The physiology of multifactorial problems limiting the establishment of pregnancy in dairy cattle

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1 CSIRO PUBLISHING Reproduction, Fertility and Development, 2012, 24, The physiology of multifactorial problems limiting the establishment of pregnancy in dairy cattle Alexander C. O. Evans A,B and Siobhan W. Walsh A A School of Agriculture and Food Science, University College Dublin, Belfield, Dublin 4, Ireland. B Corresponding author. alex.evans@ucd.ie Abstract. The failure of cows to successfully establish pregnancy after insemination is an important limiting factor for the efficiency of dairy production systems. The physiological reasons for this are many and pertain to the post partum and early pregnancy periods. Cows that suffer severe negative energy balance after parturition are prone to diseases (including uterine infection) that are, in part, explained by reduced function of the immune system, having negative consequences for subsequent fertility. In high-producing dairy cows, the duration and intensity of oestrus is low as a consequence of low circulating oestradiol concentrations, and after insemination, high embryo mortality is the single biggest factor reducing calving rates. Embryo mortality occurs as consequences of poor oocyte quality (probably caused by the adverse metabolic environment) and by poor maternal uterine environment (probably caused by carry-over effects of uterine infection and low circulating progesterone concentrations). Immediate improvements in the fertility of lactating cows on many farms can be achieved by applying existing knowledge, but longer-term sustained improvement will require additional knowledge in many areas including the physiology of the tissues that contribute to reproduction. Additional keywords: embryo loss, fertility, negative energy balance, progesterone. Introduction It is well documented that intense selection pressure for milk production over the last 50 years has been associated with a global decline in dairy cow fertility (reviewed by Crowe 2008; Dochi et al. 2010; Galon et al. 2010; Thatcher et al. 2010; Walsh et al. 2011). In a recent study conducted in Ireland, infertility was ranked as the number one priority needing to be resolved by both experts in the dairy sector and by dairy farmers themselves (More et al. 2010). In addition, the potential exists for expansion within the dairy industry as demands for its products increase. For this to be realised, there will be a need for both increased cow numbers and increased yield per cow. Being mindful of the environmental consequences of increased cow numbers, the effort to achieving this increase in milk production through use of higher yielding cows (through more milk per lactation and more lactations per cow) is increasingly important. Achieving this increase requires a multifactorial approach that, in broad terms, includes genetics and the management of nutrition, disease and reproduction, the interaction of which is complex (LeBlanc 2010; Walsh et al. 2011). All of these factors impact on reproduction, and this review summarises the main physiological events encompassing the period from parturition to the establishment of the next pregnancy. Journal compilation Ó IETS 2012 Postpartum events and the resumption of oestrous cycles Parturition Parturition is a complex event, the physiology of which has been recently reviewed (Taverne and van der Weijden 2008) and the consequences of which on future reproduction are often undervalued. Dystocia (leading to calving assistance), the birth of twins or a dead calf and retained fetal membranes are all factors that have negative effects on subsequent reproductive performance, the physiology of which revolves around increased prevalence of uterine disease and the longer-term inhospitable uterine environment for the establishment of pregnancy (LeBlanc 2008; Sheldon et al. 2009; Walsh et al. 2011). Immune function During the early post partum period, cows experience a period of negative energy balance; marked changes in endocrine, metabolic and physiological status; and an increased oxidative stress. Coupled with the stress of parturition, these all play a role in compromising the immune and inflammatory response (Sordillo and Aitken 2009). Consequently, high-producing dairy cows may have reduced immune competence and are more

2 234 Reproduction, Fertility and Development A. C. O. Evans and S. W. Walsh susceptible to disease, especially invading pathogens causing mastitis (Ingvartsen et al. 2003; Sordillo and Aitken 2009), metritis (Sheldon et al. 2009) and other production diseases (Roche 2006; Mulligan and Doherty 2008). Uterine infection Uterine contamination with bacteria at parturition or in the following days is unavoidable and normal, with % of animals having bacteria in the uterus in the first 2 weeks after calving (Sheldon et al. 2006). Many cows deal with this bacterial contamination successfully; however, some cows are unable to resolve the contamination and develop metritis within 3 weeks post partum. More importantly, in,20% of cows, pathogenic bacteria persist for 3 or more weeks, resulting in endometritis (Sheldon et al. 2009). The risk of infection is increased in cows with twins, stillbirth, dystocia or retained fetal membranes (LeBlanc 2008), and uterine infection has negative consequences for the subsequent establishment of pregnancy (Gilbert 2012). Energy balance High-producing dairy cows require sufficient nutrients to facilitate the dramatic increases in energy requirements for milk production that peaks 4 8 weeks post partum. This requirement is only partially offset by increased feed consumption (due to limitations in intake and appetite), with the remainder being met by mobilisation of body reserves, resulting in animals entering negative energy balance (NEB; Grummer 2007). The physiological consequences of NEB are loss in body condition score (BCS) as body reserves are mobilised; low circulating concentrations of glucose, insulin, insulin-like growth factor I (IGF I) and cholesterol; and higher concentrations of fatty acids and urea compared with cows in positive energy balance (Gross et al. 2011; Wathes et al. 2011). These are subsequently associated with an increased risk of metabolic diseases (that largely occur within the first month of lactation), reduced immune function and a reduction in subsequent fertility (Roche et al. 2009). Minimising the severity and duration of NEB and loss in BCS in the first few weeks post partum is an imperative. It is recommended that cows have a BCS of 3.00 to 3.25 (scale 0 to 5) at calving and that they are managed to suffer a BCS loss of not more than 0.5 between calving and first service (Roche et al. 2009). Resumption of oestrous cycles A normal post partum dairy cow is one that has resolved uterine contamination, ovulated early post partum, has normal oestrous cycles, and has homeostatic concentrations of circulating insulin, IGF I and glucose (Roche 2006). Factors determining the circulating concentrations of these hormones are complex and inter-related. During the period of NEB, insulin concentrations remain low, which prevents an increase in liver growth hormone receptors and IGF I secretion, causing the somatotropic axis to be uncoupled (Lucy 2008). This negatively impacts reproduction as insulin and IGF I are unable to synergise with the gonadotrophins on ovarian cells, preventing the dominant follicle from ovulating (Beam and Butler 1999) and delaying the resumption of cyclicity (Gutierrez et al. 1999). In addition, adequate luteinising hormone (LH) concentrations are necessary for pre-ovulatory follicle growth, oestradiol secretion and ovulation (Diskin et al. 2003; Crowe 2008) but low BCS, coupled with severe NEB, suppresses LH secretion and oestradiol production (Diskin et al. 2003) resulting in delayed ovulation (Butler 2003). The incidence of anovulatory anoestrus ranges from 10% to 50%, depending on many factors (reviewed by Walsh et al. 2011) and up to 50% of modern dairy cows have abnormal post partum oestrous cycles, resulting in increased calving to first insemination intervals (Opsomer et al. 1998) and decreased conception rates (Garnsworthy et al. 2009). As lactation progresses, the somatotropic axis becomes recoupled due to greater nutrient intake and improved energy balance, resulting in increased insulin concentrations, expression of growth hormone receptors in the liver and, finally, liver production of IGF I (Lucy 2008). Cows that have a shorter and less severe period of NEB resume oestrous cycles sooner than those with more severe NEB (Dochi et al. 2010) and early post partum ovulation is associated with improved uterine health and fertility (Galvao et al. 2010). Expression and detection of oestrus Expression and detection of oestrus are crucial so that insemination can occur at the appropriate time relative to ovulation. Unfortunately, the proportion of animals that stand to be mounted has declined from 80% to 50%, and the duration of oestrus has declined from 15 h to 5 h over the past 50 years (Dobson et al. 2008). Coupled with poor oestrus expression, an inability to detect oestrus easily further hinders insemination at the correct time. Different methods of oestrus detection yield different detection efficiencies (Roelofs et al. 2010). To overcome the need for detection of oestrus, the use of oestrus synchronisation and timed inseminations has become widespread in some production systems (MacMillan 2010; Pursley et al. 2012). Several physiological events also affect the expression of oestrus. First, high-producing dairy cows ($39.5 kg per day) have a shorter oestrus (6.2 h vs 10.9 h), less total standing time (21.7 s vs 28.2 s) and lower serum oestradiol concentrations (6.8 pg ml 1 vs 8.6 pg ml 1 ) compared with lower producing dairy cows (,39.5 kg per day; (Lopez et al. 2004). The root cause of low oestradiol concentration (and hence poor intensity and duration of oestrus) is both the high metabolic clearance rate of oestradiol (Sangsritavong et al. 2002) and low LH and IGF concentrations brought on by NEB (Diskin et al. 2003) and stress (e.g. lameness, mastitis, heat; Dobson et al. 2007a). Establishment of pregnancy A disappointingly low proportion of cows that are inseminated actually calve, with values ranging from 30% to 50% (Pryce et al. 2004; Dillon et al. 2006; Macdonald et al. 2008; Norman et al. 2009; Dochi et al. 2010). This range covers different production systems, with lower input and milk production systems having higher values compared with higher input and higher milk production systems. The majority of pregnancy loss occurs in the first 2 3 weeks after insemination and the timing of

3 The establishment of pregnancy in dairy cattle Reproduction, Fertility and Development 235 Pregnant (%) Cows Heifers Days of pregnancy Fig. 1. Schematic presentation of the proportion of high milk producing dairy cows (closed squares) and heifers (open circles) pregnant after insemination, highlighting the substantial loss in the first few weeks of gestation (redrawn from Walsh et al. 2011). embryo mortality in the first 7 versus the first 24 days of gestation has recently been reviewed (Walsh et al. 2011). However, there is no doubt that pregnancy loss in this period far exceeds loss that occurs after the establishment of pregnancy (Fig. 1). Fertilisation Fertilisation rates are not considered to be a main contributor to the poor fertility seen in dairy cows, as rates remain above 80% in most situations (Sartori et al. 2010). The physiological reasons for fertilisation failure are many, including sperm characteristics (Saacke et al. 2000), heat stress and oocyte quality (Roth et al. 2001; Chebel et al. 2004; Sartori et al. 2010). Oocyte quality is still a poorly defined characteristic but the hypothesis is that exposure of oocytes to an unfavourable environment (including heat stress, NEB and disease, mentioned above) up to 3 months before ovulation may have a negative effect on the ability of the oocyte to be fertilised and develop into an embryo (Fair 2010). Embryo mortality The ability of the very early embryo to develop to the blastocyst (Day 0 to 7 after insemination) is dependent on its inherent ability to develop, as a consequence of oocyte quality, sperm quality and the timing of fertilisation, or as a consequence of the uterine environment. Factors such as genetic merit (Snijders et al. 2000; Leroy et al. 2005) and lactation (Leroy et al. 2005) impact very early embryo development, and surveys of the literature conclude that only 45 55% of inseminated lactating cows are pregnant by Day 7 of gestation compared with,75% in heifers (Sartori et al. 2010; Walsh et al. 2011). The uterine environment before Day 7 may also be suboptimal for supporting early embryo development in lactating dairy cows. In a recent zygote transfer (to the oviducts) experiment, Holstein-Friesian heifers were better able to support very early embryo development compared with post partum lactating Holstein-Friesian cows (Rizos et al. 2010). Attempts to explain this at present are only speculation, but would reasonably include persistent issues of the post partum uterine environment and involution (as alluded to above), all of which strongly suggest that the reproductive tract of lactating dairy cows provides a less favourable environment for very early embryo development than that of heifers, late lactation cows or dry cows. For some time, failure of maternal recognition of pregnancy about the time of luteolysis has been considered the main cause of embryo mortality in cattle (Sreenan and Diskin 1983; Diskin and Morris 2008). The challenge of the elongating conceptus at this time is to produce adequate concentrations of interferon tau to signal maternal recognition of pregnancy and alter the release of luteolytic prostaglandin F2a from the uterus (Spencer et al. 2008). Several physiological events can conspire to prevent this from happening successfully. Approximately 5% of embryos die because of gross chromosomal abnormalities preventing development (Peters 1996), but otherwise it is thought that it is the ability of the uterus to support embryo development that dictates success (Lonergan 2010). The microenvironment of the uterus plays a leading role in determining embryo quality (Rizos et al. 2002) with concentrations of progesterone (Diskin and Morris 2008; Lonergan 2010) and IGF (Leroy et al. 2008) and the presence of pathogenic bacteria (Sheldon et al. 2006) affecting the chances of embryo survival (recently reviewed by Sartori et al. 2010; Walsh et al. 2011). Late embryo and fetal mortality Late embryo mortality is the death of the embryo between Days 25 and 45 of gestation, and fetal mortality is from Day 46 until parturition (Committee on Bovine Reproductive Nomenclature 1972). In cows managed on extensive pasture systems, embryo and fetal loss between Days 24 and 80 is reported to be 6 7% in lactating cows and heifers with about half of this loss occurring by Day 42 of gestation (Silke et al. 2002). However, in intensively managed higher producing cows, the loss is up to 20% between Days 28 and 98 of gestation (Vasconcelos et al. 1997). Factors causing late embryo and early fetal loss are genetic, physiological, endocrinological or environmental (Diskin and Morris 2008) in nature, or one of the many possibilities for infection (Givens and Marley 2008). Guidelines to minimise embryo mortality have been suggested (Diskin et al. 2012). Conclusion Immediate improvements in the fertility of lactating dairy cows on many farms can be achieved by applying existing knowledge in the areas of nutrition, reproductive management and animal health. Longer-term sustained improvement will require additional knowledge in many areas, including the physiology of the tissues that contribute to reproduction. This will further shape our thinking on reproductive management, but also has the potential to contribute to efforts to improve fertility in a major way through methods of animal breeding and selection. Acknowledgements The authors research is currently funded by Science Foundation Ireland (07/SRC/B1156).

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