During this event, Dr Abraham Zavala, Fertility Specialist at Clínica Tambre, discussed the science of PCOS and how it impacts fertility. PCOS affects millions of women worldwide, if you want to learn more about its impact on fertility and how to overcome that, check out this video recording.
Dr Abraham Zavala started his presentation with a statement that polycystic ovary syndrome (PCOS) is a topic that affects countless women around the world and is often misunderstood.
It’s essential to understand that:
PCOS is the most common endocrine disorder and yet remains shrouded in misconceptions. To simplify, PCOS is characterized by hormonal imbalances, irregular ovulation, and often the appearance of multiple follicles on the ovaries. However, having polycystic ovaries—or ovaries with many follicles or cysts—does not automatically mean you have PCOS.
“polycystic ovary syndrome” refers to a constellation of signs that occur together. Diagnosis requires careful evaluation of symptoms, which we’ll discuss in more depth during this presentation. Symptoms such as irregular menstrual periods, multiple follicles, and hormonal imbalances characterize PCOS. However, it’s important to note that some signs can be normal during adolescence, especially within the first year of menstruation. Hormonal imbalances during this time may cause hallmarks of PCOS, such as acne or irregular periods, so this population requires different considerations when diagnosing PCOS.
Many people wonder about the causes of PCOS. While the exact cause remains a mystery, several factors contribute, including genetic or epigenetic predispositions, insulin resistance, environmental factors, hormonal imbalances, and even vitamin D deficiency. Think of PCOS like a puzzle—no single piece defines it, but together, they create the bigger picture we call PCOS.
Depending on how it is defined, PCOS affects anywhere from 6% to 13% of the female population worldwide. Certain areas, such as Southeast Asia and parts of Eastern Europe, report a slightly higher incidence.
The symptoms of PCOS help us identify it, and as you can see, these symptoms can vary widely. They may include irregular periods, acne, weight gain, and excessive hair growth. It’s also important to screen for non-physical symptoms such as anxiety and depression, as these can accompany PCOS. Importantly, not all women with PCOS will experience the same symptoms at the same time, making it a complex condition that requires a personal approach to treatment.
Diagnosing PCOS is critical to understanding it. There is no specific test for PCOS; instead, diagnosis involves identifying at least two of the following:
These criteria, known as the Rotterdam Criteria, are the most commonly used method to diagnose PCOS. Recently, the use of AMH (anti-Müllerian hormone) has been added as an alternative to ultrasound when the scan does not provide a clear picture of polycystic ovaries. When diagnosing adolescents, special considerations must be taken into account. Teens often have polycystic-like ovaries, so ultrasound is not as effective for diagnosing PCOS in this group as it is for adults.
Beyond identifying the three hallmark characteristics of PCOS, it is essential to assess for other anomalies that may be present, such as insulin resistance. To measure this, both glucose and insulin levels are evaluated simultaneously. Patients suspected of having PCOS should also have their cholesterol levels and cardiovascular risk factors assessed. This thorough approach ensures the condition is addressed holistically.
Since there isn’t a specific test for PCOS, other endocrine disorders must be ruled out before establishing this diagnosis. Conditions such as hyperprolactinemia, which is an excess of prolactin, thyroid disease, especially hypothyroidism, and adrenal hyperplasia are some examples of other endocrine disorders that need to be addressed before establishing a diagnosis of PCOS.
Once a diagnosis of PCOS is established, and if the patient wants to improve their current condition, we always need to consider whether the patient is interested in achieving pregnancy in the short term or is not interested in pregnancy at the time. This distinction makes a very big difference in our approach and the treatment we provide. For example, non-pharmacological interventions are something that can be used in both populations, but pharmacological treatments will differ greatly depending on whether the goal is pregnancy or not.
Since we are in a setting more oriented towards assisted reproduction, we’ll focus on women actively trying to achieve pregnancy. However, for patients not currently interested in pregnancy, certain contraceptives can be used. These not only provide birth control but also help improve the hormonal imbalance.
Lifestyle changes are the cornerstone of PCOS management.
A balanced, low-calorie diet combined with regular exercise—about 150 minutes per week of moderate activity—can dramatically improve symptoms, even without actual weight loss. However, losing 5-10% of body weight can lead to more tangible improvements, including increased menstrual regularity and reduced hormonal imbalances that cause symptoms such as acne and excessive hair growth. This is one of the most important interventions for patients.
Lifestyle changes are not just about fertility; they are also about long-term health. Women with PCOS are at an increased risk of developing cardiovascular disease, type 2 diabetes, metabolic syndrome, depression, and anxiety.
As Dr Zavala mentioned, the treatment is usually started with certain supplements. For example, vitamin D deficiency can theoretically exacerbate PCOS and trigger an inflammatory response. It’s important to measure vitamin D levels, and if there is a deficiency, provide supplements to compensate. This is especially crucial during autumn and winter, when vitamin D deficiency may be more common.
Inositol is another supplement that can be provided. It has shown promise in managing PCOS by improving insulin sensitivity and regulating ovulation function, offering a more natural way to achieve results similar to other medications. Resveratrol, a potent antioxidant, may also help by addressing the oxidative stress observed in PCOS. However, it’s important to note that out of these supplements, only inositol—specifically in its forms such as myo-inositol or d-chiro-inositol—is included in the European Society for Human Reproduction guidelines for managing PCOS.
Metformin, commonly used to treat type 2 diabetes, also plays a role in managing PCOS. Its primary function is to improve insulin sensitivity, which can help regulate cycles and support ovulation. However, it is not suitable for everyone, as gastrointestinal side effects are common. It’s important to weigh the pros and cons with your doctor to determine whether metformin is right for you.
This medication is usually indicated for women with a BMI over 25, but it can also be considered for women with a lower BMI, depending on individual circumstances.
One of the hallmark characteristics of PCOS is the inability to ovulate. Many women with PCOS experience long periods without ovulation, which is a primary concern for those trying to conceive. Therefore, ovulation induction agents play a critical role in treatment, and we’ll discuss these further.
This can be difficult to achieve fertility for two reasons: one, because it becomes very hard to know when your ovulation window is going to be since you can never predict it, and two. After all, if you don’t ovulate, the sperm cannot get to the egg, and thus they cannot create an embryo that will attach to your lining and then move on to a healthy pregnancy. This is one of the more important therapies we can provide—a way to induce ovulation and achieve pregnancy.
Ovulation agents such as letrozole and clomiphene can induce ovulation in those pursuing pregnancy. Letrozole is considered the first-line treatment and the first option we can provide. It is particularly effective, and when combined with metformin, it can yield excellent results. However, you should not take these agents without medical supervision, as careful monitoring is necessary to avoid complications such as multiple pregnancies.
When letrozole and clomiphene are not effective enough, or they don’t work, there is another option we can try, which would be second-line treatment: gonadotropins. These are hormones that your body naturally produces, but we provide them at a slightly higher dose. When we talk about gonadotropins, we are referring to medications with an FSH or LH effect. These are injectable hormones and are a second-line treatment for women who don’t respond to the oral agents mentioned earlier. These treatments require meticulous monitoring via ultrasound to optimize outcomes and reduce risks.
Speaking of assisted reproduction techniques that use gonadotropins, these are an option when lifestyle changes and ovulation induction are not enough. ART options like IUI (intrauterine insemination) or IVF (in vitro fertilization) may be considered. Women with PCOS can benefit from specific protocols in IVF to undergo a safe procedure and achieve the same results as other patients who don’t suffer from PCOS.
Before trying any of this, it’s crucial to understand that the risks associated with pregnancy and PCOS include higher rates of gestational diabetes, pre-term delivery, and hypertensive disorders. With proper management and monitoring, these risks can be mitigated, ensuring a safer pregnancy. Beyond pregnancy, it is important to remember that PCOS may increase the risk of developing endometrial cancer later in life. Therefore, even if you’re not considering pregnancy, you should seek medical help in managing PCOS.
When it comes to ensuring safety in patients with PCOS undergoing IUI or, more importantly, IVF, it’s essential to remember that specific stimulation protocols involve certain gonadotropins for a set period. The medication used is crucial to ensuring safety during an IVF stimulation protocol. Different protocols, such as agonist or antagonist protocols, may be chosen to ensure safety during stimulation.
Another aspect that patients with PCOS should consider is cycle segmentation. Typically, in these cases, we aim to stimulate the ovaries, retrieve the eggs, generate embryos, and freeze them. This allows the body to shed the hormonal stimulation effects from ovarian stimulation before transferring the embryo in a frozen embryo transfer cycle. This approach helps avoid complications such as ovarian hyperstimulation syndrome.
To conclude, we must remember that PCOS is diagnosed when two out of three characteristics are present: ovulatory dysfunction, hyperandrogenism (an increase in male-type hormones), and a polycystic ovary image upon ultrasound. AMH can also be used as an alternative for this particular ultrasound finding.
Women with PCOS are at an increased risk for certain metabolic conditions, including cardiovascular diseases and diabetes. Due to the anovulatory nature of PCOS, it can also cause infertility.
Regarding treatment, lifestyle modifications are an important part of managing PCOS. Additionally, specific medications can improve PCOS, although most medications used for PCOS are off-label. This means the companies that manufacture these medications haven’t applied for their use in PCOS. Lastly, assisted reproduction technologies offer an effective treatment for women with PCOS.
That’s a great question and something we know very well. Patients with PCOS are very different, which is why we’ve established different types of PCOS patients, known as PCOS phenotypes. There are four phenotypes described in the literature: A, B, C, and D. For example, phenotype A includes patients presenting all the characteristics, such as anovulation cycles and hyperandrogenism. Other phenotypes may present only two of these characteristics.
Treatment is oriented to the type of phenotype the patient has, making this an essential part of PCOS diagnosis. It’s worth noting that some critical characteristics of PCOS are not considered symptoms for diagnosis. One example is insulin resistance, which is a significant aspect of PCOS but isn’t considered in diagnostic criteria. It’s crucial to evaluate insulin resistance whenever we’re thinking about diagnosing PCOS.
I can’t mention specific brand names. Inositol is considered, in a way, an experimental therapy. However, many preconception vitamin supplements include inositol, particularly the myo-inositol version.
That’s an interesting question. Do I believe? Yes, of course, we can all believe it. However, when I have a patient in front of me, I need to inform them whether there’s evidence to support that belief.
I believe certain beliefs and our state of mind can have a hormonal translation. For example, stress isn’t just a psychological idea; it has a physical impact, particularly on cortisol levels.
Therapies such as acupuncture won’t harm any other treatment we’re doing. If it helps you personally, I think it’s an option you can pursue, as it won’t interfere with treating your condition or achieving a healthy pregnancy.
First of all, I’m sorry that you had to go through this experience. Endometriosis is a chronic condition, and it’s very hard, especially when it’s that advanced.
There are certain aspects of endometriosis, like inflammation, that we can also see in PCOS. Some supplements can be used to reduce some of this inflammation and oxidative stress. However, managing endometriosis and managing PCOS are entirely different.
Achieving pregnancy in this context is challenging because we need to address the age factor and its impact on ovarian reserve. Additionally, endometriosis may also impact ovarian reserve. If it has affected your ovaries, and you’ve undergone surgery, this could further decrease the ovarian reserve available.
It makes sense. Once they are no longer taking combined oral contraceptives, ovulation may resume, enabling them to achieve pregnancy.
During the presentation, I mentioned that one of the harder parts of achieving pregnancy with PCOS is not knowing the ovulation window. By regularizing their periods, you are helping increase the chances of pregnancy.
Combined oral contraceptives work in two ways. First, they increase SHBG (sex hormone-binding globulin), which binds to free androgens, lowering circulating androgen levels. Second, depending on the contraceptive, it may have an anti-androgenic effect, which also helps lower androgen levels. These mechanisms can increase the chances of achieving pregnancy.
In what context? Do you mean during ovarian stimulation or just normally?
In general, there can be a small amount of free fluid within the abdomen. Excessive free fluid is often observed right after ovulation, which could be a cause.
Letrozole and Clomid are both oral medications used for ovulation induction. Guidelines and recommendations are constantly changing. When I mentioned letrozole as a first-line treatment for ovulation induction, I was citing the 2023 guidelines on PCOS management from the ESHRE guidelines.
Both medications aim to induce ovulation but act slightly differently. Back in 2012, one of the trials compared letrozole and Clomid. It found both to be effective for inducing ovulation. However, letrozole had a slightly safer profile as it was less associated with multiple pregnancies compared to Clomid.
Both can be used starting on day two, three, four, or five of the cycle, typically for five days. The dose can range from 50 to 150 milligrams, but is usually on the lower end of the spectrum.
First of all, with time, especially over the last few years, severe OHSS is rarely seen nowadays. The dosages we use for gonadotropins, both FSH and LH, have been greatly reduced. It’s very rare to see doses above 450 units nowadays, and most will stay somewhere between 200 to 300–375 units. This has been a big change in avoiding OHSS in general.
When I mentioned specific protocols for patients with PCOS, I did mean sticking to these dosages, especially because PCOS patients tend to be what we call high responders—patients with a greater ovarian reserve. This might cause a lot of follicles to grow, and a lot of growing follicles will increase the amount of estrogen produced. This increase in estrogen can cause OHSS.
Segmentation helps in this sense. Before the trigger (the final medication used to induce ovulation before egg retrieval), we measure hormones or count the number of follicles to decide the best trigger medication to avoid OHSS. Measuring estrogen levels will help determine whether to use a trigger medication that reduces the risk of OHSS. It will also guide whether we should freeze embryos and transfer them in another cycle.
If we were to transfer during a fresh stimulation cycle with a higher amount of estrogen, a positive pregnancy would only increase these hormones and worsen OHSS. While OHSS can still occur even with these measures, segmentation and proper dosage reduce the risk dramatically.
Well, we usually use one to two tablets, but as long as you’re being followed up and getting scans, you can find the right dosage with your doctor.
Egg quality is debatable, but yes, there are ways to improve outcomes. By improving the hormonal stimulation that the follicles receive, using medications such as metformin and ovulation inductors, you can help improve egg quality.
When choosing the right protocol, the focus is on ensuring safety by avoiding OHSS. However, with a lower AMH and a smaller number of follicles, the risk of ovarian hyperstimulation syndrome is reduced. The best protocol is the one your gynaecologist selects for you, as we wouldn’t need to take the same precautions as we would for a PCOS patient.
