Dr. Harry Karpouzis, Obstetrics and Gynecology Consultant at Pelargos IVF, Greece, answers patients’ questions about PCOS, infertility and IVF treatment for patients with polycystic ovary syndrome.
We are talking here about two different medication which works differently. Clomiphene is a selective estrogen receptor modulator, which means it combines with some receptors in the hypothalamus in the brain and what it actually does, is cheat the brain that there is no estrogen and, as a result, it increases the FSH production and in this way actually triggers ovulation. Letrozole, on the other hand, is an aromatase inhibitor and acts in a completely different way. Actually, it acts in the ovaries and stops the production of estrogen, and the body and brain think there is no estrogen, as it is not produced in the same amounts as before and it again sends a signal to the brain to produce more FSH and trigger ovulation. Clomiphene used to be the first choice when we talk about natural conception methods, but now our clinic has found some advantages that Letrozole could have over Clomiphene. First of all, Clomiphene has more side effects. It can cause hot flashes, it can affect the endometrium as it acts as an antagonist there. It means that it does not increase the thickness of the endometrium, so very often it would make it to thin for implantation. There has been some research recently, that if we analyse the modulators of the implantation in the endometrium, the things that actually cause the implantation in the IVF and IUI, it is mainly affected more by Clomiphene than Letrozole. Also, there is some research showing there is a higher rate of live births with Letrozole than Clomiphene and equal miscarriage rate for both of them. So, the answer is that they are both first-line treatment, worse, of course than injections with gonadotrophins. According to our data, Letrozole sometimes works better. Sometimes when a patient is resistant to Letrozole and does not produce ovulation we can even combine it with Clomiphene, and we can do a combination of them. But what actually happens, is that with Letrozole the estrogen is reduced more severely and it gives a better signal to the brain to start producing more FSH and start ovulation.
Metformin is a very well studied medication, there are more studies in Metformin than any other drug regarding PCOS. First of all, Metformin is a medication that is mainly used in diabetes. The way that it is used in polycystic ovaries is that it actually reduces the insulin resistance. It makes the body more sensitive to insulin. So, it reduces the insulin and by this mechanism both centrally, in the brain, and locally, in the ovaries, it can reduce the androgen. It can help with weight control, which is very important for people with PCOS because the vast majority of them have got a weight problem as well. Of course, it is not working by itself. It has to be associated with the actual weight loss. In the initial stage, Metformin can act very well, and it can stimulate the ovulation. The latest research and meta-studies showed that it is worse than Clomiphene or Letrozole if it is used by itself. Also, the new studies point out that the combination of Metformin and Clomid does not change significantly the acting of Clomid. I would say this is not the first-line medication unless somebody wants to try by themselves without follicular tracking, without actually having controlled ovulation and just wants to help the body ovulating better and controlling the cycle. It is recommended mainly for women who are obese and who suffer from insulin resistance. I wouldn’t use it for women who are not insulin resistant or lean. It could be used as a second-line medication if someone is resistant to Clomiphene, but not because it will significantly change the live birth rate, but because it can produce more follicles. If we increase the dose of Clomid, we risk that there can be two or more follicles and if we add Metformin, we can make things better, and we can have just one follicle. Metformin, however, could be used, and there is support in research for that, in pre-treatment for IVF, because it can reduce the risk of hyperstimulation. It does not decrease the miscarriage rate, we are not sure that it helps with the live birth rate, but it can help with hyperstimulation in IVF.
It used to be a big problem in the past. It can actually be very risky for the patients, and it can even cause death, and there are not a lot of things in IVF or reproductive medicine that can cause that, so we need to be very careful. The target of IVF nowadays is a zero degree of hyperstimulation. So nowadays we have many ways of doing that, it was an issue in the past. First of all, we need to make the diagnosis that we have PCOS. Sometimes we miss the diagnosis, and this is when things like hyperstimulation happen when we put someone on the wrong protocol. When we know that someone has PCOS, we can put them on the right protocol, and this is usually antagonist short protocol. Sometimes it is inevitable to have multiple follicles and high estrogen, and this increases the risk of hyperstimulation. In these cases, we need to choose the right trigger. If we use the antagonist protocol we can use the agonist trigger. In comparison to HCG, which is Ovitrelle that we all know, or the Pregnyl, this reduces, not putting it down to zero, but reduces a lot the risk of hyperstimulation. The problem with the agonist trigger is that it has been shown that if we give the agonist trigger and we do a fresh transfer there are reduced chances of pregnancy. Because the luteal support, the progesterone which is needed to support the pregnancy is not good enough. So this is when vitrification comes in. Vitrification is a special form of freezing which gives us almost the same chances of success with a frozen cycle in comparison with a fresh cycle. Sometimes even better. So, in the situation when we suspect hyperstimulation we can give the agonist trigger and freeze [the eggs] and if we do these two things we can put the hyperstimulation at zero degrees. Of course, we can adjust the doses of the medication. Usually, with PCOS we want to have a very low dose and a step-up dose, but it is not always the case. As far as we use the right protocol, the antagonist protocol, the right trigger when it is needed, and we use a frozen cycle, when we think it needs to be a frozen cycle, then we can lower the hyperstimulation level a lot.
Even though it is quite difficult for patients with PCOS to get pregnant spontaneously, as they do not ovulate, they react quite well to fertility treatment. If we read that a woman has not got pregnant through sexual intercourse than Clomid or Letrozole, injections and IUI, we need to go to IVF. Even in the IVF, the problem is the ovulation induction. What often happens with PCOS is that we cannot give the patient a high dose of medications as we are afraid of hyperstimulation, and we cannot give a low dose because she will not respond to it. Sometimes with the IUI, we give the dose of 150, and there is no reaction. Why?
Generally, the antagonist protocol is the best protocol in PCOS, especially in resistant PCOS. But sometimes when we see the ovary, we determine the ovary from the ultrasound. Because when I see the ovary I can determine if it will be easy to stimulate or difficult to stimulate. There is a specific appearance in the ultrasound that shows the way the ovary will react during the IVF protocol. With the ovaries that seem difficult to stimulate sometimes, we need to attack with really high FSH, and sometimes we even increase it to the level of 225 or 300. We create high FSH, we reduce the resistance that the ovaries have, and make a coordinated stimulation of the follicles. Sometimes it is a trick on the antagonist protocol to do a step-down protocol. This means starting with a high dose and then reducing it rather than doing it carefully. So the answer to that question is in the ultrasound. The ovaries that are difficult to stimulate have a specific appearance which will show in the ultrasound. If you can see many small follicles of about three or four millimetres the ovary will be difficult to stimulate and poorly react to the medication. When you see that you should increase the dose. If you see eight to nine millimetres follicles you can go along with a low dose. Then you always have the weapon of agonist trigger and the transfer of a frozen cycle to increase the chances of success.
It is a very general question. We need to remember to consider age as well. Women with PCOS, even when they are older, generally have more eggs, because they haven’t ovulated before. But the success rate of the IVF depends on age as well. There is a difference if someone is 35, 38 or 40 years old because the quality of eggs also depends on the age. For proper PCOS and not very resistant PCOS, we are able to get a lot of eggs usually. the chances of success of a woman who is under 35 are 75%. In many cases though, we see many immature eggs and embryos, and we get a smaller amount of good quality eggs and embryos than we would expect. In many cases, it is the wrong protocol, but often it is the problem with the low quality of eggs in PCOS. In a small percentage of patients with persistent PCOS, that is usually 35 to 40 years old and lean, it is more difficult to treat. In the past, we used to believe that obese patients are more difficult, but in fact, the treatment of slimmer patients is more challenging. There are different ways of treating the patients, but the success rates are quite good. The chances for a positive pregnancy test is about 75%. You must remember that a rate of miscarriages is quite high in PCOS, so the rates of live birth will be about ten per cent lower, like 65% for a woman under 40.
I think it is a frozen cycle, especially if we suspect or if we are afraid of hyperstimulation. Research and data are proving that even in women with low estrogen, with no risk of overstimulation, the success rate of live birth is higher with a frozen cycle in comparison to a fresh cycle. The reason behind it is probably that every little follicle, and there are many follicles is PCOS produces estrogen, granulosa cells produce estrogen, so the levels are going up. The steroids in the body are going higher, the progesterone, the estrogen is going higher so this affects the coordination of endometrium, and reduces the chances of implantation of an embryo, even if we do not hyperstimulate.
Generally, in PCOS we get more eggs by definition, so more eggs will be immature or not good quality. But as a rule, if we take the mature eggs of an IVF protocol of a woman with PCOS, there is no evidence that the quality will be any worse. the number of mature eggs we get depends on the protocol we use as well. There are quite resistant PCOS that will cause discordant growth of the follicles, this means that in one cycle we can get some eggs that are good and that are on the correct timing and some eggs that are from smaller follicles before it is very difficult to reach all follicles at the same time in PCOS. The amount of mature eggs is bigger in PCOS, and if we compare no data is showing there is worse quality. Apart from one category of patients which is lean PCOS. Patients that are slim and have an issue with androgens rather than obesity or weight. In this specific category when they grow older, between 30-40, there is data showing a reduction in the androgen levels. In these patients, the levels of androgens drop more significantly than in other PCOS patients, which creates a paradox that we have higher AMH levels, more eggs but at the same time quite increased FSH as well. These patients with high AMH and TSH are difficult patients, and in those patients, we see the reduction in the quality of eggs. But I wouldn’t say it really is a matter of the quality of mature eggs, but a matter of a lower number of mature eggs in an IVF protocol than in other patients with PCOS.
Yes, it is the combined pill like progesterone pill, Duphaston for example. If you can start the cycle from the first day of the period I usually prefer it. If you want to schedule your trip or pre-book tickets, you can start the combined pill from the previous cycle.
Another way is to take progesterone for 10 to 14 days, and this way provoke the bleeding and start stimulation like that. There is some research suggesting that with progesterone we can have some advantage as well.
We know that PCOS has an increased rate of miscarriages in comparison to other patients. Sometimes when we have more embryos and can afford PGT-A, it reduces the risk of miscarriages in PCOS pre-genetic selection as we call it. Because PCOS is usually associated with other problems like obesity, we do have a higher risk of hypertension, pre-eclampsia, and some women with PCOS have an increased level of gestational diabetes. So we need to take very good care of the woman, do NGPT early in the pregnancy in order not to miss it.
Usually, it depends on the dose. If it is very low, I would increase it. With Metformin we usually start very low, because it causes problems with the stomach. If it does not work, we can increase it to reach 1,5. I wouldn’t go over that, although some research suggests it. If you have been trying to conceive for a year, and the cycle hasn’t shortened at all, it is time to go to the next step. As I said, Metformin is not the first-line medication for ovulation induction, and especially if you are slim and you don’t have insulin resistance, it may not be a medication for you. You can try Clomid or Letrozole to stimulate ovulation.
No, not at all. AMH is associated with age. So if someone is 40 it is high AMH. It’s only one of four things I explained in my initial talk that can point out to PCOS. So if you are 39 and have AMH of 1,5 it could prove you have PCOS.
In PCOS most patients have irregular periods, sometimes no period for three or four months, so then they do not ovulate. Some women have PCOS and have regular cycles but shorter and with rare ovulation. These are often women with androgenic symptoms like facial hair, acne and polycystic ovaries in the ultrasound.
As I said, there are specific criteria to look for in the ultrasound – if there are twelve or more follicles of less than 10 millimetres in size, the follicles make up a pearly chain. Another ultrasound criterion is the increased size of the ovary itself. But if we only have a woman who has ultrasound appearance of polycystic ovarian, but does not have facial hair or acne, does not have irregular cycles, does not have infertility then this by itself is not enough to say she has Polycystic Ovarian Syndrome.
The problem is that women with PCOS do not ovulate regularly, as they do not have regular cycles. Without ovarian stimulation, they do not produce eggs. We need to do ovulation induction to help the body create ovulation and produce the eggs. We can do it with medication like Clomiphene, Letrozole or IVF. With IVF we have good response most of the time. We have a lot of follicles, a lot of eggs and a lot of good embryos and, if a woman is of appropriate age, we do have a good success rate as I said.
High testosterone, which is caused by PCOS and high androgen, which cause symptoms like facial hair and acne.
If you consider that the risk of a miscarriage in a twin pregnancy is higher than in a single pregnancy and combine it with a generally higher risk of miscarriage connected with PCOS then, of course, implanting multiple embryos carries a higher risk. But, if you implant two embryos, you also have a better chance of carrying at least one of them to term and having a healthy baby.
If it is a discrete fibroid it depends on the size and the position of the fibroid as well as your age. If it is a fibroid smaller than 5 cm and not protruding inside the lining of the womb, it is better to leave it. If it is bigger than 5 cm and especially if it is protruding inside the lining of the womb, it is better to remove it, as it can decrease the chances of implantation. Regarding the progesterone intake, it is safe.
Maybe you should do hysteroscopy to make sure there is nothing left inside the womb and see if the endometrium is ok. Check if there is no chronic endometritis because a course of antibiotics before the transfer can help. Also, the fact you are close to fifty increases the risk of miscarriage. It is a combination of things. If there is a history of problems with the endometrium, surrogacy and egg donation may be the solution for you.