Hormones and Growth Factors

Although the mouse blastocyst is capable of metabolizing exogenous steroid hormones (225), there is limited data on the direct action of hormones on the early embryo (226-229). Certainly, estradiol appears to have a direct negative impact on mouse embryo development (230,231). However, prolactin at a concentration of 300 ng/mL, has been shown to improve the rate of blastocyst formation from cultured 2-cell mouse embryos (232). Available evidence indicates that the effects of maternal hormones on the developing embryo are mediated through the cells of the reproductive tract (233).

Figure 4 Effect of hyaluronate in the transfer medium on subsequent viability of cultured mouse blastocysts. Mouse zygotes were cultured to the blastocyst stage in sequential media DM2/DM3 without protein or macromolecule supplement. Blastocysts were placed in either medium DM3 or DM3 containing hyaluronate and transferred to pseudopregnant recipients and subsequent viability was assessed. Open bars represent medium DM3 without protein or macromolecule. Solid bars represent medium DM3 supplemented with hyaluronate. Note: *Significantly different to medium DM3 (P < 0.05). "Significantly different to medium DM3 (P < 0.01). Source: From Ref. 221.

Implantation reïdl development

Figure 4 Effect of hyaluronate in the transfer medium on subsequent viability of cultured mouse blastocysts. Mouse zygotes were cultured to the blastocyst stage in sequential media DM2/DM3 without protein or macromolecule supplement. Blastocysts were placed in either medium DM3 or DM3 containing hyaluronate and transferred to pseudopregnant recipients and subsequent viability was assessed. Open bars represent medium DM3 without protein or macromolecule. Solid bars represent medium DM3 supplemented with hyaluronate. Note: *Significantly different to medium DM3 (P < 0.05). "Significantly different to medium DM3 (P < 0.01). Source: From Ref. 221.

The role of growth factors in the development of the preimplantation mammalian embryo has been the subject of intensive research in recent years resulting in a wealth of literature. Studies on the embryos from several mammalian species have identified the transcripts for the ligand and/or receptor for the following: insulin, IGF-I, IGF-II, EGF, TGF-a, TGF-p, PDGF-A, FGF-4, LIF. These growth factors have been shown to stimulate either cleavage, amino acid transport, protein synthesis, blastocoel formation, or ICM development. Several detailed reviews on the action of specific growth factors have now been published (234-239). In the human there is growing evidence that growth factors are present within the female tract and embryo. Martin et al. (240) demonstrated that adding heparin-binding epidermal growth factor to the culture medium for human embryos significantly increased both blastocyst development and subsequent hatching.

Similarly, the addition of IGF-I stimulated blastocyst formation and increased development of the ICM (241). Therefore, growth factors are potential regulators of human embryo development (242-245). However, it is possible that synergies may exist between two or more growth factors and that simply adding an individual growth factor may not result in a response by the embryo. Furthermore, many growth factors exhibit pleio-tropic properties such that cells can be directed down certain pathways of differentiation, even improper pathways, by exposure to inappropriate growth factors.

Platelet-activating factor (PAF) has been implicated as one of the earliest embryonic signals produced and its appearance, or otherwise, in culture medium associated with viability. Furthermore, it has also been shown that the addition of exogenous PAF is associated with an increase in pregnancy rate (246).

However, as most human embryos are currently transferred around the 2- to 8-cell stage, it is likely that expression of almost all growth factor receptors occurs after the embryo is transferred to the female tract. Due to the high costs of growth factors for media supplementation and the lack of data on their role in human embryo development, it is considered prudent that they are not included in media formulations for clinical IVF. With the advent of culture systems for prolonged embryo culture, the inclusion of growth factors in culture media will have to be re-evaluated, though extreme care and extensive animal studies are required, especially at the molecular level.

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