Hyperinsulinemia, hyperprolactinemia, hypothyroidism and immune thyroid disease causing recurrent IVF failure

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.

Factors that play a role in successful IVF

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.

Immune factors that can lead to IVF failure

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.

Hyperinsulinemia

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.

High insulin levels and/or PCOS — diet

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.

Hyperinsulinemia — treatments

• Metformin

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.

• Inositol

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.

Hyperprolactinemia

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:

• poor eggs and embryos because of the change in FSH and LH
• lack of ovulation
• a thin uterine lining

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.

Hypothyroidism/underactive thyroid

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.

Autoimmune thyroid disease

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.