Polycystic Ovary Syndrome

A woman that 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 percent of women of child-bearing age and approximately 70-90 percent of women with irregular menstrual cycles (Azziz et al 2004). Among its many symptoms, PCOS causes hormonal imbalances, including elevated testosterone (male hormone) and estrogen (female hormone) levels, as well as increased insulin levels (Azziz 2006, Moran 2010).

Although PCOS is the most common female endocrine disorder in the United States, its cause remains unclear (McCartney 2004). 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 (Diamanti-Kandarakis 2007, Sasaki 2011).

If left untreated, women with PCOS often develop severe clinical manifestations, such as hirsutism (excess facial and body hair), adult acne, infertility, and depression (Diamanti-Kandarakis 2008, Drosdzol 2007). Women with PCOS are at significantly higher risk for developing cardiovascular disease (Teede 2010) and endometrial cancer (Chittenden et al 2009).

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 (Pasquali 2011).

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.

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 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 (Ma 2010).

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 (Lowenstein 2006).

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 (Azziz 2004).

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 (van der Spuy 2004).

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 (Martínez-Bermejo 2007, Moran 2010). 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 (Faloia 2004).

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 (Moran 2010). Moreover, a majority of obese PCOS women and more than half of those of normal weight are insulin resistant (Pasquali 2006), and a significant number develop type 2 diabetes mellitus by the age of 40 (Pelusi 2004).

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 (Higgins 2008).

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 (Azziz 2004). 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 (5–7mm) follicles that never reach the pre-ovulatory 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 (Artini 2010), ultrasonographic scanning has substantially broadened the phenotypic spectrum of PCOS (Azziz 2004).

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 (Artini 2010).

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 (Shi 2007).

Some doctors now screen for high levels of Anti Mullerian Hormone (AMH) since it is considered a potential diagnostic marker for PCOS (Chen 2008, Dewailly 2010). 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 (van Houten 2010). Women with PCOS typically have a high number of antral follicles; they have correspondingly high AMH levels as well (Pellatt 2010).

Causes and risk factors for PCOS

PCOS was once regarded solely as a reproductive disorder affecting women of child-bearing age. Anovulation (a menstrual cycle in which ovulation does not occur) and androgen excess have been considered the hallmark diagnostic criteria of the syndrome (Azziz 2004). 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 (Pasquali 2011). 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 (Chang 2000).

Hyperinsulinemia and Androgen Excess: Hyperinsulinemia produces hyperandrogenism in women with PCOS via two distinct and independent mechanisms:

First by stimulating ovarian androgen production. Studies have shown that insulin acts synergistically with LH to enhance androgen production in ovarian theca cells (Guzick 2004, Tsilchorozidou 2004; and Second by directly and independently reducing serum sex hormone-binding globulin (SHBG) levels. Insulin decreases hepatic synthesis and SHBG secretion, thus increasing the amount of free, biologically active testosterone (Carmina 2003). The net result of these two actions increases circulating free testosterone concentrations.

Genetics and Androgen Excess: An increase in LH, as well as hyperinsulinemia, leads to an increase in androgen production by ovarian theca cells (Tsilchorozidou 2004). 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 (Tsilchorozidou, 2004, Jakubowski 2005, Diamanti-Kandarakis 2006, Bremer 2008). Indeed, abnormal theca cell activity seems to be a primary source for excess androgens (Wood 2003).

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 (Martínez-Bermejo 2007). 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 (Villa 2011).

Age at onset. Some research suggests that girls who develop pubic hair early (often before the age of eight, and a condition known as premature pubarche) have many of the signs and symptoms of PCOS. In one study that followed pre-pubescent 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 (Witchel 2006).

Other risk factors that may play a role in the pathogenesis of PCOS include chronic inflammation (Escobar-Morreale 2011); exposure to endocrine-disrupting chemicals (Takeuchi 2004); autoimmune disorders, especially those involving the ovaries, pancreas, thyroid and adrenal glands (Petríková 2010); and the use of medications that increase prolactin production (Hernández 2000).

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 (Tsilchorozidou 2004). 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 (Schuring 2008, Pasquali 2011).

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 non-existent 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 literally 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 clomifenem tamoxifen and gonadotrophins 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 a 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.

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, 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 (Kopera 2010).
• 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 (Rathnayake 2010).
• Even more promising are insulin-sensitizers like metformin (see text box below), which also holds promise for managing hirsutism in PCOS patients (Kopera 2010).

Infertility:

Ovulation induction remains a milestone in the treatment of women with anovulatory infertility (Polyzos 2009).

• Clomiphene citrate (CC), an oral anti-estrogen medication, is considered the first line treatment for inducing ovulation in women with PCOS (Polyzos 2009).
• Since insulin resistance plays a central role in PCOS, insulin reduction strategies are a possible treatment for infertility in PCOS patients (Fica 2008). For instance, if CC alone is not effective, metformin can be added to help induce ovulation (Abu Hashim 2010).
• 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 (Nugent 2000, Polysoz 2009).
• Aromatase inhibitors, such as anastrozole and letrozole, are a relatively new treatment for ovulation induction (Polyzos 2009). 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 (Mitwally, 2001).
• 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 side bar).
• 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 (Cianci 2007).
• To date, there are no known clinical studies on bio-identical 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 (National Institute for Health and Clinical Excellence 2004).
• This recommendation proved to be well-founded, as Metformin is known to be an effective treatment for both hyperinsulinemia and hyperandrogenism (Azziz 2001, Romualdi 2011, Yasmin 2011).
• 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 (Grundy 2002). 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 (Polyzos 2009). To increase metformin tolerance, patients start with 500 mg daily with food. After one week, the dose increases to 1000 mg for another week and then to 1500 mg daily. Clinical response is usually seen at the 1000 mg daily dose (Harborne 2005). Studies have found that PCOS patients who do not respond to metformin at the 1500 mg dose, respond favorably to 2000 mg (Harborne 2005). 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 (Glueck 2002). 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 (Tang 2010). 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)(Palomba 2010).

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 (Mastorakos 2006).
• 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