Strategies and Rationale for Resynchronization of Ovulation in Lactating Dairy Cows

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1 The Dairy Cattle Reproduction Council does not support one product over another and any mention herein is meant as an example, not an endorsement. Strategies and Rationale for Resynchronization of Ovulation in Lactating Dairy Cows J. Richard Pursley Michigan State University INTRODUCTION Scientists continue to study ways to enhance fertility of lactating dairy cows, while at the same time reduce days to subsequent inseminations in nonpregnant (open) cows using Ovsynch technology (Pursley et al., 1995). This presentation will discuss the most efficient ways to resynchronize and time-ai cows diagnosed open utilizing the latest information in reproductive research. It is a dairy producer s guide to understanding and implementing resynchronization strategies that will improve profit. Why Is Resynchronization Important? Optimally all cows would become pregnant to the first artificial insemination (AI). Even though progress is being made with regard to first service conception rate (CR) in a number of laboratories across the US, it doesn t appear we will reach this goal in my lifetime. In fact, right now the vast majority of inseminations are second plus inseminations. Thus, it only makes sense that we put significant effort into understanding the most economically efficient ways to synchronize cows for AI following an open diagnosis. If nothing formal was scheduled for cows diagnosed open, when would cows receive their next AI? It is possible that a few of the cows would never receive another AI, if nothing is done to insure this outcome. Most data indicate that about 35 % of cows will be detected in estrus every 21 d. Mathematically this not only leaves a few cows that will never see another AI, it also ensures longer lactations and dry periods, as well as increased number of cows culled due to hands-off reproductive management. The key idea behind resynchronization is to ensure that cows receive sufficient chances to become pregnant before late lactation. The bottom line: by maximizing the proportion of cows in early lactation, producers take advantage of greater average milk production and reduced costs of lengthy dry periods. Previous Work in Resynchronization Resynchronization was first reported by Pursley et al. (1997, Table 1). This was the first CR study in which controls were inseminated via only estrous detection compared to using Ovsynch for all inseminations throughout an entire lactation until cows either became pregnant or were culled. The intent was to show how Ovsynch could control days to first and subsequent inseminations without the need for any estrous detection. Ovsynch treated cows were diagnosed for pregnancy with ultrasound on d 32. If diagnosed open, cows were resynchronized beginning that day with Ovsynch. This is the way most resynchronizations were carried out on farms (still an alternative) until recently. In 2000, the idea of initiating Ovsynch prior to a pregnancy diagnosis was reported by Moreira et al. These data opened the door for producers to push the limits on conserving days open (DO) by reinitiating Ovsynch in all cows (pregnant or open) prior to pregnancy diagnosis. In 2003, Fricke et al., reported an experiment that tested the timing of the first of Ovsynch at 3 different times (d 19, 26 or 33) following first AI and prior to pregnancy diagnosis. From these data it appeared that CR from the resynchronized AI were optimized when initiating the first of Ovsynch on d 26 or 33 compared to d 19. In 2005, Bartolome et al. published a series of three papers that reported the use of resynchronization in lactating dairy cows using Ovsynch and Heatsynch following pregnancy diagnosis, the outcomes of pregnancy rates when Table 1. Median days to AI, CR, and median days to conception in lactating dairy cows inseminated after a detected estrus (control) vs. timed artificial insemination after synchronization of ovulation (Ovsynch). First AI (n=298) Second AI (n= 163) Third AI (n= 83) % Pregnant Median d to Treatment d PP CR ( %) d PP CR ( %) d PP CR ( %) 60 d PP 100 d PP Conception Control Ovsynch Probability<0.001 >0.25 <0.001 >0.15 <0.001 >0.15 <0.01 <0.01 <

2 various Ovsynch programs were initiated at specific stages of the estrous cycle, and the initiation of resynchronization with Ovsynch technology prior to pregnancy diagnosis. These data and data from other groups (El-Zarkouny and Stevenson, 2004; Rivera et al., 2005; Chebel et al., 2006; Walsh et al., 2007; and Cavalieri et al., 2007) reported using CIDR as a tool to improve resynchronization outcomes. Based on these studies and other synchronization studies, this presentation will work through the programs that make sense from a physiological perspective and point out the strengths and weaknesses of each. All of the programs discussed in this presentation have a number of variations that could be used depending upon frequency of pregnancy diagnoses, if ultrasound is being utilized, and most importantly the day of the week that the veterinarian can perform the diagnoses relative to the weekly injection schemes. For simplicity, 5 programs will be discussed. WHAT PROGRS MAKE SENSE PHYSIOLOGICALLY CONSIDERING THE CURRENT SCIENTIFIC UNDERSTANDING OF RESYNCHRONIZATION? Is it best to put diagnosed open cows on a program that includes pre-synchrony injections, or directly on Ovsynch, or start the first of Ovsynch 7 d prior to pregnancy diagnosis? Unfortunately, there is a limited amount of research that really investigated the best program to resynch. In addition, ovarian function from the time of expected return to estrus (approx. 21 d following AI) to pregnancy diagnosis is a black box. Most researchers, including myself, would assume that the majority of open cows should return to estrus between d 19 and 25 post-insemination. The reality is we do not have complete information regarding the percent of open cows that cycle or are anovular during this time. Ovsynch at a 32 d Pregnancy Exam (Calendar 1) Ovsynch can be utilized as a resynchronization program, as shown previously, but we now know that when Ovsynch is initiated in the latter half of the estrous cycle synchronization rates and CR suffers (Vasconcelos et al., 1999). It is likely, especially in herds that are performing pregnancy exams every week and pregnancy diagnosing at approx. d 35, that most cows would be in late stages of the estrous cycle. Once again, this is assuming that most open cows cycled at approx. d 21. Anecdotally, most herds that do this have much lower CR to this AI. The key reason cows don t perform well in this regard is because the corpus luteum (CL) naturally regresses prior to the PGF 2α (PGF in calendars) of Ovsynch. Unless these cows are detected in estrus (generally around the time of the PGF 2α injection) and inseminated to that estrus they will not become pregnant to the timed-ai. About the latest that Ovsynch can be started following a pregnancy diagnosis of open on a weekly basis to avoid the latter stages of the estrous cycle is d 32 following the previous AI. One way to avoid the problems with initiating Ovsynch in the late estrous cycle is to use a CIDR (Pfizer Animal Health, New York, NY) during the time from the first to PGF 2α (Bartolome et al., 2005; and Walsh et al., 2007). This would keep progesterone elevated in cows that have luteal regression prior to PGF 2α and allow a greater chance for synchrony. This would be the case for herds that are evaluating cows for pregnancy weekly, every other week, or monthly. Calendar 1. Using Ovsynch to resynch cows at d 32 from previous AI.* 32 d Preg to open cows PGF to open cows AI PM *If pregnancy diagnosing anytime after d 33 insert a CIDR at first and remove at PGF 2α when using this program. Advantages: Simple, conserves days between inseminations Disadvantages: If started past d 32 following AI, CR will likely be compromised due to inefficient synchronization. A CIDR may attenuate this problem, but adds cost and greater compliance issues to the program. 38

3 Calendar 2. Using Ovsynch to resynchronize cows beginning 7 d prior to pregnancy diagnosis. d 25 post- AI d 32 Preg AI PGF to open cows PM Advantages: Easy to implement and most efficient conserving DO. There is flexibility in day of pregnancy diagnosis as long as cows are evaluated for CL function. Disadvantages: is wasted on about 35 % of cows injected. In addition, synchronization rates are not optimal, so CR are not optimal. Alternatives: The use of a CIDR between the first and the PGF 2α may improve CR, especially in herds that are not diagnosing for pregnancy weekly. Pre-Pregnancy Diagnosis Resynch (Calendars 2 and 3) This is just plain and simple Ovsynch. The only difference is that all the cows that were diagnosed pregnant received an injection of they didn t need. There is no pre-synchronization here. Research from Fricke et al. (2003) indicate that cows receiving 7 d prior to pregnancy diagnosis at d 26 or 33 followed by the remainder of Ovsynch in open cows, resulted in greater CR when compared to starting the first of Ovsynch at d 19. Even though a pregnancy diagnosis was not performed on the d 33 group 7 d earlier at d 26, these data suggest that sufficient pregnancy losses exist between d 26 and 33 to wait for a pregnancy diagnosis at this time. A follow-up study confirmed that d 33 initiation of Ovsynch had greater CR compared to d 26 (Sterry et al., 2006). A caveat to this program (Calendar 3) that a number of veterinarians are utilizing is when pregnancy diagnosing 7 d after the first of Ovsynch cows are checked for a CL. In cows diagnosed open with a CL (best to do this with ultrasound) the Ovsynch program is completed. If cows do not have a CL, it is not clear if these cows are anovulatory or have recently undergone CL regression; thus many veterinarians are not finishing the Ovsynch program with these cows. Instead they are opting to place them directly on a CIDR-synch program. Results in the field look promising for this add-on to the Pre-Pregnancy Diagnosis Resynch program. Calendar 3. Using Ovsynch to resynchronize cows beginning prior to pregnancy diagnosis, but also evaluating the presence or absence of a corpus luteum (CL) at pregnancy diagnosis to treat cows without a CL differently. d 25 post- AI Week 3 d 32 Preg AI PGF to open cows with CL PM or + CIDR to open cows w/o CL Remove CIDR + PGF AI to open cows w/o CL PM Advantages: Gives anovular cows and cows with CL regression prior to PGF 2α a greater opportunity for pregnancy. Disadvantages: Must evaluate ovaries to determine if a CL is present. 39

4 G6G Resynch (Calendar 4) New published data from our laboratory (Bello et al., 2006) indicated that when lactating dairy cows are treated with a presynchronization program utilizing PGF 2α then, more cows have an ovulatory response to that first. Cows that ovulate to the first likely initiate emergence of a new follicular wave. Thus, these cows have a greater percentage of follicles in an ideal stage of development at the time of the final injection of with regards to the relationship between age, size, and estradiol concentrations and the increased probability of a pregnancy. Attaining consistent ovulation in response to the first of Ovsynch constitutes the first key step to optimizing synchronization of ovulation to Ovsynch in the lactating dairy cow. Ovulation to first of Ovsynch is followed by emergence of a new follicular wave, from which the ovulatory follicle of Ovsynch develops. Thus, variation in response to first leads to extreme variation in the timing of emergence of the ovulatory follicle of Ovsynch. This, in turn, translates into substantial variation in age and size of ovulatory follicles at the time of the final of Ovsynch. This variation may lead to a reduced chance of conception. Our laboratory tested a Pre-Ovsynch program that maximizes ovulation to first of Ovsynch, which decreased the variability in size of the preovulatory follicle and increased synchronization rate to Ovsynch. Based on previous data, we designed an injection scheme using PGF 2α and prior to Ovsynch in which cows were treated with 25 mg PGF 2α then 2 d later 100 μg. Then, either 4 (G4G), 5 (G5G) or 6 (G6G) d later, cows received the first of Ovsynch, and continued the Ovsynch program. Controls received only Ovsynch. Figure 1 describes the primary outcomes of these data (Bello et al., 2006). Compared to Ovsynch alone, G6G dramatically improved percent of cows ovulating to first (A), percent of cows responding to PGF 2α by luteolysis (B), and percent of cows with both a luteolytic response to PGF 2α and ovulation to the final of Ovsynch (C). The key is that G6G initiates a new cycle in most cows and allows optimal response to the first of Ovsynch. This in turn will allow for optimal synchronization rates. The trade off is in increased DO. However, if CR is significantly enhanced, the trade off may be cost effective. Fricke Presynch Resynch (Calendar 5) Another way to get cows into a stage of the estrous cycle to ensure ovulation of a follicle to the first is this program. The Calendar 5 program, soon to be published in the Journal of Dairy Science, also is designed to synchronize cows into early stages of the estrous cycle to start Ovsynch. The idea behind this program is similar to the G6G program, in that a new cycle is initiated, although time to ovulation following the first PGF 2α is not controlled. Although cows will likely be between d 5 and 9 of the estrous cycle, it is clearly dependent on time to estrus following the PGF 2α. Conception rates in this program must be significantly increased to pay for the additional DO. A 1st (%) Cows ovulated to Cows responded to PGF2α (%) Cows synchronized to Ovsynch (%) B C D 60 Cows pregnant (%) * P < * Control G4G G5G G6G * P < * P = * Control G4G G5G G6G P = * * * Control G4G G5G G6G 50.0 Control G4G G5G G6G Pre-Ovsynch Treatments Figure 1. Effect of Pre-Ovsynch treatment at 4, 5, or 6 d prior to Ovsynch on percent ovulating following Ovsynch, CL regression during Ovsynch, synchronization rate to Ovsynch and percent cows pregnant (n = 130). 40

5 Calendar 4: Utilizing G6G as a resynchrony program to enhance synchronization rates and possibly pregnancy rates. Pregnancy diagnosis ( 31 d) Open cows receive PGF Week 3 PGF AI PM Advantages: Improves synchronization rate dramatically; and thus will likely improve CR. Flexibility in day of pregnancy diagnosis (can be anytime past d 31 post-ai). Disadvantages: Costs at least 14 more DO compared to the Pre-Pregnancy Diagnosis Resynch and is more difficult to maintain compliance levels due to the number of different days that cows are injected. Calendar 5. Utilizing the Fricke Presynch Resynch strategy to synchronize cows into an optimal time of the estrous cycle to begin Ovsynch. Pregnancy diagnosis ( 27 d) Open cows receive PGF Week 3 Week 4 PGF PM AI Advantages: This program may improve CR by synchronizing cows into the optimal stage of the estrous cycle to start Ovsynch. Also, this program is straightforward to implement and provides flexibility in day of pregnancy diagnosis (can be anytime past d 27 post-ai). Disadvantages: Costs at least 14 more DO compared to the Pre-Pregnancy Diagnosis Resynch if pregnancy diagnosis is on d 27 post-ai. WHERE IS THE RESEARCH GOING? The real dilemma in designing a resynchronization program is understanding what is happening with follicle and CL development following expected time of return to estrus so that an early, yet effective, strategy can be implemented. This is especially true if new ways are discovered to pregnancy diagnose earlier than current practices. A black box of information exists from approximately d 18 to 35 following timed-ai. It would be expected that most cows that did not conceive would have luteal regression around d 18 and estrus and ovulation 3 to 5 d later. Recent preliminary data from our laboratory refute this dogma. Our data suggest that many of the cows diagnosed open at 31 d following AI do not have CL regression by d 20 following AI. Our understanding of pregnancy losses following AI is insufficient and does not allow for a clear understanding of when we can expect a new estrous cycle from cows that may lose a pregnancy 41

6 during the period from around maternal recognition of pregnancy until early pregnancy diagnosis (day 18 to 35). Our laboratory is working to develop a program that maximizes the fertility of the ovulatory follicle. It is quite possible that the reason for lower fertility levels in healthy lactating cows is aging of the follicle and the egg housed inside of it. We are making progress, but, until a program is developed to solve this problem there will be a significant number of cows that need to be re-inseminated and some a multitude of times. COMPLIANCE IS ALWAYS A KEY INGREDIENT Regardless of the program chosen, the injections must be given correctly. Compliance is the key ingredient to making any program work. Anecdotally, we have found the best compliance in herds where the person in charge of most of the inseminations is also in charge of the injections. Letting milkers or someone else that has little buy-in when it comes to reproduction handle injections is generally a mistake. Finally, whether it is a calendar, or PCDart, Dairy Comp 305, or other means of record keeping, there has to be a consistent and ACCURATE way to develop lists of cows for injections. REFERENCES Bartolome, J. A., S. Kamimura, A. C. M. Arteche, P. Melendez, D. Kelbert, J. McHale, K. Swift, L. F. Archbald, and W. W. Thatcher Resynchronization of ovulation and timed insemination in lactating dairy cows I: use of the Ovsynch and Heatsynch protocols after nonpregnancy diagnosis by ultrasonography. Theriogenology 63: Bartolome, J. A., A. Sozzi, J. McHale, P. Melendez, A. C. M. Arteche, F. T. Silvestre, D. Kelbert, K. Swift, L. F. Archbald, and W. W. Thatcher Resynchronization of ovulation and timed insemination in lactating dairy cows II: assigning protocols according to stages of the estrous cycle, or presence of ovarian cysts or anestrus. Theriogenology 63: Bartolome, J. A., A. Sozzi, J. McHale, K. Swift, D. Kelbert, L. F. Archbald, and W. W. Thatcher Resynchronization of ovulation and timed insemination in lactating dairy cows III: Administration of 23 days post AI and ultrasonography for nonpregnancy diagnosis on day 30. Theriogenology 63: Bello, N.M., J.P. Steibel, and J.R. Pursley Optimizing ovulation to first improved outcomes to each hormonal injection of ovsynch in lactating dairy cows. J. Dairy Sci. 89: Cavalieri, J., G. Hepworth, V.M. Smart, M. Ryan, and K. L. Macmillan Reproductive performance of lactating dairy cows and heifers resynchronized for a second insemination with an intravaginal progesterone-releasing device for 7 or 8 d with estradiol benzoate injected at the time of device insertion and 24 h after removal. Theriogenology 67: Chebel, R. C., J. E. P. Santos, R. L. A. Cerri, H. M. Rutigliano, and R. G. S. Bruno Reproduction in dairy cows following progesterone insert presynchronization and resynchronization protocols. J. Dairy Sci. 89: El-Zarkouny, S. Z. and J. S. Stevenson Resynchronizating estrus with progesterone or progesterone plus estrogen in cows of unknown pregnancy status. J. Dairy Sci. 87: Fricke, P. M., D. Z. Caraviello, K. A. Weigel, and M. L. Welle Fertility of dairy cows after resynchronization of ovulation at three intervals following first timed insemination. J. Dairy Sci. 86: Pursley, J.R., M.O. Mee, and M.C. Wiltbank Synchronization of ovulation in dairy cows using PGF 2α and. Theriogenology 44: Pursley, J.R., M.R. Kosorok, and M.C. Wiltbank Reproductive management of lactating dairy cows using synchronization of ovulation. J. Dairy Sci. 80: Rivera, H. H. Lopez, and P. M. Fricke Use of intravaginal progesterone-releasing inserts in a synchronization protocol before timed AI and for synchronizing return to estrus in Holstein heifers. J. Dairy Sci. 88: Sterry, R. A., M. L. Welle, and P. M. Fricke Effect of interval from timed artificial insemination to initiation of resynchronization of ovulation on fertility of lactating dairy cows. J. Dairy Sci. 89:

7 Vasconcelos, J.L., R.W. Silcox, G.J. Rosa, J.R. Pursley, and M.C. Wiltbank Synchronization rate, size of the ovulatory follicle, and pregnancy rate after synchronization of ovulation beginning on different days of the estrous cycle in lactating dairy cows. Theriogenology 52: Walsh R. B., S. J. LeBlanc, T. F. Duffield, D. F. Kelton, J. S. Walton, and K. E. Leslie The effect of a progesterone releasing intravaginal device (PRID) on a pregnancy risk to fixed-time insemination following diagnosis of non-pregnancy in dairy cows. Theriogenology 67:

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