Premature Ovarian Failure – inspiring clinical case

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.

Premature Ovarian Insufficiency (POI) – definition

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.

Premature Ovarian Insufficiency (POI) – real-life case

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.

• a 33-year-old with low BMI (17), no menses for 6 months, diagnosed with POI

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.

POI – testing

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.

POI – causes

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.

Conclusions

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.