In this session, Dr Elias Tsakos, FRCOG, Medical Director at EmbryoClinic, Thessaloniki, Greece, provided one of his past patient diagnosed with diminished ovarian reserve, endometriosis, tubal factor and mild male factor successful story. Dr Tsakos, also explained protocols that work best in patients with (DOR) and how important pre-IVF evaluation is.
Low ovarian reserve – assessment
Low ovarian reserve is one of the bigger mysteries in life and fertility. It is something that has attracted a lot of interest from scientists all over the world. Dr Tsakos explained that from 2005 onwards, he and his team studied the AMH, and they performed quite a few investigations at the time, they also tried to compare the AMH with the previous assessment methods of poor ovarian reserve and low ovarian reserve. They were able to publish a few papers and produced the PhD thesis of Dr Tsakos’s business partner, Dr Tolikas, and they presented all the data in 2010-2011. Now, we know that AMH is not something new anymore, we rely on AMH to make some predictions of low ovarian reserve. This is a very significant factor in determining how we approach those women in the stimulation protocols and the expectation that we have as clinicians, and they have as patients, for their ovarian response to stimulation.
The whole issue of AMH is based on the ability we now have to predict and design adequate protocols for stimulating the ovaries of those women based on the AMH. It’s not just the AMH, we still use the FSH and LH, estradiol as a baseline, although we’re moving away from them quite rapidly at the moment. We use the AFC, the Antral follicle count, therefore, the question is: How do we define low ovarian reserve? What AMH is normal? What AMH level is suboptimal, and what AMH level is high enough to indicate an excessive ovarian response? This is very important to be aware of before stimulation and avoid the hyperstimulation syndrome, but also diagnose the polycystic ovarian syndrome that may be missed by other methods of diagnosis.
AMH has now become the standard hormonal test and measurement before IVF, and it is now recommended to be checked once or twice a year, always in conjunction with the AFC, which is a subjective method by the use of scanning technology. By combining the two, we can have an accurate prediction of ovarian reserve.
Low ovarian reserve– real IVF patient case
The first case presented by Dr Tsakos was a relative of his who was 38 years old at the time, with low ovarian reserve associated with severe endometriosis.
- a 38-year-old woman with low ovarian reserve of 0.7 ng/ml, severe endometriosis, mild male factor, no IVF before
The couple never had gone through IVF, it was their first cycle which was indicated because of her tubal factor endometriosis, low ovarian reserve and a mild male factor. The woman had a normal BMI of 24, the ovarian reserve at 0.7 ng/ml is a pretty low level of AMH for a 38-year-old woman, and that was in line with AFC -4, so there were 4 potential eggs. After discussing with the couple we defined the successful outcome of stimulation of 4 eggs, secondly, we tried to do any modifications that we could do to optimize the environment before the stimulation. We evaluated the vitamin D levels, we improved the vitamin D levels at the time by giving supplementation. The woman was perfectly healthy, had a normal diet, was a non-smoker, and a non-drinker, so we didn’t have very much to do there. We discussed the value of DHEA supplementation, which we have been empirically providing for patients, in the hope that some of them would benefit from it and very few of them would have the side effects. We give this for a minimum of 6 to 8 weeks before stimulation at a dose of 25 milligrams 2 or 3 times, and we planned a stimulation protocol.
Regarding protocols, some schools are providing maximum stimulation hoping to stimulate even smaller follicles that wouldn’t stimulate otherwise, some other groups are in favour of mild stimulation, and some other ones are somewhere in the middle. Taking that into account, we thought that there was no point in excessive stimulation if we knew AFC was 4. However, because this woman hadn’t been stimulated before, we thought we would give a normal stimulation as opposed to mild stimulation, so she had taken 250 units daily of purified FSH, which we think was a standard dose, and that was an antagonist protocol. She produced 4 follicles out of those 3 mature eggs, we performed ICSI in this particular case as there was a mild male factor. We had 3 mature eggs, and out of those, we had 2 blastocysts produced. We did the first embryo transfer, we transferred 1 fresh blastocyst, and we froze the other. We had a perfect endometrium, we had the perfect level of hormones and in particular, we had low progesterone on the day of the trigger, it was under 1 ng/ml, so we had a pregnancy, however, this pregnancy ended up in an early miscarriage, it was a six-week miscarriage. We performed an evacuation of retained products, it was a clinical pregnancy, and we performed DNA tests on the concept it was normal, however, that was a miscarriage.
We had 1 frozen blastocyst, we prepared the endometrium and we transferred that blastocyst on the frozen cycle and that resulted in another pregnancy which was ongoing and ended up with a healthy birth by Caesarean section at about 39 weeks, that was a maternal request, this C-section was based on the fact that this woman had a single kidney, we got a fit and healthy young boy.
The message from this case is that although it was a case of a relatively advanced reproductive age of 38 with compromised ovarian reserve and endometriosis, it was very important that we identified and did our best to optimize everything. It’s hard to say whether DHEA played a role or not, the good news was that 4 eggs were produced and out of those, we got 2 blastocysts.
The importance of the Pre-IVF examination
Pre-IVF phase is everything you’ve done in your lives until now until you see a fertility specialist for the first time. All the simple things have to be optimized, lifestyle habits, and a bit of exercise, it’s of great importance to prepare your body and your soul before you embark on the IVF journey. F.e., intensive weight loss before IVF does not alter the outcome and it does not improve the outcome, however, it is essential to investigate women and men before any fertility interventions.
I see couples who’ve had multiple IVFs, multiple failures, and they have adverse factors that have been undiagnosed from the simple stuff like low vitamin D levels, normal vitamin D levels have been associated with a lot of health issues positively, so we do need to optimize as much as we can. We don’t need to go over the top, we shouldn’t try to look for rare diseases, but we should ensure that harmonically the female and the male are properly checked. Checking the thyroid, having a breast assessment to eliminate any pre-existing breast cancer, which is becoming more and more common in women in their 40s or even before that. It’s also about ensuring that you’re up to date with smears, focusing not only on the ovaries, but also on the uterus to exclude any pathology of the tubes. I cannot emphasize enough the importance of pre-IVF tests.
Low AMH and having lower ovarian reserve don’t mean that you’re sub-fertile unless you’ve tried and haven’t succeeded. It doesn’t have a huge relation with a spontaneous natural pregnancy, so if everything is normal and after 6 months or 1 year at the normal age of mid-thirties, you find low ovarian reserve, don’t be alarmed, it doesn’t mean that you’re subfertile, it may be important if you end up having IVF, but by itself, it’s not a factor of infertility, and it doesn’t hugely natural conception provided that everything else is normal.
When you identify seriously abnormal AMH at a young age, it’s essential to proceed with further investigations, there can be an autoimmune disease associated with that. You need to try to eliminate any other associated factors related to low AMH. Checking autoimmune diseases like thyroid disease or other autoimmune conditions and it’s not over the top to request a karyotype testing, DNA genetic testing to ensure that the structure of the DNA is normal. It’s very essential to sit down with your doctors when they design the stimulation protocol for you based not only on your AMH but also on your antral follicle count, which most likely will be aligned with your AMH levels but also with your age, your weight, previous performance and stimulation, and by defining the successful outcome of stimulation, you get more confidence in the overall procedure and the outcome.