The endometrium undergoes cyclic changes each month, under the overall control of fluctuating levels of estrogen and progesterone. This hormone dependent endometrial remodelling is a continuum of structural and functional changes that make up the menstrual cycle. The endometrium regenerates and grows under the influence of estrogen during the proliferative phase of the cycle, while during the secretory phase it undergoes secretory transformation under the combined influence of estrogen and progesterone. In the absence of pregnancy, the abrupt fall in the levels of circulating estrogen and progesterone leads to the functional layer of the endometrium being shed during menstruation. The typical menstrual cycle lasts for about 28 days, although its normal length can vary from 21 to 35 days.
The significant histological, biological and physiological changes that occur during the proliferative, secretory and menstrual phases of the cycle are ultimately the result of changes that occur at the level of gene transcription. Although the use of chronological and histological dating has improved the understanding of anatomical changes within the endometrium during the menstrual cycle, most of the molecular pathways that are responsible for these changes remain unknown. Viewing the broader transcriptional map of the endometrium throughout the menstrual cycle is likely to enhance overall understanding of endometrial function as well as giving an insight into the molecular processes that initiate histological changes throughout the menstrual cycle.
Implantation is an early and critical event in human pregnancy. At 6 – 7 days post-fertilization, the free-floating blastocyst is liberated from its zona pellucida, attaches to the endometrial lining and invades the underlying stroma. The dynamics of these spatial interactions depend on a strict temporal sequence of estradiol (E2) priming that induces endometrial proliferation followed by progesterone differentiation, resulting in the establishment of a ‘window of implantation. Although there is still not full agreement as to the exact timing of embryo implantation in the human, clinical studies suggest that the window is temporally confined to days 20– 24 of a normal, ovulatory cycle. Data from the assisted reproduction setting have demonstrated that the optimal time for embryo transfer to the uterus is 3 days, the so-called ‘window of receptivity. For 2 day old IVF embryos, the window extends between the third to the fifth day following treatment with exogenous hormones (E2 and progesterone). The dynamics of the transition of the nonreceptive to a receptive endometrium are poorly understood, but in humans, an increased rate of spontaneous abortions was observed with human embryo transfers performed beyond the putative window of receptivity. The correct temporal-spatial elaboration and balance of various growth factors, cytokines, lipid mediators, transcription factors and other putative molecules regulated by steroid hormones is thought to play an important role in uterine preparation for implantation. Estrogen and progesterone actions are primarily mediated by their nuclear receptors, estrogen receptor (ER) ERa and ERb and progesterone receptor (PR) PR-A and PR-B respectively. The rise in progesterone during the early secretory phase is responsible for the expression of a myriad of proteins, many of which appear to be critical for normal implantation. This effect may be direct (acting through PR in the epithelial cells) or indirect by stimulation of stromal factors that, in turn, induce specific epithelial gene products. In the pre-genomic era, a ‘one-by-one approach was adopted to investigate gene expression during the window of implantation. However, it is more realistic to view the process of normal implantation as a condition of equilibrium in the up- and down-regulation of diverse endometrial genes under control of steroid hormones and probably other local (paracrine and autocrine) regulatory factors. Altered expression of endometrial regulatory genes/proteins has been postulated as an underlying cause of infertility and recurrent pregnancy loss. A genomic-wide approach using microarray technology now allows us to investigate global gene expression during the various phases of endometrial development under physiological and pathological condition.
Many women undergoing IVF are unable to get pregnant, even after transferring good quality embryos. Although a good quality embryo is an important starting point, it is also important to transfer the embryo into a uterus that is ready to receive the embryo.
The timing of embryo transfer must coordinate with your body´s menstrual cycle, neither too early nor too late, but at just the right time. For most women, the best time to transfer an embryo is the same, but for some women, it can be different.