estrogen: good or bad?

Let's talk about IVF paradigms. In a nutshell, IVF involves stimulating the ovaries to produce multiple eggs all at once. The egg are then removed, fertilized with sperm and embryos are created. The embryo(s) are then put into a woman's uterus in hopes a pregnancy will occur.

As the eggs grow in the ovaries, they produce estrogen. We watch the estrogen levels rise through blood tests done every few days while the eggs are growing. The more eggs that are growing this higher the estrogen level risess. It is typical to see estrogen levels between 5,000 and 15,000 pmol/L at the end of the ovarian stimulation phase. What we have come to learn is that all that estrogen can be harmful to the uterus, making it less "receptive" or willing to allow an embryo to stick. We learned this by comparing women whose embryos are put back into the uterus while the estrogen is stlll high (i.e. a fresh embryo transfer) to women whose estrogen level has dropped back down and we wait a few weeks and then do a frozen embryo transfer. Overall, the pregnancy rates with frozen embryo transfers are the same or higher. than fresh. If the estrogen level is above 20,000 pmol/L there is evidence that pregnancy rates are lower if the embryo is put in fresh (high estrogen environment) compared to frozen.

There is also a concern that, in some women ,high estrogen is harmful to embryos. Obviously this isn't the majority of women, as the majority of women have high estrogen levels and good embryos in IVF, but there is this subset of women who develop unexpectedly poor embryos and we are now studying whether this is due to a toxic effect of estrogen. Stay tuned on this concept - studies are ongoing.

In any case, we are confident in saying pregnancy rates are lower after fresh embryo transfer if the estrogen is really high (i.e. > 20,000 pmol/L). So, our patients who have estrogen levels that high should have all their embryos frozen, their body allowed to return to a more natural estrogen state, and then do a frozen embryo transfer. Indeed, we are often advising this even if estrogen levels are > 15,000 pmol/L, but that's a more nuanced decision based on the whole scenerio and patient status/history/etc.

Following this "high estrogen might be bad" line of thinking, natural cycle IVF, minimal stimulation IVf and now NATOS (NATural Ovarian Stimulation) have come into the spotlight. In these protocols, estrogen levels are low. In the first two treatments (natural cycle IVF and minimal stimulation IVF) estrogen is typically low because the woman is a low egg producer so rather than bombard a woman who can only produce 1-3 eggs with aggressive (standard) IVF, we back off and try no or minimal medications to gently coax out those few eggs we can get. NATOS is new and I like the concept. It comes out of France and there are no real studies on it yet, just a small "test of concept" trial on 11 patients. The concept is quite simple: block estrogen production early with GnRH antagonist medication (e.g. Orgalutran). We use GnRH antagonists often - in fact nearly 70% of our cycles incorporate a GnRH antagonist but we typically start it once the estrogen level has started to rise. Why? You don't technically need it early as its main use is to block ovulation which doesn't happen early AND it is expensive so if you don't need it don't use it. NATOS raises the point that perhaps using it early has a benefit in suppressing estrogen levels and thereby resulting in better embryos and improved uterine receptibity.

Given the paucity of information on NATOS I would not yet jump to start GnRH antagonist early on every woman but certainly in those women with a history poor egg quality it is worth considering. It might be a trial we do at Olive to explore the concept further. Stay tuned!