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.- Questions and Answers
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.
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.