Multiple Ovulation Embryo Transfer is a biotech method with more than 50 years of history and an esta- blished position in cattle breeding. This procedure is beneficial in many ways, but it also carries a risk of failure. The study presents the overview of the most important risk factors that may affect conception rates in the course of embryo transfer, including the factors associated with the embryo sourcing (embryo pro- duction method, embryo quality, development stage and breed, embryo storage method), embryo transfer procedure (synchrony/asynchrony, embryo transfer difficulty, the time of the transcervical insemination gun passage, depth of embryo deposition, localization and structure of the corpus luteum relative to the follicle and both individual characteristics of donors and recipients (level of concentration of progesterone, the state of health of the udder, lactation level, body condition score and age) and some environmental factors. Running title: Risk factors for embryo transfer in cows Keywords: embryo transfer, cattle reproduction, assisted reproduction techniques Department of Basic and Preclinical Sciences, Institute of Veterinary Medicine, Faculty of Biological and Veterinary Sciences, Nicolaus Coperni- cus University, Toruń, Poland Department of Clinical Sciences and Diagnostics, Institute of Veterinary Medicine, Faculty of Biological and Veterinary Sciences, Nicolaus Coper- nicus University, Toruń, Poland Department of Reproduction and Clinic of Farm Animals, Faculty of Veterinary Medicine, Wroclaw University of Environmental and Life Scien- ces, Wrocław, Poland *Correspondence: firstname.lastname@example.org Full list of author information is available at the end of article 124 Wieczorkiewicz et al. Medical Journal of Cell Biology (2021) bryo transfer of 6- 8-day-old embryos ensured high- Introduction er pregnancy rates than 5-day and 9-day-old . Multiple Ovulation Embryo Transfer (MOET) is a According to Znaniecki et al. a higher CR was ob- biotech method with more than 50 years of history served in the case a transfer of blastocyst than mor- and an established position in cattle breeding. The ula (53.8% vs. 46.2%) . A similar dependence advantages of this method include the possibility to was observed by Hasler. The percentage of pregnant use the genetic potential of valuable mothers, rap- females after application of frozen embryos in the id valuation of bulls, creation of genetic reserves of morula stage was 54.3% and in the early blastocyst disappearing cattle breeds and elimination of many stage 59.7% . In the newest studies by Ferraz et infectious diseases [1,2]. Approximately 1 million al.  and Erdem et al.  a significantly higher of embryos are transmitted annually around the probability of pregnancies after embryo transfer in world. In the EU countries this number is about 140 the expanding blastocyst stage than in the blasto- thousand . Every embryo transfer procedure car- cyst, early blastocyst and morula stage were record- ries the risk of failure. Under these conditions, any ed (Tab. 1). The effects of embryo transfer with a action aimed to reduce this danger to an acceptable reduced number of cells, so called demi- embryos, level and increase the conception rate (CR) in recip- was also studied. This method allows doubling the ients is fully justified. The study presents the over- number of transferred germs. As a result, despite view of the most important individual and environ- the lower CR compared to conventional embryo mental risk factors that may affect CR in the course transfer (36.3 vs. 57.7), due to the possibility of of embryo transfer. fertilization twice as many cows, it is an interesting Factors associated with the embryo sourcing alternative in the case of a limited number of avail- Conventional in vivo embryo deriving (IVD) is a able embryos. However, some researchers do not technique used for decades. On the other hand, the attribute any significant influence of the embryo de- following increase in in vitro embryo production velopment stage on the results of conception rates (IVP) is a result of improvement in the technique in recipients [15,16]. of obtaining cumulus oocyte complexes (COC), as Different CR are also recorded depending on the well as in vitro maturation (IVM), in vitro fertiliza- genetic origin of the transferred embryo [20,21]. tion (IVM) and in vitro culture (IVC) . Recently, Significantly higher results were recorded in the numerous comparative studies on the efficiency of case of transfer the embryos obtained from meat IVD and IVP embryos transfer have been conducted. cows, among which the best values were noted in Recorded pregnancy rates were lower in the group such breeds as: Hereford, Charolaise, Angus and of recipients receiving IVP embryos than in the fe- Brangus (Tab.1). males after IVD embryo transfer (Tab. 1) . These results were confirmed by Ferraz et al.  with con- A transfer of frozen embryos results in a slightly ception rates higher in case of IVD embryo trans- lower CR than the transfer of fresh embryos. Ferraz fer than IVP - both fresh and frozen (49.3 vs. 39%). et al. recorded a significant fall in conception rates Significantly lower, not exceeding 30.9%, results of (12.5 % and 6.1%) in case of frozen IVD and IVP em- fertilization after IVP embryo transfer were also ob- bryos compared to the transfer of fresh ones (Tab. served by Feres et al . 1). Alternate results were noted by Rodrigues et The best quality embryos guarantee the highest al. and Roper et al., who, by transferring fresh or fro- effectiveness of ET [6–9]. Lindner and Wright  zen in vitro-produced embryos, did not report any reported that after transfer of the IVD embryos, significant effect of this variable on CR in recipients which were evaluated as excellent, good or suffi- [9,16]. The data provided by Do show that the trans- cient quality, pregnancy was obtained in respective- fer of IVP vitrified embryos did not cause any dete- ly: 45%, 44%, 27% of recipients. This dependence rioration of the conception rates compared to the was confirmed by Znaniecki, who by transferring transfer of fresh embryos. On the 35th day after the high quality embryos reached 60% of pregnancy transfer of fresh embryos, pregnancy was found in rate, while the transfer of good or sufficient quality 41.3% of recipients, while after the transfer of vitri- embryos allowed to fertilize adequately: 43.8% and fied embryos it was found in 40% . 26.1% of heifers . The newer studies confirm The use of modern technologies has made it pos- this correlation in both dairy and meat cattle (Tab. sible to select embryos. However, manipulations 1) [12–14]. The probability of conception after the carried out on semen used for the production of IVF transfer of poor quality embryos was even 31% embryos contributed to the reduction of CR in re- lower than in the case of 1st class embryos . Spell cipients. It was shown that the procedure of sperm et al. and Roper et al. do not attribute any signifi- sexing using flow cytometry may inhibit the pro- cant effect of the embryo quality on CR in recipients cess of gametes capaciation, indirectly lowering the [15,16]. rate of blastocyst development and negatively in- The effectiveness of embryo transfer is also de- fluencing CR [23,24]. Mikkola et al., comparing the termined by the stage of their development. Em- effectiveness of fresh and frozen embryos transfer 125 Wieczorkiewicz et al. Medical Journal of Cell Biology (2021) obtained after insemination by sexed semen with ra et al. determined whether the biopsied embryos conventionally produced germs, proved both sig- are capable of implantation and whether these ma- nificant decrease in the probability of pregnancy nipulations affect the various stages of pregnancy after sorted embryo transfer and a negative effect development. CR was evaluated three times during of vitrification on the results of CR (Tab. 1) . pregnancy, both in the group of biopsied embryos’ Similarly, Sanches et al. transferred the embryos recipients (group B, n=103) and the control group produced from sorted semen and noted that both in which transferred embryos were not subjected to these processes significantly reduce the probability the abovementioned treatments (group C, n=82). In of pregnancy in recipients . It was found, how- the first month of pregnancy the conception rates in ever, that the negative effects of vitrification can be the study group decreased in comparison with the minimized by using the original protocol for direct control group (B=50.9% vs. C=62.5%). Pregnancy transfer of frozen embryos. The results of concep- rates in the 3rd and 8th month were respectively: tion were 51% for fresh embryos and 35% and 40% B=50.9% vs. C=47.6% and B=49.6% vs. C=45.2%. for vitrified and frozen embryos - directly trans- Birth rates recorded at 47.1% in group B and 42.0% ferred. Gutnisky et al. also reported that using the in group C. It was found that embryos manipulation commercial Cryotech Vitrification Kit to freeze IVP may cause their developmental incompetence and embryos, the same CR were obtained as after the consequently disturbances in the implantation pro- transfer of fresh embryos produced in the same way cess and loss of pregnancy . In turn, results pre- (P/ET = 46.8%) . sented by de Sousa et al. show that this technology Initially, when cytometric sorting of gametes was can be successfully used in commercial programs not available, the sex of embryos was determined by aimed at associating assisted reproduction technol- their biopsy [27,28]. Currently, the biopsy of com- ogy with genomic selection, because biopsy viola- mercially produced IVF embryos is mainly used to tion of the continuity of a pellucid zone produced evaluate their breeding potential on the basis of bi- both in vivo and in vitro has no significant effect on ological markers present in the genome . Olivei- the conception rates (Tab. 1) . TABLE 1 Effects of factors related to in vivo or in vitro embryo production on conception rates (own compilation based 1 2 3 4 5 6 on: Pontes et al , Ferraz et al , Donaldson et al , Arreseigor et al , Mikola et al , De Sousa et al ) CR FOR THE TRANSFER FACTOR CR FOR THE TRANSFER OF EMBRYOS PRODUCED OF EMBRYOS PRODUCED IN VITRO IN VIVO 1 33.5 Embryo production method 41.5 Embryo quality Excelent 42.2 Good 32.8 Sufficient 23.7 Embryo development stage Morula 36.5 early blastocyst 38.1 Blastocyst 45.3 3,4 Embryo breed 3,4 36.8 Brangus 47 3,4 32.9 Angus 39 4 36.7 Nelore 4 22.7 HF Hereford 75 Charolaise 53 Storage method Fresh 49.3 32.9 Frozen 36.8 Sorting process 37.3 Sorter 40 42.3 not sorter 48.7 Biopsy 26.4 Biopsied 54.2 19.8 not biopsied 55.9 126 Wieczorkiewicz et al. Medical Journal of Cell Biology (2021) One of the strategies to improve the survival of the percentage of pregnancies occur at ± 12 hours IVP embryos is to modify the composition of the asynchrony. Donaldson  reported, that the dif- media in order to approximate the parameters of ferences in the CR for asynchronous animals of -24 the microenvironment of the culture to the condi- and +24 hours were 6.9% and 4.8%, respectively, tions in which the embryo develops in vivo. Under while in the case of -36 and +36 hours asynchronous physiological conditions, endometrial cells produce - 4.7% and 9.8%, respectively. According to more growth factors, cytokines, hormones and other reg- recent studies, the conception rates for ±30 hours ulatory molecules. Hyaluronate, Insulin Growth asynchrony ranges from 36 to 50%. Ledgard Factors (IGF-1, IGF-2), Colony Stimulating Factor et al. , transferring 7-day-old blastocysts pro- 2 (CSF-2), Fibroblast Growth Factor (bFGF), Trans- duced in vitro to synchronized (7 days after heat) forming Growth Factor (TGF-β1), Granulocyte and and unsynchronized (5 or 9 days after heat) recipi- Macrophage Colony Stimulating Factor (GM-CSF) ents, obtained the highest percentage of pregnancies and Leukemia Inhibiting Factor (LIF) are among in the group of recipients in whom asynchronization the specific molecules whose supplementation may was +48 hours (Table 2). Additionally, the analysis of increase the survival of transferred embryos, both the recipients’ histotroph proteom showed the high- fresh and vitrified [31–34]. It has also been shown est expression of protein factors facilitating embryo that a medium supplementation with 40 ug/ml of implantation on the 9th day of the cycle. heparin in the case of embryo production using The functional status of the recipient’s uterus sexed semen yields a pregnancy rate similar to that is also mentioned as an important factor that may of conventional embryo transfer . Taking into cause the failure of ET procedure. The intensified account the increased susceptibility to cryopres- contractility of this organ may lead to immediate or ervation of IVP embryos caused by higher concen- delayed expulsion of embryos. The presence of cer- tration of lipids in their structure, Sanches et al. in- vical mucus, which may clog the end of the catheter vestigated the effect of lipolytic factor (forslokine) or surround the embryo and keep it in the cervix on culture media. It was shown that forslokine sup- during the withdrawal of equipment, is also one of plementation caused an increase in the pregnancy the factors determining the effectiveness of the pro- rate in comparison to the control group (48.8% vs. cedure. Moini et al.  pointed out the relation- 18.5%) . ship between the degree of cervical stenosis due to mucus filling and the results of embryo transfer. Factors related to embryo transfer The removal of the clog from the cervical lumen procedure increased the probability of implantation and fa- Spell et al.  and Frade et al.  report that voured an improvement in pregnancy rate by 1/3. strong expression of the heat symptoms positively The prolonged time of cervical catheterization, correlates with progesterone levels and the con- usually caused by acute uterine and cervical an- ception rates. However, opinions on CR after em- gulation, cervical stenosis or anatomical distor- bryo transfer after natural and synchronized heat tion of the cervical canal, may significantly hinder are divided. Some authors indicate that the higher the placement of embryos in the uterine cavity percentage of pregnancies is obtained after natural ,. It is also more difficult to penetrate the heat than that induced by prostaglandin (PGF2α) or cervix in the case of Bos indicus cows, in which the its analogues [36,37]. Problems associated with a organ is longer than in Bos taurus cows [47,48]. The poorly expressed heat observation can be eliminat- relationship between the degree of difficulty during ed by using timed embryo transfer (TET) [38,39]. embryo transfer procedure and its effectiveness It has been shown that the use of optimised syn- was studied by Roper et al. . The study was con- chronisation programmes results in a significant ducted on a three-stage scale based on the opinion increase in the number of recipients available for of ET technicians, in which “1” meant “easy”, “2” transfer  and correlates with the amount of meant “moderate” and “3” meant “difficult” embryo pregnancies per transfer session , as well as has transfer. The results of conception rates in the group a positive effect on the value of the conception rate of animals in which the ET procedure was found to in recipient cows, making TET suitable for transfer be easy were significantly higher than in the other of both fresh (IVP-F) and vitrified (IVP-V) in vitro two (Tab. 2). A significant linear relationship be- produced embryos . tween the time of the transcervical insemination According to some authors, the asynchronous, in gun passage (TTIGP) to the place of embryo depo- other words, the difference in the time of occurrence sition in the horn and the results of conception was of synchronized heat between donor and recipient, observed. The longer the manipulation time, the observed in field conditions, has no significant in- fewer cows were pregnant. When TTIGP was over fluence on the results of CR in recipients [6,15,42]. a minute, the percentage of pregnant females was However, opinion of others, an asynchronism has a 50% lower than in the case of manipulation lasting significant effect on conception rates [9,37,43]. Ac- shorter . More recent studies by Roper et al. cording to Misra et al. , significant differences in confirm earlier reports . The highest percent- 127 Wieczorkiewicz et al. Medical Journal of Cell Biology (2021) age of pregnancies was observed in cows from the et al. analyzing transcriptomes of uterine horns lo- group where the total time of cervical catheteriza- cated ipsilaterally and contraterally to CL showed tion and embryo deposition was 6-9 minutes, while that there are differences in the expression of endo- in cows where the procedure lasted longer (10-13 metrial genes, but they are not correlated with the minutes and 14-25 minutes) the CR were relatively pregnancy survival up to 14 days after conception lower (Tab. 2) . . Trigal et al. confirmed that there are dispropor- Worse results of pregnancies are obtained in the tions in the concentrations of progesterone, glucose case of embryo transfer in cows than in the case of and other components essential for the embryonic heifers [18,50]. It is suspected that one of the rea- survival due to the asymmetry of the reproductive sons is a longer TTIGP and larger uterus size [18,51]. system, preferring the left horn of the uterus . Similarly, the multiple use of a female as a recipient However, field studies did not show that the ipsilater- reduces the likelihood of pregnancy after embryo al introduction of the embryo into the left horn of the transfer. The mechanism of this phenomenon is not uterus would guarantee a significantly higher rate of entirely clear and it is difficult to explain it only by conception than when the right horn was in the ipsi- the relation of the time of gun passage through the lateral position (53.2 vs. 51.0%) . cervix. Manipulations within the cervix, especially The depth of embryo insertion into the uterus its broadening, cause an increased concentration of may also influence the transfer effectiveness. The prostaglandin metabolites, shortened luteal phase, results of embryo placement were significantly weakened secretory functions of the corpus luteum, higher in recipients in which embryos were depos- and increased synthesis of oxytocin, which may lead ited deep in the horn of the uterus than in those in to embryo loss . Prolonged cervical manipula- which embryos were placed in the middle of the tion causes stress and its consequences - increased horn or in the area of the uterus body (43% vs. 31% concentrations of ACTH and cortisol [53,54]. and 24% respectively) (Tab. 2) [16,54]. The relationship between the place of embryo Individual characteristics of donors and deposition in the uterus relative to the localization of the corpus luteum and the results of conception was recipients also discussed [13,17,18,37,54–56]. The placement The percentage of pregnant recipients with easily of the embryo ipsilaterally to the corpus luteum al- palpable corpus luteum is higher than in those with lows to obtain higher pregnancy rates in comparison less developed CL [15,57]. This is related to the lev- with contraternal deposition (Tab. 2) . Sanchez el of progesterone recorded in the recipients. The TABLE 2 Influence of factors related to embryo transfer on the conception rates ((own compilation based on: Ledgard et 2 3 3 4 al. , Roper et al. , Jaśkowski JM et al.  Del Campo et al. , Jaśkowski BM et al.  FACTOR CR Asynchrony - 48h (5d) 25% none (7d) 30% + 48h (9d) 40% Embryo transfer difficulty Easy 43% Moderate 32% Difficult 18% TTIGP 10-60s 53.4% > 60 s 20.4% Depth of embryo deposition Deep in the horn 43% In the middle part of uterus horn 31% In the uterus body 24% Localization of the CL relative to the follicle Ipsilaterally 65% Contrlaterally 33% Structure of corpus luteum Cavitary CL 52% Compact CL 33% 128 Wieczorkiewicz et al. Medical Journal of Cell Biology (2021) concentration of progesterone in the blood of fe- Some authors correlate the transfer results with males on the day of embryo transfer and 7 days later the age of the recipients . The CR were found correlates with the conception rates ,. The to be higher in recipients older than 525 days . higher the progesterone level on the day of embryo Ferraz et al. recorded significantly lower conception transfer and the lower the estradiol level, the better rates in multiparae than in primiparae and heifers the results of embryo transfer . There is a sig- (31.6% vs. 37.8% vs. 42%, respectively) . A sim- nificant positive correlation between the degree of ilar pattern was observed in Mikkola et al. in both development of the corpus luteum measured by its conventional and sexed semen (57.8 and 54.8% for volume and the level of progesterone [46,60–62]. It heifers, 17.7 and 18.2% for the primiparae and 24.5 was shown that with a blood progesterone concen- and 27% for multiparae, respectively) . tration above 2- 2.5 ng/ml on the day before or on A lot of attention was also focused on the influ- the day of embryo transfer, a higher pregnancy rate ence of the condition of recipients (BCS) on the was obtained after fresh embryo transfer compared effectiveness of embryotransfer. It was shown that to recipients with a lower progesterone concen- the pregnancy rates were significantly higher in re- tration than indicated [8,12,63]. Kenyon et al.  cipients whose condition was evaluated at 3 and 4 state the minimum level of progesterone necessary (on a 5-point scale) than in those whose condition to keep pregnancy in recipients. Between 0 and 7 was assessed at 1, 2 or 5 points [39,73]. Fernandes days after insemination it should amount to 2.71 et al.  analyzed the effect of daily weight gain of ng/ml, and between 8-14 days after insemination- recipients on the effectiveness of pregnancy main- 1.48 ng/ml. According to Jaśkowski et al. [65,66], tenance obtained from IVP embryos. It was shown the type of corpus luteum is also a significant factor that the percentage of pregnancies increases with correlated with the recorded progesterone levels. daily weight gain to 350g/day, which suggests that In recipients with cavernous structure of the corpus this is the threshold for obtaining an optimal preg- luteum, both P4 concentrations and CR were higher nancy rate in recipients. In addition, the assessment than in females with solid structure (12.1 +/- 3.58 of daily weight gain allows the detection of even and 8.1 +/ 3.96 for P4 and 37.3% and 30.4% for CR, minimal fluctuations that make this method more respectively). Some authors  do not share this sensitive than the evaluation of animal condition on theory, attributing the high results of embryo trans- the basis of BCS. fer only to the precision of heat detection. The pres- ence of the first wave follicle may be relevant for the Environmental factors conception rate. In addition to its increased size, the The demand for nutrients in lactating cows rises dominant follicle is distinguished from secondary with the increase in production, which may result follicles by its ability to produce more oestradiol, in a negative energy balance. This has a significant maintain low concentrations of intrafollicular bind- impact on the hormonal management of the female ing proteins of insulin-like growth factor -2, -4 and and may cause impairment of its condition and -5 and folistatin and increase free intrafollicular lowering of progesterone level in blood, and conse- IGF-I concentrations . quently result in deterioration of conditions of em- The results of research on the dependence of fer- bryo implantation in the uterus [36,75–77]. tility rates of cows on the level of milk production Reduced effectiveness of embryo transfer may indicate that in the case of donor cows with high also be associated with simultaneous occurrence of milk production in the period preceding the super- lameness or mastitis. Mental stress associated with ovulation protocol, the probability of fertilization changes in technological groups, transport or treat- the recipient after ET was lower than in the case of ment of animals by the personnel also leads to low- donor cows with significantly lower milk production er pregnancy rates [76,78,79]. before embryo flushing [49,68,69]. This relationship There are some differences between the CR as a was explained by the lower quality of embryos col- result of embryo transfer depending on the period lected from donors with high milk production and of time during which ET was performed . It was increased likelihood of early embryo mortality. Each shown that the results of embryo transfer in sum- subsequent day of lactation in donors increased the mer were worse than those obtained in spring and chances of fertilization the recipient . winter [17,37,79,81]. Inappropriate climatic con- In a study by Skrzypek et al.  a strong correla- ditions - too high temperature and environmental tion between inflammation of the udder and cow’s hyperthermia - may lead to hormonal disorders reproductive functions was found. It is the conse- and increased embryonic mortality in the second quence of changes in the hormonal system, result- week of pregnancy [17,78,79,82,83]. High tempera- ing in disorders in the sexual cycle and ovulation ture and humidity index (THI) (≥ 80) had a nega- and early embryo mortality. Risco et al.  noted tive effect on the results of embryo transfer in the that the risk of losing pregnancy was 2.7 times high- 8th, 7th and 6th day after heat . Nabenishi et er in the case of udder inflammation up to 54 days al.  noted differences between CR in Japanese after conception compared to cows who did not black and HF cattle in different seasons of the year. have any mastitis cases during this period. 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Advances in Cell Biology – de Gruyter
Published: Sep 1, 2021
Keywords: embryo transfer; cattle reproduction; assisted reproduction techniques