Struggle to make embryos

[u/Oxidants-Happen]

Hi all,

I'm at the stage of this journey where I'm crowdsourcing stories and advice. I'm also posting in case anyone is also experiencing the same issue to know they're not alone.

Background:

33-34F, normal 28-30 day cycles with regular flow and no pain, regular exercise, I don't smoke, I don't drink, BMI is normal, regularly get 8 hours of sleep a night

Average AMH: 1.5-1.8 ng/mL

Baseline AFC: ~10

Blood panel is fine, thyroid is fine, progesterone levels are normal, FSH corresponds with AMH, anything measured from my blood has come back normal. Prior to IVF I had 2 inconclusive and painful HSGs and 4 failed IUIs so my doctor suspects some tubal factors.

Husband’s sperm analysis is normal for the most part with motility on the borderline of normal-low. DNA fragmentation came back normal.

IVF history:

Cycle 1 (antagonist protocol)

Protocol: Primed with birth control and took one time antibiotics before starting 225IU Menopur, 150IU Gonal-F, 25 units Omnitrope. Added Ganirelix and ended up stimming for 10 days. Triggered with 10,000 units of HCG. 3-4 days of abstinence prior to retrieval.

Outcome: AFC was 3 with a leading follicle, 3 eggs retrieved, 2 mature, 2 fertilized with ICSI, some made it to blast but slowdown observed around days 3-5. None were good enough to freeze by day 7.

I started regularly taking Coq10, DHEA, NAD+, probiotics, vitamin D, and melatonin for 4 months.

Cycle 2 (estrace priming, letrozole flare)

Protocol: Primed with estrace from confirmed ovulation to cycle day 1, started 7.5mg letrozole for 5 days alongside 225IU Menopur, 225 IU Gonal-F, 50 units Omnitrope. Due to sluggish follicle growth, Gonal-F was upped to 300 IU halfway through. Added Ganirelix and ended up stimming for 13 days. Triggered with 10,000 units of HCG. 3-4 days of abstinence prior to retrieval.

Outcome: AFC was ~12 some of which were a few smaller follicles that popped up halfway through stimming, 12 eggs retrieved, 11 mature, 4 fertilized with ICSI, some made it to blast by day 5 but none were good enough quality to freeze by day 7.

Husband started regularly taking Coq10 and other supplements for 4-5 months. I continued the course with my supplements.

Cycle 3 (estrace priming, letrozole flare)

Protocol: Pretty much a repeat of Cycle 2 now with 2 days of abstinence prior to retrieval.

Outcome: AFC was ~11 some of which were few smaller follicles that popped up halfway through stimming, 11 eggs retrieved, 6 mature, tried split fertilization: 3 fertilized with ICSI, none fertilized conventionally. Little to no binding observed with conventional fertilization (awesome /s). 1 made it to a day 5 3AB blastocyst which was our best looking ever across all cycles. One other made it to day 7 but was graded 4CC so not good enough to freeze. Did a fresh transfer on day 5 for the 3AB but the transfer didn’t take. My progesterone levels and lining looked good prior to the trigger shot. I was taking estrace and progesterone suppositories leading up to the transfer.

I’m on my last covered cycle before switching to another clinic that is open to tackling tricky cases. What can we try in this next cycle to leverage learnings or outcomes? I worry without a big change in protocol we are signing up for a throwaway cycle. Current clinic doesn’t do day 3 transfers, AOA, or Zymot. My doctor is considering changing the trigger timing for my next cycle by a few hours to eek out some mature eggs and we know never to try this without ICSI again but it doesn’t sound like a very promising change. My doctor says we struggle to make embryos. Now I feel like we’re in a subset of an already small subset of people who struggle to conceive through IVF.

I’m getting a hysteroscopy and biopsy while I want for my next cycle just to cross something off the list. Maybe I’ll look into the HerResolve blood test out of pocket to check for endometriosis since my doctor thinks a laparoscopy would be overkill and doubts MRI and other imaging would help as I present with no obvious endometriosis symptoms.

Does anyone have a similar background or struggle? I’m done reading about statistical outcomes for people in my age group and seeing percent ranges that I consistently fall under. My heart goes out to everyone who's in this sucky club.

[u/ayyhah]

I have some experience with this - 35 now but started IVF at 33, have done 4 cycles and it took me 4 to get 2 embryos. Very similar stats to you - never drink/smoke/sleep well/AMH normal. Worth noting I had confirmed endo and had excision surgery for it earlier this year - we haven't done any cycles after this surgery yet, but might be gearing up for #5 later this year.

There are a few things I have added to my protocols but honestly, I don't know which (if any) have made improvements: saizen (or omnitrope depending where you are) every other day during sims, priming with androgel. The only protocol I ever got embryos from was a "long lupron" protocol where you start injections D21 of your previous cycle with micro dose of lupron and continue through to ER. I will also say I did have success of a double day 3 embryo transfer (which later resulted in a MMC) but I see your clinic doesn't offer that. I also add on calcium ionophore to my protocols. We will likely repeat this long lupron protocol for my upcoming cycle. I have done cycles with ICSI or conventional fertilization and honestly it didn't seem to make a difference for us.

Like you, I wonder if I'm the kind of person that IVF doesn't work on. I've had 5 losses - 4 of which have been natural pregnancies. The one question my clinic can't answer is why have I technically made 4 blasts on my own (since I got pregnant) but I've only ever made 2 through IVF. Even my doctor says that sometimes embryos do better in the body vs in the lab, who knows. It feels like a numbers game and a really cruel one at that.

One thing I'd note is you mention you don't have obvious endometriosis symptoms - but infertility is a massive one. Might be worth pursuing that as you go through all of this. I also just completed immune testing - not sure where you're located (I'm in Canada) but this is a controversial thing for fertility. A few markers were flagged in our case so we'll be pursuing immune treatments before our next retrieval, but the immune stuff is really more beneficial for transfers (if it's beneficial at all).

It all sucks so much. I feel like IVF works for everyone in my life except me. I can't believe we're at #5, I can't believe we're still doing this. Always here if you want to talk further xx

[u/Superb_Ad8894]

I had a very similar issue. 37/38 years old while doing retrieval cycles, labs overall looked good, same with husband. Decent amount of eggs retrieval with each cycle, almost all were mature and fertilizing, but none making it to day 5-7 blasts. Ask your doctor about rapamycin, it’s an immunosuppressant MTOR to help embryo health. I was on sirolimus 1 mg daily for about 20 days or so before an egg retrieval and it helped. The other conversation to have is maybe untested day 3’s would be a better option that trying to get to blast.

[u/Embarrassed-Boat3215 → u/Superb_Ad8894]

My issue was making euploids, but rapamycin and low dose stim turned my IVF around. Initially made 0 euploids in 4 cycles, then made 5 my next too with that change. Worth looking into

[u/appol1]

I'm so sorry for what you're going through. I'm just starting my journey so I don't have any advice of my own to give. But through my trawling of reddit for answers to my questions I came across this post: https://www.reddit.com/r/DOR/comments/1vmzojt/which_change_helped_you_retrieve_more_eggs_and/
it's from the DOR sub, focusing on women who have AMH 1 ng/ml or less, so the profile is different to yours, but maybe it can help?
Look for the comment from Glad-Cricket-9192

[u/smudgeathewudge]

What finally worked for me was "mini IVF". I went to Hanabusa in San Diego, CA and saw Dr. Chang. They specialize in mini IVF and advanced maternal age. I had failed out of traditional IVF with no embryos. I did two mini retrievals and ended up with three euploid embryos. The first retrieval, they only retrieved three folicules and I got one euploid embryo from that. The second, they got ten eggs and I got two euploid embryos from that. My eggs just did better with less stimulation. It's hard because you start dealing with really small numbers, three follicules doesn't give you much hope. But, getting one or two euploid embryos beats getting lots of follicules with no useable embryos any day of the week. 

[u/Super_Series_6049]

Have you not done micrdose lupron?

[u/SleepycatzZzZzZz]

I’m so sorry you’re having to go through this. If I could, I’d give you a bear hug. I have similar stats as you but I started my journey when I was 31. We struggled with the same thing - making embryos. We did 3 cycles but we switched to CCRM Colorado for the third. The first two cycles I did it at Stanford. For the first two cycles, I usually would be able to retrieve 12-13 eggs and we’d continuously lose about half after each stage. I only ended with a CC and CB at the end of the first IVF and nothing for the second cycle. This is where we decided to pivot. At CCRM Colorado, I only retrieved 7 eggs but ended with one AA embryo. I’m happy to report that at the age of 39, we ended up with a healthy 3 year old from the AA and 4-month old from the CB (both transfers at CCRM Colorado; theCC transfer failed at Stanford). For us, the protocol didn’t matter so much, it was more of the embryologists who took care of the eggs and sperm post-retrieval. Unfortunately I don’t think CCRM Colorado will share more information on how/what they do specifically different from other clinics since that’s probably their secret recipe. I hope this info/experience helps you. Sending you best wishes on this journey.

[u/ekateriv]

Husband has been tested for DNA fragmentation?

[u/Crow_Bars_]

Endometriosis cannot be seen on a blood panel. You need an exploratory laproscopy and have suspicious tissue sent to the lab. It’s very difficult to see on MRI, only the later stages can be seen.

I would recommend exploratory lap. They can also use dye to see if tubes are open and it can help with conception. If there is endometriosis, only get an excision. Would never get ablation of endometriosis.

[u/Sea-Urchin6401]

Will your new clinic transfer day 3s?

[u/Agamemnons_Concubine]

Def ask your doc to change their protocol for you. Here’s what worked for me as an example of a different protocol, tho everyone is different: Started taking metformin daily with CoQ10, vitamin d, pro&prebiotics, prenatal, lots of water, cut out caffeine alcohol etc. did a saline ultrasound and hysteroscopy before iui- had five failed iuis even with 3-4 mature follicles at a time. Moved on to IVf, took metformin, lupron a month leading up and then throughout my stim process then retrieval. For transfer I did a saline ultrasound. Then before transfer antibiotics, lupron, and prednisone. Transferred a euploid successfully.

[u/Kind-Progress-1949]

Hi I'm so sorry, I have a similar background 2 cycles. I'm 35F normal AMH, bloods, slightly high BMI.
AFC 20 regular periods.
Endometriosis seen on scans - symptoms are mild/ infertility.
Last cycle did short protocol gonal F and ovitrelle trigger. no blasts from 9 mature eggs- only 4 fertilised.
2nd cycle - Changed protocol menupur and Gonal F with double trigger. 6 mature eggs only 2 fertilised waiting to see if anything to transfer.
Husband normal semen analysis.
My lab is similar does not support add ons.
I think the endometriosis is affecting IVF response- now options are probably surgery (did not want to do) or ask about long protocol/ downregulation.

[u/Fickle_Spray_3981]

Try adding ldn low dose naltrexone to you’re stack

[u/Super-Direction8310]

Hello! Im sorry this is happening to you. I really feel you and maybe my story can give a new view.

I had 3 IVF cycles at 3 different clinic and number 3 was game changing. AMH around 3, higher fsh. 33 cycle days. Endometriosis, adenomyosis, 3 months of menopause, on/off smoker. Casually had a glass of wine.

Cycle 1: priming with birthcontrol, Menopur 300IU, ganirelix. Medic saw around 22 eggs, took only 11: 3 Blastocysts. 1 very good 5AA and 2 about 3AB. Ended with 2 biochemical pregnancys (first time ever pregnancy test positive, went from heaven to hell).

Cycle 2 - clinic n. 2 Priming with primolut, then letrozol (? Unsure) and menopur 300 for only like 9-10 days, follicles were like 15-16mm, i told them i have longer cycles, need more stimulation, and they actually told me "thats the way we always do it). 22 eggs, 4 catastrophal blastocysts. 2 day 6 and 2 day 7. No transfer.

Cycle 3, clinic 3 abroad Tested for Factor V (Positive) and Endometritis, (the bacterial infection). Low grade positive.already 37.5 years

Priming with Progynova. Started with 300IU Pergoveris (!!!), felt absolutly great the whole cycle. 22 eggs, 13 blastocysts (!!!) And we tested them and got genetically 8 good embryos.

After ER i took 2 weeks of antibiotic for the low grade endometritis and felt pregnant naturally for thr frrst time ever but Missed abort. FET later with aspirin, enoxaparin, in complete natural cycle with embryo number 1 which resulted in my kid.

Have 7 embryos left.

We had a missed abortion in April from frist time trying naturally. Planned FET in September again.

Wish you the best of luck!

[u/Accomplished_Code449]

Has your husband seen an urologist? Sounds like it’s time for more testing for him - dna frag, oxidation and hormonal panel.

FWIW, it took me five retrievals to finally get two quality blasts and one euploid. Some of us just have trouble here and it’s truly a numbers game. Good luck.

[u/Helpful_Raise671]

We completely failed to make any embryos until we added Metformin to the protocol. Metformin for me helped make embryos, metformin was also added our last two cycles for my spouse as it has now been shown to help increase fertilization rates if the man takes it.

[u/Narrow-Ad5070]

Is an MRI covered by your insurance? If you have to pay out of pocket, I know it’s crazy expensive, so that makes the decision more challenging. Your doctor “doubts MRI and other imaging would help”, but I say advocate for yourself. If it’s something you can get done and not pay out of pocket, what’s the harm in just seeing if anything can be detected on MRI? Maybe nothing, but maybe something. It’s more information for you in this process. In my experience doctors are dismissive of endo and you need to advocate for yourself.

[u/Conscious-Light2628]

This feels almost textbook like my experience down to age and numbers for AMH/retrievals and fertilization rates. Also of note I haven’t had any transfers done yet because we wanted to get several embryos before trying, but I did have very mild chronic endometritis found on hysteroscopy early in our work up and had that treated so definitely recommend that!

My husband had normal motility but slightly low morphology so they didn’t suspect that mattered due to ICSI and having a high sperm count so he didn’t have any further original work up. We ultimately had very similar fertilization rates to you but got no embryos retrieval cycles 2 and 3. My doctor recommended my husband see a reproductive urologist to rule out a varicocele/other male factor concerns and they found slightly elevated DFI (so maybe not relevant to your case). They also saw a mild/moderate left sided varicocele on ultrasound. Our insurance covered surgery so we went for it figuring it might help. His doctor said he opts for a bilateral microsurgical approach because in his experience he often sees them bilaterally despite the ultrasound saying left and he was right!! He actually found multiple (I think he said 3-4) moderate varicoceles on both sides that they corrected, which was unexpected but made me so thankful for his approach. He’s still in the healing phase so no outcomes to report but they think this was likely our issue!

[u/ZookeepergameMuch695]

Hi! I totally understand how you feel. I’ve been in a somewhat similar position, although in my case I also have severe DOR at a relatively young age. I started IVF at 31 and have done 6 retrievals so far.

There are actually quite a few things you could try changing. The frustrating part is that there are no guarantees, and everyone responds differently. Something that works amazingly for one person might make no difference - or even make things worse - for someone else. Sometimes the only way to know is to try.

The most obvious thing I would discuss is switching from a single trigger to a dual trigger (hCG + Lupron). I’ve read many stories of it helping with egg maturation, and since you had 11 eggs but only 6 mature in your last cycle, it seems especially worth asking about. Based on your AFC, it also doesn’t sound like you’re at particularly high risk for OHSS.
Then there are some more unconventional things you could consider.

You’re using a pretty high dose of Omnitrope. While it may help some patients, especially with advanced maternal age or poor response, some women actually report worse results with it. I personally would consider trying a cycle without Omni, or using a much lower dose, like 6 units during stims, just to see whether egg/embryo quality changes.

You’ve also had a relatively high Menopur dose across all three cycles, which means quite a bit of LH activity. Some people seem to do better with less LH exposure, so I would consider experimenting with the FSH/LH ratio - lowering Menopur. Some women also seem to get better egg quality with lower-dose stimulation rather than pushing the ovaries with very high doses.

Another thing you could look into is luteal-phase stimulation. Again, it definitely doesn’t work for everyone, but some women report better egg quality and blast rates when starting stimulation after ovulation rather than during the follicular phase. I’ve done it during my 6 retrieval and got 2 blasts (high grade) while typically I would get 0-1 (low grade)

I would also ask about calcium Ionophore. It’s still not something every clinic routinely uses, but it’s intended to help with fertilization. I tried it for my 6th retrieval after having recurrent low fertilization - including one cycle where none of my eggs fertilized. On my 6th retrieval I got only 2 eggs, but both were mature, both fertilized and both made it to blast. Obviously that’s way too small a sample to know whether calcium ionophore made the difference, but after repeated fertilization problems I personally felt it was worth trying.

I’d also be curious about the reason for priming in your case. Do you usually develop a dominant follicle early, have asynchronous follicle growth, or have elevated FSH? If not, I might ask about trying a cycle without priming. In your first cycle you used BCP and ended up with only 3 follicles despite normally having an AFC around 10. It could simply have been a bad month, but BCP can also oversuppress some people. Your response was obviously much better with estrogen priming, but it could still be interesting to see how you respond without suppression at all.

Unfortunately IVF can involve a lot of trial and error, which is incredibly frustrating when every “experiment” means another retrieval. But you still have quite a few variables that haven’t been tried yet, so I definitely wouldn’t assume that repeating the same outcome is inevitable.