Polycystic Ovary Syndrome (PCOS) was once known as Stein-Leventhal syndrome, named for the researchers, Stein and Leventhal, who originally reported the syndrome in 1935. Stein and
Leventhal described the symptoms of the syndrome as being amenorrhea, polycystic ovaries, and hirsutism. At the time the syndrome was named, wedge resections were replacing castration as the preferred method of treatment. In the 1960’s researchers understood that PCOS may have a genetic link. Today, researchers are trying to isolate and identify specific genes and environmental causes responsible for PCOS (1).
PCOS is the most common endocrine disorder in women with symptoms ranging from hyperandrogenism, anovulation, and metabolic disturbances (1, 2, 3, 4). The symptoms of PCOS are interrelated and synergistic. Androgens are produced in the theca interna layer of the ovarian follicle and in the zona fasciculata in the adrenal cortex under the control of Luteinizing
Hormone (LH) and adrenocoricotrophic hormone (ACTH), respectively. Women without PCOS convert androgens into estrogen via a chain of reactions in response to follicle stimulating hormone (FSH). Women with PCOS have an LH / FSH imbalance, leading to an increase in androgen levels in the body (1, 2).
The LH/ FSH hormonal imbalance leads to abnormal follicle development resulting in unreleased eggs from the immature follicles. The follicles accumulate on the outer wall of the ovary, creating the appearance of cysts. Polycystic ovaries are characterized by thick, white, outer covering and an enlargement of the ovary by two to five times (3, 4).

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Elevated insulin acts to increase serum androgen levels in two ways in women with PCOS.
Insulin acts on the ovarian follicle, enhancing androgen production in response to LH. Insulin regulates androgen blood transport and androgen activity on target tissues. With elevated insulin, serum androgen levels increase. Elevated insulin also inhibits the production of sexhormone binding globulin (SHBG) in the liver. SHBG binds androgens in the body. A decrease in SHBG leads to increased free testosterone in the body (2, 1). Increased free testosterone promotes the clinical features seen in hyperandrogenism: hirsutism, acne, oily skin and virilisation (3). Elevated insulin levels put women with PCOS at greater risk for cardiovascular disease and type 2 diabetes (5).
The prevalence of PCOS is increasing. The literature notes the increasing prevalence could be linked to the rise in obesity and sedentary lifestyles, as seen in western cultures (2). PCOS affects roughly 4-10% of women of reproductive age. The prevalence of PCOS among
American women is roughly 4-6% (6). The highest prevalence of PCOS is among South Asian immigrants in Britain, with as many as 49% showing signs of PCOS. South Asian immigrants in
Britain manifest symptoms earlier than other British women (2).
Polycystic Ovary Syndrome has no known etiology, although a genetic link may exist (7). In a study of sisters of women with PCOS, 50% of sisters had elevated testosterone (8, 6). In Franks et al., the authors propose that PCOS is the result of a genetically predetermined ovarian dysfunction. The ovarian dysfunction is caused by exposure to excess andrenal androgens in utero. The authors support this theory by noting the common presence of polycystic ovary during infancy and childhood (9). Women with PCOS often have a deficiency in

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21-hydroxylase, an enzyme that acts with cholesterol in the adrenal glands to produce coritsol and aldosterone. The build up of the cortisol and aldosterone precursors leads to the production of excess androgens in the adrenal gland (2). The authors cite the 21-hydroxylase deficiency as support for the ovarian dysfunction theory of PCOS development (9).
In PCOS, there are no universally-accepted diagnostic criteria nor are there universally accepted laboratory data confirming diagnoses of PCOS. Recommendations for lab tests include: serum
DHEA-S tests, androstenedione, free testosterone, TSH, prolactin, a lipid panel, fasting blood glucose, glucose tolerance, and a pregnancy test (10). The American Diabetic Association recommends diabetes screening for women diagnosed with PCOS (11). These tests will aid in making a PCOS diagnosis by ruling out alternative diagnosis. By testing blood glucose and measuring serum lipids, metabolic symptoms associated with PCOS can be identified.
The most preferred diagnostic criteria for PCOS is from the European Society of Human
Reproduction and Embryology (ESHRE)/ American Society for Reproductive Medicine
(ASRM). The criteria allow for diagnosis of PCOS if a woman manifests two of the following three symptoms: signs of hyperandrogenism including hirsutism, acne, and virilisation; oligomenorrhoea, amenorrhoea, and/or annovulation; and visual signs of ovarian cysts upon ultrasound (12, 5, 3, 6).
Hyperandrogenism refers to the increase in serum androgens: androstenedione, dehydroepiandrosterone sulphate (DHEA-S), and testosterone. The symptoms of hyperandrogenism, hirsutism, acne, and virilisation, may cause a woman to become depressed or

4 have a negative self image. Treatment may help a woman feel better (3). The symptoms of hyperandrogenism present due to reduction in SHBG, causing excess free testosterone in the body.
DHEA-S is the blood form of DHEA, the precursor to sex hormones in the body. The literature shows that serum levels of DHEA-S vary according to age and race among women with PCOS.
As age increases, excess DHEA-S decreases. Black PCOS patients have a higher excess percentage of DHEA-S than white PCOS patients (13).
Anovulation, a common clinical characteristic of women with PCOS, is literally the absence of ovulation. Anovulation is characterized by either oligomenorrhoea (infrequent menses), amenorrhoea (absence of menses), and/or infertility. The hyperandrogenism seen in women with
PCOS can lead to anovulation. Chronically high levels of serum androgens may inhibit the production of mature eggs in women with PCOS. The LH/ FSH imbalance may lead to abnormal follicle development, and therefore may also cause anovulation (3, 7 , 4).
Metabolic syndrome is characterized by insulin resistance, obesity, dyslipidemia, and hypertension (7). Women with PCOS manifest the symptoms of metabolic syndrome. Elevated serum androgen levels are directly linked to increased insulin resistance (1, 2, 7). The literature notes that 25% to 80% of women with PCOS have insulin resistance (5, 14). The literature shows that 40% of women with PCOS have impaired glucose tolerance (IGT) or type 2 DM (15).
Of women with PCOS, 25-31% have IGT and 7.5-15% have type 2 DM (15).

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Insulin resistance is often related to obesity or excess abdominal body fat. Obesity and excess abdominal fat are characteristics of patients with PCOS. Obesity is seen in 50-60% of women with PCOS (6, 14). The android body type is also more prevalent among women with PCOS than in women without PCOS. In Chekir et al. and Wright et al, PCOS women, as compared with non-PCOS controls, showed a significant increase in waist-to-hip ratio and BMI. The excess abdominal fat and obesity seen in PCOS women may be related to increased serum androgen levels and insulin resistance (14, 16).
It has been suggested that women with PCOS may have a higher craving for sweets, thus leading to the increase in obesity. Wright et al. demonstrated no significant dietary intake differences between women with and without PCOS. When stratified by BMI, significant differences in dietary intake were seen in normal weight women with and without PCOS. Normal weight women with PCOS ate significantly fewer overall calories than normal weight women without
PCOS (14).
Conversely, Hirschberg et al. demonstrated that women with PCOS do have greater cravings for sweets. Hirschberg et al. showed a significant relationship between free testosterone, as is seen in PCOS women, and a reduced cholecystokinin (CCK) response. CCK is a peptide secreted as the stomach begins emptying that stimulates feelings of satiety in the hypothalamus (17). Thus, women with PCOS may have impaired satiety response.
The lipid profiles of women with PCOS differ from those of women without PCOS. Women with PCOS often have higher triglyceride levels, higher total cholesterol, and lower HDL

6 cholesterol than women without PCOS (16, 3). This dysfunction in lipid profiles can lead to cardiovascular disease. Women with PCOS are two to five times more likely to have a major cardiovascular event than women without PCOS (3). The abnormal lipid profiles in PCOS women is the result of high serum androgen levels, obesity, android body type, and/or insulin resistance (7).
In treating PCOS patients, the aim is to treat the symptoms: hyperandrogenism, anovulation, and metabolic disturbances. Surgical procedures are rarely used in the treatment of PCOS. Wedge resection is a surgical procedure that removes a piece of each ovary. This procedure reduces the hormone production of each ovary and in some cases, restores normal menses. This procedure is no longer performed due to scaring and adhesions (4, 2, 1). Laproscopic ovarian diathermy, also known as ovarian drilling, is preferred to wedge resection. In laproscopic ovarian diathermy, a laser is used to puncture holes in the ovary in order to restore normal function. Surgical treatment is a subsequent treatment for women who do not respond to pharmacological treatment
(2, 1).
Pharmacological treatments aimed to treat the hyperandrogenism and the associated characteristics include: GnRH (Gonadotropin-releasing hormone) agonists, bicalutamide, acarbose, cyproterone acetate, and spironolactone (Aldactone) (10, 15, 3, 18). Pharmacological treatments aimed to treat anovulation include: pioglitazone, rosiglitazone, combined oral contraceptives, medroxyprogesterone acetate (Provera), and clomiphene citrate (10, 19, 3, 18).
The pharmacological treatments used to treat metabolic disturbances include: metformin,

7 pioglitazone, and rosiglitazone (19, 3, 10). A list of pharmacological treatments and modes of action are summarized in Table 1 on page 12.
The side effects of hyperandrogenism in women are often treated using non-pharmacological treatments as the pharmacological treatments may take 4-6 months before becoming effective.
To treat the hirsutism, women may try waxing, electrolysis, bleach, and laser therapy. Treatment of acne with spot treatments or over the counter topical creams may be effective (1,2,7,19).
Nutritional interventions are a primary focus of treatment for women with PCOS. Obesity affects nearly 50-60% of women with PCOS (6,14). Obesity, insulin resistance, and dyslipidemia put PCOS women at increased risk for type 2 diabetes and cardiovascular disease.
Managing these risk factors through weight loss and physical activity is recommended. Weight loss and physical activity may help decrease insulin resistance and may restore normal menses.
Although a single diet has not been shown to be most effective when treating women with
PCOS, some key features have been studied. Polyunsaturated fatty acids have been shown to help lower serum androgen levels and regulate blood glucose (10). Metformin, combined with a hypocaloric diet, has shown a greater reduction in serum insulin, free testosterone, hirsutism, abdominal region weight reduction, and a greater regulation of normal menses than hypocaloric diet alone (6).
Exercise has been shown to increase HDL levels, decrease LDL levels, decrease blood pressure, decrease insulin resistance, and increase insulin sensitivity (14, 1, 2). It has been shown that

8 weight loss decreases serum androgen levels and increases SHBG concentrations (10, 6).
Lifestyle modifications, including weight management and physical activity, have shown the greatest improvement in decreased insulin resistance and decreased androgen excess (7,1,2,14).
Much of the research is devoted to treating the symptom of anovulation, as this may lead to infertility. Clomiphene citrate to induce ovulation has been the most widely studied treatment.
About 40-60% of women will conceive after induced ovulation via clomiphene. One side effect of clomiphene is ovarian hyperstimulation syndrome (OHSS) (1, 2). This syndrome results from overstimulation of ovarian follicles, leading to cramping, distension, nausea and the more serious side effects of ascites, plural effusion, electrolyte imbalance, and thromboembolism. The OHSS activates the ovarian renin-angiotensin pathway and leads to excessive secretion of vascular endothelial growth factor (VEGF). This, in combination with the ascites and plural effusion, may lead to the imbalance in electrolytes and the resultant thromboembolism. Identification of
OHSS is through elevated serum E2 concentrations (10,000-15,000 pmol/L) and 20 or more ovarian follicles. OHSS may be prevented by monitoring women on clomiphene and gonadotrophin therapy through transvaginal ultrasonography (1, 2).
Alternative and complementary therapies have been shown to help women with PCOS.
Northrup recommends an emotionally based treatment approach. She purports that a woman’s ovulation may stop due to negative feelings about being a woman. Specific recommendations for improvement include: evaluation of feelings, getting in touch with emotions, and sitting in natural light and within nature daily (4).

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Complementary therapies that may be beneficial to women with PCOS include weng-jing-tang and Ganshao Capsule, both Chinese herbal remedies (20,21). In Ushiroyama et al., weng-jingtang was shown to decrease LH levels and increase ovulation among women (20). In Yang &
Zhang, Ghanshao Capsule was tested in clomiphene resistant women suffering from PCOS.
After 8 weeks of treatment, the number of dysfunctional follicles was significantly reduced and ovulation via clomiphene induction was improved (21).
There is no known etiology of PCOS, therefore prevention is not viable. Prevention of symptoms is best accomplished through lifestyle modifications and pharmacological treatments.
Prevention of PCOS is not mentioned in the literature.
Current research is focusing on the effects of satiety hormones: leptin, ghrelin, CCK, and plasma protein CRP in PCOS. Preliminary studies have presented contradictory findings. In Jahanfar et al., the concentration of leptin in PCOS patients did not significantly differ from that of BMImatched controls (22). Conversely, Ravishankar Ram et al., found that underweight and morbidly obese PCOS subjects had elevated serum leptin levels when compared to BMI-matched controls (23). Bahceci et al., found that CRP levels in women with PCOS was elevated when compared to age and BMI-matched controls (15). Hirschberg et al. found that CCK secretion was impaired in women with elevated free testosterone, thereby leading to impaired appetite regulation (17). The satiety hormones and proteins are a new area of research. How these hormones and proteins relate to PCOS is not well understood. Further investigation is needed to fully understand the effects of these hormones on PCOS.

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Current research is aimed at treating the side of effect of infertility in PCOS. Genetically modified gonadotropin analogs for parenteral and oral administration are under investigation.
These compounds may have a longer half life, thereby reducing the frequency of administration
(2). The National Institute of Health and the Massachusetts General Hospital are conducting a clinical trial examining the effects of synthetic GnRH on anovulatory infertility. The effectiveness of the OV-Watch is being investigated in the stimulation of ovulation for women on clomiphene. A clinical trial comparing the effectiveness of ovarian drilling to hormonal stimulation is underway (24).
Efforts to determine a specific genetic or environmental link in PCOS is under investigation. A current study involving 1500 twins is exploring the genetic and environmental causes of PCOS.
This study is a multi-step study sponsored by the National Institute of Environmental Health
Sciences. A second study looking at relatives in Iceland is seeking to identify the genetics of
PCOS. This study is sponsored by the National Institute of Child Health and Human
Development (24).
PCOS is a complex disorder that manifests a wide array of symptoms in women. While the etiology is not well understood, research is underway seeking to identify causes of PCOS. The available treatment methods aim to treat the symptoms. PCOS increases a woman’s risk of having cardiovascular disease and type 2 diabetes. For this reason, lifestyle modifications are a primary treatment with multiple benefits for obese and non-obese women with PCOS. At this time, there is not a preferred diet for women with PCOS, although a reduction in weight improves symptoms. Exercise has multiple benefits for women with PCOS, and is especially

beneficial in decreasing insulin resistance. Lifestyle modifications in combination with pharmacological treatments have shown the greatest improvement in symptoms. A method of preventing PCOS is not known. The origin of PCOS is not known. As more becomes known about the related causes of PCOS, more will become known about treating and preventing
PCOS.
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Table 1 . Comparison of treatment methods and mode of action on symptoms of PCOS
Method
Surgical
Treatment
Wedge Resection
Laproscopic ovarian diathermy
Aim of Treatment
Restore ovulation
Restore ovulation
Mode of Action
By removing parts of the ovary, hormone function is decreased and cyclic function is restored. Side effects include scaring and adhesions (4).
Through a laproscopic incision in the abdomen, a surgeon views the reproductive organs and burns parts of the ovary with a laser to restore normal ovulation. Restores ovulation in about 80% of women, and roughly
50% become pregnant (1, 2).
Pharmacological Acarbose
Bicalutamide
Clomiphene Citrate Restore Ovulation
Combined Oral
Restore ovulation and decrease signs of hyperandrogenism
Decreases hyperandrogenism
Improves hyperandrogenism, decreases testosterone, increases ovulation, reduces weight and BMI (19).
Anti-androgen drug that decreases testosterone levels and increases SHBG
(15). Bicalutamide is commonly used to treat prostate cancer.
This is an anti-oestrogen drug used to induce ovulation and improve the chance of pregnancy. Possible side effects include OHSS (3).
Hyperandrogenism and Oral contraceptives help to maintain constant levels of ostrogen and

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Contraceptives restoration of normal menses
Cyproterone acetate Hyperandrogenism and spironolactone
Gonadatropin releasing hormone
Hyperandrogenism agonists (GnRH)
Medroxyprogestero Restore menses and ne acetate ovulation progesterone, increase normal menses, decrease the risk of endometrial cancer, and improve hirsutism and acne (3, 10).
Both of these medications are anti-androgen treatments used to treat hirsutism and acne (3, 10).
GnRH agonists are given in extreme cases of hyperandrogenism. GnRH agonists decrease LH/ FSH secretion (3, 10).
Metformin
(Glucophage)
Thiazolidinediones
(Pioglitazone and
Rosiglitazone)
Decrease insulin resistance
Decrease insulin resistance
Medroxyprogesterone acetate is a synthetic progesterone used to decrease the risk of endometrial cancer, increase menses, suppress LH, and restore ovulation (10, 18).
Metformin is an insulin-sensitizing agent that has also been shown to help decrease body weight when used in combination with diet and exercise (19, 3,
10).
Pioglitazone has been shown to decrease insulin resistance, increase normal cycles, and decrease hirsutism and acne (19).