In this session, Dr Mauricio Gómez, Gynaecologist, specialized in Endocrinology and Reproductive Medicine at Reproclinic, Barcelona, Spain, has shared 2 of his past patients’ cases. Both women were diagnosed with low (diminished) ovarian reserve, and Dr Gómez explained protocols, medication provided to overcome this and achieve a pregnancy.
Low ovarian reserve – real IVF patients cases
- a 34-year-old woman with hypothyroidism and low vitamin D levels, partial uterine septum
The first case presented by Dr Mauricio Gomes was of a 34-year-old woman, with no allergies or toxic habits, no previous family history. The patient was suffering from hypothyroidism treated with Thyroxine and had low vitamin D levels treated with vitamin D supplementation once a week. One year before, she had a hysteroscopy to remove a partial uterine septum, which after another control 2 months later showed all was normal. The patient had regular menstrual cycles and has never been pregnant. Her last gynaecological examination, including pap smear, was normal. She’s married, and her husband was a healthy 35-year-old and has never had a child. They came to the office after 3 years of primary infertility and 2 previous failed IVF treatments in another centre.
In both attempts, a high dosage of gonadotropins was used. The first one was cancelled before the collection as only 1 follicle was found. In the second one, it was an antagonist cycle and an FSH plus LH combination (Menopur) of 300 units was used instead of r-FSH (Gonal). This time 2 follicles were found, and only 1 egg was retrieved, but it did not fertilize. Therefore, there was no embryo to transfer.
The results of the tests requested showed a normal spermogram and a very low AMH level of 0.2 ng/ml (1.42 pmol/l). The rest of the tests, including Karyotypes, X-fragile chromosome study, serologies, biochemistry cell scan and thyroid function were within the normal range. The gynaecological ultrasound showed very low antral follicle count (AFC), two follicles were found with normal uterus and endometrium. After studying all the results and considering that the patient didn’t want to go ahead with egg donation treatment at that moment, another IVF treatment with her own eggs was recommended and accepted by the patients.
Modified natural cycle
However, considering 2 previous failed cycles, it was a moment to change the strategy of ovarian stimulation. Dr Gomez and his team offered the possibility of doing a modified natural cycle. After the first day of menstruation, a gynaecological ultrasound was performed to see the situation of the ovaries. At the beginning of that cycle, there were 2 antral follicles, a second ultrasound was done on the 7th day of the cycle, and the ultrasound showed 1 follicle growing at the right ovary, it was 11 millimetres. After two days, an ultrasound was done again, and the follicle was 15 millimetres. That is when added Orgalutran antagonist of GnRH and Menopur to decrease the risk of spontaneous ovulation and give some extra vitamins to regulate the growth and the modulation of this egg.
After another 2 days, the follicle had become bigger at 19 millimetres, the endometrial lining was good at 9 millimetres, and it was trilaminar. At that moment, we used a dual trigger with Decapepyle and Ovitrel. The egg retrieval was done after 36 hours of the triggering, we got a mature egg which was collected and inseminated in the laboratory by ICSI with one spermatozoon. We prescribed 400 milligrams of vaginal progesterone twice a day.
The day after we had the embryo, we decided to culture it for 5 days. The patient continued her treatment with progesterone, Thyroxine, folic and antioxidative diet supplementation. We got a 4 AB blastocyst which was ready to be transferred. A pregnancy test was done 12 days after the result of the beta hCG was 350, and posterior ultrasound 2 weeks later showed an intrauterine evolution pregnancy. The pregnancy passed normally, without any complication, and at 40 weeks of pregnancy, it was a vaginal delivery of a 3-kilogram newborn.
This case report showed us that some important facts should be considered in patients with very low ovarian reserve. The first one is that more dosage of gonadotropins doesn’t mean better. It’s significant to think about controlled ovarian stimulation to achieve as many eggs as possible. It’s also crucial to inform the patients of the situation and their real chances to succeed. They have to accept a high chance of not having an egg or embryo, but at least the treatment is going to be less stressful. Finally, the most significant is the patient’s age. This case demonstrates that the main factor of a good prognosis is age, while AMH and AFC are only markers of quantity, not quality. That’s why it’s recommended to try with your own eggs for patients less than 36, even though they have a very low ovarian reserve.
- a 42-year-old patient, recurrent pregnancy loss
The patient had no allergies or toxic habits, her last gynaecological examination, including pap smear and mammography, was normal. Her husband was 49 years and was a healthy patient, he also had a daughter from a previous relationship. The patient got spontaneously pregnant two times. First, she had to do a voluntary interruption of the pregnancy at 14 weeks after Edward’s syndrome diagnosis. The second pregnancy was a twin pregnancy that finished in abortion at 12th week. The Chromosomal study of one of these embryos diagnosed Patau’s Syndrome (a 13 chromosome), the other was euploid. The test requested showed a normal spermogram, and DNA Double Chain Fragmentation was also normal. The patient’s AMH level was very low (0.06 ng/ml). Other tests, including Karyotypes, thyroid function and vitamin D level, were within the normal range. The gynaecological ultrasound showed only 1 follicle.
Minimal/Mild Combined Stimulation Cycle
The couple wasn’t ready to go ahead with egg donation, that’s why IVF treatment with PGT-A was offered. After analysing all the results and considering a very low ovarian reserve, a combined treatment with Letrozole 5 milligrams a day in 2 doses and 150 units of Menopur. The idea was to stimulate the recruitment from 1 different mechanism following the previously described protocol. The answer was surprisingly good, 3 follicles were found. The ovarian triggering was based on Ovitrel and Decapeptyle. We’ve managed to retrieve 3 eggs, and 2 of them were fecundated. Finally, we got 1 embryo that arrived at the blastocyst stage, it was biopsied and frozen. Four days after the egg collection, another ultrasound was done. We saw 2 follicles of 6 and 8 millimetres and decided to start another ovarian stimulation with 225 units of Menopur the day after.
The idea was to get more embryos at the same cycle, considering a low chance of having a euploid embryo in a 42-year-old patient with a clinical history. After 5 days of stimulation, the first ultrasound control was done. Two follicles had grown, one in each ovary, and after another two checkups, they were ready to be collected. The dual triggering was done again in the same way, and two eggs were collected. All of them were fecundated, unfortunately, 1 of them became a blastocyst. That’s why it was biopsied and frozen.
After three weeks PGT-A result showed that the first blastocyst was aneuploid, the second one retrieved after the luteal phase stimulation was euploid. The chances of a successful pregnancy were much higher now, the most difficult step was done. We decided to do an extra study of the endometrial receptivity that showed us 24 hours before the implantation window. According to this result, we started a substituted cycle with 60 milligrams daily dose of oral oestrogens at the beginning of the next cycle. When the endometrial line reached 8 millimetres, we started progesterone treatment vaginally, and after 6 days, 1 day more than usual considering the result of the ERA test, we transferred this euploid embryo.
After 2 uncertain and stressful weeks, the pregnancy and test were positive, and after that, the patient finally delivered a healthy baby delivered by Caesarean section at 40 weeks of pregnancy. By contrast with the first case, this patient had an extra factor that added more difficulty to achieve pregnancy. She was more than 40, it’s important to know that the average number of eggs required to get a healthy euploid embryo at the 42 patient is more than 15 eggs more or less. However, in this case, we were only able to collect 5 eggs between 2 procedures at the same cycle. That’s why, considering these 15 eggs required, we were really lucky.
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Conclusions
In the first case, considering the patient was 34 years old and considering the statistics, we should have collected between 3 or 4 eggs to assure 1 healthy embryo. We only get 1, but at 34, we didn’t recommend performing a genetic study. We were lucky in both cases, but sometimes this luck deserves to be solved.
In the second case, the decision of trying a non-conventional ovarian stimulation protocol has been decided because of the patient’s very low ovarian reserve. The idea of accumulating embryos was obvious, so we could get as many embryos as possible. PGT-A is strongly recommended from the 38 years old and older it’s very important to share
We also need to remember to do an extra study of the endometrial receptivity to prepare the best endometrium for the best embryo. That’s why we prefer to do the ERA test before the transfer.
