CSIRO PUBLISHING

Reproduction, Fertility and Development, 2014, 26, 1–11

http://dx.doi.org/10.1071/RD13304

Genetic control of reproduction in dairy cows

Stephen T. Butler

Teagasc, Animal & Grassland Research and Innovation Centre, Moorepark, Fermoy, Co. Cork,
Ireland. Email: [email protected]

Abstract. The advent of AI has markedly improved the production potential of dairy cows in all systems of production
and transformed the dairy industry in many countries. Unfortunately, for many years breeding objectives focused solely on
milk production. This resulted in a major decline in genetic merit for fertility traits. In recent years, the underlying
physiological mechanisms responsible for this decline have started to be unravelled. It is apparent that poor genetic merit
for fertility traits is associated with multiple defects across a range of organs and tissues that are antagonistic to achieving
satisfactory fertility performance. The principal defects include excessive mobilisation of body condition score,
unfavourable metabolic status, delayed resumption of cyclicity, increased incidence of endometritis, dysfunctional
oestrus expression and inadequate luteal phase progesterone concentrations. On a positive note, it is possible to identify
sires that combine good milk production traits with good fertility traits. Sire genetic merit for daughter fertility traits is
improving rapidly in the dairy breeds, including the Holstein. With advances in animal breeding, especially genomic
technologies, to identify superior sires, genetic merit for fertility traits can be improved much more quickly than they
initially declined.

Additional keywords: fertility traits, genetic selection, oestrous cycle, pregnancy, reproductive physiology.

Introduction cattle fertility. This ignored the fact that the physiological
Dairy cow fertility can be defined as ‘the ability of the animal to environment of the dairy cow abruptly undergoes a fundamen-
conceive and maintain pregnancy if served at the appropriate tal change following initiation of lactation. It is now generally
time in relation to ovulation’ (Darwash et al. 1997). Repro- accepted that the hormonal and metabolic adaptations neces-
ductive performance of high-yielding dairy cows has undergone sary for the initiation and maintenance of lactation are antago-
a major decline over the past five decades (Washburn et al. nistic to optimal reproductive performance in modern dairy
2002; Butler 2003; Evans et al. 2006). Data compiled from over cows (Lucy et al. 2001). There is evidence that selection for
800 000 cow records in New York indicate a decline in increased milk yield has had unfavourable effects on some of
conception rate to first service from 66% in 1951 to an average the hormonal and metabolic signals to the reproductive axis
of approximately 30% in 2001 (Butler and Smith 1989; Butler (Bonczek et al. 1988; Crooker et al. 2001). Although intensive
2003). Similar trends have been reported in The Netherlands research has been performed in the area of reproductive physi-
(van Knegsel et al. 2005), the UK (Royal et al. 2000) and in ology, the precise underlying physiological mechanisms
pasture-based systems. Data compiled by Evans et al. (2006) responsible for the decline in fertility remain poorly under-
from 14 seasonal spring-calving dairy farms in Ireland indicated stood. However, it is widely accepted that: (1) breeding values
a reduction in calving rate to first service from 55% in 1990 to for fertility traits underwent a major decline while breeding
44% in 2001. Similarly, in the UK, pregnancy rate to first service objectives were focused solely on milk production (Weigel
declined by 1% per annum between 1975 and 1998 (Royal et al. 2004); and (2) metabolic stressors associated with the initiation
2000). All these studies noted an opposite trend in milk yield, and maintenance of lactation perturb the finely tuned biological
with a steady increase in genotypic and phenotypic milk output processes necessary for pregnancy establishment to occur
per cow observed over the same time frame. Pregnancy rates to a (Butler et al. 2006; Leroy et al. 2008). The present review
single AI have been reported to be as low as 30%–44% (Royal outlines phenotypes under genetic control that are related to
et al. 2000; Norman et al. 2009). fertility. A lot of the data are drawn from pasture-based systems
The decline in fertility is not apparent, or at least not as because much of the relevant research has been conducted
marked, in heifers. For many years, this was suggested to under this system. It is likely that many (and perhaps all) of
indicate that there was no underlying genetic influence on dairy the phenotypes are also relevant to confinement systems.

Journal compilation Ó IETS 2014 www.publish.csiro.au/journals/rfd

2 Reproduction, Fertility and Development S. T. Butler

Major genes affecting fertility that were homozygous for the TT mutation. Single nucleotide
It is generally accepted that fertility traits are affected by a large polymorphisms (SNPs) in the signal transducer and activator of
number of genes, each with very small individual effects transcription 5A (STAT5A) and fibroblast growth factor 2
(Wiggans et al. 2011). However, there is clear evidence that (FGF2) genes associated with IVF and embryo development
individual recessive mutations exist with marked unfavourable were identified using the DNA-pooling sequencing approach
effects on phenotypic fertility. For example, deficiency of (Khatib et al. 2008a, 2008b). The in vitro findings were vali-
uridine-50 -monophosphate synthase (DUMPS) is inherited as an dated using estimated relative conception rate for 222 AI sires
autosomal recessive trait in Holstein–Friesian cattle and causes genotyped for the STAT5A and FGF2 SNPs (Khatib et al. 2010),
embryonic mortality in homozygous carriers (Shanks and demonstrating that incorporation of STAT5A and FGF2 SNP
Robinson 1989), but DUMPS has essentially been eliminated in information into genetic improvement programs could improve
most countries (VanRaden and Miller 2006). Seventy-seven per reproductive efficiency in cows.
cent of fetuses generated from dam and sire carriers of the Genome-wide association studies (GWAS) have been con-
complex vertebral malformation (CVM) mutation were aborted ducted to identify regions of the genome associated with fertility
before gestation Day 260 (Nielsen et al. 2003). Brachyspina traits in dairy cattle. In general, these studies were hampered by
syndrome (BS) is a rare congenital defect (,1 per 10 000 births) inadequate study size and/or lacked detailed reproductive phe-
in Holstein–Friesian cattle. The carrier frequency in Holstein– notypes. Pryce et al. (2010) identified a putative fertility
Friesian cattle is 7.4%, suggesting that birth rates should be quantitative trait locus (QTL) on chromosome 18 and listed 30
much higher (Charlier et al. 2012). Matings between BS carrier potential genes in the region of the SNP. Berry et al. (2012)
dams and BS carrier sires had a greater likelihood of pregnancy identified associations between SNPs on chromosomes 2 and 21
failure than matings where neither parent was a BS carrier or and commencement of luteal activity. Huang et al. (2010) used a
when only one parent was a BS carrier (Charlier et al. 2012). bovine IVF population to identify SNPs related to fertilisation
This partially explains the low birth rate relative to the popu- and blastocyst formation. These GWAS results are valuable for
lation carrier frequency. identifying genomic regions associated with fertility traits and
Until recently, it was not possible to identify genetic defects identifying genomic regions and candidate genes for resequen-
if early embryo mortality occurred in all homozygous mutant cing and bioinformatic analysis to determine the causative
conceptuses. Using genotype data, five new lethal recessive mutations.
alleles were recently identified by examining haplotype inheri- Selecting for improved fertility
tance; the absence of homozygous carriers was used to identify
recessive defects causing embryonic mortality (VanRaden et al. The initial selection indices in most dairy countries focused
2011). Three of the haplotypes are in the Holstein, one is in the primarily on milk production traits. In addition to selecting for
Brown Swiss and one is in the Jersey. The Jersey haplotype cows that produced more milk, greater angularity or sharpness
(JH1) had a carrier frequency in the US of 20%–25% for 40 was also considered favourable (i.e. cows also looked like they
years. With such a high carrier frequency, the likelihood of no produced more milk). It has been well established that body
homozygotes by chance is essentially nil. Sonstegard et al. condition score (BCS) is a key driver of cow health and fertility
(2013) identified the cause of the JH1 defect as a nonsense (Berry et al. 2003; Buckley et al. 2003; Lucy 2003; Weigel
mutation in the CWC15 gene; the protein product of this gene 2006; Roche et al. 2009; Cummins et al. 2012b). However,
is an integral component of the spliceosome complex. The favourable BCS is the opposite of favourable angularity. It is
nonsense mutation reduces the size of the CWC15 protein likely that selecting for angularity directly contributed to the
product from 241 to 54 amino acids, removing the conserved decline in phenotypic fertility and increased the incidence of
Cwf_Cwc_15 domain that exists in the wild-type protein. The metabolic disorders (Hansen 2000). Selecting for improved
CWC15 protein plays an important role in placental develop- BCS has been identified as a strategy to improve health and
ment, and this is likely a key mechanism responsible for fertility (Berry et al. 2003; Shook 2006; Weigel 2006).
conception failure in homozygous carriers (Sonstegard et al. For many decades, fertility and health traits (most notably
2013). The causative mutations for the remaining haplotypes mastitis) have been incorporated into the breeding index of the
identified by VanRaden et al. (2011) will presumably also be Scandinavian breeds. Although fertility declined globally
identified in the near future. Diagnostic tests to screen for these between 1985 and 2005, non-return rates, culling rates due to
deleterious haplotypes could be rapidly developed. infertility and calving interval remained relatively constant in
the Norwegian Red breed (Refsdal 2007). The incidence of
veterinary treatments for reproductive disorders in 503 683 first-
Minor genes affecting fertility lactation daughters of 1058 Norwegian Red sires was 3.1% for
Several studies have identified regions of the genome associated silent heats, 0.9% for metritis, 0.5% for cystic ovaries and 1.5%
with fertility using either genome-wide associations or candi- for retained placenta (Heringstad 2010). The low incidence of
date gene approaches. Garcia et al. (2006) identified an asso- fertility disorders and maintenance of high phenotypic fertility
ciation between a mutation in exon 3 of the calpastatin (CAST) performance provide support for the objective of selecting for
gene (CAST:c.283; CC, CT or TT), a gene widely expressed in improved fertility. In the US, productive life was incorporated
reproductive tissue, and female fertility. Daughters that were into the index in 1994 and daughter pregnancy rate was added in
homozygous for the CC mutation of the CAST gene had an 2003 (Cole et al. 2009). Currently, these two traits account for
improvement in days open (3.28 days) compared with cows 33% of the Net Merit index (22% and 11%, respectively). This
Genetics and fertility Reproduction, Fertility and Development 3

(a) 0.25
halted roughly 40 years of a continuous decline in sire and dam
FR
breeding values for fertility (Weigel 2006). It has also been
HO
reported that the decline in phenotypic fertility performance 0.20
JE
has similarly been halted and started to improve (Norman SR
et al. 2009). In 2003, the mean relative emphasis on production,
0.15
durability and health and reproduction traits across 15 countries
was 59.5%, 27.9% and 12.6%, respectively (Miglior et al.
2005). 0.10
In Ireland, liberalisation of semen importation regulations
and intense selection for milk production traits led to the 0.05
introgression of North American Holstein genes into the pre-
dominantly British Friesian national herd. During the period
0
1990–2001, genetic merit for milk yield increased by 25 kg per

Proportion
16 12 8 4 0 4 8 12
year, the proportion of Holstein genes increased from 8% to
PTA for calving interval (d)
63% and the calving rate to first service declined from 55% in
1990 to 44% in 2001 (Evans et al. 2006). High milk production (b) 0.40
North American Holstein Friesian cows were bred for a con- FR
0.35
finement-based system, where energy-dense total mixed ration HO
(TMR) diets were the standard feeding practice. In a grass-based 0.30 JE
system, the energetic demands associated with milk production SR
0.25
could not be met solely by grass dry matter intake (DMI),
rendering the cows susceptible to excessive tissue mobilisation, 0.20
negative energy balance and reproductive failure (Buckley et al.
0.15
2000a; Horan et al. 2004). To address the problem of declining
fertility, the Irish national breeding program introduced a multi- 0.10
trait selection index called the Economic Breeding Index (EBI)
0.05
in 2001 (Veerkamp et al. 2002). This index included production
and non-production traits, thus identifying animals of superior 0
genetic merit for delivering on-farm profit. Since its introduc- 8 6 4 2 0 2 4 6 8 10
tion, the EBI has evolved to encompass traits such as milk PTA for survival
production, fertility and survival, beef performance, calving
performance and health. Within the index, each trait is given an Fig. 1. Probability density functions illustrating predicted transmitting
economic weighting calculated using the Moorepark dairy ability (PTA) for (a) calving interval and (b) survival for the main dairy
systems model (Shalloo et al. 2004). As its name suggests, the breeds. FR, Friesian (n ¼ 224); HO, Holstein (n ¼ 1882); JE, Jersey (n ¼ 41);
SR, Scandinavian Reds (Swedish and Norwegian Red breeds; n ¼ 21). The
EBI is designed to identify genetically superior animals for
dataset was filtered to retain only sires with $60% reliability for fertility
profitability (Veerkamp et al. 2002). Since its introduction, the traits. Data were obtained from http://www.icbf.com/services/evaluations/
EBI has evolved to include six subindices (relative emphasis in dairy.php file (accessed 22 June 2013).
parenthesis), namely milk production (33%), fertility (35%),
calving performance (10%), beef carcass (9%), maintenance
(6%) and health (3%) (http://www.icbf.com, accessed June and that these lines can be quickly dispersed. The distributions
2003). The fertility subindex comprises two traits: calving of Holstein sire PTA for both fertility traits based on year of birth
interval (24%) and survival (11%). are shown in Fig. 2. The PTA for both fertility traits was poorest
before the introduction of the EBI in 2001. Successive genera-
Breed variation and improvement over time tions now provide superior genetics for fertility traits compared
A file of dairy sire proofs was downloaded from the Dairy with the last. Of course, the PTA for calving interval is positively
Evaluation Results on the ICBF website (http://www.icbf.com/ correlated with the PTA for milk (Fig. 3a), so the challenge is to
services/evaluations/dairy.php, accessed 22 June 2013). The identify sires with good genetic merit for fertility and milk
initial list was composed of 3700 sires with 1 066 789 daughters. production traits. A scatterplot of sire milk and fertility sub-
Sires with low reliability for fertility traits (,60%) were indices is shown in Fig. 3b. Arbitrary divisions at .h50 for the
removed, resulting in a final dataset of 2247 sires, born between milk subindex and .h100 for the fertility subindex were
1 January 1986 and 16 November 2009, with 1 040 260 inserted to identify superior sires. Of the 814 bulls that were born
daughters in Irish dairy herds. The distributions of sire predicted between 1996 and 2000, 236 had a milk subindex .h50 (,29%),
transmitting ability (PTA) for calving interval and survival for 89 had a fertility subindex .h100 (,11%) and 16 had both a milk
the main dairy breeds are shown in Fig. 1. On average, the subindex .h50 and a fertility subindex .h100 (,2%). Of the 55
Holstein breed is genetically inferior to the other breeds for both bulls born in 2011, 45 had a milk subindex .h50 (,82%), 48 had
calving interval and survival. However, it is apparent that the a fertility subindex .h100 (,87%) and 39 had both a milk
greatest variation for both traits also exists within the Holstein subindex .h50 and a fertility subindex .h100 (,71%). This
breed. This means that Holstein sires with good fertility exist, highlights the plasticity of animal genetics when placed on a
4 Reproduction, Fertility and Development S. T. Butler

(a) 0.12
concentrate supplementation, with little emphasis on traits such
1996 to 2000
as fertility. The NZ strain had been selected for increased milk
2001 to 2005
0.10 solids yield (fat plus protein kg) and improved fertility
2006 to 2010
and survival in a pasture-based production system (Horan
0.08 et al. 2005a). In general, these studies highlighted lower milk
volume, similar milk solids production, higher BCS, lower
0.06
bodyweight and superior reproductive performance for the NZ
Holstein–Friesian compared with NA Holstein–Friesian (Harris
and Kolver 2001; Horan et al. 2004, 2005b). Improved surviv-
0.04
ability in the NZ strain resulted in these animals being more
profitable in pasture-based systems (McCarthy et al. 2007b).
0.02 The mechanisms responsible for the improved fertility
performance in the NZ strain are partially understood. In
0 general, earlier resumption of oestrus cyclicity is favourably
Proportion

16 12 8 4 0 4 8 12 associated with subsequent uterine health and likelihood of

PTA for calving interval (d) conception (Galvão et al. 2010). The post partum interval
to first ovulation is under genetic control, with heritability
(b) 0.35 estimates ranging from 0.13 to 0.16 (Royal et al. 2002; Berry
1996 to 2000 et al. 2012). Interestingly, the post partum interval to resumption
0.30 2001 to 2005 of cyclicity has been reported to be similar in both NZ and NA
2006 to 2010 strains (Horan et al. 2005b) or earlier in the NA compared with
0.25 NZ strain (Harris and Kolver 2001). Hence, it can be concluded
that prolonged post partum anoestrus is not a principal cause of
0.20
the inferior fertility performance of the NA strain on pasture-
based systems.
0.15
There is a large body of evidence linking post partum BCS
loss and BCS at the time of breeding with improved phenotypic
0.10
fertility performance (Buckley et al. 2003; Roche et al. 2009).
0.05
Compared with NA cows, NZ cows maintain a higher threshold
BCS throughout the gestation–lactation cycle, mobilise less
0 BCS after calving (but at a similar initial rate) and partition
8 6 4 2 0 2 4 6 8 more nutrients to body reserves in mid- to late lactation
PTA for survival (Roche et al. 2006; McCarthy et al. 2007a). However, daily
measurements of DMI indicated no difference in calculated
Fig. 2. Probability density functions illustrating predicted transmitting energy balance during the first 20 weeks of lactation (Patton
ability (PTA) for (a) calving interval and (b) survival for dairy bulls based on et al. 2008). Glucose tolerance tests indicated greater glucose
birth date. The number of AI bulls born in the periods 1996–2000, 2001– clearance rates in the NZ strain in early (Chagas et al. 2009) and
2005 and 2006–2010 was 450, 361 and 162, respectively. The dataset was mid-lactation (Patton et al. 2009), suggesting greater insulin
filtered to retain only sires with $60% reliability for fertility traits. Data
resistance in the NA strain. This indicates a stronger predisposi-
were obtained from http://www.icbf.com/services/evaluations/dairy.php
tion to partition available nutrients towards the mammary gland
(accessed 22 June 2013).
in NA cows, at the expense of maintaining BCS.
Insulin-like growth factor (IGF) 1 is a metabolic hormone
that is correlated with bioenergetic status, and is well established
particular breeding objective, and also that herd owners are as having a positive association with reproductive outcomes
acutely interested in selecting for improved fertility. (Taylor et al. 2004; Patton et al. 2007). Several studies have
reported greater circulating concentrations of IGF1 in NZ cows
North American vs New Zealand genetics (Patton et al. 2008; Lucy et al. 2009). A study conducted in New
Several studies have compared lactating cows with North Zealand examining hormone profiles and hepatic gene expres-
American (NA) and New Zealand (NZ) ancestry. The NZ dairy sion indicated that the NZ cows retained a coupled somatotropic
industry is primarily focused on export markets, and hence milk axis during early lactation (lower circulating growth hormone
with high solids produced at low cost is required. Low-cost milk concentrations, higher IGF1 concentrations and greater hepatic
production is achieved by using grazed pasture as the principal growth hormone receptor 1A (GHR1A) expression) allowing
feed, but this requires excellent herd fertility to achieve a con- maintenance of BCS, whereas NA cows had an uncoupled
centrated period of calving that coincides with the onset of somatotropic axis with consequent BCS loss (Lucy et al.
spring pasture growth. At the time that the animals used in these 2009). Of note, that study did not detect any difference in hepatic
studies were assembled, the NA strain had been selected for IGF1 gene expression. A similar study conducted in Ireland did
increased milk yield, body size and angularity in a production not detect any differences in hepatic GHR1A expression, but NZ
system based on year-round calving and high levels of cows had greater hepatic IGF1 gene expression and altered
Genetics and fertility Reproduction, Fertility and Development 5

(a) 1200
R 2  0.3752
1000
800

PTA for milk (kg)

600
400
200
0
200
400
600
800
1000
15 10 5 0 5 10 15 20
PTA for calving interval (days)

(b) 300
Poor milk Good milk
200 Good fertility Good fertility
Fertility sub-index ( )

100
1996 to 2000
0 2011

100

200 Poor milk Good milk

Poor fertility Poor fertility
300
100 50 0 50 100 150
Milk sub-index ( )

Fig. 3. Breeding for better milk and fertility. (a) Scatterplot of the relationship between predicted
transmitting ability (PTA) for milk kg and calving interval. The general relationship is positive, so
increasing genetic merit for milk yield reduces genetic merit for calving interval. The bulls of interest
are those that combine good milk and calving interval traits. (b) Scatterplot of the Economic Breeding
Index (EBI) milk and fertility subindices for dairy bulls born between 1996 and 2000 (open circles) or
in 2011 (closed circles). Data were obtained from http://www.icbf.com/services/evaluations/dairy.php
(accessed 22 June 2013).

expression of IGF binding proteins to support a longer half-life phenotypic milk production per se is directly responsible for
of IGF1 in the circulation (McCarthy et al. 2009). There were poor fertility. Indeed, several studies have indicated similar or
possibly some genetic and management differences between even superior fertility in high-yielding cows compared with
these two studies, making a direct comparison difficult. How- lower-yielding cows (Nebel and McGilliard 1993; Gröhn and
ever, it is apparent that during the early post partum period Rajala-Schultz 2000; Bello et al. 2013). As a result, it is difficult
orchestrated changes in the endocrine system and whole-body to identify specific mechanisms under genetic control respon-
metabolism are necessary to support mammary milk synthesis. sible for poor fertility using animal models that differ in phe-
Most cows experience at least some degree of negative energy notypic milk production potential in addition to a wide range of
balance during early lactation, with consequent body tissue associated phenotypes (milk composition, bodyweight, feed
mobilisation, and this is associated with uncoupling of the intake capacity etc.).
somatotropic axis. Data from these studies collectively suggest To address this issue, a lactating cow model with similar
that early lactation adaptations may have more severe effects in genetic merit for milk production, but either good (Fertþ) or
the NA compared with the NZ strain of dairy cow, and that this is poor (Fert) genetic merit for fertility traits was recently
likely related to their greater genetic potential for milk output. developed and validated (Cummins et al. 2012b). A schematic
outline of how the animals were assembled is shown in Fig. 4,
Fert1 and Fert2 cows and reported in detail by Cummins et al. (2012b). These animals
It is desirable to disentangle the effects of high merit for milk have similar proportions of Holstein genetics, and similar body-
yield and poor merit for fertility traits. Cows with high genetic weight, milk yield and milk composition. However, fertility
merit for milk production have generally been reported to have performance is markedly poorer in Fert–compared with Fertþ
poorer fertility than cows with average genetic merit for milk cows. The research conducted to date with this animal model has
production (Lucy and Crooker 1999; Buckley et al. 2000b; clearly demonstrated that the causes of reduced fertility in the
Kennedy et al. 2003). However, it is unlikely that high Fert cows are multifactorial.
6 Reproduction, Fertility and Development S. T. Butler

Breeding value for milk production Table 1. Summary of oestrus-related differences between heifers with
good (Fert1) or poor (Fert2) breeding values for fertility traits

Fertþ Fert P-value

Silent oestrus (%) 2 22 0.02

Oestrus without ovulation (%) 0 14 0.04
High milk High milk Duration of oestrus (h) 7.53 5.86 0.08
production production Peak oestrus activity 168 119 0.01

Low fertility (Fert) High fertility (Fert)

Oestrus behaviour
Another major area of reproductive loss highlighted was the
Breeding value for fertility trait incidence of silent heats (defined as an ovulation event that was
not preceded by oestrus behaviour) and the incidence of cows
failing to ovulate after expressing oestrus (Cummins et al.
Fig. 4. Schematic outline of the derivation of the animal model. Pregnant 2012a). Oestrus behaviour (measured using automated activity
heifers with good (Fertþ) or poor (Fert) breeding values for fertility traits meters and electronic mount detectors) and the timing of ovu-
were identified within the national herd database. Within these two lation (measured using transrectal ultrasound) were recorded at
extremes, animals with similar breeding values for high milk production the synchronised oestrus and the subsequent spontaneous oes-
were identified and purchased.
trus, and the main findings are summarised in Table 1. There was
a significant difference in the incidence of silent heats. In a dairy
farm operation, these cows do not get inseminated at the
appropriate time and at least 3 weeks is added onto the calving
Oestrous cycle interval. A greater proportion of Fert cows also exhibited signs
Our initial investigation focused on examining characteristics of of oestrus, but subsequently failed to ovulate. In a dairy farm
the oestrous cycle around the normal time of breeding operation, these cows do get inseminated, but fertilisation can-
(Cummins et al. 2012a). The oestrous cycle of lactating cows not occur, again adding at least 3 weeks to the calving interval.
was synchronised at 80–100 days post partum, and ultrasound Of the oestrus events recorded, 36% fell into the combined
examinations and blood sample collection were conducted categories of silent heats and heats without ovulation in Fert
daily. The oestrous cycle was 4.1 days longer in Fert– compared cows, whereas only 2% fell into the combined categories in
with Fertþ cows (25.1 vs 21.0 days, respectively; P ¼ 0.01), and Fertþ cows. Interestingly, mean circulating oestradiol (E2)
this was associated with Fert cows tending to have more fol- concentrations during the period of preovulatory follicle
licular waves than Fertþ cows (2.7 vs 2.2, respectively; development were similar in both strains. Potential differences
P ¼ 0.07). Circulating progesterone (P4) concentrations were between genotypes could exist in the threshold E2 concentra-
similar during the first 5 days of the oestrous cycle, but from tions and duration of exposure to E2 required for oestrus and the
Day 5 to Day 13 circulating P4 concentrations were 34% greater LH surge to occur, as has been documented in the ewe (Fabre-
in Fertþ than Fert cows (5.15 vs 3.84 ng mL1, respectively; Nys et al. 1993). In addition, differences in luteal-phase P4
P , 0.001). The difference in circulating P4 was associated priming of the neural mechanisms involved in gonadotrophin-
with a 16% larger corpus luteum (CL) volume in Fertþ cows. releasing hormone (GnRH) release, as observed in sheep
A follow-up study also detected greater circulating P4 con- (Skinner et al. 2000; Evans et al. 2002), could explain some of
centrations in Fertþ cows, but failed to detect differences in the variation. The bulk of the literature examining the effect of
metabolic clearance rate of P4 or hepatic mRNA abundance of P4 is concerned with post-breeding uterine environment and
genes responsible for P4 catabolism (i.e. CYP2C, CYP3A, embryo development. It is possible that suboptimal P4 con-
AKR1C family; Moore et al. 2012). This suggests that the centrations in the oestrous cycle before breeding interferes with
greater circulating P4 concentrations in Fertþ cows are pri- the normal endocrine feedback mechanisms that are required to
marily a result of greater luteal P4 synthetic capacity (larger CL facilitate appropriately timed oestrus behaviour and ovulation.
size and greater P4 output per unit CL tissue). Considerable Clearly, this is a major area of reproductive loss that does not
evidence in the literature supports the pivotal role of P4 from presently receive adequate research attention.
Day 5 to Day 13 of the oestrous cycle to influence functional
changes in histotroph composition (Green et al. 2005), structural Metabolic status and BCS
changes in endometrial glandular duct density (Wang et al. Differences in the concentrations of metabolic hormones in
2007), endometrial gene expression (Forde et al. 2009), Fertþ and Fert cows are broadly similar to those outlined for
maternal recognition of pregnancy (Mann and Lamming 2001) NZ and NA cows above and, accordingly, differences in BCS
and likelihood of subsequent pregnancy establishment (Herlihy are also similar. Circulating concentrations of IGF1 are greater
et al. 2013). Inherent differences in circulating P4 concentra- in Fertþ cows throughout lactation (Cummins et al. 2012b), and
tions likely represent a key phenotype responsible for fertility the molecular mechanisms underlying greater hepatic IGF1
differences in these two strains. synthesis have been reported (Cummins et al. 2012c). Despite
Genetics and fertility Reproduction, Fertility and Development 7

1.0
Fertþ cows having greater circulating IGF1 concentrations,

Proportion endometritic
hepatic IGF1 gene expression is greater only in mid- to late P  0.09 P  0.04
0.8
lactation. The half-life of IGF1 in the circulation is approxi- Fert
Fert
mately 10 min as a free peptide, approximately 30–90 min when 0.6
bound to a low molecular weight binding protein (i.e. IGFBP2,
IGFBP4, IGFBP5 and IGFBP6) and 12–15 h in the ternary 0.4

complex of IGF1, IGFBP3 and insulin-like growth factor 0.2

binding protein, acid labile subunit (IGFALS; Jones and
Clemmons 1995). The greater circulating IGF1 concentrations 0
in early lactation appear to be mediated by reduced expression of Week 3 Week 6
low molecular weight binding proteins, allowing longer IGF1
half-life in the ternary complex. Hence, genetic merit for fertility Fig. 5. Incidence of endometritis in cows with good (Fertþ) or poor
traits affects components of the somatotropic axis regulating the (Fert) breeding values for fertility traits 3 and 6 weeks post partum based
synthesis, bioavailability and stability of circulating IGF1. In on polymorphonuclear neutrophil count in uterine cytology samples.
addition to greater circulating concentrations of IGF1, Fertþ
cows have greater insulin and glucose levels during the imme-
diate post partum period (Cummins et al. 2012b; Moore et al. Fertþ cows were capable of mounting a stronger and/or timelier
2013). Elevated glucose in the immediate peripartum period has immune response following exposure to microbial pathogens.
been linked to likelihood of early ovulation (Butler et al. 2006) Endometritis directly affects fertility through the altered local
and likelihood of conception at breeding (Garverick et al. 2013). uterine environment, but also indirectly affects fertility through
Consistent with their superior metabolic status, Fertþ cows altered follicle development and function (Sheldon et al. 2002),
maintained greater BCS during lactation and had reduced BCS delayed resumption of cyclicity (Galvão et al. 2010), altered
loss after calving compared with Fert cows. Maintenance of follicle steroidogenesis (Green et al. 2011) and development of a
greater BCS in Fertþ cows during early lactation is facilitated smaller CL (Williams et al. 2007).
by greater DMI (Moore et al. 2013) and requires endocrine
signalling to orchestrate appropriate partitioning of nutrients
Effect of management interventions
across multiple tissues and organs.
During the past 20 years, a large amount of research has been
conducted to optimise protocols for presynchronisation,
Uterine health synchronisation and resynchronisation of ovulation (oestrus)
The reproductive tract of all cows becomes exposed to microbial in lactating dairy cows. Much of the research was conducted in
pathogens while the cervix remains open after delivery of the confinement-based systems in the US. The proportion of US
fetal–placental unit. The development of uterine disease herds that used synchronisation for the first breeding increased
depends on the type of bacteria involved and on the immune from 2% of herds and cows in 1996 to 20% of herds and 35% of
response of the cow, and is associated with reduced subsequent cows in 2005 (Miller et al. 2007). Synchronisation allows cows
fertility (Sheldon et al. 2009). Clinical disease, lower DMI, to be inseminated after a predetermined voluntary waiting
increased presence of bacteria and greater non-esterified fatty period, with re-insemination at 30–35 days after AI if pregnancy
acid and b-hydroxybutyrate concentrations during the transition establishment does not occur. Hormonal intervention has
period have been associated with the incidence of endometritis improved the reproductive efficiency of confinement herds by
between 4 and 6 weeks post partum (LeBlanc 2012). We avoiding the requirement for oestrus detection, which can be
examined uterine health in Fertþ and Fert cows by assessing ,50% (McArt et al. 2010), thereby shortening the calving
vaginal mucus scores weekly after calving and also by exam- interval (Norman et al. 2009). What are the implications of
ining uterine cytology at 3 and 6 weeks post partum (Moore et al. selecting for improved fertility in this scenario? If cows are
2013). The vaginal mucus score was determined based on the synchronised (and resynchronised) to induce ovulation, what is
criteria outlined by Williams et al. (2005) as follows: 0, clear the importance of oestrous expression as a fertility trait? Should
and translucent mucus; 1, mucus containing flecks of white or bulls be selected on the basis of daughter response to synchro-
off-white pus; 2, ,50% white or off-white mucopurulent nisation? What would happen if hormones to synchronise oes-
material; or 3, $50% white or off-white mucopurulent material. trus were no longer available?
Cows were classified as having endometritis if polymorphonu- It is difficult to answer these hypothetical questions. However,
clear neutrophil (PMN) counts were greater than 18% and 10% it is important that genetic selection programs simultaneously
in uterine cytology samples collected 3 and 6 weeks post partum, improve all fertility traits, because not all herd owners use
respectively (Sheldon et al. 2006). Both the vaginal mucus synchronisation and perhaps more herd owners would forego
scores and uterine cytology results indicated a greater incidence synchronisation if they could achieve satisfactory submission
of clinical endometritis in the Fert– cows. A striking contrast rates without intervention. In any case, selecting for improved
between the rates of uterine recovery based on cytology exam- fertility should increase the likelihood of pregnancy establish-
inations is shown in Fig. 5. Despite similar management and ment following synchronisation, because many of the factors
housing, Fertþ cows had a more rapid recovery in uterine that affect the likelihood of pregnancy are similar for synchro-
health compared with Fert cows. This likely indicates that the nised and non-synchronised cows (Herlihy et al. 2013).
8 Reproduction, Fertility and Development S. T. Butler

Table 2. Summary of the physiological mechanisms responsible for Buckley, F., O’Sullivan, K., Mee, J. F., Evans, R. D., and Dillon, P. (2003).
greater fertility in Fert1 cows compared with Fert2 cows Relationships among milk yield, body condition, cow weight, and
IGF1, insulin-like growth factor 1; P4, progesterone reproduction in spring-calved Holstein–Friesians. J. Dairy Sci. 86,
2308–2319. doi:10.3168/JDS.S0022-0302(03)73823-5
Early post partum At breeding Butler, W. R. (2003). Energy balance relationships with follicular develop-
(parturition to Week 7) (Weeks 8–16 post partum) ment, ovulation and fertility in postpartum dairy cows. Livest. Prod. Sci.
83, 211–218. doi:10.1016/S0301-6226(03)00112-X
Higher dry matter intake Stronger oestrus expression Butler, W. R., and Smith, R. D. (1989). Interrelationships between energy
Greater body condition score Fewer silent heats balance and postpartum reproductive function in dairy cattle. J. Dairy
Earlier resumption of cyclicity Less ovulation failure after oestrus Sci. 72, 767–783. doi:10.3168/JDS.S0022-0302(89)79169-4
Superior uterine health Greater luteal-phase circulating P4 Butler, S. T., Pelton, S. H., and Butler, W. R. (2006). Energy balance,
More favourable metabolic status More favourable uterine metabolic status, and the first postpartum ovarian follicle wave in cows
(glucose, IGF1) environment administered propylene glycol. J. Dairy Sci. 89, 2938–2951.
More favourable metabolic status doi:10.3168/JDS.S0022-0302(06)72566-8
(IGF1) Chagas, L. M., Lucy, M. C., Back, P. J., Blache, D., Lee, J. M., Gore, P. J. S.,
Sheahan, A. J., and Roche, J. R. (2009). Insulin resistance in divergent
strains of Holstein–Friesian dairy cows offered fresh pasture and
increasing amounts of concentrate in early lactation. J. Dairy Sci. 92,
216–222. doi:10.3168/JDS.2008-1329
Conclusions Charlier, C., Agerholm, J. S., Coppieters, W., Karlskov-Mortensen, P.,
Li, W., de Jong, G., Fasquelle, C., Karim, L., Cirera, S., Cambisano, N.,
The main phenotypes that are different between cows with good Ahariz, N., Mullaart, E., Georges, M., and Fredholm, M. (2012).
and poor genetic merit for fertility traits are summarised in A deletion in the bovine FANCI gene compromises fertility by causing
Table 2. The next step is to delve deeper into the different tissues fetal death and Brachyspina. PLoS One 7, e43085. doi:10.1371/
to identify the genes and gene networks that regulate these JOURNAL.PONE.0043085
phenotypic differences. New markers can be rapidly incorpo- Cole, J. B., VanRaden, P. M., and Multi-State Project S-1040 (2009). ‘Net
rated into genomic selection techniques. Alternatively, nutri- Merit as a Measure of Lifetime Profit: 2010 Revision.’ Available at
genomics approaches or management interventions may be http://aipl.arsusda.gov/reference/nmcalc.htm#Genetic [Verified 3 Sep-
identified to up- or downregulate specific genes and gene net- tember 2013).
works that are involved in a particular undesirable phenotype. Crooker, B. A., Weber, W. J., Ma, L. S., and Lucy, M. C. (2001). Effect of
energy balance and selection for milk yield on the somatotropic axis of
After many decades of declining fertility, genetic merit for
the lactating Holstein cow: endocrine profiles and hepatic gene expres-
fertility and phenotypic reproductive performance now appears sion. (Eds A. Chwalibog and K. Jacobsen.) pp. 345–348. (Waginengen
to be on the opposite trajectory. Press: Wageningen, The Netherlands.)
Cummins, S. B., Lonergan, P., Evans, A. C., and Butler, S. T. (2012a).
Genetic merit for fertility traits in Holstein cows: II. Ovarian follicular
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