What is Polycystic Ovary Syndrome?

Polycystic ovary syndrome (PCOS) involves hormone and metabolic imbalances and affects multiple body systems. Individuals with polycystic ovary syndrome often experience absent or irregular periods, ovarian cysts, infertility, facial hair growth, acne, weight gain, problems with blood sugar metabolism, and may have increased cardiovascular disease risk.

Healthy eating habits and losing weight, along with nutrients such as inositol and N-acetylcysteine (NAC), may help reduce polycystic ovary syndrome symptoms when combined with appropriate medical care.

Nutrients for Polycystic Ovary Syndrome

• Myo-inositol and D-chiro-inositol (DCI): These two inositol compounds have been found to help improve insulin sensitivity and triglyceride levels, and may improve menstrual regularity and reproductive health in women with polycystic ovary syndrome.
• Vitamin D: Many women with polycystic ovary syndrome have low levels of vitamin D, and supplementation has been found to improve hormone balance and metabolic health.
• Omega- 3 fatty acids: Clinical trials have found omega-3 fats from fish oil can reduce inflammation and improve markers of glucose and lipid metabolism.
• N-acetylcysteine (NAC): NAC has been shown to improve insulin sensitivity and support improved fertility when combined with ovulation-inducing medications.
• Chromium: Chromium picolinate has been shown to improve glucose tolerance in women with polycystic ovary syndrome.
• Lipoic acid: Women with polycystic ovary syndrome who supplemented with lipoic acid showed an improvement in insulin sensitivity and a reduction in triglycerides, while improvements in menstrual regularity were also seen with a combination of lipoic acid and inositol.
• L-carnitine: Clinical trials have found that L-carnitine and acetyl-L-carnitine may improve glucose metabolism and insulin signaling, BMI, unwanted hair growth (hirsutism), and blood lipid levels in women with polycystic ovary syndrome.
• Melatonin: The sleep-wake cycle may be disrupted in women with polycystic ovary syndrome. Some evidence suggest supplemental melatonin, a sleep-wake (circadian) hormone, may improve unwanted hair growth, insulin levels, levels of male hormones, blood lipid levels, and menstrual regularity among women with polycystic ovary syndrome.

Diet & Lifestyle Changes for Polycystic Ovary Syndrome

• Losing weight can help restore ovulatory cycles and improve metabolic health. Weight loss is generally the first-line treatment consideration for women with polycystic ovary syndrome who are overweight.
• Dietary changes that have been shown to be of benefit are reducing intake of carbohydrates and saturated fat and increasing intake of monounsaturated fats (such as those found in olive oil) and fiber.
• Engage in daily physical activity and regular exercise to improve insulin sensitivity and hormone balance.

Conventional Polycystic Ovary Syndrome Treatment

• Weight loss along with dietary and lifestyle changes
• Oral contraceptives
• Antiandrogens
• Metformin and statins
• Ovulation inducers

Polycystic ovary syndrome (PCOS) involves hormone and metabolic imbalances and affects multiple body systems. It is characterized by high levels of androgens (testosterone) with ovarian changes that result in menstrual cycle disturbances. polycystic ovary syndrome can affect adult and adolescent females.^1,2

Most adult women with polycystic ovary syndrome have multiple ovarian cysts and enlarged ovaries due to overexposure to androgens. Women with polycystic ovary syndrome typically experience symptoms related to hormonal imbalance, such as menstrual irregularity and infertility.³ Others develop additional distressing signs and symptoms, such as excess facial and body hair, adult acne, hair loss, and increasing body weight.² Psychological issues, possibly related to body image distress, are significantly higher in women with polycystic ovary syndrome.⁴ Many women with polycystic ovary syndrome experience mild and ambiguous symptoms.⁵

Figure 1: How PCOS affects the ovaries. Credit: VectorMine, Shutterstock⁶

Polycystic ovary syndrome is the most common hormonal disorder in women of reproductive age and usually develops during the early stages of puberty.^1,7 The true prevalence is unknown because many women with polycystic ovary syndrome are undiagnosed, but it is believed that about 5‒20% of women of reproductive age are affected.^8,9

Women with polycystic ovary syndrome are at increased risk of high blood sugar, type 2 diabetes, and other changes that may increase cardiovascular disease risk.^10-12 Therefore, lifestyle modification is critical to polycystic ovary syndrome management. Physical exercise and dietary changes may improve metabolic status and reduce levels of male hormones.

Oral contraceptives are generally the first-line pharmacologic treatment for the menstrual irregularities of polycystic ovary syndrome, as well as signs of hyperandrogenism (eg, unwanted hair growth and acne). Other antiandrogenic medications may be considered if the response to birth control is not satisfactory, and medications that promote ovulation can be used to treat infertility related to polycystic ovary syndrome.^1,13,14 Metformin, an insulin-sensitizing agent, is a second-line treatment option for metabolic concerns when oral contraceptives and lifestyle changes do not provide satisfactory results.^1,13,15,16

In addition, clinical trials show the use of targeted nutrients such as inositol, vitamin D, omega-3 fatty acids, and N-acetylcysteine (NAC) may help relieve polycystic ovary syndrome symptoms and reduce the risk of related chronic health problems.

Figure 2: Symptoms of PCOS. Credit: Anana_go, Shutterstock¹⁷

Common symptoms of polycystic ovary syndrome include:

• Menstrual irregularity. An unpredictable menstrual cycle is a common presenting symptom of polycystic ovary syndrome. This may manifest as cycles longer than 35 days or shorter than 21 days. Despite this, regular menses can occur in polycystic ovary syndrome.⁸
• Infertility. The menstrual irregularities and absence of ovulation caused by polycystic ovary syndrome can contribute to difficulty becoming pregnant.
• Skin and hair changes. Increased male hormone levels are a key feature of polycystic ovary syndrome and may result in excess facial and body hair, adult acne, and hair loss that resembles male-pattern baldness.¹⁸ Still, a substantial fraction of women with PCOS have polycystic ovaries and abnormal ovarian function without hyperandrogenism and the related skin and hair changes.⁹
• Overweight and obesity. It has been estimated that 50‒80% of women with PCOS are obese.⁸
• Psychological issues. Women with polycystic ovary syndrome have a greater risk of experiencing psychological issues including low self-esteem, depression, anxiety, eating disorders, and of attempting suicide.^19,20 Studies suggest these psychological challenges are often related to body image issues.⁴

Polycystic ovary syndrome is associated with a range of reproductive, metabolic, and psychological disorders.³ It is associated with a high prevalence of cardiovascular risk factors including hyperlipidemia and vascular disease, as well as metabolic abnormalities including type 2 diabetes.⁸

Reproductive Disorders

Ovarian dysfunction and hyperandrogenism (high levels of male sex hormones) are the main reproductive system-related functional disturbances in polycystic ovary syndrome. Polycystic ovary syndrome is also characterized by a large number of ovarian cysts, which can be viewed with ultrasound; however, evidence of this feature is not required for diagnosis. These reflect a failure of normal follicle or oocyte (ovarian cells that may become eggs) development.⁹ Many women with PCOS have trouble becoming pregnant due to infrequent ovulation or lack of ovulation altogether, although there still may be menstrual bleeding (known as “anovulatory cycling”). In fact, polycystic ovary syndrome is the most common cause of female infertility.²¹

PCOS is also associated with complications of both pregnancy and delivery, including miscarriage, gestational diabetes, gestational high blood pressure, preeclampsia, preterm delivery, and perinatal death, as well as increased need for labor induction and Cesarean-section.^2,22

Metabolic Disorders

Insulin resistance affects 50–70% of women with PCOS.²³ PCOS increases the odds of having impaired glucose tolerance by an estimated three-fold or more.²⁴ These metabolic derangements put women with PCOS at higher risk of type 2 diabetes, obesity, and non-alcoholic fatty liver disease.^3,25 In fact, as many as one in 10 women with PCOS develop type 2 diabetes by age 40.²³ In addition, high insulin levels resulting from insulin resistance can further increase hyperandrogenism and worsen hormone imbalance.¹³

Obesity frequently co-occurs with PCOS, and difficulty losing weight is reported to be one of the most distressing aspects of this condition.²⁴ The nature of the relationship between obesity and PCOS appears to be bi-directional, with each contributing to the onset and progression of the other.²⁶

Some evidence suggests obstructive sleep apnea may be more common in women with PCOS. Obstructive sleep apnea is a sleep disorder characterized by partial or complete obstruction of the airways during sleep, leading to intermittent pauses in breathing, low oxygen levels, and fragmented sleep. It is linked to obesity and cardiometabolic diseases.²⁴

Psychological Disorders

Depression, anxiety, eating disorders, reduced quality of life, negative body image, and psychosexual dysfunction all can occur in women with PCOS.³ Studies indicate women with PCOS are more than three times as likely to experience depressive symptoms and over six times more likely to experience anxiety symptoms than those without PCOS.²⁴ A strong association between these psychological issues and body image distress has been shown.^3,27 Biochemical features of the disease, such as insulin resistance, systemic inflammation, and high circulating male hormone levels, as well as PCOS manifestations (menstrual problems and infertility), may be contributing factors in the elevated risk of psychological complications.^3,27 A heavy emphasis on weight loss as a treatment strategy combined with difficulty losing weight may also contribute to the higher prevalence of eating disorders seen particularly in adolescents with PCOS, thus, a weight neutral approach may be better for addressing women with PCOS who experience psychological issues.^23,28 Other psychiatric ailments including personality disorders, schizoaffective disorder, obsessive-compulsive disorder, and panic disorder may also be more common in PCOS patients.²⁷

While the underlying cause of PCOS is unknown, abnormal insulin and hormone secretion and signaling appear to be key factors. Genetic, epigenetic, and environmental factors likely contribute as well.^37-39

Abnormal Gonadotropin and Androgen Secretion and Signaling

Excessive secretion of luteinizing hormone (LH), one of the pituitary hormones that stimulates maturation of ovarian follicles, appears to play a role in PCOS.⁹ A complex interaction of LH, FSH (follicle-stimulating hormone), and GnRH (gonadotropin-releasing hormone) appears to cause increased androgen production and disrupt normal development of follicles.⁸ At the same time, excessive male hormone levels provoke excessive LH secretion.¹³ Complicating this further, excessive insulin levels—another prominent feature of a high percentage of cases of PCOS—also contribute to hyperandrogenism.⁸

Abnormal Insulin Secretion and Signaling

Women with PCOS are prone to defects in insulin signaling, which increases the risk of gaining weight and becoming obese, aggravates the overproduction of androgens in the ovaries and adrenal gland.^40,41 Meanwhile, excess androgens encourage insulin resistance, leading to dysfunctional signaling by fat tissue and further elevated insulin levels, which in turn stimulate weight gain and androgen synthesis. The result is a vicious cycle of worsening hormonal and metabolic symptoms and progression of the syndrome.^42,43

Premature Sexual Maturation (Adrenarche)

Girls who develop premature signs of puberty (before the age of eight) often have signs and symptoms similar to PCOS. In fact, premature signs of puberty have been found to correlate with high androgen production and irregular menstrual periods, suggesting premature puberty may be an early manifestation of PCOS.^44-46

Chronic Inflammation

Chronic systemic inflammation is thought to play a role in PCOS as well. Women with PCOS have been found to have higher levels of markers of inflammation independent of their weight status.^47,48 Dysregulated inflammatory signaling by fat tissue and release of growth factors, cytokines, and free radicals from the ovaries, liver, and other tissues contribute to the inflammatory state and promote further metabolic imbalance and insulin resistance.^49,50 Inflammation and oxidative stress can also impair ovarian function and follicular maturation.⁵¹

Developmental and Early-Life Exposures

Some evidence suggests that certain exposures can affect the development of fetal and immature ovaries. These include in utero exposure to high levels of androgens, as well as fetal or childhood exposure to hormone-disrupting chemicals or drugs. This may even extend to certain foods.^1,7 Other maternal factors such as gestational hypertension, gestational diabetes, or smoking have been suggested as contributors to PCOS risk, and the risk may be compounded by environmental contributors in childhood such as poor diet and lack of exercise.⁷

Inositol

Inositol is a sugar alcohol found in plants and made in the body that occurs in multiple structural forms, or isomers. Myo-inositol is the most widely distributed isomer in nature and is abundant in the ovaries. The D-chiro-inositol (DCI) isomer is found in smaller amounts in the body. Some myo-inositol is converted to DCI in the body.^52,53

Inositol isomers are present in cells in free form and as components of membrane phospholipids, and are active in cell-to-cell signaling.⁵² In addition, inositol compounds called inositol phosphates act as second messengers to several hormones, including insulin and FSH, by transmitting external signals to the working interior of cells.^53-55 Dysregulation of the inositol phosphate system is associated with insulin resistance and related disorders, including PCOS.^55,56 Both myo-inositol and DCI have been found to have positive effects on glucose regulation in clinical trials; however, myo-inositol and DCI appear to have different effects on ovarian and pituitary hormone production, and the optimal ratio of myo-inositol to DCI for treatment of PCOS remains unresolved.⁵⁴

Myo-inositol. A number of clinical trials have demonstrated that myo-inositol can improve insulin sensitivity and metabolic markers, also influencing ovarian function in women with PCOS.^53,57,58 A meta-analysis of six randomized controlled trials with a total of 355 participants found myo-inositol was comparable to metformin with regard to its effects on fasting insulin and insulin sensitivity, testosterone, sex hormone binding globulin (SHBG), and body mass index (BMI) (a measure of body weight status) in women with PCOS, while metformin treatment carried a higher risk of adverse effects.⁵⁹

Myo-inositol supplementation has also been shown to improve fertility. A randomized controlled trial compared metformin plus 1,800 mg myo-inositol per day to metformin alone for three months in 120 women with PCOS-related infertility undergoing ovulation induction. Women who received metformin plus myo-inositol had more than double the successful childbirth rate compared with those who received metformin alone (55% vs. 27%, respectively).⁶⁰ Another randomized controlled trial in 116 women with PCOS-related infertility found that those who received 4 grams myo-inositol per day for six months had comparable improvements in metabolic markers and hormone levels to those who received both myo-inositol and metformin. There was no significant advantage for conception with the addition of metformin compared to myo-inositol alone. There were more side effects, mostly gastrointestinal, in the metformin group.⁶¹ Other research indicates myo-inositol supplementation reduces the risk of ovarian hyperstimulation syndrome during infertility treatment in patients with PCOS.^58,62

D-chiro-inositol (DCI). D-chiro-inositol is important for mediating the insulin response and has been shown to improve insulin sensitivity and improve metabolic conditions related to insulin resistance in PCOS patients.⁶³ By restoring insulin activity, DCI supplements may support improved ovarian function. However, DCI has also been found to inhibit aromatase (the enzyme that promotes conversion of androgens to estrogens in the ovaries), and higher doses have been found to increase circulating testosterone levels in women with PCOS.^54,64 In addition, high doses of DCI could interfere with absorption of myo-inositol and thereby decrease the likelihood of a therapeutic benefit, though conclusive data on this relationship is not yet available.⁵⁴

Myo-inositol plus D-chiro-inositol. Because of differences in their effects, it is possible that myo-inositol and DCI may have complementary actions. A 40:1 ratio of myo-inositol to DCI has been recommended as it is believed to reflect the physiological balance of these compounds in plasma.^54,65 One randomized controlled trial in 56 PCOS patients compared the effects of 4 grams of inositol per day for three months using seven different formulations to DCI alone, or myo-inositol to DCI in the following ratios—1:3.5, 2.5:1, 5:1, 20:1, 40:1, or 80:1. The 40:1 ratio of myo-inositol to DCI was most effective for restoring ovulation and normal levels of a range of reproductive hormones, while all formulations improved metabolic markers.⁶⁵

A randomized controlled trial in 46 participants with PCOS and obesity compared the effects of six months of combined daily treatment with myo-inositol and DCI in a 40:1 ratio (containing 1,100 mg myo-inositol) plus 400 mcg folic acid to 400 mcg folic acid per day alone. Those receiving myo-inositol plus DCI had greater reductions in LH, free testosterone, and fasting insulin levels, increased estrogen levels, and improved insulin sensitivity.⁶⁶ In another controlled trial in 44 overweight or obese PCOS patients, 10 were treated with diet, 4 grams myo-inositol, and 400 mcg folic acid; 13 with myo-inositol and DCI in a 40:1 ratio containing 1,100 mg myo-inositol; and 21 with diet alone. Weight, BMI, and hip and waist circumference decreased significantly in all groups, while only the 40:1 ratio group experienced a significant return of menstrual regularity.⁶⁷

In a controlled trial, the quality of oocytes retrieved from 11 women with PCOS-related infertility undergoing a type of in vitro fertilization (IVF) was assessed after 12 weeks of treatment with 550 mg myo-inositol plus either 300 mg or 27.6 mg DCI per day. The higher dose of D-chiro-inositol was found to have a greater positive effect on oocyte quality.⁶⁸

Vitamin D

Vitamin D is increasingly recognized for its important role in reproductive and metabolic health, and vitamin D deficiency may contribute to hormonal, metabolic, and mental health disorders in women with PCOS.^69-71 One observational study found vitamin D deficiency was associated with higher male hormone levels and BMI in women with PCOS, while another found that vitamin D deficiency was more common in women with than without PCOS.^72,73

Multiple randomized controlled trials and meta-analyses have demonstrated the beneficial effects of vitamin D therapy on metabolic and hormonal health in women with PCOS. A meta-analysis that included data from 11 randomized controlled trials with a combined total of 483 women with PCOS found that vitamin D, at doses ranging from 4,000–7,143 IUs (100–179 mcg) per day, resulted in lower total testosterone, insulin resistance, total cholesterol, and low-density lipoprotein (LDL)-cholesterol.⁷⁴ Other meta-analyses of many of these same trials have reached similar conclusions, finding that vitamin D can have broad positive impacts on lipid profile and glucose metabolism in women with PCOS, particularly those with vitamin D deficiency. In a 12-week, randomized, placebo-controlled trial in which 50,000 IUs (1,250 mcg) vitamin D was given weekly to 30 overweight women (age 18‒49) with PCOS and vitamin D deficiency, supplementation led to reduced unwanted hair growth and male hormone levels.^75,76 In another randomized controlled trial that included 180 women with PCOS and 150 without, all of whom had serum 25-OH vitamin D levels below 30 ng/mL, those with PCOS who received 20,000 IU (500 mcg) vitamin D per week experienced an improved LH:FSH⁷⁷ ratio versus placebo.⁷⁸

Omega-3 Fatty Acids

The anti-inflammatory activity of omega-3 fatty acids may reduce cardiovascular, metabolic, and hormonal complications of PCOS.⁷⁹ A case-control study in 325 women with PCOS and 325 healthy controls found that omega-3 fats in serum phospholipids were lower in women with PCOS. Women in the highest third of these omega-3 levels had 30‒40% lower odds of having PCOS compared with those in the lowest third.⁷⁸

A statistical analysis that included nine randomized controlled trials, involving a total of 591 women with PCOS, also reported finding omega-3 fatty acid supplementation improved insulin sensitivity, lowered total cholesterol and triglyceride levels, and raised levels of adiponectin (a signaling peptide primarily produced by fat tissue that improves insulin sensitivity and has anti-inflammatory properties).^80,81 Omega-3 fatty acid supplements were also found to lower high-sensitivity C-reactive protein (hs-CRP) levels and increase adiponectin levels in women with PCOS in another statistical analysis.⁸²

In one randomized controlled trial in 88 women with PCOS, supplementing with 2,000 mg omega-3 fatty acids from fish oil (including 360 mg EPA and 240 mg DHA) per day for six months resulted in reductions in waist circumference and triglyceride and cholesterol levels.⁸³

N-acetylcysteine (NAC)

N-acetylcysteine (NAC) is a form of the sulfur-containing amino acid cysteine and a precursor to glutathione, one of the body's most important antioxidants and detoxifiers.

One randomized controlled trial in 100 subjects with PCOS compared treatment with NAC (1,800 mg/day) to metformin (1,500 mg/day) for 24 weeks. NAC treatment significantly improved BMI, waist circumference and waist-to-hip ratio, while metformin did not. Additionally, markers of insulin sensitivity such as fasting insulin, fasting glucose, and fasting glucose/insulin ratio improved significantly with NAC but not with metformin. A greater reduction in total testosterone levels and fewer side effects were seen in NAC-treated participants.⁸⁴

Multiple controlled trials have shown NAC can improve the effectiveness of ovulation-inducing medications in women with infertility due to PCOS. A randomized controlled trial in 162 women with PCOS-related infertility being treated unsuccessfully with the fertility drug clomiphene citrate (Serophene, Clomid) compared the effects of adding NAC or L-carnitine to treatment for three months. The NAC group experienced greater improvement in free testosterone levels and insulin resistance markers, while both groups experienced similar improvements in menstrual regularity and LH and FSH levels; however, only the L-carnitine group had improvements in lipid levels.⁸⁵ In another controlled trial, 1,800 mg NAC per day was compared to 1,500 mg metformin as an addition to clomiphene citrate therapy in 108 women with clomiphene-resistant PCOS-related infertility. NAC led to greater reductions in unwanted hair growth and fasting glucose levels; metformin led to greater reductions in BMI and insulin levels. Also, NAC and metformin had similar positive effects on ovulation and fertility rates after 12 weeks.⁸⁶

NAC may also be helpful in women undergoing infertility treatment with letrozole (Femara). A double-blind, randomized, placebo-controlled trial in 130 PCOS patients showed the combination of letrozole plus 1,200 mg NAC per day resulted in more follicles greater than 18 mm in diameter (a size associated with greater likelihood of ovulation) after five days than letrozole alone or placebo. In addition, those who received NAC as an adjunct to letrozole had higher rates of ovulation and pregnancy.⁸⁷ However, another randomized controlled trial that included 97 women with PCOS found 1,200 mg NAC per day did not improve the effects of combination therapy with clomiphene citrate plus letrozole for inducing ovulation.⁸⁸

NAC may also have value as a supportive therapy prior to IVF. In a placebo-controlled trial in 80 women with PCOS preparing for IVF, 1,800 mg NAC per day for six weeks appeared to improve the quality of oocytes.⁸⁹

Berberine

Berberine is a bioactive alkaloid found in several medicinal plants including goldenseal and phellodendron.⁹⁰ These plants have been widely used in traditional Asian medicine for infections, metabolic disorders, and other indications. Its efficacy in improving insulin sensitivity, reducing serum androgens, and modulating chronic inflammation have made berberine a subject of interest in PCOS research.^91-94

A trial in 89 women with PCOS and insulin resistance found that berberine, in combination with hormone treatment, improved lipid profiles and SHBG levels, as well as glucose metabolism and waist circumference compared with combinations of either metformin or placebo and the same hormone treatment.⁹⁵ In a small clinical trial, 12 women with newly diagnosed PCOS were given 550 mg of a berberine-phospholipid complex twice daily for 60 days. After treatment, there were significant improvements in insulin sensitivity, testosterone levels, and markers of inflammation.⁹¹ Berberine may also improve IVF outcomes: 150 women with PCOS undergoing IVF treatment were randomized to receive either metformin, berberine, or placebo for three months before ovarian stimulation. The women given metformin or berberine had reductions in testosterone and insulin resistance, as well as increased pregnancy rates compared with those given placebo. The women who took berberine also had improved rates of live births and fewer adverse effects than metformin.⁹⁶

Berberine has been proposed to affect hormone levels and insulin metabolism by inhibiting the PI3K/AKT and MAPK pathways, activating AMPK, and interacting with multiple other targets.^94,97 Additionally, berberine may ameliorate certain aspects of PCOS pathology by reducing levels of several pro-inflammatory markers such as nuclear factor-kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), and interleukins 1 (IL-1) and 6 (IL-6).⁹⁸

Although berberine has been studied in human clinical trials and shown to have several metabolic benefits, concerns about long-term use of berberine have been raised on the basis of certain preclinical studies.^99-101 Some evidence suggests long-term berberine use, especially at high doses, may impair some aspects of cellular metabolism in specific types of cells. The implications of this preclinical research are yet to be determined by long-term human clinical trials; therefore, Life Extension currently recommends short-term use of berberine.

Probiotics

The gut microbiome plays a critical role in modulating immune function and metabolism, and may play a role in the unwanted hair growth that is part of PCOS.²⁹ A statistical analysis of 17 randomized controlled trials that included a total of over 1,000 participants found that intake of probiotics, prebiotics (partially or completely indigestible carbohydrates that enhance growth of beneficial gut bacteria), or synbiotics (combinations of probiotics and prebiotics) was of benefit for metabolic aspects of PCOS. Specifically, improvements occurred in fasting glucose and insulin levels, insulin sensitivity, total and LDL-cholesterol, and triglyceride levels.³⁵ Another statistical analysis of findings from nine randomized controlled trials with a combined total of 587 participants found treatment with probiotics or synbiotics for eight weeks or longer improved unwanted hair growth, fasting blood sugar and insulin, insulin sensitivity, and BMI. Testosterone as well as measures of inflammation and oxidative stress improved as well.³⁴

However, in a placebo-controlled trial in 99 subjects with PCOS, 12 weeks of treatment with a synbiotic supplement providing the prebiotic inulin plus a combination of seven probiotic strains improved LDL- and high-density lipoprotein (HDL)-cholesterol levels, but did not alter triglyceride levels, body weight, or body composition.¹⁰²

Magnesium

Magnesium plays an important role in regulating glucose metabolism and insulin sensitivity, and low magnesium status may be a contributing factor in the progression of insulin resistance to type 2 diabetes and heart disease.¹⁰³ A statistical analysis of eight studies in a total of over 2,000 women found that serum magnesium concentrations were lower in overweight or obese women with PCOS than normal-weight women with PCOS.¹⁰⁴ Furthermore, a study that examined the magnesium status of more than 1,000 women with PCOS found lower magnesium levels were associated with worse insulin resistance and higher testosterone levels.¹⁰⁵

Another placebo-controlled trial in 60 PCOS-affected subjects found 250 mg magnesium oxide per day for eight weeks increased LH levels and reduced BMI but did not affect markers of glucose or lipid metabolism, or multiple indices of hormonal status.¹⁰⁶

Curcumin

Curcumin, a polyphenol from turmeric (Curcuma longa), reduces oxidative stress and inflammation and has been shown to improve glucose and lipid metabolism as well as insulin sensitivity.¹⁰⁷ A statistical analysis of three randomized controlled trials with a combined total of 168 participants found curcumin supplementation, at doses of 500–1,500 mg per day, led to improvements in fasting glucose, insulin levels, measures of insulin sensitivity, and HDL- and total cholesterol in women with PCOS.¹⁰⁸

In one trial included in the meta-analysis, 60 women with PCOS received 500 mg curcumin or placebo twice daily for six weeks. The curcumin-treated women experienced a significant reduction in serum insulin and an improvement in insulin sensitivity compared with placebo.¹⁰⁹ In another trial in the statistical analysis, 67 women with PCOS received 500 mg curcumin three times daily or placebo for 12 weeks. At the end of the trial, levels of fasting plasma glucose and androgens decreased significantly in the curcumin group compared with controls.¹¹⁰ Treatment with 1,500 mg curcumin per day for 12 weeks was also shown to upregulate expression of a PPAR-γ activator molecule and improve markers of oxidative stress more than placebo in a controlled trial in 72 women with PCOS.¹¹¹

Cinnamon

A review of multiple clinical trials concluded that cinnamon (Cinnamomum zeylanicum) bark powder, in doses of 1‒6 grams per day, has glucose-lowering effects in people with type 2 diabetes.¹¹² Cinnamon has demonstrated anti-hypertensive, anti-obesity, and lipid-lowering properties in both clinical and preclinical settings, making it a likely candidate for metabolic syndrome (a cluster of co-occurring risk factors for cardiovascular disease and type 2 diabetes) and PCOS treatment.^113,114

A statistical analysis of five randomized controlled trials found that cinnamon improves a measure of insulin resistance in women with PCOS.¹¹⁵ In one of the trials 80 women with PCOS were randomly assigned to receive either a total of 1.5 grams cinnamon powder daily, taken in three divided doses, or placebo for 12 weeks. The cinnamon group experienced significantly greater reductions in fasting insulin, insulin resistance, and LDL-cholesterol than the placebo group.¹¹⁶ In a placebo-controlled trial in 84 subjects (age 20‒38 years) with PCOS and overweight or obesity, 1.5 grams of cinnamon daily for eight weeks increased antioxidant status, decreased a measure of oxidative stress, and improved total, LDL-, and HDL-cholesterol levels.¹¹⁷ In an rodent model of PCOS, the addition of cinnamon to androgen treatment blunted the changes in ovarian function and structure that occurred with androgen treatment alone. The addition of cinnamon also resulted in more normal levels of multiple sex hormones.¹¹⁸

Lipoic Acid

Lipoic acid (alpha-lipoic acid, ALA; R-lipoic acid, R-LA [a highly bioavailable form]) is an important antioxidant nutrient that has been shown to support healthy glucose metabolism.¹¹⁹ A large statistical analysis found that ALA lowers serum insulin and improves insulin sensitivity.¹²⁰ In an uncontrolled trial in 32 women with PCOS and obesity, 12 weeks of daily treatment with 400 mg ALA resulted in reduced insulin and glucose levels, BMI, and a measure of insulin resistance.¹²¹ In another small uncontrolled trial, 600 mg twice daily of controlled-release lipoic acid was administered to six normal-weight women with PCOS for 16 weeks. Insulin resistance, triglyceride levels, and LDL particle size improved. In addition, menstrual irregularities improved in the two subjects not taking oral contraception.¹²²

Several clinical trials have noted positive effects of a combination of lipoic acid and inositol on biomarkers and symptoms of PCOS. In a case-control study in 23 adolescents with PCOS and 21 healthy controls, myo-inositol plus lipoic acid treatment for six months was studied. Treatment significantly reduced insulin resistance and serum insulin levels.¹²³ In an uncontrolled pilot study in 40 women with PCOS, the combination of myo-inositol and lipoic acid decreased male hormone levels, improved menstrual regularity, and reduced unwanted hair growth and BMI without affecting glucose or insulin parameters.¹²⁴ Long-term treatment with daily lipoic acid at 800 mg and myo-inositol at 2,000 mg for 24 months resulted in significant reductions in menstrual irregularities in an uncontrolled trial in 44 PCOS patients with a history of infrequent menstrual periods. Insulin response to a glucose challenge improved as well.¹²⁵ In a six-month uncontrolled trial in 71 women with PCOS, 800 mg ALA plus either 1,000 or 2,000 mg of inositol daily improved menstrual regularity. However, substantially fewer women who received 1,000 mg derived this benefit.¹²⁶

Chromium

The mineral chromium may benefit women with PCOS due to its ability to support glucose regulation and metabolic health.¹²⁷ A case-control study in 42 women with PCOS (14 with metabolic syndrome and 28 without) found lower intake of chromium, as well as of several antioxidant micronutrients, in participants with metabolic syndrome and PCOS.¹²⁸

In a double-blind, randomized, controlled trial in 85 women with PCOS who received either 1,000 mcg chromium picolinate or placebo daily for six months, chromium picolinate supplementation led to significant improvements in BMI and fasting serum insulin levels. Chromium supplementation also increased the chances of ovulation and regular menstruation nearly two-fold after five months.¹²⁹ In a small pilot trial that enrolled 10 women with PCOS and randomized them to receive 200 mcg chromium picolinate or placebo daily for four months, chromium supplementation improved glucose tolerance but did not improve ovulatory frequency.¹³⁰ Another small study also reported improvements in glucose metabolism in response to 1,000 mcg chromium picolinate supplementation in obese women with PCOS.¹³¹

A statistical analysis of data from seven randomized controlled trials found chromium supplementation significantly reduced BMI and free testosterone levels.¹³² However, another meta-analysis that included six randomized controlled trials with a total of 351 participants found that although chromium supplementation decreased insulin resistance it also markedly increased total and free testosterone levels.¹³³ On the basis of these divergent conclusions from meta-analyses regarding free testosterone levels, it would be prudent for women with PCOS who choose to take chromium to regularly monitor their free testosterone levels.

L-carnitine

L-carnitine is an amino acid with a critical role in lipid metabolism. Clinical evidence shows it may be useful for treating metabolic disorders such as type 2 diabetes and non-alcoholic fatty liver disease (NAFLD).^134,135 An observational study found women with PCOS, especially those with obesity, had lower L-carnitine levels than those without PCOS.¹³⁶

In an uncontrolled trial of 74 women with PCOS, daily treatment with 3 grams L-carnitine over a period of three months resulted in significant improvements in insulin sensitivity, BMI, unwanted hair growth, lipid levels, and menstrual cycle regularity.¹³⁷ A randomized controlled trial enrolled 170 women with PCOS-related infertility who had proven to be resistant to the effects of clomiphene. The participants were randomized to receive 150 mg clomiphene in addition to placebo or 3 grams of L-carnitine on days 3‒7 of their menstrual cycles. Compared with the placebo, L-carnitine improved the ovulation rate (64.4% vs. 17.4%) and pregnancy rate (51.5% vs. 5.8%).¹³⁸

In a randomized placebo-controlled trial in 147 women with PCOS, L-carnitine in the form of acetyl-L-carnitine (ALC), at a dosage of 500 mg twice daily, was found to add to the benefits of the anti-diabetes medications metformin and pioglitazone (Actos). One group received only the medications, another received the medications plus ALC, and the third group received placebo. Both active treatments resulted in decreased serum insulin levels, though the effect was more pronounced in the group that received ALC. Luteinizing hormone (LH) decreased, and psychological scores improved, in a similar manner. Both treatments increased serum adiponectin and insulin sensitivity, and improved testosterone and FSH levels. Menstrual regularity and waist circumference improved only in those who received ALC.¹³⁹

Resveratrol

Resveratrol, a polyphenol found in grape skins, red wine, peanuts, Japanese knotweed, and berries, is a phytoestrogen that has demonstrated estrogenic effects in both animal studies and clinical trials.^140,141 Findings from animal and human studies suggest resveratrol may improve metabolic parameters, male hormone levels, ovarian function, and fertility in PCOS.¹⁴²

In a randomized placebo-controlled trial in 78 PCOS patients, 1,000 mg resveratrol daily for three months resulted in increased menstrual regularity and reduced hair loss, though other reproductive and metabolic indices were unchanged.¹⁴³ A randomized controlled trial in 30 women with PCOS found 1,500 mg resveratrol daily for three months reduced total testosterone, dehydroepiandrosterone-sulfate (DHEA-S), and fasting insulin levels; resveratrol treatment also increased insulin sensitivity.¹⁴⁴

In a randomized controlled trial, 61 women with PCOS-related infertility were given either 800 mg resveratrol or placebo daily for 40 days prior to ovulation induction and oocyte retrieval for IVF. Those who received resveratrol had a greater number of high-quality oocytes and post-fertilization embryos. They were also found to have reduced total testosterone and LH levels and increased FSH levels compared with placebo.¹⁴⁵ An open trial in 40 subjects with PCOS found 40 days of 800 mg resveratrol per day reduced inflammatory cytokine and CRP levels as well as levels of markers of a type of cellular stress called endoplasmic reticulum stress.¹⁴⁶ Abnormal proteins resulting from endoplasmic reticulum stress are thought to play a role in PCOS-related ovarian dysfunction.¹⁴⁷

Melatonin

Melatonin is a hormone secreted by the pineal gland that regulates sleep-wake (circadian) cycles in the body and has free radical-scavenging effects. In healthy individuals, melatonin levels exhibit a daily pattern, peaking at night and dipping in the morning. Genetic variants of melatonin receptors have been linked to increased risk of PCOS, and sleep disturbances including sleep apnea are common in women with PCOS.¹⁴⁸

Circadian control systems appear to be dysregulated in women with PCOS. In a study that included 321 female volunteers with and without signs of PCOS, higher morning melatonin levels were associated with expression of a higher number of PCOS-related features (hyperandrogenism, few or no periods, and cystic ovaries), suggesting PCOS may be associated with disrupted circadian signaling. The study also found a relationship between excessively high morning cortisol levels and number of PCOS features. Since cortisol secretion also follows a regular circadian pattern roughly opposite to that of melatonin, this finding provides additional confirmation of possible day-night cycle disturbance in women with PCOS.¹⁴⁹ A cross-sectional study in adolescent girls noted a relationship between morning circadian misalignment, based on irregular melatonin secretion, and PCOS-related metabolic disturbance.¹⁵⁰

A randomized, double-blind, placebo-controlled trial in 84 women with PCOS found that 6 mg of melatonin, along with 250 mg magnesium oxide, daily for eight weeks reduced unwanted hair growth, serum insulin, total testosterone, total and LDL-cholesterol, and raised HDL-cholesterol and total antioxidant capacity compared with baseline.^151,152 A prospective cohort study in 40 women with PCOS found that melatonin supplementation reduced male hormone levels, normalized other reproductive hormones, and improved menstrual regularity.¹⁵³ In a randomized controlled trial in 526 women with PCOS-related infertility, the addition of 3 mg melatonin per day to treatment with myo-inositol led to improvement in quality of eggs before and after IVF.¹⁵⁴

Flaxseeds and Flaxseed Oil

Flaxseeds are a source of lignans (plant compounds that modulate estrogenic activity) and the omega-3 fatty acid alpha-linolenic acid. In animal models, flaxseed oil has been found to modulate hormone signaling, improve lipid metabolism, and reduce inflammation related to PCOS partly through altering gut microbiome composition.^155-157 Flaxseed powder is also a source of dietary fiber, which also may be of benefit in PCOS.

In a randomized, open-label, controlled trial completed by 41 participants with PCOS, those who undertook lifestyle modification and received 30 grams flaxseed powder (about 2 tablespoons) per day for 12 weeks exhibited several improvements compared with lifestyle modifications alone. These changes included improvements in body weight, insulin resistance, triglycerides, hs-CRP, leptin (an appetite-regulating hormone, high levels of which are often associated with obesity), HDL-cholesterol, and adiponectin.¹⁵⁸ In a case report, 30 grams flaxseed powder daily for four months was associated with reductions in androgen levels and unwanted hair growth in a 31-year-old PCOS patient.¹⁵⁷

Weight Loss

Losing as little as 5‒10% of bodyweight can reduce insulin resistance, cardiometabolic risk, and male hormone levels while improving menstrual function and possibly fertility in women with PCOS.^8,14 The primary method for accomplishing this is diet, exercise, and lifestyle measures, although in indicated cases bariatric surgery has proven remarkably successful when a more conservative approach does not suffice.

Exercise

For women with PCOS, participation in a regular exercise regimen has many potential benefits, including improving menstrual problems, ovulation, cardiovascular and metabolic health, and mental health.¹⁵⁹ However, two studies that compared the response of women with PCOS to that of healthy controls found that, while exercise did deliver many of the expected benefits to women with PCOS, it failed to alter the glucose-insulin dynamic in the body as a whole and in skeletal muscle, and it did not have the expected effect on fat burning. Exercise improved these parameters in the control group; thus, metabolic response to physical activity appears to be blunted in individuals with PCOS.^160,161 A meta-analysis of 19 trials that included 777 women found that exercise intensity is more important than duration to derive benefits to insulin sensitivity and waist circumference. The authors concluded that a minimum of 120 minutes per week of vigorous-intensity exercise is needed for women with PCOS.¹⁶² A systematic literature review concluded that vigorous aerobic exercise and resistance training can lower male hormone levels and improve insulin sensitivity, while a randomized controlled trial in 61 women with PCOS found that a program of yoga exercise also may be of benefit as it reduced unwanted hair growth, abdominal circumference, and hip circumference compared with controls.^163,164

Diet

Eating fewer calories and reducing dietary glycemic value (a measure of a food’s potential to raise blood glucose levels) may be beneficial in women with PCOS, especially those who are overweight or obese. In a 24-week trial in 62 overweight or obese women, 28 with PCOS and 34 without, a reduced-calorie, low-glycemic index diet significantly improved acne, menstrual regularity, and testosterone and SHBG levels.¹⁶⁵

Reduced-carbohydrate diets may be beneficial in PCOS patients. A meta-analysis that included data from eight randomized controlled trials with a total of 327 participants with PCOS found reduced-carbohydrate diets, most lowering carbohydrate intake to 40–45% of daily calories versus 55‒60% of calories in control diets, reduced BMI, insulin resistance, and total and LDL-cholesterol levels. Maintaining carbohydrate restriction for more than four weeks raised SHBG and FSH levels and reduced testosterone levels. Diets with reduced amounts of both carbohydrate and fat had greater effects on FSH and SHBG.¹⁶⁶

A ketogenic diet is a high-fat (approximately 55‒60% of calories) diet that severely restricts carbohydrates (approximately 5–10% of daily calories). Although the medium-term effects and safety of ketogenic diets, followed for as long as two years, have been established in the medical literature, long-term health consequences have not been sufficiently studied.¹⁶⁷

Very-low carbohydrate diets such as “keto” cause a steep decline in insulin secretion. At the same time, the body shifts from burning glucose, a readily available fuel given normal carbohydrate consumption, to eventually beginning to produce and burn ketones from fat as a primary energy source. Benefits such as weight loss, increased insulin sensitivity, and improved glucose metabolism have been attributed to keto diets, based on a long history of clinical use as well as clinical studies of up to two years in duration.¹⁶⁷

A study in 14 women with PCOS found that eating a hybrid ketogenic-Mediterranean diet, along with food supplements and some phytoextracts, for 12 weeks led to reductions in body weight, BMI, and abdominal fat. Importantly, the diet was designed to emphasize monounsaturated fats such as those found in olive oil and nuts, and limit saturated and polyunsaturated fat intake by restricting the intake of eggs, meat, and fish. Significant reductions were also observed in glucose levels, insulin levels, and an index of insulin resistance.¹⁶⁸

Eating a diet high in animal products and low in plant-based foods is associated with insulin resistance, heart disease, and type 2 diabetes.¹⁶⁹ Moreover, the quality of carbohydrates in the diet appears to be a critical factor for long-term weight management and cardio-metabolic health. While sugar-sweetened beverages and refined grains are low-quality carbohydrates that raise the risk of obesity, heart disease, and type 2 diabetes, complex and high-fiber carbohydrate foods, such as beans and lentils, vegetables and fruits, and whole grains, have been associated with weight loss and decreased risk of heart disease and type 2 diabetes.^170,171

In a study of 87 women with PCOS and 50 women without, those with PCOS and insulin resistance were found to consume less dietary fiber and magnesium and a higher glycemic load diet. Glycemic load, like glycemic index, measures the effect of diet and food on blood sugar. Lower fiber consumption in women with PCOS was associated with insulin resistance, higher fasting insulin and worse glycemic control, and higher levels of androgens.¹⁷² An eight-week low-starch/low-dairy dietary intervention study, without calorie restriction, in 10 women with PCOS also reduced body weight and fasting insulin levels.¹⁷³

The Dietary Approaches to Stop Hypertension (DASH) diet is a mainly plant-based diet that emphasizes vegetables, fruits, whole grains, beans, nuts and seeds, lean meats, low-fat dairy products, and restricts saturated fat, cholesterol, red meat, refined grains, and sweets and salt.^174,175 In a randomized controlled three-month trial in 60 women with PCOS, participants were assigned to one of two energy-restricted diets, either DASH or a control. The DASH diet group experienced greater body weight and fat loss compared with controls. Improvements in androstenedione (an androgen) and SHBG levels, as well as antioxidant status, were also observed in the DASH diet group.¹⁷⁶

The Rotterdam Criteria were established in 2003 and are the basis of current diagnostic guidelines for PCOS. Diagnosis using these criteria requires the presence of two of the following three features¹⁷⁷:

• Oligomenorrhea (absent or irregular periods) or oligo-ovulation (low frequency of ovulation)
• High male hormone levels, based on symptoms or lab tests
• Polycystic ovaries on ultrasound

A complete medical history and physical exam are critical for the diagnosis of PCOS.¹³ Laboratory testing can also establish the presence of hyperandrogenism, and assessment of cardiometabolic risk, through both blood tests and medical history, is recommended. The third main feature of PCOS is polycystic ovaries, sometimes referred to as polycystic ovarian morphology (PCOM), which is diagnosed by ultrasound.⁹ Psychological screening is also important given the high prevalence of mood and other related disorders in patients with PCOS.⁹

Importantly, PCOS is a diagnosis of exclusion, meaning that other causes of ovarian dysfunction and hormone imbalance must be excluded to confirm a diagnosis.¹⁷⁷ Other conditions with similar clinical features include thyroid disease, hyperprolactinemia (high levels of the hormone prolactin), an androgen-producing tumor of the ovary or adrenal gland, and nonclassic congenital adrenal hyperplasia due to 21-hydroxylase-deficiency (an uncommon inherited disorder).^13,178

Although the onset of PCOS frequently occurs near the onset of puberty, diagnosing PCOS in girls and younger women is complicated by the fact that high levels of androgens and menstrual irregularities are common during puberty.^1,7 Another consideration is that large, polycystic ovaries can be a normal finding in adolescents.¹³

Ultrasound

Transvaginal ultrasound is used to visualize the ovaries in suspected cases of PCOS in which hyperandrogenism and ovulatory dysfunction have not been confirmed.⁸ Most women with PCOS are found to have polycystic ovaries with a high number of ovarian follicles and greater-than-normal ovarian volume visible on ultrasound. However, there is still disagreement regarding the exact number of follicles and volume of ovaries considered to be diagnostic.^13,177 Ultrasound is not a useful diagnostic tool in adolescents who have been menstruating for less than eight years.³

Lab Tests

Blood work is used to measure levels of hormones, assess metabolic disturbance, and exclude other possible causes of menstrual abnormalities or androgen excess that mimic PCOS.

Androgens:

• Testosterone. Levels of total testosterone and free testosterone (the fraction that is biologically active) are generally used to diagnose women suspected of having PCOS.⁷ Free testosterone is currently recognized as a more accurate test for identifying androgen excess, in part because insulin resistance can interfere with measurement of total testosterone.^13,179 Free testosterone can be measured directly, or indirectly by means of a calculation from measurements of total testosterone and SHBG.⁸
• Androstenedione. Androstenedione is an androgen hormone produced from progesterone by the adrenal gland and is a precursor hormone to testosterone. While some PCOS patients have high androstenedione levels, very high levels may indicate an adrenal disorder as the cause of hyperandrogenism.¹⁷⁷
• Dehydroepiandrosterone. DHEA is another adrenal androgen and is mostly found in circulation as DHEA-S. Elevated DHEA-sulfate (DHEA-S) levels may be an indicator of PCOS. In fact, in approximately 5% of PCOS patients, the only laboratory sign of androgen excess is an increased DHEA-S level.¹³

Regulatory Proteins:

• Sex hormone-binding globulin (SHBG). SHBG, a protein involved in regulating sex hormone bioavailability, has emerged as an important biomarker of PCOS, informing both diagnosis and treatment. There is some evidence that it could be useful for early diagnosis as well.^180,181 Because SHBG binds to sex hormones and reduces their bioavailability, decreased SHBG levels lead to increased androgen signaling and is closely associated with both ovarian dysfunction and metabolic disturbance. In addition, insulin resistance can reduce production of SHBG.^181,182
• Anti-Müllerian hormone (AMH). AMH is a protein produced by growing ovarian follicles that helps regulate follicular growth. Blood levels of AMH are correlated with number of ovarian follicles and have been found to be two to four times higher in women with PCOS than without.¹⁸³ Some evidence suggests AMH may not only be an indicator of polycystic ovaries but may also be related to PCOS-associated ovarian dysfunction, hyperandrogenism, and infertility, as well as insufficient response to treatment.^183-185 Its use in diagnosing and guiding treatment for PCOS is being refined.¹⁸⁶

Other Hormones:

• Luteinizing hormone (LH) and follicular stimulating hormone (FSH). LH and FSH are pituitary hormones that regulate ovarian function. Hormonal imbalance in women with PCOS disrupts feedback mechanisms that regulate LH and FSH release, resulting in increased LH production, decreased FSH production, and a rise in the ratio of LH to FSH.^1,7
• 17-hydroxyprogesterone. A 17-hydroxyprogesterone level may be necessary to rule out an adrenal cause of androgen excess.¹⁸⁷
• Prolactin. Prolactin is a hormone related to growth hormone and secreted from the pituitary. It has many functions but is best known for its role in lactation and breast development.¹⁸⁸ Excessive secretion of prolactin, known as hyperprolactinemia, can lead to symptoms that mimic PCOS, so prolactin level are sometimes obtained to rule this out.^9,13
• Thyroid stimulating hormone (TSH). TSH levels are measured to rule out a thyroid disorder as the cause of PCOS-like symptoms.¹³ Additional information about thyroid dysfunction is available in Life Extension’s Hypothyroidism protocol.

Other Blood Tests:

• Metabolic tests. Recommended testing for metabolic dysfunction has been insufficiently utilized by many clinicians, despite the high prevalence of insulin resistance, impaired glucose tolerance, metabolic syndrome, type 2 diabetes, and dyslipidemia in PCOS patients compared with their healthy counterparts. Guidelines from the American College of Obstetricians and Gynecologists and the Endocrine Society recommend that all PCOS patients be tested for impaired glucose tolerance and dyslipidemia by means of a two-hour oral glucose tolerance test and fasting lipid profile at diagnosis, and at regular intervals thereafter. Many gynecologists either do not order any metabolic lab tests or order only fasting glucose and hemoglobin A1C tests.¹⁸⁹ Lab tests are ultimately ordered at the discretion of the clinician, and may include any or all of these tests.
• Vitamin D. The prevalence of vitamin D deficiency is far higher in women with PCOS than in the general population.^190-192 The assessment of vitamin D status has important clinical implications in PCOS, as vitamin D deficiency has been shown to be associated with higher male hormone levels, insulin resistance, ovulatory dysfunction and infertility, and mental health problems.¹⁹³
• Homocysteine. Several studies have noted levels of homocysteine, an independent cardiovascular risk factor, are elevated in PCOS patients. Higher homocysteine levels are frequently seen in those with insulin resistance and other cardiovascular risk factors; however, high homocysteine levels have been found to be correlated with PCOS diagnosis independently of other indicators of cardio-metabolic risk.^194,195 In addition, some studies suggest elevated homocysteine levels may be correlated with high androgen levels and fertility problems in women with PCOS.¹⁹⁴
• Inflammatory markers. Chronic low-grade inflammation is a prominent though subclinical feature of PCOS and is implicated in PCOS sequela and co-occurring conditions. These include obesity, insulin resistance, metabolic syndrome, type 2 diabetes, and cardiovascular disease. The inflammatory markers C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), white blood cell count (WBC), and others have all been found to be higher in PCOS patients than in matched healthy individuals.⁴⁷ These tests can be used to assess baseline status, risk of complications, and response to treatment.

Polycystic ovary syndrome treatment is individualized to address the patient’s main concerns, which may include menstrual problems, infertility, unwanted hair growth, acne, weight gain, or metabolic disturbance. Dietary and lifestyle changes aimed at improving insulin sensitivity and body composition are a central pillar of an effective treatment plan. Drug therapies are commonly used to bring clinical symptoms and biochemical abnormalities under control, either while the patient attempts diet and lifestyle changes or in the event a patient does not improve sufficiently with nutrition and lifestyle strategies.

Oral Contraceptives

Hormonal contraception providing both estrogen and progestins are the first choice medical treatment for managing menstrual irregularities, unwanted hair growth, acne, and for providing contraception.^8,13 Estrogens and progestins lower LH levels, inhibiting androgen production in the ovaries, and increase levels of SHBG, reducing androgen activity.¹ Oral contraception is preferred for its beneficial effects on SHBG concentrations.⁹ In addition, combined oral contraceptives appear to limit conversion of testosterone into the more potent androgen 5-α-dihydrotestosterone by inhibiting the enzyme 5-α-reductase.¹³

Antiandrogens

Spironolactone (Aldactone) is a drug with an antiandrogenic effect due to its ability to block androgen receptors.¹⁹⁶ The use of spironolactone and oral contraceptives has been shown to be more effective than either alone for PCOS-related unwanted hair growth, and is often recommended for treating moderate-to-severe unwanted hair growth, or mild unwanted hair growth that is not sufficiently resolved after six months of treatment with oral contraceptives.^1,13

Spironolactone might also be helpful in treating hair loss and acne related to androgen excess.¹ For more information about therapies for these conditions, see the Hair Loss and Acne protocols.

Sexually active women should always use contraceptives with spironolactone since it is a strong teratogen (an agent that can cause birth defects). For the same reason, spironolactone should not be used during pregnancy.^13,196 Spironolactone can also cause electrolyte imbalance and dehydration.^1,196

Finasteride (Proscar) is an antiandrogen that works by inhibiting the conversion of testosterone into its more potent metabolite, dihydrotestosterone. It has been shown to improve hirsutism in women with PCOS. Some evidence indicates finasteride may also improve insulin resistance and glucose metabolism.¹⁹⁷

Metformin

Metformin (Glucophage) is an anti-diabetes medication that inhibits liver glucose production, decreases intestinal glucose uptake, and increases insulin sensitivity in peripheral tissues.¹⁹⁸ After hormonal contraception metformin is considered second-line therapy in PCOS, although its effects can be variable. Metformin has been shown to improve ovulation and fertility in PCOS patients.^199,200 It generally reduces androgen levels but is not a reliable anti-hirsutism agent. Metformin may also support weight loss, but this effect is likely to be modest.^8,9,13 Metformin’s effects may be greatest in those at high risk of type 2 diabetes, especially in the presence of obesity.^15,16 One setting in which metformin is sometimes considered first-line treatment is in adolescents with PCOS, although oral contraceptives are important as well.^1,13

Metformin often causes gastrointestinal side effects (eg, gas and diarrhea). Beginning with a lower dose and working up to a higher dose may help some individuals avoid these side effects.²⁰¹ Although current evidence suggests metformin may be safe in pregnancy, its use during pregnancy is still controversial.^200,202,203

Importantly, metformin can increase homocysteine levels. A statistical analysis of 11 studies found metformin at doses of ≥1,700 mg per day increased serum homocysteine and decreased folic acid levels in non-pregnant women with PCOS.²⁰⁴ Another clinical study using metformin at 500 mg twice daily also reported increased homocysteine levels in overweight and obese women with PCOS.²⁰⁵ Therefore, using the lowest effective dose of metformin and supplementing with folate may be advisable for maintaining healthy homocysteine levels.^204,206

Statins

Statins are a family of cholesterol-lowering drugs that includes atorvastatin (Lipitor), lovastatin (Mevacor), simvastatin (Zocor), and others. In addition to improving lipid levels, some research suggests statins, particularly atorvastatin, reduce low-grade inflammation and high testosterone levels in women with polycystic ovary syndrome.¹⁹⁷ The potential benefits of statin therapy in PCOS patients are still under investigation.

Weight Loss Surgery

Bariatric surgery improves multiple aspects of PCOS sequela.¹⁴ Bariatric surgery should be reserved for women with extreme obesity or with moderate obesity plus additional health concerns. Of course, it is also only indicated after diet, exercise, and lifestyle measures have been applied. One statistical analysis of 13 studies of bariatric surgery in PCOS patients found a marked reduction in symptoms accompanied by an over 50% loss of body weight.⁹ Another statistical analysis of 21 studies found that bariatric surgery resulted in decreases in hirsutism, menstrual irregularity, infertility, type 2 diabetes, high blood pressure, and depression. Total testosterone, fasting insulin, and LH levels decreased while estradiol increased after three months of follow-up. Longer follow-up times of six months or ≥12 months revealed decreases in testosterone and fasting insulin, blood glucose, and triglyceride levels. High-density lipoprotein and SHBG were significantly improved only ≥12 months after bariatric surgery.²⁰⁷

Hair Removal

Hirsutism that does not respond adequately to hormonal contraception or anti-androgen therapy can also be treated by waxing, shaving, electrolysis, or laser hair removal. In addition, eflornithine hydrochloride cream (Vaniqa) is a topical drug that inhibits hair growth, but it must be used indefinitely to prevent regrowth.¹⁴