In this session, Dr Alejandra Aguilar Crespo, Gynaecologist at Equipo Juana Crespo, Valencia, Spain, has discussed past patient’s case story, and explained what diagnostic tests needed to be taken, what protocols had to be changed which helped to achieve the final successful result.
Dr Alejandra Aguilar Crespo presented a study case about a Spanish couple who came to the clinic at 40, she has never been pregnant, she and her partner were trying to conceive for 3 years already, and her periods were regular, but she suffered from severe dysmenorrhea which is painful periods and dyspareunia which means pain during sexual intercourse. She was diagnosed with endometriosis, and she was psychologically affected because of her infertility, and her painful periods. The male partner was 36 years old, his sperm analysis was normal, and sometimes other semen analyses showed that he had oligospermia, a low quantity of spermatozoids.
They did previous treatments in a public hospital in Spain, they underwent 3 transfers. In the first transfer, 2 day-3 embryos were transferred, and the rest was vitrified, the transfer was very difficult, and it was painful. They performed an embryo transfer in a substituted cycle with patches, they transferred the 2 remaining day-3 embryos, but she didn’t get pregnant. Again they performed a second, and they vitrified 2 day-3 embryos, they didn’t perform a fresh embryo transfer because the patient asked for it. She didn’t feel well after the egg collection, so that’s why they vitrified the embryos. A couple of months later, they transferred those remaining embryos in a substituted cycle with estrogen pills, but she did not get pregnant.
After that, they perform a hysteroscopy just to check the endometrium, and it was normal, the biopsy showed that there was no endometritis, and they performed a karyotype and thrombotic risk profile, which were normal.
We did a vaginal examination, and we saw that the uterus was fixed, and it was very painful. This ultrasound scan was done on the 21st day in the luteal phase, she had a swollen uterus with diffuse adenomyosis, the endometrial thickness was very thick measuring, 18 millimetres, and in both ovaries, we saw 2 endometriomas and 3 antral follicles in each ovary which was a low ovarian reserve. After the previous examination, the diagnosis was deep endometriosis, adenomyosis, low ovarian reserve and a possible male factor due to his previous sperm analysis showing oligospermia.
The plan was to improve the oocyte quality, so we prescribed vitamins and antioxidants, and we recommended losing a couple of kilos because her BMI was 26. Secondly, we decided on a short protocol with letrozole, which is an inhibitor that helps to decrease estrogen levels, which is good if we are dealing with endometriosis as the oestrogens can affect the uterus. Letrozole increases the FSH and LH levels, so it can also help with the stimulation. It was a short protocol using recommended FSH and Menopur.
We did the first simulation, and the estradiol, and FSH levels were good, so we were able to start the stimulation, and we got 5 eggs, but we only got 1 day 3 embryo. We tried to make the embryos develop to the blastocyst stage, but there was no evolution. After that, we did an MRI in the luteal phase, just a couple of days after the egg collection, and it showed an anteverted uterus with a normal endometrial thickness, we also saw the endometriomas and a thickness junction zone in the fundus and the anterior wall which is a sign of adenomyosis. We also did the hysterosalpingography that showed her right hydrosalpinx was patent and a distal blockage of the left tube.
As we only had 1 embryo, we decided to perform a second stimulation with the same protocol, this time, we got 2 day-3 embryos of very good quality and 1 blastocyst of a medium-low quality. The patient wanted to do a third stimulation because she wanted to have as many embryos as possible. Therefore, we did the next stimulation, and we got 2 day-3 embryos, and 2 blastocysts (day-5 and day-6). In total, we had 5 day-3 embryos and 3 blastocysts.
We started the treatment of the uterus and the fallopian tubes treatment, we planned surgery, we did hysteroscopy to remove all fibrosis and to increase the implantation area to make some different cuts to improve the vascularization of the uterus and improve the implantation, and we also did a laparoscopy to remove both fallopian tubes, the endometriomas and the uterosacral node. The findings were as we expected, bilateral hydrosalpinx, a uterine fibroid, and a very small uterine fungus were also removed. We also found severe adherential syndrome and deep endometriosis with a vaginal node. We injected her with quarterly Decapeptyl, which is an analogue of the GnRH to treat endometriosis because they make the ovary rest, which makes the woman menopausal for at least 3 months. Endometriosis is an estrogen-dependent pathology, so if there are oestrogens and ovulation, endometriosis can get worse.
After 3 months, we started endometrial preparation with low doses of oestrogens, it was 2 mg. After 8 days of uterine preparation, we did a scan, and the endometrium was great, so we decided to go ahead with the embryo transfer. We did a double embryo transfer, we decided to transfer 2 day-3 embryos of the second cycle and a blastocyst of the third cycle, which means that we put 3 embryos. Why? We had to take into account that it was a woman who had 6 day-3 embryos transferred before, she had endometriosis and was 40 years old, so it meant that from those 3 embryos she would probably get 1 baby, that’s why sometimes in women with endometriosis and pathological uterus, we need to transfer more to get a pregnancy.
After 10 days, they did a positive pregnancy test, and a scan that was done a couple of weeks later showed an evolutive single clinical pregnancy, and we could see also the heartbeat, and everything was going well.
Nowadays, we are facing a delay in maternity, women are deciding to delay maternity because of several reasons including social, economic factors as well as medical reasons:
Over the last decades, we are witnessing a delay in which the woman has her first child, the average, for example, in Spain, is around 33 years old. This can have a severe implication because the older the woman is, the lower probability of pregnancy. On the graph shown, we can see that after the age of 35 years old, there is a decrease in fertility, and therefore, there is an increase in infertility. There are a lot of women going ahead with assisted reproductive techniques.
What are the causes of the decrease in fertility due to maternal age?
Normally, when a woman is born, there are 1-2 million oocytes, but then among them, only 400 000 will reach maturation and will reach puberty. However, among them, only 400 will reach ovulation, and the rest of them reach atresia. In a single menstrual cycle, for example, there is follicular recruitment, but among them, only 1 will be in charge of releasing the oocyte. If there is no fertilization, 15 days later the period starts, and the rest of the follicles die, and there is another follicular recruitment.
How can we measure ovarian reserve? We have several tools to measure it:
The increase in the FSH level is the first endocrine sign of reproductive ageing, and it explains the accelerated depletion of the follicle, the shortening of the follicular phase and the increase in the incidence of dizygotic twins.
One of the main causes of low ovarian reserve is age. The older woman is, the lower amount of eggs she’ll have, but we also need to take into account all the factors or the cause of low ovarian reserve, which could be a genetic disease such as fragile X syndrome, some autoimmune disease, environmental factors, cancer treatment, chemo- radiotherapy, ovarian surgery or idiopathic when we don’t know the cause.
The second cause is a decrease in the oocyte quality and the older the woman is, the lower amount of eggs she has and the quality of that oocyte are also worse. The older woman is a higher probability of having abnormal oocytes. If a woman has an incorrect number of chromosomes in their oocytes, the higher chance of having abnormal embryos. This will increase the implantation failure and miscarriage rate. We should take into account that at the age of 40, at least 60% of the embryos will be abnormal. If we transfer an abnormal embryo, there is a high chance that it won’t implant or end in a miscarriage. The 3rd thing and most important one is the probability of having a baby with a chromosomal abnormality, for example, Down syndrome.
The third cause of decreasing infertility by maternal age is the uterus. A woman of advanced maternal age can have:
However, endometrium remains stable through age. Women can also have a higher risk of obstetric complications, such as gestational diabetes, hypertensive disorders like preeclampsia, placenta previa, risk of instrumental delivery, preterm delivery, and fetal deaths.
Currently, we now only use Letrozole for the stimulation for 5 days of the stimulation. Letrozole will maintain the endometrial sickness and with that, we can also increase the size of the follicles in all the women. We don’t use Letrozole for more than 5 days. Sometimes Letrozole is used in patients with breast cancer, and we need to stimulate women with breast cancer, we use it but only for the stimulation.
We don’t use Letrozole for months. We also use Letrozole in people who have severe adenomyosis, and we use it with Decapeptile, then we use Letrozole for at least 15 days or a month, but no more than that. It doesn’t mean that it has bad effects, but we don’t like to use that for too long because it has been demonstrated, it can help with that kind of period. We have good results with this time frame.
When we have 2 failed embryo transfers, it means that there is something wrong, and we need to focus on different things because it’s not just bad luck, it means that we are doing something wrong, and we need to investigate in other ways to find this issue.