Transition cow physiology related to fertility in lactation. W. Ron Butler Cornell University

Transcription

1 Transition cow physiology related to fertility in lactation W. Ron Butler Cornell University

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3 Positive association between early ovulation postpartum and pregnancy during lactation DIM; n=89 Open 49 DIM; n=242 35% 21 DIM; n=114 15% Time to pregnancy, d This important relationship has focused research attention on the regulation and re-initiation of postpartum ovarian activity. Galvao et al., Reprod. Dom. Anim. 2009; DOI: /j x

4 Periparturient transition period Cascade of metabolic and physiological changes important for milk production, health and future reproductive performance Nutrient accrual body reserves and fetus Calving Rapid mobilization of lipid & protein stores for energy metabolismlactation -3 weeks weeks

5 The importance of energy metabolism in the lactating dairy cow Milk Production Health -Liver (Trigs, genes) -Uterus (infection) Energy Metabolism Ovarian Function - early Ovulation Reproduction/fertility during Lactation

6 Negative energy balance in early lactation- energy intake lags requirements NEBAL during transition period results in marked shifts in metabolic hormones (insulin, IGF-I, GH) and metabolites (low glucose; NEFA & BHBA)

7 Resumption of ovulation postpartum requires recovery from pregnancy and parturition Removal of suppression by hormones of pregnancy Gluconeogenesis Fatty Acid Oxid. IGF- I Gonadotropins LH & FSH Pulses

8 Negative Energy Balance Inhibits Activity of Reproductive Tissues-low glucose & insulin; high NEFA Negative Hypothalamus/ Pituitary (LH pulses) MILK DM Intake NEGATIVE ENERGY BALANCE Liver IGF-I Low plasma insulin Uterus E2 (rate of involution) Progesterone Ovary

9 Ovulation Failure: Follicle grows to similar large size Estradiol production from large follicle (<60% of peak levels) LH pulse frequency (50%) and LH responsiveness due to low plasma glucose and insulin IGF-I (70%) Delayed NEBAL nadir Physiologically the metabolic and gonadotropin signals are related: FSH stimulates granulosa cell receptors (Ins, GH, IGF-I); Ins, IGF-I and LH pulses provide the positive stimuli for follicle growth, maturation, and ovulation.

10 OVARIAN RECRUDESCENCE POSTPARTUM E 2 IGF-I FSH LH Parturition EB nadir + Ovulation

11 Ovary examination by ultrasound

12 Onset of Postpartum Ovarian Activity and 1st Ovulation One medium-large follicle develops in all cows by 6-8 days postpartum. Follicle has 3 outcomes affecting days to 1st ovulation. Outcome Incidence Days to Ovulation Ovulation 45 % 20 Regression 35 % 51 Cystic 20 % 48 Average 30

13 Postpartum patterns of follicular development and estradiol production

14 Plasma Estradiol (pg/ml) Ovulatory 1 st DF has greater steroidogenesis NOV OV P< Pooled S.E. d5 to d21 = Days After Parturition

15 Metabolic Adaptation in Transition Cows Schoenberg, K.M.,2010 by permission Increased mobilization of fatty acids Impaired glucose disposal Increased hepatic gluconeogenesis Decreased insulin response of adipose tissue Changes in intake Glucose sparing for gravid uterus and eventually the mammary gland

16 EBAL (MCal/d) NEFA (meq/ml) Feed intake and energy balance begin decreasing prepartum resulting in increased NEFA during trans ition pe riod blood NEFA. Optimum BCS ~ Days from parturition Ovulatory n=14 OV n=31 Non-Ovulatory Days Relative to Parturition NOV OV NOV

17 Overconditioning (BCS>4) or BCS loss in late pregnancy increases risk of metabolic disorders- maintain BCS ~3.0

18 Field study to evaluate NEBAL status of transition cows in dairy herds (n=100)

19 Guidelines for evaluating NEBAL status of dairy herds (n= 100) Sampled population, N=15 healthy animals 14-2 days prepartum 3-14 days postpartum Herd alarm level (> 3 sampled animals above threshold level) 15% of sampled animals with NEFA > 0.30 meq/l 15% of sampled animals with NEFA > 0.60 meq/l 15% of sampled animals with BHBA > 10 mg/dl % of herds above herd alarm level: incidence of DA, ketosis, or Met/RP (Risk Ratio) Above herd alarm level, cows decrease in ME- 305 milk 74% - (1.8) kg 65% - (4.4) -593 kg 42% - (4.4) -358 kg business.com/eastern dairybusiness/vol.1,20-21,2009; JDS 93:546, 2010.

20 Prepartum differences in dry matter intake (DMI), energy balance and metabolic hormones are associated with postpartum follicle outcome Not surprising, if we consider that full follicular development requires many weeks for completion ie. does not begin after calving.

21 Metabolic effects on follicular development during the dry period.

22 IGF-I (ng/ml) Insulin (ng/ml) Dry Matter Intake (kg/day) OV NOV Day relative to parturition NOV IGF-I OV IGF-I NOV Insulin OV Insulin Days Relative to Parturition As early as 3 weeks prepartum, differences in DMI, insulin, IGF-I and EBAL

23 Links during transition period to delay of early ovulation Decreased DMI. Low blood glucose and insulin levels. High blood NEFA levels. Increased blood ketone levels (BHBA). Liver triglyceride accumulation from NEFA inhibits gluconeogenesis Metabolic signals of NEBAL conditions to brain regulates gonadotropins - LH pulses and FSH isoforms.

24 Variation among cows in NEBAL is more related to feed intake than milk production - DMI is related to timing of ovulation DMI (kg/d) BWT** Milk* Loss(kg) (kg/d) OV NOV Days relative to calving ** 1 body condition score = 56 kg * Avg. energy corrected milk, d 0-30

25 Days to Ovulation Body Condition Loss BCS Loss during 30 DIM vs. Ovulation PP < >1.0 Body Condition Loss (units) (Beam and Butler, 1997;1998)

26 FCM/DMI Gross Efficiency (FCM/DMI) first 30 DIM vs. Days to Ovulation N=86 N= < >60 Days to first ovulation Early Ov Mid Ov Late Ov Gross efficiency: kg fat corrected milk (FCM) compared to kg DMI in early lactation dairy cows in two studies. Cows were grouped by days from calving to first ovulation. Cows with high efficiency had delayed ovulation because they were in more severe NEBAL and used more body reserves for energy requirement. High efficiency is not beneficial!!

27 High efficiency is not beneficialbecause delayed onset of ovulatory cycles results in lower fertility The Bottom line-high producing cows that increase DMI to better match their energy requirements for milk production will have better energy status and likelihood of higher fertility during breeding.

28 Carryover effects of early NEBAL on fertility Prolonged anovulatory periods

29 Milk Production and Reproduction Kg/d Breeding Period cycles Months

30 Proportion of Cows Ovulating Proportion of Pregnant Cows Early NEBAL & BCS loss delays first ovulation and relates to poor fertility/increased risk of culling 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% BCS Loss of < 0.5 BCS Loss of > Days Postpartum 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 1st Ovulation BEFORE 50 DIM 1st Ovulation AFTER 50 DIM Days Postpartum Culling

31 Carryover effects of early NEBAL on fertility Conception rate to AI

32 Relationships between negative energy balance (NEBAL), body condition score (BCS) and conception rate (CR) to first insemination in high producing dairy cows High milk production and NEBAL results in tissue mobilization and BCS loss. Greater BCS loss during early lactation lowers fertility to insemination; Higher AI = Higher fertility. Strong agreement among many studies.eg BCS < 2.75 > CR% = 51 vs. 23; Galvao and Santos, Reprod.Dom.An. 45:439,2010. BCS change from calving to AI (70 DIM; 6400 cows) Pregnancy % Odds Ratio Pregnancy loss, % > 1 unit 28 Referent 20.5 < 1 unit No Change Santos et al., An.Reprod.Sci. 110:207, 2009 CR% BCS loss

33 CR % Days open Body condition score at peak milk production affects conception rate (CR%) to AI ( DIM) and resulting days open CR% in mature dairy cows n=861 Days open and BCS < to 2.9 > < to 2.9 > 2.9 BCS at peak milk BCS at peak milk

34 Effects of energy metabolism on fertility to insemination Oocyte health and embryo quality

35 Endocrine signals associated with early postpartum ovulation success or failure Ins, IGF-I and LH pulses provide the positive stimuli for follicle growth, maturation, and ovulation. NEFA & BHBA negatively impact follicle function The developmental competence of the oocyte is linked to the growth and health of developing follicles. NEBAL is hypothesized to also affect the health of primary follicles and may have a carry-over effect on oocyte quality/competence. Beam and Butler, JRF (Suppl.54) :411, 1999; Butler, Livestock Prod.Sci. 83:211,2003; Butler et al., JDS 89:2938, 2006; Patton et al., JDS 90:649, 2007; Konigsson et al., Acta Vet.Scand. 50:3, 2008; Vanholder et al, 2005, 2006 a&b; Leroy et al, 2008, : Leroy et al., Reprod.Dom.An. 43(Suppl.2):96, 2008;

36 Communication between oocytes and granulosa cells M. M. Matzuk et al., Science 296, (2002) Published by AAAS

37 Postpartum Ovulation??Oocytes in ovarian follicles developing during negative energy balance may be detrimentally imprinted?? Energy Balance (Mcal/d) Postpartum Ovulations Days Postpartum

38 NEBAL and high milk yield on oocytes/embryos in dairy cows Embryos flushed from early lactation vs non-lactating dairy cattle have much lower viability Sartori et al. JDS 85:2803, 2002 High genetic merit cows ( d PP) had lower BCS and lower early embryo development compared with medium merit herdmates- Snijders et al., Embryos flushed from lactating cows (~230 DIM) were darker ( lipid) and fewer excellent (13% vs. 63%) than from non-lactating cows- Leroy et al., Therio.64:2022, Overall: detrimental effects of early NEBAL on embryo viability, but also evidence that metabolic effects continue during lactation in high producing cows ie. lactation has a major effect on oocyte/embryo quality.

39 Pregnancy rate following AI vs. ET Cows detected in estrus hr after PGF 2α received AI (n=227) or ET (n=160) 6-8 d later. Preg detection d 28 & 42. Embryos from nonlactating cows. For cows ovulating: AI ET Positive effect of progesterone (d7 & 14) and negative effect of milk production for AI group, not ET. Higher Preg Rate % with ET than AI suggests that high milk production is associated with lower oocyte/embryo viability ie. cows own oocyte. CR% d CR% d Emb. Loss % Demetrio et al., JDS 90:5073, 2007.

40 Carryover effects of early NEBAL and energy metabolism on fertility Is there memory or genetic effects involved or are these the same?? We Observe that: Cows begin cycles at different times in lactation. Some cows become pregnant to first AI. Others fail to become pregnant after multiple AI. WHY??

41 Genomics of Dairy Cattle Fertility: Genes and polymorphisms STAT5A embryonic survival Khatib et al., J Dairy Sci. 91 (2): , STAT5A, PRLR, UTMP embryo survival in vitro Khatib et al., J Dairy Sci 92 (5): , STAT5A, FGF2 in vitro fertility of Holstein bulls Khatib et al., J Dairy Sci 93 (5): , ZNF496 variants association with milk protein% and fertility Golik et al., J Dairy Sci 94 (4): , Leptin SNP (UASMS1, UASMS2,A1457G, A59V), Fertility; and NPY SNP (NPY1) pregnant by 100 DIM Clempson et al., J Dairy Sci 94 (7): , Genetic differences may shift energy metabolism or alter the tissue responsiveness -- not only directly affecting oocytes in ovarian follicles. Genomic evaluation is already having a major impact on selection of dairy bulls in the AI industry more on cows in near future.

42 Prepartum DMI and Health Prepartum DMI Acute phase proteins (haptoglobin & ceruloplasmin) released from liver Normally results from Cytokines (infection, inflammation) D -7 from calving Hammon et al., 2006 Health disorders Puerperal Metritis Retained placenta SC endometritis Fever Reduced fertility

43 Nutritional and management strategies Feeding specific dietary fatty acids in rumen protected form. Decreased dry period length especially for mature cows. Prepartum stocking density and social behavior. Controlled energy system for dry cows high-straw low energy diets.

44 Importance of selective uptake of FA by ovarian follicles Saturated FA has toxic effect on granulosa cells in vitro. (Vanholder et al., 2005) Saturated FA had negative effects on oocyte maturation, fertilization, cleavage and blastocyst yield in vitro. (Leroy et al., 2005) NEFA concentration is 3.3-fold higher in atretic vs. E2-active follicles. (Zachut et al., 2008) PUFA = >57% of FA in FFL (C18:2n-6 predominant). Cows fed flaxseed- ALA (C18:3n-3) early pregnancy losses (Ambrose et al., 2006), 5-fold ALA in FFL, and oocyte cleavage rate (Zachut et al., 2010) ALA in vitro improved oocyte maturation, embryo development and quality (Marei et al., 2009) LA (C18:2n-6) in vitro had adverse effects on same outcomes (Marei et al., 2010)

45 Effects trans (18:1)-fatty acids on reproduction- Field Trial 511 cows; 2 diets from -21 to ~80 DIM Ca salts FA vs. Ca salts LA(18:2) + trans-fa; 250 gm/cow/d N.S. Milk yield-- fat% (3.6 vs. 3.3) Milk fat-- 18:2, trans-fa CR to 1 st AI 25.8 vs % (P<.05) Results of follow-up study suggested improved CR% likely due to fertilization rates of oocytes and embryo quality Juchem et al.,2010; Cerri et al., 2009

46 Increasing Embryo Quality Due to Feeding Unsaturated Fats to Dairy Cows (154 cows) Ca-18:2 + Measure Ca-Palm Trans 18:1 Fertilized structures 73% 87%* Sperm attached to each structure 21 34*** Classified as high quality *P = 0.11; ** P = 0.06; ***P = % 73%** Cerri et al., 2009

47 Effects of conjugated linoleic acid (CLA) on reproduction CLA = group of isomers of linoleic acid (oil seeds and forages) uniquely found in ruminant milk and meat. Milk fat % Anti-carcinogenic trans-10, cis-12 CLA cis-9, trans-11 CLA linoleic acid

48 Decreased dry period length reduces NEBAL and improves fertility Short dry period may improve energy status and enhance DMI after calving (Grummer, Therio. 68S:S281, 2007). May aid in reducing overconditioning ( NEFA). Reducing dry period length from 55 to 34 days = days to ovulation and median days open (110 d vs. 127 d). (Watters et al., JDS 92:3081, 2009). No difference in total milk yield. Most advantageous for cows entering third or greater lactation. Grummer et al., J.Reprod.Dev. 56(suppl.):S22-28, 2010

49 Take Home Message Metabolic changes in periparturient cows associated with onset of negative energy balance appear most responsible for the contemporary and coordinated detrimental effects on health and reproductive performance. Negative energy balance during early lactation is the major nutritional link to low fertility in lactating dairy cows. Negative energy balance delays recovery of postpartum reproductive function and exerts carryover effects (BCS, oocytes, uterus) that reduce fertility during the breeding period.

50 Management of feed intake, nutrition and health of dairy cows for improved reproductive performance begins in the transition period Maintain energy and dry matter intake during the prepartum period to calving and increase intake rapidly thereafter. Reduces negative energy balance and fat mobilization for improved metabolic health and also benefits recovery of ovarian activity. A WIN-WIN situation!

51 Questions???

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53 Carryover effects of early NEBAL on fertility Oocyte health and embryo quality

54 Dietary CLA supplement improves fertility in dairy cows (meta-analysis) CLA (lipid encapsulated trans-10,cis 12) fed from ~2 wk prepartum to ~ 60 DIM (5 studies). CLA reduced the median time to pregnancy by 34 d (117 vs. 151 DIM) CLA 10 g/d de Veth et al., JDS 92:2662, 2009 Mechanisms for increased pregnancy rate. Earlier first ovulation postpartum. Increased plasma IGF-I concentration. Improved estradiol production from the ovarian follicle and subsequently the corpus luteumprogesterone. No differences in uterine PGF 2α response to oxytocin.

55 Take Home Message Feeding, nutrition, and health of lactating cows for improved reproductive performance begins in the transition period and continues through early lactation. Maintain energy intake through the prepartum period to calving and increase intake rapidly thereafter to reduce NEBAL and the detrimental effects on coordinated ovarian and liver function and health. Health of cow and reproductive performance are inter-related: DMI, TNFα, NEBAL

56 Body Condition and Fertility CR % BCS= BCS= BCS=2.5 BCS= BCS= 2.0

57 Plasma concentrations of IGF-I related to fertility in dairy cows Low IGF-I concentrations after calving delays first ovulation, estrous cyclicity, and progesterone for embryo development/survival. Cows with higher IGF-I at AI are more likely to conceive (IGF-I embryo growth and development via IGFIR). IGF-I also acts through receptors in the oviduct and uterus to promote secretions that influence early embryo growth.

58 Metabolic responses to NEBAL Liver undergoes biochemical shifts and differential gene expression: up regulation for lipid oxidation and gluconeogenesis; down regulation of IGF-I, GHR, & IGFBP-3 Combined elevations of GH and NEFA antagonize insulin action and cause insulin resistance (IR). IR contributes to prioritization of body reserves and glucose for milk production.

59 EBAL (MCal/d) Energy Balance and First PP Ovulation N=47, 14=OV, 33=NOV P= Days Relative to Parturition OV NOV

60 N = 640 cows Chebel and Santos, JDS 93:4632,2010

61 Factors affecting resumption of ovarian activity in postpartum cows Ovary, follicles,oocyte, corpus luteum

62 Endocrine signals associated with ovulation failure during postpartum NEBAL: Follicle grows to similar large size Estradiol production from large follicle (<60% of peak levels) LH pulse frequency (50%) and LH responsiveness due to low plasma glucose and insulin IGF-I (70%) Delayed NEBAL nadir Ins, IGF-I and LH pulses provide the positive stimuli for follicle growth, maturation, and ovulation. The developmental competence of the oocyte is linked to the growth and health of developing follicles. NEBAL is hypothesized to also affect the health of primary follicles and may have a carry-over effect on oocyte quality/competence.

63 IGF-I (ng/ml) Insulin (ng/ml) Dry Matter Intake (kg/day) O NL NH C Day relative to parturition NOV IGF-I OV IGF-I NOV Insulin OV Insulin Days Relative to Parturition As early as 3 weeks prepartum, differences in DMI, insulin, IGF-I and EBAL