Physician-To-Physician Consult

Dear Colleagues

I have a 39 yr old patient who has undergone 2 cycles of IVF (history of unexplained subfertility/ recurrent miscarriage). On both occasions 8 eggs were collected but all were immature, despite a modified protocol on the second occasion. Is In-vitro maturation likely to improve her chances?
Many thanks,

Kevin Harrington

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Answer by Johan Smitz

You come up with a case that is 1/1000 and very difficult to handle, because multiple reasons might be there for the low maturation.
Nevertheless the lady got pregnant already ... Spontaneously ?
Over the last 4 years we collected nearly 10 such cases.
First thing would be to make the diagnosis of the defect ? Using some follicle material + some oocytes.
One similar case here had an autoimmune disorder with thyroid disorder and deficiency in the steroid conversion cascade . She never made high estrogens . She became pregnant after multiple ivms . Ivm is rather a way to finetune diagnosis ( with the aim to help future cases better ) , however it should be considered experimental in this cases . As Ivm needs optimization , many eggs are needed to get enough good embryos .
In short : in this case Ivm is not a miracle solution.
I'd like to see more history of this case and how she was handled , and here monitored hormone values might also be informative.
Hope this is helpful to further decide for this lady

Best regards
Johan Smitz, Belgium

Answer by Sherman Silber

It is hard to answer this questions without seeing exactly what their protocol was. However, I would recommend a mini-IVF approach for all such cases, and make sure to carry on the stimulation with clomid and every other day FSH until for sure the follicles are large enough. if the threatens premature ovulation, you can stop it with 8 micrograms of Ganerelix only because the clomid is still acting to blunt the positive feedback from estradiol increase. then trigger with GnRH agonist instead of with HCH.

if that does not give you mature eggs, then i am afraid it is an intrinsic egg problem in her genome, and will not be amenable to in vitro maturation either. then her only next option is donor eggs.

Sherman Silber, USA

Answer by Seang Lin Tan

Without knowing other details but knowing that she suffered recurrent miscarriages, she is likely to ovulate ( on her own) a mature egg. In other words she is unlikely to have a maturational arrest.
Repeat the cycle and trigger when follicular diameter average 20 mm.
Give IM hCG to trigger and be ready to do IVM if the oocytes are morphologically suggestive of GV.
Pasquale Patrizio, USA

I would ask at what size follicle trigger was done at? Conventionally, one would delay trigger to 23-24 mm and then use hCG 10000 to see if it helps. If not, then I would try IVM. You can put him in contact with me.
Seang Lin Tan, Canada

Answer by Ariel Weissman

Dear Kevin, What is your modified protocol? I would do the following: 1. Long protocol 2. Large follicles 22-23 mm 3. Double the dose of hCG for the ovulatory trigger. 4. Maximise the interval between hCG to egg retrieval to 36 hours. If this fails, you could try IVM, although I have no personal experience with IVM in such cases. These cases might be sometimes very ddifficult with no easy solution, as you can see from the following publication: Maturation arrest of human oocytes as a cause of infertility: case report.
Levran D, Farhi J, Nahum H, Glezerman M, Weissman A.
Hum Reprod. 2002 Jun;17(6):1604-9. Erratum in: Hum Reprod. 2002 Oct;17(10):2781..
We also tried cytoplasmic transfer but it didn't work.

Good luck!
Ariel Weissman

Answer by Yoshiharu Morimoto

IVM will not work for this case well. Because your oocytes had some failure for maturation mechanism of oocytes.
I recommend you had better check hCG titter after hCG injection and extend duration of hCG-OPU.
Yoshiharu Morimoto, Japan

Answer by Gab Kovacs

The answer is difficult, IVM only seems to work on very few units, and we have no success with it.
I would try a higher dose of HCG and maybe longer hCG to OPU interval?

Gab Kovacs , Australia

Answer by Matts Wikland

Thank you for your question. It is not easy to give a good answer to your question with regard to the little information about the patient and her IVF treatments. The patient age is in my opinion a major negative factor. The first thing I would try is to see if it is possible to retrieve a mature oocyte in a non stimulated cycle. I don´t think In-vitro maturation is an option in this case since mainly due to the patient age.

Matts Wikland , Sweden

Answer by John Yovich

With respect to the issue of immature eggs, there are several approaches which have worked - different ones for individual cases:

1. Stronger Trigger eg Pregnyl 20,000 iu or Ovidrel X3 amps
2. Combined HCG + Lucrin trigger in Antagonist cycle (eg Ovidrel X2 amps + Lucrin 50iu)
3. Longer Trigger-TVOA interval - currently 38hrs with Ovidrel works well (no premature ovulations over 100 cases).
4. IVM (i) with standard schedule. Overnight culture in IVM media and ICSI next a.m. (± calcium ionophore).
5. IVM (ii) with IVM protocol - only works with women with high AFC i.e. PCO group, perhaps worth a try if AFC ≥ 12 oocytes or AMH >12 pm/l

If Kevin sends more details about the case, I can advise or direct further.

John Yovich , Australia

Answer by Juan Carlos

Th inmature oocyte syndrome (IOS) is a rare and challenging situation. I would recommend standard ovarian stimulation under antagonist protocol and DUAL trigger (hCGr 250 ug + Triptoreline 0,2 mg) for final follicular maturation. A more physiologic induction of final follicular maturation in terms of gonadotrophin surge duration and/or the addition of natural FSH/LH activity directly from de hypophysis may optimize the signaling mechanisms from the surrounding cumulus and the oocyte, resulting in adequate oocyte maturation in this subset of patients.

Castillo et. al. J Med Cases • 2013;4(4):221-226. Successful Pregnancy Following Dual Triggering Concept (rhCG + GnRH Agonist) in a Patient Showing Repetitive Inmature Oocytes and Empty Follicle Syndrome: Case Report. 

Best regards and good luck...¡

Juan Carlos Castillo





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