By fertility experts from Spain.
In this webinar, Dr Laura Garcia de Miguel, MD, Medical Director at Clinica Tambre, explains PCOS in detail and talks about fertility solutions for female patients affected by this health problem.
Polycystic ovary syndrome (PCOS), which affects 1 in 10 women of reproductive age, is one of the most common endocrinological disorders. It happens when ovaries – that regularly develop numerous small collections of follicles – fail to regularly release eggs during ovulation. This results in hormonal imbalance and metabolism problems that may affect women’s overall health and appearance. Some of the most common PCOS symptoms are hair loss or its opposite – hirsutism, pelvic pain, overweight, acne, high testosterone levels and irregular periods. The latter may lead to infertility.
Dr Garcia explains that the exact cause of PCOS is still unknown. Experts think that many factors may play a role. PCOS is thought to be often related to insulin resistance. Insulin resistance is when the body’s cells do not respond normally to insulin. As a result, a woman’s insulin blood levels become higher than normal, which, in turn makes the ovaries produce too much testosterone. Too much testosterone interferes with the development of the follicles and prevents normal ovulation.
Another possible cause is hormonal imbalance. It is understood not only as raised levels of testosterone but also as high levels of luteinising hormone (LH). Normally, the latter stimulates ovulation, but if its levels are too high, it may have an abnormal effect on the ovaries. Hormonal imbalance causing PCOS may refer to low levels of sex hormone-binding globulin (SHBG) as well. SHBG is a protein in the blood, which binds to testosterone and reduces its effect.
Additionally, Dr Garcia mentions a genetic cause of polycystic ovary syndrome. It is true that PCOS sometimes runs in families. It means that if any female relatives of yours (such as your mother, sister or aunt) have PCOS, the risk of you developing it is increased, too.
When it comes to the way PCOS is diagnosed, there is no single way either. Dr. Garcia mentions a pelvic ultrasound that is used to diagnose all the small follicles in ovaries – women affected with PCOS can have more than 12 follicles accumulated in each ovary. Then, there is also a hormonal blood test conducted to check for abnormalities of sex hormone-binding globulin (SHBG), dehydroepiandrosterone sulphate (DHEAS), androstenedione, oestradiol (oestrogen), follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Women who are not affected by PCOS have twice as much FSH as LH. By contrast, PCOS patients have increased LH levels – as compared to FSH. In addition to the above, there is also the need to do the glucose metabolism/tolerance blood test, as well as tests showing the risk of cardiovascular disease. Dr. Garcia explains that in PCOS patients, there is always the possibility of having increased cholesterol and blood pressure.
What is more, women affected by PCOS are more likely to have thyroid disorders. In their case, the prevalence of subclinical hypothyroidism and thyroid autoimmunity is increased. That’s why it’s highly important to check the thyroid function in these patients (with a blood test for TSH, T4 and antithyroid antibodies).
As it was mentioned before, PCOS negatively impacts fertility. Women with this condition do not ovulate regularly, their periods become irregular and increased levels of hormones such as testosterone affect their eggs’ quality. However, getting pregnant is still possible – but it often requires serious lifestyle modification and pharmacological interventions.
According to Dr Garcia, the first step is the so-called non-pharmacological interventions, including a healthy diet and exercise. Dr. Garcia admits that if a PCOS patient is of healthy weight, it is much easier to regulate her ovulation. That’s why it is recommended to use a low-calorie diet with adequate nutritional intake and healthy food choices. It is also very important to do exercise – a minimum of 150 min/week of moderate intensity physical activity or 75 min/week of vigorous intensity and muscle strengthening activities on 2 non-consecutive days/week. For a modest weight loss, a minimum of 250 min/week of moderate intensity activities or 150 min/week of vigorous intensity activities is recommended. All of it helps to improve the metabolism of glucose and makes the ovaries work much better.
The second way that women affected with PCOS can boost their fertility with is the pharmacological intervention. Dr. Garcia says there is the possibility of using oral ovulation induction agents, such as Letrozole or Clomiphene Citrate. The first one is administered at 2.5 to 7.5 milligrams daily for five days. Many studies show that Letrozole is a superior drug to Clomiphene Citrate in terms of clinical pregnancy rate and live birth rate. However, Clomiphene Citrate is used more frequently. It is administered typically for five days, starting on the second day of the period. A course of three to six cycles of oral ovulation induction is recommended in such a case.
Another pharmacological solution for PCOS patients is Metformin. It is a drug that inhibits hepatic glucose production, decreases intestinal glucose uptake and increases insulin sensitivity in peripheral tissues. Dr. Garcia admits that it plays an important role in improving ovulation induction in women with PCOS. Metformin is available as 500-, 850- or 1000-mg tablets, with an average dose of 1500 mg per day. Metformin may be used as an adjunct to other ovulation inductions agents or by itself in women with PCOS and with no other fertility factors.
Regarding pharmacological interventions, there is also the possibility of using ovulation induction with gonadotropins. Dr. Garcia says there are various preparations of gonadotropins for therapeutic use with FSH and LH effect. They are used as second-line agents for ovulation induction, following unsuccessful treatments with first-line oral ovulation induction agents. However, it’s very important to remember about careful monitoring of the treatment cycles with serial ultrasound scans to avoid multiple pregnancies.
When neither non-pharmacological or pharmacological interventions prove to be helpful in achieving pregnancy, many PCOS women need to seek care from fertility specialists. Dr. Garcia mentions two of the assisted reproductive techniques used in such cases: IUI (intrauterine insemination) and IVF (in vitro fertilisation).
In IUI, sperm, which has been washed and concentrated, is placed directly in the uterus right after the ovulation. The technique doesn’t need to be performed under anesthesia and is a relatively painless and non-invasive procedure. In IVF, the woman has medicines given to stimulate the ovaries to produce eggs. The eggs are then collected and mixed with sperm in a laboratory. If fertilisation is successful, the embryos are left to develop for between 2 and 6 days. This helps to select the strongest embryo, which is then transferred back to the woman’s uterus to implant. Dr. Garcia says that this moment is carried out with the monitoring scan to leave the embryo in the correct place. If there are other good quality remaining embryos, they will be frozen. 10 days after the embryo transfer, the patient is asked to do a pregnancy test.
Unfortunately, in IVF, women with PCOS are at a greater risk of a high response to controlled ovarian stimulation and the development of ovarian hyperstimulation syndrome (OHSS). According to Dr Garcia, this is the major risk of IVF in this type of patients – even when using low dosages of hormones.
OHSS is divided into three categories: mild, moderate and severe. The symptoms of mild OHSS may include mild abdominal bloating, nausea/vomiting, diarrhoea and enlarged ovaries. Women with moderate OHSS typically have more or less the same symptoms (plus ascites). Mild OHSS also includes laboratory abnormalities such as hypoproteinemia – and that’s why it requires careful monitoring. Women with severe OHSS usually have vomiting and cannot keep down liquids. They experience significant discomfort from swelling of the abdomen and rapid gain weight. They can develop shortness of breath (dyspnea) and blood clots can form in their legs. Patients who experience severe OHSS have to be immediately hospitalised and monitored in intensive care units.
OHSS is a serious condition – but the good news is that its risk can be significantly reduced nowadays. There are different methods to avoid it. Dr. Garcia mentions the use of a different medication to induce ovulation (GnRH agonist instead of Ovitrelle) or the use of Metformin as an adjunct during IVF.
There is also another strategy which is cycle segmentation. It means no transfer in the same cycle and going for an elective freeze-all policy (freezing of all the embryos). With the latter, the first frozen embryo can be transferred when there is no risk of OHSS. For women who don’t have a regular cycle (like the most of PCOS patients), additional estrogen and progesterone medications are used to prepare the endometrium and develop it to the right stage before the embryo transfer.
Polycystic ovary syndrome (PCOS) is a multi-faceted condition. That’s why, when choosing an effective treatment option for the woman with PCOS, it is crucial to use a holistic approach. A multi-disciplinary care addresses not only subfertility or anovulation but also metabolic and psychological issues that are often associated with its spectrum.
We use Metformin only when there is an abnormality in the glucose tolerance test. But according to medical literature, it’s recommended to use Metformin in all IVF treatments when we have PCOS because this will give us more chances to have an ongoing pregnancy and a baby. Regarding GLP-4 analogue peptides, there is no evidence data so everything is experimental and we cannot give you any specific information about that.
I’m very sorry to hear about your unsuccessful pregnancies. Yes, in case of PCOS, the quality of the eggs is lower when compared to the eggs of the same age woman with no PCOS. All the physiology I explained in my presentation, may lead to immature eggs that have a higher
risk of a miscarriage. It is quite common in the general population. In your particular case, as you are 43 years old, we would need to consider two strategies. Firstly, we would consider egg donation – at the age of 43, what we generally recommend is egg donation to increase the success rates. But if you want to go for another round of IVF and you have lots of embryos, then I would recommend to go for PGS – the screening of your embryos before transferring them.
If you’re going for egg donation and you have normal glucose metabolism and normal weight, the success rates will not be decreased by PCOS.
Ok, let me explain it in more detail. Not only in case of PCOS but also in general IVF – before transferring an embryo, we need to confirm that the levels of estradiol and progesterone are all right. Otherwise, increased levels of estradiol or progesterone would decrease the chances of embryo implantation. If estradiol is very high (if we have more than 3000 pg/mL) or if we retrieve more than 15 eggs, then there is a risk of ovarian hyperstimulation syndrome (OHSS). And for us, the safety and health of our patients are the most important. So if it is the case, the fresh transfer is not recommended because of two reasons. Firstly, the implantation rate is going to be decreased (as the abnormalities in the hormones are going to affect the endometrium receptivity), and secondly, because you will have a very huge risk of having OHSS. So in this case, it’s recommended to use the freeze-all strategy. However, if during the ovarian stimulation, everything is all right and you don’t have a big risk of OHSS, then we can directly go for a fresh cycle.
Yes, of course it’s possible. Then the strategy is to choose the best dosage in terms of the gonadotropins to avoid both hyperstimulation and the production of more than 15 eggs.
We don’t have any evidence on how to improve egg quality. But regarding PCOS, we think that perhaps having pre-vitamins treatment could improve it a little bit. But as I said, there is no evidence. Every patient has her own eggs’ quality – not only regarding their age but also other factors, such as PCOS syndrome. So there’s really not a lot we can give to these patients. There are some publications saying about antioxidants, such as melatonin, there are others suggesting folic acid for this type of women specifically. But I would say that diet, exercise and the use of Metformin are more recommended – in parallel to the ovarian stimulation.
It’s very important to use a short protocol – to start the gonadotropins at low dosage (no more than 150 units) and then have a very strict control every few days. If we don’t have enough information with the regular scan, we also add estradiol and progesterone blood tests. Then, if there is a risk of OHSS, the trigger shot will be with GnRH agonist (Decapeptyl) instead of hCG. And if there is a high risk of OHSS, then we will not do the fresh cycle transfer but the embryo transfer in the freeze-all strategy.
Generally, the implantation rate is not considered lower when glucose metabolism is controlled correctly. However, if a woman having PCOS does not have good glucose metabolism and she is overweight, then yes – we can say there is a decreased implantation rate for her. In such cases, before the embryo transfer, we need to have the pre-treatment for overweight or glucose abnormalities disorders.
Yes, it’s possible to have a fresh embryo transfer in your case. But it’s very important to avoid ovarian hyperstimulation syndrome (OHSS). So regarding your case and depending on your weight and your BMI, it would be best to use not more than 150 units with the gonadotropin stimulation.
Yes, it is correct. If you’re having PCOS, the quality of your eggs is decreased. And it is also true that women having PCOS normally have higher levels of AMH – so a higher ovarian reserve.
Of course. We have lots of women who have failed IVF procedures or have had long fertility problems and they are not aware of PCOS. There is a percentage of PCOS cases that have important clinical symptoms but sometimes it’s more difficult to do the diagnosis. However, I think that any gynecologist should know how to diagnose PCOS. Generally speaking, it’s two out of three Rotterdam criteria for polycystic ovary syndrome (PCOS): the first one refers to clinical abnormalities of PCOS ( such as hirsutism, irregular periods, acne, etc.), the second one is the pelvic scan that is really relevant for PCOS because we have lots of follicles in such ovaries. The third criteria refers to abnormalities in the blood test. So if you have two out of these three criteria, then you have PCOS. So it’s very important to have a clinical examination: to do the scan and the blood test.
Abnormalities in any hormone level could affect eggs’ quality. But in the case of progesterone, it could affect the endometrium receptivity more than the eggs’ equality. So if you’re having an increased progesterone level, it’s going to be more important in terms of its effect on the endometrium and the problems with that – compared to your oocytes’ quality. However, we also know that cycles with an increased progesterone level are not excellent in terms of ongoing pregnancy and the quality of embryos.
Yes, it does. There was a question before about PCOS and if it could cause a miscarriage in the first trimester. In fact, that’s the main issue that we can have in pregnant PCOS patients.
I was talking about different types of folic acid before and yes, inositol could improve the quality of the eggs. Of course, it is not 100% sure in terms of evidence but we suspect this will have a positive impact on PCOS women before going for IVF procedure.
Yes, as I explained in my presentation, there is a genetic part of PCOS causes. So we need to ask every patient if they are having the background of PCOS in their mothers.
There are always experimental articles and experimental works in the field of IVF, but this is not 100% sure and it’s not a protocol technique to improve the result.