Watch the recording of the live webinar with Dr Antonio Rodrigues, Director of Medfem Fertility Clinic, who is explaining IVF failure and hyperinsulinemia, hyperprolactinaemia, hypothyroidism and other immune diseases.
Dr Antonio Rodrigues started by explaining that insulin, prolactin and thyroid disease are critical in creating an environment in egg, sperm, and uterus that will lead to a situation where someone has better pregnancy rates. Dr Rodrigues emphasized that it is crucial to focus on these simple things sometimes which we forget about, or we don’t over-manage and treat properly we can get recurrent IVF failures.
The first two important things you need are what we call chromosomally normal or euploid eggs and sperm. Unfortunately, in the female, approximately 60+% of eggs are abnormal, and in the rest of the group, we call it normal or euploid eggs. In males, the sperm can also be chromosomally abnormal, so to achieve a healthy, chromosomally normal embryo, you need a normal egg and a normal sperm to fertilize. The majority of failed IVF attempts are related to abnormal embryos. If you’ve got a normal embryo, you’re starting at a positive point.
The next step is, you need an anatomically normal uterus. It must have a normal lining, triple lining, there’s a thickening in the uterus, there are no growths, no fibroid is pushing on it, there are no polyps or septum in the uterus that can prevent an embryo from implanting. There shouldn’t be anything that is going to inhibit the area that the embryo implants. Fibroids, polyps push on that uterus, a septum, or a wall in the uterus, all of those things can lead to failure due to what we call an anatomical problem.
The last thing we need is an immunologically normal uterus. The embryo is coming from the male, it is what we call an antigen. That means that if you put sperm into someone’s bloodstream, it would recognize it as abnormal and create a reaction. The uterus is designed very cleverly. The uterus behaves in a way that sets up what is called blocking antibodies. These antibodies sit in the uterus and prevent rejection of the actual embryo, and when this immune system is not functioning properly, these blocking antibodies aren’t made. There are a lot of immune factors called Tumour Necrosis Factors (TNF), which lead to the embryo being rejected. If someone has high insulin levels, hyper prolactin levels, or immune thyroid disease, and an underactive thyroid without an immune factor, these factors are disturbed.
Dr Rodrigues continued and explained that insulin, prolactin and thyroid diseases increase poor quality eggs as well as sperm. Therefore, we need to test male partners as well. Unfortunately, most of the time, males aren’t tested for insulin, prolactin or thyroid disease, even though those play a critical role. Sperm is not just about putting sperm into an egg, and it will make a healthy embryo, not at all, for a male to be healthy, he needs to have normal hormonal levels. It is very significant to mention this because about 15 years ago, we would have blamed everything on the egg, we would say that these embryos are not good because of that. The eggs play a big role, but we started our research on insulin levels in men around 15 years ago. It came to our knowledge they had high insulin levels and as soon as you corrected the insulin levels, the quality of the embryo was improved, and your pregnancy rates went up.
We are all aware that certain things like overweight, diabetes, hypertension lead to increased predisposition to the disease. When you have a normal insulin level, and when you wake up in the morning, it should be at a low level. You have your breakfast, the insulin goes up to deal with the sugar load that came from your breakfast and brings the sugars back to normal, and the insulin goes down again. As Dr Rodrigues explained, what they have found in a lot of patients, and they don’t need to have a weight problem, is that they have a high insulin level. It needs to be fasting insulin, a level of anything around 9 is abnormal.
If that level is higher than 9, patients have a predisposition to creating problems with their sugars. On the right side, we can see that what insulin does helps glucose move to cells. When the insulin goes up, you move more sugar and glucose into cells. There can be weight gain because of increased fatty acids, and it gets deposited into fat tissue. However, what is more important, is what happens in the ovary during the development of the egg, you need a constant flow of sugar, not an up and down flow of the sugar. Anyone who has high insulin levels will often find that they get tired, post eating their blood sugars drop, they’ve got to eat again, they get cravings, they can be moody and irritable. All of those are a sign that you’ve got a hypersensitivity to insulin, and the ovary doesn’t like it, it cannot develop a strong, healthy egg.
You can have a chromosomally normal egg developing, and if your insulin is high, it can change that chromosomally normal egg into an abnormal egg during the final division of the egg, which happens once you trigger ovulation. This egg divides, it puts out off the chromosomes. During that division, it can make abnormal eggs. This particular problem leads to an increased incidence of abnormal eggs and an increased incidence of chromosomally abnormal embryos, including an incidence of higher miscarriage rates.
The good thing is that it can be easily diagnosed. It’s a blood test, and once you’ve got the diagnosis, you can manage it. The reason it is happening is quite clear, we do have very high carbohydrate diets generally worldwide. Dr Rodrigues explained if you’re trying to have a child, it is important to avoid certain foods. There’s nothing wrong with having certain pots of these things in your diet, but it has to be in moderation.
We’ve all heard of metabolic syndrome, which means that there’s a tendency to have high insulin levels, and with that comes an overweight, which is usually in the abdominal area. However, there are a lot of thin women who have high insulins, once you get to the metabolic syndrome phase, you often find that people will have gut pre-diabetes they will have hypertension coronary artery disease. In terms of the female, insulin plays a big role in polycystic ovarian syndrome (PCOS).
A patient might have what is called insulin sensitivity, which means that they have sugar loads related to normal insulin levels, and then you’ll get someone who has high insulin level. If you have many eggs, your insulin levels are high, the egg that is going to become the dominant egg will find it very difficult to suppress all other eggs that have been recruited during the early phase of the cycle. Because of this fluctuation of sugars, the energy in that particular egg cell cannot get the follicle to grow, usually beyond 14 millimetres. If it does sometimes grow, it grows very slowly, so the egg becomes abnormal with time, or in a certain group of patients, they don’t ovulate at all. You can have abnormal eggs and abnormal embryos. Another thing that happens if the insulin levels are high is that the uterine lining is often thin. The uterine lining is critical for the implantation of a healthy embryo.
If we look at the male, they can have normal semen analysis and fertilize an egg perfectly, or they can have very low sperm counts and abnormal sperm. It’s a spectrum, but it’s important to remember that males can have normal semen analyses and yet that particular sperm from someone with high insulin level will create an embryo that is not healthy. Dr Rodrigues added that they’ve done a lot of research at his clinic over the last 10 years. Men can create an abnormal poor embryo and have abnormal semen analysis if their insulin levels are high.
If your insulin levels are normal, you should have a balanced diet, maintain your weight. If you have polycystic ovaries with high insulin levels, and you have a high carbohydrate diet, then you should go on to a low glycaemic diet, just look for carbohydrates that have a low glycaemic index. A balanced eating plan, watching your refined carbohydrates will generally work.
If you’re struggling with poor eggs or poor sperm and cannot lose weight, this works particularly well in men that are overweight, it is called the banting diet or the high-protein diet with no carbohydrates. That kind of diet has a benefit in certain people and works very well. Keep in mind that if you’re eating properly, the eggs and sperm quality will improve, and you will have a better quality embryo. IVF mostly fails because something’s wrong with the embryo. If the insulin is high, there’s a higher chance that you will have a lot of abnormal embryos. If you manage your diet and your insulin levels, the chances of having better quality and chromosomally normal embryos are higher.
Lastly, the uterus will be more receptive because the endometrial lining is fine, the receptors for estrogen and progesterone work better when the cells in the uterus have the right amount of carbohydrates to gain the energy to those particular cells in the uterus.
It is generally prescribed for polycystic ovaries. Long-acting Glucophage XR is used at our clinic (MedFem). That’s because the quick-acting metformin that you have to take many times a day have a lot of side effects. We use a long-acting Glucophage tablet, which is taken once a day, and those doses are increased until one achieves normal insulin levels.
Another natural product that’s on the market and has had a lot of research done on it. That has a definite positive benefit in IVF patients, improved egg quality, and therefore improved chromosomally normal embryos, and therefore there are higher pregnancy rates and higher live birth rates.
Prolactin is made in the pituitary gland, the same place that FSH and LH come from. It is a follicle-stimulating hormone, luteinizing hormone and thyroid-stimulating hormone. Those four hormones are critical for the hypothalamus. The only time prolactin should be high is in pregnancy as soon as a woman is pregnant, the election goes up naturally, and during breastfeeding, it goes up very high.
If we look at breastfeeding women, they have a lower fertility rate, so they almost have a natural contraceptive during breastfeeding. Raised prolactin levels reduce the ability of FSH and LH to be made from the pituitary. They also cause problems with the thin lining of the uterus.
Three main things can occur:
In men, it is again important, it causes abnormal semen analysis in the male. They will have lower motility and lower counts.
What causes this to go up in situations which are not related to pregnancy or breastfeeding? Both in males and females, stress plays a big role. There is also a correlation between high prolactin and the patients having underlying endometriosis. Those two do go together. Certain medications and antidepressants play a big role in that too. A lot of psychiatric drugs can cause raised prolactin levels, and if they’re scarring on the breast area, the scarring can also promote high prolactin levels. The most common symptoms are headaches and breast tenderness in the female. Both in the male and female, there can be lactation or breast milk secretion, and obviously, the other things on the fertility side can lead to lack of periods and no ovulation.
The treatment is really simple, a dopamine agonist is used, it’s something that acts like dopamine, and by that, it starts to actually inhibit the prolactin and get the environment back to normal, the ones used are the trade name for Cabergoline is Dostinex and bromocriptine as Parlodel, and they work very well.
Another cause of very high prolactin is a prolactin tumour in the pituitary gland. This is not a common cause, but it is there, the treatment is usually medical, and usually, those patients have a four to five times higher level of prolactin.
From a fertility point of view, we need to treat any prolactin levels even if they’re raised marginally. It’s very important to treat prolactin to get that chromosomally normal embryo and a good environment in the uterus.
Thyroid disease is very common. Approximately 30% of a woman and a certain percentage of men will have an underactive thyroid. More and more males are getting this, and it’s probably related to the speed of life, and the amount of work we have to do. The thyroid plays a critical role in cellular health and cellular metabolism, and how the cell works.
In fertility, the level of TSH has to be below 2.5. If it’s above 2.5, it’s abnormal. This is a fertility-related diagnosis, we see a lot of women who come in and will have a thin lining in the uterus, will not ovulate properly, will have either infertility or recurrent miscarriages, they have TSH levels that are above 2.5, and it hasn’t been treated. It can be treated with a very cheap thyroid hormone which fixes the problem.
The most common symptoms that you can have with hypothyroidism is weight gain, coldness of the hands and feet, so lower body temperature, dry skin, fogginess of the head, no ovulation. There are a lot of symptoms, so if you are suffering from it, you need to treat this and make sure that the thyroid functions properly. It causes poor egg quality, poor embryos, and that means abnormal embryos in terms of chromosomes, lack of ovulation and then a thin or a very thick uterine lining that is not receptive.
In men, it causes abnormal semen analysis, it can cause problems with motility count and the ability of the sperm to bind the egg and fertilize an egg naturally. The treatment is simple, it’s a tablet a day and needs to be controlled accurately.
The human body sometimes develops antibodies against a particular tissue. Autoimmune thyroid disease is a common problem. In simple terms, the patient’s immune system attacks and can damage the thyroid. If you have antibodies, it doesn’t always mean that your thyroid will be overall underactive at that moment in time, but the studies have shown that thyroid antibodies are associated with two factors in the uterus. The first is what we call uterine receptor problems, so this is the ability of the uterus to respond to estrogen, progesterone and implantation of an embryo. The second one means that there are antibodies, and it’s a marker for other immune causes of recurrent implantation miscarriages and reduced live birth rates. In this group, there’s a raised level of tumour necrosis factor (TNF), which treats the embryo as a tumour.
These blocking antibodies and the immune system in the uterus are at a level that the embryo is not rejected. Yet, when you’ve got these other factors available, it can be rejected. For this kind of situation, there is a treatment protocol, which includes 80- 200 of Disprin, that’s for helping the blood supply to the uterus. We also use Cortisone in small doses to inhibit the antibody, and we use immunoglobulins both pre-transfer and during the first 10 weeks of pregnancy.
To sum up, Dr Rodrigues once again emphasized that those simple factors play such a critical role both in the male and female in the context of good eggs, good sperm, therefore, a chromosomally normal embryo. In the end, treating all these factors makes the uterus receptive, not only to the lining and the way it looks when one does a scan but also to the immune system to prevent the rejection of the embryo.
IVF from a donated embryo, we’re now getting an embryo that is potentially very normal. If we don’t treat the thyroid in such a way that you’ve got the levels of thyroid hormone right, and if we don’t treat the immune side of it we will have reduced implantation rates. Your hypothyroidism needs to have thyroid hormone replacement. It needs to have levels of hormones that are controlled perfectly, and then as far as the antibody goes as I’ve said we use that protocol that I described which contains different cortisone and immunoglobulins. From our experience, that deals with this problem perfectly.
I think that’s an important question. I’m making assumptions that the uterus and things like fibroids pushing in the uterus, a septum in the uterus have been ruled out. It’s also important that the fallopian tubes have been checked, that they are not blocked because if there’s a blocked fallopian tube, and it causes what we call a hydrosalpinx or water on the tube, that will prevent a normal embryo from implanting. There’s a lot of other immunological factors that need to be looked at. Like as anti-cardiolipins and antinuclear factors, the thyroid is important, and I don’t know if they’ve done your thyroid antibody, but if they haven’t, that’s important. I
’m presuming again the fact that been through so much, that the lining looks good and what we found in our particular experience with tested normal embryos that it’s critical if you can to put them back in the natural cycle, so you get a much better pregnancy rate if you use the natural cycle in terms of timing the natural cycle, releasing the egg and timing the transfer for 5 days afterwards. There are also some new tests available these days where you can go and biopsy the uterus and see if the uterus is synchronized, with the time that you’re putting the embryos back. I don’t know how much you’ve done, but those little tips will help.
The answer to that could be yes, so if your thyroid is well controlled hopefully they have checked your antibody levels, and if there are antibodies again, we found that the protocol we use is really very effective. If it’s not a tested embryo even though it was a donor egg, you’ve still got around 60% pregnancy rate with one embryo transfer, and it might go up to 75% if you’re having 2 embryos, but it’s not a 100%. As I said, in the beginning, most of the time the failure will be related to the embryo, but I must say that because you have a thyroid problem make sure you’ve had your antibodies checked, and one needs to manage that antibody environment to prevent rejection of the embryo.
As long as that thyroid is controlled, then it wouldn’t have been directly related to the thyroid, but it needs to be properly controlled, so the levels need to be normal, and then the other thing is that needs to be checked is what we discussed fasting insulin levels, which can play a big role, and then prolactin can definitely play a big role. The thyroid and prolactin are linked. So your prolactin levels need to be normal. What I often do if someone’s got a thyroid problem, I tend to let them come in a natural cycle and have a look at that physiology in that natural cycle and see if their lining is perfect when they’re not having an IVF program. If it’s not right to try and find a way of improving the natural look of that uterus, the natural physiology. If you can get the natural physiology to go well, then one should be able to retrieve better eggs the next time, and sometimes it’s also just changing the stimulation in order to achieve a better result.
In terms of hypothyroidism often has a similar effect. So, if you have a hypothyroid, overactive thyroid, those patients are going to be jittery, they’re going to lose weight, they are irritable. From a thyroid point of view, it can affect the lining of the uterus. It is best to make sure that the overactive thyroid is controlled. Once it’s in the normal range it doesn’t have an effect on that. Just remember that often those patients also have an antibody, so if you’re either fall pregnant naturally, or you would have had an IVF, it’s important to treat the antibody in terms of that protocol that I mentioned.
Yes, absolutely, any of those central nervous system drugs can affect prolactin levels, so it should be checked and controlled. You cannot generally have too low prolactin, but it can fluctuate, usually, it shows up on a program because the lining is not good during the program. Obviously, patients can have headaches, and they have other symptoms, but it should be checked in anyone that’s going to have an IVF program should have the insulin, prolactin and thyroid checked.
When it comes to the levels of thyroid, you want your TSH, T3 and T4 and antithyroid antibodies, so those things in terms of control you want your TSH to be below 2.5 and you want your T4 levels which is the level of hormone that is active in the body to be in the mid to high-range. As soon as pregnancy takes place, the demand for thyroid hormone goes up, and you don’t need more tests than that. It’s a really simple and straightforward test.
You’ve been diagnosed as diabetic, and generally, people with type 2 diabetes always have raised insulin levels. If one’s trying to manage one just by diet in terms of fertility, it’s better to be on Metformin and to try and bring that insulin level below 9. It plays an important role, I gather from a cyst you have probably you’ve got polycystic ovaries, so you will get better quality eggs if you control insulin levels, and as far as the thyroid goes back to the story we need to control, it properly because it can also cause problems with the quality of eggs and number of eggs, and a number of blastocysts that are formed. From our point of view if fibroids are close to the lining of the uterus so if they are closer than about 3-5 millimetres, they’re not pushing on the cavity of the uterus they will definitely affect implantation. We do see in a lot of people worldwide, that they don’t pay attention to that. From our point of view, if a fibroid is close to the uterus, it’s going to cause a problem with implantation. These days if one focuses on getting rid of those fibroids, you definitely will have a better success rate especially if you’ve been having failures, and 4 failures is a lot. I think you need to also just make sure that there are no antibodies whether that’s thyroid or antinuclear factors or endocardial lipids. There’s a lot of immune factors that they should be paying attention to as well. They should be managed from the transfer up to the 6-8 up to 10 weeks of pregnancy.
HbA1C is a measure of glucose in the haemoglobin, in our bodies. That is for a diagnosis of diabetes insulin is a separate factor it’s measured separately it’s not routinely measured, we measure it routinely. Most people that come for treatment are not diabetic. We see diabetics, but they’re not diabetic, their insulin is raised, they are called insulin resistant, they are called pre-diabetics sometimes, and at the end of the day it’s a different measure. It’s a specific thing that needs to be asked for and it actually quite dramatic how many people have raised insulin and how rewarding it is to treat it, and in some people, that’s the only reason they’re not falling pregnant because their insulin is playing a role in the female in creating an abnormal egg and creating an abnormal environment you put them on it the insulin goes to normal, and you get pregnant. It plays a big role in the male, so they are different tests.
If we look at fibroids they will definitely not be affected by acupuncture. They definitely can’t get smaller, it is a benign tumour, it is there, it’s got a blood supply, it won’t disappear with acupuncture. As far as healthy embryos go, acupuncture has some value in some people where it has an anti-stress mechanism, it has been shown in some studies to be helpful in terms of implantation of the embryo. Having said that I personally do not believe it will make an abnormal egg into an abnormal egg, but I think acupuncture for people that like going for it and enjoy it and are not stressed, it has definite benefits for that group of people.
That happens to some of the patients. That natural product that I mentioned is inositol, and different types of inositol are available. In research projects, it has been shown, it is effective during IVF to be of benefit, but you know so you can take that but what is critical then is also to be then on a strict eating plan in relation to carbohydrates. There is also another drug that we are using in a very specific people called Galvus, it’s a relatively new anti-diabetic drug, and it might be tolerated more in fibromyalgia, and that could be used if you’re really struggling to manage the insulin levels, but otherwise, inositol which is a natural product that’s very strict dietary habits will get that right.
That is a good question because you’ll find people over worry about TSH levels. What we need is a TSH level below 2.5 and anything below it, and then the T4 level, which is the measure of the hormone that’s actually doing the work needs to be normal. There is no such thing as a too low TSH level, so long as the T4 is now not becoming overactive so you don’t want to overtreat someone so the T4 needs to be in the normal range and then one can ignore the TSH level so long as it’s below 2.5.
Endometriosis has always been a contentious thing. From our point of view, it’s played a major role. It can play a major role in egg quality, so if we look at someone who we know has endometriosis and they go through an IVF process, 80% of the time the IVF will not be affected by it. 15-20% of the time the endometriosis hasn’t been treated. Usually, that treatment would be a laparoscopy. In that 15 to 20% it can affect egg quality, it can affect embryo quality, therefore, and it can affect implantation, so if you’re having recurrent failed blastocyst transfers in our opinion it’s important to manage endometriosis and not ignore it.
If you are deficient of vitamin D, you should be on vitamin D, coenzyme q10 plays a role in women with very low egg reserve, DHEA can play a role in helping eggs. We do put all our patients on a combination of inositol which is the thing that helps insulin, coenzyme q10, certain vitamins and certain amino acids. We use these products almost routinely in our female patients and in our male patients in South Africa. We use a product called StaminoGro which has high protein amino acids in it, and those amino acids have been designed in such a way to boost growth hormone, and that’s given to our males at night to boost sperm together with all the other essential antioxidants and those are all important things, so balanced eating plan and taking extra minerals and vitamins and amino acids do play a role. They’ve all been shown to be worthwhile.
The Labetalol is a beta-blocker so that won’t prevent pregnancy, so no problem with that.
The interesting thing about endometriosis is it doesn’t directly affect implantation, so it has more effects on egg quality and what kind of quality of egg you get and obviously natural pregnancies if there’s endometriosis it has a dramatic effect on the mucus and mucus is affected at the time of ovulation, it acts as a barrier to entry for the sperm. In terms of this particular patient, the endometriosis wouldn’t have played a direct role. Having said that endometriosis is an autoimmune disease you’re having cells growing in the abdomen, so there is definitely an association between endometriosis and other conditions including thyroid including the other antibodies such as endocardial lipid antinuclear factor and obviously as I mentioned earlier prolactin levels can also be raised.
It’s a question of just making sure that that uterine environment is perfectly fine, the problem with the polyurethane usually they are not ovulating or not properly so you cannot use a natural transfer and so these extra little things need to be taken care of to make sure that environment’s right and as I mentioned earlier your fallopian tubes open or any of them blocked which can actually then lead to fluid killing off the egg are there any fibroids or septums in the uterus, so those things have all need to be answered but endometriosis on its own, will not affect this outcome.
That’s a bit contradictory but at the end of the day if the fibroid was removed and the uterus was normal, and the operation was done fine then the loss of the baby would not be directly linked to the fibroid unless there were more fibroids. Having said that there is a condition that looks like fibroids called adenomyosis and I’m not saying you have that, but adenomyosis is like having endometriosis in the uterus, and it causes a very thickened muscle in the uterus. Those particular patients definitely have a higher incidence of losing babies between 12 and 28 weeks. It’s actually affected the muscle, you can’t cut that tissue away, so again hard to judge this particular situation but if the uterus was normal after the operation then generally you would not have lost the baby related to the fibroid itself or the removal of the fibroid.