Polycystic Ovary Syndrome (PCOS)

Polycystic Ovary Syndrome (PCOS)

1 Overview

Summary and Quick Facts

  • Polycystic ovary syndrome (PCOS) is a hormonal-metabolic disorder that causes irregular menstrual cycles ovarian cysts along with expression of male characteristics such as facial hair growth.
  • This protocol describes factors that may contribute to PCOS and how the condition is medically treated. You’ll also learn about the important link between PCOS and insulin resistance, and how a common diabetes drug, metformin, may benefit women with PCOS.
  • Healthy eating habits and losing weight, along with supplements such as inositol and N-acetylcysteine (NAC), may help reduce PCOS symptoms when combined with appropriate medical care.

Polycystic ovary syndrome (PCOS) is a hormonal disorder that affects 5‒10% of women of childbearing age. PCOS can cause troublesome signs and symptoms, including:

  • Irregular menstrual cycles
  • Excess male hormone production, resulting in excess facial and body hair (hirsutism), adult acne, and male pattern baldness (in women)
  • Chronic lack of ovulation

Fortunately, integrative interventions like inositol and N-acetyl-L-cysteine (NAC) can help improve symptoms and quality of life for women who suffer with PCOS.

Conditions Associated with PCOS

  • Infertility
  • Obesity, especially central
  • Insulin resistance and type 2 diabetes
  • Stroke and cardiovascular disease

Causes and Risk Factors for PCOS

  • High levels of insulin or insulin resistance
  • Excess luteinizing hormone
  • Obesity
  • Early age at onset of puberty

Conventional Medical Treatments

  • Metformin is therapeutic for both elevated insulin and male hormone excess
  • Hirsutism and menstrual cycle regulation: oral contraceptive pills, metformin, spironolactone
  • Infertility: clomiphene citrate (Clomid), metformin, gonadotropins, surgery to destroy extra ovarian follicles

Dietary and Lifestyle Changes

  • Reduce dietary carbohydrates and saturated fat and increase monounsaturated fats and fiber from low-glycemic index foods
  • Daily physical activity and regular exercise to improve insulin sensitivity

Integrative Interventions

  • D-chiro inositol, Myo-inositol, D-pinitol: These three inositol compounds have been found to help improve insulin sensitivity, blood pressure, triglyceride and testosterone levels, and ovulatory function.
  • N-acetyl-L-cysteine (NAC): NAC improves insulin sensitivity and restores fertility when added to the drug clomiphene citrate better than clomiphene citrate alone.
  • Chromium: Chromium picolinate improves glucose tolerance in women with PCOS.
  • Lipoic acid: Women with PCOS who supplemented with lipoic acid showed a sharp improvement in insulin sensitivity and a reduction in triglycerides.
  • Cinnamon: Researchers at Columbia University have found that cinnamon extract reduces the insulin resistance of women with PCOS.

2 Introduction

A woman who finds herself with irregular menstrual cycles, excess facial and body hair, adult acne, weight gain, infertility and enlarged ovaries may have polycystic ovary syndrome (PCOS), an unfortunate condition that afflicts 5‒10% of women of childbearing age and approximately 70‒90% of women with irregular menstrual cycles.1 Among its many symptoms, PCOS causes hormonal imbalances, including elevated testosterone (male hormone) and estrogen (female hormone) levels, as well as increased insulin levels.2,3

Although PCOS is the most common female endocrine disorder in the United States, its cause remains unclear.4 Perhaps this is why “syndrome” is most commonly used in conventional medicine to describe PCOS since the word itself alludes to its varied signs and symptoms but does not indicate a precise cause of the condition.

However, research largely overlooked by mainstream medicine reveals a strong association between PCOS, obesity, and insulin resistance, including characteristic features of insulin insensitivity such as dyslipidemia (abnormality of metabolism of fats) and hypertension.5,6

If left untreated, women with PCOS often develop severe clinical manifestations, such as hirsutism (excess facial and body hair), adult acne, infertility, and depression.7,8 Women with PCOS are at significantly higher risk for developing cardiovascular disease9 and endometrial cancer.10

Integrative medicine recognizes the seriousness of PCOS, as well as the need to approach the management of PCOS as a disease of insulin resistance in order to offer hope to the millions of women who suffer from this disease. For example, metformin, an insulin sensitizing agent that also helps to reduce excessive androgen production, promotes weight loss, restores fertility, and enhances glucose metabolism in patients with PCOS, is drastically underutilized by conventional medicine for this disease. However, management strategies commonly used to control individual symptoms of PCOS are known to have a number of undesirable side effects.11

Fortunately, for the millions suffering with PCOS published clinical studies support the use of natural therapeutics, such as inositol and N-acetyl-cysteine (NAC), for controlling the symptoms and side effects.

3 Symptoms of PCOS

One of the challenging aspects of diagnosing PCOS is that the signs and symptoms vary from person to person, in both type and severity. Frequently, PCOS symptoms are mistaken for other medical illnesses. However, common symptoms include:

Menstrual Abnormality

Menstrual abnormality is the most widespread characteristic of PCOS. These include cycles longer than 35 days (fewer than eight menstrual cycles a year); failure to menstruate for four months or longer; and prolonged periods that may be scant or heavy.12

Excess Androgen Production

Increased androgen levels are a key feature of PCOS and may result in excess facial and body hair (hirsutism), adult acne, and male-pattern baldness (in women). Worth noting, however, is that the physical signs of androgen excess vary with ethnicity. As an example, the prevalence of hirsutism in PCOS patients is at least 40% in European and American females, yet is even more common in darker skin types, but women of Asian descent may not be affected.13

Polycystic Ovaries

Enlarged ovaries containing numerous small cysts can be detected by ultrasound. However, some women with polycystic ovaries may not have PCOS, while some women with the condition have ovaries that appear normal.14

4 Other Conditions Associated with PCOS

Infertility

PCOS is the most common cause of female infertility. Many women with polycystic ovary syndrome experience infrequent ovulation or lack of ovulation altogether and may have trouble becoming pregnant. PCOS also is associated with spontaneous abortion and preeclampsia.15

Obesity

Compared with women of similar age who don't have polycystic ovary syndrome, women with PCOS are significantly more likely to be overweight or obese.3,16 Furthermore, about half of all women with PCOS manifest central obesity, in which there is a greater deposition of visceral fat around internal organs in the abdominal region, as opposed to the fat being located on the thighs and hips. Abdominal fat distribution is associated with increased risk of hypertension, diabetes and lipid abnormalities.17

Insulin Resistance and Type 2 Diabetes

Studies have found that women with PCOS have higher incidences of insulin resistance and type 2 diabetes than age and weight-matched controls.3 Moreover, a majority of obese PCOS women and more than half of those of normal weight are insulin resistant,18 and a significant number develop type 2 diabetes mellitus by the age of 40.19

Acanthosis Nigricans

Acanthosis nigricans is a dark, poorly defined, velvety hyperpigmentation found on the nape of the neck, armpits, inner thighs, vulva, or under the breasts. This condition is a sign of insulin resistance, which leads to higher circulating insulin levels. Insulin spillover into the skin results in hyperplasia, an abnormal increase in skin growth.20

5 Diagnosis of PCOS

There is no specific test to definitively diagnose polycystic ovary syndrome. The diagnosis is one of exclusion, which means the doctor considers all signs and symptoms to rule out other possible disorders.14 A standard diagnostic assessment for PCOS includes a full medical history, at which time a doctor will consider irregular or absent periods, obesity, hirsutism (coarse facial and body hair), and poor breast development. During a physical exam, doctors typically look for physical signs of PCOS like acne, facial hair, male pattern baldness and acanthosis nigricans.

A pelvic or transvaginal ultrasound is used to detect "follicular arrest," or the development of small (5–7 mm) follicles that never reach the preovulatory size of 16 mm or more. Though not all women with PCOS have polycystic ovaries (PCO), nor do all women with ovarian cysts have PCOS,21 ultrasonographic scanning has substantially broadened the phenotypic spectrum of PCOS.14

Diagnostic criteria published by the Androgen Excess Society in 2006 require the presence of clinical or biochemical hyperandrogenism, with either menstrual dysfunction or polycystic ovarian morphology (PCOM), which are detected via transvaginal ultrasonography.21

Blood work is used to measure the levels of several hormones and to exclude the many possible causes of menstrual abnormalities or androgen excess that mimic PCOS. Along with tests used to measure elevated androgen levels, doctors may look for high levels of luteinizing hormones (LH) or an elevation in the ratio of LH to follicle stimulating hormone (FSH), prolactin, thyroid stimulating hormone (TSH), 17-hydroxyprogesterone, testosterone and DHEA-S. Other associated conditions such as high levels of glucose, insulin, cholesterol and triglycerides, as well as insulin resistance may also be assessed.22

Some doctors now screen for high levels of anti-Müllerian Hormone (AMH) since it is considered a potential diagnostic marker for PCOS.23,24 AMH is a protein released by cells that are involved with the growth of the egg follicle. AMH levels correlate with the number of antral follicles (small follicles that are 2 to 8 mm in size and appear in the beginning of the menstrual cycle) found on the ovary; the higher the antral follicle count, the higher the AMH levels.25 Women with PCOS typically have a high number of antral follicles; they have correspondingly high AMH levels as well.26

6 Causes and Risk Factors for PCOS

PCOS was once regarded solely as a reproductive disorder affecting women of childbearing age. Anovulation (a menstrual cycle in which ovulation does not occur) and androgen excess have been considered the hallmark diagnostic criteria of the syndrome.14 However, insulin resistance is now identified as a significant contributor to the pathogenesis of PCOS, the metabolic and cardiovascular consequences of which are widely acknowledged within the scientific community.11 To date, several factors involved in the development of PCOS have been identified.

LH Secretion and Androgen Excess

Past research has emphasized the role of neuroendocrine abnormalities in the persistent and excessive secretion of luteinizing hormones (LH), one of two glycoprotein hormones that stimulate the final ripening of the follicles and the secretion of progesterone. Excessive LH triggers premature ovulation, disrupting the follicle’s maturation process and leading to an increase in androgen production by ovarian theca cells. Some research points to increased LH as the driving force for PCOS in slender and normal body-weight women.27

Hyperinsulinemia and Androgen Excess

Hyperinsulinemia produces hyperandrogenism in women with PCOS via two distinct and independent mechanisms. The first is the stimulation of ovarian androgen production. Studies have shown that insulin acts synergistically with LH to enhance androgen production in ovarian theca cells.28,29 The second is by directly and independently reducing serum sex hormone-binding globulin (SHBG) levels.

Genetics and Androgen Excess

An increase in LH, as well as hyperinsulinemia, leads to an increase in androgen production by ovarian theca cells.29 Research indicates that morphological changes in the ovaries, including ovarian cyst development and theca-cell (steroid-producing cells in the ovaries) dysfunction, may be an indication of a genetic basis for PCOS. Researchers suspect there is a genetically determined ovarian defect present in women with PCOS, causing the ovary to overproduce androgen.29-32 Indeed, abnormal theca cell activity seems to be a primary source for excess androgens.33

The following risk factors are also thought to have a strong influence over the progression of PCOS.

Obesity

Studies have found that obesity not only contributes to the development of PCOS, but arises also as a result.16 The adipose tissue of women with PCOS is characterized by enlarged fat cells (hypertrophic adipocytes) and impairments in the body’s ability to break down fat (lipolysis) and regulate insulin. Whether these abnormalities are primary or secondary to hyperandrogenism or other PCOS-related abnormalities is not yet known.34

Age at Onset

Some research suggests that girls who develop pubic hair early (often before the age of eight, a condition known as premature pubarche) have many of the signs and symptoms of PCOS. In one study that followed prepubescent girls throughout puberty, premature pubarche resulted in excess testosterone production and irregular periods consistent with PCOS, leading researchers to conclude that premature pubarche may be an early form of PCOS.35

Other Risk Factors

Other risk factors that may play a role in the pathogenesis of PCOS include chronic inflammation36; exposure to endocrine-disrupting chemicals37; autoimmune disorders, especially those involving the ovaries, pancreas, thyroid and adrenal glands38; and the use of medications that increase prolactin production.39

Laying aside etiology, women with PCOS are prone to defects in insulin signaling, which aggravates the synthesis of androgens in the ovaries and adrenal gland.29 Excess androgens encourage insulin resistance, leading to elevated insulin levels, which in turn stimulate further androgen synthesis. This vicious cycle results in a “snowball effect” worsening PCOS symptoms and making sufferers especially susceptible to obesity and diabetes, conditions that significantly compound the syndrome’s progression.11,40

What You Need to Know

  • Polycystic ovary syndrome is a common female endocrine disorder.
  • Though symptoms vary from person to person, it is characterized by multiple ovarian cysts, irregular, heavy or nonexistent periods, excessive facial/body hair, male pattern baldness, decreased sex drive, skin tags, infertility, depression and weight gain.
  • Insulin resistance is one of the most common features of PCOS, and a condition in which the cells of the body become resistant to the effects of insulin.
  • The root cause of PCOS is unknown but genetic predisposition, insulin resistance, excess androgen production, and obesity all play a role.
  • Since the symptoms of PCOS vary in severity and form, many treatments are used. Conventional options include drug treatments for hirsutism and acne; drugs such as clomiphene, tamoxifen and gonadotropins to induce ovulation for infertility; surgery to induce ovulation by reducing androgen levels, and promising insulin-sensitizing drugs such as metformin.
  • The most important aspect of long term care of PCOS is managing cardiovascular risks such as obesity, insulin resistance, diabetes, hypertension and elevated blood cholesterol. Early recognition and intervention are considered to be the cornerstones of PCOS treatment.
  • Emerging evidence suggests that lifestyle choices such as weight reduction and exercise, along with specific nutraceuticals targeted to safely and effectively deal with symptoms, underlying causes and associated risk factors, might help reduce the incidence and severity of PCOS.

7 Conventional Treatment of PCOS

Polycystic ovary syndrome treatment generally focuses on management of the individual main concerns, such as infertility, hirsutism, acne or obesity.

Hirsutism

  • Oral contraceptive pills, consisting of estrogen-progesterone combinations, are preferably used. Estrogens lower LH levels and androgen production. Progesterone is crucial, as it may increase the liver production of SHBG, reducing free testosterone levels.41
  • Another medication called spironolactone (Aldactone) is used as a primary medical treatment for hirsutism and female pattern hair loss since the accidental discovery of its antiandrogenic effects. Spironolactone reduces testosterone production and inhibits its action on target tissues. It also is an effective alternative treatment for acne in women. Spironolactone should not be used in pregnancy since it can disturb the growth and development of the embryo and fetus.42
  • Even more promising are insulin-sensitizers like metformin (see text box below), which also holds promise for managing hirsutism in PCOS patients.41

Infertility

Ovulation induction remains a milestone in the treatment of women with anovulatory infertility.43

  • Clomiphene citrate (CC), an oral antiestrogen medication, is considered the first line treatment for inducing ovulation in women with PCOS.43
  • Since insulin resistance plays a central role in PCOS, insulin reduction strategies are a possible treatment for infertility in PCOS patients.44 For instance, if CC alone is not effective, metformin can be added to help induce ovulation.45
  • If the CC and metformin combination fails, gonadotropins—follicle stimulating hormone (FSH) and luteinizing hormone (LH) medications that are administered by injection—may be another option.43,46
  • Aromatase inhibitors, such as anastrozole and letrozole, are a relatively new treatment for ovulation induction.43 Aromatase inhibitors selectively block the peripheral conversion of androgens to estrogens, causing a reaction in the pituitary gland, increasing FSH, and optimizing ovulation. The advantage of aromatase inhibitors is that they avoid the unfavorable side effects seen frequently with antiestrogens.47
  • If medication does not work, a surgical procedure called laparoscopic ovarian drilling (LOD) may be considered. During LOD, a surgeon makes a small incision in the abdomen and inserts a tube attached to a tiny camera (laparoscope) providing detailed images of the ovaries and neighboring pelvic organs. The surgeon then inserts surgical instruments through other small incisions and uses electrical or laser energy to destroy the extra, androgen producing follicles on the surface of the ovaries. The goal of the operation is to induce ovulation by reducing androgen levels.

Regulation of the Menstrual Cycle

  • Metformin improves ovulation and leads to regular menstrual cycles (see sidebar).
  • Birth control pills containing a combination of synthetic estrogen and progesterone decrease androgen production, correct abnormal bleeding, and decrease the risk of endometrial cancer as well. Low-dose birth control pills have been proven effective for regulating the menstrual cycles of those who are not trying to become pregnant.48
  • To date, there are no known clinical studies on bioidentical hormone replacement therapy (BHRT) and PCOS.

Long-term PCOS Management

  • Managing cardiovascular risks such as obesity, elevated cholesterol, high blood pressure and diabetes is considered the most important aspect of PCOS treatment.
  • Since medications such as metformin and thiazolidinedione improve insulin sensitivity, in 2004 Great Britain’s National Institute for Health and Clinical Excellence recommended that women with PCOS that have a BMI above 25 be given metformin when other therapies fail to produce results.49
  • This recommendation proved to be well-founded, as Metformin is known to be an effective treatment for both hyperinsulinemia and hyperandrogenism.50-52
  • Indeed, metformin may be the most promising conventional medical treatment for PCOS.

Metformin: An Underutilized Treatment for PCOS

  • Metformin, a medication currently used to lower blood sugar, is approved by the US Food and Drug Administration (FDA) to manage type 2 diabetes mellitus. Metformin inhibits liver glucose production, though it also decreases intestinal glucose uptake and increases insulin sensitivity in peripheral tissues.53
  • Metformin improves the likelihood of ovulation in women with PCOS through a variety of actions, including reducing insulin levels and altering the effect of insulin on ovarian androgen synthesis, theca cell proliferation, and endometrial growth.43
  • To increase metformin tolerance, patients start with 500 mg daily with food. After one week, the dose increases to 1,000 mg for another week and then to 1,500 mg daily. Clinical response is usually seen at the 1,000 mg daily dose.54
  • Studies have found that PCOS patients who do not respond to metformin at the 1,500 mg dose respond favorably to 2,000 mg.54
  • For many years, oral hypoglycemic agents were regarded as teratogenic, and their use was contraindicated during pregnancy. However, the latest data supports the safety of metformin throughout pregnancy. Glueck et al reported that metformin was not teratogenic and did not affect the motor or social development of infants age 3 and 6 months.55 Recently, Tang et al concluded that metformin improves ovulation and pregnancy rates, findings they noted while updating the Cochrane Review of insulin-sensitizing drugs (metformin, rosiglitazone, pioglitazone, d-chiro-inositol) for women with PCOS, oligo/amenorrhea and subfertility.56
  • A recent clinical study of 50 PCOS patients reported that metformin exerts a slight but significant deleterious effect on serum homocysteine levels. Therefore, supplementing with folate is considered useful for lowering homocysteine and increasing the beneficial effect of metformin on the vascular endothelium (the inner lining of the blood vessels).57

Side Effects with Conventional Treatments

A pitfall of mainstream approaches to PCOS is that they are often associated with unwanted side effects, for example:

  • For trouble conceiving, a doctor typically prescribes fertility drug Clomid. In some women, Clomid causes no side effects. In others, side effects may include mood swings, hot flashes, breast tenderness, abdominal cramps, and nausea. Roughly 30% of women who take Clomid experience the more serious side effects of hostile fertile mucous (HFM, a condition in which the cervical mucus become too thick to allow sperm to penetrate the cervix) and uterine lining thinning. HFM prevents conception and a thin uterine lining decreases the likelihood of implantation and may lead to early miscarriage, both are undesirable effects of using Clomid.
  • Birth control pills are still the treatment of choice for irregular periods. However, a 2006 study concluded that birth control pills increase insulin resistance, making the symptoms of PCOS more pronounced and increasing the risk of major heath complications.58
  • In fact, many medications used in the treatment of PCOS do not adequately address the lifestyle and hormonal imbalances that are at the root of PCOS, nor do they hold much promise for managing associated cardiovascular risks and type 2 diabetes.

8 Lifestyle and Dietary Recommendations

For women with polycystic ovary syndrome, daily physical activity and participation in a regular exercise regimen are essential for treating or preventing insulin resistance, lowering blood sugar levels and for helping weight-control efforts.

Since a majority of PCOS women are obese, and insulin resistance plays a critical role in the development of PCOS, a diet that is high in fiber, vitamins, minerals and disease-fighting phytonutrients, and low in saturated fatty acids may reduce certain risk factors and improve overall well-being.

Additional research may determine which specific dietary approach is best for PCOS, but it is clear that losing weight by reducing total caloric intake benefits the overall health of women with polycystic ovary syndrome.

Researchers reported that short-term treatment with an ultra-low-calorie (350‒450 kcal per day) decreased androgen signaling and reduced serum insulin in obese women with PCOS.59

A study by Italian researchers concluded that comprehensive dietary change designed to lower insulin resulted in a significant decrease in testosterone, body weight, waist/hip ratio, total cholesterol, fasting blood glucose and insulin.60

Diets high in monounsaturated fats have been shown to increase insulin sensitivity and lower the overall glycemic index. High fiber foods are slowly absorbed, causing less insulin to be released. High fiber diets increase SHBG, which binds to and lowers free testosterone. Fibers also can lower PAI-1 (plasminogen activator inhibitor, a glycosylated protein that plays a significant role in metabolic syndrome) as well as cholesterol and blood lipids.59

A study reported that just a moderate reduction in dietary carbohydrates reduced fasting and post-challenge insulin concentrations among women with PCOS, improving reproductive/endocrine outcomes.61 Echoed a 2005 report, "On the balance of evidence to date, a diet low in saturated fat and high in fiber from predominantly low-glycemic-index-carbohydrate foods is recommended [in the dietary management of PCOS]."62

9 Integrative Interventions

Inositol

Inositol is a sugar alcohol that has many possible forms, or isomers. Myo-inositol (MI) is the most common of these isomers, while D-chiro-inositol (DCI) makes up a small percentage. Some MI is converted to DCI in the body.63,64

Inositol is a crucial structural component of cell membrane lipids and is active in cell-to-cell signaling.63 In addition, by transmitting external signals from insulin to the working interior of cells, inositol compounds called inositol phosphoglycans act as second messengers of insulin. Dysregulation of the inositol phosphoglycan second messenger system is associated with insulin resistance and related disorders, including PCOS.65,66 MI and DCI supplements have been shown to positively impact the hormonal and reproductive disturbances associated with PCOS.66

Myo-inositol. A number of controlled trials have demonstrated that MI can improve insulin sensitivity and metabolic markers, normalize reproductive hormone levels, and restore menstrual cycles in women with PCOS.67-70 MI supplementation has been shown to increase quality and maturity of oocytes (ie, cells that may go on to become eggs) retrieved from ovaries of PCOS patients71-73 and may enhance fertility in women affected by this condition.74 In a comparison study, 4 grams of MI plus 400 mcg of folic acid per day was more effective than 1,500 mg per day of metformin (Glucophage) in restoring ovulation in infertile women with PCOS. In addition, the total pregnancy rate was higher in women treated with MI (48.4%) than metformin (36.6%).75

In a randomized controlled trial, 50 overweight PCOS patients were given either 2 grams of MI plus 200 mcg of folic acid or 200 mcg of folic acid daily. After 12 weeks, the women taking MI had decreased insulin, testosterone, and prolactin levels, and increased markers of insulin sensitivity. In addition, menstrual cycles were restored in all of the subjects receiving MI who reported few or no menstrual cycles at the beginning of the trial. No changes occurred in the control group.76 Another controlled clinical trial included 92 participants with PCOS treated with either 4 grams of MI plus 400 mcg of folic acid per day or 400 mcg of folic acid daily. After 14 weeks, the MI-treated women had improvements in ovulation, reduced leptin levels, and significant weight loss versus the control group whose body weight increased.77 A six-month study involving 50 women with PCOS also reported benefits on hormonal parameters and found that MI supplementation reduced hirsutism and acne.78

D-chiro-inositol. Clinical evidence suggests DCI is important for mediating the insulin response and may play a role in the therapeutic effect of blood glucose-lowering drugs such as metformin and pioglitazone (Actos) in women with PCOS.79-81 Insulin resistance is associated with low serum levels and increased urinary loss of DCI, and a high ratio of MI to DCI is considered a marker of insulin resistance.63,64 In women with PCOS, deficiency of DCI has been noted despite normal MI availability.65,82,83 Although DCI does not act directly on the ovaries, its systemic insulin-sensitizing effect appears to benefit women with PCOS.63,84

In a controlled trial, 44 obese women with PCOS were given 1,200 mg of DCI or placebo daily for six to eight weeks. The DCI group had significant reductions in glucose-induced insulin release, blood pressure, and triglyceride and testosterone levels, while none of these parameters changed significantly in the placebo group. Moreover, 86% of subjects receiving DCI ovulated during the study period compared with 27% in the placebo group.85 Similar results were seen in normal weight PCOS patients treated with 600 mg of DCI daily for six to eight weeks.86 DCI supplementation has resulted not only in improvements in metabolic and hormonal parameters, but also resumption of menstrual cycles87,88 and reduced body mass index (BMI) in overweight or obese PCOS patients.89

It is important to note that some evidence suggests high-dose DCI supplementation may have a negative impact on oocyte maturation: one study found oocyte maturity diminished with DCI supplementation of 600 mg per day and higher, but not at 300 mg per day,90 and another found DCI-treated women had more immature oocytes than MI-treated women with PCOS.73

Myo-inositol plus d-chiro-inositol. Because of differences in their effects, it is possible that MI and DCI may have complementary actions.91,92 A randomized controlled trial compared the effects of six months combined treatment with 1,100 mg of MI plus 27.6 mg of DCI plus 400 mcg of folic acid to 400 mcg of folic acid per day in 46 women with PCOS. The 40:1 ratio of MI to DCI used in the treatment protocol was chosen to reflect normal conditions in the blood. MI plus DCI was more effective than folic acid alone in correcting hormonal disturbances and improving insulin sensitivity.93 Treatment with the same ratio of MI to DCI led to improved metabolic profiles and reduced cardiovascular risk in obese subjects with PCOS after six months.94 In another six-month trial, PCOS-affected women were treated with either MI plus DCI or MI alone. Markers of metabolic health improved in both groups, but those who received DCI plus MI had more improvement after three months of treatment.95 In PCOS patients undergoing in vitro fertilization, combination therapy with 1,100 mg MI plus 27.6 mg DCI daily resulted in improved oocyte and embryo quality, higher pregnancy rates, and was superior to 500 mg DCI per day alone.96

D-pinitol. D-Pinitol is 3-O-methyl-D-chiro-inositol that occurs naturally in several different foods, including legumes and citrus fruits.97 D-Pinitol is converted into d-chiro-inositol in the body. Like d-chiro-inositol, pinitol appears to favorably influence the action of insulin.98 In a double-blind study of patients with type 2 diabetes, administration of 600 mg of pinitol twice a day for three months reduced blood glucose concentration by 19.3%, decreased hemoglobin A1c (HbA1c) concentration by 12.4% and significantly improved insulin resistance.99 In a shorter-term double-blind study, administration of pinitol at a dose of 20 mg per kg of body weight per day for four weeks decreased mean fasting plasma glucose concentration by 5.3%.100

N-acetyl cysteine (NAC)

N-acetyl cysteine (NAC) is a stable derivative of the sulfur-containing amino acid cysteine and an antioxidant that is needed for the production of glutathione, one of the body's most important natural antioxidants and detoxifiers. While cysteine is found in high protein foods, n-acetyl cysteine is not. A large body of evidence supports the use of NAC in women with PCOS.

  • Improving Insulin Sensitivity
    Women with PCOS frequently have an abnormally high insulin response to sugars and refined starches. A 2002 study evaluated the effect of NAC on insulin secretion and peripheral insulin resistance in women with PCOS.101 The study subjects who had an exaggerated insulin response to a glucose challenge and were treated with NAC showed an improvement in insulin function in their peripheral tissues. The NAC treatment also produced a significant decline in testosterone levels and in free androgen index values. The researchers concluded, "NAC may be a new treatment for the improvement of circulating insulin levels and insulin sensitivity in hyperinsulinemic patients with polycystic ovary syndrome."102
  • Restoring Fertility
    NAC may also be useful for improving fertility in women with PCOS. In one study, NAC appeared to improve the effects of Clomid, the widely used fertility drug. Clomid plus NAC significantly improved ovulation rates in a study of 573 women with PCOS. According to the researchers, 52% of the study participants who took Clomid plus NAC ovulated, whereas only 18% ovulated in the Clomid alone group. The authors concluded: "N-Acetyl cysteine is proved effective in inducing or augmenting ovulation in polycystic ovary patients."103

Similarly, a study of Clomid-resistant women has shown that NAC appears to make Clomid more effective. In the study, 150 Clomid-resistant women with PCOS were divided into two groups: one group took Clomid and NAC. The other group took Clomid and a placebo. In the NAC group, 49.3% ovulated and 1.3% became pregnant. In contrast, in the placebo group, only 21% ovulated and there were no pregnancies.104

Worth noting, the same researchers compared the effects of a NAC-Clomid combination with the metformin-Clomid combination on ovulation induction in anovulatory Clomid-resistant women with PCOS. The efficacy of the metformin-Clomid combination therapy is significantly higher than that of NAC-Clomid for inducing ovulation and achieving pregnancy among Clomid-resistant PCOS patients.45

  • Tackling Homocysteine
    Women with PCOS are often given metformin to deal with their insulin problems. But metformin may increase homocysteine levels and many women with PCOS have high homocysteine levels to begin with.105 Elevated homocysteine is associated with coronary artery disease, heart attack, chronic fatigue, fibromyalgia, cognitive impairment, and cervical cancer. A 2009 study showed that people taking NAC for two months had a significant decrease in homocysteine levels.106

Magnesium

Many women with PCOS have significantly low serum and total magnesium, contributing to the progression of insulin resistance to type 2 diabetes and heart disease.107

Magnesium insufficiency is common in poorly controlled type 2 diabetes patients. In one study, 128 patients with poorly controlled type 2 diabetes received a placebo or a supplement with either 500 mg or 1,000 mg of magnesium oxide (300 mg or 600 mg elemental magnesium) for 30 days. All patients were treated also with diet or diet plus oral medication to control blood glucose levels. Magnesium levels increased in the group receiving 1,000 mg magnesium oxide daily but did not significantly change in the placebo group or the group receiving 500 mg of magnesium. The author suggested prolonged use of magnesium in doses that are higher than usual is needed in patients with type 2 diabetes to improve control or prevent chronic complications.108

In a related study, 63 diabetics with below normal serum magnesium levels received either 2.5 grams of oral magnesium chloride daily or a placebo. At the end of the 16-week study period, those who received the supplement had higher blood levels of magnesium and improved control of diabetes, as suggested by lower hemoglobin A1c (HbA1c) levels.109

Another study found that oral magnesium supplements helped insulin resistant individuals avoid developing type 2 diabetes.110

Since magnesium improves insulin-mediated glucose uptake and insulin secretion in type 2 diabetes patients, it is considered a critical mineral for women with PCOS.

Chromium

Research shows a clear link between chromium and glucose metabolism. Indeed, chromium is one of the most widely studied nutritional interventions in the treatment of glucose and insulin-related irregularities. Chromium picolinate specifically is the form that has been used in a number of studies on insulin resistance. Researchers at the University of Texas Health Science Center at San Antonio found that chromium picolinate (200 mcg/day) improves glucose tolerance when compared with a placebo111 in women with PCOS.

Lipoic Acid

Overwhelming evidence suggests that lipoic acid may be critical not only for maintaining optimal blood sugar levels (by helping the body use glucose), but also for supporting insulin sensitivity and key aspects of cardiovascular health, such as endothelial function. A review of experimental studies reveals that lipoic acid helps relieve several components of metabolic syndrome—a constellation of risk factors that often precedes full-blown type 2 diabetes. It appears that lipoic acid reduces blood pressure and insulin resistance, improves lipid profile, and reduces weight. Based on the results of key clinical studies, scientists are sanguine about lipoic acid’s potential as a therapeutic agent for individuals with metabolic syndrome.112 Similarly positive effects have been observed in women with PCOS. In a 16-week study, women with PCOS were given 600 mg of lipoic acid twice daily, and, over the course of the study period, exhibited a sharp improvement in insulin sensitivity, and a reduction in triglycerides. Lipoic acid therapy also is associated with an improved LDL-particle pattern (or “bad” cholesterol particles), indicating a reduction in cardiovascular risk.113

Vitamin D

In an insightful associative study that highlighted the link between PCOS and vitamin D status, researchers found that women with higher blood levels of vitamin D were much less likely to be insulin resistant.114 A separate study found that vitamin D when administered with metformin was helpful for regulating the menstrual cycles in PCOS women.115

A study conducted by researchers at Columbia University found that Vitamin D combined with calcium supplementation helped normalize menstrual cycles for seven of 13 women with PCOS. Of the seven, two became pregnant and the others maintained normal menstrual cycles. These results suggest that abnormalities in calcium balance may be responsible, in part, for the arrested follicular development in women with PCOS and contribute to its pathogenesis.116

Omega-3 Fatty Acids

Evidence suggests that the anti-inflammatory activity of omega-3 fatty acids ameliorates non-alcoholic fatty liver disease, a common condition in women with PCOS. In an Australian study, omega-3 fatty acid supplementation reduced liver fat content and other cardiovascular risk factors in women with PCOS, including triglycerides, and systolic and diastolic blood pressure. In particular, said the researchers, omega-3 fatty acids were helpful in reducing hepatic fat in PCOS women with hepatic steatosis, which is defined as liver fat content greater than 5%.117

Flaxseeds

The powerful lignans—plant compounds that have both estrogenic and antiestrogenic properties—in flaxseed may help reduce androgen levels in PCOS women. Flaxseed consumption have been shown to stimulate sex hormone-binding globulin (SHBG) synthesis.118 Changes in SHBG concentration result in relatively large changes in the amount of free and bound hormones.

In a 2007 study, daily flaxseed supplementation reduced androgen levels and hirsutism in PCOS patients, leading researchers to conclude, “The clinically-significant decrease in androgen levels with a concomitant reduction in hirsutism reported in this case study demonstrates a need for further research of flaxseed supplementation on hormonal levels and clinical symptoms of PCOS.”119

Cinnamon

Scientists at the US Department of Agriculture (USDA) have been studying the effect of cinnamon on blood glucose for over a decade, leading to several interesting discoveries, including that of unique compounds in cinnamon bark that in laboratory studies produce a 20-fold increase in sugar metabolism.120,121 According to one government expert, “These polyphenolic polymers found in cinnamon may function as antioxidants, potentiate insulin action, and may be beneficial in the control of glucose intolerance and diabetes.”122

In a 2003 study, 60 diabetics taking 1, 3, or 6 grams/day of ground cinnamon for 40 days lowered their fasting serum glucose by 18% to 29%; triglycerides by 23% to 30%; LDL cholesterol by 7% to 27%; and total cholesterol by 12% to 26%.123

A 2007 study by researchers at Columbia University found that cinnamon reduced insulin resistance in fifteen women with PCOS. In the study, the women were divided into two groups: one group took cinnamon extract while the other group took a placebo. After eight weeks, the cinnamon group showed significant reductions in insulin resistance while the placebo group did not. The authors did point out that, "A larger trial is needed to confirm the findings of this pilot study and to evaluate the effect of cinnamon extract on menstrual cyclicity."124

Licorice Root

A 2004 study by Italian researchers investigated the effect of licorice on androgen metabolism in nine healthy 22- to 26-year-old women in the luteal phase of their menstrual cycle and found that licorice reduces serum testosterone. The authors suggested that licorice could be considered an “adjuvant therapy of hirsutism and polycystic ovary syndrome." This study was the first to follow up on earlier trials, which found that an herbal formula containing licorice reduced testosterone secretion in women with polycystic ovary syndrome.125-127

Spironolactone (Aldactone), an antagonist of mineralocorticoid and androgen receptors, is used as a primary medical treatment for hirsutism and female pattern hair loss. It is also associated with several side effects related to the diuretic activity of spironolactone. Interestingly, licorice was shown in a study of women with PCOS to counteract the side effects of spironolactone when the two were used in combination.128

Green Tea (Epigallocatechin Gallate)

Green tea may be of benefit to women with PCOS. Green tea is known to have positive effects on glucose metabolism.129 In both human and animal studies, green tea has been shown to improve insulin sensitivity.130,131 Animal research suggests that green tea epigallocatechin gallate (EGCG) may help prevent the onset of type 2 diabetes and slow its progression.132 A clinical study from Japan found that daily supplementation of green tea extract lowered the hemoglobin A1c (HbA1c) level in individuals with borderline diabetes.133 Hemoglobin A1c is a form of hemoglobin that is used to help identify plasma glucose concentration over a period of time.

Green tea also is thought to lower tumor necrosis factor (TNF)-alpha.134 TNF-alpha is involved with systemic inflammation. Green tea is a potent antioxidant and, a study in the American Journal of Clinical Nutrition showed that just 90 mg of EGCG before each meal increased the body’s 24-hour metabolism rate by 4% and the metabolism of fat by an impressive 40%.135

Spearmint

A recent study by British researchers published in the journal Phytotherapy Research found a positive link between spearmint tea consumption and a reduction in hirsutism in PCOS women. In the study, 42 women were divided into two groups: one that took spearmint tea twice a day for a one-month period and the other a placebo herbal tea. The spearmint tea group showed significant decreases in free and total testosterone levels and an increase in LH and FSH, leading the researchers to conclude that “spearmint (tea) has the potential for use as a helpful and natural treatment for hirsutism in PCOS.”136

Saw Palmetto

Saw palmetto inhibits the activity of an enzyme, 5-alpha reductase, thereby reducing the conversion of testosterone to dihydrotestosterone, the more androgenic form of male hormone. This may have implications for reducing acne, excess facial and body hair, as well as male pattern hair loss. Oral administered saw palmetto has been studied as part of a formula that slowed hair loss and improved hair density in patients with testosterone related hair loss.137

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