Berberine is a supplement that is commonly recommended to females with PCOS due to its potential to improve insulin sensitivity, metabolic health, and cardiovascular health. Since insulin resistance is almost always at the root of PCOS, interventions that improve insulin sensitivity can also improve PCOS symptoms, such as acne, excessive facial and/or body hair growth (i.e. hirsutism), and male pattern baldness.

This article talks about several research studies that quantify the effects of berberine supplements on insulin resistance, cardiovascular health, reproductive hormone levels, menstrual cycle regularity, in vitro fertilization (IVF) outcomes, and non-IVF fertility treatment outcomes.

While the studies all find positive benefits of berberine supplementation, results vary across studies and across individuals within a given study.

I think this is important to highlight because when I first started trying out supplements for PCOS (before digging into the literature myself), I'd see posts and articles saying that supplement/herb X would help with symptom Y. Then I'd try the herb or supplement and it wouldn't help! And I'd feel like there was something wrong with me. But there wasn't! There is just a lot of variation in how PCOS presents and how different people respond to any given treatment. 

You're not weird. You just haven't found the thing that works for YOU yet!

What is berberine?

Berberine, often abbreviated BBR, is an isoquinoline alkaloid, which is a fancy name for a kind of chemical found in plants. This broad category of plant-based chemicals includes commonly used medicines like morphine and codeine. Others have antiviral, antibacterial, and anti-cancer properties. 

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. There is also evidence that berberine may improve gut health and reduce inflammation.

With all of these potential benefits, it sounds like an ideal supplement for females with PCOS!

Let's see what the research says!

The Use of Berberine to Improve Menstrual Cycle Regularity, Improve Insulin Sensitivity, and Lower the Risk of Heart Disease

This first study (Orio et al. 2013) does not use a randomized control trial (our gold standard for researching interventions), but its methods still provide support for the use of berberine among women with PCOS. This study recruited 50 obese women with PCOS from Salerno University Hospital and the Antidiabetic Center in Salerno, Italy.

Participants in this study were told not to implement any lifestyle changes and were told to continue their current level of physical activity. 

Participants in this study consumed:

• 588 mg of berberine two times per day (before breakfast and dinner)

Their specific berberine supplement was Berberol, provided by PharmExtracta.

The intervention lasted for 6 months.

The table below provides the percent change in various metrics tracked by this study.

At the start of the study, none of the participants had regular menstrual cycles. By the end of the study, 22 of them (or 48.3%) had regular menstrual cycles. 

Unlike other studies that will be discussed below, this study found only marginal improvements in terms of weight management. Participants lost about 2% of their average waist circumference. However, changes in waist-to-hip ratio and BMI were statistically insignificant. Studies that find significant weight loss combine berberine with a physical exercise component (discussed below) and this combination might be important for effective weight loss efforts.

While weight loss was limited, participants saw improvements in insulin resistance, as measured by HOMA-IR as well as decreases in the area under the insulin curve. This latter measure is an indicator of how much insulin is released in response to consuming carbohydrates and how quickly that insulin is cleared from the body. Excess insulin stimulates the theca cells of the ovaries of women to secrete testosterone, and these cells in women with PCOS tend to be more sensitive to insulin. Insulin also tends to take longer to be cleared in women with PCOS. A decrease in the area under the insulin curve, thus, represents a significant impact that should result in improvement in PCOS symptoms.

Given the impact on insulin secretion, it is not surprising that they also found a decrease in total testosterone, free androgen index, and androstenedione (a precursor to estrogen and testosterone) and an increase in sex hormone-binding globulin. 

This study also found a decrease in total cholesterol, LDL cholesterol, and triglycerides, indicating a decreased risk of cardiovascular disease. 

The Use of Berberine to Improve Menstrual Cycle Regularity and Cardiovascular Health

This next study (Li et al. 2015) does not use a randomized controlled trial, but its methods also support the use of berberine for irregular periods among females with PCOS. This study recruited 102 women of reproductive age who had been diagnosed with PCOS and who experienced either oligomenorrhea (menstrual cycle > 35 days but less than 6 months) or amenorrhea (menstrual cycle of 6 months or longer). All participants were patients at the Department of Gynecology in Sun Yat-sen Memorial Hospital in China. This study categorized participants as normal weight if they had a BMI less than 23 or overweight/obese with a BMI of 23 or greater. It should be noted that the U.S. Centers for Disease Control uses 25 as the dividing BMI line between normal and overweight.

All participants in this study took 400 mg of berberine three times per day for four months. 

While no participants had regular menstrual cycles at the start of the intervention, by the end of the four-month intervention period, 14% of participants had achieved regular menstrual cycles (cycles between 21 and 35 days long). While 9% of participants experienced amenorrhea before the intervention, only 3% had amenorrhea at the end of the intervention period. Interestingly, the percentage with oligomenorrhea slightly increased, likely from a shift from irregular or absent periods to cycles between 35 days and 6 months.

Participants with a BMI less than 23 were more likely to reach a regular menstrual cycle (16% of participants with a BMI < 23) than those with a BMI of 23 or more (10% of these participants). 

Each month, the study team tested for ovulation using serum progesterone levels. Progesterone levels increase only after ovulation occurs, so we can use this test as a way to confirm ovulation. The graph below shows the percentage of participants with confirmed ovulation for the whole group as well as for the two BMI subsets. As we can see, both subgroups and the whole group experienced an increase in the percentage experiencing ovulation. However, the group with a BMI less than 23 experienced a greater improvement in ovulation rate.

This study also measured several reproductive hormones and measures of cardiovascular and metabolic health. The table below contains these results.

Unlike the previous study, this study did not find an effect of berberine consumption on levels of total testosterone, free testosterone, or DHEAS, and it finds a significant decrease in sex hormone binding globulin which is not a positive change for females with PCOS. They also find no effect on fasting blood glucose, fasting insulin, or HOMA-IR. However, some portion of the sample experienced an increase in insulin sensitivity because the percentage of the sample that met the criteria for insulin resistance (HOMA-IR > 2.14) decreased by about 14%.

The study did find improvements in total cholesterol levels, LDL cholesterol levels, and triglyceride levels. 

The Use of Berberine to Improve Acne, Excessive Hair Growth, and Menstrual Cycle Regularity... for Some Females with PCOS

A very recent clinical study measured a broader range of metrics than previous studies and also tracked important symptoms of PCOS that are often not considered by research studies (di Pierro et al. 2023). However, these symptoms are often the most bothersome aspects of PCOS, and studies should absolutely consider the effects of interventions on them.

This study recruited 130 females with PCOS with BMIs ranging from 18.5 (lower bound on normal weight) to 35 (a BMI of 30 or higher indicates obesity), aged 18 to 45 years old. 106 of the participants made it through the duration of the study. All participants were patients at one of five hospitals in Pakistan. 

Half of the starting participants were assigned to the berberine treatment group. This group consumed:

• 550 mg of berberine, consumed two times per day (after breakfast and after dinner)

The supplement was produced by Indena S.p.A. in Milan, Italy.     

The control group was not provided with any supplements or placebo pills. 

All participants were provided with advice to reduce carbohydrate consumption and to either continue their normal exercise routine or to add cycling and walking if they previously had no exercise routine. 

The intervention lasted for 90 days.

The table below shows the results of the intervention.

Both groups experienced reductions in body weight, BMI, and hip circumference. Interestingly, neither group experienced a reduction in waist circumference despite losing weight. A pattern of central adiposity (aka belly fat) indicates metabolic disorders, so we would hope to see an improvement in this measure.

Along these same lines, despite testing 4 measures of insulin resistance, this study finds no effect of berberine supplementation (or the diet and lifestyle changes made by the control group) on any measure of metabolic health. 

While this study found decreases in total cholesterol for both the treatment and control groups, the impact found in the treatment group is actually a bit smaller than that found in the control group. This suggests that the impact is coming from the dietary and lifestyle changes, not the berberine supplement.

This study finds no effect of berberine on triglycerides or HDL or LDL cholesterol levels. 

While this study finds a decrease in free testosterone levels in the berberine treatment group, it is not statistically significant. The data on symptom improvement below, suggests that for some women, supplementation did meaningfully lower free testosterone levels, but the supplementation did not result in a uniform reduction in symptoms across participants. 

The first symptom tracked was menstrual cycle regularity. The graphs below show the portion of participants that had normal menstrual cycles (35 or fewer days), the percent with irregular cycles (more than 35 days), and for the post-intervention graphs, the percent with cycles that are still irregular (more than 35 days) but shorter in duration than at the start of the intervention.

While the same percentage of participants taking berberine had regular periods (12%) before and after the intervention, 70% of these participants experienced a decrease in cycle duration, indicating more frequent ovulation. Only 17% of the control group experienced improved menstrual cycle regularity and 2% actually experienced a shift from having a regular cycle to having an irregular cycle. 

The second symptom tracked was the abnormality of the ovaries, found via ultrasound. Females with PCOS tend to have many enlarged, but immature follicles in their ovaries that are visible with ultrasound, in contrast to females without PCOS, who will have a single developing follicle forming during the follicular phase of their cycles. The excess follicles associated with PCOS are the symptom behind the “polycystic” portion of the name of the disorder.

The graphs below show the percent with normal ovaries (not polycystic), polycystic ovaries (many enlarged follicles visible), or improved relative to baseline, but still polycystic (fewer enlarged follicles visible).

65% of participants taking berberine experienced a reduction in the number of developing follicles found with ultrasound, while only 25% of the control group experienced a reduction. 2% of both groups experienced a shift from normal to polycystic ovaries. 

The third symptom tracked was acne. Acne was categorized as either severe, mild, or absent. Again, the research team also tracked those who still had severe acne but who experienced some improvement within this category. The graphs below show the percentage of participants falling into these categories.

Among those taking berberine, the percentage without acne increased from 43% to 51%, and 24% still had acne but experienced an improvement in it. Among the control group, those without acne increased from 49% to 55%, and another 9% experienced an improvement. 

The last symptom tracked was excessive hair growth, as measured by the Ferriman-Gallway score. The control group experienced no improvement in this score, on average, while the berberine group experienced a 13.5% reduction in this metric, indicating a decrease in excessive hair growth. 

Beneficial Effects of Berberine for Females Undergoing In Vitro Fertilization (IVF)

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 in vitro fertilization (IVF). This study recruited 150 patients 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. The study excluded anyone with diabetes mellitus, liver or kidney disease, or Cushing's syndrome, and all participants had stopped oral contraceptives at least 3 months before the intervention.

All participants were counseled on lifestyle changes 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.

The study specifically used BBR hydrochloride, provided by Northeast General Pharmaceutical Factory, in Harbin, China.

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.

All three groups experienced reductions in body mass index (BMI). However, the group taking berberine experienced the largest decrease, on average. All groups also experienced decreases in waist circumferences and waist-to-hip ratio, indicators of metabolic syndrome. Both treatment groups experienced larger improvements in these metrics, but there were no statistically significant differences in results between those who took berberine and those who took metformin.

In terms of hormone levels, all groups experienced decreases in luteinizing hormone, which tends to be elevated in women with PCOS. However, there was no statistically significant difference among the three groups; all groups experienced similar results. 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. Androgen hormones tend to be elevated in females with PCOS, and these high androgen levels are the primary cause of many of the symptoms of PCOS including acne, excessive hair growth, and hair loss. These elevated androgen levels can be exacerbated by low sex hormone-binding globulin (SHBG), which binds to androgens like testosterone, preventing the androgens from acting on cells. 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.

In terms of cardiovascular health, all groups experienced decreases in total cholesterol and LDL cholesterol (the "bad" kind of cholesterol). Berberine led to the largest reductions in both of these measures. All three groups experienced reductions in triglycerides and an increase in HDL cholesterol (the "good" kind of cholesterol), but all three groups experienced similar changes. 

The study, of course, was most interested in IVF outcomes. The table below compares the main outcomes across the groups.

The number of oocytes collected, the diploid fertilization rate, the embryo utilization rate, and the number of embryos transferred did not vary significantly across the three groups. 

However, the berberine and metformin groups had higher rates of biochemical pregnancies (positive pregnancy test), higher rates of clinical pregnancies (pregnancy 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 and reductions in BMI, total cholesterol, and LDL cholesterol. 

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. 

Berberine vs. Letrozole for Ovulation Induction and Fertility

While the previous study demonstrated that berberine supplementation was at least as effective as metformin for females with PCOS undergoing IVF, this next study demonstrates that berberine is not as effective as letrozole for non-IVF fertility treatment outcomes. 

Wu et al. (2016) recruited 644 women with PCOS across 19 different clinical sites in China. All participants were between 20 and 40 years old, met the Rotterdam criteria for PCOS, and had been trying to conceive for at least one year before the study. All participants were also examined to ensure that no other obvious impediments to fertility were playing a role.

This study was interested in exploring the use of berberine relative to and in combination with the use of letrozole. Letrozole is a medication that blocks estrogen production. When estrogen production is blocked, female bodies respond by producing more follicle-stimulating hormone (FSH). In females with PCOS, the ratio of luteinizing hormone (LH) to FSH tends to be too high, impeding ovulation. Increasing FSH decreases this ratio and can induce ovulation in females with PCOS.

One-third of the participants were assigned to the Letrozole-only group. This group received:

• 2.5 mg tablets of letrozole, taken daily on days 3 - 7 of the first three treatment cycles

• 5 mg tablets of letrozole, taken daily on days 3 - 7 of the last three treatment cycles, if conception had not occurred in the first three cycles.

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

• 1.5 g (or 1500 mg) of berberine daily

The remaining one-third of participants received letrozole and took berberine, according to the dosages listed above.

The medication/supplementation stage of the study continued for up to 6 months for all participants and was stopped before 6 months if conception occurred. Any participant who conceived was followed until the pregnancy was terminated either by delivery or miscarriage.

The table below reports the outcomes of this study.

The primary goal of this study was to determine which intervention led to the highest rate of successful births. 36.3% of participants taking only letrozole had a successful birth, followed closely by 34.4% of those taking both berberine and letrozole. Only 22% of participants taking only berberine successfully gave birth.

In terms of ovulation rate, the combination group experienced ovulation during 61% of monthly cycles, and 59.4% of the letrozole-only group ovulated each cycle. The difference between these two groups was not statistically significant, so we cannot say that the combination outperformed letrozole alone. The berberine-only group only ovulated during 36.3% of cycles.

The trends in chemical pregnancies (pregnancy confirmed by a pregnancy test) and clinical pregnancies (pregnancy confirmed by ultrasound) mirror the trends for ovulation, with the combination and letrozole-only groups outperforming the berberine-only group.

The researchers also considered pregnancy outcomes only among those who ovulated to determine if outcomes were driven only by ovulation rate. In terms of chemical and clinical pregnancy rates, the combination and letrozole-only groups experienced higher rates than the berberine-only group, and this difference was statistically significant. In terms of live birth rates, there is no statistically significant difference between the groups, after controlling for ovulation. 

TAKE HOME POINTS on the Use of Berberine supplementation for PCOS

Berberine may reduce insulin resistance for women with PCOS, but these results are not consistently found across all studies

Berberine may improve testosterone levels, but again, these results are not consistently found across studies or across participants in the same study.

Berberine may reduce total cholesterol, LDL cholesterol, and triglycerides but... again, these results are not consistent!

For some females with PCOS, the use of berberine may improve menstrual cycle regularity, ovulation rate, and IVF success. 

Berberine appears to be at least as effective as metformin at improving IVF outcomes, although success rates are still relatively low per round of IVF.

There is no evidence that berberine alone improves ovulation rates relative to the use of letrozole.

For some females, berberine may decrease acne and hirsutism, symptoms associated with elevated free testosterone levels.

The studies used dosages of

• 550 mg, 2x/day

• 588 mg, 2x/day

• 400 mg, 3x/day

• 500 mg, 3x/day

Supplementation with berberine may cause gastrointestinal effects. Starting with a lower dose and gradually increasing the dose can help mitigate effects as can taking the supplement with food. 

Warnings

Berberine should not be taken by females who are pregnant or breastfeeding because it can cause harm to fetuses and infants. Its safety in older children has not yet been established.

Berberine can interact with prescription medications. Always talk to your healthcare provider before starting any new supplement.

Disclaimer: This post is not intended to diagnose or treat any medical issues. It is intended for informational purposes only. I am not a medical practitioner. Always consult a trusted healthcare provider with any questions you may have about a medical condition or treatment and before starting any new health care regimen.

References                                                

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 

Di Pierro F, Sultana R, Eusaph AZ, Abrar S, Bugti M, Afridi F, Farooq U, Iqtadar S, Ghauri F, Makhduma S, Nourin S, Kanwal A, Bano A, Bugti AA, Mureed S, Ghazal A, Irshad R, Recchia M, Bertuccioli A, Putignano P, Riva A, Guasti L, Zerbinati N, and Khan A, 2023. Effect of Berberine Phytosome on reproductive, dermatologic, and metabolic characteristics in women with polycystic ovary syndrome: a controlled, randomized, multi-centric, open-label clinical trial. Frontiers in Pharmacology, 14:1269605. doi: 10.3389/fphar.2023.1269605                                   

Li L, Li C, Pan P, Chen X, Wu X, Ng EHY, and Yang D. 2015. A Single Arm Pilot Study of Effects of Berberine on the Menstrual Pattern, Ovulation Rate, Hormonal and Metabolic Profiles in Anovulatory Chinese Women with Polycystic Ovary Syndrome. PLoS ONE, 10(12):e0144072. doi:10.1371/journal. pone.0144072    

Orio F, Muscogiuri G, Palomba S, Savastano S, Volpe A, Orio M, Colarieti G, La Sala GB, Colao A, Marciano F, Ascione A, and Putignano P. 2013. Berberine improves reproductive features in obese Caucasian women with polycystic ovary syndrome independently of changes of insulin sensitivity. e-SPEN Journal, 8:e200ee204 http://dx.doi.org/10.1016/j.clnme.2013.07.002

Wu X, Wang Y, Liu J, Liang R, Xue H, Ma H, Shao X, and Ng EHY. 2016. Randomized controlled trial of letrozole, berberine, or a combination for infertility in the polycystic ovary syndrome. Reproductive Endocrinology, 106(3):757-766. 

Zhanga S, Zhoua J, Goberd H, Leunga WT, and Wang L. 2021. Effect and mechanism of berberine against polycystic ovary syndrome. Biomedicine & Pharmacotherapy 138:111468. https://doi.org/10.1016/j.biopha.2021.111468