The importance of understanding paracrine pathways for endometrial diseases

Fernando Reis kicked off day 3 with his presentation, Progesterone-induced paracrine factors in human endometrium: the key for decidualization and receptivity.

The cyclical phenomenon that is decidualization

Decidualization occurs in the mid-luteal phase of the menstrual cycle, with paracrine and autocrine factors causing changes in the endometrium to enable receptivity and therefore implantation of the embryo. These changes, include enlargement of endometrial stromal cells (ESCs), the presence of decidual white blood cells (leukocytes), and vascular changes to maternal arteries. In pregnancy, this decidualized endometrial lining (desidua) remains in order to prolong receptivity and therefore pregnancy, the decidua of course forms the maternal part of the placenta.

How does it occur?

The decidualization process is induced by progesterone binding to progesterone a and b receptors, following oesterogen priming. The progesterone’s effects are then mediated by multiple downstream mechanisms involving an array of growth factors, cytokines and regulatory peptides in the endometrium.

Progesterone essential but so is oestrogen

We know that progesterone is essential for this process and as such, it increases in the mid-luteal phase in order to inititate the decidualization process. However, increased availability of both progesterone receptors a (PGR-A) and b (PGR-B) also needs to occur, animal studies have shown that without progesterone receptors decidualization is not possible. This increased availability of receptors is caused by oestrogen priming, meaning oestrogen is also essential for decidualization.

Progesterone receptors in gene activation

Despite the fact PGR-A is most abundant in the endometrium, a recent study found that actually PGR-B is the most important for decidua genes like prolactin – a hormone producer and marker of decidualization. In studies where cells expressed exclusively PGR-A or PGR-B, those with B showed the most prolactin release and therefore most intense decidualization. However, both receptors are essential, as some genes are related by PGR-A, some by PGR-B, and some by both. The cAMP (cyclic adenosine monophosphate) signal transduction cascade also appears to be activated in decidualization with an independent initiating pathway. As well as increasing the availability of progesterone receptors, oestrogen also targets different essential genes. Many genes are involved in decidualization, some are critical like Hoxa10, but there are many others.

Which mediators are essential?

Ramathal et al, 2010 documented a long, but not exhaustive, list of genes that studies have found to be critical in decidualization and implantation. The number of essential genes required to be correctly activated makes this an extremely complex and finely balanced process – with just one gene not activated pregnancy cannot occur.

Cytokines attract leukocytes

Cytokines, glycoprotein mediators, are cyclically upregulated in the endometrium, at least in part by oestrogen. Leukocytes are continually attracted to the cytokines in an inflammatory response, this enables the endometrium to remain active and androgenic, but also tolerate the foetus.

Lack of prolactin expression in unexplained infertility

In the last 20 years, since Fernando first presented this topic at ISGE, his team in Brazil have been studying many growth factors. He explained that unfortunately they’ve not managed to decipher the process using one factor at a time and so going forward they will change their thinking for studies. Interestingly though, a 2004 study found that prolactin may not just be a marker of decidualization, but also an active hormone that shapes the endometrium after decreased expression was seen in women with unexplained infertility.

Understanding holds potential for endometrial disease therapy development

Understanding the complex cascading processes initiated by progesterone receptor activation could aid in defining the pathology of endometrial disease, and in the development of medications that target endometrial immune response, cell growth/survival and tissue remodeling.