Polycystic ovary syndrome (PCOS) is the most common cause of infertility in females. The hormonal imbalances experienced by women with PCOS often prevent ovulation from occurring at all. Without ovulation, pregnancy cannot occur without the use of fertility treatments. Other women with PCOS experience irregular menstrual cycles, which makes it challenging to know when ovulation and the fertile window are occurring.

While there are a variety of fertility treatment options, those who struggle with fertility often end up pursuing in vitro fertilization (IVF). IVF is extremely costly, and pregnancy is not guaranteed. Consequently, interventions that improve IVF success rates can be highly valuable.

This article discusses several interventions that have been shown to increase IVF success for women with PCOS.

IVF Success Rates without Nutrition or Lifestyle Interventions

A recent study explored IVF success rates for women of reproductive age with PCOS and separated results by PCOS phenotype (de Vos et al. 2018). For those who are unfamiliar, to be diagnosed with PCOS, patients must meet at least 2 of the following three criteria (known as the Rotterdam criteria):

1. High levels of androgens (male hormones), as measured either by blood tests or by signs of high androgens like acne and hirsutism.

2. Irregular menstrual cycles, which are defined as a menstrual cycle that is longer than 35 days in length.

3. Polycystic ovaries observed by intrauterine ultrasound.

This study categorized its study participants into five groups:

1. Those participants with polycystic ovaries observed by ultrasound with no other PCOS symptoms (272 participants)

2. Participants meeting all three of the Rotterdam criteria (66 participants)

3. Participants with high androgens and irregular menstrual periods without polycystic ovaries (0 participants)

4. Participants with high androgen levels and polycystic ovaries with normal menstrual cycles (54 participants)

5. Participants with irregular menstrual cycles and polycystic ovaries but normal androgen levels (175 participants)

The study followed participants through up to three IVF cycles and found significantly different live birth rates per cycle and across cycles for the four groups of women, as shown in the table below. Those with polycystic ovaries only (so not technically women with PCOS) had the highest pregnancy rates (66.6%), live birth rate per IVF cycle (39.5%), and cumulative live birth rate (53.3%) across up to three IVF cycles.

Those women with PCOS who did not have high androgen levels had the second-highest pregnancy and live birth rates. 61% of these participants experienced a pregnancy per cycle. 37.8% had a successful pregnancy outcome in any given cycle, and 48% had a successful pregnancy outcome within 3 IVF cycles.

In contrast, those women with high androgens, with or without irregular periods, had pregnancy rates of only 58% and only about 20% experienced a successful pregnancy in any given round of IVF. About 26 to 28% experienced a successful pregnancy within 3 IVF cycles.

The differences in success rates across these two groups speak to the impact of having high androgen levels on the success of the IVF process.

But... there's good news! Because there are a variety of interventions that can lower androgen levels and correct this hormone imbalance in women with PCOS! 

High Androgen Hormones and PCOS

While the exact cause of PCOS is still under debate, it is estimated that about 75% of women with PCOS have some degree of insulin resistance and that many women with PCOS have genetic abnormalities affecting insulin signaling and/or insulin receptors (Moghetti and Tosi 2021). Other studies have shown that women with PCOS have a harder time clearing insulin from their systems than women without PCOS (Peppard et al. 2001).

Whenever we consume carbohydrates, they get broken down into glucose and fructose molecules that get absorbed into our bloodstream. Our bodies then secrete insulin to ask our cells to take in this glucose. When we are insulin resistant, our cells are less responsive to insulin, forcing our bodies to release even more insulin to get our blood sugar levels under control. 

Our ovaries also contain receptors for insulin, and insulin tells theca cells in the ovaries to produce testosterone. Women with PCOS have theca cells that produce higher than normal amounts of testosterone in the presence of insulin (Wood et al. 2004)

So PCOS is the perfect storm for producing high androgen levels. A tendency towards insulin resistance causes high insulin levels. High insulin causes testosterone production, and our ovaries are extra sensitive to insulin so they produce even more testosterone in the presence of insulin. Yikes!

In addition to affecting fertility, these high testosterone levels lead to the common symptoms of PCOS which include excessive facial and body hair, hair loss, weight gain, difficulty losing weight, and acne.

But.. again, there's good news!

Because a healthy diet, lifestyle changes, and/or supplements can improve insulin resistance, which will lower androgen hormone levels.

Let's explore what the research says about specific tools we can use to improve insulin resistance and increase the possibility of successful IVF treatment. 

Using Berberine Supplements to improve IVF Outcomes with PCOS

Berberine, often abbreviated BBR, is an isoquinoline alkaloid, which is a fancy name for a kind of chemical found in plants. Berberine has long been used in traditional Chinese medicine and has been the subject of substantial research in recent years due to some evidence that it might improve insulin signaling and increase glucose uptake and utilization, both of which are important for people with insulin resistance, like women with PCOS (Zhang et al. 2021). It has also been shown to increase sex hormone-binding globulin and suppress androgen signaling and synthesis in some individuals, which can improve hormonal imbalances common in females with PCOS.

A randomized control trial by An et al. (2014) compared the use of berberine and metformin relative to each other and relative to a placebo among females trying to conceive via IVF. This study recruited 150 women of childbearing age with PCOS from the IVF unit of the First Affiliated Hospital of Harbin Medical University in China. All participants had struggled with infertility for at least two years before the study. All participants were counseled on lifestyle modifications and were advised to follow a diet commonly provided to type 2 diabetic patients. All participants were advised to increase physical activity.

One-third of the participants were randomly assigned to the berberine treatment group. This group consumed:

• 500 mg of berberine, taken three times per day.

One-third of the participants were randomly assigned to the metformin treatment group. This group consumed:

• 500 mg of metformin, taken three times per day

The remaining one-third of the participants were randomly assigned to the placebo group. This group consumed:

• Placebo pills that looked identical to the berberine and metformin pills, taken three times per day.

All participants continued on their treatment/placebo protocol for 12 weeks, during which time, they underwent a cycle of in vitro fertilization (IVF).

The table below includes the effects of berberine, metformin, or placebo on body weight and body composition, reproductive hormones, metabolic health, and cardiovascular health.

While we often do not expect to find any effects of taking a placebo, in this study, even the placebo group was making dietary and lifestyle changes, so it is not surprising that this group experienced improvements in many metrics over the twelve weeks of the study.

In terms of total testosterone levels and free androgen index, all three groups again saw decreases, with the berberine and metformin groups experiencing larger decreases in testosterone than the placebo group. All three groups experienced increases in SHBG, but the berberine and metformin groups experienced increases that were more than double the increase of the placebo group. In terms of metabolic health, all three groups experienced a decrease in insulin resistance, as measured by HOMA-IR. Again, the berberine and metformin groups outperformed the placebo group.

The table below compares the main IVF outcomes across the groups.

There were no significant differences in the number of oocytes collected during egg retrieval, the diploid fertilization rate, the embryo utilization rate, and the number of embryos transferred across the three groups. 

However, the berberine and metformin groups had higher rates of biochemical pregnancies (positive pregnancy tests), higher rates of clinical pregnancies (pregnancies confirmed via ultrasound), and live births. The berberine group had the highest live birth rate, with 18% of participants in this group successfully delivering a baby. 14% of the metformin group had a successful pregnancy, while only 6% of the placebo group had a successful pregnancy. 

This study demonstrates significant positive effects of supplementation with berberine for PCOS patients who are trying to conceive via IVF. Along all metrics, berberine did at least as well as metformin, and berberine outperformed metformin for live births. 

Study participants did experience some adverse effects from taking berberine or metformin, with 22.7% of participants reporting gastrointestinal effects from the berberine supplementation, 34.1% from taking metformin, and only 14.0% from taking the placebo. Nausea and abdominal pain were most common but some also experienced vomiting and diarrhea. 

Using Inositol to improve IVF Outcomes with PCOS

Inositol is a common PCOS supplement, which can be found in two primary forms: myo-inositol and d-chiro-inositol. 

Myo-inositol (MI) helps with the conversion of glucose into energy our cells can use, and it can also enhance the effects of follicle-stimulating hormone (FSH). Females with PCOS tend to have low FSH levels, especially relative to luteinizing hormone (LH). LH and FSH control ovulation and a high LH relative to FSH leads to follicles that do not reach the critical size needed for ovulation (To learn more about phases of menstrual cycles, check out this post.). Decreased concentrations of MI in follicle fluid is also associated with poorer oocyte (egg) quality and reduced likelihood of conception (Chiu et al. 2002). D-chiro-inositol (DCI) helps with the creation of glycogen, one form of glucose storage that occurs in muscle cells and the liver. You can read more about inositol in my article on it.

Artini et al. (2013) recruited 50 females with PCOS among patients for Assisted Reproductive Technology Services at the University of Pisa Division of Obstetrics and Gynaecology. The participants were randomly assigned to one of two groups:

1. The treatment group: consumed 2 grams of myo-inositol + 200 micrograms of folic acid each day

2. The control group: consumed 400 micrograms of folic acid daily

Both groups followed their respective supplement plan for 12 weeks. 

Following 12 weeks of supplementation, each participant underwent one cycle of in vitro fertilization. The table below summarizes the results of this cycle.

While the group only supplementing with folic acid had more oocytes (immature eggs) retrieved, the percent of “top-quality” oocytes was substantially lower for the folic acid-only group. Both groups had similar fertilization rates, similar numbers of embryos transferred, and similar percent of top-quality embryos.

The myo-inositol group experienced higher rates of chemical pregnancies (pregnancies confirmed with pregnancy test), clinical pregnancies (pregnancies that progress far enough along to be observed by ultrasound), and delivery rate (live birth). The group taking myo-inositol and folic acid had more than twice the likelihood of a successful live birth for the round of IVF than the group taking folic acid alone. This is a pretty substantial finding!

Using The Ketogenic Diet to Improve IVF Outcomes with PCOS

​The ketogenic diet is a low-carb diet that restricts carbohydrate intake to less than 50 grams per day and emphasizes consuming the majority of your calories from fat, for the body to move into ketosis. In ketosis, the body is primarily fueled by ketones instead of glucose. 

Keeping carbohydrates minimal is one (but not the only!) way to keep blood glucose levels stable without the need for a large release of insulin, and this can lead to significant reductions in PCOS symptoms.

A recent study made use of data from the Ingenes Institute, a fertility clinic in Mexico City (Palafox-Gomez et al. 2023). At this clinic, when an overweight or obese patient experiences a failed first in vitro fertilization (IVF) cycle, they are advised to try one of several nutritional interventions before trying a second IVF cycle. 

Between 2020 and 2022, 32 patients with PCOS were referred by their fertility specialist for nutritional counseling. Of those 32, 12 chose to follow a ketogenic diet before starting their next IVF cycle. These patients were advised to:

• Consume 1800 - 2000 calories/day (adjusted based on individual needs)

• Consume ≤ 50 g of carbohydrates per day

• Consume 1.5 g of protein per kilogram of body weight (or about 0.7 g per lb of body weight)

• Consume the remainder of calories from fat (≥60% of calories)

The duration of the intervention depended on the patient's needs. 

The table below shows the effects of the ketogenic diet on body composition indicators and metabolic health.

All markers of insulin resistance showed significant improvements, including a 12% decrease in fasting glucose, a 53% decrease in fasting insulin, and a 59% decrease in HOMA-IR (a measure of insulin resistance using both fasting glucose levels and fasting insulin levels). Unfortunately, this study did not measure testosterone levels, but improving insulin resistance likely decreased testosterone levels. 

Of the 12 patients, 7 successfully gave birth from their next round of IVF and 1 was pregnant at the time of publication. Two patients experienced miscarriages and two did not get pregnant during their next IVF cycle. 

This group of patients had a 58% success rate (or 67% if the pregnancy at the time of publication resulted in a live birth).  Leijdekkers et al. (2018) report success rates for two cohorts with a total of 115,384 women of reproductive age and find only a 24% success rate for those undertaking a second cycle of IVF after a failed first cycle. 

The ketogenic diet resulted in an IVF success rate of more than double the reported rate for a second cycle of IVF.

The table below summarizes these results.

The ketogenic diet study uses a much smaller sample size, so it is possible that the group was just an exceptionally lucky group. Further research would help to determine if this is the case. 

It should also be noted that patients self-selected to use the ketogenic diet instead of alternative options. It is possible that their inclination towards a low carbohydrate diet was due to biological factors that made the diet more effective for them. A randomized control trial would be helpful to know if the results are generalizable to all women with PCOS.

In the meantime, the ketogenic diet might still be something for women with PCOS to try before a cycle of IVF.

Other Potential Ways to Improve IVF Outcomes

​While studies looking at the effects of nutrition and supplementation on IVF outcomes are limited, there is substantial research on the effects of other interventions on testosterone levels in women with PCOS. It seems likely that such interventions could also increase IVF success rates.

These interventions include: 

• Following a time-restricted eating window (also known as intermittent fasting) from 8 AM to 4 PM.

• Shifting caloric intake earlier in the day.

• Following a low glycemic index or low glycemic load diet.

• Following a bean-based diet similar to Karen Hurd's Bean Protocol.

• Doing aerobic training for 45 minutes, 5 days per week.

• Drinking spearmint tea twice per day.

take-home points

• Peer-reviewed research indicates that supplementing with 500 mg berberine, three times per day OR 2 grams of myo-inositol + 200 micrograms of folic acid each day is associated with higher IVF success rates than following neither intervention for women with PCOS.

• Following a ketogenic diet may substantially increase IVF success rates for women with PCOS.

• Other nutrition and lifestyle interventions may potentially also increase IVF success rates, but they have not specifically been studied in the context of IVF.

If you'd like help figuring out how to implement any of these interventions, please reach out! I'd love to work with you!

References

Abel ED, O’Shea KM, and Ramasamy R. 2012. Insulin resistance: Metabolic mechanisms and consequences in the heart. Arteriosclerosis, Thrombosis, and Vascular Biology 32(9):2068-2076. 

An Y, Sun Z, Zhang Y, Liu B, Guan Y and Lu M. 2014. The use of berberine for women with polycystic ovary syndrome undergoing IVF treatment. Clinical Endocrinology, 80:425–431. doi: 10.1111/cen.12294 

De Vos M, Pareyn S, Drakopoulos P, Raimundo JM, Anckaert E, Santos-Ribeiro S, Polyzos NP, Tournaye H, Blockeel C. 2018. Cumulative live birth rates after IVF in patients with polycystic ovaries: phenotype matters. Reproductive BioMedicine Online, 37(2):163-171, https://doi.org/10.1016/j.rbmo.2018.05.003.

Moghetti P and F Tosi. 2021. Insulin Resistance and PCOS: Chicken or Egg? Journal of Endocrinological Investigation 44:233-244.

Peppard HR, Marfori J, Iuorno MJ, Nestler JE. 2001. Prevalence of polycystic ovary syndrome among premenopausal women with type 2 diabetes. Diabetes Care 24:1050–1052. 

Wood JR, Ho CKM, Nelson-Degrave VL, McAllister JM, and Strauss JF. 2004. The molecular signature of polycystic ovary syndrome (PCOS) theca cells defined by gene expression profiling. Journal of Reproductive Immunology, 63(1):51-60, https://doi.org/10.1016/j.jri.2004.01.010.