In this session, Vladimiro Silva
, PharmD, Embryologist, Founder & IVF Lab Director at Ferticentro, Coimbra, Portugal, has discussed undertaken steps that resulted in successful pregnancy in patients diagnosed with diminished ovarian reserve.
Anti-Müllerian hormone (AMH) & FSH
Dr Silva started by explaining what AMH level is and how is it measured. All women at birth are born with around 2 million eggs which are not mature, they are primordial follicles, and they peak in number during fetal life, and then they undergo atresia thereafter and do not regenerate. It means that the ovaries get to the maximum number of eggs at birth, and then it goes only down from there at puberty when women start to ovulate to release an egg every month. They only have 400 000, but by the age of 30, they have 100 000 eggs, and in menopause, they have no eggs. We know that fertility declines with age, however, it is difficult to predict the pace of a reproductive decline in an individual woman. Therefore, when we talk about the ovarian reserve, we are talking about the reproductive potential as a function of the number and the quality of remaining oocytes that are still inside the woman’s ovaries, this is the definition by the American Society of Reproductive Medicine (ASRM). When we say that the woman has a decreased or diminished ovarian reserve, we are comparing her with women of the same age having regular menses, and so when we say that a woman has a diminished or a low ovarian reserve, it means that her ovaries are working worse than the average women of her age. This is not the same as being in menopause, it is different. Menopause or premature ovarian failure (POF), or primary ovarian insufficiency (POI) is about the moment when the ovaries stop working. Low ovarian reserve means we have low numbers and probably also low-quality eggs.
How can we measure it? There are 2 ways to measure the ovarian reserve:
- blood (FSH and AMH)
- ultrasound scan (Antral Follicle Count -AFC)
FSH declines with age, as shown on the graph, for all age groups the number of women with normal FSH declines in every age group and the more elevated the FSH, the lower the delivery rate, it is only getting worse when we are approaching menopause. With the low value of FSH, the pregnancy rate is higher, while with higher numbers of the efficacy of FSH, the pregnancy rate is lower. For example, an older woman with a low FSH has a worse probability of pregnancy than a younger woman with a high FSH, so age is more important than FSH, however, these parameters are very important. How does it work? There is a part of the women’s brain called the pituitary gland or the hypothesis, which releases the FSH, which stimulates the ovaries to mature the follicles with which all women are born. Those follicles develop into ovulatory follicles while growing inside the ovary, they release oestrogens, and then the level of oestrogens is detected by the brain, and it lowers the amount of FSH that is produced. When a woman has a very high level of FSH, it just means that her brain is not detecting the response from the ovaries, so it produces more and more and tries to get a reaction from the ovaries. This is why having a high value of FSH is a bad sign.
There is also Anti-Müllerian hormone (AMH), which is considered the best parameter to define ovarian reserve. This single parameter correlates with the probability of pregnancy. We go from primordial follicles, the ones that women are born with, to the antral follicles, which takes about 300 days, and then, when the antral follicles are there, we can also detect them by an ultrasound scan at the beginning of the cycle, they are available to be recruited by the FSH and develop into ovulatory follicles. When they are available to be recruited, they are producing AMH, so the more follicles we have, the higher the AMH will be. While it is better to have a low FSH, in the case of AMH, the higher, the better the prognosis.
The AMH is very high on average until the age of 35, more or less. Then, it starts to go down, and so this is why the pregnancy rates are better below the age of 35 and tend to decline after the age of 35. To establish a normal prognosis, we need to have:
- FSH < 15 UI/L
- AMH > 0.5 ng/mL
- AFC above 5
When we are outside these values, so when the AMH is lower than 0.5 ng/mL and FSH is higher than 15, and we have less than 5 antral follicles, the prognosis is bad, but it doesn’t necessarily mean that it is impossible, but the prognosis is low.
If we look at a natural conception and the graph shown, you can see that a man and a woman without any fertility problems have a 25% chance of getting pregnant. Humans are not a very fertile species, and at the same time, it only declines, it’s relatively steady until the age of 34-35 and then it starts going down, and the risk of having a miscarriage increases very steeply. At the age of 46, it goes even above 50%, it’s never zero for any age group.
- Ovarian reserve assessment
- Is it still possible to do treatment with your eggs?
- Should we think about egg donation instead?
- Should we do pre-implantation genetic testing (PGT-A)?
- Implantation conditions (uterine integrity, receptivity, etc.)
Low ovarian reserve – real-life cases
The first case presented a 28-year-old woman with a low AMH level, married, her husband had no male factor, she took the contraceptive pill for a lot of years and then decided to have a baby, she did have a pregnancy 2 years before, but she had a miscarriage. She had regular cycles, after evaluating her ovarian reserve, we saw that she only had 5 antral follicles, which are borderline with the values that we were talking about, her AMH was 0.5 ng/mL, which is also very borderline, and the FSH was 6. At her age, we would expect her to have more than 10 antral follicles.
- 28-year-old with husband, low ovarian reserve, 1 previous miscarriage, regular cycles
We did an ovarian stimulation to do ICSI because she had a very low ovarian reserve, we didn’t get many eggs, we had only 3 eggs, and from these 3 eggs, only 1 was mature, so we decided to freeze this egg. We did a second ovarian stimulation on a consecutive cycle, it is already proven that when you stimulate the patients in 2 consecutive cycles, the effectiveness of the ovarian stimulation is better. We got another 3 eggs this time, all were mature, we were already stimulating her with the highest dosage that we could give her, we warmed the frozen eggs, we’ve injected all 4 eggs, and we got 4 embryos that reached the blastocysts stage which was an amazing result. We performed a single embryo transfer, and she got pregnant, the pregnancy is now ongoing, and everything is fine.
This case is an example of how important age is. If we have a low ovarian reserve in a younger patient, the prognosis can still be good. With these parameters, the prognosis was not very good, but the age effect was significant, and we ended up having brilliant results.
The second case presented a single woman at 41, who wanted to get pregnant with a sperm donor, she had one pregnancy at the age of 22, but she did an abortion because it was an accident, and then she never got pregnant again. She had regular cycles, her AFC was very low, she had 5 follicles, and her AMH was 0.7, which was compatible with her age. FSH was 8 UI/mL, which was a bit borderline, we don’t like it when the FSH is above 8, but it’s certainly below 15, which is our cut-off for a bad prognosis case.
- 41-year-old single woman who wanted to use a sperm donor, low AMH
The plan was to do ICSI with sperm donation. We started an ovarian stimulation, we got 4 eggs, but only 1 was mature, we’ve frozen that egg, and we vitrified it and did a second ovarian stimulation. We got 4 embryos, and 2 of them were blastocysts, we did the PGT-A because this patient was 42 and normally above the age of 39 we consider that the risk of having an abnormal embryo is very high and so we always advise all patients to do that. One out of the 2 embryos was euploid and since we only had 1 very precious embryo, we did an endometrial assessment test called the ERA test to find the implantation window. We wanted to control all that we could because we knew that we had only 1 euploid embryo, so we tried to control as many factors as we could. We transferred the only embryo we had, luckily, the patient got pregnant, and she had a beautiful baby girl.
What’s the alternative that we also need to take into account? For the majority of patients with low AMH, the prognosis is not that good and in some situations, there is the possibility of doing an egg donation. It’s kind of the last resource, it’s also the most reliable one. On the graphic shown, the probability of success with egg donation is around 60% in all age groups, while for women using their own eggs, it starts at 50%, and it only goes down as long as the age increases. Egg donation is kind of the last resource, if we try to do a simulation and we don’t get a pregnancy, this doesn’t necessarily mean that you will never become a mother, it will just mean that you will probably need to use another strategy. It is something that we should always inform patients about because sometimes trying to get pregnant with a low AMH can be a very long process. Sometimes we need to do multiple simulations with multiple protocols, freeze eggs, start over, freeze the other 2 eggs, and start over, and this is not for everyone in terms of financial but also emotional terms. Egg donation is kind of the backup plan that’s also available, and for some patients, it can also be the only solution.