Diminished Ovarian Reserve – IVF case studies (patients’ stories)

Foteini Chouliara, MD, MSc
Obstetrician & Gynaecologist , Assisting Nature – Human Reproduction & Genetics

Low Ovarian Reserve, Success Stories

From this video you will find out:
  • How do maternal age impact oocyte and embryo competence?
  • What is the value of Anti-Müllerian Hormone (AMH) in the prediction of pregnancy?
  • Does Preimplantation Genetic Testing for Aneuploidy (PGT-A) really improve IVF outcomes in advanced maternal age patients?
  • Does the accumulation of embryos improve the outcome of poor responders?

What treatment options/protocols are best to manage diminished ovarian reserve?

In this webinar, Dr Foteini Chouliara, Obstetrician & Gynaecologist at Assisting Nature, Thessaloniki, Greece presented a topic on Diminished Ovarian Reserve (DOR). Dr Chouliara has talked about 4 different cases and presented the diagnosis, protocols, and treatment protocol that allowed them to have a positive outcome.

Diminished Ovarian Reserve – real-life cases

In the first case, Dr Foteini presented a couple who attended the clinic (Assisting Nature) a year ago. The female patient was 37-years-old with a normal BMI, she had the hysteroscopic polypectomy and laparoscopic myomectomy in the past. She has also mentioned a family history of early menopause. She wasn’t a smoker nor a drinker, her husband was 47-years-old without any serious health problems. The couple was faced with infertility for about 11 months, they did mention a previous IVF cycle in the past, and after diagnostic workup, which involved meticulous history taking, ultrasound evaluation, blood work, AMH levels, sperm analysis, karyotypes and so on. Everything came back normal except for an AMH of 0.4, which is pretty low for a woman who is 37 years old.

  • a 37-year-old with a 47-year-old partner, 1 previous failed IVF cycle, low AMH level, all the tests

In their previous attempt, they tried a classical antagonist protocol, they managed to retrieve 8 oocytes, and in the end, we were able to produce 2 blastocysts, which were transferred, and unfortunately, without obtaining a pregnancy. Before starting a new IVF cycle, we went ahead with vitamin D supplementation and multivitamins to help with the low ovarian reserve. We also chose to start with a classical antagonist protocol, which is a very patient-friendly protocol and chose a combination of Gonal-F and Menopur with a total of 300 UI administered per day. In this stimulation cycle, however, we didn’t manage to get as many oocytes as the couple had in the very first attempt, we had two follicles growing, but we were very lucky, and both of the follicles had mature oocytes, and out of the 2 mature oocytes we managed to produce 2 pretty good blastocysts. We performed a fresh embryo transfer of both embryos, and we did have a positive pregnancy test on our initial ultrasound examination. We had 2 sacks, and 2 heartbeats, unfortunately, 1 of the twins regressed at around the 13th week of pregnancy. However, the remaining twin was delivered by a C-section at 39 weeks, and we had a healthy baby boy.

Key points

The main key point of this case study is that the most important factor for a woman’s fertility is age, unfortunately, we might age nicely, but our oocytes have got a declining quality as we’re growing older.

The same happens with ovarian reserve, when we are born with a set number of oocytes that are available throughout the reproductive life, and this number of oocytes starts to decline even while we’re in the uterus, so we might start with 6 to 7 million eggs, and by the time we are born, we have 1 or 2 million eggs. By the time we hit puberty, around 3 to 4 hundred thousand are available. As time goes by and with every cycle, many of these eggs are recruited. As this initial ovarian reserve is being consumed when it is worn out, we enter menopause.

As time goes by, so does our ovarian reserve, this is normal, unfortunately, there is a very small proportion of women that might have a lower ovarian reserve than expected for women their age. This could be because of genetics or other factors such as endometriosis, smoking, having certain previous surgery on their ovaries or therapy such as chemo or radiotherapy.

An excellent marker to assess this available ovarian reserve is that of AMH, and this is a marker we usually use in IVF to determine the ovarian reserve and predict the ovarian response. AMH is produced by the little follicles that we see on the ultrasound, and we can see that the value of AMH is also declining with age. It’s important to check the AMH early on and to seek specialist advice, if we’re with a partner and our AMH levels are very low, then we can either start trying to conceive right away and if we’re unsuccessful or if there are other infertility factors seek specialist advice right away, or if we are single we’re still pursuing a career, or we haven’t met the right guy then maybe social like freezing could be a very good option for us to maintain our fertility for later on.

The second case study presented a couple where the woman was 39 years old with a normal BMI level, she had hypothyroidism which was treated regularly with thyroxine and was well regulated, and she also mentioned repeated E Coli infections. She had a diagnostic hysteroscopy in the past, and biopsies taken showed chronic endometritis. Her husband was 39 years old with no serious health problems, and he had good habits of no smoking and no drinking.

  • a 39-year-old female, diagnosed with treated hypothyroidism, chronic endometritis in the past

This couple was trying to have a baby for about 4 years, and after our initial check-up, we had an AMH of 0.7, karyotypes were normal, thrombophilia screen was negative. We performed PCR of sexually transmitted diseases because of her history of constantly having vaginal infections, which came back negative. Hysterosalpingography and the sperm analysis were very good. Therefore, the main infertility factor was low AMH. The couple had 1 previous IVF attempt about a year before visiting Assisting Nature. The classical antagonist protocol was used at the time, they managed to retrieve 16 oocytes producing 5 day-5 embryos, which were gradually transferred in 3 separate endometrial preparation cycles, unfortunately without achieving any pregnancy.

We decided to go ahead with a different protocol and tried a long agonist protocol that could yield better results. We started our overcompensations on the luteal phase of the cycle before the stimulation cycle and then again used a combination of Gonal-F and Menopur injections. We managed to retrieve 16 oocytes, which was a very good result and in the end, culture 5 very good quality blastocysts. We performed PGT-A, and out of the 5 blastocysts, 2 were found to be euploid. Before transferring the blastocysts, we wanted to evaluate the endometrial cavity, and that’s why we performed the hysteroscopy. The endometrial cavity was found normal, but we did go ahead with endometrial fundal scratching, which is something we regularly do at our clinic. We decided to transfer both blastocysts, and a healthy baby girl has been delivered at 37 weeks along.

Key points

The main key point from this case study is the importance of changing the therapeutic approach. Not all couples are the same, and not all couples respond well to the same protocols. There isn’t one size fits all, so it’s very important to try to have an individualized approach. In this case, we had seen that the classical antagonist protocol didn’t work that well for the couple, and although it’s much more patient-friendly, we decided to change it. We also chose to do PGT-A, which is a method that is not regularly done for every single couple, it’s not for everybody as it is an invasive procedure, it is a biopsy done on every embryo, and we usually perform it for women who are over 40. It is also recommended for patients with repeated implantation failures, recurring pregnancy failures, and severe male factor. PGT-A is a diagnostic tool, and at the same time, it helps us decrease the time until we achieve pregnancy. It saves us from all the heartache and pain of transferring embryos with no chance of implanting and giving live birth.

A 3rd case study was about a couple where the female patient was 40 years old, with normal BMI, she had Hashimoto thyroiditis and was under T4 thyroxine supplementation. She wasn’t a smoker nor a drinker, her husband was. 41 years old, had nothing significant in his own personal or family history. This couple have been trying for a baby for about 6 months and never had any previous IVF attempts. The female patient’s AMH was 0.2, which was pretty low for her age. She had an intramural fibroid that was, and we were suspecting 1 or 2 polyps. There was also a tubal factor, 1 of the tubes seemed to be off on the hysterosalpingography. The sperm analysis was overall good.

  • -a 40-year-old with Hashimoto, intramural fibroids and polyps, tubal factor, no previous IVF attempts

We started with some vitamin supplementations and chose to start with a classical antagonist protocol using Gonal-F. However, we only managed to have 1 follicle, and there was no oocyte found after the oocyte pickup. Since the couple didn’t want to waste any time and wait for about 3 to 4 months to have another full dose stimulation cycle, we decided to go with the package of natural cycles. In the first packet of the natural cycles in the MNC Gonal cycle, we managed to get 2 very good quality blastocysts that we vitrified, and then we moved on to another 3 cycles where we accumulated 1 more blastocyst, and in our 3rd package, we accumulated 1 more. In the end, we had 4 embryos for transfer. Before doing so, as we had some uterine factors, we started with the laparoscopic myomectomy, afterwards, we went ahead with ERA testing before doing embryo transfers, and we did a hysteroscopic evaluation of the uterine cavity and endometrial fungal scratching. When everything was set and checked, we transferred 2 of our blastocysts, we did get a positive pregnancy test the first time around, but unfortunately, our patient lost the pregnancy at around 8 weeks long. We still had our 2 last blastocysts, we did transfer on a natural cycle, at the moment, our patient is at 30 weeks and expecting a baby girl.

Key points

In this case, the main message is not to be discouraged easily. Women who have got a lower AMH, it doesn’t mean that they’re infertile, it just means that they respond more poorly to ovarian stimulation, and this means that they might need more cycles to accumulate more oocytes and have a better chance of having good embryos within this group of accumulated oocytes.

The 4th case study presented a female patient who was 41 years old, she had 3 hysteroscopic polypectomies in the past. She already was on preconception vitamins, and fish oil and her partner didn’t have any significant health problems either. The couple were trying for about 2 years to conceive, her AMH was 0.9. On ultrasonography, a septum was found, and again an intramural fibroid. The sperm analysis revealed mild male factor, and this couple had already 3 previous attempts.

  • a 41-year-old with a very low AMH, after 3 previous history hysteroscopic polypectomy, 3 previous failed attempts; mild male factor

In the first attempt, they had a classical antagonist protocol with the oral contraceptive pill priming, 9 oocytes were retrieved, and 4 blastocysts were produced leading to 3 frozen embryo cycles that ended in a biochemical pregnancy. Then on the second cycle, they had the classical antagonist protocol, but unfortunately, none of the 3-day embryos that were transferred led to any pregnancies. Their 3rd attempt was also with an oral contraceptive pill, and then stimulation with Gonal-F didn’t lead to any pregnancy either. Therefore, we decided to start with the hysteroscopic evaluation of the uterus, resected the septum, and we excised the polyp, then we decided to go ahead with the long agonist protocol since the classical antagonist protocol wasn’t helpful for this couple. Unfortunately, we didn’t have any luck either, the cycle was cancelled because of low response, so we tried to do the classical antagonist protocol since it seemed to work better for this couple.

We retrieved 4 oocytes, 2 quite good blastocysts were cultured, and we did a fresh embryo transfer, but unfortunately, we had a biochemical pregnancy. The couple came back again, and we tried the classical antagonist protocol. This time, we had 2 oocytes, one day-3 embryo, which we let to reach day-5, but unfortunately, it arrested. Since we couldn’t help this couple with these stimulation cycles, we opted for the natural cycle package, and we tried everything, we tried the natural cycle, we weren’t successful, we tried minimal stimulation cycle, we managed to get 3 follicles, but they were all abnormal. We tried Aromatase inhibitors (AIs), and again we didn’t manage to produce a day-5 embryo. After all these attempts, we had a conversation with the couple, and they decided to take a step further and chose to go ahead with oocytes donation. The donor was carefully selected and matched, from the stimulation cycle we retrieved 10 mature oocytes, and we ended up having 6 very good quality blastocysts, which were vitrified. They were vitrified to give us time to have a second hysteroscopy and endometrial fundal scratching before proceeding with the embryo transfer. We did an intra-lipid infusion before embryo transfer to enhance our chances of implantation, and once everything was ready, we transferred the first 2 blastocysts, and 9 days later, we had a positive pregnancy test, and 40 weeks later, the couple had a healthy baby girl delivered.

Key points

It’s always a good idea to have a backup plan, unfortunately, low ovarian reserve is very challenging and sometimes, despite our best efforts, things don’t go our way, so oocyte donation can be the answer for these couples who struggle to make it with their own eggs. The whole process involves a donor going through the process of the stimulation cycle, the oocytes that are retrieved are then fertilized with the husband’s sperm, and they are either transferred fresh, or they’re frozen and transferred later on as a part of an endometrial preparation cycle.

Egg donation is voluntary and anonymous in Greece. For the egg donors to enter the donation program, they have to go through a whole evaluation process that involves a meticulous medical history, clinical examination, gynaecological examination, a series of lab tests and psychological evaluation, and once all these tests came back good, then they are accepted into the donation program. The matching process is done based on phenotypic characteristics, and also, but not necessarily on the blood groups of the couple, and the donor and oocyte donation is a very good plan b since it’s got very high success rates for all ages. The success rates reach about 50%, and they can get even higher while we’re repeating oocyte donation cycles. Even if we don’t get pregnant in the first embryo transfer by having a second or even a third, most couples will have managed to achieve a pregnancy.

Related reading

- Questions and Answers

When you find diminished ovarian reserve and fertility indication for surgery, do you advise oocyte freezing first and then go on with the surgery?

Every surgery done on the ovaries, regardless of how careful the surgeon is, is always going to end up damaging ovarian tissue. There is always going to be a follicle loss. In that case, I would advise doing some social freezing first and then performing the gynaecological surgery.

I am 42, I have a low ovarian reserve. All the tests are clear. I did 2 IVF sessions. The first one was estrogen flare, 2 eggs were retrieved but didn’t fertilize. The second IVF, of which 4 eggs, 2 fertilized, but didn’t implant. My BMI is 23, I’m a non-smoker in great health, and all tests were clear. My husband’s sperm analysis was normal. Is it worth trying one more time?

You’ve had 2 attempts so far, so I think that if you have the emotional stamina and the financial backup to maybe try one more time, I wouldn’t be against it. You can try one more time, but if that fails, I think that it wouldn’t be bad to consider egg donation.

Why is PGT-A proposed for a severe male factor if ICSI is performed and the best sperm is chosen?

ICSI is a very good option when we have a male factor. The spermatozoa are chosen on their motility, morphology, but then again, it doesn’t show that the genetic material is perfect, so it might look good, but on the inside, it’s like judging a book by its cover. PGT-A helps us determine that the result, which is the embryo, is normal.

Although the best spermatozoa are selected, it doesn’t necessarily mean that the end product, the embryo, is also going to be normal. Most of the time, a bad embryo is because of bad oocyte quality, let’s say 90% is because of bad oocyte quality. A smaller percentage is because of sperm, and it’s usually because of very bad sperm parameters on sperm analysis. In those cases where the couple has tried, and they’ve had embryo transfers, and they’ve been successful, it’s worthwhile doing a PGT-A, and if the results are not very good, maybe they could consider a sperm donation.

Have you worked with anyone with AMH as low as 0.4 pmol/mL and were able to retrieve any eggs? I am 32.

It’s a very low AMH, but 32 is not that bad because we might not have the quantity of the oocytes, but at least we’re hoping for better quality. Possibly the stimulation cycle is not going to work very well for you, but you can always try with natural cycles.

For as long as you’re having periods, you have a chance every month to monitor your cycle and to try to retrieve that oocyte, and maybe you will get lucky. I wouldn’t give up, I would try with every cycle for as long as I would have my periods. Things would have been different if you were 42 or 43, possibly, it wouldn’t be so much worthwhile, but at 32, I would try.

Why did you do intra-lipid infusion in case 4?

We’ve tried everything with this couple, we tried to do anything that we could do to help them out. The intra-lipid infusion is like a fat emulsion solution that might help with the implantation by regulating these natural killer cells in the uterine lining. It’s not proven to be 100% effective, but some studies suggest that modulating this immune response in the uterus environment could favour implantation, so we did try it out.

What is your opinion on PRP ovarian rejuvenation method?

I can understand the way of thinking behind it. Platelet-rich plasma (PRP)  is being used in different specialities such as orthopaedics and dermatology as a way of rejuvenating various tissues. I’m not very convinced that it can work, I think we still need a bit more evidence before actually applying it for most of our patients.

The theory is that it might sort of rejuvenate and increase the available follicles, but I will wait and see more data and more evidence on how effective it is before applying it to my patients. We’re not using ovarian PRP at our clinic, but we’re doing endometrial PRP for resistant thin endometrium. There is no harm done by the procedure, but I am not yet convinced, at least PRP for ovaries. When it comes to PRP for thin endometrium, we have very encouraging results so far. 

Is AMH fluctuating during the cycle?

When we’re talking about the hormonal profile, we always tell our patients to do their hormone levels between the second and the fourth day of the cycle. The AMH is fluctuating throughout the cycle, but not so much. You can check it whenever, it’s not that crucial. The most important thing is to perform it at a very reliable lab to get credible results.

Why do you do endometrial scratch every time before embryo transfer?

We’re very fond of endometrial fundal scratching in our clinic (Assisting Nature). It would be a very good idea to do a hysteroscopic evaluation every time before doing any embryo transfer, unfortunately, this is not always easy, and it’s a bit expensive as well. We only go ahead with the hysteroscopy if there is valid evidence from our ultrasonographic evaluation that there is an abnormality, like a fibroid, polyp or septum.

Even if no pathology is found, the hysteroscopy doesn’t go to waste because we do perform this procedure, which is called endometrial fundal scratching, it is like a scar that is done in the fundus of the uterus using the endoscopic micro scissors, and in a way, this injury to the endometrium seems to be activating regeneration factors, and it’s another way of sort of rejuvenating the endometrium.

We started doing this procedure, and we were very amazed by the results, and so it’s something that we regularly do, and we’re carrying out a study to be able to prove what we can say in our experience to have the statistics back us up as well. 

When would you advise women to check their AMH?

That’s so, so important, it’s so crucial.  I would say to take it at least in their 30s when they are 28-30 years old to check their AMH levels. If they are in that very small proportion of women faced with a low ovarian reserve, and premature ovarian failure, at least they will have their options open before it’s too late, and then there isn’t much that IVF can do for them.

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Foteini Chouliara, MD, MSc

Foteini Chouliara, MD, MSc

Dr Foteini Chouliara is an Obstetrician and Gynaecologist with a special interest in Reproductive Gynaecology at Assisting Nature since 2018. She was awarded the Bachelor of Medicine and Bachelor of Surgery degree (M.B., Ch. B) by the University of Glasgow School of Medicine in 2005. After completing Foundation Year 1 post-graduate training she started her residency in surgery following by the residency in Obstetrics & Gynaecology at Hippokration Hospital of Aristotle University of Thessaloniki/ Greece. Since 2017 she is working as a qualified Obstetrics & Gynaecology Consultant. She received her Master of Science (M.Sc.) Degree in “Human reproduction” from the Democritus University of Thrace in 2019. She is also a Research Fellow of the Aristotle University of Thessaloniki carrying out research work on the role of particular biomarkers in the pre-surgical assessment of ovarian tumours as part of her Doctorate. Dr Foteini Chouliara is deeply committed to the supervision of the International Patient Department at Assisting Nature. Her current scientific interests include: Biomarkers of ovarian cyst and their value in Human Reproduction, PCO, Prenatal first trimester diagnosis in Reproductive Patient. She has been a part of scientific publications, presentations, papers, such as: Najdecki R, Chouliara F, Timotheou E, Tatsi P, Chartomatsidou T, Asouchidou E, Pakaki F, Bouchlariotou S, Humaidan P, Papanikolaou E. Single follicular degarelix, a new long-acting GnRH-antagonist for LH surge suppression during ovarian stimulation in oocyte donors. A randomized controlled trial. ESHRE Annual Meeting, Vienna 2019 (oral presentation) Prevalence of antenatal depression and associated factors among pregnant women hospitalized in a high-risk pregnancy unit in Greece, Social Psychiatry and Psychiatric Epidemiology, 2016 Jul. Antenatal depression among women hospitalized due to threatened preterm labour in a high-risk pregnancy unit in Greece, Journal of Maternal and Fetal Medicine, 2017 Mar 21.
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Caroline Kulczycka is managing MyIVFAnswers.com and has been hosting IVFWEBINARS dedicated to patients struggling with infertility since 2020. She's highly motivated and believes that educating patients so that they can make informed decisions is essential in their IVF journey. In the past, she has been working as an International Patient Coordinator, where she was helping and directing patients on their right path. She also worked in the tourism industry, and dealt with international customers on a daily basis, including working abroad. In her free time, you’ll find her travelling, biking, learning new things, or spending time outdoors.
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