Effect of dose and timing of prostaglandin F2α treatments during a 7-d Ovsynch protocol on progesterone concentration at the end of the protocol and pregnancy outcomes in lactating Holstein cows
The objective of this study was to evaluate the effect of two prostaglandin F2α (PGF) treatments 24 h apart (500 μg of cloprostenol) and treatment with a double PGF dose on d 7 (1000 μg of cloprostenol) during a 7-d Ovsynch protocol on progesterone (P4) concentration and pregnancy per artificial ins...
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| description | The objective of this study was to evaluate the effect of two prostaglandin F2α (PGF) treatments 24 h apart (500 μg of cloprostenol) and treatment with a double PGF dose on d 7 (1000 μg of cloprostenol) during a 7-d Ovsynch protocol on progesterone (P4) concentration and pregnancy per artificial insemination (P/AI) in lactating Holstein cows. We hypothesized that treatment leads to a decreased P4 concentration at the second GnRH treatment (G2) and an increase in P/AI compared to the traditional 7-d Ovsynch protocol. A secondary hypothesis was that the treatment effect is influenced by the presence of a corpus luteum (CL) at the first GnRH treatment (G1). Two experiments were conducted on 8 commercial dairy farms in Germany. Once a week, cows from both experiments were assigned in a consecutive manner to receive: (1) Ovsynch (control: GnRH; 7 d, PGF; 9 d, GnRH), (2) Ovsynch with a double PGF dose (GDPG: GnRH; 7 d, 2xPGF; 9 d, GnRH), or (3) Ovsynch with a second PGF treatment 24 h later (GPPG: GnRH; 7 d, PGF; 8 d, PGF; 32 h, GnRH). All cows received timed AI (TAI) approximately 16 h after G2. Pregnancy diagnosis was performed by transrectal palpation (38 ± 3 d after TAI, experiment 1) or transrectal ultrasonography (35 ± 7 d after TAI, experiment 2). Whereas farms from experiment 1 used a Presynch-Ovsynch protocol (PGF, 14 d later PGF, 12 d later GnRH, 7 d later PGF, 2 d later GnRH, and 16–18 h later TAI) to facilitate first postpartum TAI, no presynchronization protocol was used on farms from experiment 2. In experiment 1, we enrolled 1581 lactating dairy cows (60 experimental units) from 2 dairy farms. At G2, blood samples were collected from a subsample of cows (n = 491; 16 experimental units) to determine P4 concentration at G2. In experiment 2, we enrolled 1979 lactating dairy cows (252 experimental units) from 6 dairy farms. Transrectal ultrasonography was performed to determine the presence or absence of a CL at G1. In experiment 1, treatment affected P/AI (P = 0.01) and P/AI was greater for GDPG (38.2%) and GPPG (38.9%) than for control cows (29.8%). Both, GDPG and GPPG cows had decreased P4 concentration at G2 compared with control cows (P |
| doi_str_mv | 10.1016/j.theriogenology.2020.12.020 |
| format | Article |
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We hypothesized that treatment leads to a decreased P4 concentration at the second GnRH treatment (G2) and an increase in P/AI compared to the traditional 7-d Ovsynch protocol. A secondary hypothesis was that the treatment effect is influenced by the presence of a corpus luteum (CL) at the first GnRH treatment (G1). Two experiments were conducted on 8 commercial dairy farms in Germany. Once a week, cows from both experiments were assigned in a consecutive manner to receive: (1) Ovsynch (control: GnRH; 7 d, PGF; 9 d, GnRH), (2) Ovsynch with a double PGF dose (GDPG: GnRH; 7 d, 2xPGF; 9 d, GnRH), or (3) Ovsynch with a second PGF treatment 24 h later (GPPG: GnRH; 7 d, PGF; 8 d, PGF; 32 h, GnRH). All cows received timed AI (TAI) approximately 16 h after G2. Pregnancy diagnosis was performed by transrectal palpation (38 ± 3 d after TAI, experiment 1) or transrectal ultrasonography (35 ± 7 d after TAI, experiment 2). Whereas farms from experiment 1 used a Presynch-Ovsynch protocol (PGF, 14 d later PGF, 12 d later GnRH, 7 d later PGF, 2 d later GnRH, and 16–18 h later TAI) to facilitate first postpartum TAI, no presynchronization protocol was used on farms from experiment 2. In experiment 1, we enrolled 1581 lactating dairy cows (60 experimental units) from 2 dairy farms. At G2, blood samples were collected from a subsample of cows (n = 491; 16 experimental units) to determine P4 concentration at G2. In experiment 2, we enrolled 1979 lactating dairy cows (252 experimental units) from 6 dairy farms. Transrectal ultrasonography was performed to determine the presence or absence of a CL at G1. In experiment 1, treatment affected P/AI (P = 0.01) and P/AI was greater for GDPG (38.2%) and GPPG (38.9%) than for control cows (29.8%). Both, GDPG and GPPG cows had decreased P4 concentration at G2 compared with control cows (P < 0.01). Whereas both treatments increased the percentage of cows with very low P4 concentration (0.00–0.09 ng/mL) at G2, only the GPPG treatment decreased the percentage of cows with high P4 concentration (≥0.6 ng/mL) at G2 compared to the control group. In experiment 2, P/AI was greater for GPPG (37.4%) than for control cows (31.0%; P = 0.03) and tended to be greater than for GDPG cows (31.8%; P = 0.05). Cows from the GDPG group had similar (P = 0.77) P/AI compared to the control group. Pregnancy per AI did not differ between cows with a CL at G1 and cows without a CL at G1 (34.1% vs. 32.6%; P = 0.50). There was no interaction between treatment and presence of a CL at G1 on P/AI (P = 0.61). Combining data from the 2 experiments but excluding cows from experiment 1 receiving presynchronization before first TAI (n = 2573; 312 experimental units), P/AI was greater for GPPG (40.3%; P < 0.01) than for control (31.8%) and GDPG cows (33.4%). Between GDPG and control cows, P/AI did not differ (P = 0.46). We conclude that overall the addition of a second PGF treatment on d 8 during a 7-d Ovsynch protocol increased P/AI compared to the traditional 7-d Ovsynch including a single PGF dose on d 7 and to a double PGF dose on d 7. Doubling the PGF dose on d 7 in a 7-d Ovsynch protocol did not affect P/AI. Use of a presynchronization protocol, however, seems to influence the effect of a dose frequency modification of PGF treatment in an Ovsynch protocol. Presynchronized cows receiving first postpartum TAI had similarly increased P/AI treated with a double PGF dose compared with treatment with a second PGF dose. Future studies need to elucidate whether the treatment effect is modified by presynchronization of the first postpartum TAI.
•A second PGF dose on d 8 during a 7-d Ovsynch protocol decreased percentage of cows with high progesterone (P4) concentrations at G2 and increased pregnancy per AI (P/AI) compared to a single PGF dose on d 7.•Doubling the PGF dose on d 7 in a 7-d Ovsynch protocol did not affect the percentage of cows with high P4 concentration at G2 and had only a marginal effect on P/AI compared to a single PGF dose on d 7.•There was no interaction between treatment and presence of a CL at G1 on P/AI.•Presynchronized cows receiving first postpartum TAI had similarly increased P/AI treated with a double PGF dose compared to treatment with a second PGF dose</description><identifier>ISSN: 0093-691X</identifier><identifier>EISSN: 1879-3231</identifier><identifier>DOI: 10.1016/j.theriogenology.2020.12.020</identifier><language>eng</language><publisher>Elsevier Inc</publisher><subject>Dairy cow ; Fertility ; Prostaglandin ; Timed artificial insemination</subject><ispartof>Theriogenology, 2021-03, Vol.162, p.49-58</ispartof><rights>2021 Elsevier Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c278t-a06f414688522d17a1eff6453549d869832b0f635aa7e702ad3427f253b8419b3</citedby><cites>FETCH-LOGICAL-c278t-a06f414688522d17a1eff6453549d869832b0f635aa7e702ad3427f253b8419b3</cites><orcidid>0000-0002-7839-9299</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0093691X2030652X$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27903,27904,65309</link.rule.ids></links><search><creatorcontrib>Tippenhauer, C.M.</creatorcontrib><creatorcontrib>Steinmetz, I.</creatorcontrib><creatorcontrib>Heuwieser, W.</creatorcontrib><creatorcontrib>Fricke, P.M.</creatorcontrib><creatorcontrib>Lauber, M.R.</creatorcontrib><creatorcontrib>Cabrera, E.M.</creatorcontrib><creatorcontrib>Borchardt, S.</creatorcontrib><title>Effect of dose and timing of prostaglandin F2α treatments during a 7-d Ovsynch protocol on progesterone concentration at the end of the protocol and pregnancy outcomes in lactating Holstein cows</title><title>Theriogenology</title><description>The objective of this study was to evaluate the effect of two prostaglandin F2α (PGF) treatments 24 h apart (500 μg of cloprostenol) and treatment with a double PGF dose on d 7 (1000 μg of cloprostenol) during a 7-d Ovsynch protocol on progesterone (P4) concentration and pregnancy per artificial insemination (P/AI) in lactating Holstein cows. We hypothesized that treatment leads to a decreased P4 concentration at the second GnRH treatment (G2) and an increase in P/AI compared to the traditional 7-d Ovsynch protocol. A secondary hypothesis was that the treatment effect is influenced by the presence of a corpus luteum (CL) at the first GnRH treatment (G1). Two experiments were conducted on 8 commercial dairy farms in Germany. Once a week, cows from both experiments were assigned in a consecutive manner to receive: (1) Ovsynch (control: GnRH; 7 d, PGF; 9 d, GnRH), (2) Ovsynch with a double PGF dose (GDPG: GnRH; 7 d, 2xPGF; 9 d, GnRH), or (3) Ovsynch with a second PGF treatment 24 h later (GPPG: GnRH; 7 d, PGF; 8 d, PGF; 32 h, GnRH). All cows received timed AI (TAI) approximately 16 h after G2. Pregnancy diagnosis was performed by transrectal palpation (38 ± 3 d after TAI, experiment 1) or transrectal ultrasonography (35 ± 7 d after TAI, experiment 2). Whereas farms from experiment 1 used a Presynch-Ovsynch protocol (PGF, 14 d later PGF, 12 d later GnRH, 7 d later PGF, 2 d later GnRH, and 16–18 h later TAI) to facilitate first postpartum TAI, no presynchronization protocol was used on farms from experiment 2. In experiment 1, we enrolled 1581 lactating dairy cows (60 experimental units) from 2 dairy farms. At G2, blood samples were collected from a subsample of cows (n = 491; 16 experimental units) to determine P4 concentration at G2. In experiment 2, we enrolled 1979 lactating dairy cows (252 experimental units) from 6 dairy farms. Transrectal ultrasonography was performed to determine the presence or absence of a CL at G1. In experiment 1, treatment affected P/AI (P = 0.01) and P/AI was greater for GDPG (38.2%) and GPPG (38.9%) than for control cows (29.8%). Both, GDPG and GPPG cows had decreased P4 concentration at G2 compared with control cows (P < 0.01). Whereas both treatments increased the percentage of cows with very low P4 concentration (0.00–0.09 ng/mL) at G2, only the GPPG treatment decreased the percentage of cows with high P4 concentration (≥0.6 ng/mL) at G2 compared to the control group. In experiment 2, P/AI was greater for GPPG (37.4%) than for control cows (31.0%; P = 0.03) and tended to be greater than for GDPG cows (31.8%; P = 0.05). Cows from the GDPG group had similar (P = 0.77) P/AI compared to the control group. Pregnancy per AI did not differ between cows with a CL at G1 and cows without a CL at G1 (34.1% vs. 32.6%; P = 0.50). There was no interaction between treatment and presence of a CL at G1 on P/AI (P = 0.61). Combining data from the 2 experiments but excluding cows from experiment 1 receiving presynchronization before first TAI (n = 2573; 312 experimental units), P/AI was greater for GPPG (40.3%; P < 0.01) than for control (31.8%) and GDPG cows (33.4%). Between GDPG and control cows, P/AI did not differ (P = 0.46). We conclude that overall the addition of a second PGF treatment on d 8 during a 7-d Ovsynch protocol increased P/AI compared to the traditional 7-d Ovsynch including a single PGF dose on d 7 and to a double PGF dose on d 7. Doubling the PGF dose on d 7 in a 7-d Ovsynch protocol did not affect P/AI. Use of a presynchronization protocol, however, seems to influence the effect of a dose frequency modification of PGF treatment in an Ovsynch protocol. Presynchronized cows receiving first postpartum TAI had similarly increased P/AI treated with a double PGF dose compared with treatment with a second PGF dose. Future studies need to elucidate whether the treatment effect is modified by presynchronization of the first postpartum TAI.
•A second PGF dose on d 8 during a 7-d Ovsynch protocol decreased percentage of cows with high progesterone (P4) concentrations at G2 and increased pregnancy per AI (P/AI) compared to a single PGF dose on d 7.•Doubling the PGF dose on d 7 in a 7-d Ovsynch protocol did not affect the percentage of cows with high P4 concentration at G2 and had only a marginal effect on P/AI compared to a single PGF dose on d 7.•There was no interaction between treatment and presence of a CL at G1 on P/AI.•Presynchronized cows receiving first postpartum TAI had similarly increased P/AI treated with a double PGF dose compared to treatment with a second PGF dose</description><subject>Dairy cow</subject><subject>Fertility</subject><subject>Prostaglandin</subject><subject>Timed artificial insemination</subject><issn>0093-691X</issn><issn>1879-3231</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNqNUU2LFDEQbUTBcfU_5ODBS4_56E6nwYssO7vCwl4UvIVMUunN0J2MSWZlfpa_wbu_yWpGBG-eqqiqV-9VvaZ5y-iWUSbfH7b1EXJIE8Q0p-m85ZRji28xPGs2TA1jK7hgz5sNpaNo5ci-vmxelXKglAop2ab5eeM92EqSJy4VICY6UsMS4rSWjjmVaqYZqyGSHf_1g9QMpi4QayHulNc5Q4bWkYenco72cYXUZNNMUlzzCUqFnCIQm6JFWDY1YMtUgtoJIB3yrOlf4CrhmGGKJtozSadq0wKFoIDZ2Ipw5LxLM-7Fkk3fy-vmhTdzgTd_4lXzZXfz-fquvX-4_XT98b61fFC1NVT6jnVSqZ5zxwbDwHvZ9aLvRqfkqATfUy9Fb8wAA-XGiY4Pnvdirzo27sVV8-6yF6V-O-FhegnFwozvgXQqmneD6lUvqcTRD5dRix8sGbw-5rCYfNaM6tU7fdD_eqdX7zTjGgPCdxc44DlPAbIuNgD-z4WMbmmXwv8t-g1v5LCG</recordid><startdate>20210301</startdate><enddate>20210301</enddate><creator>Tippenhauer, C.M.</creator><creator>Steinmetz, I.</creator><creator>Heuwieser, W.</creator><creator>Fricke, P.M.</creator><creator>Lauber, M.R.</creator><creator>Cabrera, E.M.</creator><creator>Borchardt, S.</creator><general>Elsevier Inc</general><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-7839-9299</orcidid></search><sort><creationdate>20210301</creationdate><title>Effect of dose and timing of prostaglandin F2α treatments during a 7-d Ovsynch protocol on progesterone concentration at the end of the protocol and pregnancy outcomes in lactating Holstein cows</title><author>Tippenhauer, C.M. ; Steinmetz, I. ; Heuwieser, W. ; Fricke, P.M. ; Lauber, M.R. ; Cabrera, E.M. ; Borchardt, S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c278t-a06f414688522d17a1eff6453549d869832b0f635aa7e702ad3427f253b8419b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Dairy cow</topic><topic>Fertility</topic><topic>Prostaglandin</topic><topic>Timed artificial insemination</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tippenhauer, C.M.</creatorcontrib><creatorcontrib>Steinmetz, I.</creatorcontrib><creatorcontrib>Heuwieser, W.</creatorcontrib><creatorcontrib>Fricke, P.M.</creatorcontrib><creatorcontrib>Lauber, M.R.</creatorcontrib><creatorcontrib>Cabrera, E.M.</creatorcontrib><creatorcontrib>Borchardt, S.</creatorcontrib><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Theriogenology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tippenhauer, C.M.</au><au>Steinmetz, I.</au><au>Heuwieser, W.</au><au>Fricke, P.M.</au><au>Lauber, M.R.</au><au>Cabrera, E.M.</au><au>Borchardt, S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effect of dose and timing of prostaglandin F2α treatments during a 7-d Ovsynch protocol on progesterone concentration at the end of the protocol and pregnancy outcomes in lactating Holstein cows</atitle><jtitle>Theriogenology</jtitle><date>2021-03-01</date><risdate>2021</risdate><volume>162</volume><spage>49</spage><epage>58</epage><pages>49-58</pages><issn>0093-691X</issn><eissn>1879-3231</eissn><abstract>The objective of this study was to evaluate the effect of two prostaglandin F2α (PGF) treatments 24 h apart (500 μg of cloprostenol) and treatment with a double PGF dose on d 7 (1000 μg of cloprostenol) during a 7-d Ovsynch protocol on progesterone (P4) concentration and pregnancy per artificial insemination (P/AI) in lactating Holstein cows. We hypothesized that treatment leads to a decreased P4 concentration at the second GnRH treatment (G2) and an increase in P/AI compared to the traditional 7-d Ovsynch protocol. A secondary hypothesis was that the treatment effect is influenced by the presence of a corpus luteum (CL) at the first GnRH treatment (G1). Two experiments were conducted on 8 commercial dairy farms in Germany. Once a week, cows from both experiments were assigned in a consecutive manner to receive: (1) Ovsynch (control: GnRH; 7 d, PGF; 9 d, GnRH), (2) Ovsynch with a double PGF dose (GDPG: GnRH; 7 d, 2xPGF; 9 d, GnRH), or (3) Ovsynch with a second PGF treatment 24 h later (GPPG: GnRH; 7 d, PGF; 8 d, PGF; 32 h, GnRH). All cows received timed AI (TAI) approximately 16 h after G2. Pregnancy diagnosis was performed by transrectal palpation (38 ± 3 d after TAI, experiment 1) or transrectal ultrasonography (35 ± 7 d after TAI, experiment 2). Whereas farms from experiment 1 used a Presynch-Ovsynch protocol (PGF, 14 d later PGF, 12 d later GnRH, 7 d later PGF, 2 d later GnRH, and 16–18 h later TAI) to facilitate first postpartum TAI, no presynchronization protocol was used on farms from experiment 2. In experiment 1, we enrolled 1581 lactating dairy cows (60 experimental units) from 2 dairy farms. At G2, blood samples were collected from a subsample of cows (n = 491; 16 experimental units) to determine P4 concentration at G2. In experiment 2, we enrolled 1979 lactating dairy cows (252 experimental units) from 6 dairy farms. Transrectal ultrasonography was performed to determine the presence or absence of a CL at G1. In experiment 1, treatment affected P/AI (P = 0.01) and P/AI was greater for GDPG (38.2%) and GPPG (38.9%) than for control cows (29.8%). Both, GDPG and GPPG cows had decreased P4 concentration at G2 compared with control cows (P < 0.01). Whereas both treatments increased the percentage of cows with very low P4 concentration (0.00–0.09 ng/mL) at G2, only the GPPG treatment decreased the percentage of cows with high P4 concentration (≥0.6 ng/mL) at G2 compared to the control group. In experiment 2, P/AI was greater for GPPG (37.4%) than for control cows (31.0%; P = 0.03) and tended to be greater than for GDPG cows (31.8%; P = 0.05). Cows from the GDPG group had similar (P = 0.77) P/AI compared to the control group. Pregnancy per AI did not differ between cows with a CL at G1 and cows without a CL at G1 (34.1% vs. 32.6%; P = 0.50). There was no interaction between treatment and presence of a CL at G1 on P/AI (P = 0.61). Combining data from the 2 experiments but excluding cows from experiment 1 receiving presynchronization before first TAI (n = 2573; 312 experimental units), P/AI was greater for GPPG (40.3%; P < 0.01) than for control (31.8%) and GDPG cows (33.4%). Between GDPG and control cows, P/AI did not differ (P = 0.46). We conclude that overall the addition of a second PGF treatment on d 8 during a 7-d Ovsynch protocol increased P/AI compared to the traditional 7-d Ovsynch including a single PGF dose on d 7 and to a double PGF dose on d 7. Doubling the PGF dose on d 7 in a 7-d Ovsynch protocol did not affect P/AI. Use of a presynchronization protocol, however, seems to influence the effect of a dose frequency modification of PGF treatment in an Ovsynch protocol. Presynchronized cows receiving first postpartum TAI had similarly increased P/AI treated with a double PGF dose compared with treatment with a second PGF dose. Future studies need to elucidate whether the treatment effect is modified by presynchronization of the first postpartum TAI.
•A second PGF dose on d 8 during a 7-d Ovsynch protocol decreased percentage of cows with high progesterone (P4) concentrations at G2 and increased pregnancy per AI (P/AI) compared to a single PGF dose on d 7.•Doubling the PGF dose on d 7 in a 7-d Ovsynch protocol did not affect the percentage of cows with high P4 concentration at G2 and had only a marginal effect on P/AI compared to a single PGF dose on d 7.•There was no interaction between treatment and presence of a CL at G1 on P/AI.•Presynchronized cows receiving first postpartum TAI had similarly increased P/AI treated with a double PGF dose compared to treatment with a second PGF dose</abstract><pub>Elsevier Inc</pub><doi>10.1016/j.theriogenology.2020.12.020</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-7839-9299</orcidid></addata></record> |
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| ispartof | Theriogenology, 2021-03, Vol.162, p.49-58 |
| issn | 0093-691X 1879-3231 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2478585606 |
| source | Elsevier ScienceDirect Journals |
| subjects | Dairy cow Fertility Prostaglandin Timed artificial insemination |
| title | Effect of dose and timing of prostaglandin F2α treatments during a 7-d Ovsynch protocol on progesterone concentration at the end of the protocol and pregnancy outcomes in lactating Holstein cows |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-27T12%3A42%3A09IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Effect%20of%20dose%20and%20timing%20of%20prostaglandin%20F2%CE%B1%20treatments%20during%20a%207-d%20Ovsynch%20protocol%20on%20progesterone%20concentration%20at%20the%20end%20of%20the%20protocol%20and%20pregnancy%20outcomes%20in%20lactating%20Holstein%20cows&rft.jtitle=Theriogenology&rft.au=Tippenhauer,%20C.M.&rft.date=2021-03-01&rft.volume=162&rft.spage=49&rft.epage=58&rft.pages=49-58&rft.issn=0093-691X&rft.eissn=1879-3231&rft_id=info:doi/10.1016/j.theriogenology.2020.12.020&rft_dat=%3Cproquest_cross%3E2478585606%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2478585606&rft_id=info:pmid/&rft_els_id=S0093691X2030652X&rfr_iscdi=true |