Influences of Non-Steroidal Anti-Inflammatory Drugs on Dairy Cattle Reproductive Performance

Dr. Amin Ahmadzadeh Professor of Animal & Dairy Science

College of Agricultural and Life Sciences Jennifer A. Spencer -Texas A&M

The Fatty Acid Forum sponsored by Influences of Non-Steroidal Anti-Inflammatory Drugs on Dairy Cattle Reproductive Performance Outline

• Setting the stage • NSAID and prostaglandin • Early embryonic loss–PGF-NSAID interactions • NSAID after AI • NSAID and early postpartum • NSAID and ET • Summary and future research Influences of Non-Steroidal Anti-Inflammatory Drugs on Dairy Cattle Reproductive Performance Embryonic Loss

• Dairy cows have fertilization rates of 85% –Conception rates on d 27 to 31 after AI are only 40% –35-40% undergo embryonic loss (Sreenan et al., 2001; Whitlock et al., 2016) • 70-80% occurs early—day 8 to 16 after fertilization –Coincides with maternal recognition of pregnancy (Dunne et al., 2000; Sreenan et al., 2001; Silke et al., 2002) Influences of Non-Steroidal Anti-Inflammatory Drugs on Dairy Cattle Reproductive Performance Economic Impact of Pregnancy Loss

$ • Every pregnancy loss costs: 640 (Thurmond et al., 1990) • Decrease embryonic loss reduces the number of repeat breeding, days open, and associated costs • Decrease embryonic loss increase overall pregnancy rate (PR) –Every 1% increase in PR can bring $18-25/cow in return (Overton, 2005) Influences of Non-Steroidal Anti-Inflammatory Drugs on Dairy Cattle Reproductive Performance Prostaglandins

• The prostaglandins are a group of lipids made at sites of tissue damage or infection that are involved in dealing with injury and illness. • They control processes such as inflammation, blood flow, the estrous cycle, and the induction of labor.

COOH

HO OH Influences of Non-Steroidal Anti-Inflammatory Drugs on Dairy Cattle Reproductive Performance

Phospholipids PLA2 AA NSAID, Aspirin, Coxib COX 1 PGHS 1/2 COX 2

PGH2

PGIS PGES PGFS PGDS TxS PGI2 PGE2 PGF PGD2 TxA2

IP EP1-4 FPA, FPB DP1, DP2 TP , TP Influences of Non-Steroidal Anti-Inflammatory Drugs on Dairy Cattle Reproductive Performance Non-Steroidal Anti-Inflammatory Drugs

• Inhibitors of cyclooxygenase (COX) –Stops conversion of arachidonic acid into PGF2α • Non-Steroidal Anti-Inflammatory Drugs (NSAID) –Carprofen, Ketoprofen, meloxicam, flunixin meglumine, and aspirin • NSAID have been used in various settings and shown to affect PGF2α, prostaglandin metabolites, and reproductive performance in cattle.

(Aiumalami et al., 1990; Breuhas et al., 1999; Strahringer et al., 1999; Elli et al., 2001; Schrick et al., 2001; Purcell et al., 2005; Kafi et al., 2006; Guzeloglu et al., 2007; Amiridis et al., 2009; Erdam and Guzeloglu, 2010; Sanchez-Rodriguez et al., 2011; Gramulia et al., 2015; Pfeifer et al., 2016; Spencer et al., 2016a,b) Influences of Non-Steroidal Anti-Inflammatory Drugs on Dairy Cattle Reproductive Performance

Phospholipids PLA2 AA NSAID, Aspirin, Coxib COX 1 PGHS 1/2 COX 2

PGH2

PGIS PGES PGFS PGDS TxS PGI2 PGE2 PGF PGD2 TxA2

IP EP1-4 FPA, FPB DP1, DP2 TP , TP Influences of Non-Steroidal Anti-Inflammatory Drugs on Dairy Cattle Reproductive Performance NSAID

• In buffalo, Meloxicam treatment after insemination successfully reduced prostaglandin metabolite (PGFM) concentrations (Rajkumar et al., 2010) • Flunixin inhibited prostaglandin biosynthesis in heifers and PGFM metabolites in dairy cows (Odensvik, 1995; Spencer et al. 2016) • Aspirin decreased blood prostaglandin metabolites (PGFM) in beef and dairy cows (Stahringer et al., 1999, spencer et al., 2018) Influences of Non-Steroidal Anti-Inflammatory Drugs on Dairy Cattle Reproductive Performance Maternal Recognition & Embryonic Loss

Uterus

Interferone tau = IFN Prostaglandin F2α= PGF Progesterone = P4 Corpus luteum = CL

CL Influences of Non-Steroidal Anti-Inflammatory Drugs on Dairy Cattle Reproductive Performance Maternal Recognition & Embryonic Loss

Uterus ↑ PGF

Luteolysis Interferone tau = IFN Prostaglandin F2α= PGF Progesterone = P4 Corpus luteum = CL

↓ P2 CL Influences of Non-Steroidal Anti-Inflammatory Drugs on Dairy Cattle Reproductive Performance Embryo Survival & Pregnancy Maintenance

Uterus

IFN

↓ PGF Interferon tau = IFN Prostaglandin F2α= PGF Progesterone = P4 Corpus luteum = CL

CL Influences of Non-Steroidal Anti-Inflammatory Drugs on Dairy Cattle Reproductive Performance Untimely PGF2α Secretion

CL P4 Embryo Development Problem

PGF2α

Follicle E2

COX

Arachadonic Acid PGF2α= Prostaglandin F2α IFNτ = Interferon-tau COX = Cyclooxygenase Influences of Non-Steroidal Anti-Inflammatory Drugs on Dairy Cattle Reproductive Performance Untimely PGF2α Secretion

CL P4 Embryo Development IFNτ Problem PGF2α

Follicle E2

COX

CL P4 Embryo Development IFNτ Problem PGF2α

Follicle E2

COX

NSAID Arachadonic Acid PGF2α= Prostaglandin F2α IFNτ = Interferon-tau COX = Cyclooxygenase Influences of Non-Steroidal Anti-Inflammatory Drugs on Dairy Cattle Reproductive Performance Untimely PGF2α Secretion

CL P4 Embryo Development IFNτ Problem PGF2α

Follicle E2

COX

High incidence of Embryonic loss, in part, is related to embryonic mortality untimely secretion of PGF2α and in dairy cows premature luteolysis

Mgt. strategy to delay the synthesis and secretion of PGF2α may reduce the risk of early embryonic loss

Potential use of PGF2α inhibitors to address the risk of embryonic loss Influences of Non-Steroidal Anti-Inflammatory Drugs on Dairy Cattle Reproductive Performance Influences of Non-Steroidal Anti-Inflammatory Drugs on Dairy Cattle Reproductive Performance NSAID After AI and Reproduction

• 17 Studies (15 in dairy and 2 in beef cattle) –6 improved Pregnancy –9 no change –2 decrease pregnancy • This lack of P/AI response may be related to the non- specificity of NSAID on prostaglandins, resulting in the inhibition of the luteolytic hormone PGF2α, and the luteotropic hormone PGE2 . Influences of Non-Steroidal Anti-Inflammatory Drugs on Dairy Cattle Reproductive Performance

Phospholipids PLA2 AA NSAID, Aspirin, Coxib COX

PGG2 PGHS 1/2 POX

PGH2

PGIS PGES PGFS PGDS TxS PGI2 PGE2 PGF PGD2 TxA2

IP EP1-4 FPA, FPB DP1, DP2 TP , TP Influences of Non-Steroidal Anti-Inflammatory Drugs on Dairy Cattle Reproductive Performance PGE2 – A Luteoprotective Mediator

• During establishment of pregnancy: –Prostaglandin synthesis selective towards PGE2, away from PGF2α (Arosh et al., 2004) • PGE2 protects the CL from luteolysis, and the shift from PGF2α to PGE2 is essential for establishment of pregnancy • While NSAID inhibit PGF2α and reducing the chance of premature luteolysis, it may also interfere with embryonic implantation by inhibiting prostaglandin E2 (PGE2) Influences of Non-Steroidal Anti-Inflammatory Drugs on Dairy Cattle Reproductive Performance NSAID After AI and Reproduction

• Ketoprofen, providing analgesic, antipyretic, and anti- inflammatory effects (Agrawal and Gupta, 2010). –Alleviating fever, pain, and inflammation associated with mastitis –Practical treatment for dairy producers as it does not require a milk withdrawal Influences of Non-Steroidal Anti-Inflammatory Drugs on Dairy Cattle Reproductive Performance Meloxicam (MLX) Early Postpartum Use

• MLX attenuated systemic inflammation and improved indicators of energy balance, No affect on uterine inflammation and health. • A NSAID-induced inflammation suppression may run the risk of disrupting parturition and placental expulsion as well as slowing immune responses to infection (Bradford et al., 2015) • The potential early postpartum use of an NSAID, such as MLX, must be evaluated against possible risks to animal health and the food supply. • MLX requires meat and milk withdrawal periods Influences of Non-Steroidal Anti-Inflammatory Drugs on Dairy Cattle Reproductive Performance NSAID and Embryo Transfer

Uterine horn manipulation

Increase in uterine PGF2α Courtesy of Lander Vet Clinic, CA Influences of Non-Steroidal Anti-Inflammatory Drugs on Dairy Cattle Reproductive Performance NSAID and Embryo Transfer

• Uterine release of PGF2α and its metabolites are elevated following embryo transfer in cattle • Uterine concentrations of PGF2α have been negatively associated with embryo quality and pregnancy rates • Can NSAID help with reduction of PGF2α , hence improving P/ET? Influences of Non-Steroidal Anti-Inflammatory Drugs on Dairy Cattle Reproductive Performance NSAID and Embryo Transfer Influences of Non-Steroidal Anti-Inflammatory Drugs on Dairy Cattle Reproductive Performance NSAID After AI and Reproduction

• 8 Studies (4 in dairy and 4 in beef cattle) –6 improved pregnancy –2 no change • PGF2α inhibitor administration at the time of embryo transfer improved pregnancy rates. Influences of Non-Steroidal Anti-Inflammatory Drugs on Dairy Cattle Reproductive Performance Summary

• Little effect of Post-AI NSAID administration on P/AI • Early embryonic loss may be influenced by other factors – other than insufficient P4 –PGF2α may not be the limiting factor for embryonic loss • NSAID is a non-specific prostaglandin inhibitor –May inhibit luteotrophic prostaglandins (PGE2) Influences of Non-Steroidal Anti-Inflammatory Drugs on Dairy Cattle Reproductive Performance Summary

• NSAID do not consistently improve reproductive efficiency. • The potential detrimental effects of NSAID on subsequent reproductive performance brings into question their routine use during the postpartum period, especially for cows that do not have inflammation. • NSAID in the form of flunixin meglumine or ibuprofen consistently improved fertility in cattle when administered at the time of embryo transfer. Influences of Non-Steroidal Anti-Inflammatory Drugs on Dairy Cattle Reproductive Performance Future Research

• The non-specificity of NSAID suggests that more investigations for finding a more specific PGF2α inhibitor is needed. • The investigation on specific PGF2α inhibitor either intravaginally or orally, without a milk or meat withdrawal may provide a management strategy to improve pregnancy in cattle by reducing embryonic loss.