooper et
al., 1986). This pattern might be similar in cattle.
Progesterone blocks the increase in OTR for about the first 10-12 days of the
luteal phase, but the mechanism of its prolonged effect, followed by upregulation,
is still unclear. McCracken et al. (1984) found
that increasing progesterone concentration in the luteal phase down regulates
the progesterone receptor for about 10 days. But there was no evidence whether
the progesterone receptors increase prior to the OTR increase or the treatment
with progesterone reduces its own receptor (Wathes and Lamming,
Interferon, oxytocin receptors interaction and luteal function: During
early pregnancy the rise in OTR concentration is inhibited probably by the action
of embryo derived IFN. The mechanism of action of IFN may involve suppression
of both oestradiol and oxytocin receptors probably at the transcriptional level
(Bazer et al., 1994). Bovine Interferon-alpha
(bIFNα) has been shown to stimulate progesterone production by luteal cells
in vitro, without affecting oxytocin output (Luck
et al., 1992). Imakawa et al. (1993)
reported that maternal granulocyte macrophage colony stimulating factor might
be involved in stimulating embryo IFN production.
Types of abnormal luteal function: Abnormal luteal function is associated
with reduced pregnancy rates (Hommeidaa et al., 2004).
Two distinct type of abnormal luteal function have been reported (Troxel
and Kesler, 1984):
Type-I (short luteal phase): It is observed after a period of sexual rest and when breeding is initiated for the first time. In this condition short life span of corpus luteum (6-12 days) is observed.
Type-II (inadequate luteal phase): It is observed at any stage during the reproductive life. Life span of corpus luteum is of more than 14 days but with depressed plasma progesterone.
Mechanisms contributing to reduced luteal function: Mechanism contributing
to reduced luteal function can be classified into three main categories:
||Deficiencies in the maturational process within the preovulatory
follicle and/or inadequacies of ovulatory stimulus
||Short comings in the support of the CL once they have formed
||Premature activation of the luteolytic process
Follicular deficiencies may reflect in the form of subnormal progesterone concentration
and short lived CL may be the consequence of premature activation of the luteolytic
WHY IS THE FIRST POSTPARTUM OVULATIONS RESULTS IN SHORT CYCLES?
During early postpartum period when the reproductive system is recovering to
its normal anatomical and functional status, especially ovaries (ovarian rebound),
presence of dormant follicles in ovaries and adequate pattern of LH secretion
leads to first postpartum ovulation after few weeks (Perea
and Inskeep, 2008) but the fertility in the first postpartum oestrus is
poor as compared with subsequent cycles. During normal luteal phase of estrous
cycle progesterone (P4) causes increase in estrogen concentration
to promote synthesis of progesterone (P4) receptors (Zollers
et al., 1993) and to inhibit synthesis of uterine receptors for oxytocin
(OTR) through the mid-luteal phase (Kieborz-Loos et al.,
2003). But lack of priming of uterus for progesterone followed by estrogen
prior to first ovulation causes decrease in progesterone receptors and up regulation
of oxytocin receptors which results in premature PGF2α secretion
(Cooper et al., 1991). During the transition
period from morula to blastocyst, i.e., during first 2 weeks of insemination
(Inskeep, 2002) maternal recognition of pregnancy is
prevented by premature release of PGF2α from uterus and luteal
origin resulting in early demise of CL (Cooper et al.,
1991; Inskeep, 2004). Since, the PGF2α
is secreted prematurely the exogenous supplementation of progesterone is also
ineffective in prevention of embryonic death.
Theoretically, CL could be influenced by two tropic stimuli:
||Increasing the CLs secretory activity
||Prolonging CLs life span
Deficiencies prior to ovulation: Proper maturation of preovulatory follicle
is essential as follicle after maturation results in CL formation (Garverick
et al., 1988). Gonadotropin treatment prior to the induction of ovulation
results in improved functioning of resulting CL (Sheffel
et al., 1982). Changes within maturing follicle may influence functional
CL in the form of decreased cell numbers, cell sizes or proportions of large
to small luteal cells (Oshea et al., 1984) or
deficiency of receptors to luteotropin could result in the CL failing to recognize
or respond luteotropin (Rutter and Randel, 1984). Increased
concentrations of preovulatory LH could promote secretion of P4 via
cells of granulosa or thecal origin (Fitz et al.,
1982), with the evidence favouring an effect of LH on the small luteal cells.
Why are the mature follicles scarce at the time of sexual rest?: During
the period of anoestrum or sexual rest no. of mature follicles is less due to
low plasma LH concentration (Nett, 1987). This was partly
the result of low pituitary reserves of LH during the early postpartum period
consequently, the deficiencies were considered to include inadequate release
of LH, either for several days prior to ovulation, or in short coming (duration
and/or peak concentration) of preovulatory surge of LH.
Hormonal mechanisms involved in follicular maturation: The final stages
of follicular maturation are associated with marked increase in the frequency
of LH episodes (Karsch et al., 1983). The frequency
of LH increases from one per 3 to 12 h from luteal regression to 1 to 2 immediately
per LH peak (McLeod et al., 1982). During ovarian
acyclicity these LH frequency were low (Savio et al.,
1990). Thus, during the early postpartum period in dairy cows, the pulsatile
release of LH was insufficient to promote the final maturation of follicles
(Hunter and Southee, 1987). To support follicular maturation
a pulsatile delivery of LH to the ovary may be preferable to constant exposure
(McNatty et al., 1981). However, widely differing
patterns of LH stimulation during the pre-ovulatory period have resulted in
normal follicular maturation and some CL function (Keisler
et al., 1985). PGF2α may also be involved in follicular
development in early postpartum cows (Guilbault et al.,
1987). Accordingly, either the quantity or pattern of PGF2α
release is inappropriate prior to ovulation resulting in subnormal CL function.
Why LH pulses infrequent during early postpartum?: Lowered pituitary
concentration of LH is one of the limitations to the re-establishment of oestrous
cycles rather than alterations in the sensitivity of the organ to GnRH (Moss
et al., 1985). Nett (1987) suggested that
deficiencies of the hypothalamic hypophysial axis could result in a reduced
secretion of LH during the early part of the postpartum period.
Nett (1987) concluded that during the postpartum period
the hypothalamus although, contained sufficient stores of GnRH to stimulate
the anterior pituitary. Once the pituitary stores of LH had been replenished,
then pulses in the secretion of LH could increase in frequency to culminate
in the first postpartum oestrus (Humphrey et al.,
1983). Ovarian acyclicity thus appeared to be the result of a failure of
follicle development, possibly due to an inadequate frequency of LH pulses reflecting
inadequate pulsatile release of GnRH (Wise et al.,
Feedback response to estrogen: Peters (1984) has
proposed that although, the positive feedback mechanism of E2 in
triggering the preovulatory LH release may be functional, recovery of maximal
activity may continue over an extended period. Therefore, the hypothalamic-pituitary
axis would need to recover responsiveness to increasing plasma concentrations
of E2 before the first ovulation can occur.
Parfet et al. (1986) stated that the absence
of oestrous cycles in suckled cows near 30 days postpartum was not due to deficiencies
||Ovarian follicular development
||Anterior pituitary concentration of LH and FSH or in vitro releasibility
of LH or
||Pituitary receptors for GnRH
In the properly fed cow, at about one month after calving, the hypothalamic-pituitary
axis is fully able to support resumption of ovarian cycles, but the suckling
stimulus inhibits the release of LH (Williams, 1989).
Is FSH deficit during early postpartum period?: FSH plays a permissive
role in the onset of ovarian cycles postpartum. Deficiency of FSH during the
late luteal to early follicular phase could inhibit the development and function
of the preovulatory follicle (Fortune and Quirk, 1988).
FSH concentrations are lower over the last four days before the first preovulatory
LH surge induced by weaning in cows. FSH concentrations were also lower compared
to the same period prior to second preovulatory LH surge (Remirez-Godinez
et al., 1982). The former preceded short lived CL, while the later preceded
normal luteal function.
Lack of follicular maturation in the postpartum cow: Nett
(1987) used a model to explain the inadequate maturation of follicles in
the postpartum, anoestrous cows. For low concentrations of LH during early lactation
he suggested that during pregnancy the high concentrations of P4
and E2 resulted in a prolonged negative feedback on the hypothalamic-hypophyseal
pituitary axis. Accordingly, the synthesis of LH was inhibited and pituitary
stores become depleted so that basal release of LH was reduced. After parturition,
a two phase recovery of the hypothalamic-pituitary gonadal axis occurred with
the first phase (lasting 2-5 weeks) characterized by infrequent release of GnRH
(one pulse/4-8 h). Once pituitary stores of LH had been replenished then the
amplitude of the LH pulses was sufficient to stimulate follicular growth. This
denoted the start of second phase of the recovery process, during which the
increased circulating concentration stimulated growth of ovarian follicles,
which in turn produced E2. At this point of time, the frequency of
release of GnRH also increased with a consequent increase in the frequency of
LH pulses. The final stages of follicular development ensued and culminated
in the first ovulation.
Intrafollicular receptors for LH and the role of estrogen (E2):
Even if luteotropin secretion is sufficient to support normal CL function, then
short lived or inadequate CL may not recognize LH. This might be due to insufficient
LH receptors possibly within the maturing follicle and in the subsequent CL.
Both E2 and FSH are necessary for production of LH receptors before
luteinization of granulosal cells (Richards, 1980).
According to Fortune and Quirk (1988), estrogen (E2)
also acts within the follicle to regulate its development and function. They
proposed that as the preovulatory follicle mature the initial action of E2
of positive feedback is on its own production, via increased androgen
During preovulatory growth, follicles become more responsive to LH and acquire an increased ability to synthesize E2. This increased responsiveness to basal levels of LH was due to increased LH receptors in the granulosal cells.
Estrogen (E2) and luteal lifespan: Larson
(1987) reported that administration of hCG (to induce ovulation) leads to
CL with a normal lifespan in cows with high plasma E2 than in cows
with low E2. Inskeep et al. (1988)
reported largest preovulatory follicle possessed decreased numbers of receptors
for LH in granulosa and theca cells in cows which were predicted to have short
luteal phases than in Norgestomet pretreated cows which were expected to show
normal luteal lifespans.
Garcia-Winder et al. (1987) and Inskeep
et al. (1988) found a higher concentration of E2 in largest
follicle and CL with normal life span in cows implanted with synthetic progestogen
(Norgestomet). Evidences from number of sources support that estradiol within
the preovulatory follicle is associated with function of resulting CL.
Deficiencies at the time of ovulation/postovulation
Could abnormalities of preovulatory LH surge result in a short lived Cl or defective
CL?: Troxel and Kesler (1984) stated that the magnitude
and duration of GnRH induced LH surge appeared to be associated with enhanced
CL function and lifespan. Cruz and Kesler (1988) reported
that cows with normal luteal function had a greater GnRH induced LH release
than cows with short luteal phases.
Shirar et al. (1989) emphasized the importance
of duration of the preovulatory LH release. They observed that progestogen treatment,
prior to GnRH, changed the pattern of LH release and possibly thereby improved
Can the reduced lifespan or lowered secretory activity of the first CL be
attributed to suboptimal luteotropic support?: Manns
et al. (1984) reported the presence of FSH receptors in luteal cells
of cows. Walters and Schallenberger (1984) suggested
that since 97% of separate FSH pulses during the mid-luteal phase in cow were
associated with P4 pulses, it is possible that FSH could be the principal
hormone that stimulates P4 secretion. They maintained that this did
not exclude a luteotropic action of LH in addition to a stimulatory action of
FSH on release of P4 in the cow. Pekala et
al. (1983) proposed that there might be an interaction between oxytocin
(from the CL) and LH in regulating P4 synthesis, with oxytocin increasing
the response to LH.
Mallory et al. (1986) reported premature luteal
regression or reduced CL function if the luteotropic support from pituitary
is disrupted during the formation of CL (±day 1 of the cycle).
Deficiencies in luteotropic support: Deficiency in luteotropic support
might be due to:
||Short lived CL
Short lived CL: Several studies have been carried out on insufficient
luteotropic stimulus to maintain lifespan of subsequent CL during early postpartum
period. Injection of microencapsulated GnRH promote normal luteal function by
elevating LH concentration (Roberts et al., 1989).
Inadequate CL: If it is accepted that luteotropin may not be sufficient to realize normal luteal function, then the question arises that when should the endogenous supplies need to be augmented.
Pearson and Lishman (1989) demonstrated that a luteotropic
stimulus provided early in the induced cycle (day 3-5) improved luteal function
to a greater extent than when PMSG was provided after day 5.
Progesterone concentration on day 10 after AI were higher in pregnant buffaloes
than in buffaloes that showed embryonic mortality not associated with infectious
agent. Similarly higher progesterone concentrations on day 20 of AI were found
in pregnant buffaloes as compared to non-pregnant ones and buffaloes that showed
embryonic mortality (Campanile et al., 2005).
LH receptors within the CL and luteal function: Increased numbers of
receptors for LH, on the granulosal cells of the bovine CL, could be a major
factor in regulation of secretion of P4 by the ensuing CL (McNeilly
et al., 1981). They also believed that there may not be a simple
relationship between the binding of LH to luteal cells and the secretion of
P4. Consequently, the failure of the short lived CL to recognize
LH was not a factor that caused early luteal regression (Rutter
et al., 1985).
LH receptors are not deficient in the inadequate CL (Braden
et al., 1989). Hunter et al. (1988)
concluded that lack of gonadotropin receptors was probably not a fundamental
cause of premature regression of the short lived CL.
The role of the uterus and PGF2α in subnormal luteal function
Presence of PGF2α during early lactation: Thatcher
et al. (1980) have demonstrated increased jugular plasma concentrations
of prostaglandin metabolite (PGFM) during the early postpartum interval in milked
dairy cows. Odde et al. (1980) suggested that
premature regression of CL, which appeared to function normally for approximately
7 days after induced ovulation, was due to the luteolytic effect of PGF2α
Oxytocin and the release of PGF2α: Luteolysis occur due to positive mechanism between luteal oxytocin and uterine PGF2α which occurs at specific time of the oestrus cycle. Progesterone suppresses PGF2α secretion when the concentration of progesterone receptors is high by inhibiting oxytocin in early part of oestrus cycle but as the cycle progresses these progesterone receptors decreases resulting in secretion of estrogen and oxytocin receptors. This result in uterine responsiveness to oxytocin which further facilitates positive mechanism between oxytocin and endometrial PGF2α. Various research studies conducted on normal oestrus cycles suggests that progesterone regulates the PGF2α release by timing the initial peaks of secretion early in the oestrus cycle and later on by modulating the PGF2α secretion until the corpus luteum regresses completely.
Increase in oxytocin concentrations in association with increase concentration
of PGFM in cows with short luteal phases has also been reported by Peter
et al. (1989). Zollers et al. (1989)
compared short and normal luteal phases in beef cattle and found oxytocin induced
premature release of PGF2α on day 5 in short cycle which was
not seen in normal cycles but the oxytocin induced PGF2α release
was similar to that observed at luteolysis on day 16 of normal cycle. Lesser
No. of progesterone receptors as compared to more No. of endometrial oxytocin
receptors were reported on Day 5 after estrus in postpartum beef cows expected
to have short luteal phase than in cows with normal luteal phase (Zollers
et al., 1993). Evidences indicate involvement of oxytocin in release
of PGF2α in cows with short luteal cycles.
Research studies on anoestrus cows have suggested that progesterone treatment
results in development of larger preovulatory follicles containing more esrtadiol
17-β than in control or short cycled cows and greater concentration of
LH receptors in granulosa and theca layer in largest preovulatory follicle in
postpartum cows pretreated with norgestomet than controls (Inskeep
et al., 1988). Increase in concentration of estradiol is associated
with induction of endometrial progesterone receptors (Ing
and Tormesi 1997). Cooper et al. (1991) and
Kieborz-Loos et al. (2003) reported lower concentration
of estradiol secretion by preovulatory follicle in short cycled cows will result
in less no. of progesterone receptors in uterine endometrium and the first rise
in progesterone and early PGF2α secretion with short luteal
Oxytocin administration during the early part of the cycle has short luteal
lifespan in cycling cows and it was suggested that oxytocin functioned via elevated
levels of uterine PGF2α (Milvae and Hansel,
1980) in a manner similar to that of an IUD inserted early in the cycle
in the ewes. Suckling has same effect via the pituitary release of oxytocin
(Troxel and Kesler, 1984). When the CL releases oxytocin,
it may cause PGF2α release which in turn regresses the CL (Schams
et al., 1985). An imbalance in luteal levels of oxytocin was proposed
as a cause of the eventual demise of the CL. Peter et
al. (1989) were able to detect parallelism between concentration of
PGFM and oxytocin in early postpartum dairy cows. Inskeep
(1995) reported oxytocin to be an important factor that plays an important
role in embryonic death of cows with short luteal phases. While McCracken
et al. (1984) had earlier reported that luteal oxytocin and uterine
prostaglandin facilitate luteolysis through reciprocal positive feedback mechanism.
Zollers et al. (1993) reported that concentration
of endometrial oxytocin receptors are greater at day 5 after estrus in cows
with short lifespan of CL than in cows receiving progesterone and are expected
to have normal lifespan.
Niswender et al. (2007) concluded that luteal
PGF2α is involved in luteolysis in sheep. According to him uterine
PGF2α initiates increased secretion of PGF2α
by corpus luteum and it also initiates mobilization of Ca++ in large
luteal cells and secretion of oxytocin in large luteal cells. Oxytocin secreted
by large luteal cells acts on small luteal cells and triggers mobilization of
Ca++ in small luteal cells. Increase in intracellular levels of calcium
leads to apoptotic death of the large and small luteal cells.
Negating the effect of PGF2α: Involvement of PGF2α
in premature regression of the CL is supported by the observation that treatment
with substances which block the action of PGF2α increased the
functional lifespan of CL destined to be short lived in dairy cows (Dobson
et al., 1987).
Removing the source of PGF2α (experimentally): Strong
evidence that a premature release of PGF2α from the uterus could
be responsible for the early demise of the first induced CL in cows has been
provided by Copelin et al. (1987). They demonstrated
that the CL formed after early weaning of calves did not possess an inherently
short lifespan because removal of the uterus did not result in premature luteolysis.
Wright et al. (1988) showed that the previously
gravid uterus had to be present to induce premature regression of the first
CL, subsequent to induced abortion in heifers.
Demonstrating the release of PGF2α: Peter
et al. (1989) showed increased concentrations of metabolite of PGF2α
(15 keto-13, 14 dihydro [PGFM] PGF2α) were detected early in
the cycle when, the CL was short lived. Schrick et al.
(1993) found greater concentrations of PGF2α with lower
embryo quality in uterine flushing of cows with short lived CL than normal luteal
phases on day 6 and concluded that detrimental uterine environment was major
cause of lowered fertility in cows with short luteal phases. Buford
et al. (1996) concluded that inhibition of prostaglandin synthetase
and lutectomy prevents detrimental effects of endogenous PGF2α
on the early embryonic stage in postpartum cows whereas lutectomy alone was
effective in doing so in non-lactating cycling cows. Therefore, the lower survivability
of embryos in postpartum cows might to be due to the combined effect of uterine
PGF2α secreted on Days 4 through 9 (Cooper
et al., 1991) and luteal secretion of PGF2α in response
to the uterine signal (Buford et al., 1996).
Hockett et al. (2004) reported that PGF2α
might interfere with process of compaction of morula stage of embryo resulting
in lower quality and viability of embryos.
||Sequence of endocrinal events conducive to embryonic death
or survival in short and normal estrous cycles (Perea
and Inskeep, 2008)
This might occur as alterations in gap junctions and cell adhesion molecules,
induction of apoptosis mechanisms or alterations of gene transcription during
embryonic development in compaction morula stage of embryo (Scenna
et al. 2004).
Perea and Inskeep (2008) described the sequential endocrine
events conducive to embryonic death or survival in short and normal estrous
cycles (Fig. 2). According to them after parturition, the
hypothalamic-pituitary axis stimulates progressive ovarian follicular development,
estradiol production and expression of LH receptors in follicle. Without a previous
cycle or exposure to progesterone (P4)/progesterone priming followed
by estrogen (E2), uterine progesterone receptors (P4R)
are low and increase in progesterone after ovulation initiates immediate secretion
of uterine PGF2α which causes luteolysis and, if the animal
has been mated, it is embryotoxic. Exposure of the uterus to progesterone followed
by estrogen prior to first postpartum ovulation up regulates uterine progesterone
receptors and contributes to establishment of progesterone dominance of the
uterus. As the estrus cycle progresses progesterone binding to its receptors
delays uterine secretion of PGF2α. If the animal is not mated/pregnant
luteolysis is initiate by uterine secretion of PGF2α that starts
around day 14 to 17 and decreases progesterone production. If the animal is
pregnant, the embryo produces Interferon-tau (IFNι) while the
uterus increases PGE and the corpus luteum is maintained allowing the embryo
to survive. The whole process is known as maternal recognition of pregnancy.
Early embryonic deaths before regression of CL are indistinguishable from fertilization failure in that both cow and ewe return to estrus at the normal time. Death of one embryo in twin ovulating ewes may be undetected as pregnancy will continue. Several methods are used to determine embryonic mortality in cattle. The main being:
Examining embryos: Examining embryos collected by in vivo flushing of reproductive tract at different days after breeding.
Determining progesterone in blood, milk and saliva: Determination of
progesterone in blood and milk, 21 days after oestrus is the most common method
used in the pregnancy diagnosis of ruminants until the early nineties (Zoli
et al., 1992; Karen et al., 2003).
Prvanovic et al. (2009) in his study on monitoing
of early pregnancy and embryonic mortality using blood progesterone concluded
that it is impossible to determine embryonic mortality alone on the basis of
progesterone profile while pregnant and non-pregnant cows can be easily distinguished
21 day post AI. They also concluded that it is very easy and accurate to distinguish
non-pregnant cows from cows that have suffered early embryonic mortality.
CL dysfunction in human reproduction is identified by either of two criteria namely estimation of plasma or salivary P4 levels or endometrial biopsy. Two or three plasma samples could be processed for the assay. Progesterone levels should not be less than 10 ng/ml during the luteal and mid luteal phase.
Pregnancy associated glycoprotein (PAG) test: The main advantage of
Pregnancy Specific Proteins (PSP) for pregnancy diagnosis in cattle is their
ability to prove the existence of placentation and the presence of live, vital
embryos, while progesterone only proves the existence of corpus luteum. The
most commonly used pregnancy specific protein for pregnancy diagnosis in cows
is PAG (pregnancy-associated glycoprotein). Pregnancy-associated glycoprotein
has been found in the serum of pregnant cattle and used as a pregnancy marker
(Perenyi, 2002). As pregnancy failure occurs, PAG concentrations
drop and disappear from maternal blood. The Pregnancy-Associated Glycoproteins
(PAG) are synthesized by the monothand binucleate cells of the ruminant's trophectoderm.
Apart of it is released into maternal blood circulation which can be assayed
by RIA and ELISA. RIA methods are very precise for measuring PAG concentrations
in the maternal blood and milk of the ruminants. The sensitivity and specificity
of this method are very high. The results are encouraging and use of milk and
in blood for PAG test is helpful in detection of embryonic mortality in the
ruminants (Sousa et al., 2008). Prvanovic
et al. (2009) in his study on monitoing of early pregnancy and embryonic
mortality using PAG test concluded that embryonic mortality between 18-24 days
after AI was evident from drastic decrease in PAG seven and half to nine days
later and using PAG for pregnancy diagnosis enables us to prove the existence
of live, vital embryos in utero 24 days after conception.
Ultrasound examination: Transrectal ultrasonography has been used to
detect early pregnancy and to determine embryo/fetal death in recent years (Kahn,
1992; Romano and Magee, 2001). It is advantageous
as it is a safe technique with no effects on embryo/fetus viability (Kahn,
1992; Ball and Logue, 1994; Baxter
and Ward, 1997). It is advantageous over palpation per rectum pregnancy
diagnosis in earlier diagnosis of pregnancy/non-pregnancy, determination of
embryo/fetus viability, determination of number of embryos, reduction of misdiagnosis
(false negatives and false positives) and reduction of potential iatrogenic
embryo/fetus attrition (Romano and Magee, 2001). In
research studies maximum sensitivity and negative predictive values were obtained
from day 29 on in cows and from day 26 on in heifers.
TREATMENT TO IMPROVE PREGNANCY RATES
Various methods have been tried using different preparations for improving pregnancy rates by reducing embryonic mortality. They are as under:
Supplementing progesterone/progestogen: Research studies have reported
that low concentration of progesterone can result in the development of a stronger
luteolytic signal and hence it might be concluded that cows with lower plasma
concentrations are apparently more prone to embryo loss. Macmillan
and Peterson (1993) found that the conception rates to first insemination
were increased when the CIDR device was inserted 6-8 days after insemination.
Broadbent et al. (1992) recorded a significant
increase in conception rate among cattle when Crestar ear implants (Norgestomet)
were given on day 7.
Peters and Ball (1995) stated that progesterone supplementation
might also cause suppression of endogenous luteotropic support due to increased
negative feedback. While, Mann and Lamming (1999) demonstrated
that supplemental progesterone was beneficial to fertility increasing conception
rates when administered prior to day 6 after AI in lactating dairy cows.
Use of human chorionic gonadotropin (hCG): An alternative approach to
increase the progesterone levels is by use of Human Chorionic Gonadotropin (hCG)
to enhance the production of progesterone by the animals own corpus luteum.
Administration of human chorionic gonadotropin (hCG) induces ovulation with
the subsequent formation of a functional accessory CL which in turn increases
progesterone and may enhance embryo survival. Studies have supported that conception
rate is better in cows with three follicular waves after insemination as compared
to cows with two follicular waves and hCG induction of three-wave cycles may
also contribute to higher pregnancy rates. Thatcher and Collier
(1986) and associates have indicated that the injection of hCG (2000 IU)
i.m.; (1000 IU) i.v. 5 days after oestrus induces ovulation of the first wave
dominant follicle and formation of accessory corpus luteum and increases plasma
progesterone levels during the luteal phase. Santos et
al. (2001) demonstrated that injecting 3300 IU of hCG in lactating cows
5 days after AI resulted in increased number of CL and higher plasma progesterone
concentrations. Conception rates on days 28, 42 and 90 were improved by hCG
treatment. The findings of Santos et al. (2001) were
supported by findings of Nishigai et al. (2002),
they administered hCG on day 6 and the pregnancy rates were increased (67.5%)
with formation of accessory corpora lutea as compared to control cows (45.0%).
or cows receiving hCG on day 1 (42.5%) after Lopez-Gatius
et al. (2002) reported that cows having an additional spontaneous
CL were eight times less prone to fetal loss than those with a single CL.
PMSG (pregnant mare serum gonadotropin) administration: Hirako
et al. (1995) in their study on luteotropic effect of PMSG in cattle
and reported significant increase in progesterone concentration on administration
of 500 IU of PMSG on day 7 after estrus. They concluded that PMSG treatment
increases progesterone secretion and luteal function without excessive follicular
Gonadotropin releasing hormone (GnRH) treatment: Administration of GnRH
(250 μg or greater) at the time of insemination increases pregnancy rates
by 12.5% and effect was more pronounced in repeat breeder cows (22.5%) (Morgan
and Lean, 1993). Administration of GnRH at oestrus increases serum progesterone
levels and the proportion of large luteal cells in the corpus luteum (Mee
et al., 1995).
MacMillan et al. (1986) reported an enhancement
of the conception rate in dairy cows when GnRH (10 μg Buserelin) was injected
on day 11 after breeding by AI. Injecting Buserelin at 3 days interval from
day 12 (luteal phase) increases progesterone concentrations and maintains at
luteal levels till the injections are continued, i.e., until day 48 after the
preceding oestrus (Thatcher et al., 1989). This
indicates that buserelin exerts a continued luteotropic or antiluteolytic effect
under these circumstances.
Administration of hCG during luteal phase of the cycle induces ovulation of
the dominant follicle (Price and Webb, 1989). Administration
of GnRH on day 6 of the cycle resulted in ovulation in 75% animals with the
formation of accessory corpora lutea (Webb et al.,
1992). This not only induces additional progesterone secretion, but also
downregulates oestradiol production.
Mann et al. (1995) reported that administration
of buserelin on day 12 after insemination results in reduced plasma oestradiol
concentrations and suppression of pulses of the PGF2α metabolite
(13, 14-dihydro-15-keto-PGF2α (PGFM) from about day 13 onwards,
confirming its antiluteolytic effect. Reduction in oestradiol concentrations
at this time might inhibit the luteolytic mechanism and hence, pregnancy is
maintained. They also concluded that GnRH treatment weakens rather than delays
the luteolytic signal. The timing of buserelin/GnRH treatment appears critical
since treatment at other times after insemination did not have any effect (MacMillan
et al., 1986; Drew and Peters, 1994).
Interferons: Intrauterine administration of recombinant ovine/bovine
IFNι resulted in extension of the oestrous cycle and abolished the oxytocin
induced PGF2α secretion on day 17 (Meyer
et al., 1995). IFNι is more effective than IFNα in preventing
embryonic mortality as it has no side effects.
Omega-3 and reproductive performance: Research studies by workers (Mattos
et al., 2000, 2002; Thatcher
et al., 2001) have indicated that omega-3 fatty acids decreases secretion
of PGF2α. Trials by research workers (Bonnette
et al., 2001; Mattos et al., 2002;
Petit and Twagiramungu, 2002; Ambrose
and Kastelic, 2003) with natural sources of omega-3 fatty acids such as
Eicosapentaenoic Acid (EPA), Dehydroascorbic Acid (DHA) and α-linolenic
acids have indicated that these fatty acids are capable of decreasing the secretion
of PGF2α and compliment the antiluteolytic action of IFNι
thereby improve pregnancy rates. EPA and DHA also have anti-inflammatory and
immunosuppressive effects that compliment the normal immunosuppressive and anti-inflammatory
effects of progesterone and IFNι in early pregnancy.
EED is the major cause of reproductive and economic loss in cattle. Though many factors have been incriminated but luteal function plays an important role. Embryonic death occurs the time of maternal recognition of pregnancy, probably related to a failure of the IFNι secretory mechanism. Recent research, both in terms of physiological mechanisms and pharmacological treatments has mostly focused on the period of maternal recognition of pregnancy or the anti-luteolytic effect. Ovarian examination, blood/milk progesterone levels, PAG test and ultrasound appear to be the only practical tool presently available. hCG/GnRH/P4 supplementation have shown positive results. Supplementation of interferon as anti-luteolytic agent and supplementing Omega-3 has shown encouraging results.
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