In this session, Dr Mauricio Gómez, Gynaecologist specialized in Endocrinology and Reproductive Medicine at Reproclinic, Barcelona, Spain, has talked about the concept of poor ovarian response (POR), its strong relationship with age, and the concept of personalized treatment.
Before defining the complex concept of POR (Poor Ovarian Reserve), Dr Gómez explains the main parameters considered defining it, such as:
The Antral follicle count is the number of follicles that can be seen on an ultrasound, which have the potential to be stimulated during ovarian stimulation. They are considered to be less than 10 millimetres observed at the beginning of the cycle, and they will be able to mature and grow after an ovarian stimulation of that cycle. It has been demonstrated that less than six total follicles are associated with higher cancellation rates. This cancellation, as the interruption of the cycle, is due to a poor response during the stimulation phase.
The Anti-Müllerian Hormone is a blood test parameter not influenced by the moment of the cycle. It’s produced by the granulosa cells of the antral follicles, and levels under 1.0 nanograms per millilitre are treated with a low response to stimulation. In addition to this, values of 0.4 ng/mL are associated with an 8 percent chance of obtaining less than 4 eggs at first stimulation.
The ovarian response to stimulation is the number of eggs retrieved after a standard ovarian stimulation cycle.
The process of reproduction is genetically programmed and progressively declines with ageing. From birth to the age of 30, the number of follicles decreases slowly, and the follicular depletion accelerates, having a dramatic reduction from the mid-30s. At the same time, the rate of poor oocyte quality increases with age, much earlier than you can imagine.
As can be seen, near the age of 40, it’s very difficult, theoretically, to find eggs able to give a rate of healthy embryos.
Moreover, Dr. Gómez shows the relationship between age, quantity, and quality of oocytes.
The quality is the ability of the egg after an immediate insemination in an assisted reproductive treatment to create an euploid embryo, meaning an embryo without chromosomal disorders. In order not to be confusing, Dr. Gómez states that a healthy embryo is a synonym of an euploid embryo.
An important concept to take into account is that approximately 4 eggs are needed to obtain at least one healthy blastocyst or embryo. With ageing, more oocytes are needed for this aim, and it’s a fact that with ageing, fewer eggs can be retrieved.
In patients older than 42 years, more than 20 oocytes are needed to achieve at least one healthy embryo. As you can imagine, this is an extremely difficult situation in this case.
In the past, the lack of consensus on the definition made the standardized management of this condition very difficult to compare and, consequently, an ideal treatment had never been defined.
From 1983 to 2011, 47 random studies were conducted, with 41 different definitions of this concept. For this reason, the BOLOGNA criteria were introduced as the first complete attempt to write an international consensus on the definition of POR by following evidence-based guidelines. The main aim was to unify all the definitions into only one.
What criteria must be present to classify a patient as a poor responder according to Bologna criteria?
According to the Bologna criteria, at least two of three features are required to define poor ovarian responders.
In spite of the success of the Bologna definition, some criticisms arose due to the fact that the population of patients embraced by this definition was too broad, not distinguishing sufficiently based on a woman’s age, ovarian function, and clinical history.
What is the POSEIDON (Patient-Oriented Strategy Encompassing Individualized Oocyte Number) classification?
In 2016, a group of researchers gathered together to establish the POSEIDON group to improve the diagnosis and management of patients with POR. POSEIDON is an acronym meaning Patient-Oriented Strategy, Encompassing Individualized Oocyte Number.
Regarding age, ovarian biomarkers, and the number of oocytes retrieved in the previous ovarian stimulation cycle, Dr. Gómez classified patients into 4 groups.
Dr Gómez reiterates that the main aim of the classification is to stratify the groups to personalize treatment or to optimize the number of oocytes retrieved to improve pregnancy rates.
To explain why a poor ovarian response occurs, Dr. Gómez states that the main reason is a reduced number of functioning follicles. The main cause is age; however, other causes decrease the number of eggs, such as the following:
For this reason, it’s important to ask for a karyotype in all cases before starting an IVF treatment and to take into account whether a low number of follicles is the only cause of POR or if there are others.
Dr Gómez explains that there’s not always a single correct dosage of Gonadotropin for a given patient, and not all patients have the same response to the same kind of Gonadotropin. On the other hand, the genetic variability of FSH and LH receptors can show differences between patients depending on how the hormones interact with follicular cells.
Considering the defining concepts of the main classification of POR and its causes, Dr. Gómez talks about the management strategies for patients with POR.
The first important concept to know is that no treatment is better than another. However, every treatment can help in selected patients, and each of them should have their personalized approach, including one, two, or several of these strategies.
Dr Mauricio explains the first strategy with a real example, clarifying what would happen if they started ovarian stimulation from the second day of the cycle with a previous pretreatment with estrogens or contraceptive pills.
As can be seen in the upper picture shown by the doctor, some of the follicles have been activated before others, and the growth is irregular and asynchronous. At the moment of the collection, not all of them have the same size, and the oocytes inside present different maturation stages; therefore, the doctor can retrieve fewer mature eggs than expected initially.
Conversely, if they use pretreatment, they have more chances of synchronized follicle development, and this is why the probability of retrieving more mature eggs increases.
In the following graph, it can be seen how they use medications. The estrogens are given 7 days before menstruation, between 4 and 6 milligrams daily. After menstruation, on the day when the estrogen is needed, they can start ovarian stimulation the day after.
Moreover, contraceptive pills are given from the first day of menstruation, continuing for 10, 12, or 14 days. After stopping this intake, a 5-day break takes place, and then ovarian stimulation starts.
According to Dr. Gómez, for a long time and even nowadays, there has been discussion about which ovarian stimulation protocol is the best to collect more eggs. In the following graph shown by the doctor, the main protocol types can be seen: the long cycle with agonists or the antagonist cycle.
The main aim of this medication is to block the gonadotropin-releasing hormone (GnRH) to prevent a surge of luteinizing hormone (LH) before oocyte retrieval, and the timing is very important to avoid premature ovulation that could happen during ovarian stimulation.
In the long agonist cycle, this agonist medication starts one week before menstruation and maintains the suppression of pituitary function at the beginning of stimulation with gonadotropins.
During stimulation, the medication must be continued with half doses until the triggering phase, which is the final medication provided to complete oocyte maturation. This must be given around 36 hours before retrieval.
In the antagonist cycle, ovarian stimulation starts on the 2nd or 3rd day of the cycle. The antagonist is introduced from the 6th or 7th day of stimulation when the size of the biggest follicle reaches approximately 14 millimetres. Then, maturation continues until triggering.
Dr Gómez goes on to state that ovarian stimulation with progestins from the beginning of the cycle has been demonstrated to be a patient-friendly option to avoid the use of agonists and antagonists, while still achieving similar results in terms of oocyte numbers and pregnancy rates. This could be another alternative to avoid the GnRH surge.
Furthermore, the doctor explains the comparison between the agonist and antagonist cycles. The final and most important concept is that there are no significant differences in pregnancy rates between them; however, the difference noted by Dr. Gómez is in how patients respond to the protocols.
For the agonist cycle there’s a classical treatment and more days are needed; nevertheless, the risk of irregular or asynchronic growing of the follicles is lower. On the other hand, the treatment can only be done with Human Chorionic Gonadotrophin.
In the antagonist cycle, there are fewer days of medication needed, but there’s a higher risk of asynchrony that can be improved with the addition of contraceptive pills or estrogens. Also, the final triggering can be done with two different medications. Dr. Gómez clarifies that he hasn’t talked about the risk of ovarian stimulation syndrome because in POR, as you can imagine, it is less common. However, it’s interesting to know that in the antagonist cycle, they can prevent it with the GnRH agonist.
Actually, Dr Gómez recognizes that the antagonist cycle is more used in daily practice, yet in some cases, for instance in asynchronic cycles, the agonist cycle is used with success. In patients with very low ovarian reserve, group 3 or 4 of Poseidon or patients with a previous and very low response in the standard high doses of gonadotrophins, a paradigm change must be done. In the cases presented by Dr Gómez, he clarifies that more hormones don’t mean more oocytes or better results.
The four examples presented show the same number of oocytes with less stress and medication.
Proper planning starts the antagonist at the right time and right moment.
They can add clomiphene to stimulate the androgynous reproduction of FSH and add gonadotrophins to the oocytes every 48 hours. After that, the response can be monitored closely. The extreme of this treatment or group, is the natural cycle or modified natural cycle. In the cases presented by the doctor, they wait for the development of one follicle with difficulty to achieve one healthy embryo. Moreover, the idea to accumulate eggs or embryos, repeating several cycles, is interesting.
With regards the kinds of gonadotrophins, there are no differences in pregnancy rates and it has been demonstrated between urinary or recombinant FSH. The decision of using one or another can be taken attending the availability, cost, experience or physician’s preferences.
Dr Gómez goes on by explaining the question related to the LH activity of the Human Menopause Gonadotrophin. The main activity is effective in all groups of POR and it’s important to include the number and maturity of oocytes. Usually, physicians use a combination of more than one.
There are new gonadotrophins like FSH Delta that try to personalize the treatment including the egg, AMH, and the weight of the patients with no worse results.
What dose of gonadotrophins is recommended? Before starting an ovarian stimulation, physicians must check the eggs, ovarian reserve markers, answers to previous treatments, and weight of the patient.
The average starting dosage is about 150-225 International Units or FSH, adding a combined therapy between 75-150 of Human menopausal gonadotropin. In addition, it’s very important to weight the patient;
On the other hand, this would be considered a very low ovarian reserve, thus the paradigm must change. The doctor states they’re working with a lower dosage of hormones and the idea is always to personalize the treatment.
Dr Gómez mentions 3 additional therapies to increase the chances of pregnancy in patients with POR.
This is a steroid, androgen precursor related with a positive effect in follicular development and oocyte quality. Between 6 and 12 weeks before the ovarian stimulation, the intake of this 3 times per day, is related to best pregnancy rates and less miscarriage incidents.
This hormone increases estrogen synthesis, increasing the receptors for FSH, which stimulates the growth of eggs. This intake between 5 days or 5 months before the ovarian stimulation can increase the answer.
This is injected daily from the 3rd day of ovarian stimulation influences the egg maturation, increasing the ovarian sensibility for stimulation medication, and promoting the early follicular development.
We have to consider there are few studies about these 3 options and the complete protocol with high-tech measures has not been established yet. – states Dr Gómez.
According to Dr Mauricio Gómez, several substances added as nutritional supplementation can increase the quality of oocytes and enhance reproduction.
The main fact is the decrease of the oxidative stress which may be useful for other patients; however, there seems to be better results in young patients with low ovarian reserve.
These supplements are:
There are also benefits to having a healthy lifestyle. This has been demonstrated in all areas of medicine. Reproductive medicine isn’t an exception; Mediterranean diet, frequent regular exercise including activities of high impact, and other activities like yoga and mindfulness can be effective to contribute to better results.
On the contrary, you must stop toxics and have a life less stressful. This should be one of the most important strategies to optimize your chances, considering that the same process of fertility and treatment becomes stressful.
Dr Gómez mentions other strategies. He explains that the increasing knowledge of human ovarian molecular waves open new options, providing stimulation to improve effectiveness and efficacy of an IVF treatment.
The classic area stating that a single cohort of antral follicles could only grow during the follicular phase has been overtaken by the evidence that follicles may be recruited at any time of the menstrual cycle, as it can be seen in the picture shown by the doctor. There you can see the molecular cycle, post-ovulatory cycle, and pre-ovulatory.
This gave new possibilities or control of ovarian stimulation to further explore the ovarian microenvironment, especially for patients with POR.
According to this evidence, a new strategy called DUOSTIM was applied by various collaborators. It consists of two stimulations in the same cycle. After the first collection, there’s a 5-day stop or cleaning to start the ovarian stimulation again.
The oocytes obtained from the second phase of stimulation or luteal phase, seems to be, at least, far more competent than those obtained from the first part of the stimulation or first phase.
Therefore, the increased number of oocytes collected during the ovarian cycle with the Duostim approach, may significantly increase the chance to produce a healthy embryo to transfer, especially in patients who have a reduced ovarian reserve.
Dr Gómez further talks about three obvious strategies:
This may be a good option to increase the number of eggs, especially in patients with very low ovarian response.
It’s an interesting idea, but a cost-benefit study must be done because they’re talking about repeating more stimulation cycles. This means more education, more cycles, and more.
This is before the egg collection and must be considered if the ovarian answer during the stimulation is lower than expected. This can happen in group 1 or 2 of Poseidon, patients with unexpected negative answers.
If physicians observe this unexpectedly low response before the punction, they can stop the stimulation after consulting with the patients, try to study the cause and find another strategy for better results.
The egg donor is always the last chance, and even though is not related to this topic, Dr. Gómez states that people have to know that this is the best choice to have success in terms of ongoing pregnancy.
The most important difficulty is giving up the chance of becoming pregnant with your oocytes and accepting the contribution of a donor in their productive project.
This is a very personal decision, always respected. – clarifies the doctor.
After the doctor’s presentation, he mentions some take-home messages or conclusions.
Gonal F is a recombinant gonadotrophin. Theoretically, the bioactivity is the biggest of all the families of the gonadotrophin, but there are other hormones with the same capacity to stimulate your ovaries. We cannot talk about the best drug because, for example, Gonal F is a commercial name. The main active hormone is recombinant follicular stimulant hormone, and we can find it in the same hormone, with other commercial names with the same effect. The reactivity is good, but for example, this hormone, probably in this case, Gonal F doesn’t contain LH that in some patients, especially in low ovarian responders from an age, can be necessary to increase the quality. We prefer, in our treatments and apart from a donor or any equivalent, to add medication with LH activity. Talking about any commercial name, it’s recommended to combine it with another hormone.
Firstly, we have to consider that this other treatment I have explained on the testosterone hormone, is a co-treatment that until now has demonstrated a small increase in several eggs in quality. In terms of pregnancies, it’s very difficult to establish because we haven’t done any complete study with scientific evidence, but the action of a medication that must be given between 6 and 12 weeks before starting the ovarian stimulation increases the local follicular levels of this testosterone to get converted in estrogens. There are patients with high levels of testosterone who aren’t the ideal patients to give this medication.
That’s why before starting a treatment with this hormone, it would be useful to ask for a complete blood test to see the levels. When the basal testosterone levels are high, it’s more about the discussion for the companies to add this medication as a pre-treatment. The theatrical dose is about 3 a day, 25 milligrams, every 8 hours. In this case, it should be in discussion, but for example, it’s interesting to know about this patient who has all the information and if she wants to make an appointment, it would be nice to talk to her.
HMG means Human Menopause Gonadotrophin. It’s a hormone obtained from the urine, of the menopausal woman, that contains the same proportion between FSH and LH, liquid stimulant hormone, and luteinizing hormone. In this case, for example, when we’re talking about patients more than 40 years old, we have seen that the addition of this hMG can increase the answer and the quality of the eggs. In this particular case, I’d like to personally talk with the patient, but the body mass index may be difficult to answer for the treatment because more BMI, more difficulties to answer to medication, and more doses are needed to have the same result and fewer eggs can be obtained. The age, as I said before, makes it more difficult to obtain a healthy embryo and, theoretically, at a medium rate, 20 eggs are needed to obtain at least one healthy embryo. That’s why we ask that age, BMI, and doses are important, but it’s not the main problem in this case. However, for example, apart from the FSH, talking about the stimulation, I would recommend the addition of the other hormone, but always individualizing the case. It should be analysed.
Yes, obviously. I have written about it because there’s little evidence. I can give, for example, to this question, these studies show a small increase in the choice of having the best quality and good results. There are studies and resonance studies which are talking about this. It’s important to know that these medications, in some countries, are controlled substances. For example, here in Europe, sometimes it’s not like a supplementary nutritional complement of hormone, that’s why it’s always in discussion: to what point is it easy to take and use? However, the recommendation is always individualized in any case and evaluates the balance between possible side effects and benefits.
In this case, I have to recognize we’re talking about a difficult case. Sometimes, after trying with high doses of gonadotrophins, we haven’t collected eggs to find a healthy embryo or an embryo, it’s a moment to think about changing the strategy. That’s why, in some cases, before arriving at the egg donor, which would be the last option, it would be possible to try the basic alternative strategies of ovarian stimulation, like the natural cycle with less medication, because this is the right example that not with even more hormones we can obtain more eggs. That’s why a change of paradigm, in this case, might be done. Taking into consideration, the choices of becoming pregnant with their own eggs must be difficult in this case.
Just to clarify, yes, this is a correct proportion. Some centres add more [unheard] from the beginning, and this is a correct proportion, but just near the top recommended because, in these cases, there’s a top, and over this top has not been demonstrated to have more eggs. Apart from the cost of the treatment, the circumstances with the treatment, and not giving more than 450 doses of FSH and LH, we can get better results. In this case, I consider this a top or a medication option for the oocytes. About the proportion, this is a good option.
This patient would be in group 1 in the Poseidon classification because we’re talking about a young patient. Theoretically, a young patient has better problems because of the quality of these eggs, the possibility of having a healthy embryo increases radically, and it’s a good ovarian reserve, that’s why ovarian stimulation is your only answer. The protocols with the dosage of FSH, perverts that are combined with FSH, and long Pergoveris are very low in response. Sometimes, one of the possible causes of low ovarian response is a small disorder in the receptors of FSH at the cells of the follicles that can do, with theoretically a good dosage to young patients, the answer is not as good as expected, it’s a bad response.
That’s why there’s a possibility to study a structure called Polymorphism of the same receptor, and this is a test that many laboratories can do to see if there’s any disorder in these receptors that makes this patient especially sensible or resistant to any complete kind of gonadotrophin. I can send this patient the test to see if she’s a patient with a particular receptor more resistant to the action of the gonadotrophin because we have to recognize this is an unexpected negative answer. That’s why more studies might be drawn to know what happens like all the cases should be studied in a consultation.
This is a question very difficult to answer because if we’re talking about success rates with own eggs, I have to recognize that from 45 to 50 years old, the choice in the possibility of having success is not 0% but near 0. After all, the best approach for the 44, 45-year-old, patients that are asking me for advice to become pregnant is donor eggs. I know it’s difficult to tell patients, but the statistics show a reality that we have to assume. In this case, you have to be true, and choices are very difficult. From 40 to 43 years old, it’s important to say, it’s very difficult because we add two difficulties on the number of eggs; in some patients, it can be good with 40–43 years old, but the bigger difficulty is the quality and the chances of having a euploid embryo.
That’s why, it’s important to know that every year, from 40 to 43, important, I cannot give only one person to apply the same statistics to everyone, talking about 20, 25% of ongoing pregnancy rates with own eggs, the better promising rates for own eggs. If we talk about donor eggs, I know it’s not today’s topic, we are talking about raising the choices by more than 60, 70% the first time, and it would be the paradigm to be completed. Connected with the other question, you have to consider that from 38 years old, not 40, we strongly recommend the embryo biopsy to study if it has chromosomic disorders; PGD or PGT, depending on the name. That’s why this is a more difficult step because the choice to have an euploid, meaning a healthy embryo, from 40 years old, is not easy. When we have taken this healthy embryo from the patient, the choices increase dramatically to 80, to 90% because the quality of the embryo is the most important, not promising, to have a healthy baby. In this case, not only pregnancy test positive, we’re talking about a healthy pregnancy and a healthy baby.
It depends on many factors, for example, the number of eggs and finally, the number of embryos they get after a treatment. For instance, from a first ovarian stimulation, we take less than 3 eggs, there’s a low ovarian response, and for these eggs, we aren’t able to achieve any embryo, maybe any embryo to make this PGT study. That’s why we talk to the patients, and sometimes a second try with a different kind of stimulation, with different strategies, we can try looking for another better response. That’s always thinking about taking a few months and, if after one, or 2 treatments, there’s a moment in which a physician talks to the patient and tries to consent to the possibility or to accept the fact of donor eggs.
This is a very good question because there’s an opinion from some groups that, to justify the increase of the quality of the eggs, the increase of the quality of these embryos, and the possibility of having a healthy embryo, they relate with the dosage of hormones. This natural [unheard] opinion, talking about decreasing the doses of stimulation to have fewer eggs with the best quality, it’s very controversial because when we’re talking about having it become a healthy embryo, we prefer to have from the beginning more eggs considering that it’s like an obstacle race: more eggs we start, more choices to become to have an embryo.
But when we’re talking about patients with low ovarian reserve, sometimes the idea of decreasing this ovarian stimulation can produce the same amount of eggs, but with less pharmacological or hormonal stress. This is an interesting theory, there are studies about it, is always difficult to be evident. This is an interesting question; how our philosophy from the beginning, still finding a low ovarian response, is to try to start with a good dosage stimulation to have more eggs? If after the first time, we’re not able to get a normal number of eggs, that’s why we change the strategy. In these cases, we try to decrease the dosage to have better quality, considering normal means more eggs.
About the number of dosages, we use the top hormonal level between FSH recombinant and hMG about 375, not more dosages. This combination treatment, between recombinant FSH and human menopausal gonadotrophin, is very useful to stimulate the ovarian from both different kinds of hormones; the FSH, like a colloquial term, is more laboratory, a more synthetic hormone, and the hMG is a more natural, coming from the human patient, and with this extra [unheard] activity that seems to be useful in patients low ovarian and with ageing.
This is a very good question because there’s an opinion from some groups that, to justify the increase of the quality of the eggs, the increase of the quality of these embryos, and the possibility of having a healthy embryo, they relate with the dosage of hormones. This natural stimulation opinion, talking about decreasing the doses of stimulation to have fewer eggs with the best quality, it’s very controversial because when we’re talking about having it become a healthy embryo, we prefer to have from the beginning more eggs considering that it’s like an obstacle race: more eggs we start, more choices to become to have an embryo.
But when we’re talking about patients with low ovarian reserve, sometimes the idea of decreasing this ovarian stimulation can produce the same amount of eggs, but with less pharmacological or hormonal stress. This is an interesting theory, there are studies about it, is always difficult to be evident. This is an interesting question; how our philosophy from the beginning, still finding a low ovarian response, is to try to start with a good dosage stimulation to have more eggs? If after the first time, we’re not able to get a normal number of eggs, that’s why we change the strategy. In these cases, we try to decrease the dosage to have better quality, considering normal means more eggs.
About the number of the dosage, we use the top hormonal level between FSH recombinant and hMG, about 375, not more dosage. This combination treatment, between recombinant FSH and human menopausal gonadotrophin, is very useful to stimulate the ovarian from both different kinds of hormones; the FSH, like a colloquial term, is more laboratory, a more synthetic hormone, and the hMG is a more natural, coming from the human patient, and with this extra LH activity that seems to be useful in patients low ovarian and with ageing.
In this case, the dual triggering we do with one Ovitrelle attempt with 0.2 milligrams of Decapeptyl to add more [unheard] with medication. We administrate, maybe separately half an hour, before 36 and 34 hours before the ovarian stimulation. There are different theories about the separation between both of them; when there is an antral follicle sometimes some physicians use, firstly, Decapeptyl or in this case, GnRH to stimulate the discharge of the egg after 36 hours, and 36 hours before, we add this point. Some physicians, for example like me, prefer to do first of all Decapeptyl just 36 hours before and, half an hour later, Ovitrelle. Theoretically, the action can happen at the same time as the ovarian retrieval.
With the names of some studies, I have them, not now, that’s why I can send them to you. In this case, for example, it’s a personal decision with the scientific evidence. I like the Human menopause gonadotrophin very much, consider it the balance between what hormones get from the beginning with a bit of [unheard] activity, they show me good results with the reality of low ovarian reserve, for example, in this case, we’re talking about a low Anti-Müllerian hormone. With the number of follicles, we can always try with 6 follicles.
