During this event, Dr Abraham Zavala, Fertility Specialist at Clínica Tambre, discussed the science behind how body weight can influence hormone balance, egg quality, and IVF outcomes, while also addressing why BMI alone isn’t always the best indicator of fertility health.
Looking at obesity from a purely medical context, obesity is a chronic and highly prevalent condition. It can be defined as an abnormal or excessive accumulation of fat. It is diagnosed and measured through something called BMI, which stands for Body Mass Index. BMI is a formula that takes into account your weight and height; weight is divided by height squared, and this gives a number.
If this number is between 18.5 and 24.9, it is considered a normal BMI. When the number is under 18.5, it is considered underweight. Everything above 24.9 is considered at least overweight. If the BMI is between 25 and 29.9, it is overweight. Everything above 29.9 is considered obesity. There are different obesity groups. Obesity group 1, or category one, is for people with a BMI from 30 to 34.9. Severe obesity or grade 2 obesity is when the BMI is above 35.
Is BMI the best way to define and measure obesity? No. It is not the best way because it does not take many important factors into account. For example, muscle mass, the amount of fat tissue, or the amount of water a person may be holding. It also does not consider gender. There are many areas in which we could improve how we define and measure obesity.
About 600 million adults worldwide are at least overweight or may be going through obesity. Among developed nations, the United States of America has the highest obesity rates in the world.
There are two moments when BMI is of great importance. One is during infertility treatments, such as egg donation, IVF, or artificial insemination. The other moment is during pregnancy. We know that a higher BMI can be associated with negative outcomes in pregnancies.
In 2019, almost 52.7% of adults in the European Union were considered overweight. There is a link between higher BMI and fertility. The ideal BMI is between 18.5 and 24.9, and anything over a BMI of 30 will decrease success outcomes in assisted reproduction.
However, many factors come into play when we talk about these outcomes. It is not black and white. We know that a BMI over 30 may affect reproductive outcomes, but we are not entirely sure how or why. Some factors come into play that we will discuss later. We are also not sure whether correcting BMI improves outcomes.
In the slide below, you can see something that is called the hormonal axis. The way hormones impact the ovary starts with a hormone secreted from the hypothalamus that goes to the pituitary gland. This hormone is called GnRH (gonadotropin-releasing hormone). GnRH stimulates two gonadotropins: FSH and LH. Once FSH and LH are secreted from the pituitary gland, they go to the ovary and stimulate the follicle. The follicle is the area where the egg develops.
FSH and LH stimulate the follicle, but not at the same time or in the same way. Depending on the rate at which GnRH is secreted, it stimulates more FSH or more LH release. This is a tightly calibrated system so that the follicle receives optimal stimulation from both hormones. This is a purely endocrine system, but one of the most important endocrine organs we have is adipose tissue or fat tissue.
Fat tissue releases hormones called cytokines. When released from adipose tissue, these are called adipokines. Four important adipokines are leptin, ghrelin, omentin, and adiponectin. You might have heard of them before, as they serve to balance impulses like hunger and satiety.
If these hormones are not secreted properly because of excess adipose tissue, they might affect how sex hormones are regulated. This can affect how GnRH is secreted, which influences FSH and LH pulses in the pituitary gland, ultimately affecting follicle stimulation and egg development inside the follicle. This shows why the impact of increased fat tissue is so important, and why it is necessary to differentiate between weight (which can be a combination of tissues) and purely fat tissue.
An increased BMI not only affects egg development but can also affect sperm quality. Excess fat tissue can reduce sperm production and quality, affect sperm motility, morphology, and reduce fertilization rates. In males, maintaining a healthy BMI below 30 kg/m² improves sperm quality and fertilisation rates.
How does this alteration in the endocrine axis affect reproductive outcomes? Starting with follicular development. If the follicle does not receive the right stimulation, it creates an abnormal environment within the follicular fluid. The follicle contains fluid where the egg develops and matures. In patients with obesity, follicular fluid often lacks the right concentration of normal components, which can affect egg quality.
An increased BMI may affect the way that the ovary responds to the natural hormones that your body produces, but it can also affect the way that your ovary responds to the medication that we provide during treatments such as IVF. That’s one of the first steps in which obesity can affect reproductive outcomes.
It can also make certain procedures more difficult. We must know that the tools, such as an ultrasound scan, the aspiration needle during IVF, or the catheter used during an embryo transfer, may be affected if there’s more atapose tissue. When there’s more atapose tissue or more fat tissue, we may not be able to see in the same way that we would with less fat tissue.
This can affect the way that we monitor an IVF stimulation cycle, the way that we do the egg collection after a stimulation cycle, and also the way that we see and perform an embryo transfer, mainly because of the way these procedures are usually done by ultrasound guidance.
Does an increased BMI affect egg maturity, number of eggs collected, or fertilisation? Some studies seem to show that an increased BMI may be associated with less mature eggs, fewer eggs collected, and fewer eggs correctly fertilised. Some studies seem to show that once the eggs are fertilised, there is no difference in the amount of euploid or aneuploid embryos when compared to patients with a BMI under 25.9. There are a few studies that show it may impact the genetic development of the embryos.
It’s hard to say for sure how obesity can impact, or specifically, at what point obesity can impact reproductive outcomes. However, it seems to reduce implantation rates and increase miscarriage rates. Ultimately, it has been shown to reduce live birth rates.
It can come with certain complications for pregnant women. It can increase the rate of women with high blood pressure, gestational diabetes, and diabetes. It can also increase the risks of a C-section or having a premature delivery. Depending on BMI, it could also increase mortality risk in pregnancy. There are dangers of malformations and high birth weight in babies from obese mothers.
These types of complications may or may not be related purely to obesity. Many of the risks are usually in the context of obesity, along with gestational diabetes or diabetes mellitus. We must understand that we’re not talking about just having a BMI over 30, meaning you’re exposed to all of these potential complications. However, it does open the door to other complications such as high blood pressure and diabetes, which in turn can increase the rate of complications during pregnancy and delivery.
How are people with an increased BMI treated? While it is a good idea to try to decrease the amount of fat tissue when the BMI is above a certain threshold, we’re not entirely sure what amount of positive impact that may have on treatment because we have mixed results from different studies.
One of the ways that obesity may affect reproductive outcomes is that women with an increased amount of Adipose tissue or fat tissue may not ovulate regularly. That’s something we also see in other conditions, such as PCOS. We know that decreasing your weight usually restarts the ovulation process. That is one good reason to reduce the weight and to try to achieve that weight reduction.
However, in other studies with patients with obesity who go through egg donation treatment, there is an increased rate of adverse outcomes. Therefore, it is not entirely clear at what stages of the reproductive process a decrease in weight can have the most impact. It is beneficial to lose weight for your overall health and certain improvements in reproductive outcomes; however, it’s not clear whether that may impact the treatment as a whole. There are also different medications used to try to decrease BMI when lifestyle changes and diet haven’t been effective.
Is there a specific diet recommended for weight loss? A lot of patients ask whether there is a diet that is recommended. A lot of patients think it may be a good idea to reduce fats. What is recommended is going into a healthy caloric deficit. That means consuming fewer calories than you’re using. That would be the most important advice in terms of diet. Most of the hormones that are important to the hormonal axis come directly from cholesterol. That doesn’t mean that if you take more cholesterol or have a higher fat intake that it’s going to improve; certainly cutting them out is going to benefit the way those hormones behave.
What happens when diets aren’t enough? Some medications can be used. The four more common ones: Orlistat, Phentermine, the combination of bupropion and naltrexone, and one that is very popular right now, semaglutide or Ozempic. These four are the ones approved in the US, and some of these are approved in Europe. These drugs are great at reducing weight, but it doesn’t seem like there’s an improvement in fertility rates with these drugs. There are certainly some promising results with drugs like Ozempic, but with it being contraindicated during pregnancy, there are very few studies that can be used to assess the effect it can have on fertility outcomes.
Most clinics set a BMI rule for IVF, and the limits differ by country. Fertility Clinics Abroad’s guide to BMI limits for IVF reports that “NHS IVF in the UK is funded at a BMI of 19 to 30, private UK clinics usually treat to 35 and some to 40, US clinics set 35 to 45 with hospital units going higher, and no European country except Serbia limits IVF by BMI in law.” The guide also lists which clinics in Spain, Greece, North Cyprus and the Czech Republic assess patients above 35 case by case.
It’s going to depend a lot on how much your TSH hormone is, which is the hormone that we use to define whether it’s hypothyroidism, and how closely you are controlling it with that dose of levothyroxine. We’ve seen that hypothyroidism may not have much of an impact on the stimulation protocol that we use. Results should not be that different, but it is going to have an impact on the embryo transfer and subsequent pregnancy.
We know that having uncontrolled TSH levels or thyroid hormone levels is related to adverse pregnancy outcomes, such as miscarriages and implantation failures. It’s also very important to have that regulated for the fetus’s neurodevelopment. This shouldn’t affect your chances of achieving pregnancy through IVF.
TSH levels in the normal population are going to be, depending on the lab, guidelines, and country, around 0.4 to about 4 to 4.5. That’s the normal level. However, there are two special populations where we use different levels to measure TSH: patients undergoing fertility treatment and pregnant women.
In these two populations, we want the TSH hormone to be below 2.5. That’s why I wanted to clarify for everyone — you need to remember that it’s 2.5. We’ve spoken about this during our webinars many times, but it’s good to repeat that over and over again to make sure we remember it.
Yes, there is some evidence that some nutrients and some supplements can improve outcomes, including live birth rate and weight loss.
This is true. With fertility treatments, sometimes we prescribe weight loss like it’s as easy as going to the pharmacy, getting medication, and losing 10 kilos. It doesn’t work like that.
It involves changing your lifestyle to be able to achieve an important weight loss, whatever the amount of weight that you need to lose. As we said, one of the ways that an increased BMI or an increased amount of fat tissue can affect the fertility outcome is through the follicular development.
We may have inadequate stimulation of the follicle, which affects how the egg develops and matures.
There are certain supplements that may aid the development of the follicle. One of those is inositol. Inositol acts in a way similar to how metformin would act. In fact, some studies have shown that inositol is even able to resume ovulation, which is one of the reasons we use metformin in patients with PCOS. So, inositol is one of the important supplements we may take — either myo-inositol or chiro-inositol — both are adequate for this purpose. Other supplements that have an impact on follicular development include ubiquinol and coenzyme Q10.
Five years is quite a long time. I know what you’re saying because we’ve seen it. This goes back to what we were talking about at the beginning of the presentation. BMI is going to evaluate weight as a whole. It’s not going to evaluate what is increasing that weight or what that weight is composed of. So, it’s not going to distinguish whether there are two extra kilograms of water, or two kilograms of muscle tissue, or two extra kilograms of fat tissue.
Hormones, especially hormones such as progesterone or corticosteroids, have been shown to increase the retention of fluids. That can be a factor.
It’s also important to remember that IVF stimulation increases the amount of estrogens, the amount of FSH, and the amount of LH. The impact this can have on our hunger centres and how that impacts our everyday life is hard to tell. That’s why it’s important to address this issue and see what behavioural or pharmacological change we can make to improve this condition.
It’s something quite difficult. I haven’t gone through IVF, but I’ve struggled with weight gain and weight loss. I know a lot of people around me who have also gone through that. Many of my patients are in this situation. It’s very common. We all either are going through that struggle ourselves or know people who are. Most of the time, it’s not as easy as “just eat less and exercise more.”
There are a lot of caveats and pitfalls to what the right nutrition should be, something that is sustainable throughout time. The same goes for exercise, something that is sustainable, not just for a month or two. That’s part of the difficulty in treating obesity: we fall back into it after a certain amount of time. My advice would be to take it up with your doctor. Discuss the difficulties you’re having so that we may find the best way to help you and make it a permanent change in your lifestyle.
That’s a difficult question. An increased BMI doesn’t just affect the way that the egg develops. It might also affect the way that the receptivity of your endometrium is expressed. There are a few studies I can think of that have been done on this subject. One of these studies was in women with an increased BMI who were receiving egg donors. Those did see a decrease in pregnancy rates and implantation.
However, the donor’s BMI wasn’t taken into account. So, we don’t know where those eggs were coming from or how they were developing.
Another study took a cohort of about 10,000 egg cells from donors with a normal BMI and didn’t see much of a difference in pregnancy rates between increased and normal BMI. It’s hard to give a clear yes or no answer to that question. But our recommendations stand the same — it is always recommended to lose weight when undergoing fertility treatments.
That’s a good point that I didn’t mention in the presentation. One of the effects that obesity can have on fertility treatments is that patients with an increased BMI often need more medication to get the same effect. It could be a factor in the way the medication is distributed, maybe we’re not getting the same result that we would see with a decreased BMI.
Now, is there a difference between overweight and obesity grade one? And how does that impact the amount of medication that we need? Hard to tell. BMI just tells us there’s increased weight, but it doesn’t tell us what that weight is composed of. I’m not sure what would be the appropriate dose in this case, but we have seen that patients with an increased BMI often need higher doses of the same medication.
We were talking about how TSH levels in the general population, depending on lab values, specific guidelines, and the country where you are being tested, are usually considered normal between 0.4 and 4.5. Now, in women, there are two populations in which we may want different values:
women trying to achieve pregnancy through fertility treatments, and pregnant women. In these populations, we are going to want TSH values below 2.5.
At some clinics, yes. According to Fertility Clinics Abroad’s guide to BMI limits for IVF, NHS IVF in the UK is funded at a BMI of 19 to 30, private UK clinics usually treat to 35 and some to 40, US clinics set 35 to 45 with hospital units going higher, and no European country except Serbia limits IVF by BMI in law. In the UK, Concept Fertility and TFP GCRM treat to 40 and the Lister sets no upper limit; abroad, clinics in Spain, Greece and North Cyprus assess patients above 35 individually, and for donor egg transfers the limit is usually looser.
