Effects of Progesterone on Endometrium, Egg Cells and Embryo Development

The Effect of Progesterone on Endometrium

• Molecular Biology Mechanism

The progesterone receptor is a special high-affinity nuclear receptor that can directly regulate the expression of a large number of endometrial genes. It has two subtypes, type A and type B, which are derived from the transcription and translation process of a single gene. Each subtype is capable of direct action. Progesterone exerts its influence on the endometrium through this receptor. In addition, its effect also depends on other signaling factors and transcription factors. Progesterone can cause decidualization of the endometrium. However, the entire decidualization process requires progesterone receptors and cyclic adenosine monophosphate (cAMP) to transmit signals. cAMP induces the expression of many transcription factors, and these transcription factors can directly affects or modulates progesterone receptors. These transcription factors and progesterone receptors together form a multimeric complex that causes gene transcription and translation into a decidualization phenotype. Without the interaction between these cells signaling factors and transcription factors, progesterone would be unable to exert its effects on the endometrial matrix. Progesterone-induced decidualization of the endometrium may serve as a biosensor between the embryo and the uterus during early embryo implantation.

Figure 2. Signaling cross talk drives progesterone-dependent endometrial receptivity and decidualization.(Maurya VK, et al.; 2021)

• Endometrial Receptivity

Progesterone regulates the cyclic proliferation and decidualization of the endometrium during the menstrual cycle, improves the receptivity of the endometrium, and facilitates embryo implantation. Appropriate progesterone levels after fertilization not only promote embryo implantation, but also maintain pregnancy by promoting endometrial development and inhibiting myometrial contraction. However, the time window for the emergence of endometrium that allows the embryo to implant is very short, and this window period is affected by progesterone. The expression and local distribution of progesterone receptors and their co-regulators are different at different stages of the menstrual period. During the implantation window, immunohistochemical staining of progesterone receptors in endometrial epithelial tissue gradually fades. In the middle and late stages of endometrial proliferation, progesterone receptors A and B are easily detected in epithelial tissue and stroma. Progesterone receptor A is not expressed in the epithelial tissue during the secretory phase, while progesterone receptor B is maintained at a low dose and even drops even lower in the late secretory phase. However, in the endometrial stroma, there are always more progesterone receptor A than progesterone receptor B.

• Effective Progesterone Level

During the endometrial secretory phase, progesterone enhances endometrial receptivity and facilitates implantation. However, only a very small amount of progesterone is required during this process. Therefore, during the luteal phase, women with normal endometrial function only need a small amount of progesterone to exert reproductive effects. For those women with infertility caused by endometrium factors, there may be progesterone resistance, and treatment effects can be achieved by increasing progesterone levels, but this hypothesis needs to be confirmed. When studying endometrial gene expression in young healthy women, it was found that high progesterone levels can overexpress many biological processes controlled by genes, such as cell adhesion, immune system and organ development, etc., which can affect the endometrium and embryonic implantation bed. The gene expression in the endometrium after ovulation induction at the end of the follicular phase is different between women with elevated progesterone levels (>4.77 nmol/L) and women with normal progesterone levels, further proving that human chorionic gonadotropin (hCG) High levels of progesterone on the day of injection lead to poorer outcomes in vitro fertilization (IVF) cycles mainly because they affect endometrial receptivity and result in lower implantation rates. Therefore, it is of high value to closely monitor changes in serum progesterone levels during ovulation induction in IVF cycles. When progesterone increases, you can choose to freeze the embryos first and then perform embryo transfer in the natural cycle.

Effects of Progesterone on Embryonic Development

The development of embryos in microenvironments such as the fallopian tube and uterus is mainly regulated by progesterone. Early pregnancy failure and poor embryonic development are often related to low progesterone levels. The impact of progesterone on embryonic survival and development is divided into two aspects. On the one hand, progesterone directly affects the growth and development of the embryo as a pro-survival factor. On the other hand, progesterone promotes the secretion of related cell activity factors and indirectly affects the growth and development of the embryo. Progesterone receptors are expressed at all stages of embryonic development, allowing progesterone to directly affect embryonic development. Supplementing progesterone during ovulation can increase the pregnancy rate, but delaying the time of supplementation will invalidate the promotion effect. Therefore, the key to affecting embryonic development is the time of progesterone supplementation rather than the content of progesterone. Under the regulation of progesterone, the embryo and endometrium can secrete a granulocyte-macrophage colony-stimulating factor to promote embryonic development. Progesterone can increase the growth factors secreted by endometrial stromal cells.