In this webinar, Dr Ksenia Khazhylenko, Obstetrician-gynecologist, Fertility Specialist & Geneticist at IVMED – Fertility Center presented a case about a patient who was diagnosed with Premature Ovarian Failure in her 30s. Dr Khazhylenko explained all steps taken to help the couple achieve a pregnancy.
Generally, Premature Ovarian Insufficiency (POI) or failure (POF) is not a very common condition, and approximately about 1% of all women suffer from this. Premature Ovarian Insufficiency is a clinical syndrome defined by loss of ovarian activity before 40 years old.
It is characterized by changing menstrual function, raised gonadotropin levels, and a very low estradiol level. There are various reasons for its occurrence, it can be the iatrogenic reason, so it appears in women after a different kind of surgery on ovaries and uterine tubes, after chemotherapy and different types of aggressive therapy, there can be genetic causes, it can also be because of autoimmunity, infections.
However, in almost half of all cases of premature ovarian failure, the cause is not identified, and it is described as an unexplained or idiopathic cause.
The patient was previously pregnant and had 2 children conceived naturally, she wanted to have another child, but she didn’t have menstrual bleeding for the last 6 months. She had hot flashes, so she went to see a doctor, she was a busy, occupied woman with 2 small children and was constantly stressed. Her menstrual bleeding was regular all her life, and just for over half a year, it changed. Firstly, the cycles were prolonged, and then they completely stopped.
We performed hormonal tests, and she had a high level of FSH 56UI/L, a very low AMH level (0.09 ng/mL), ultrasound revealed that there were no antral follicles. The patient also had a raised level of TSH, we repeated the tests the next month, and the results were similar. The conclusion was that she suffered from Premature Ovarian Insufficiency.
We can do some tests to try to find the reason for this condition. So we advised to perform Karyotype, the result was normal. We also tested for FMR1 mutation, and there were no genetic problems, but we found some problems with thyroid function, it was a bit higher level of TSH and also a very high level of antibodies TPO-ab and normal prolactin level. The association between thyroid dysfunction and ovarian insufficiency is very common. Some data suggests that approximately 20% of all such patients have this association. Unfortunately, data is very conflicting, and there is no evidence that if we treat the thyroid and normalize this function, the ovary function will also become normal. In most cases, we don’t achieve this, but we should always try.
We decided to prescribe artificial Hormone Replacement Therapy (HRT), it was a small dosage of estradiol and micronized progesterone (200 mg).
I want to emphasize that we usually start from a very low estradiol level, and if a patient feels good, there is no need to increase this dosage because we are talking about quite a long time for replacement hormone therapy. Regarding the thyroid dysfunction, we added Levothyroxine 25mcg and advised to come to me after 6 months, but 4 months later, she came with a positive pregnancy test, and it was a normal pregnancy, it was a normal birth and healthy baby. She breastfed for a long time, but it wasn’t a miracle, it was great news, but we know that the patient with Premature Ovarian Insufficiency can become pregnant, and we always need to keep that in mind.
Even if women have any menstrual disturbance or amenorrhoea, they still can become pregnant, almost 5% of them have this chance.
The same patient came back to the clinic (IVMED) 2 years later, she was 36 at a time, she has been breastfeeding for more than 1 year, she just stopped it, her BMI was normal (20), and she had regular menstrual cycles for the last year. It was very surprising, we checked her gonadotropins levels, and FSH and LH levels were normal, TSH was also in the normal range, what’s even more surprising is that her AMH level has increased to 2.4 ng/mL. During an ultrasound examination, there was a normal number of antral follicles. The reason for this change wasn’t known, but it is possible.
It could have been the stress, we know that almost half of all patients with Premature Ovarian Insufficiency have a history of anxiety, depression and negative emotions, so it can trigger this condition. The patient came back to the clinic after 5 years, and she still has normal menstrual bleeding, she has normal gonadotropin levels, normal ovarian function, and she is a healthy woman.
As we know, Premature Ovarian Insufficiency is unexplained and idiopathic in most cases. When we cannot explain the reason for the condition, we cannot prognose what to expect. For example, one of the things suspected was the patient’s weight loss. The patient’s Body Mass Index decreased in a very short time, 11 kg loss is 20% which is very high, and that could trigger ovarian insufficiency. It’s also well known that stress may damage female ovarian function because cortisol can influence the downregulation of this function, theoretically, we know that can be a trigger for ovarian insufficiency.
We also need to remember that there are different follicles in the ovaries, and we can assess just part of them. We cannot assess so-called primordial follicles, preovulatory follicles, primary and secondary follicles, and also small antral follicles. We cannot assess them because when we perform a routine ovarian reserve assessment, we use two standard markers, AMH level and AFC (Antral Follicle Count). However, when we count follicles during ultrasound examination, we can just count follicles from 2 millimetres and more because if they are less than 2 millimetres, we cannot physically see them. Those pre-antral and primordial follicles are very small, and we cannot assess them without a biopsy of the ovaries and morphological examination.
Another thing is that when we assess AMH levels, it’s very important to understand that AMH is not produced by all follicles but by follicles starting from small size preantral follicles. Even big antral follicles do not produce AMH, which means that primordial and small preantral follicles don’t produce AMH, and when we assess the level, we can miss this potential. Therefore, in this patient’s situation, stress possibly induced a break in follicular genesis, her body reacted in this way to protect itself in a way and took a break, then after the conditions normalized and her BMI increased to a normal range, the situation changed.
To summarize, it is crucial to note that things are not always as they look, so thorough examinations, investigations and looking for solutions are of great importance.
I think the problem was very low BMI. Gonadotropin levels were very high, and also I didn’t see any antral follicles on the ultrasound. When women don’t eat enough, and they lose weight, it can be dangerous. The regulation of menstrual function comes from our cortex, from the brain, and during a stressful time can be the reason for amenorrhoea. After you deal with stress, the menstrual function can recover.
It’s a very difficult question to answer, how many eggs is enough for the process. Unfortunately, in patients of older age, we need more and more eggs, however, ovaries cannot produce more. If we are talking just about 7 eggs at 40 years old, generally it’s a good result, but it may be not enough for our aim, we don’t only want to get just the eggs but take-home baby. This number may not be enough, but it’s not a sign of stopping ovarian function. Seven eggs mean that, at least for some years, you will have a normal ovarian function. When we are talking about IVF, it’s different, and even in the case of premature ovarian insufficiency, sometimes there is this situation when the patient has more chance of natural conception than in IVF result. In IVF, we require more eggs than for natural conception, it’s a paradox of reproductive medicine because, in natural conception, we need just 1, and in IVF, sometimes we need much more to get the result. Some patients have good euploid embryos and live birth with just 1-3 eggs at 40 years.
Regarding laparoscopy, in Ukraine, we don’t use laparoscopy just for checking the tubes and trying to unblock them. The success of this procedure is quite low. We use laparoscopy just when we need to do something else, for example, when we need to remove some myomas or when endometriosis is very big in the ovary, it’s not a routine precision.
If we are talking about just this case, I think this was just that she worked with her stress. Generally, it’s a very common question of what to do to decrease FSH and increase AMH, unfortunately, I don’t have any recipes for this treatment. We cannot increase AMH by 100%, we can use vitamins, androsterone and testosterone, but they are not very effective. For some patients, we can improve folliculogenesis a bit, and when we get more eggs than we previously thought, it may be due to this therapy or it’s just due to some lifestyle changes.
About FSH, we cannot decrease a very high level of FSH when it is more than 20 units per millilitre. However, sometimes if this level increases a bit and we start the stimulation, if we have some 3 or 4 antral follicles and a bit higher level of FSH, there are some options like using Estradiol before starting the stimulation. In some cases, we need to use agonist gonadotropin-releasing hormones Diphereline or Decepeptyl, but we need to be very careful with this second option. Taking estradiol is less dangerous, but is also less effective.
No, she hasn’t taken any medication and even thyroid function normalized after delivery, so for her, I think the delivery, breastfeeding was like therapy to control stress. If your body mass index increases from 17 till 20, so it means almost 15-20%, I think it was enough to decrease stress level. Also, breastfeeding is very important.
The general recommendation for controlling stress is to have enough sleep, have some physical activity, eat healthy food, take some vitamins, that’s all and stop smoking, limit caffeine intake.
Usually, when we start the IVF program, we recommend making an appointment with psychologists for any patient, any situation, even without these severe factors. Then a patient should decide if they both need this support or only one of the partners. If they choose this support, they are working together with psychologists, which is very helpful for the result of the IVF program. Some patients refuse this support, and also sometimes some of my colleague psychologists call me and say that this patient or this couple not only need to work with the psychologist individually or in a group, but also require medication. We need to treat such patients before they start the program, and not all medication is compatible with pregnancy planning. Sometimes we need to take a break, but if we can do something to improve the result, to control stress, we need to do this.
It’s a very important part of the treatment according. Despite our new methods and experience, the success of IVF programs is more than 50%. That means that half of the patients don’t become pregnant on the first try. We also have a group of patients with severe problems, recurrent implantation failure, with the same ovarian insufficiency and all of these patients need support during the treatments.
It’s not a good idea to lose weight during stimulation. We need to decrease BMI if it is high before starting the stimulation. Losing weight is stressful for the ovaries, and the ovary can be sensitive to a high cortisol level. In the case when a woman is 40 years old with a very low AMH level, having just 1 oocyte can happen despite this diet situation. We don’t know if it would be the same or a different outcome.
Any changes in BMI can influence ovarian function. We are talking about a normal BMI from 20 to 25, it’s ideal, but it’s not always the case. The patient I talked about today had a unique situation, I found just one similar case, where recovery of the ovaries was seen. When we suffer from premature ovarian insufficiency or failure and if you have any associated thyroid dysfunction, lowering BMI, we should try and
change it because we never know the reason.
If we are talking about genetic factors, surgery, changing your BMI won’t work. If the ovarian reserve is very low after surgery of endometriosis, BMI or thyroid dysfunction won’t change much, but if there is an idiopathic factor without any explanation, it means that any changes in your condition, in your health, can be helpful for the ovarian function. It can be helpful or not, but we should try it. Taking supplements is a good idea, but before starting, it will be better to lose weight, you should try, it can be helpful.
We don’t usually use very high dosage, generally, most clinics use so-called standard stimulation with the highest dosage of FSH, not more than 300 units per day. Mild stimulation means using not more than 225 units. For patients of advanced age, it can be crucial, as for me, it’s not a good idea to use this stimulation for patients over 35, especially for low ovarian reserve, they need a higher dosage. Mild stimulation is not a very popular strategy nowadays because the aim of any IVF program is not only to retrieve oocytes but get pregnant and have a baby. The aim of stimulation should be to take enough oocytes to have a baby. In the case of mild stimulation, as for me, the aim is to take a few oocytes. It is a so-called patient-friendly option, but it’s not about a live birth. I am not familiar with any publications where they showed better results in this group of patients with mild stimulation.