Image by Sarah Pflug
Recently, healthcare professionals, people with fertility problems and others (healthcare funders, healthcare providers, healthcare regulators, research funding bodies and researchers) were brought together in an open and transparent process resulting in an article that was published in Human Reproduction in November 2020 outlining the top future infertility-related research priorities. The initial survey was completed by 388 participants from 40 countries, and 423 potential research questions were submitted. Fourteen clinical practice guidelines and 162 Cochrane systematic reviews identified a further 236 potential research questions. The top 10 research priorities for the four areas of male infertility, female and unexplained infertility, medically assisted reproduction and ethics, access and organization of care for people with fertility problems were identified. These top ten research priorities in each topic area outline the most pressing clinical needs as perceived by healthcare professionals, people with fertility problems and others, to assist research funding organizations and researchers to develop their future research agenda.
The first of the top ten research priorities for medically assisted reproduction is “What are the causes of implantation failure?” In this post we will dissect the various hypotheses, tests, treatments and potential avenues of research.
The placental paradox
The riskiest moment in any human pregnancy is when the fertilized egg attaches to the uterine wall and tries to establish a link between embryo and mother. About half of IVF pregnancies fail during this implantation stage, and we all know how many natural pregnancies end at that time as well.
At some stage in the evolution of animals, we went from mammals that lay eggs, like the monotreme family (the platypus and echidna are the living members of), to marsupials or pouch gestating mammals like kangaroos, koalas and possums, to placental mammals like us. But even among placental mammals NOT all placentas are the same. For example, in cows there are specific spots of attachment between the fetus and the mother called cotyledons, and this is soooo different than in humans where we have a total attachment between the placenta and the uterus. That is why you do NOT see cows bleeding out form a uterine rupture or suffering from, for example gestational diabetes or high blood pressure. Their blood supply is just not that connected to the developing fetus. We really see that our complex placenta developed evolutionarily to protect the embryo from our own immune system.
There is a kind of paradox that perplexes researchers of infertility, a mother’s inflammatory reaction to the embryo is the biggest threat to pregnancy, it also seems necessary for the pregnancy to be successful.
Implantation failure or RIF is an imprecisely defined clinical disorder characterized by failure to achieve pregnancy after repeated embryo transfers with genetically normal embryos. multicomponent, bidirectional signaling between the embryo and endometrium. A healthy uterus, free from endometriosis, polyps, fibroids, and with a thick lining is one piece of the puzzle, a euploid, or chromosomally normal embryo is another piece, less than 60% of euploid embryos result in pregnancy.
There are 4 main culprits or areas of active research investigations- and that means, identifying all of the biological components involved in these, developing tests to definitively say if that process is in a disease or abnormal state, and then drug treatments that work!
Those 4 are; progesterone resistance, shifted window of receptivity, decreased integrin expression, and immune system disturbances.
Estrogen stimulates endometrial proliferation, estrogen also causes an increase in progesterone receptor expression, enabling the establishment of the “window of receptivity”. Progestogen is directly responsible for the timing – the opening and closing of the window of receptivity. Endometriosis can actually cause progesterone resistance, disrupting the establishment, and opening or closing of the window. There is a gene called BCL6 and its expression in the endometrium has been correlated in patients with unexplained or endometriosis-associated infertility. There is a test to see what the activity of this gene is called the Receptiva DX test.
Shifted window of receptivity
The window of receptivity itself has a molecular signature – meaning certain genes are expressing certain proteins- and this can be determined with a test called the ERA test. Implantation itself is actually a tightly controlled inflammatory response that coordinates the embryo “invasion”. The embryo is essentially a foreign invader. It is half NOT your own DNA but the partner or sperm source. So the uterine lining and muscular wall must allow invasion by this foreign entity, without alerting your immune system to attack, and establish a vascular blood supply that can support pregnancy.
Decreased integrin expression
Integrins are cell to cell adhesion molecules. They are the principal receptors on animal cells for binding most extracellular matrix proteins. They are basically a little ladder that crosses the membranes of both cells, in this case the embryo’s and the uterine endometrium.
Endometrial integrins are key molecules that promote embryo attachment. Right now, we have one good drug candidate to increase integrin expression, called letrozole. Letrozole is known as an “aromatase” inhibitor there is another very common mild aromatase inhibitor – Aspirin! Aromatase, is also called estrogen synthetase or estrogen synthase, because it is an enzyme responsible for a key step in the biosynthesis of estrogens.
There are so many features of embryo implantation that are consistent with the hallmarks of cancer and tumor invasion. In fact, it is often noted that “all the tricks cancer knows, were learned from the embryo”. The tricks here being invading tissue, establishing a blood supply for uncontrolled cell growth, and evading detection by the immune system. There are dozens of drug molecules from the cancer treatment world that can inhibit aromatase.
Immune system disturbances
Two immune system components cytokines (which are generally associated with inflammation) and uterine natural killer cells have important roles in successful implantation.
Excessive and altered inflammatory signaling has long been suspected in implantation failure and recurrent pregnancy loss. Natural killer (NK) cells are members of a rapidly expanding family of innate lymphoid cells (ILCs). During pregnancy, NK cells are the most abundant lymphocytes in the uterus at the maternal-fetal interface and are involved in placental vascular remodeling. So discovering the complete set of cells and all their functions is still necessary.
We had one good drug molecule called glucocorticoids to investigate – they are a type of corticosteroid hormone that is very effective at reducing inflammation and suppressing the immune system. Glucocorticoids were selected to study, based on the biologic plausibility of restoring a normal immunologic response in the endometrium to promote healthy embryo implantation- however many gold standard clinical trials and meta-analysis of the data have failed to show improvement. For this reason, ASRM guidelines currently recommend against the routine use of glucocorticoids to improve implantation rates.
But there are dozens of other suspected immune pathways and drug molecules to explore.