From lab to livestock: Harnessing hormones to revolutionize in vitro embryo development

Introduction

In recent years, optimization and improvement of in vitro oocyte maturation and embryo production in livestock species has been focused mainly due to increased infertility problems. The use of various assisted reproductive technologies like in vitro maturation (IVM), in vitro fertilization (IVF), and in vitro embryo culture (IVC) has been progressively increasing for enhanced in vitro embryo production (IVEP). Yet, the transfer of yielded embryos is very low. Many factors are responsible for the success of IVP embryos, including embryonic factors, maternal/paternal factors, and in-vitro culture factors like light exposure, media composition, and temperature fluctuations (Ealy et al., 2019; Hansen, 2020) [30,36] . Most in vitro culture media do not contain formulations like hormones, growth factors, and cytokines that mimic the oviduct during the first 7 to 8 days post-estrus (Martins et al., 2018) [53] . Supplementation of hormones in livestock embryo culture media plays a significant role in mimicking in vivo conditions, enhancing the maturation of oocytes, and promoting embryonic development, including the quality and development of blastocysts (Choi et al., 2024; Bahrami and Cottee, 2022; Shabankareh et al., 2011) [23,7,38] . Progesterone (P4) is crucial for maintaining pregnancy and plays a role in uterine receptivity, fertilization, and embryonic development (Barrera, Avila, and Díaz, 2007; Loutradis et al., 2008) [10,49] . Estrogen, particularly estradiol (E2), is essential for oocyte maturation and has a complex role in IVM (Bevers et al., 1997) [14] . Guo et al., 2009 [34] reported that E2 increases the proportion of oocytes that undergo nuclear maturation. Thyroid hormones are important for post implantation-development and may improve embryo development, and hatching rates, and reduce apoptosis in cryopreserved embryos (Ashkar et al., 2010; Medina, Buttler, and Gilbert, 2014) [6,1] . The addition of gonadotropin like follicle-stimulating hormone (FSH) can improve nuclear maturation in oocytes, meiotic resumption, and early embryonic developmental competency (Pereira et al., 2013) [60] . Most studies reported that supplementation of FSH in IVM media enhances the maturation rates in bovine (Sirard et al., 1988; Calder et al., 2003; Takada et al., 2012) [71,18,74] . This review summarizes the importance of supplementing different hormones for in vitro embryo production in various livestock species.

Progesterone

Progesterone is a 21-carbon cholesterol-derived steroid hormone synthesized within several cell types like corpus luteum, adrenal gland, and placenta (Golub et al., 2006) [33] and too much lower levels in Leydig cells (Rossato, 1999) [62] and adipose tissues (Zhang et al., 2009) [34] . P4 secretion from the ovary regulates gonadotropin secretion (Mahesh, 1987) [51] , influences mating behavior (Dudley, 1980) [28] , and stimulates uterine and placental development (Spencer, 2004) [73] . P4 is essential for high rates of embryogenesis (Dumesic et al., 2003) [29] , embryo implantation, and sustaining pregnancy (Bulletti et al., 2022) [15] . Some studies suggest that cocultured cumulus cells (Shimada and Terada, 2002) [67] produce P4 that enhances the in vitro maturation rates and blastocyst development in cattle (Ryan et al., 1992) [64] , sheep (Kyasari et al., 2012) [43] , goat (Wang et al., 2011) [80] and porcine (Yoon et al., 2015) [83] . Yuan et al., 2016 [85] reported that P4 inhibits the apoptosis of blastocyst by enhancing the quality of porcine oocytes and minimizing the polyadenylation. The in vitro supplementation of P4 had no positive effect on the bovine secondary follicular growth but it enhanced the gene expression levels of GDF9 and cyclin B1 in bovine oocytes (Paulino et al., 2020) [58] . P4 and EGF did not show any synergic effect in bovine preantral follicles. Progesterone mediates its effect by interacting with genomic P4 receptors A (nPR-A) and B (nPR-B) (Bain et al., 2007) [9] in female reproductive organs. However, classical activation of genomic receptors is a slow and complex process as nPR expression in the follicle is speciesspecific (Lodde et al., 2023) [48] . In sheep, nPR is expressed in the granulose cells of growing antral follicles (Ding et al., 2022) [27] and in granulosa cells of primordial, primary, secondary, and tertiary follicles in cattle (Haeseleer, Simoens, and Broeck, 2007) [25] . P4 interaction with nongenomic membrane progestin receptors (NPR α, β, and γ) (Zhu et al., 2003) [87] and non-genomic receptor membrane components 1 (PGRMC 1) and 2 (PGRMC 2) had shown rapid signaling events void of the transcriptome (Cahill, 2007) [16] . Aparicio et al., 2011 [3] reported the localization of both genomic and non-genomic P4 receptors in bovine cumulus-oocyte complexes (COCs) and supplementation of P4 enhanced the maturation rates in bovine. PGRMC 1, the most abundant P4 non-genomic receptor membrane transcripts were found in bovine morula (Sang et al., 2021) [65] and porcine embryos (Cho et al., 2020) [22] depicted their role in the cleavage by regulating cell division (Lodde et al., 2022) [47] . Larson et al., 2011 [44] reported that in vitro supplementation of P4 did not improve the embryo characteristics in the in vitro-produced bovine embryos. Ferguson, Kesler, and Godke, 2012 reported the positive effect of P4 supplementation for the in vitro production of bovine embryos. There are a lot of gaps in knowledge to determine the optimum concentration of in vitro supplementation of P4 due to different genomic and nongenomic progesterone receptors in livestock species.

17β-Estradiol 17β-Estradiol (E2) is an isomer of estradiol produced mainly in the ovaries, promotes the growth of the uterine lining, and enhances the LH surge for ovulation. It also regulates the release of pituitary hormones through negative feedback. The proportion of E2 produced in testes is much lower. Maksura et al., 2021 [52] reported the effect of 17β-Estradiol on nuclear maturation of buffalo and goat oocytes. In Buffalo, the MetaphaseⅡ (MⅡ) stage oocytes number progressed with the increased supplementation of 17β-Estradiol in a concentration-dependent manner. Still, in the goats, treatment with 1 μg/ml of 17β-Estradiol increased the proportions of MⅡ stage oocytes than the control and other treatment groups. Supplementation of 1 μg/ml of 17β-Estradiol is considered to mimic the presence of estradiol in the preovulatory follicle in vivo. 1 μg/ml of E2 is commonly supplemented in an in-vitro maturation medium for the maturation of oocytes in bovine (Beker et al., 2002) [12] , ovine (Leoni et al., 2007, Catala et al., 2012, Wang et al., 2013) [45,20,81] , and caprine (Hammami et al., 2013) [35] . 17β-Estradiol also enhances the cumulus cell expansion as well as the nuclear and cytoplasmic maturation of oocytes in bovine (Sirotkin, 1992) [72] , caprine (Pawshe et al., 1996) [59] , equine (Carneiro et al., 2001) [19] , and porcine (Kubo et al., 2015) [42] . Vlu and Kuz'mina, 2005 studied the interaction of 17β-Estradiol with prolactin and theophylline release of calcium ions from intracellular stores of porcine oocytes. E2 supports the growth and viability of oocyte granulosa complexes in bovine (Taketsuru et al., 2012) [75] . Showed a significant inhibitory effect of 10-100 μg/ml concentration of 17β-Estradiol on the progression of oocyte maturation to MetaphaseⅡ (MⅡ) in prepubertal goats. No effect was observed with 1 μg/ml E2 supplementation on the progression of in-vitro matured oocytes to MⅡ stage compared to control groups. Transient supplementation of E2 improved the developmental competence of oocytes and enhanced the blastocyst formation rates in porcine (Kim et al., 2012) [41] . In conclusion, supplementation with 1 μg/ml of E2 is the best concentration recommended in the in-vitro development of oocytes and embryos in several livestock species.

Follicle-stimulating hormone (FSH)

Follicle-stimulating hormone (FSH) is a gonadotropin and a glycopeptide protein hormone (Cahoreau, Klett, and Combarnous, 2015) [17] synthesized and secreted by the anterior pituitary gland. In several vertebrates, FSH is essential in reproductive processes (Ulloa-Aguirre et al., 1999; Loof et al., 2001) [77,26] . FSH consists of two polypeptide chains (α and β subunit) associated noncovalently and exhibit no biological activity when present alone; however, they regain this activity upon recombination. FSH is involved in the development process, like folliculogenesis and steroidogenesis in the ovary (Santi et al., 2018) [66] , by acting on the ovarian granulosa cells and the sertoli cells in the testis. Supplementation of FSH in the in vitro maturation studies showed improved fertilization rates, enhanced embryonic developmental competency (Izadyar, Zeinstra, and Bevers, 1998) [37] , and cumulus cell expansion (Calder et al., 2003) [18] . The action of FSH on oocyte maturation is poorly understood, but many reports have suggested that its action is mediated by cumulus cells. Observations have shown that FSH receptor mRNA is present in granulosa and cumulus cells but not detected in oocytes isolated from bovine antral follicles (vanTol et al., 1996) [78] . Ferreira et al., 2016 [32] reported that in vitro supplementation of FSH (100 μg/ml) with 10 μg/ml insulin improved follicular and oocyte growth in caprine. Bahrami, Morris, and Day, 2019 [8] reported that supplementation of 1μg/ml FSH to the culture media enhanced the number of metaphase Ⅱ oocytes in bovine. in vitro supplementation of FSH (10 U/ml), LH (10 U/ml), and glutathione (GSH) enhanced the maturation rates of Grade B and Grade C oocytes in ovine (Ren et al., 2021) [61] . No significant increment was observed in Grade A oocyte maturation rates. Takada et al., 2012 [74] reported 0.5-1 μg/ml FSH as the best-suited concentration for in vitro developmental competency of bovine embryos. FSH (20 μg/ml) supplementation in oocyte maturation media resulted in higher MII rates (Roth and Hansen, 2005) comparable to 0.05 IU/ml FSH (Beker, Colenbrander, and Bevers, 2002) [12] . Singha et al., 2015 reported that 5 μg/ml FSHsupplemented media showed significantly higher maturation rates than the gonadotrophin-supplemented counterpart in indigenous zebu cattle. FSH is essential for in vitro maturation of oocytes and cumulus cell expansion in buffaloes (Pandey et al., 2010) [56] . Some studies reported no increment in maturation rates after supplementing with FSH (Younis et al., 1989) [84] . FSH supplementation enhances the in vitro maturation rates. It helps in the activation and survival of preantral follicles in ovarian tissues of equine (FSH-50 ng/ml) (Aguair et al., 2016) [2] , caprine (FSH-50 ng/ml) (Celestino et al., 2011; Barros et al., 2013) [21,11] , ovine (FSH-100 ng/ml) (Patel et al., 2013) [57] , and bovine (FSH-50 ng/ml) (McLaughlin et al., 2010) [54] . Widayati and Pangestu, 2020 [82] studied the effect of supplementation of FSH (50 IU/L) on in vitro maturation and embryonic development of caprine. In conclusion, FSH enhances the preantral follicular development, in vitro maturation of oocytes, and developmental competency of embryos in livestock species. No fixed concentration is found for the individual supplementation of FSH due to species variation and different research contexts.

Triiodothyronine and Tetraiodothyronine

Triiodothyronine (T 3 ) and Tetraiodothyronine (T 4 ) are the two tyrosine-containing thyroid hormones produced by the thyroid glands and are primarily responsible for metabolism regulation. T 3 and T 4 are produced by thyroid-stimulating hormone (TSH) released from the anterior pituitary gland (Li et al., 2021) [46] . Both T 3 and T 4 with their active metabolites are essential for promoting the development of the brain, supporting the functions of heart, muscle, and bone health, and regulating metabolic rates in the body (Kim and Mohan, 2013; Mullur et al., 2014) [40,55] . Thyroid hormone supplementation in the culture media plays a vital role in the enhancement of in vitro maturation, fertilization, and blastocyst development in various livestock species. Asadpour et al., 2021 [5] reported that the addition of thyroid hormone to the IVM medium had controversial effects on the development of ovine oocytes. The lower dose of T 3 (10 ng/ml) reduced the apoptosis rate in blastocysts, and the higher dose (100 ng/ml) had detrimental effects significantly (p<0.001) decreasing cumulus expansion and blastocyst rates compared to control and other treatment groups. Some studies reported that in vitro supplementation of culture media with thyroxine hormone at 100 ng/ml showed a significant increase in cleavage rates and early embryo development (Singh et al., 2020) [69] . The cleavage and morula rates were significantly higher (p<0.05) in the T 3 (50 ng/ml and 100 ng/ml) supplemented groups, suggesting that triiodothyronine may have increased the morula rate after fertilization (Singh et al., 2017) [68] . Conducted a study to evaluate the effect of 1,000 ng/ml recombinant bovine somatotropin (rbST) and 20 ng/ml thyroxine (T 4 ), which did not exert beneficial effects on the survival and growth of bovine preantral ovarian follicles (PAOF) cultured in vitro. Combinatorial effect of T 3 (50 ng/ml) and T 4 (50 ng/ml) in the IVC improved embryos' developmental competency in bovine (Ashkar et al., 2010) [6] . Costa et al., 2013 [24] reported that adding 50 nM and 100 nM T 3 to the IVM medium significantly increased (p<0.05) the rate of hatched blastocysts compared to the control and 25 nM groups. The thyroid hormone-treated embryos exhibited a significant (p<0.05) increase in blastocyst formation and hatching rates, with embryo quality demonstrated by higher total cell counts and reduced proportions of apoptotic cells (Ashkar et al., 2010) [6] . Supplementation of T 4 (1 µg/ml) combined with follicle-stimulating hormone (FSH), insulin growth factor 1 (IGF-I), and growth hormone (GH) enhanced the maturation of oocytes to the Metaphase-II stage in preantral follicles of ovine (Arunakumari, Shanmugasundaram, and Rao, 2010) [4] . Bera et al., 2024 [13] reported the combination of T 3 (100 ng/ml) and T 4 (100 ng/ml) enhanced the developmental competence of immature cattle oocytes and increased the blastocyst rate. The optimum concentration of T 3 and T 4 for the development of embryos in bovine ranges between 50-100 ng/ml. Very few studies reported the in vitro supplementation of T 3 and T 4 in porcine, caprine, and ovine embryo development.

Conclusion

In conclusion of this overview, the supplementation of different hormones in the in vitro culture media has shown promising results in the in vitro maturation of oocytes, enhancing the embryonic developmental competency and promoting a higher success rate of in vitro embryo production. Including these hormones in the maturation medium can improve the nuclear and cytoplasmic maturation of oocytes, enhancing the quality of oocytes and influencing the success of embryogenesis. However, it is important to note that the supplementation of these hormones in the culture medium needs to be optimized in combinations and concentrations, as they may vary based on individual circumstances such as age, breed, species, and reproductive history. Further studies need to be done to understand the mechanism of their effects on in vitro embryo development.

Author contributions

Writing-Original draft preparation, S.B., R.S., S.D; reviewing and editing-S.B., R.S. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement Not applicable

Informed Consent Statement

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