Infertility, IUI, Ivf

Size of follicles at trigger: is bigger always better?

You responded pretty well to your stimulation protocol for IUI or IVF and you are approaching the finish line.

Your ovaries are growing a certain number of follicles (the more the merrier for IVF, under 5, usually, for IUI) and you are anxiously waiting for the liberating trigger shot.

Be it a urinary-derived hCG like Novarel or Pregnyl, a recombinant hCG  like Ovidrel, or an agonist such as Lupron or Decapeptyl, the trigger shot will provoke a surge of LH which will add a final touch to your follicles and will help them burst.

If choosing the right protocol for the right patient is a work of art, please know that timing the trigger shot is not less important!

Trigger too early and your oocytes will be immature. Trigger too late and it may be…too late.

How do we decide when to trigger? Is follicle size the only indicator? Or are there other aspects we should consider?

As the follicles grow in size during the follicular phase of your cycle they start putting out estrogen, which in turn thickens your endometrial lining, preparing it for implantation, in case conception occurs. In natural cycles, when only one dominant follicle is being recruited, the pituitary gland will release the LH surge that will start ovulation based on the level of estrogen your follicle is releasing. To put it in simpler words: your brain doesn’t know what size your follicle is, so it will rely on your detected estrogen level.

This is why Reproductive Endocrinologists prefer to check your estrogen levels during stims, and not rely solely on your follicle sizes when triggering you.

When a follicle is mature enough, it usually puts out between 200-400 pg/ml estrogen.

Studies show us that if the total estrogen level does not impact IVF outcome, the serum estradiol per mature follicle is extremely important. How does that translate into plain English? Basically you may have a total estrogen level of 450 pg/ml at trigger, for two mature follicles and have success, and fail with a total estrogen level of 2000 pg/ml for 20 follicles.

One question that occurs obsessively on infertility groups and forums is “what size should my follicles be at trigger?” The truth is no one can answer this question for you. For some women, follicular maturity occurs when lead follicles measure between 15 and 18 mm, for others when follicles are well over 20 mm. Hence the importance of having the serum estradiol level tested before trigger, and doing the math.

Last but not least, different protocols may influence the size of follicles. It has been demonstrated that in Clomid and Letrozole IUI cycles, higher pregnancy rates were achieved when the lead follicles were in the 23 to 28 mm range.

What happens if estradiol levels are not tested before trigger, and we end up with immature follicles? In case of IUI not much can be done to save the situation. The released egg has to meet the sperm on its own and be “fertilizable”. If the egg is immature, fertilization most likely won’t occur.

In case of IVF, the situation is a little bit different. There are clinics that offer the In Vitro” oocyte maturation. This technique, initially used for patients with PCOS and patients who confronted with severe Ovarian Hyperstimulation in their previous IVF treatments, is now being used for many other reasons: oocyte maturation problems, poor responders, rescuing IVF cycles, older patients. But the treatment is not considered to be a conventional one, it is only used as an alternative, and again, not every fertility clinic has the means to do it.

What happens when we trigger too late? The term “over mature”/ “post-mature” oocyte does come up often in patient/doctor conversations but the truth is it is not well documented in medical literature. The proven risks of triggering too late are premature LH surge- despite the administration of an antagonist to prevent it, premature raise in progesterone levels- impacting endometrial quality and therefore implantation in case of fresh transfer, and also ovarian hyperstimulation in the case of women with normal ovarian reserve or PCOS.

Bottom line: modern assisted reproduction has come a long way since the early days of ART, yet much of it is still trial and error, because every patient is unique. A bespoke approach is much more likely to improve your odds, so make sure you are being properly assessed and nothing is left to chance or taken for granted. YOU are YOURSELF and whatever may work for someone else, is not necessarily the best option for you!

Sources

 Mittal, S., Gupta, P., Malhotra, N., & Singh, N. (2014, April). Serum estradiol as a predictor of success of in vitro fertilization. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/24757341

 Palatnik, A., Strawn, E., Szabo, A., & Robb, P. (2012, May). What is the optimal follicular size before triggering ovulation in intrauterine insemination cycles with clomiphene citrate or letrozole? An analysis of 988 cycles. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/22459633/

 Hatırnaz, Ş., Ata, B., Saynur Hatırnaz, E., Dahan, M., Tannus, S., Tan, J. and Tan, S. (2019). Oocyte in vitro maturation: A systematic review. [online] Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022428/ 

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