Watch the webinar with Dr Alejandra Aguilar Crespo, a Gynaecologist and Consultant Specialist at Equipo Juana Crespo, Valencia, Spain, where she discussed how patients can achieve a successful outcome with IVF and low ovarian reserve.
Dr Alejandra Aguilar Crespo started with the definition of ovarian reserve
and explained that it is defined by the number of available eggs that a woman has at a given moment in her life and is closely related to the potential to reproduce.
It’s a prognostic marker for both a woman’s fertility and the time remaining until menopause.
Ovarian reserve decreases throughout life. When a woman is born, there are more or less 2 million oocytes, but then at puberty, there is only 4 000
among them, only 400 will mature and ovulate, and the rest of them will reach atresia. On the contrary, male sperm regenerates through life, and the quality also decreases with age, but they always have some fertility capacity.
Dr Aguilar pointed out that in each menstrual cycle, there is follicular recruitment, but only one will be in charge of maturation and releasing the oocyte. The rest of them reach atresia, which means that they die. If there is no fertilization 40 days later, the period comes and another cycle. As age increases, the probability of pregnancy decreases per month. The quality and the quantity of eggs decreases with age. Due to this, fertility is maximum at the age of 20 to 25 years old. The probability of pregnancy when a woman is around 20 to 25 years old is 30%, but then after the age of 20 to 35 years old, this probability drops considerably, and then at the age of 40 years old this probability decreases drastically and therefore also miscarriage probability increases. From the age of 38 to 40 years old, the prevalence of infertility increases and the probability of going ahead with an assisted reproductive technique.
Measurement of ovarian reserve
There are several tools to measure ovarian reserve. The first one is to measure the Anti-Müllerian hormone (AMH)
, which is done by a blood test. We can perform this test anytime during the cycle. If the level is below 1.1 nanograms per millilitre, it means we are facing a low ovarian reserve.
Then we can also perform an ultrasound scan
and to check the number of antral follicles
. If we see there are fewer than 3 follicles in each ovary, that probably means we are looking at the low ovarian reserve. It depends on the time the scan is performed during the cycle and if the woman is taking the contraceptive pill.
The third tool we have is to measure the Oestradiol and FSH levels
on day three of the cycle. This tool is not very used because the previous ones give a more accurate measurement of ovarian reserve. As Dr Aguilar suggests, we should take into account that the measurement of the ovarian reserve has to predict the response to an ovarian cycle to an IVF treatment, and it doesn’t inform us about the quality of the oocyte.
Causes of low ovarian reserve
Several causes are leading to a low ovarian reserve, and the most frequent one is age
. As age increases, the quantity and the quality of oocytes decrease. However, some other causes can provoke low ovarian reserve, and they are not related to age.
The first one is a genetic cause. Some genetic diseases, such as the X-fragile syndrome, BRCA mutation, can lead to ovarian failure. When we are facing a woman with a low ovarian reserve, and she’s young, we have to perform those genetic tests. We also have to perform a karyotype test.
Other causes are autoimmune diseases
. The most frequent one is thyroid problems
, which can cause a low ovarian reserve. There are also some environmental factors
, such as the smoking habit
, this one is controversial, but it has been correlated with a low ovarian reserve. It’s important to decrease the smoking habit.
The treatment with chemo or radiotherapy for any cancer treatment
is also associated with a low ovarian reserve. Especially, breast cancer, Hodgkin lymphoma (HL) and leukaemia. The chemotherapy and radiotherapy treatments are gonadotoxic, which means they kill or can mutate the reproductive cells.
Another cause is ovarian surgery
, for example, for an ovarian cyst or endometriosis
. Especially, if those treatments are not performed by a reproductive surgeon. Sometimes, when we remove an ovarian cyst, we can also remove healthy ovarian tissue. Then we can decrease the ovarian reserve.
Finally, there are also idiopathic causes
. It means that despite ruling out every possible cause of low ovarian reserve, we still do not know the cause.
Implications of low ovarian reserve
As Dr Aguilar explained, most women with low ovarian reserve don’t know about it. If they look for pregnancy when they are young, they will probably succeed because when they are young, the oocytes have very good quality, and probably they will get pregnant in the first year of trying to conceive.
Nowadays, women are delaying pregnancy until their mid-30s or even older, and therefore they are sometimes struggling with getting pregnant, and they have to use the assisted reproductive techniques. Any woman over the age of 30 years old who wants to delay motherhood should check her ovarian reserve. If they have a low ovarian reserve, she needs to organize the family planning. A low ovarian reserve can lead to premature ovarian failure and early menopause.
The low ovarian reserve represents a major challenge in reproductive medicine. It is often associated with a poor ovarian stimulation response, a high cycle cancellation rate and a low pregnancy rate. The number of oocytes is a direct indicator of the ovarian reserve and ovarian response to ovarian stimulation.
Dr Aguilar emphasized that:
Having a low ovarian result doesn’t necessarily mean that conception is impossible, but it can lead to an increase in FSH levels, and this is associated with impaired oocyte quality and decreased number of follicles that are ready to be stimulated. It’s vital to perform any screening before trying to conceive.
Low ovarian reserve (LOR) & Poor ovarian response (POR)
We should not confuse a low ovarian reserve with a poor ovarian response. Women with poor ovarian response are those, who have a reduced number of follicles responding to the FSH, the hormones – gonadotropins
. This results in poor IVF outcomes.
Normally, women with a low ovarian reserve have a low ovarian response, and this is because they have less amount of follicles. They will produce a low amount of eggs.
To define the poor ovarian response, there is ‘The Bologna criteria
‘, which was created in 2011 and these criteria include:
- advanced maternal age
- the previous cycle cancelled or less than 3 oocytes retrieved in a stimulation
- low AMH or low antra follicle count
To diagnose a poor ovarian response, we need 2 of these 3 criteria. The expert criticized these criteria because they didn’t give tools for the physicians to help these patients. Therefore, in 2016, ‘The Poseidon criteria
‘ was created, and these criteria will serve as a guide to personalized treatment protocols, and it was a set of newly established criteria for low prognosis patients, and they took into account:
- the age
- the antral follicle county (AFC) & AMH
- the ovarian response provided that the previous stimulation cycle was performed
With that, the Poseidon group created 4 groups. For each group, they had a specific treatment for improving the outcomes.
Strategies for improving the outcome
If the woman has a low ovarian reserve and doesn’t want to get pregnant soon, we have to inform her about fertility preservation through oocyte vitrification. The first step is to prevent it.
When we are facing a couple with a history of infertility and a low ovarian reserve, we have several tools to try to improve the outcome. Some strategies can help those patients. It’s very important to personalize the treatment, as every patient is different. The treatment should be based on age, BMI, previous treatment, etc.
Examples of treatments that can improve the oocyte yield:
It has been demonstrated that the treatment with testosterone or with DHEA (testosterone precursor) offered before the stimulation (at least 21 days before) can improve the oocyte yield, and so it can improve the embryo yield. Every single oocyte matters in these patients because they have a very low number of them, so if we can improve the oocyte yield, we can always improve the embryo yield. Therefore, the pregnancy rate increases.
- personalized ovarian stimulation protocols
We have different protocols where different drugs are used. They are non-standard drugs for this kind of patient. The use of high doses of hormones doesn’t help. If we gave a high dose, it wouldn’t mean we will get more eggs, we could even do more harm to the patient.
It means that we perform a few cycles and then only perform an embryo transfer when we have at least 2 or even 3 good quality embryos. To get to that point, we sometimes have to repeat several cycles.
- double stimulation; DuoStim
It means we would perform two stimulations in a single menstrual cycle. It’s one stimulation in a follicular phase, and then 5 days later, we start stimulation during the luteal phase. In this kind of patient, it has been demonstrated that it can improve the oocyte yield, and therefore, the pregnancy rates. Dr Aguilar added that at Equipo Juana Crespo, they offer this to foreign patients when they have a very short frame of time to do their stimulation. It’s always better to perform two cycles in a short time than just wait 1 or even 2 months to perform another cycle.
- PGT-A (Pre-implantation genetic testing)
Dr Aguilar advice is to perform PGT-A if there is advanced maternal age. Dr Aguilar added that some authors argue that in women with less than 4 oocytes retrieved, the PGT-A doesn’t help because sometimes they can’t even get any blastocysts to be biopsied, so it doesn’t improve the pregnancy rates, although it can decrease the miscarriage rate. However, as she mentioned, performing PGT-A in a patient of advanced age who has low ovarian reserve can increase the pregnancy rate.
One of them is called ovarian rejuvenation. We can perform an ovarian surgery to do some cuts on the ovary, and these cuts help to increase some molecules, some growth factors that can increase the antral follicles. There is also another treatment called Platelet Rich Plasma (PRP) infusion. It contains a lot of growth factors that can activate the primordial follicles and then can improve the number of follicles.
In the end, if we have performed all available options and we have not been successful, there is an egg donation option, but it’s only advised when we have tried everything up to that point.
Dr Aguilar concluded that low ovarian reserve is an entity with several causes. The most frequent one is the one related to age. The older the woman is, the lower quantity of eggs we have. It’s very important to perform a screening of the ovaries before trying to spontaneously conceive, and if we see that we have a low ovarian reserve, we have to consider family planning. This entity represents one of the most challenging issues of assistive reproduction, but there are some strategies to improve the result. It’s crucial to individualize treatments according to patients’ characteristics.
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