WHAT IS THE ‘IMPLANTATION WINDOW’ IN FERTILITY TREATMENT AND HOW TO IMPROVE IT?
SIGN UP AND GET ANSWERS LIVE >

How can we predict IVF outcome in poor ovarian responders?

Dr Ángela Llaneza
Fertility Specialist, Clinica Tambre

Category:
Advanced Maternal Age, Low Ovarian Reserve

poor-ovarian-reserve-ivf-outcomes
From this video you will find out:
  • What is ovarian reserve & and how is it measured?
  • What does low ovarian reserve mean, and how can it be improved?
  • What role does age play, and does it make a difference?
  • What strategies can help with improving the prognosis?

How can we predict IVF outcome in poor ovarian responders?

In this webinar session, Dr Ángela Llaneza, Fertility Specialist at Clinica Tambre shared her expertise on the intriguing topic of predicting IVF outcomes in poor ovarian responders. Poor ovarian response, also known as low ovarian reserve, poses a significant challenge in fertility treatments. However, with advancements in reproductive medicine, there have been promising developments in identifying markers and predictors that can assist in determining the success rates of IVF in such cases.

Woman’s physiology & age

In essence, the production of oocytes occurs during fetal development when our mothers were pregnant with us. Even then, the ovaries were capable of producing millions of follicles. At birth, there are already millions of oocytes present, but by the time puberty begins, this number decreases to around 400,000-600,000. From that point onward, there is a constant loss of oocytes until menopause. This loss is initially slow but accelerates significantly after the age of 35.

Nowadays, due to various reasons, women often postpone their plans for motherhood, leading to situations where there are not enough retrievable oocytes in the ovaries to achieve a good prognosis and high success rates during IVF treatments. Some women may experience premature ovarian failure, where there is a loss of menses and a lack of follicles in the ovaries before the age of 40. On the other hand, some women may have a slower decline in ovarian reserve and still have a good number of follicles in their ovaries, even at unexpected ages.

Assessing the ovarian reserve, which refers to the reproductive potential of the ovaries, is crucial before starting any IVF treatment. It helps us understand the status of the ovaries and their ability to respond to ovarian stimulation. It’s important to note that ovarian reserve is not very useful in predicting pregnancy rates, but is valuable in predicting the response to ovarian stimulation.

Ovarian stimulation is the process we use to maximize the number of growing follicles in the ovaries. In a natural cycle, only one dominant follicle is typically selected for ovulation, while the others undergo atresia (follicular death). However, with ovarian stimulation, we create conditions that allow multiple follicles to continue growing, thereby saving them from atresia. It’s essential to dispel any myths or misinformation surrounding ovarian stimulation, as it does not trigger early menopause or lead to a premature loss of follicles. We are merely utilizing the follicles that would have been lost otherwise.

Before starting the IVF process and ovarian stimulation, it’s crucial to have an idea of the number of oocytes that can be obtained. The more oocytes, the greater the potential for producing more embryos during the culture process. Studying the ovarian reserve can be done through two accepted methods: measuring anti-Mullerian hormone (AMH) levels and performing a transvaginal ultrasound scan in the first days of the menstrual cycle to assess the ovaries and count the follicles.

Ovarian reserve

Follicles are an important indicator of ovarian reserve. Typically, we consider ovarian reserve to be normal when the AMH (anti-Mullerian hormone) level is higher than 1.1 nanograms per millilitre or when there are between 6 and 10 follicles. If both the AMH level and the antral follicle count are normal, it suggests that the patient will likely have a normal response to ovarian stimulation. This means we could potentially retrieve between 10 and 15 oocytes, which is considered within the normal range. On the other end of the spectrum, a high ovarian reserve indicates a higher response to stimulation, with more than 15 oocytes. However, today we will focus on a lower ovarian reserve, which poses significant challenges.

A low ovarian reserve refers to a situation where the reproductive potential is diminished due to a decrease in the number of remaining follicles in the ovary. This results in a lower number of retrievable oocytes. We diagnose a low ovarian reserve when the AMH level is below 5.5 pmol or 1.1 ng/mL. The units used may vary depending on the country or laboratory. Additionally, an AFC below 5 is also an indicator of low ovarian reserve. There are other criteria to diagnose and classify patients with lower ovarian reserve, such as the Poseidon criteria, which consider age (above or below 35 years) and past response to previous cycles of ovarian stimulation.

When we face a low ovarian reserve, we are concerned because it means the response to ovarian stimulation will likely be low. A lower response means having fewer than four oocytes retrieved. This could be due to a lack of follicular growth or even when follicles grow, none of the oocytes are collected. It’s worrisome because the first step to having embryos is having oocytes, and the more oocytes we have, the more chances and embryos we could have at the end of the embryo culture.

You might be interested in: IVF with Low AMH – Exploring Treatment Choices

Ovarian reserve & age

Age does make a difference. There’s an ongoing discussion regarding the causes behind the low reserve. After the age of 40, there is a natural decrease in the number of follicles. However, the process can occur earlier or later for different patients, even without chromosomal or genetic abnormalities explaining the low reserve.

We cannot predict individual outcomes accurately. Success rates and statistics can give us an idea, but the results vary from person to person. We can’t say with certainty how many oocytes will be retrieved or how many will result in viable embryos. It’s a challenge, but we always strive to maximize our chances and provide the best care.

Using up-to-date, individualized protocols and an experienced medical team and lab can make a difference in the ovarian response. Each extra oocyte counts. While we cannot perform miracles or dramatically increase the number of available follicles, every additional oocyte contributes.
It’s essential, to be honest with patients and not discourage them, even if the chances are low. Each patient is unique, and each ovary responds differently. Second opinions are valuable if there are doubts or hesitations about the treatment or expectations.

Conclusion

In conclusion, do not be discouraged before consulting with fertility specialists. Knowledge and experience of the centre make a difference when it comes to the number of potential oocytes that can be retrieved. Beware of false promises and seek reputable centres with the latest knowledge and technology.

- Questions and Answers

Can you explain to us how AMH is measured? Is it an absolute value based on the blood sample provided or extrapolated to the weight of the person? I am asking because I accidentally gave my clinic the wrong weight.

The weight itself does not play a role in AMH measurement. The weight does play a role in adjusting the dosage, and initially, the measurement of AMH in picomoles was used for a specific gonadotropin whose dosage is calculated based on the patient’s weight. But don’t worry, it shouldn’t affect the value of AMH.

If you have premature ovarian failure, can you take DHEA? What dosage?

Here, I want to clarify something. We talk about premature ovarian failure when the patient has already gone into menopause, which is a clinical diagnosis. There’s a lot of misunderstanding between premature ovarian failure (early menopause) and low ovarian reserve. DHEA might be useful to treat some symptoms related to premature ovarian failure, but the advised treatment is hormonal replacement therapy or the contraceptive pill in some cases. As for DHEA’s utility to improve overall ovarian reserve, it is not proven yet. The recommended dosage should be between 50-75 milligrams a day, and it might even improve oocyte quality, but I insist that it is not proven. Normally, considering it is something cheap over the counter with no side effects, I’m very fond of it and always advise you to use it. We stop it once we start the ovarian stimulation, and if not, we change it to the active form, which is testosterone. But I insist that there’s no clear scientific evidence behind it.

If you have previous referrals, is it better to do a natural IVF?

This is a very controversial topic, and I’m not a big fan of natural IVF. I think that if we are going to go for medical treatment, we need to, at least at the beginning, try the most accepted strategy, which is ovarian stimulation with gonadotropins. We can reduce the dose and cost by using oral drugs like clomiphene or letrozole. But we know that many naturally occurring cycles might be anovulatory, meaning that we won’t have an oocyte. Making a patient undergo monitoring ultrasounds and potentially retrieval under sedation with a low likelihood of having an oocyte is not an option. These kinds of situations outside the norm need to be discussed together in the consultation, and we decide on a case-by-case basis.

I’m from Ethiopia. My wife’s AMH result is 16 ng, and all FSH, LH, estradiol, and prolactin results are normal. But still, there is no menstruation, my wife is 26. What shall we do?

An AMH higher than 16 ng points towards a high ovarian reserve, which is very compatible with polycystic ovaries, a situation in which there is anovulation, and in some cases, even amenorrhea. My advice is to go to a gynaecologist to get an in-depth assessment. There are many exams we do, general hormone profiles, and try to see if actually, the reason is polycystic ovaries in that situation. What we do normally is try to improve the situation with metformin, and it’s also important to control weight as there are many endocrinological issues behind it. Normally, if we know that menstruation is not coming because the cycles are anovulatory, one of the classical treatments was trying to help those ovaries recruit follicles, release oocytes, and then sustain the luteal phase after ovulation.

You mentioned that to diagnose someone with low ovarian reserve, you look at AMH and follicles. Which is more important, or are they both just as important?

To me, they are both just as important. It is not very clear which one weighs more, whether it’s AMH or the follicle count. When we’re assessing ovarian reserve, we take into account both factors to have a comprehensive understanding of the patient’s ovarian function. So both AMH and follicles are considered equally important in the diagnosis of low ovarian reserve.

Are there specific things that can help improve ovarian response in individuals with endometriosis and low ovarian reserve? Can DHEA worsen endometriosis?

Endometriosis can affect fertility in multiple ways, including damaging the ovaries. To improve the ovarian response in endometriosis, we usually focus on treating ovarian reserve using standard protocols. There is no specific protocol for endometriosis that has proven to be better. As for DHEA, its impact on endometriosis is not clear. However, maintaining lower estrogen levels during ovarian stimulation may be beneficial for improving the response.

I am allergic to metformin, and the gynaecological evaluation is normal. Any other advice in this situation?

Without a detailed assessment and blood tests, it is challenging to provide specific advice. However, there are alternatives to metformin, such as inositol and certain B-group vitamins, that may help with PCOS or polycystic ovaries. Lifestyle changes, including dietary improvements and increased aerobic exercise, may also be beneficial. It is important to address any hormonal imbalances through proper testing.

Does PRP (platelet-rich plasma) ovarian rejuvenation help increase the Antral Follicle Count (AFC)? What is your experience with DHEA, CoQ10, and other supplements?

PRP is a trending topic in fertility treatment. It involves using platelet-rich plasma, which contains growth factors, to potentially stimulate dormant follicles. However, PRP is still experimental, and its effectiveness in ovarian rejuvenation has not been proven. It is important to note that ovarian rejuvenation is not currently possible. Regarding supplements like DHEA and CoQ10, their impact on fertility varies, and individual experiences may differ. It is essential to consult with a healthcare professional before starting any supplements.

I’m 43. Went from AMH 0.5 one month ago to 0.2 last week. I’m currently undergoing dual stimulation. My doctor prescribed 150 UI of FSH, planning to increase it to 225 UI. I’ll be using a dual trigger. After two shots, I had four mature eggs from four follicles. Two eggs fertilized, one made it to day three, and the other was pushed to day six for PGTA testing but didn’t develop further in the second stimulation. Despite increasing the treatment, I only had two small follicles. I’m losing hope of getting any embryos. Is there a chance for more follicles to appear or for the existing ones to mature enough for retrieval? If so, when might it happen? My doctor mentioned the 29th of May but wasn’t certain. Could the drop in AMH be the reason for the poor response in the second stimulation?

Answering your question is tricky because I need more information about the stimulation you’re undergoing. There isn’t a clear protocol that works best for dual stimulation. Regarding your first retrieval, 4 out of 4 follicles yielding 4 eggs is an excellent result. 2 fertilized eggs are still good, although it would have been ideal if both embryos had made it to the blastocyst stage for biopsy. The quality of the embryos is a concern. The drugs used in the first stimulation, including the dual trigger, may have impacted the luteal phase response in the second stimulation. If you have only 2 small follicles, it might be best to cancel this cycle and discuss the situation in a consultation. Regarding your hope for embryos, if this is your first stimulation, there are potential changes that can be made to improve the outcome. The chances of success, based on the results you’ve shared, are less than 10%. If you still want to try, a new stimulation could be feasible with some modifications. However, I cannot predict when a good embryo will be produced.

Is it safe to do double stimulation before retrieval in hopes of getting a greater number of eggs after a failed cycle?

If by double stimulation you mean doubling the dosage of the gonadotropins, it won’t change anything. Using more than 300 international units of gonadotropins is generally useless. Increasing the dosage before retrieval would only increase costs without significantly improving outcomes.

Is it better to repeat with the same dosage in a second stimulation?

It depends on the medication used and your overall situation. If it’s your first stimulation and you had two empty follicles, trying a different protocol might be beneficial.

My doctor recommended DHEA. How long do you recommend taking it?

The evidence regarding DHEA’s impact on egg quantity and quality is unclear. I recommend taking it for at least one month, but ideally, 3 months would be the ideal duration if we assume it works similarly to how ovaries naturally function.

Do you prefer using FSH only or FSH + LH in stimulations for those with low ovarian reserve? Do you ever use high doses?

There isn’t enough evidence to support one protocol being better than the other for patients with low ovarian reserve. The response can be managed with either an antagonist protocol, long protocol, or ultra-flare protocol. No specific protocol has proven to be superior in terms of egg yield.
Understanding the Importance of Carrier Genetic Testing
Hysteroscopy before IVF:  can it improve outcomes?
Recurrent Pregnancy Loss challenges: causes and solutions
How to prepare for an embryo transfer to improve your chances: There’s more to consider than just the endometrium
Endometrial factor and recurrent failures in IVF: diagnosis and treatment
How old is too old for my IVF treatment?
Authors
Dr Ángela Llaneza

Dr Ángela Llaneza

Dr Ángela Llaneza is a Fertility Specialist at Clinica Tambre, Madrid, Spain.
Event Moderator
Caroline Kulczycka

Caroline Kulczycka

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.
Have questions about what factors will affect your IVF success?
Join our live event to directly ask your questions to three IVF experts.