Abstract
Animals that exhibited estrus had greater pregnancy success compared to animals that did not exhibit estrus before fixed-time AI (FTAI). Estradiol is synthesized in bovine ovarian follicles under gonadotropin regulation and can directly and indirectly regulate the uterine receptivity and luteal function. Estradiol concentrations at FTAI impacted oviductal gene expression and has been reported to play an important role in establishing the timing of uterine receptivity. These changes have been reported to impact uterine pH and sperm transport to the site of fertilization. After fertilization, preovulatory estradiol has been reported to improve embryo survival likely by mediating changes in uterine blood flow, endometrial thickness and changes in histotroph. Cows with greater estradiol concentrations at the time of GnRH-induced ovulation also had a larger dominant follicle size and greater circulating progesterone concentrations on day 7. Therefore, it is impossible to accurately determine the individual benefit of greater estradiol concentrations prior to ovulation and greater progesterone concentrations following ovulation to pregnancy establishment, as these two measurements are confounded. Research has indicated an importance in the occurrence and timing of increasing preovulatory concentrations of estradiol, but increasing estradiol concentrations by supplementation may not be sufficient to increase fertility. Increased production of estradiol by the preovulatory follicle may be required to enhance fertility through the regulation of sperm transport, fertilization, oviductal secretions, the uterine environment, and embryo survival.
Keywords:
estradiol; uterus; corpus luteum; oviduct
Introduction
Estrous synchronization and AI remain an important and widely applicable reproductive biotechnology available for cattle (Seidel, 1995Seidel GE. Reproductive biotechnologies for profitable beef production. In: Beef Improvement Federation 27th Research Symposium and Annual Meeting; 1995 May-Jun 31-3; Sheridan, WY, United States. Beef Improvement Federation; 1995. p. 28.). However, time and labor deter its widespread utilization. With development of FTAI protocols, estrus detection is not necessary as a gonadotropin-releasing hormone (GnRH) agonist can cause ovulation (Ryan et al., 1998Ryan M, Mihm M, Roche JF. Effect of GnRH given before or after dominance on gonadotrophin response and fate of that follicle wave in postpartum dairy cows. J Reprod Fertil. 1998;21:61.). Nevertheless, successful implementation of a FTAI protocol requires a large proportion of females to express estrus, as a positive relationship between estrus expression at time of insemination and pregnancy success has been established in both beef and dairy cattle (Vasconcelos et al., 2001Vasconcelos JL, Sartori R, Oliveira HN, Guenther JG, Wiltbank MC. Reduction in size of the ovulatory follicle reduces subsequent luteal size and pregnancy rate. Theriogenology. 2001;56(2):307-14. http://dx.doi.org/10.1016/S0093-691X(01)00565-9. PMid:11480622.
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). Animals that exhibited estrus averaged 27% greater pregnancy success compared to animals that did not (Richardson et al., 2016Richardson BN, Hill SL, Stevenson JS, Djira GD, Perry GA. Expression of estrus before fixed-time AI affects conception rates and factors that impact expression of estrus and the repeatability of expression of estrus in sequential breeding seasons. Anim Reprod Sci. 2016;166:133-40. http://dx.doi.org/10.1016/j.anireprosci.2016.01.013. PMid:26805603.
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). Furthermore, the technology of embryo transfer provides the opportunity to increase the quantity of genetically superior offspring in a shorter period of time (Lohuis, 1995Lohuis M. Potential benefits of bovine embryo-manipulation technologies to genetic improvement programs. Theriogenology. 1995;43(1):51-60. http://dx.doi.org/10.1016/0093-691X(94)00016-N.
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); however, for this technology to be successful, recipient females need to express estrus as pregnancy per embryo transfer (P/ET) are greater among estrual recipients (Baruselli et al., 2003Baruselli PS, Marques MO, Carvalho NA, Berber RA, Valentim R, Carvalho AFD Fo, Costa WP No. Follicular dynamics and pregnancy rate in embryo recipient (Bos taurus indicus x Bos taurus taurus) treated with” Ovsynch” protocol for fixed-time embryo transfer. Braz J Vet Res Anim Sci. 2003;40:96-106. http://dx.doi.org/10.1590/S1413-95962003000800003.
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).
Estradiol is synthesized in bovine ovarian follicles under gonadotropin regulation, described by the two cell-two gonadotropin model (Fortune and Quirk, 1988Fortune JE, Quirk SM. Regulation of steroidogensis in bovine preovulatory follicles. J Anim Sci. 1988;66(Suppl 2):1-8.). Preovulatory estradiol has several physiological roles in pregnancy establishment, including the expression of estrus (Coe and Allrich, 1989Coe BL, Allrich RD. Relationship between endogenous estradiol-17 beta and estrous behavior in heifers. J Anim Sci. 1989;67(6):1546-51. http://dx.doi.org/10.2527/jas1989.6761546x. PMid:2768112.
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), induction of the preovulatory gonadotropin surge (Chenault et al., 1975Chenault JR, Thatcher WW, Kalra PS, Abrams RM, Wilcox CJ. Transitory changes in plasma progestins, estradiol, and luteinizing hormone approaching ovulation in the bovine. J Dairy Sci. 1975;58(5):709-17. http://dx.doi.org/10.3168/jds.S0022-0302(75)84632-7. PMid:1170219.
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), facilitating the transport of sperm (Hawk and Cooper, 1975Hawk HW, Cooper BS. Improvement of sperm transport by the administration of estradiol to estrous ewes. J Anim Sci. 1975;41(5):1400-6. http://dx.doi.org/10.2527/jas1975.4151400x. PMid:1238386.
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), and inducing endometrial progesterone receptors (Zelinski et al., 1982Zelinski MB, Noel P, Weber DW, Stormshak F. Characterization of cytoplasmic progesterone receptors in the bovine endometrium during proestrus and diestrus. J Anim Sci. 1982;55(2):376-83. http://dx.doi.org/10.2527/jas1982.552376x. PMid:6890550.
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).
The role of estradiol in regulating fertility
Estrus
Estrus refers the time period when a female is sexually receptive. Standing estrus refers to the behavioral response of a female standing to be mounted by a male or another female. Initiation of estrus occurs due to increased circulating concentrations of estradiol when progesterone concentrations are low (Allrich, 1994Allrich RD. Endocrine and neural control of estrus in dairy cows. J Dairy Sci. 1994;77(9):2738-44. http://dx.doi.org/10.3168/jds.S0022-0302(94)77216-7. PMid:7814742.
http://dx.doi.org/10.3168/jds.S0022-0302...
). Among cattle, concentrations of estradiol peak approximately 36 hours before ovulation (Chenault et al., 1975Chenault JR, Thatcher WW, Kalra PS, Abrams RM, Wilcox CJ. Transitory changes in plasma progestins, estradiol, and luteinizing hormone approaching ovulation in the bovine. J Dairy Sci. 1975;58(5):709-17. http://dx.doi.org/10.3168/jds.S0022-0302(75)84632-7. PMid:1170219.
http://dx.doi.org/10.3168/jds.S0022-0302...
), and increased preovulatory concentrations of estradiol have been correlated with increased pregnancy success (Perry et al., 2005Perry GA, Smith MF, Lucy MC, Green JA, Parks TE, MacNeil MD, Roberts AJ, Geary TW. Relationship between follicle size at insemination and pregnancy success. Proc Natl Acad Sci USA. 2005;102(14):5268-73. http://dx.doi.org/10.1073/pnas.0501700102. PMid:15795381.
http://dx.doi.org/10.1073/pnas.050170010...
). Furthermore, estrus expression, when compared to no estrus expression, reduced pregnancy loss from day 32 to day 60 following FTAI (Pereira et al., 2014Pereira MH, Rodrigues AD, Carvalho RJ, Wiltbank MC, Vasconcelos JL. Increasing length of an estradiol and progesterone timed artificial insemination protocol decreases pregnancy losses in lactating dairy cows. J Dairy Sci. 2014;97(3):1454-64. http://dx.doi.org/10.3168/jds.2013-7287. PMid:24393173.
http://dx.doi.org/10.3168/jds.2013-7287...
). While expression of estrus contributes to the establishment of pregnancy, there has been no repeatability of expression of estrus reported (Richardson et al., 2016Richardson BN, Hill SL, Stevenson JS, Djira GD, Perry GA. Expression of estrus before fixed-time AI affects conception rates and factors that impact expression of estrus and the repeatability of expression of estrus in sequential breeding seasons. Anim Reprod Sci. 2016;166:133-40. http://dx.doi.org/10.1016/j.anireprosci.2016.01.013. PMid:26805603.
http://dx.doi.org/10.1016/j.anireprosci....
).
Oviduct
The oviductal environment is unique and governed by steroid hormones throughout the estrous cycle. Lipid and enzyme production by the oviductal epithelium increases in response to estradiol (Witkowska, 1979Witkowska E. Reactivity of the epithelial cells of the bovine oviduct in vitro on the exogenic gonadotrophic and steroid hormones. Folia Histochem Cytochem. 1979;17(3):225-38.), and oviductal fluid during estrus also contains a sperm capacitation factor (Parrish et al., 1989Parrish JJ, Susko-Parrish JL, First NL. Capacitation of bovine sperm by heparin: inhibitory effect of glucose and role of intracellular pH. Biol Reprod. 1989;41(4):683-99. http://dx.doi.org/10.1095/biolreprod41.4.683. PMid:2620077.
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). Perhaps most notably, oviductal glycoprotein secretion is maximized at estrus (Stanke et al., 1974Stanke DF, Sikes JD, DeYoung DW, Tumbleson ME. Proteins and amino acids in bovine oviducal fluid. J Reprod Fertil. 1974;38(2):493-6. http://dx.doi.org/10.1530/jrf.0.0380493. PMid:4134580.
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; Malayer et al., 1988Malayer JR, Hansen PJ, Buhi WC. Secretion of proteins by cultured bovine oviducts collected from estrus through early diestrus. J Exp Zool. 1988;248(3):345-53. http://dx.doi.org/10.1002/jez.1402480313. PMid:3209983.
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) in response to estradiol associating with its stromal receptor (Nancarrow and Hill, 1994Nancarrow CD, Hill JL. Co-culture, oviduct secretion and the function of oviduct-specific glycoproteins. Cell Biol Int. 1994;18(12):1105-14. http://dx.doi.org/10.1006/cbir.1994.1037. PMid:7703951.
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). Estrus-associated glycoprotein is produced by both the ampulla and isthmus regions of the bovine oviduct (Boice et al., 1990Boice ML, Geisert RD, Blair RM, Verhage HG. Identification and characterization of bovine oviductal glycoproteins synthesized at estrus. Biol Reprod. 1990;43(3):457-65. http://dx.doi.org/10.1095/biolreprod43.3.457. PMid:2271726.
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), and interacts with spermatozoa (King and Killian, 1994King RS, Killian GJ. Purification of bovine estrus-associated protein and localization of binding on sperm. Biol Reprod. 1994;51(3):34-42. http://dx.doi.org/10.1095/biolreprod51.3.34. PMid:7803605.
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) and oocytes (Wegner and Killian, 1991Wegner CC, Killian GJ. In vitro and in vivo association of an oviduct estrus-associated protein with bovine zona pellucida. Mol Reprod Dev. 1991;29(1):77-84. http://dx.doi.org/10.1002/mrd.1080290112. PMid:2054184.
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) in such a way that improves fertilization, cleavage rates, and blastocyst formation in a dose-dependent manner (Hill et al., 1996Hill JL, Walker SK, Brown GH, Nancarrow CD. The effects of an estrus-associated oviductal glycoprotein on the in vitro fertilization and development of ovine oocytes matured in vitro. Theriogenology. 1996;46(8):1379-88. http://dx.doi.org/10.1016/S0093-691X(96)00317-2.
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; Martus et al., 1998Martus NS, Verhage HG, Mavrogianis PA, Thibodeaux JK. Enhancement of bovine oocyte fertilization in vitro with a bovine oviductal specific glycoprotein. J Reprod Fertil. 1998;113(2):323-9. http://dx.doi.org/10.1530/jrf.0.1130323. PMid:9861173.
http://dx.doi.org/10.1530/jrf.0.1130323...
). Additionally, when cyclic ewes were ovariectomized, production of estrus-associated glycoprotein was abolished, but administration of estradiol benzoate (EB) restored estrus-associated glycoprotein production (Sutton et al., 1986Sutton R, Nancarrow CD, Wallace AL. Oestrogen and seasonal effects on the production of an oestrus-associated glycoprotein in oviducal fluid of sheep. J Reprod Fertil. 1986;77(2):645-53. http://dx.doi.org/10.1530/jrf.0.0770645. PMid:3735255.
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).
In addition to changes in oviductal fluid, oviductal gene expression is different across the estrous cycle, such that expression of 37 genes related to protein secretion and modification were upregulated during estrus compared to diestrus in the oviduct of heifers (Bauersachs et al., 2003Bauersachs S, Blum H, Mallok S, Wenigerkind H, Rief S, Prelle K, Wolf E. Regulation of ipsilateral and contralateral bovine oviduct epithelial cell function in the postovulation period: a transcriptomics approach. Biol Reprod. 2003;68(4):1170-7. http://dx.doi.org/10.1095/biolreprod.102.010660. PMid:12606461.
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). More specifically, expression of Microsomal Prostaglandin E Synthase-1 (MPGES-1) mRNA, a member of the prostaglandin family known for regulation of ovulation, fertilization, and implantation (Lim et al., 1997Lim H, Paria BC, Das SK, Dinchuk JE, Langenbach R, Trzaskos JM, Dey SK. Multiple female reproductive failures in cyclooxygenase 2-deficient mice. Cell. 1997;91(2):197-208. http://dx.doi.org/10.1016/S0092-8674(00)80402-X. PMid:9346237.
http://dx.doi.org/10.1016/S0092-8674(00)...
) as well as oviductal contraction (Wijayagunawardane et al., 2001Wijayagunawardane MP, Miyamoto A, Taquahashi Y, Gabler C, Acosta TJ, Nishimura M, Killian G, Sato K. In vitro regulation of local secretion and contraction of the bovine oviduct: stimulation by luteinizing hormone, endothelin-1 and prostaglandins, and inhibition by oxytocin. J Endocrinol. 2001;168(1):117-30. http://dx.doi.org/10.1677/joe.0.1680117. PMid:11139776.
http://dx.doi.org/10.1677/joe.0.1680117...
), was greater during periods of estrogen dominance compared to progesterone dominance in all regions of the bovine oviduct (Gauvreau et al., 2010Gauvreau D, Moisan V, Roy M, Fortier MA, Bilodeau JF. Expression of prostaglandin E synthases in the bovine oviduct. Theriogenology. 2010;73(1):103-11. http://dx.doi.org/10.1016/j.theriogenology.2009.08.006. PMid:19875162.
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). Additionally, loss of the oviductal estrogen receptor increases protease activity, which subsequently results in embryonic mortality within the first two days of pregnancy (Winuthayanon et al., 2015Winuthayanon W, Bernhardt ML, Padilla-Banks E, Myers PH, Edin ML, Lih FB, Hewitt SC, Korach KS, Williams CJ. Oviductal estrogen receptor alpha signaling prevents protease-mediated embryo death. eLife. 2015;4:e10453. http://dx.doi.org/10.7554/eLife.10453. PMid:26623518.
http://dx.doi.org/10.7554/eLife.10453...
).
Estradiol concentrations at FTAI impact oviductal gene expression, such that 1386 and 61 genes were up- and down-regulated, respectively, at the ampullary-isthmic junction, while 349 and 202 genes were up- and down-regulated, respectively, in the isthmus of cows with increased circulating estradiol concentrations (Quail et al., 2021 Quail LK, Cushman RA, Keel BN, Gonda MG, Perry GA. Preovulatory estradiol concentrations influence oviductal gene expression. In: Society for the Study of Reproduction Annual Meeting; 2021 Dec 15-18; St. Louis, United States. Reston: Society for the Study of Reproduction; 2021. p. MO2021.). More specifically, KEGG pathways associated with metabolism and hormone signaling were associated with up-regulated genes at the ampullary-isthmus junction, while up-regulated genes in the isthmus were associated with the cell adhesion KEGG pathway in cows with increased estradiol concentrations at FTAI (Quail et al., 2021 Quail LK, Cushman RA, Keel BN, Gonda MG, Perry GA. Preovulatory estradiol concentrations influence oviductal gene expression. In: Society for the Study of Reproduction Annual Meeting; 2021 Dec 15-18; St. Louis, United States. Reston: Society for the Study of Reproduction; 2021. p. MO2021.).
Uterine environment
Estradiol has been reported to play an important role in establishing the timing of uterine receptivity (Ozturk and Demir, 2010Ozturk S, Demir R. Particular functions of estrogen and progesterone in establishment of uterine receptivity and embryo implantation. Histol Histopathol. 2010;25(9):1215-28. PMid:20607663.). The uterine environment is necessary to fertilization, early embryo development, recognition of pregnancy, as well as conceptus elongation and attachment. During the estrous cycle, endometrial changes in composition and differentiation are regulated by estradiol, progesterone, and oxytocin (Spencer and Bazer, 2004Spencer TE, Bazer FW. Uterine and placental factors regulating conceptus growth in domestic animals. J Anim Sci. 2004;82(E-Suppl):E4-13. PMid:15471813.), and the timing of these changes is critical to embryo survival. Thus, estradiol plays an important role in establishing the timing of uterine receptivity (Ozturk and Demir, 2010Ozturk S, Demir R. Particular functions of estrogen and progesterone in establishment of uterine receptivity and embryo implantation. Histol Histopathol. 2010;25(9):1215-28. PMid:20607663.). In cattle, synchrony between the embryo and uterus must be ± 24 hours (Hasler, 2001Hasler JF. Factors affecting frozen and fresh embryo transfer pregnancy rates in cattle. Theriogenology. 2001;56(9):1401-15. http://dx.doi.org/10.1016/S0093-691X(01)00643-4. PMid:11768807.
http://dx.doi.org/10.1016/S0093-691X(01)...
).
Uterine gene expression
A study conducted by Zelinski et al. (1982)Zelinski MB, Noel P, Weber DW, Stormshak F. Characterization of cytoplasmic progesterone receptors in the bovine endometrium during proestrus and diestrus. J Anim Sci. 1982;55(2):376-83. http://dx.doi.org/10.2527/jas1982.552376x. PMid:6890550.
http://dx.doi.org/10.2527/jas1982.552376...
concluded that estradiol induces synthesis of endometrial cytoplasmic estrogen and progesterone receptors (Zelinski et al., 1982Zelinski MB, Noel P, Weber DW, Stormshak F. Characterization of cytoplasmic progesterone receptors in the bovine endometrium during proestrus and diestrus. J Anim Sci. 1982;55(2):376-83. http://dx.doi.org/10.2527/jas1982.552376x. PMid:6890550.
http://dx.doi.org/10.2527/jas1982.552376...
), which further supports work from (Koligian and Stormshak, 1977Koligian KB, Stormshak F. Progesterone inhibition of estrogen receptor replenishment in ovine endometrium. Biol Reprod. 1977;17(3):412-6. http://dx.doi.org/10.1095/biolreprod17.3.412. PMid:901893.
http://dx.doi.org/10.1095/biolreprod17.3...
) concluding progesterone inhibited the replenishment of cytoplasmic estradiol receptors during the luteal phase in the ovine endometrium. More recently, it has been reported that progesterone receptors in the deep glandular epithelium, as well as endometrial estradiol receptor (ERα) mRNA, were up-regulated on day 15.5 in cows with elevated preovulatory estradiol concentrations (Bridges et al., 2012Bridges GA, Mussard ML, Pate JL, Ott TL, Hansen TR, Day ML. Impact of preovulatory estradiol concentrations on conceptus development and uterine gene expression. Anim Reprod Sci. 2012;133(1-2):16-26. http://dx.doi.org/10.1016/j.anireprosci.2012.06.013. PMid:22789700.
http://dx.doi.org/10.1016/j.anireprosci....
).
Differences also exist in endometrial and corpus luteum (CL) gene expression between estrual and nonestrual females, with endometrial transcripts related to prostaglandin synthesis (OTR and COX-2) as well as the immune system and cell adhesion (CXCL10, IGLL1, MX1, MX2, MMP19, MYL12A, and SLPI) influenced by the expression of estrus (Davoodi et al., 2016Davoodi S, Cooke RF, Fernandes AC, Cappellozza BI, Vasconcelos JL, Cerri RL. Expression of estrus modifies the gene expression profile in reproductive tissues on day 19 of gestation in beef cows. Theriogenology. 2016;85(4):645-55. http://dx.doi.org/10.1016/j.theriogenology.2015.10.002. PMid:26525398.
http://dx.doi.org/10.1016/j.theriogenolo...
). Furthermore, the abundance of facilitative and sodium-dependent glucose transporters, which are responsible for altering the composition of uterine luminal fluid (ULF) and providing glucose to the developing conceptus, is impacted by estradiol, such that females with elevated preovulatory estradiol concentrations had a greater abundance of SLC2A1 and SLC5A1 in both intercaruncular and caruncular tissues (Northrop et al., 2018Northrop EJ, Rich JJJ, Cushman RA, McNeel AK, Soares EM, Brooks K, Spencer TE, Perry GA. Effects of preovulatory estradiol on uterine environment and conceptus survival from fertilization to maternal recognition of pregnancy. Biol Reprod. 2018;99(3):629-38. http://dx.doi.org/10.1093/biolre/ioy086. PMid:29672673.
http://dx.doi.org/10.1093/biolre/ioy086...
).
The TGF-β superfamily is involved in endometrial changes, placental development, and pregnancy maintenance (Jones et al., 2006Jones RL, Stoikos C, Findlay JK, Salamonsen LA. TGF-beta superfamily expression and actions in the endometrium and placenta. Reproduction. 2006;132(2):217-32. http://dx.doi.org/10.1530/rep.1.01076. PMid:16885531.
http://dx.doi.org/10.1530/rep.1.01076...
). At estrus, there is also up-regulation of several genes involved in remodeling the extracellular matrix (Bauersachs et al., 2005Bauersachs S, Ulbrich SE, Gross K, Schmidt SE, Meyer HH, Einspanier R, Wenigerkind H, Vermehren M, Blum H, Sinowatz F, Wolf E. Gene expression profiling of bovine endometrium during the oestrous cycle: detection of molecular pathways involved in functional changes. J Mol Endocrinol. 2005;34(3):889-908. http://dx.doi.org/10.1677/jme.1.01799. PMid:15956356.
http://dx.doi.org/10.1677/jme.1.01799...
), as well as changes in expression of inhibin A subunit (a member of the TGF-β signaling pathway) in the bovine intercaruncular area, suggesting the involvement of estradiol in coordinating endometrial remodeling (Ishiwata et al., 2003Ishiwata H, Katsuma S, Kizaki K, Patel OV, Nakano H, Takahashi T, Imai K, Hirasawa A, Shiojima S, Ikawa H, Suzuki Y, Tsujimoto G, Izaike Y, Todoroki J, Hashizume K. Characterization of gene expression profiles in early bovine pregnancy using a custom cDNA microarray. Mol Reprod Dev. 2003;65(1):9-18. http://dx.doi.org/10.1002/mrd.10292. PMid:12658628.
http://dx.doi.org/10.1002/mrd.10292...
). Milk protein (SERPINA14) is expressed in the endometrium of ruminants during pregnancy, and is likely involved in nutrition of the embryo/fetus, embryonic/fetal growth, and suppression of the maternal immune system (Ing and Roberts, 1989Ing NH, Roberts RM. The major progesterone-modulated proteins secreted into the sheep uterus are members of the serpin superfamily of serine protease inhibitors. J Biol Chem. 1989;264(6):3372-9. http://dx.doi.org/10.1016/S0021-9258(18)94076-7. PMid:2464597.
http://dx.doi.org/10.1016/S0021-9258(18)...
). Expression of SERPINA14, as determined by Real-time RT-PCR, was greatest on the day of estrus, and was also up-regulated after stimulation with estradiol. Furthermore, detection of the SERPINA14 protein revealed the protein was localized to the glandular epithelium and was increased on the day of estrus (Ulbrich et al., 2009Ulbrich SE, Frohlich T, Schulke K, Englberger E, Waldschmitt N, Arnold GJ, Reichenbach HD, Reichenbach M, Wolf E, Meyer HH, Bauersachs S. Evidence for estrogen-dependent uterine serpin (SERPINA14) expression during estrus in the bovine endometrial glandular epithelium and lumen. Biol Reprod. 2009;81(4):795-805. http://dx.doi.org/10.1095/biolreprod.108.075184. PMid:19494250.
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). This suggests a possible preparatory role for preovulatory estradiol in establishing a uterine environment that is conducive to pregnancy.
CLOCK genes regulate biological oscillations and the transcription of other genes in a tissue specific manner in response to changes in nutrient status, day length, and possibly other environmental influences (Albrecht, 2006Albrecht U. Orchestration of gene expression and physiology by the circadian clock. J Physiol Paris. 2006;100(5-6):243-51. http://dx.doi.org/10.1016/j.jphysparis.2007.05.004. PMid:17643274.
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). Decreased litter size, lower frequency of successful matings, and increased cycle length have been reported in ClockΔ19 (mice in which CLOCK is not functional) female mice (Chappell et al., 2003Chappell PE, White RS, Mellon PL. Circadian gene expression regulates pulsatile gonadotropin-releasing hormone (GnRH) secretory patterns in the hypothalamic GnRH-secreting GT1-7 cell line. J Neurosci. 2003;23(35):11202-13. http://dx.doi.org/10.1523/JNEUROSCI.23-35-11202.2003. PMid:14657179.
http://dx.doi.org/10.1523/JNEUROSCI.23-3...
). When ClockΔ19 female mice were treated hormonally to induce ovulation and mated with fertile males, ClockΔ19 females produced fewer embryos than control females (Kennaway, 2005Kennaway DJ. The role of circadian rhythmicity in reproduction. Hum Reprod Update. 2005;11(1):91-101. http://dx.doi.org/10.1093/humupd/dmh054. PMid:15569698.
http://dx.doi.org/10.1093/humupd/dmh054...
). From these results, it is possible that circadian clock gene defects at the level of the uterus may disrupt the synchrony between the uterine environment and the developing embryo. He et al. (2007He PJ, Hirata M, Yamauchi N, Hattori MA. Up-regulation of Per1 expression by estradiol and progesterone in the rat uterus. J Endocrinol. 2007;194(3):511-9. http://dx.doi.org/10.1677/JOE-07-0172. PMid:17761890.
http://dx.doi.org/10.1677/JOE-07-0172...
) reported that Period 1 mRNA (part of the positive feedback loop of CLOCK) was expressed in the uterus of diestrus rats, and that both estradiol and progesterone stimulated uterine Period 1 mRNA expression in ovariectomized rats. Furthermore, Nakamura et al. (2005)Nakamura TJ, Moriya T, Inoue S, Shimazoe T, Watanabe S, Ebihara S, Shinohara K. Estrogen differentially regulates expression of Per1 and Per2 genes between central and peripheral clocks and between reproductive and nonreproductive tissues in female rats. J Neurosci Res. 2005;82(5):622-30. http://dx.doi.org/10.1002/jnr.20677. PMid:16273538.
http://dx.doi.org/10.1002/jnr.20677...
reported that estradiol altered the normal circadian rhythms in the uterus. Therefore, the circadian clock genes may influence fertility at the uterine level.
Uterine pH
In estrual females, there was a transient decline in uterine pH from 36 hours prior to the onset of estrus until estrus. From the onset of estrus to approximately 6 hours after the onset of estrus, uterine pH increased rapidly. Neither the decrease in uterine pH prior to estrus, nor the rise after estrus was observed in females that did not express estrus (Perry and Perry, 2008a Perry GA, Perry BL. Effect of preovulatory concentrations of estradiol and initiation of standing estrus on uterine pH in beef cows. Domest Anim Endocrinol. 2008a;34(3):333-8. http://dx.doi.org/10.1016/j.domaniend.2007.09.003. PMid:17980539.
http://dx.doi.org/10.1016/j.domaniend.20...
). Overall, females expressing estrus had a decreased uterine pH (pH = 6.72) compared to females that did not express estrus (pH = 7.0). The effect of preovulatory estradiol on uterine pH was evaluated in females that were or were not treated with 1 mg of estradiol cypionate (ECP) 36 hours prior to the final administration of GnRH in a CO-Synch protocol. Nonestrual females that did not receive ECP had an elevated uterine pH (7.0 ± 0.07) compared to estrual females that were not administered ECP (pH = 6.72 ± 0.10; P = 0.02) and nonestrual females that were administered ECP (6.81 ± 0.09; P = 0.06; Perry and Perry, 2008bPerry GA, Perry BL. Effects of standing estrus and supplemental estradiol on changes in uterine pH during a fixed-time artificial insemination protocol. J Anim Sci. 2008b;86(11):2928-35. http://dx.doi.org/10.2527/jas.2008-1181. PMid:18641170.
http://dx.doi.org/10.2527/jas.2008-1181...
). Bolzenius et al. (2016)Bolzenius JK, Cushman RA, Perry GA. Expression of Na(+)/H(+) exchanger isoforms 1, 2, 3, and 4 in bovine endometrium and the influence of uterine pH at time of fixed-time AI of pregnancy success. Anim Reprod Sci. 2016;171:98-107. http://dx.doi.org/10.1016/j.anireprosci.2016.06.004. PMid:27338797.
http://dx.doi.org/10.1016/j.anireprosci....
reported that as uterine pH decreased at the time of FTAI, pregnancy rates increased. They also noted that NA+/H+ exchanger isoforms 1, 2, and 3 played a role in altering uterine pH during the onset of estrus (Bolzenius et al., 2016Bolzenius JK, Cushman RA, Perry GA. Expression of Na(+)/H(+) exchanger isoforms 1, 2, 3, and 4 in bovine endometrium and the influence of uterine pH at time of fixed-time AI of pregnancy success. Anim Reprod Sci. 2016;171:98-107. http://dx.doi.org/10.1016/j.anireprosci.2016.06.004. PMid:27338797.
http://dx.doi.org/10.1016/j.anireprosci....
). Given that Jones and Bavister (2000)Jones JM, Bavister BD. Acidification of intracellular pH in bovine spermatozoa suppresses motility and extends viable life. J Androl. 2000;21(5):616-24. PMid:10975407. reported that as pH decreased, motility of bull sperm decreased and longevity increased, a transient change in uterine pH around estrus may provide a mechanism for increasing sperm longevity in the reproductive tract.
Hawk (1983)Hawk HW. Sperm survival and transport in the female reproductive tract. J Dairy Sci. 1983;66(12):2645-60. http://dx.doi.org/10.3168/jds.S0022-0302(83)82138-9. PMid:6365994.
http://dx.doi.org/10.3168/jds.S0022-0302...
reported that in order for sperm to be efficiently transported in the female reproductive tract, females needed exposure to estradiol. At initiation of estrus, uterine pH was decreased which may have led to greater longevity of sperm through a transient decrease in motility (Wong et al., 1981Wong PY, Lee WM, Tsang AY. The effects of extracellular sodium on acid release and motility initiation in rat caudal epididymal spermatozoa in vitro. Exp Cell Res. 1981;131(1):97-104. http://dx.doi.org/10.1016/0014-4827(81)90410-9. PMid:7447992.
http://dx.doi.org/10.1016/0014-4827(81)9...
). The peak in uterine pH observed 6 hours after estrus may play a role in aiding sperm transport, as Goltz et al., (1988) reported as pH increased, so did sperm motility (Goltz et al., 1988Goltz JS, Gardner TK, Kanous KS, Lindemann CB. The interaction of pH and cyclic adenosine 3′,5′-monophosphate on activation of motility in Triton X-100 extracted bull sperm. Biol Reprod. 1988;39(5):1129-36. http://dx.doi.org/10.1095/biolreprod39.5.1129. PMid:2851335.
http://dx.doi.org/10.1095/biolreprod39.5...
). Cows that initiated standing estrus had decreased uterine pH (6.78) and increased pregnancy success (52%) compared to cows that did not initiate standing estrus, but were induced to ovulate (6.96 and 38%, respectively). This increase in pregnancy success among cows that exhibited standing estrus is likely due to increased sperm transport to the site of fertilization (Larimore et al., 2015Larimore EL, Amundson OL, Bird SL, Funnell BJ, Kruse SG, Bridges GA, Perry GA. Influence of estrus at fixed-time artificial insemination on early embryonic development in beef cattle. J Anim Sci. 2015;93(6):2806-12. http://dx.doi.org/10.2527/jas.2015-8892. PMid:26115268.
http://dx.doi.org/10.2527/jas.2015-8892...
). In a FTAI scenario, the second administration of GnRH can induce ovulation approximately 30 hours after administration in the absence of elevated estradiol concentrations (Pursley et al., 1995Pursley JR, Mee MO, Wiltbank MC. Synchronization of ovulation in dairy cows using PGF2α and GnRH. Theriogenology. 1995;44(7):915-23. http://dx.doi.org/10.1016/0093-691X(95)00279-H. PMid:16727787.
http://dx.doi.org/10.1016/0093-691X(95)0...
; Vasconcelos et al., 1999Vasconcelos JL, Silcox RW, Rosa GJ, Pursley JR, Wiltbank MC. 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. 1999;52(6):1067-78. http://dx.doi.org/10.1016/S0093-691X(99)00195-8. PMid:10735113.
http://dx.doi.org/10.1016/S0093-691X(99)...
), and sperm survival until ovulation may be compromised as the interval from insemination to ovulation is lengthened.
Fertilization
A review by Santos et al. (2004)Santos JE, Thatcher WW, Chebel RC, Cerri RL, Galvao KN. The effect of embryonic death rates in cattle on the efficacy of estrus synchronization programs. Anim Reprod Sci. 2004;82-83:513-35. http://dx.doi.org/10.1016/j.anireprosci.2004.04.015. PMid:15271477.
http://dx.doi.org/10.1016/j.anireprosci....
reported fertilization failure in lactating beef and dairy cows was as high as 45%. A study in beef cows, where embryos were flushed from cows with high or low estradiol concentrations at the time of FTAI, revealed that cows with greater concentrations of estradiol at GnRH-induced ovulation were more likely to yield a fertilized embryo than an unfertilized oocyte (Jinks et al., 2013Jinks EM, Smith MF, Atkins JA, Pohler KG, Perry GA, Macneil MD, Roberts AJ, Waterman RC, Alexander LJ, Geary TW. Preovulatory estradiol and the establishment and maintenance of pregnancy in suckled beef cows. J Anim Sci. 2013;91(3):1176-85. http://dx.doi.org/10.2527/jas.2012-5611. PMid:23296810.
http://dx.doi.org/10.2527/jas.2012-5611...
). Additionally, animals that exhibited estrus prior to FTAI had increased accessory sperm numbers and improved embryo quality compared to animals that did not exhibit estrus (Larimore et al., 2015Larimore EL, Amundson OL, Bird SL, Funnell BJ, Kruse SG, Bridges GA, Perry GA. Influence of estrus at fixed-time artificial insemination on early embryonic development in beef cattle. J Anim Sci. 2015;93(6):2806-12. http://dx.doi.org/10.2527/jas.2015-8892. PMid:26115268.
http://dx.doi.org/10.2527/jas.2015-8892...
). Although accessory sperm are not involved in fertilization, they represent sperm that were able to access the oviduct, undergo capacitation and the acrosome reaction, recognize and bind to the oocyte, and partially penetrate the zona pellucida (Dalton et al., 2006Dalton JC, Nadir S, Noftsinger M, Bame J, Saacke RG. Management factors associated with male fertility. In: Applied Reproductive Strategies in Beef Cattle; 2006; Rapid City, United States. 2006. p. 279-290.). The number of accessory sperm trapped in the zona pellucida has been positively associated with fertility (Hunter and Wilmut, 1984Hunter RH, Wilmut I. Sperm transport in the cow: peri-ovulatory redistribution of viable cells within the oviduct. Reprod Nutr Dev. 1984;24(5A):597-608. http://dx.doi.org/10.1051/rnd:19840508. PMid:6549076.
http://dx.doi.org/10.1051/rnd:19840508...
; Hawk and Tanabe, 1986Hawk HW, Tanabe TY. Effect of unilateral cornual insemination upon fertilization rate in superovulating and single-ovulating cattle. J Anim Sci. 1986;63(2):551-60. http://dx.doi.org/10.2527/jas1986.632551x. PMid:3759689.
http://dx.doi.org/10.2527/jas1986.632551...
; DeJarnette et al., 1992DeJarnette JM, Saacke RG, Bame J, Vogler CJ. Accessory sperm: their importance to fertility and embryo quality, and attempts to alter their numbers in artificially inseminated cattle. J Anim Sci. 1992;70(2):484-91. http://dx.doi.org/10.2527/1992.702484x. PMid:1548211.
http://dx.doi.org/10.2527/1992.702484x...
; Nadir et al., 1993Nadir S, Saacke RG, Bame J, Mullins J, Degelos S. Effect of freezing semen and dosage of sperm on number of accessory sperm, fertility, and embryo quality in artificially inseminated cattle. J Anim Sci. 1993;71(1):199-204. http://dx.doi.org/10.2527/1993.711199x. PMid:8454543.
http://dx.doi.org/10.2527/1993.711199x...
), and are thought to be an indirect measure of both sperm transport and the availability of competent sperm competing for fertilization (DeJarnette et al., 1992DeJarnette JM, Saacke RG, Bame J, Vogler CJ. Accessory sperm: their importance to fertility and embryo quality, and attempts to alter their numbers in artificially inseminated cattle. J Anim Sci. 1992;70(2):484-91. http://dx.doi.org/10.2527/1992.702484x. PMid:1548211.
http://dx.doi.org/10.2527/1992.702484x...
).
Uterine blood flow
Endocrine, paracrine, and autocrine factors are all involved in the development and growth of the embryo and placenta. The bovine fetus receives nutrients through both hematotroph and histotroph. Hematotroph allows exchange of nutrients between fetal and maternal circulation (Bazer et al., 1990Bazer FW, Terqui M, Martinat-Butte F. Physiological limits to reproduction. In: Proceedings of the 4th World Congress on Genetics Applied to Livestock Production; 1990 Jul 23-27, Edinburgh, Scotland. Edinburgh: The University of Edinburgh; 1990. p. 292-8.). When transrectal doppler ultrasonography was used to characterize uterine blood flow, circulating concentrations of estradiol were determined to be greatest on day -2 (day 0 = ovulation) and uterine blood flow was greatest on day -3 (Bollwein et al., 2000Bollwein H, Meyer HH, Maierl J, Weber F, Baumgartner U, Stolla R. Transrectal doppler sonography of uterine blood flow in cows during the estrous cycle. Theriogenology. 2000;53(8):1541-52. http://dx.doi.org/10.1016/S0093-691X(00)00296-X. PMid:10883842.
http://dx.doi.org/10.1016/S0093-691X(00)...
). Similarly, a positive correlation between circulating concentrations of estradiol and uterine blood flow as well as uterine artery diameter were determined following administration of EB (10 mg; Rawy et al., 2018Rawy M, Mido S, Ali HE-S, Derar D, Megahed G, Kitahara G, Osawa T. Effect of exogenous estradiol Benzoate on uterine blood flow in postpartum dairy cows. Anim Reprod Sci. 2018;192:136-45. http://dx.doi.org/10.1016/j.anireprosci.2018.03.001. PMid:29550273.
http://dx.doi.org/10.1016/j.anireprosci....
). Blood flow increased two days prior to estrus, and remained elevated until the day after estrus, which corresponded with elevated estradiol concentrations (Ford and Chenault, 1981Ford SP, Chenault JR. Blood flow to the corpus luteum-bearing ovary and ipsilateral uterine horn of cows during the oestrous cycle and early pregnancy. J Reprod Fertil. 1981;62(2):555-62. http://dx.doi.org/10.1530/jrf.0.0620555. PMid:7252931.
http://dx.doi.org/10.1530/jrf.0.0620555...
).
Uterine blood flow was similar in pregnant and nonpregnant cows up to 13 days post-mating, at which time blood flow to the gravid horn increased. From day 25 to day 30, blood flow increased to the gravid horn and decreased to the nongravid horn. Progesterone concentrations and uterine blood flow to the gravid horn was positively correlated. The increase in blood flow to the gravid horn, caused by the preimplantation conceptus, was similar to blood flow observed when estradiol was elevated (Ford and Chenault, 1981Ford SP, Chenault JR. Blood flow to the corpus luteum-bearing ovary and ipsilateral uterine horn of cows during the oestrous cycle and early pregnancy. J Reprod Fertil. 1981;62(2):555-62. http://dx.doi.org/10.1530/jrf.0.0620555. PMid:7252931.
http://dx.doi.org/10.1530/jrf.0.0620555...
). The increase in blood flow may also increase the blood flow to the CL found on the ipsilateral ovary, thereby increasing progesterone secretion which would aid in maintaining pregnancy (Ford and Chenault, 1981Ford SP, Chenault JR. Blood flow to the corpus luteum-bearing ovary and ipsilateral uterine horn of cows during the oestrous cycle and early pregnancy. J Reprod Fertil. 1981;62(2):555-62. http://dx.doi.org/10.1530/jrf.0.0620555. PMid:7252931.
http://dx.doi.org/10.1530/jrf.0.0620555...
).
Uterine endometrial thickness
Sugiura et al. (2018)Sugiura T, Akiyoshi S, Inoue F, Yanagawa Y, Moriyoshi M, Tajima M, Katagiri S. Relationship between bovine endometrial thickness and plasma progesterone and estradiol concentrations in natural and induced estrus. J Reprod Dev. 2018;64(2):135-43. http://dx.doi.org/10.1262/jrd.2017-139. PMid:29398684.
http://dx.doi.org/10.1262/jrd.2017-139...
reported that as progesterone concentrations decrease, endometrial thickness increased; however, estradiol may also play a role in sustaining and/or enhancing these changes, as endometrial thickness was strongly correlated with the Estradiol:Progesterone ratio after natural and induced estrus (Sugiura et al., 2018Sugiura T, Akiyoshi S, Inoue F, Yanagawa Y, Moriyoshi M, Tajima M, Katagiri S. Relationship between bovine endometrial thickness and plasma progesterone and estradiol concentrations in natural and induced estrus. J Reprod Dev. 2018;64(2):135-43. http://dx.doi.org/10.1262/jrd.2017-139. PMid:29398684.
http://dx.doi.org/10.1262/jrd.2017-139...
). Endometrial thickness was measured by transrectal ultrasonography in lactating Holstein cows administered the Ovsynch protocol. Thickness of the endometrium increased from 7 to 9.5 mm following prostaglandin administration, remained thick (> 9 mm) for two days, and then became thinner on both day 1 (8 mm) and 2 (7.4 mm) following the second administration of GnRH. Supplementing estradiol-17β (1mg) eight hours prior to the second administration of GnRH increased pregnancies to AI in females with thinner endometrium. However, in females that had an endometrial thickness measurement of > 8 mm 48 hours following prostaglandin administration, estradiol supplementation did not improve pregnancies to AI (Souza et al., 2011Souza AH, Silva EP, Cunha AP, Gumen A, Ayres H, Brusveen DJ, Guenther JN, Wiltbank MC. Ultrasonographic evaluation of endometrial thickness near timed AI as a predictor of fertility in high-producing dairy cows. Theriogenology. 2011;75(4):722-33. http://dx.doi.org/10.1016/j.theriogenology.2010.10.013. PMid:21196031.
http://dx.doi.org/10.1016/j.theriogenolo...
).
Histotroph
Uterine histotroph is composed of nutrients, growth factors, proteins, glucose, immunosuppressive agents, enzymes, and ions. It is secreted by the endometrium and is necessary for early conceptus growth/survival (Geisert et al., 1992Geisert RD, Morgan GL, Short EC Jr, Zavy MT. Endocrine events associated with endometrial function and conceptus development in cattle. Reprod Fertil Dev. 1992;4(3):301-5. http://dx.doi.org/10.1071/RD9920301. PMid:1438962.
http://dx.doi.org/10.1071/RD9920301...
; Gray et al., 2001Gray CA, Taylor KM, Ramsey WS, Hill JR, Bazer FW, Bartol FF, Spencer TE. Endometrial glands are required for preimplantation conceptus elongation and survival. Biol Reprod. 2001;64(6):1608-13. http://dx.doi.org/10.1095/biolreprod64.6.1608. PMid:11369585.
http://dx.doi.org/10.1095/biolreprod64.6...
). Any changes can greatly influence early embryonic viability. In particular, glucose is a major fuel source used by the conceptus for growth and development. Animals that exhibited estrus during a FTAI protocol had greater glucose concentrations in the ULF compared to nonestrual animals (Northrop et al., 2018Northrop EJ, Rich JJJ, Cushman RA, McNeel AK, Soares EM, Brooks K, Spencer TE, Perry GA. Effects of preovulatory estradiol on uterine environment and conceptus survival from fertilization to maternal recognition of pregnancy. Biol Reprod. 2018;99(3):629-38. http://dx.doi.org/10.1093/biolre/ioy086. PMid:29672673.
http://dx.doi.org/10.1093/biolre/ioy086...
). When administration of estrogen, corresponding with initiation of estrus, was omitted in ovariectomized, hormone-supplemented ewes, embryo survival following embryo transfer (Miller and Moore, 1976Miller BG, Moore NW. Effect of progesterone and oestradiol on endometrial metabolism and embryo survival in the ovariectomized ewe. Theriogenology. 1976;6(6):636. http://dx.doi.org/10.1016/0093-691X(76)90078-9. PMid:1029671.
http://dx.doi.org/10.1016/0093-691X(76)9...
), uterine weight, uterine protein, RNA to DNA ratio, and the rate of protein synthesis were decreased (Miller et al., 1977Miller BG, Moore NW, Murphy L, Stone GM. Early pregnancy in the ewe: effects of oestradiol and progesterone on uterine metabolism and on embryo survival. Aust J Biol Sci. 1977;30(4):279-88. http://dx.doi.org/10.1071/BI9770279. PMid:603457.
http://dx.doi.org/10.1071/BI9770279...
).
Overall, cows that exhibited standing estrus around the time of FTAI had increased preovulatory concentrations of estradiol (Perry et al., 2005; Perry and Perry, 2008a; Perry and Perry, 2008b), decreased uterine pH (Perry and Perry, 2008a; Perry and Perry, 2008b), increased sperm transport (Larimore et al., 2015Larimore EL, Amundson OL, Bird SL, Funnell BJ, Kruse SG, Bridges GA, Perry GA. Influence of estrus at fixed-time artificial insemination on early embryonic development in beef cattle. J Anim Sci. 2015;93(6):2806-12. http://dx.doi.org/10.2527/jas.2015-8892. PMid:26115268.
http://dx.doi.org/10.2527/jas.2015-8892...
), and increased pregnancy success (Perry et al., 2005Perry GA, Smith MF, Lucy MC, Green JA, Parks TE, MacNeil MD, Roberts AJ, Geary TW. Relationship between follicle size at insemination and pregnancy success. Proc Natl Acad Sci USA. 2005;102(14):5268-73. http://dx.doi.org/10.1073/pnas.0501700102. PMid:15795381.
http://dx.doi.org/10.1073/pnas.050170010...
) compared to nonestrual cows. Consequently, preovulatory concentrations of estradiol may play a major role in the uterine environment as well as the establishment and maintenance of pregnancy.
Subsequent progesterone effects
Two of the most important factors involved in the establishment of pregnancy are the circulating estradiol concentration preceding GnRH-induced ovulation and circulating progesterone concentration on day 7 following ovulation (Atkins et al., 2013Atkins JA, Smith MF, MacNeil MD, Jinks EM, Abreu FM, Alexander LJ, Geary TW. Pregnancy establishment and maintenance in cattle. J Anim Sci. 2013;91(2):722-33. http://dx.doi.org/10.2527/jas.2012-5368. PMid:23148248.
http://dx.doi.org/10.2527/jas.2012-5368...
; Jinks et al., 2013Jinks EM, Smith MF, Atkins JA, Pohler KG, Perry GA, Macneil MD, Roberts AJ, Waterman RC, Alexander LJ, Geary TW. Preovulatory estradiol and the establishment and maintenance of pregnancy in suckled beef cows. J Anim Sci. 2013;91(3):1176-85. http://dx.doi.org/10.2527/jas.2012-5611. PMid:23296810.
http://dx.doi.org/10.2527/jas.2012-5611...
). However, cows with greater estradiol concentrations at the time of GnRH-induced ovulation also have a larger dominant follicle size and greater circulating progesterone concentrations on day 7 (Jinks et al., 2013Jinks EM, Smith MF, Atkins JA, Pohler KG, Perry GA, Macneil MD, Roberts AJ, Waterman RC, Alexander LJ, Geary TW. Preovulatory estradiol and the establishment and maintenance of pregnancy in suckled beef cows. J Anim Sci. 2013;91(3):1176-85. http://dx.doi.org/10.2527/jas.2012-5611. PMid:23296810.
http://dx.doi.org/10.2527/jas.2012-5611...
). Among dairy cows, cows that ovulated small follicles (10 to 15 mm) had decreased concentrations of progesterone on day 7 (Sartori et al., 2006Sartori R, Gumen A, Guenther JN, Souza AH, Caraviello DZ, Wiltbank MC. Comparison of artificial insemination versus embryo transfer in lactating dairy cows. Theriogenology. 2006;65(7):1311-21. http://dx.doi.org/10.1016/j.theriogenology.2005.05.055. PMid:16226307.
http://dx.doi.org/10.1016/j.theriogenolo...
) and cows that were AIed with decreased concentrations of progesterone on day 7 had decreased P/AI, but when embryos were transferred there was no relationship between concentrations of progesterone and P/ET (Sartori et al., 2006Sartori R, Gumen A, Guenther JN, Souza AH, Caraviello DZ, Wiltbank MC. Comparison of artificial insemination versus embryo transfer in lactating dairy cows. Theriogenology. 2006;65(7):1311-21. http://dx.doi.org/10.1016/j.theriogenology.2005.05.055. PMid:16226307.
http://dx.doi.org/10.1016/j.theriogenolo...
; Demetrio et al., 2007Demetrio DG, Santos RM, Demetrio CG, Vasconcelos JL. Factors affecting conception rates following artificial insemination or embryo transfer in lactating Holstein cows. J Dairy Sci. 2007;90(11):5073-82. http://dx.doi.org/10.3168/jds.2007-0223. PMid:17954747.
http://dx.doi.org/10.3168/jds.2007-0223...
). Therefore, the direct impact of increase preovulatory estradiol likely occurs in the oocyte during final maturation or in early embryo development before day 7.
The preovulatory follicular environment is important for preparing follicular cells for luteinization and secretion of progesterone (McNatty et al., 1975McNatty KP, Hunter WM, McNeilly AS, Sawers RS. Changes in the concentration of pituitary and steroid hormones in the follicular fluid of human graafian follicles throughout the menstrual cycle. J Endocrinol. 1975;64(3):555-71. http://dx.doi.org/10.1677/joe.0.0640555. PMid:1133546.
http://dx.doi.org/10.1677/joe.0.0640555...
). McNatty et al. (1979)McNatty KP, Smith DM, Makris A, Osathanondh R, Ryan KJ. The microenvironment of the human antral follicle: interrelationships among the steroid levels in antral fluid, the population of granulosa cells, and the status of the oocyte in vivo and in vitro. J Clin Endocrinol Metab. 1979;49(6):851-60. http://dx.doi.org/10.1210/jcem-49-6-851. PMid:511976.
http://dx.doi.org/10.1210/jcem-49-6-851...
suggested that development of a normal CL depends on a follicle meeting the following criteria: 1) an adequate number of granulosa cells, 2) an adequate number of luteinizing hormone (LH) receptors on the granulosa and theca cells, and 3) granulosa cells capable of synthesizing adequate amounts of progesterone following luteinization. Within granulosa cells, estradiol is reported to cause: 1) increased cellular proliferation (Goldenberg et al., 1972Goldenberg RL, Bridson WE, Kohler PO. Estrogen stimulation of progesterone synthesis by porcine granulosa cells in culture. Biochem Biophys Res Commun. 1972;48(1):101-7. http://dx.doi.org/10.1016/0006-291X(72)90349-X. PMid:5041869.
http://dx.doi.org/10.1016/0006-291X(72)9...
; Parrott and Skinner, 1998Parrott JA, Skinner MK. Developmental and hormonal regulation of keratinocyte growth factor expression and action in the ovarian follicle. Endocrinology. 1998;139(1):228-35. http://dx.doi.org/10.1210/endo.139.1.5680. PMid:9421419.
http://dx.doi.org/10.1210/endo.139.1.568...
; Dupont et al., 2000Dupont S, Krust A, Gansmuller A, Dierich A, Chambon P, Mark M. Effect of single and compound knockouts of estrogen receptors alpha (ERalpha) and beta (ERbeta) on mouse reproductive phenotypes. Development. 2000;127(19):4277-91. http://dx.doi.org/10.1242/dev.127.19.4277. PMid:10976058.
http://dx.doi.org/10.1242/dev.127.19.427...
), 2) formation of gap junctions (Merk et al., 1972Merk FB, Botticelli CR, Albright JT. An intercellular response to estrogen by granulosa cells in the rat ovary; an electron microscope study. Endocrinology. 1972;90(4):992-1007. http://dx.doi.org/10.1210/endo-90-4-992. PMid:5011067.
http://dx.doi.org/10.1210/endo-90-4-992...
; Burghardt and Anderson, 1981Burghardt RC, Anderson E. Hormonal modulation of gap junctions in rat ovarian follicles. Cell Tissue Res. 1981;214(1):181-93. http://dx.doi.org/10.1007/BF00235155. PMid:7471172.
http://dx.doi.org/10.1007/BF00235155...
), 3) increased stimulatory action of follicle-stimulating hormone (FSH) on aromatase activity (Adashi and Hsueh, 1982Adashi EY, Hsueh AJ. Estrogens augment the stimulation of ovarian aromatase activity by follicle-stimulating hormone in cultured rat granulosa cells. J Biol Chem. 1982;257(11):6077-83. http://dx.doi.org/10.1016/S0021-9258(20)65107-9. PMid:6804461.
http://dx.doi.org/10.1016/S0021-9258(20)...
; Zhuang et al., 1982Zhuang L-Z, Adashi EY, Hsueh AJW. Direct enhancement of gonadotropin-stimulated ovarian estrogen biosynthesis by estrogen and clomiphene citrate. Endocrinology. 1982;110(6):2219-21. http://dx.doi.org/10.1210/endo-110-6-2219. PMid:6804221.
http://dx.doi.org/10.1210/endo-110-6-221...
; Reilly et al., 1996Reilly CM, Cannady WE, Mahesh VB, Stopper VS, De Sevilla LM, Mills TM. Duration of estrogen exposure prior to follicle-stimulating hormone stimulation is critical to granulosa cell growth and differentiation in rats. Biol Reprod. 1996;54(6):1336-42. http://dx.doi.org/10.1095/biolreprod54.6.1336. PMid:8724362.
http://dx.doi.org/10.1095/biolreprod54.6...
), 4) enhanced stimulation of progesterone synthesis following gonadotropin stimulation (Welsh et al., 1983Welsh TH Jr, Zhuang L-Z, Hsueh AJW. Estrogen augmentation of gonadotropin-stimulated progestin biosynthesis in cultured rat granulosa cells. Endocrinology. 1983;112(6):1916-24. http://dx.doi.org/10.1210/endo-112-6-1916. PMid:6303748.
http://dx.doi.org/10.1210/endo-112-6-191...
; Fanjul et al., 1984Fanjul LF, Ruiz de Galarreta CM, Hsueh AJ. Estrogen regulation of progestin biosynthetic enzymes in cultured rat granulosa cells. Biol Reprod. 1984;30(4):903-12. http://dx.doi.org/10.1095/biolreprod30.4.903. PMid:6428475.
http://dx.doi.org/10.1095/biolreprod30.4...
), and 5) enhanced acquisition of LH receptors (Kessel et al., 1985Kessel B, Liu YX, Jia XC, Hsueh AJ. Autocrine role of estrogens in the augmentation of luteinizing hormone receptor formation in cultured rat granulosa cells. Biol Reprod. 1985;32(5):1038-50. http://dx.doi.org/10.1095/biolreprod32.5.1038. PMid:2990583.
http://dx.doi.org/10.1095/biolreprod32.5...
; Farookhi and Desjardins, 1986Farookhi R, Desjardins J. Luteinizing hormone receptor induction in dispersed granulosa cells requires estrogen. Mol Cell Endocrinol. 1986;47(1-2):13-24. http://dx.doi.org/10.1016/0303-7207(86)90011-0. PMid:3017785.
http://dx.doi.org/10.1016/0303-7207(86)9...
; Wang and Greenwald, 1993Wang XN, Greenwald GS. Synergistic effects of steroids with FSH on folliculogenesis, steroidogenesis and FSH- and hCG-receptors in hypophysectomized mice. J Reprod Fertil. 1993;99(2):403-13. http://dx.doi.org/10.1530/jrf.0.0990403. PMid:8107022.
http://dx.doi.org/10.1530/jrf.0.0990403...
). Furthermore, luteinized granulosa cells secreted increased progesterone when they were collected from follicles having increased estradiol concentrations compared to granulosa cells from follicles that had decreased estradiol concentrations (McNatty et al., 1979McNatty KP, Smith DM, Makris A, Osathanondh R, Ryan KJ. The microenvironment of the human antral follicle: interrelationships among the steroid levels in antral fluid, the population of granulosa cells, and the status of the oocyte in vivo and in vitro. J Clin Endocrinol Metab. 1979;49(6):851-60. http://dx.doi.org/10.1210/jcem-49-6-851. PMid:511976.
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).
The relationship between pregnancy success and circulating concentrations of progesterone during early pregnancy in cattle is equivocal, as luteal secretion of progesterone is required for the survival of the embryo/fetus (McDonald et al., 1952McDonald LE, Nichols RE, McNutt SH. Study of corpus luteum ablation and progesterone replacement therapy during pregnancy in the cow. Am J Vet Res. 1952;13:446-51. PMid:12996761.). Several studies have reported elevated concentrations of progesterone in pregnant cows compared to nonpregnant cows beginning as early as day 4 (Butler et al., 1996Butler WR, Calaman JJ, Beam SW. Plasma and milk urea nitrogen in relation to pregnancy rate in lactating dairy cattle. J Anim Sci. 1996;74(4):858-65. http://dx.doi.org/10.2527/1996.744858x. PMid:8728008.
http://dx.doi.org/10.2527/1996.744858x...
) or day 6 (Henricks et al., 1971Henricks DM, Lamond DR, Hill JR, Dickey JF. Plasma progesterone concentrations before mating and in early pregnancy in the beef heifer. J Anim Sci. 1971;33(2):450-4. http://dx.doi.org/10.2527/jas1971.332450x. PMid:5570075.
http://dx.doi.org/10.2527/jas1971.332450...
; Erb et al., 1976Erb RE, Garverick HA, Randel RD, Brown BL, Callahan CJ. Profiles of reproductive hormones associated with fertile and nonfertile inseminations of dairy cows. Theriogenology. 1976;5(5):227-42. http://dx.doi.org/10.1016/0093-691X(76)90235-1. PMid:976584.
http://dx.doi.org/10.1016/0093-691X(76)9...
) after insemination. Furthermore, cows that had an earlier rise in progesterone had embryos that were more advanced developmentally, produced more interferon τ (INF-τ), and were capable of inhibiting the prostaglandin F2α release on day 16 after breeding (Kerbler et al., 1997Kerbler TL, Buhr MM, Jordan LT, Leslie KE, Walton JS. Relationship between maternal plasma progesterone concentration and interferon-tau synthesis by the conceptus in cattle. Theriogenology. 1997;47(3):703-14. http://dx.doi.org/10.1016/S0093-691X(97)00028-9. PMid:16728022.
http://dx.doi.org/10.1016/S0093-691X(97)...
; Mann et al., 1998Mann GE, Lamming GE, Fisher PA. Progesterone control of embryonic interferon tau production during early pregnancy in the cow. J Reprod Fertil. 1998;21:37.; Mann and Lamming, 2001Mann GE, Lamming GE. Relationship between maternal endocrine environment, early embryo development and inhibition of the luteolytic mechanism in cows. Reproduction. 2001;121(1):175-80. http://dx.doi.org/10.1530/rep.0.1210175. PMid:11226041.
http://dx.doi.org/10.1530/rep.0.1210175...
). Similarly, cows supplemented with progesterone during early gestation had advanced endometrial expression of several genes associated with uterine secretion and conceptus development (Forde et al., 2009Forde N, Carter F, Fair T, Crowe MA, Evans AC, Spencer TE, Bazer FW, McBride R, Boland MP, O’Gaora P, Lonergan P, Roche JF. Progesterone-regulated changes in endometrial gene expression contribute to advanced conceptus development in cattle. Biol Reprod. 2009;81(4):784-94. http://dx.doi.org/10.1095/biolreprod.108.074336. PMid:19553605.
http://dx.doi.org/10.1095/biolreprod.108...
; Forde et al., 2010Forde N, Spencer TE, Bazer FW, Song G, Roche JF, Lonergan P. Effect of pregnancy and progesterone concentration on expression of genes encoding for transporters or secreted proteins in the bovine endometrium. Physiol Genomics. 2010;41(1):53-62. http://dx.doi.org/10.1152/physiolgenomics.00162.2009. PMid:19996158.
http://dx.doi.org/10.1152/physiolgenomic...
). It is speculated that progesterone induces changes in endometrial gene expression, leading to changes in uterine histotroph composition (Spencer et al., 2008Spencer TE, Sandra O, Wolf E. Genes involved in conceptus-endometrial interactions in ruminants: insights from reductionism and thoughts on holistic approaches. Reproduction. 2008;135(2):165-79. http://dx.doi.org/10.1530/REP-07-0327. PMid:18239047.
http://dx.doi.org/10.1530/REP-07-0327...
). Bartol et al. (1981)Bartol FF, Thatcher WW, Lewis GS, Bliss EL, Drost M, Bazer FW. Effect of estradiol-17beta on PGF and total protein content in bovine uterine flushings and peripheral plasma concentration of 13, 14-dihydro-15-keto-PGF(2alpha). Theriogenology. 1981;15(4):345-58. http://dx.doi.org/10.1016/0093-691X(81)90002-9. PMid:16725594.
http://dx.doi.org/10.1016/0093-691X(81)9...
determined that protein accumulation within the uterine lumen is related to duration of progesterone stimulation. However, direct supplementation of progesterone following insemination has produced varying results. Some studies have reported a 10 to 60% increase in P/AI following progesterone supplementation (Robinson et al., 1989Robinson NA, Leslie KE, Walton JS. Effect of treatment with progesterone on pregnancy rate and plasma concentrations of progesterone in Holstein cows. J Dairy Sci. 1989;72(1):202-7. http://dx.doi.org/10.3168/jds.S0022-0302(89)79098-6. PMid:2925946.
http://dx.doi.org/10.3168/jds.S0022-0302...
; Macmillan and Peterson, 1993Macmillan KL, Peterson AJ. A new intervagional progesterone releasing device for cattle (CIDR-B) for oestrous synchronisation, increasing pregnancy rates and the treatment of post-partum anestrus. Anim Reprod Sci. 1993;33(1-4):1-25. http://dx.doi.org/10.1016/0378-4320(93)90104-Y.
http://dx.doi.org/10.1016/0378-4320(93)9...
), but others using sheep (Diskin and Niswender, 1989Diskin MG, Niswender GD. Effect of progesterone supplementation on pregnancy and embryo survival in ewes. J Anim Sci. 1989;67(6):1559-63. http://dx.doi.org/10.2527/jas1989.6761559x. PMid:2768114.
http://dx.doi.org/10.2527/jas1989.676155...
; Nephew et al., 1994Nephew KP, Cardenas H, McClure KE, Ott TL, Bazer FW, Pope WF. Effects of administration of human chorionic gonadotropin or progesterone before maternal recognition of pregnancy on blastocyst development and pregnancy in sheep. J Anim Sci. 1994;72(2):453-8. http://dx.doi.org/10.2527/1994.722453x. PMid:8157530.
http://dx.doi.org/10.2527/1994.722453x...
) and cattle (Walton et al., 1990Walton JS, Halbert GW, Robinson NA, Leslie KE. Effects of progesterone and human chorionic gonadotrophin administration five days postinsemination on plasma and milk concentrations of progesterone and pregnancy rates of normal and repeat breeder dairy cows. Can J Vet Res. 1990;54(3):305-8. PMid:2379109.; Van Cleeff et al., 1991Van Cleeff J, Drost M, Thatcher WW. Effects of postinsemination progesterone supplementation on fertility and subsequent estrous response on dairy heifers. Theriogenology. 1991;36(5):795-807. http://dx.doi.org/10.1016/0093-691X(91)90345-E. PMid:16727048.
http://dx.doi.org/10.1016/0093-691X(91)9...
; Monteiro et al., 2015Monteiro PL Jr, Nascimento AB, Pontes GC, Fernandes GO, Melo LF, Wiltbank MC, Sartori R. Progesterone supplementation after ovulation: effects on corpus luteum function and on fertility of dairy cows subjected to AI or ET. Theriogenology. 2015;84(7):1215-24. http://dx.doi.org/10.1016/j.theriogenology.2015.06.023. PMid:26255222.
http://dx.doi.org/10.1016/j.theriogenolo...
) have reported no benefit or even decreased P/ET (Monteiro et al., 2015Monteiro PL Jr, Nascimento AB, Pontes GC, Fernandes GO, Melo LF, Wiltbank MC, Sartori R. Progesterone supplementation after ovulation: effects on corpus luteum function and on fertility of dairy cows subjected to AI or ET. Theriogenology. 2015;84(7):1215-24. http://dx.doi.org/10.1016/j.theriogenology.2015.06.023. PMid:26255222.
http://dx.doi.org/10.1016/j.theriogenolo...
) of progesterone supplementation on pregnancy success.
Atkins et al. (2013)Atkins JA, Smith MF, MacNeil MD, Jinks EM, Abreu FM, Alexander LJ, Geary TW. Pregnancy establishment and maintenance in cattle. J Anim Sci. 2013;91(2):722-33. http://dx.doi.org/10.2527/jas.2012-5368. PMid:23148248.
http://dx.doi.org/10.2527/jas.2012-5368...
reported that estradiol concentrations at GnRH-induced ovulation (day 0) affected day 27 P/ET of recipient cows independently of progesterone concentrations on day 7. Furthermore, work from our laboratory has reported that when ovulatory follicle size was controlled, there was no difference in day 10 CL weight, circulating concentrations of progesterone, or expression of luteal steroidogenic enzymes between cows exhibiting standing estrus and nonestrual cows (Fields et al., 2012Fields SD, Gebhart KL, Perry BL, Gonda MG, Wright CL, Bott RC, Perry GA. Influence of standing estrus before an injection of GnRH during a beef cattle fixed-time AI protocol on LH release, subsequent concentrations of progesterone, and steriodogenic enzyme expression. Domest Anim Endocrinol. 2012;42(1):11-9. http://dx.doi.org/10.1016/j.domaniend.2011.08.002. PMid:22019093.
http://dx.doi.org/10.1016/j.domaniend.20...
). Plasma progesterone concentrations on day 7 (day 0 = induced ovulation) can be positively associated with the probability of pregnancy only when preovulatory estradiol concentrations were low. The association between plasma progesterone concentrations on day 7 and pregnancy was not observed when concentrations of preovulatory estradiol were high (Ciernia et al., 2021Ciernia LA, Perry GA, Smith MF, Rich JJ, Northrop EJ, Perkins SD, Green JA, Zezeski AL, Geary TW. Effect of estradiol preceding and progesterone subsequent to ovulation on proportion of postpartum beef cows pregnant. Anim Reprod Sci. 2021;227:106723. http://dx.doi.org/10.1016/j.anireprosci.2021.106723. PMid:33621845.
http://dx.doi.org/10.1016/j.anireprosci....
). Interestingly, on day 17, pregnant cows were reported to have greater progesterone concentrations compared to nonpregnant cows when females had: 1) decreased preovulatory estradiol and decreased subsequent progesterone, 2) decreased preovulatory estradiol and normal subsequent progesterone, or 3) increased preovulatory estradiol and decreased subsequent progesterone. However, among cows classified as having increased preovulatory estradiol and normal subsequent progesterone, progesterone concentrations on day 17 did not differ between pregnant and nonpregnant cows (Ciernia et al., 2021Ciernia LA, Perry GA, Smith MF, Rich JJ, Northrop EJ, Perkins SD, Green JA, Zezeski AL, Geary TW. Effect of estradiol preceding and progesterone subsequent to ovulation on proportion of postpartum beef cows pregnant. Anim Reprod Sci. 2021;227:106723. http://dx.doi.org/10.1016/j.anireprosci.2021.106723. PMid:33621845.
http://dx.doi.org/10.1016/j.anireprosci....
). Therefore, improved pregnancy success among cattle with elevated preovulatory concentrations of estradiol are likely independent of the impact of progesterone on the uterine environment during the subsequent estrous cycle.
Early embryo development and survival
When estrogen administration, corresponding with initiation of estrus, was omitted in ovariectomized, hormone-supplemented ewes, embryo survival following embryo transfer was decreased (Miller and Moore, 1976Miller BG, Moore NW. Effect of progesterone and oestradiol on endometrial metabolism and embryo survival in the ovariectomized ewe. Theriogenology. 1976;6(6):636. http://dx.doi.org/10.1016/0093-691X(76)90078-9. PMid:1029671.
http://dx.doi.org/10.1016/0093-691X(76)9...
). In a recent study from our laboratory, ovariectomized cows received exogenous hormones to mimic the luteal phase and luteolysis, and then received either ECP, EB, or no treatment (CON) to mimic the preovulatory period. Ovulation was stimulated with administration of GnRH (100 µg; day 0), and embryos were transferred on day 7. Cows that received preovulatory estradiol exposure (ECP or EB) had greater pregnancy establishment and embryonic survival compared to animals not receiving preovulatory estradiol exposure (4%, 29%, and 21% for CON, EB, and ECP, respectively; (Madsen et al., 2015Madsen CA, Perry GA, Mogck CL, Daly RF, MacNeil MD, Geary TW. Effects of preovulatory estradiol on embryo survival and pregnancy establishment in beef cows. Anim Reprod Sci. 2015;158:96-103. http://dx.doi.org/10.1016/j.anireprosci.2015.05.006. PMid:26022231.
http://dx.doi.org/10.1016/j.anireprosci....
). Additionally, preovulatory estradiol has been reported to have a positive impact on conceptus development, such that cows exhibiting estrus have increased conceptus length compared to nonestrual cows on day 19 of gestation (Davoodi et al., 2016Davoodi S, Cooke RF, Fernandes AC, Cappellozza BI, Vasconcelos JL, Cerri RL. Expression of estrus modifies the gene expression profile in reproductive tissues on day 19 of gestation in beef cows. Theriogenology. 2016;85(4):645-55. http://dx.doi.org/10.1016/j.theriogenology.2015.10.002. PMid:26525398.
http://dx.doi.org/10.1016/j.theriogenolo...
). Since a larger conceptus would occupy a greater amount of luminal space, INF-τ stimulated gene expression may be enhanced, which may be beneficial to pregnancy. Furthermore, in day 19 conceptuses of females expressing estrus, there were four genes that were differentially expressed (ISG15, PLAU, BMP15, and EEF1A1; Davoodi et al., 2016Davoodi S, Cooke RF, Fernandes AC, Cappellozza BI, Vasconcelos JL, Cerri RL. Expression of estrus modifies the gene expression profile in reproductive tissues on day 19 of gestation in beef cows. Theriogenology. 2016;85(4):645-55. http://dx.doi.org/10.1016/j.theriogenology.2015.10.002. PMid:26525398.
http://dx.doi.org/10.1016/j.theriogenolo...
). These results indicate that changes in reproductive gene expression around the preimplantation period were favorable towards the elongating conceptus given the expression of estrus near FTAI.
Conclusion
These studies indicate not only an importance in occurrence and timing of increasing preovulatory concentrations of estradiol, but also and that increasing estradiol concentrations by supplementation may not be sufficient to increase fertility. Increased production of estradiol by the preovulatory follicle may be required to enhance fertility through the regulation of sperm transport, fertilization, oviductal secretions, the uterine environment, and embryo survival.
Acknowledgements
This work was partially funded by Multistate Hatch (project 9835).
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Financial support: This project was funded in part by the Multistate Hatch project 9835.
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How to cite: Perry GA, Ketchum JN, Quail LK. Importance of preovulatory estradiol on uterine receptivity and luteal function. Anim Reprod. 2023;20(2):e20230061. https://doi.org/10.1590/1984-3143-AR2023-0061
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Publication Dates
-
Publication in this collection
04 Sept 2023 -
Date of issue
2023
History
-
Received
04 May 2023 -
Accepted
18 July 2023