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Theriogenology 76 (2011) 1594 1601


www.theriojournal.com

Advances in Bovine Reproduction and Embryo Technology

Influence of progesterone on oocyte quality


and embryo development in cows
Patrick Lonergan*
School of Agriculture, Food Science and Veterinary Medicine, College of Life Sciences, University College Dublin, Belfield, Dublin 4, Ireland
Received 30 March 2010; received in revised form 15 April 2011; accepted 15 April 2011

Abstract
In cattle, the majority of embryo loss occurs very early during pregnancy (approximately Day 16), around or prior to maternal
recognition of pregnancy. The actions of P4 in controlling LH pulsatility and ovarian follicular development may impinge
negatively on oocyte quality. A considerable proportion of embryo loss may be attributable to inadequate circulating progesterone
(P4) concentrations and the subsequent downstream consequences on endometrial gene expression and histotroph secretion into
the uterine lumen. Conceptus growth and development require the action of P4 on the uterus to regulate endometrial function,
including conceptusmaternal interactions, pregnancy recognition, and uterine receptivity for implantation. This review summarizes recent data highlighting the role of progesterone in determining oocyte quality and embryo development in cattle.
2011 Elsevier Inc. All rights reserved.
Keywords: Oocyte competence; Embryo mortality; Embryo transfer; In vitro fertilization; Fertility

Contents
1.
2.
3.
4.
5.

Introduction ............................................................................................................................
Effect of progesterone on the oocyte ..............................................................................................
Effects of progesterone on the endometrium ....................................................................................
Effect of progesterone on the embryo ............................................................................................
Strategies to improve pregnancy rates through increasing P4 ................................................................
5.1. Use of human chorionic gonadotrophin (hCG) to increase progesterone concentrations ........................
6. Conclusion .............................................................................................................................
Acknowledgments ....................................................................................................................
References ...................................................................................................................................

1. Introduction
The steroid hormone progesterone (P4) plays a key
role in reproductive events associated with establish-

* Corresponding author. Tel.: 353 1 7166206/6012147; fax:


353 1 6288421.
E-mail address: pat.lonergan@ucd.ie (P. Lonergan).
0093-691X/$ see front matter 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.theriogenology.2011.06.012

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ment and maintenance of pregnancy. In cattle, approximately 40% of conception loss is estimated to occur
from Days 8 to 16 of pregnancy (Day 0 ovulation)[13]. Conceptus growth and development require
the action of P4 on the uterus to regulate endometrial
function, including conceptusmaternal interactions,
pregnancy recognition, and uterine receptivity for implantation. A considerable proportion of embryo loss

P. Lonergan / Theriogenology 76 (2011) 1594 1601

may be attributable to inadequate circulating P4 concentrations and the subsequent downstream consequences on endometrial gene expression and histotroph
secretion into the uterine lumen. Furthermore, low P4
concentrations have also been implicated as a causative
factor in the low pregnancy rates observed in highyielding dairy cows [1]. Elevated concentrations of
circulating P4 in the immediate post-conception period
were associated with an advancement of conceptus
elongation [4 6], an increase in interferon-tau production [7,8], and higher pregnancy rates in cattle and
sheep [9 11]. This review will summarize recent data
highlighting the role of progesterone in determining
oocyte quality and embryo development in cattle.
2. Effect of progesterone on the oocyte
The role of P4 in mammalian oocyte maturation and
its potential impact on oocyte quality has not been well
defined. However, the well-described switch from estradiol dominance to P4 dominance in the follicular
fluid of preovulatory follicles in the period between the
LH surge and ovulation [12], coincident with resumption of meiosis and maturation of the oocyte, suggests a
role for P4 in this process. Injection of bovine preovulatory follicles with trilostane, an inhibitor of 3 beta-hydroxysteroid dehydrogenase, an enzyme that catalyses the synthesis of P4 from pregnenolone (to block the preovulatory
rise in intrafollicular P4), significantly decreased P4 production in the follicle, but did not affect ovulation rate or
CL function, as determined by serum P4 concentrations
on Days 19 of the subsequent luteal phase [13]. An effect
on oocyte quality was not determined.
Adding P4 to the culture medium during bovine
oocyte maturation in vitro reduced the proportion of
embryos forming blastocysts, an effect which was partially reversed by addition of the anti-progestin, mifepristone (RU486) [14]. In contrast, addition of the P4
inhibitor, aminoglutethimide (AGT), to in vitro maturation media, decreased germinal vesicle breakdown in
porcine oocytes in a reversible manner [15]. However,
P4 supplementation did not reverse similar affects observed in AGT-inhibited bovine oocytes [16].
In a series of recent experiments, we characterized the
presence of both genomic and non-genomic P4 receptors
in bovine oocytes and associated cumulus cells, and we
studied the effect of inhibiting P4 production by cumulus
cells on oocyte developmental competence [17]. Based on
the dynamic changes observed in protein expression of P4
receptors following in vitro maturation, or in response to
supplementation with LH, FSH or P4, there may be a role

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for P4 during bovine oocyte maturation. Inhibiting cumulus cell P4 synthesis during maturation with trilostane, an
inhibitor of 3 -hydroxysteroid dehydrogenase, significantly reduced blastocyst formation rate, an effect which
was completely abrogated by supplementation with exogenous P4 or a P4 agonist [17]. Reduced embryo development following inhibition of P4 synthesis by cumulus
cells or blocking of nuclear P4 receptor activity during in
vitro maturation supported a role for progesterone in determining oocyte quality.
Another way that P4 can affect oocyte quality is
through its effect on development of the dominant follicle.
Pulsatile secretion frequency of GnRH is regulated by
circulating concentrations of P4 during the estrous cycle,
which in turn regulate LH pulse frequency [18]. In turn,
LH pulse frequency is the primary factor determining
whether or not a dominant follicle ovulates; thus, when P4
concentrations are high, LH pulse frequency is low and
the dominant follicle undergoes atresia. High LH pulse
frequency, as occurs when P4 declines following luteolysis, stimulates continued growth of the dominant follicle
which secretes more estradiol and inhibin and ultimately
ovulates (for reviews, see [19 22]). Very low (subluteal)
progesterone concentrations (12 ng/mL) are associated
with increased LH pulse frequency. However, this increase never reaches follicular-phase-type frequencies that
are necessary for final maturation of the preovulatory
follicle and ovulation, and therefore may lead to an extended period of dominance (persistence) of the dominant
follicle [19,23]. Pregnancy rate is sequentially decreased
as the duration of dominance increases from 4 to 8 d, and
is further significantly reduced if the duration of dominance exceeds 10 d [24], due to resumption of meiosis in
many oocytes [25]. Restricting the duration of dominance
of the preovulatory follicle to 4 d at estrus, results in a
precise onset of estrus and a high pregnancy rate following a single AI at a detected estrus [26].
3. Effects of progesterone on the endometrium
Preparation of the uterine endometrium for embryo
attachment and implantation in all studied mammals,
including ruminants, involves carefully orchestrated
spatiotemporal alterations in transcriptomic profiles.
Despite the importance of P4 for establishment and
maintenance of pregnancy in mammals, paradoxically,
endometrial epithelia cease expressing P4 receptors
prior to implantation in all mammals studied [27]. The
loss of P4 receptors in uterine epithelia appears to be a
prerequisite for maternal recognition of pregnancy and
conceptus development in early pregnancy, as well as

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P. Lonergan / Theriogenology 76 (2011) 1594 1601

for epithelial cell proliferation and differentiated functions as directed by specific factors (progestamedins)
produced by P4 receptor-positive stromal cells [27].
Furthermore, elevated P4 concentrations induce early
downregulation of P4 receptors [28] and is associated
with an advancement in the normal temporal changes
that occur in the endometrial transcriptome [29].
Significant temporal changes occur in endometrial
gene expression during the estrous cycle and early pregnancy [29 31]. In both cyclic and pregnant animals, similar changes occur in endometrial gene expression up to
initiation of conceptus elongation, suggesting that the default mechanism in the uterus is to prepare for an expected
pregnancy [32]. This is supported by the fact that it is
possible to transfer an embryo to a synchronous uterus 7 d
after estrus and establish a higher rate of pregnancy, as is
routine in commercial bovine embryo transfer. It is only in
association with maternal recognition of pregnancy,
which occurs on approximately Day 16 in cattle, that
significant changes in the transcriptomic profile are detectable between cyclic and pregnant endometria, when
the endometrium responds to increasing concentrations of
interferon-tau secreted by the filamentous conceptus [32].
Elevated P4 advances the transcriptomic changes in the
endometrium, which normally occur during pregnancy,
resulting in enhanced conceptus elongation [29]. Interestingly, we have shown that the embryo does not have to be
present in the uterus during the period of P4 elevation in
order to benefit from it, supporting the concept that the
positive effect on conceptus growth is mediated via P4induced changes in the endometrial transcriptome [33].
Recently, our group reported that lower circulating P4
concentrations in postpartum dairy cows were associated
with an impaired ability of the oviduct/uterus to support
embryo development compared with that of dairy heifers
[34]. We hypothesized that part of the difference in fertility between heifers and postpartum lactating dairy cows
could be explained by differences in the ability of the
reproductive tract (oviduct and uterus) to support early
embryo development and that this would be related to
circulating progesterone concentrations. To test this
hypothesis, using endoscopy, we transferred 1800 in
vitro-produced embryos to the oviducts of nulliparous Holstein-Friesian heifers and postpartum lactating Holstein-Friesian cows and assessed their development to the blastocyst stage following recovery on
Day 7. Recovery rate was lower from cows (57%)
compared to heifers (79%); furthermore, of the structures recovered, only 18% had developed to the blastocyst stage in cows compared to 34% in heifers [34].

4. Effect of progesterone on the embryo


The effects of elevated progesterone shortly after conception on the advancement of conceptus elongation have
been convincingly demonstrated in cattle and sheep. Garrett et al [4] administered 100 mg progesterone on Days 1,
2, 3, and 4 of pregnancy which resulted in an increased
peripheral plasma progesterone concentrations on Days 2
to 5 and significantly larger conceptuses on Day 14. Using
a progesterone implant on Day 3 of pregnancy, Carter et
al. [5] significantly elevated progesterone concentrations
until Day 8; this was associated with a larger conceptus
recovered at slaughter on Day 16. Similarly, when ewes
received daily injections of 25 mg progesterone starting
36 h postmating, blastocyst diameter increased by 220%
on Day 9 and the time of elongation of blastocysts to a
filamentous conceptus on Day 12 was advanced [6]; these
effects of progesterone treatment on blastocyst development were blocked by administration of RU486, a progesterone receptor antagonist.
From the above, it is clear that the concentration of
circulating progesterone affects developing embryos. This
effect is likely as a result of downstream effects of progesterone-induced changes in gene expression in uterine
tissues [6,29,30], resulting in changes in the composition
of histroph to which the developing embryo is exposed.
The importance of histotroph for conceptus development
was demonstrated in the uterine gland knockout (UGKO)
model in sheep, in which embryos fail to develop beyond
the blastocyst stage in adult UGKO ewes [35].
To address the question of whether P4 has a direct
effect on the embryo (as opposed to an indirect effect via
changes induced in the endometrium), some authors have
added P4 to embryo culture medium in vitro, and examined development to the blastocyst stage. Results, however, have been varied and contradictory, with some authors reporting positive effects of P4 [36,37], whereas
others reported no effect [38,39]. These contradictory observations may be partially explained by the culture system used, as steroids are known to be lipophilic and
culture under oil, the system used in many laboratories,
may result in their depletion from the medium [40].
In a series of recent experiments using in vitro and in
vivo models, we addressed the issue of whether the
effects of progesterone on conceptus elongation could
be due, at least in part, to a direct effect of P4 on the
embryo [33]. The P4 receptor mRNA was present at all
stages of embryo development, raising the possibility
of a direct effect of P4 on the embryo. Exposure to P4
in vitro in the absence or presence of oviduct epithelial
cells did not affect the proportion of embryos developing to the blastocyst stage, blastocyst cell number, or

P. Lonergan / Theriogenology 76 (2011) 1594 1601

the relative abundance of selected transcripts in the


blastocyst. Furthermore, exposure to P4 in vitro did not
affect post-hatching elongation of the embryo following transfer to synchronised recipients and recovery on
Day 14. In contrast, transfer of in vitro-derived blastocysts to a uterine environment previously primed by
elevated P4 resulted in a four-fold increase in conceptus
length on Day 14. These data provide clear evidence to
support the hypothesis that P4-induced changes in the
uterine environment are responsible for the advancement in conceptus elongation reported previously in
cattle and that, interestingly, the embryo does not need
to be present during the period of high P4 in order to
exhibit advanced elongation. This is consistent with the
fact that administration of progesterone early in the estrous cycle can advance uterine receptivity for the transfer
of older, asynchronous embryos [41].
We recently developed a low P4 model, whereby
injection of PGF2 on Days 3, 3.5 and 4 of the estrous
cycle reduces circulating P4 concentrations [42]. The
use of this model can facilitate the understanding of the
mechanisms of action of low P4 on conceptus development. In a subsequent study, we demonstrated that
induction of low serum P4 concentrations in heifers
altered the normal temporal changes that occurred in
the expression of genes in the endometrium, mainly by
delaying their expression. This delay in temporal
changes in endometrial gene expression was correlated
to a delay in downregulation of the progesterone receptor from the luminal epithelium and glandular epithelium and the altered endometrial gene expression induced by low P4 was associated with a reduced
capacity of the uterus to support conceptus development after transfer of multiple embryos on Day 7 [43].
5. Strategies to improve pregnancy rates through
increasing P4
The beneficial effects of exogenous supplementation
have been known for some time. Johnson et al [44] reported higher pregnancy rate to first service following 100
mg injections of progesterone on Days 2, 3, 4, 6, and 9
after AI (68%, 36/53) compared to controls (42%, 29/69).
Robinson et al [45] reported higher pregnancy rates at Day
55 post insemination in lactating Holstein cows treated
with a PRID from Days 512 (60.7%, 17/28) or Days
10 17 (59.2%, 16/27) compared to controls (30%, 9/30).
Several treatments can be used to increase peripheral
concentrations of P4 after AI, including those that increase
endogenous function of the existing CL, induce accessory
CL, or supplement progesterone directly (see reviews by

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[46 48]. However, data on outcome in terms of pregnancy rate are often conflicting or inconclusive, and may
reflect timing of treatment, that only a proportion of animals with inherently low P4 may benefit from such treatment, or the lack of sufficient animal numbers.
Dominant follicle size is associated with subsequent
CL size [49]. Larger CLs secrete more P4 and this has,
in some studies (data in [47]), but not all [50], been
associated with improved pregnancy rates. Therefore
strategies which promote growth of the dominant follicle before ovulation and/or stimulate CL development
are likely to increase pregnancy rate [48,51].
Using a large number of animals, Stevenson et al
[52] assessed the effects of a variety of interventions
after AI on fertility, including administration of GnRH,
hCG, or an intravaginal progesterone-releasing device
(CIDR). Both GnRH and hCG effectively induced ovulation and increased CL number, but circulating P4
concentrations were only increased in hCG-treated
cows. Treatment with a CIDR or hCG increased conception rate, but only in some herds.
5.1. Use of human chorionic gonadotrophin (hCG) to
increase progesterone concentrations
Administration of hCG during the early luteal phase
induces ovulation of the first wave dominant follicle
and formation of a functional accessory CL, which
increases circulating P4 concentrations. This phenomenon has been exploited by many authors in an attempt
to improve pregnancy rate (Table 1). Administration of
hCG from 5 to 7 d after estrus or AI increased concentrations of P4 in lactating dairy cows [5254], dairy
heifers [55,56], beef cows [57], and beef heifers [58].
The clinical use of hCG in dairy cows has been recently
reviewed [59]; the authors concluded that: (1) hCG
administration leads to increased circulating progesterone concentrations which persist for 2 to 3 weeks; (2)
the effectiveness of hCG in inducing dominant follicle
ovulation is similar to that of GnRH, but hCG is preferable due to longer half-life and direct effects on the
ovary; and (3) hCG administration at AI can reduce
embryo losses, especially under conditions of heat
stress (only manifest with treatment after Day 5).
Effects of hCG administration after AI on pregnancy
rates have been variable (Table 1). Increased pregnancy
rates on Day 28, 45, and 90 were reported when lactating dairy cows were treated with hCG on Day 5 after
estrus [54]. Similarly, administration of hCG between
Days 4 and 9 after AI increased conception rates, but
only in 3 of 5 herds [52]. When administered the day
before embryo transfer in Japanese Black beef cattle,

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P. Lonergan / Theriogenology 76 (2011) 1594 1601

Table 1
Summary of data relating to use of hCG to induce accessory CL and improve pregnancy rate in cattle.
Source

Animal type

Dose

Day of treatment

Hansel et al [64]

Lactating dairy and beef


cows

1500 IU sc

Morris et al [65]

Beef heifers

10001500 IU

0
4

Eduvie and Sequin [66]

Lactating Holstein cows

10000 IU im

1012

Helmer and Britt [67]

5000 IU im

Diaz et al [56]

Holstein (105) and Jersey


(110) cows
Holstein heifers

Breuel et al [68]

Crossbred beef heifers

3000 IU (1000 iv,


2000 im)
3000 IU im

Breuel et al [62]

Beef heifers

3000 IU im

Rajamahendran and
Sianangama [69]

Lactating Holstein cows

Sianangama and
Rajamahendran [70]

Lactating Holstein cows

1000 IU im

Fricke et al [71]
Schmitt et al [72]

Mixed beef breed cows


Holstein heifers

1500 IU iv
3000 IU (1000 iv,
2000 im)

0
7
14

Success at inducing
accessory CL % (n)

Dairy:
hCG 44.8 (145)
Control: 52.8 (161)
Beef:
hCG: 54.5 (145)
Control: 54.4 (136)
Day 0:
hCG: 42.0 (40)
Control: 50.0 (40)
Day 4:
hCG: 43.0 (30)
Control: 61.0 (28)
hCG: 59 (99)
Control: 63 (101)
hCG: 60.0 (52)
Control: 66.0 (44)
hCG: 6/6
control: 0/7

hCG Day 0: 37.5 (8)


hCG Day 7: 77.8 (9)
hCG Day 14: 44.4 (9)
control: 12.5 (8)

0
7
14

6
5

hCG: 100 (5)


hCG: 91 (11)
Control: 0 (17)

Holstein heifers
Lactating Holstein cows
Kerbler et al [73]

Mixed beef breed heifers

1500 IU im

Santos et al [54]

Lactating Holstein cows

3300 IU im

Nishigai et al [57]

Japanese Black beef cattle

1500 IU im

Hanlon et al [53]

Lactating Friesian cows

1500 IU im

1
6
[Embryo Transfer]
5

Funston et al [58]

Beef heifers

3333 IU im

56

Galvao et al [60]

Lactating Holstein cows

3300 IU im

Pregnancy rate %
(n)

hCG: 100 (12)


Control: 0 (17)
hCG: 86.2 (203)
Control: 23.2 (203)

Improvement
Yes/No
No

No

No
No

hCG: 1.6 (12)


Control:54.5 (11)
hCG: 57.4 (94)
Control: 68.8 (77)
hCG Day 0: 50 (8)
hCG Day 7: 77.8 (9)
hCG d14: 44.4 (9)
control: 3/8
hCG d0:
47 (49)
hCG d7: 62 (52)
hCG d14: 55 (49)
control: 40 (50)
hCG: 36.4 (11)
Control: 58.8 (17)
hCG: 65 (122)
Control: 63 (121)
hCG: 24.2 (99)
Control: 23.5 (102)
hCG: 75 (12)
Control: 64.7 (17)
Day 25:
hCG: 45.8 (203)
Control: 38.7 (203)
Day 45:
hCG: 40.4 (203)
Control: 36.5 (203)
Day 90:
hCG: 38.4 (203)
Control: 32.0 (203)
hCG d1: 42.5 (40)
hCG d6: 67.5 (40)
Control: 45.0 (40)
hCG: 43.6 (210)
Control: 46.3 (221)
hCG: 63.1 (274)
Control: 62.6 (261)
Day 28:
hCG: 34.8 (69)
Control: 31.8 (66)
Day 42:
hCG: 30.4 (69)
Control: 28.8 (66)

Yes
No

Yes

No
No
No

Yes

Yes

No
No
No

P. Lonergan / Theriogenology 76 (2011) 1594 1601

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Table 1
(continued)
Source

Animal type

Dose

Day of treatment

Stevenson et al [52]

Lactating Holstein cows

3500 IU im

Chagas e Silva and Lopes


da Costa [55]

Holstein heifers

1500 IU im

Dahlen et al [63]

Postpartum suckled beef


cows
Beef cows

1000 IU im

1000 IU im

7
[Embryo Transfer]

Wallace et al [61]

hCG resulted improved pregnancy rates [57], whereas


treatment on Day 5 of lactating dairy embryo recipients
failed to increase Day 28 or Day 42 conception rates
[60]. Similarly, administration of hCG on the day of
embryo transfer increased the incidence of accessory CL
and serum progesterone in pregnant recipients and transfer
pregnancy rates [61]. There were no differences in pregnancy rates after hCG treatment of anestrous dairy cows,
or beef heifers after AI [53,58,62]. Chagas e Silva and
Lopes da Costa [55] reported that hCG-treated heifers
with an accessory CL had a higher Day 28 pregnancy rate
than untreated heifers; this was more evident in ET-bred
heifers (53.5 vs 38.1%, respectively) compared with AI.
Dahlen et al [63] reported improvements in fertility in 5 of
6 locations following hCG administration on Day 7 after
fixed time AI.
6. Conclusion
Clearly, P4 is a key player in the establishment and
maintenance of pregnancy. It can indirectly affect the
quality of the oocyte through its effects on LH pulsatility and the development of a persistent dominant
follicle. Furthermore, it has a crucial role in creating an
optimal uterine environment in which the embryo can
develop, through its actions on the uterine endometrium, and in turn, the composition of the histotroph.
Strategies aimed at elevating P4 in the early luteal
phase have led to variable results in terms of improving
pregnancy rates; these variable results may be due to
the type of animal treated (nonlactating heifer, lactating
dairy cow, beef cow) and/or the endogenous P4 concentrations in such animals. Identifying animals with

Treated once
between Days 4
and 9
7

Success at inducing
accessory CL % (n)

Pregnancy rate %
(n)

Improvement
Yes/No

hCG: 81.3 (37)


Control: 2.9 (34)

hCG: 33.6 (708)


Control: 28.3 (708)

Yes

hCG: 74.4 (125)

AI:
hCG: 60.9 (64)
Control: 61.4 (57)
ET:
hCG: 41.0 (61)
Control: 31.0 (63)
Total:
hCG: 1.2 (125)
Control: 45.8 (120)
hCG: 56.3 (254)
Control: 50.0 (252)
hCG: 61.8 (361)
Control: 53.9 (358)

No

hCG: 90.6 (51)


Control: 0 (51)

Yes
Yes

suboptimal P4 in a given cycle is likely to lead to more


consistent improvements following P4 therapy.

Acknowledgments
The authors work is supported by Science Foundation Ireland (Grants: 06IN1B62 and 07/SRC/B1156).

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