Endometriosis, Infertility and the Curious Role of Progesterone Resistance By: Dr. Bruce Lessey
My first blog on ReceptivaDx comes just as our Nature paper on BCL6/SIRT1 and KRAS was released in Scientific Reports on PubMed. It reminds me how far we have come in understanding implantation and provides me an opportunity to pause and reflect on the origins of progesterone resistance and how it might cause infertility. The endometrium has been my muse and a source of great mystery during my scientific adolescence. In my adult “life” it has challenged me and withheld its secrets! The uterus, it turns out, is the only place embryos won’t attach in the body, except during a narrow “window” of receptivity. The endometrium is the “mucosal” layer of the uterus that is normally a barrier to pregnancy, but undergoes a short period of perfect kindness, allowing embryos to attach, invade and thrive for up to 9 months, despite being a foreign tissue that would normally be rejected by any competent immune system. This period of uterine acceptance is, unfortunately, not available to everyone. For many women, the experience is one of ultimate frustration; they are able to fertilize embryos but never achieve pregnancy; or worse, to implant a viable embryo only to lose the pregnancy in miscarriage. For these individuals, answers were few and options were limited.
The main culprit in this scenario is endometriosis, a sinister disease that often lurks in a woman’s body with few signs and symptoms. While some women are ravaged by the disease beginning with their first period, the actual diagnosis of endometriosis may only come years later. There are several reasons for this. Often the symptoms are similar to “normal” menstruation, with moderate to severe pain but within the threshold of what others feel. This pain then becomes generalized and accepted by both the woman and her physician. On the opposite spectrum are the women who experience no physical symptoms but end up with unexplained infertility. Ironically, the one definitive endometriosis diagnostic tool available, surgical laparoscopy, is performed less and less since it is costly and invasive. Thus, the average time to diagnosis in the US has been greater than 10 years!
Those of us who are heavily involved in the research, have been noticing and reporting in the scientific literature over the past 40 years, that the endometrium of women with endometriosis was different. There are too many estrogen receptors, or too much proliferation, or a reduction in glycodelin or other proteins with long and funny names, like leukemia inhibitory factor or LIF. Anything that can inhibit leukemia can’t be bad, right? In fact, LIF was the first protein shown to be essential for implantation and pregnancy. If you “knock out” the gene in mice, embryos won’t attach and simply float within the uterus. Screening of genes using DNA microarray showed that besides LIF, a whole constellation of genes were aberrantly produced in the endometrium of women with endometriosis. From those early studies came the concept of Progesterone Resistance, or simply put, an inability to respond to that one hormone that is essential for pregnancy, progesterone.
So the studies piled up and there were breakthroughs along the way. We described an attachment receptor for embryos, called the alpha v/beta 3 integrin, that was found missing in some women with endometriosis. When you block this protein with antibodies or proteins that clog its binding site, mice or rabbits can’t get pregnant. This test became the first endometrial receptivity test and was offered by Adeza, Inc in the early 1990s. Chris Jackson, the founder of CiceroDx, was involved in educating physicians about that early test. Unfortunately, the integrin was not adequate by itself and was often missing in endometrium that was delayed in its development, another sign of progesterone resistance.
By the year 2012, my laboratory had continued to investigate inflammation and endometriosis and was studying lipoxins and other anti-inflammatory molecules made by the endometrium. But the big breakthrough came when our research led us to a protein called BCL6. Our findings showed that BCL6 was consistently and dramatically over-expressed in women with endometriosis! We now had a marker that could be used for detection. This was the origin of ReceptivaDx test, an endometrial diagnostic approach that uses both the beta 3 integrin and BCL6 to detect endometriosis, even in its most subtle forms. So even when the integrin is missing due to delayed endometrium, BCL6 by itself is still useful to help diagnose endometriosis.
Coming back to the present, we now have more clues on the role BCL6 plays in Endometriosis. We outline it in the release of our latest paper in Nature. In summary, BCL6 is induced by inflammation. BCL6 pairs with an ingenious enzyme called SIRT1, linked to longevity and generally thought to be beneficial. Like BCL6, however, SIRT1 is a double agent, linked to the highly proliferative phenotype of endometriosis, promoting progesterone resistance and favoring cell proliferation. SIRT1 is induced by KRAS, a known oncogene, and SIRT1 and BCL6 together bind to, and turn off, key pregnancy-related genes. We show that one key gene (Gli1) in major progesterone signaling pathway (COUP-TFII) is a target of BCL6/SIRT1 activity. In many ways, it now appears that BCL6 and SIRT1 are at the center of progesterone resistance that affects so many of those down-stream genes.
For a scientist and reproductive endocrinologist like myself, uncovering the pathways that lead to progesterone resistance and endometriosis is much like solving a mystery and provides our team great satisfaction. However, for my patients, the real joy is to the thousands of women with unexplained infertility who can now be tested and then treated leading to many successful outcomes. Beyond the IVF world, progesterone resistance and endometriosis is a phenomenon that affects millions of women and now may be targetable with new therapeutic approaches due to this discovery involving BCL6 and SIRT1. In women who test positive for BCL6 and negative for integrins, there is new hope that anti-inflammatory therapies can reverse progesterone resistance and improve an embryo’s ability to implant. Feel free to read this paper for yourself. It is exciting to think that after 30 years of looking, the source of progesterone resistance may now be within reach and with it a path to pregnancy.