It has been a while since I have written a blog post on my fertility journey. But I see that one of my posts has been getting a lot of views, which I can only hope that it is helping people on this journey. At least the bare minimum to say, you're not alone!
So, let's chat a bit about endometrial lining. I have done endo-prep several times now. We did a fresh donor cycle last year and did a fresh embryo transfer, which didn't take. Then we did a frozen transfer and it didn't take. So you start to question, is this the right protocol for me? Is my endometrial lining not great?
Well, it turned out that after the two failed transfers (lost embabies... may they RIP) my doctor suggested to do the ERA. The ERA or endometrial receptivity analysis involves performing a mock cycle for preparation towards an embryo transfer, but instead of transferring an embryo, the doctor performs an endometrial biopsy. Everything else is supposed to be the same as if you were preparing for a transfer.
And guess what?? My ERA was abnormal!
So what happens with the endometrium when you start adding progesterone into your protocol? The cells of the uterus start to prepare for maintenance of pregnancy when progesterone is signaled from the follicles lining and the granulosa cells of these follicles as they begin to lutealize (essentially after the LH surge, the follicles ovulate and turn into a corpus luteum). Anyway, gene expression works through turn on or off specific genes that code for proteins in the cells. These proteins could be membrane bound receptors, or some other protein (not muscle protein - don't think about macros here). If you compare fertile women with women who have had repeated implantation failure, the two groups of women differ in the expression of 313 genes (Ruiz-Alonso et al 2013)! The ERA tests 238 of those genes.
Along with the biopsy for the ERA, the sample was also tested through PCR to look for pathogenic bacteria in the uterine lining (EMMA and ALICE). Which also came back with some pathogens!
So part of me said, dang... what a waste of those embabies we transferred and the other part of me said - well, at least there is a reason that they didn't stick! Both from the perspective of having transferred at the wrong time for my uterus to be receptive, but also transferring into a 'hostile' uterus!
The tough part of this whole journey is that we started TTC four years ago now and thus far, I have had three miscarriages (natural pregnancy) and spent hundreds of thousands of dollars (Canadian dollars, mind you) on stimulation cycles, a fresh donor cycle and a frozen donor cycle with still no human baby in our arms. This journey is almost as long as my pre-veterinary journey when I applied for 7 cycles before I got accepted. Not to mention the fact that through all of this emotional turmoil, I keep working and there are only a few people in my work that I have even discussed this journey with.
So, anyway, back to the endometrial lining preparation! After I received the results from the ERA/EMMA/ALICE, I did a course of Clindamycin for treatment for the pathogenic bacteria that were not supposed to be in there.
Since statistics show that the endometrial receptivity gene expression of the majority of women with my set of genes being expressed showed that they were able to get pregnant if given additional time on progesterone prior to the transfer of a day 5 embaby, this is my fertility doctor's plan.
Endometrial Thickness
Another aspect of embryo transfer is the measurement of the lining. Essentially, estrogen (in the natural cycle it is produced by the growing follicle) signals to the uterus to thicken and create a cozy bed for the embryo to implant. So prior to transferring an embryo, whether fresh or frozen, you are to take estradiol and have serial ultrasounds of your uterus to see how thick the lining is.
But my question has always been, how thick should the lining be? Obviously, it needs to be thick enough to allow for implantation, but is a 1 mm difference better or worse??
In science, many statistics fall on a bell curve. Have you every heard of a professor in university curving the grades? The curve they are trying to aim for is that the average, being the middle folks scoring a C, 50% of the population falls above a C and 50% fall below.
In statistics with humans they may talk in odds ratio. What are the odds of a positive pregnancy test if an embryo is transfer with X mm thickness of the endometrium?
For example, a uterine lining of less than 7.5 mm at the time of trigger (usually talking about a fresh cycle or controlled natural cycle) showed a higher odds of having a pregnancy complication (Oron et al 2018). In a systematic review of the research up to October 2013 (ten years ago!), women whose uterine lining for </= 7 mm had a pregnancy rate of 23.3% compared to > 7 mm of 48.1% (Kasius et al 2014), which is twice as likely to become pregnant if the lining is > 7 mm. Back to my question, does 1 mm really make a difference?? According to Liu et al, 2018, it does, statistically anyway. For fresh cycles, women with a lining > 8 mm had a 33.7% chance of live birth, while women with 7 to 7.9 mm showed 25.5% live birth rate. That's 1 mm difference. Sadly, we all know that age is a factor, but the thickness of your endometrium is also related to your age.
Researchers have looked at whether or not having compaction after starting progesterone supplementation effects live birth rates but have found minimal statistical difference (Gill et al 2023; Ye et al 2020), so it appears that the measurement of the lining prior to progesterone supplementation is the important one.
So what if you have a thin lining? My current fertility doctor is not against performing some of the less researched protocols. I think when you get on this journey and even if you increase your chances by a small percentage, you are willing to take that risk. At the last frozen transfer, because my lining wasn't ideal (I think her goal was > 7.5 mm) she said we could try platelet rich plasma (PRP) injected intrauterine to see if this could help support the lining prior to implantation. It did help grow my lining at the time (or so we thought) but didn't help with the implantation. I had briefly blogged about PRP as a treatment for ovarian rejuvenation, but I have not tried it, so I cannot say whether it is helpful. For some patients intrauterine PRP helped improve their pregnancy rates (Kim et al 2019). Like I said, statistical improvement may be small, but we're willing to eat pineapple core if it helps!
I just wanted to say, I'm still here. I'm still on this journey, even if I haven't blogged about it recently! Think sticky baby thoughts.
References:
Gill, P., Melamed, N., Barrett, J., & Casper, R. F. (2023). A decrease in endometrial thickness before embryo transfer is not associated with preterm birth and placenta-mediated pregnancy complications. Reproductive BioMedicine Online, 46(2), 283-288.
Kasius, A., Smit, J. G., Torrance, H. L., Eijkemans, M. J., Mol, B. W., Opmeer, B. C., & Broekmans, F. J. (2014). Endometrial thickness and pregnancy rates after IVF: a systematic review and meta-analysis. Human reproduction update, 20(4), 530-541.
Kim, H., Shin, J. E., Koo, H. S., Kwon, H., Choi, D. H., & Kim, J. H. (2019). Effect of autologous platelet-rich plasma treatment on refractory thin endometrium during the frozen embryo transfer cycle: a pilot study. Frontiers in endocrinology, 10, 61.
Liu, K. E., Hartman, M., Hartman, A., Luo, Z. C., & Mahutte, N. (2018). The impact of a thin endometrial lining on fresh and frozen–thaw IVF outcomes: an analysis of over 40 000 embryo transfers. Human Reproduction, 33(10), 1883-1888.
Oron, G., Hiersch, L., Rona, S., Prag-Rosenberg, R., Sapir, O., Tuttnauer-Hamburger, M., ... & Ben-Haroush, A. (2018). Endometrial thickness of less than 7.5 mm is associated with obstetric complications in fresh IVF cycles: a retrospective cohort study. Reproductive biomedicine online, 37(3), 341-348.
Ruiz-Alonso, M., Blesa, D., Díaz-Gimeno, P., Gómez, E., Fernández-Sánchez, M., Carranza, F., ... & Simón, C. (2013). The endometrial receptivity array for diagnosis and personalized embryo transfer as a treatment for patients with repeated implantation failure. Fertility and sterility, 100(3), 818-824.
Ye, J., Zhang, J., Gao, H., Zhu, Y., Wang, Y., Cai, R., & Kuang, Y. (2020). Effect of endometrial thickness change in response to progesterone administration on pregnancy outcomes in frozen-thawed embryo transfer: analysis of 4465 cycles. Frontiers in Endocrinology, 11, 546232.
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