Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders affecting women and it is the most common cause of female infertility. It is characterised by a combination of hyperandrogenism, chronic anovulation and irregular menstrual cycle.

Polycystic Ovary Syndrome

The Medical Nutritional Institute August 2013

www.mnilifestyle.co.za

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Contents Introduction ......................................................................................................................................... 2 1.

Definition ...................................................................................................................................... 4

2.

Incidence and prevalence .......................................................................................................... 4

3.

Causes and risk factors .............................................................................................................. 4 3.1

Hyperinsulinaemia ............................................................................................................. 4

3.2

Low-grade inflammation ................................................................................................... 4

3.3

Hereditary ............................................................................................................................ 4

3.4

Abnormal foetal development .......................................................................................... 4

4.

Physiology..................................................................................................................................... 5 The normal menstrual and ovarian cycle .................................................................................. 5

5.

Pathophysiology .......................................................................................................................... 6

6.

Signs and symptoms ................................................................................................................... 7

7.

Differential diagnosis ................................................................................................................. 8

8.

Diagnosis....................................................................................................................................... 8

9.

PCOS and weight/body mass index ......................................................................................... 9

10.

PCOS and insulin resistance .................................................................................................. 9

11.

Other metabolic disorders in PCOS ................................................................................... 11

12.

Complications ........................................................................................................................ 12

13.

Management of PCOS ............................................................................................................ 14

13.1

Lifestyle modification ................................................................................................... 15

13.2

Psychological care ......................................................................................................... 16

13.3

Pharmacological treatment ........................................................................................ 16

For women who are not planning pregnancy:..................................................................... 16 For women wishing to conceive and presenting with infertility: .................................... 17 13.4

Complimentary/natural treatment ........................................................................... 18

14.

PCOS in primary healthcare setting .................................................................................. 21

15.

Summary ................................................................................................................................. 22

16.

Sources .................................................................................................................................... 23

17.

Glossary ..................................................................................................................................... 24

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Introduction Background and historical perspective Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders affecting women and it is the most common cause of female infertility. It is characterised by a combination of hyperandrogenism, chronic anovulation and an irregular menstrual cycle. Polycystic ovary syndrome affects 5-15% of women of reproductive age. It results in infertility due to ovarian dysfunction and menstrual irregularity, typically known as anovulation infertility. PCOS has been studied over a prolonged period of time and yet is still not fully understood. The “Bearded Woman” commonly displayed in Victorian circuses probably suffered from PCOS.

Timeline in the understanding of the polycystic ovary syndrome

In 1921 the scientists Achard and Thiers described a condition “the diabetes of the bearded woman” and discussed the association between a disorder of carbohydrate metabolism and hyperandrogenism. In 1935 Drs Stein and Leventhal describe the syndrome specifically, and named it ‘SteinLeventhal syndrome’. Their description included a syndrome of polycystic ovaries, in association with systemic symptoms causing reproductive, metabolic and psychological disturbances. These most commonly presented with infertility, amenorrhoea, acne and/or hirsutism. In 1947 Kierland et al reported on the frequent occurrence of the skin lesion acanthosis nigricans in women with hyperandrogenism and diabetes mellitus. In 1968 Brown and Winkelmann noted that insulin-resistant diabetes mellitus had a genetic bias.

3 In 1980 Burghen et al reported that PCOS was associated with hyperinsulinemia and it has since become clear that the syndrome has major metabolic as well as reproductive morbidities, which has led to extensive investigation of the relationship between insulin and gonadal function.

In 2003 the Rotterdam ESHRE/ASRM (European Society of Human Reproduction and Embryology/American Society of Reproductive Medicine) Consensus Group concluded that: “PCOS is a syndrome of ovarian dysfunction along with the cardinal features hyperandrogenism and polycystic ovary (PCO) morphology. PCOS remains a syndrome, and as such no single diagnostic criterion (such as hyperandrogenism or PCO) is sufficient for clinical diagnosis. Its clinical manifestations may include menstrual irregularities, signs of androgen excess, and obesity. Insulin resistance and elevated serum LH levels are also common features in PCOS. PCOS is associated with an increased risk of type 2 diabetes and cardiovascular events”. In 2004 the same consensus group broadened the diagnostic criteria to that which is used currently. The patient should experience 2 of 3 symptoms: 1. Oligo- and/or amenorrhoea; 2. Clinical and/or biochemical signs of hyperandrogenism i.e. hirsutism, acne, raised testosterone and/or 3. Polycystic ovaries. In 2007 the second ESHRE/ASRM PCOS consensus workshop focused on infertility management in PCOS. In 2010 the third workshop focused on summarizing the current knowledge on PCOS and identifying current gaps in knowledge regarding various women’s health aspects in PCOS.

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1. Definition Polycystic ovary syndrome (PCOS) is an endocrine (hormonal) disorder with an imbalance in the sex hormones resulting in anovulation and adrogenism. Most often, symptoms first appear in adolescence, around the start of menstruation. However, some women do not develop symptoms until their early to mid-20's. Although PCOS presents early in life, it persists through and beyond the reproductive years. The diagnostic criterion for PCOS has evolved and is discussed in more detail in section 8. It is important to note that while 20% of all women have polycystic ovaries, not all of these are affected by the polycystic ovary syndrome. In fact the latest definition of PCOS lists polycystic ovaries as one of the symptoms, but it is not required for the diagnosis. 30% of women with PCOS do NOT have polycystic ovaries.

2. Incidence and prevalence Prevalence figures of polycystic ovary syndrome vary depending on diagnostic criteria used, but PCOS is thought to affect 5-15% of women of reproductive age.

3. Causes and risk factors The exact cause of polycystic ovary syndrome is not known, but there are a number of factors that may play a contributing role in the development of the syndrome.

3.1 Hyperinsulinaemia Insulin resistance leads to hyperinsulinaemia as the body attempts to control glucose levels. Elevated insulin levels have been linked to increased androgen production by the ovaries.

3.2 Low-grade inflammation Research is showing that many women with PCOS have an elevated C-reactive protein level, indicating raised systemic inflammation. A diet high in inflammatory foods can trigger a systemic inflammatory response. When this occurs, white cells produce substances that can lead to insulin resistance as well as atherosclerosis. Hyperinsulinaemia can also then exacerbate this inflammatory reaction, which then becomes a self-continuing cycle.

3.3 Hereditary Maternal or sibling incidence of PCOS increases the risk of occurrence. There is some evidence that gene mutation may play a role, but the gene has not been isolated at this stage.

3.4 Abnormal foetal development During pregnancy in a woman with PCOS, the embryo may be exposed to excessive androgens in utero. This may have long-term effects, especially in female offspring and may affect genes regulating reproduction and metabolism. This may promote male pattern of abdominal fat distribution, which increases the risk of insulin resistance and low-grade inflammation.

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4. Physiology To understand that pathophysiology occurring in PCOS, it is important to understand the normal ovarian and menstrual cycle.

The normal menstrual and ovarian cycle The normal menstrual cycle lasts 28 to 29 days and involves a large number of hormones. Gonadotropin-releasing hormone (GnRh) is produced in the hypothalamus. It stimulates the production and release of follicle stimulating hormone (FSH) and luteinizing hormone (LH). Both FSH and LH are produced in the pituitary gland. FSH stimulates maturation of the ovarian follicles. LH then stimulates the release of the oocytes (eggs) from the ovary. Oestrogen and progesterone are produced by the ovaries and play an interactive role in the reproductive cycle. At the beginning of the menstrual cycle, the hypothalamus produces GnRh which stimulates the pituitary gland to secrete FSH. FSH in turn stimulates the ovaries to ripen some eggs (oocytes) and to secrete oestrogen. Oestrogen further matures the egg and begins thickening of the endothelial lining of the uterus in preparation for possible implantation of a fertilized ovum. As oestrogen levels rise, FSH decreases temporarily and then increases together with a large surge in LH. This LH surge triggers ovulation. The released egg moves into the fallopian tube where it may or may not be fertilized. Within the ovary the empty follicle collapses and becomes the corpus luteum which then produces progesterone. Progesterone causes further thickening of the uterine endothelium. If fertilisation takes place, implantation of the ovum in the endothelium occurs and progesterone levels remain high. If fertilisation does not take place, the egg disintegrates and the corpus luteum shrinks, oestrogen and progesterone levels drop and the uterine endothelium produces prostaglandins. Prostaglandins break up the endothelial lining and cause contraction of the uterus and the menstrual cycle restarts.

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5. Pathophysiology While PCOS is common, the exact cause of the syndrome remains uncertain. Polycystic ovaries develop when ovaries are stimulated to produce excessive amounts of male hormones, particularly testosterone. This stimulation is caused by: 1. excess LH (luteinising hormone) produced by the anterior pituitary in response to increased gonatotrophin-releasing hormone (GnRH), 2. Or through high levels of insulin caused by insulin resistance. High insulin levels also suppress hepatic production of sex hormone-binding globulin (SHBG) leading to higher levels of free circulating androgens, further adding to the hyperandrogenaemia. Hyperinsulinaemia goes on to cause dyslipidaemia. Both excess luteinizing hormone and hyperinsulinaemia prevent ovulation, which in turn results in a deficiency of oestrogen and progesterone. Abnormal levels of LH may result in the formation of immature follicles which instead of resolving at the end of the menstrual cycle become cysts. However, the underlying endocrine disturbance can exist in the absence of polycystic ovaries, and sufferers may have classical clinical features, yet biochemically normal androgen levels. The condition appears to be familial, but the gene involved and mode of inheritance have not yet been identified.

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6. Signs and symptoms According to Dr Adam Balen from the Department of Reproductive Medicine in Leeds, women with polycystic ovaries exhibit some common symptoms:     

>90% experience oligomenorrhoea (< 9 periods per year) 30 – 50% experience amenorrhoea >90% experience anovulatory infertility >95% have acne 60-95% have hirsutism (male pattern body hair often on upper lip, chin, around the nipples and in a line beneath the umbilicus)

Other symptoms may include:       

Subfertility Alopecia (especially male-pattern balding) Obesity or difficulty losing weight (the obesity is usually centrally distributed) Psychological symptoms such as mood swings, depression, anxiety, poor self-esteem Sleep apnoea Acanthosis nigricans (may be present and may also indicate insulin resistance) Occasionally virilisation (including clitomegaly, increased muscle mass, deep voice, these indicate severe hyperandrogenism syndromes) It is interesting to note that physical signs of androgen excess vary with ethnicity e.g. women of Northern European or Asian descent may not display the clinical characteristics of hyperandrogenism. Acanthosis nigricans: A dark brownish or blackish discoloration of the skin related to overweight and high levels of insulin in the blood. Acanthosis nigricans is most likely to develop in the groin or armpits, or around the back of the neck.

Hirsutism: male pattern body hair often on upper lip, chin, around the nipples and in a line beneath the umbilicus

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7. Differential diagnosis Other metabolic and/or hormonal disorders should be investigated and excluded. These include:  Thyroid disorder (particularly hypothyroidism)  Hyperprolactinaemia  Cushing’s syndrome  Late-onset congenital adrenal hyperplasia (very rare)  Androgen-secreting ovarian or adrenal tumours  Ovarian hyperthecosis Signs of virism and biochemical androgen excess are much more prominent in the last three.

8. Diagnosis There is still some controversy regarding the actual diagnostic criteria that should be met to make the diagnosis of PCOS. The classic diagnostic criterion for PCOS was: “PCOS is a syndrome of ovarian dysfunction along with the cardinal features hyperandrogenism and polycystic ovary (PCO) morphology. PCOS remains a syndrome, and as such no single diagnostic criterion (such as hyperandrogenism or PCO) is sufficient for clinical diagnosis. Its clinical manifestations may include menstrual irregularities, signs of androgen excess, and obesity. Insulin resistance and elevated serum LH levels are also common features in PCOS.” In 2004 the Rotterdam ESHRE/ASRM* Consensus Group revised their 2003 diagnostic criteria to: The patient should experience 2 of the following 3 symptoms: 1. Oligo- and/or amenorrhoea 2. Clinical and/or biochemical signs of hyperandrogenism i.e. hirsutism, acne, raised testosterone 3. Polycystic ovaries (either 12 or more peripheral follicles or increased ovarian volume of greater than 10cm3) There is an on-going debate about diagnostic criteria and this may evolve further over time. Diagnosis in adolescence is more complicated and should probably include all three criteria to confirm PCOS. This is due to the common menstrual irregularities and severe acne that are normal during puberty. The one major risk factor for persistent anovulation progressing into adulthood is raised body mass index. *European Society of Human Reproduction and Embryology and ASRM: American Society of Reproductive Medicine.

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9. PCOS and weight/body mass index Obesity is a high risk factor in both the development of PCOS and other health complications. In adolescence, obesity is the highest cause of anovulation that persists into adulthood. While many women with PCOS have a higher body mass index, there are those with the syndrome that have a normal or low body weight. The incidence of overweight (BMI 25 to 30kg/m2) ranges from 10% in Italy to 37% in Kuwait. The highest prevalence of obesity (BMI >30kg/m2) is reported in the United States and Australia with 61% to 76% of women with PCOS being obese. Central obesity (visceral adiposity) is associated with greater insulin resistance which could exacerbate the reproductive and metabolic abnormalities in PCOS.

10.

PCOS and insulin resistance

Several studies have reported that insulin resistance is common in PCOS women, regardless of their body mass index. PCOS-induced insulin resistance determines a higher risk for the development of type 2 diabetes, hypertension and dyslipidemia which are all elements of the metabolic syndrome. Insulin resistance is most prevalent and severe in those women with the classic type of PCOS involving hyperandrogenism and chronic anovulation. Women who are diagnosed with PCOS with the Rotterdam criteria who have regular menstrual cycles have more normal metabolic profile. The cellular mechanisms of insulin resistance in PCOS differ from those in other common insulin-resistant states such as obesity and type 2 diabetes (T2D). Insulin action is severely decreased in skeletal muscle in most women with PCOS, but hepatic insulin resistance is only present in those who are obese. There is an additive negative effect of having both PCOS and obesity on insulin action. Extensive evidence indicates that hyperinsulinaemia contributes directly to reproductive dysfunction in PCOS.

Insulin resistance in PCOS

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Other metabolic disorders in PCOS

The link between PCOS and insulin resistance explains the several metabolic components present in the syndrome and the increased risk that affected women have of developing either the individual components of the metabolic syndrome (central obesity, dyslipidaemia, glucose intolerance/diabetes and hypertension) and/or the metabolic syndrome as a whole. PCOS is now recognised as a risk factor for developing diabetes and it is therefore recommended that these women are routinely screened so that insulin resistance can be found early and treatment can be initiated early, thereby decreasing the risk or delaying the onset of diabetes. The women with hyperandrogenaemia and oligomenorrhoea have the highest risk of developing metabolic syndrome.

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Complications

PCOS increases the risk of the following conditions, especially if obesity is also a factor:             

Hypertension Cholesterol and lipid abnormalities e.g. elevated triglycerides and LDL-cholesterol and lowered HDL-cholesterol Myocardial infarction Diabetes Metabolic syndrome Elevated c-reactive protein (an inflammatory marker) Subfertility Pregnancy abnormalities Abnormal uterine bleeding Endometrial hyperplasia and/or cancer Depression and/or anxiety Non-alcoholic steatohepatitis (non-alcoholic fatty liver) Sleep apnoea

The risk of myocardial infarction in PCOS patients is 4 to 7 times higher than in those of similar weight and age without the syndrome. They are also at greater risk of hypertension. This has been attributed to cardiovascular risk factors such as obesity, hyperandrogenism, dyslipidaemia (elevated LDL and lowered HDL-cholesterol) and hyperinsulinaemia. Depression and anxiety, which are common in women with PCOS, are also major risk factors for cardiovascular disease (CVD). Risk assessment for CVD should be done regularly in PCOS and should include assessment of psychosocial stress, blood pressure, glucose, lipid profile (cholesterol, triglycerides, HDL, LDL and non-HDL cholesterol), waist circumference, physical activity, nutrition and smoking. More than 50% of women with PCOS will develop diabetes or impaired glucose tolerance before the age of 40. This is particularly evident if they are obese (BMI greater than 30), have a strong family history of type 2 diabetes or are over the age of 40 years. Screening for impaired glucose tolerance and type 2 diabetes should be performed on women with: hyperandrogenism with anovulation, acanthosis nigricans, obesity and in women with a family history of type 2 diabetes or gestational diabetes. This screening should be done using a glucose tolerance test (GTT) and measuring insulin is not useful in most cases. Women with PCOS may be subfertile. This is probably explained by the effects of obesity and/or metabolic, inflammatory and endocrine abnormalities on ovulatory function, oocyte quality and endometrial receptivity. Elevated androgen and insulin levels caused by ovarian dysfunction and disruption of growth factors may lead to immature oocytes (eggs). However, not all women with PCOS experience these symptoms and oocyte quality, fertilization and implantation rates may actually be normal in some.

13 Complications of pregnancy: there is a high risk of gestational diabetes in women with PCOS, with a 40 to 50% incidence. Women who have been diagnosed as having PCOS before pregnancy should be screened for gestational diabetes before 20 weeks of gestation, with referral to a specialist obstetrician if abnormalities are detected. Women with PCOS also have higher risks of pre-eclampsia and pregnancy induced hypertension and small-forgestational-age babies. Women planning a pregnancy should be encouraged to optimize their health prior to conception including smoking cessation, lifestyle, diet and appropriate vitamin supplementation (e.g. folic acid). Oligomenorrhoea and/or amenorrhoea are known to predispose to endometrial hyperplasia and endometrial cancer. Women with PCOS have a threefold increased risk of developing endometrial cancer. It is good practice to recommend treatment with progesterone to induce a withdrawal bleed at least every 3-4 months. Women with PCOS are an at risk group for psychological and behavioural disorders and reduced quality of life. Compared to healthy controls they are at higher risk of developing depression and/or anxiety and may be at risk for eating disorders and sexual and relationship dysfunction. It is unclear if this increased risk/prevalence is due to the disorder itself, or its manifestations (e.g. obesity, hirsutism, irregular menses and/or infertility). Based on individual consultation and the patient’s perception of her problems, appropriate counselling and intervention should be offered.

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13.

Management of PCOS

Although PCOS cannot be cured, there are various approaches available to managing the underlying contributing factors and alleviating symptoms. Women should be informed of the possible long-term risks to health that are associated with PCOS. These include obesity, dyslipidaemia and insulin resistance (all components of the metabolic syndrome) and are likely to result in increased cardiovascular risk. Treatment decisions are based on the patient’s goals or end requirements e.g. pregnancy or an improvement in the cosmetic appearance and/or prevention of complications. Management of PCOS should be done holistically with a multidisciplinary approach to achieve the most favourable patient outcome. The age of the women will also play a role in treatment decisions as desired outcomes will differ and risk factors will also change.

Schematic representation of the change in emphasis from early age reproductive disorders to long-term metabolic and cardiovascular health. (Fauser. ESHRE/ASRM PCOS Consensus. Fertil Steril 2012)

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13.1 Lifestyle modification Lifestyle modification should be the focus of treatment for the management of both PCOS as a syndrome and the underlying causes or risk factors. Weight loss and exercise have been shown to improve fertility, psychological symptoms and the metabolic features (insulin resistance and cardiovascular risks) of PCOS, even when BMI remains in the high ranges. They have also been shown to improve ovulation, pregnancy rates and outcomes. It makes sense that a low glycaemic index (GI) diet would be most beneficial in women with PCOS. The Medical Nutritional Institute (MNI) offers a free meal plan on our website: www.mnilifestyle.co.za and a holistic weight loss programme is available. Kindly visit the webpage for further information. An obese patient may find the thought of losing a large amount of weight demoralising. While achieving a normal BMI (19 to 24.9) would be ideal, it is important to remind her that a modest weight loss of as little as a 5% loss of body weight can restore fertility. In section 3.2 I mentioned that consuming inflammatory foods also has a systemic inflammatory effect which contributes to insulin resistance and atherosclerosis. Contributors to inflammation include:      

High glycaemic load Saturated and trans fatty acids Caffeine Alcohol in excess Insufficient intake of micronutrients and antioxidants Low fibre diet

It is therefore important for women with PCOS to follow a diet that is rich in antiinflammatory foods. This includes:     

Low glycaemic index and load diet Elimination of trans fats and minimal intake of saturated fats Elimination or restriction of caffeine Alcohol only in moderation or not at all Increased consumption of whole plant foods to maximise the intake of fibre, antioxidants and phytonutrients (e.g. vegetables, fruit, whole grains, nuts, seeds and beans).

Women planning a pregnancy should be encouraged to optimize their health prior to conception including smoking cessation, lifestyle, diet and appropriate vitamin supplementation (e.g. folic acid).

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13.2

Psychological care

There is evidence of increased prevalence of psychological disorders in women with PCOS. These include depression and anxiety and may include eating disorders and sexual and/or relationship dysfunction. If you suspect that the patient may be in psychological distress, refer her for appropriate counselling and intervention. A complimentary stress test is available on the MNI website www.mnilifestyle.co.za which may be useful in identifying the presence and severity of stress.

13.3

Pharmacological treatment

There is no treatment which reverses the hormonal disturbances of PCOS and which treats all the clinical features, so medical management is targeted at individual symptoms, and always in association with lifestyle changes. Physical/cosmetic approaches to remove unwanted hair, including electrolysis and laser treatments, may be of value to many patients. No effective pharmacological treatment for alopecia exists.

For women who are not planning pregnancy: 

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





Metformin (Glucophage) Has been increasingly used off-licence for PCOS. Insulin sensitizing agents such as metformin have been prescribed as first-line treatment to restore normal menstrual function in women suffering from PCOS by reducing or managing insulin resistance Co-cyprindrol Is licensed for treating hirsutism and acne, although not specifically in PCOS. It is also used to reduce endometrial bleeds and thereby reduces the risk of endometrial carcinoma. Combined oral contraceptive pill (COCP) Oral contraceptives supress LH secretion and lead to a decrease in ovarian androgen production. The oestrogen component increases the level of sex hormone-binding globulin (SHBG), which in turn results in a decrease in circulating testosterone levels. OCPs also decrease adrenal androgen function by a mechanism not clearly understood, possibly due to a decrease in adrenocorticotropin hormone (ACTH) production. OCPs are also used to control menstrual irregularity. Long term OCP use may improve cardiometabolic risk parameters including insulin resistance, lipoprotein profile and possibly body fat distribution. If risk factors deem women ineligible for COCP, progesterones may be used to induce bleeds to protect the endometrium. Eflornithine (Vaniqa) May be applied topically for hirsutism, as can cosmetic treatments such as electrolysis, laser, waxing and/or bleaching. Orlistat (Xenical, Alli) May help in weight loss in women with PCOS and may improve insulin sensitivity Remind women that prolonged medical treatment (>6 months) is normally necessary to see a notable result e.g. in managing hirsutism.

17 All anti-androgen agents should be used in combination with effective contraception due to their potential foetal toxicity.

For women wishing to conceive and presenting with infertility: 2013 NICE (National Institute for Health and Care Excellence) guidelines advise that women should be treated with clomifene, metformin or a combination of the two, after weight loss where indicated and a full fertility work-up. 

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Clomifene e.g. Clomid, Serophene Induces ovulation and has been proven to improve pregnancy rates. It should not be used for more than 6 months and it is associated with an 11% risk of multiple pregnancy. Metformin May be used instead of or together with clomifene to improve pregnancy rates. Women should be warned of possible side effects. Laparoscopic ovarian drilling or gonadotropins Are second line treatments for those who are resistant to clomifene. Women planning a pregnancy should be encouraged to optimize their health prior to conception including smoking cessation, lifestyle, diet and appropriate vitamin supplementation (e.g. folic acid).

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13.4

Complimentary/natural treatment

There are a number of naturally occurring substances and plant extracts that improve insulin receptor sensitivity and therefore alleviate insulin resistance and the cascade of effects caused by elevated plasma insulin levels (hyperinsulinaemia). Improving insulin sensitivity decreases adipogenesis (formation of fat) and increases lipolysis (fat breakdown) as demonstrated in various studies and trials. This explains the weight-loss effects seen with these natural agents. Among the insulin-sensitizing compounds, inositol has been demonstrated to be capable of restoring spontaneous ovarian activity, and consequently fertility, in many patients with PCOS. Numerous international clinical trials by accredited medical institutions have studied the effect of inositol in PCOS. The findings have been clearly summarised in “Effects of myoinositol in women with PCOS: a systemic review of randomized controlled trials” published in the Journal of Gynecological Endocrinology in 2012. The conclusion of this review was that inositol has positive effects on insulin plasma levels and on insulin response to oral glucose load. Inositol decreases insulin plasma levels and glucose levels. It also improves other hormonal parameters such as LH (Luteinising hormone), LH/FSH ratio (luteinising/follicle stimulating hormone) and testosterone. Inositol was also shown to be able to induce normal menstrual cycles. In addition, inositol treatment resulted in a significant weight loss, reduction in circulating leptin and an increase in HDL-cholesterol, with a decrease in LDL-cholesterol. The pharmacological mechanism of inositol appears to be mainly based on improving insulin sensitivity of target tissues, resulting in a positive effect on the reproductive axis (inositol restores ovulation and improves oocyte quality) and hormonal functions (inositol reduces clinical and biological hyperandrogenism and dyslipidemia) through the reduction of insulin plasma levels. Inositol is very well tolerated and no side effects have been reported in doses of 4g/day or less. In fact, only doses of 12g/day induced mild gastrointestinal side effects such as nausea, flatus and diarrhoea. The severity of the side effects does not increase with dosage.

Other complimentary medications that improve insulin receptor sensitivity include banaba leaf and chromium. Banaba leaf studies indicate that banaba extract exerts anti-diabetic and anti-obesity effects. It contains two groups of chemical compounds known to display blood glucose lowering effects, namely corosolic acid and the ellagitannins. The beneficial properties of banaba with respect to various aspects of blood glucose regulation involve multiple mechanisms which include the enhanced cellular uptake of glucose, the impaired hydrolysis of complex carbohydrates as well as decreased gluconeogenesis (the generation of glucose

19 from non-carbohydrate sources). Trials have indicated that tighter blood sugar control with reduced insulin levels accelerates weight loss, even in the absence of dietary alterations. Chromium is a mineral naturally found in certain foods. Various studies have demonstrated that it assists with improved insulin sensitivity and glucose control. Other natural substances have been scientifically proven to be beneficial to women with PCOS. Berberine has the ability to reduce insulin resistance as well as androgen synthesis. Berberine is an ammonium salt found in plants such as Berberis, Hydrastis canadensis and Coptis chinenses. Studies have shown berberine’s ability to stimulate glucose transport, lower elevated blood glucose levels, prevent or alleviate insulin resistance and increase insulin receptor expression. Berberine also inhibits adipogenesis in human white preadipocytes, the process of cell differentiation during which preadipocytes become adipocytes (fat cells), thereby displaying the potential ability to moderate adipose tissue mass (body fat).

MNI suggests a dual approach to assist in the management of PCOS: 1. AntaGolinTM is designed for the treatment of insulin resistance and to assist is weight loss. It has a triple action:  

Improves insulin receptor sensitivity Mimics the action of insulin therefore improving glucose transport and blood glucose control  Inhibits adipogenesis (slows fat formation) and stimulates lipolysis (accelerates fat breakdown) Specifically for PCOS: AntaGolin contains berberine which may decrease the production of male hormones (androgenisis) and inositol which has been shown to improve ovarian function. 2. NeuroVanceTM is used for the management of stress. Our body produces cortisol as part of the normal stress response. Elevated cortisol levels in response to prolonged stress can result in erectile dysfunction and may disrupt ovulation and the menstrual cycle resulting in decreased fertility. As an additional benefit NeuroVance also contains inositol for improved ovarian function. Both AntaGolin and NeuroVance can be taken in combination with the medications that may have been prescribed for treating PCOS. For those women whose lipid profile has been affected, RyCholTM could be recommended. RyCholTM-Q10 consists of a blend of different natural ingredients that all display unique cholesterollowering properties. Combined, these target multiple cholesterol-producing pathways simultaneously. RyCholTM-Q10 has the ability to reduce both total cholesterol and LDL-cholesterol levels.

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PCOS in primary healthcare setting

While the exact cause of PCOS has not been determined, the underlying contributing factors such as insulin resistance and overweight mean that the primary healthcare provider (HCP) can play a major role in the management of the condition and in the prevention of the associated complications. As educators, it is important to ensure a sound understanding of the condition and to keep abreast of any updates or changes in diagnostic criteria and current management strategies. While you may not personally be ordering the medical investigations or prescribing the treatments, you do need to understand what these are and how they will assist your patients. Pharmaceutical treatment will probably be prolonged and you can encourage ongoing compliance with a treatment regime by educating, supporting and encouraging your patient. Furthermore, a good understanding of the symptoms of PCOS will aid you in referring patients for investigation with confidence. The HCP is in an ideal position to inform her patients of the potential complications associated with PCOS and to offer relevant screening tests and management strategies. These complications include hypertension, dyslipidaemia and diabetes. In addition, central obesity is an accurate indicator of insulin resistance, which can be improved by a variety of means. Bear in mind that insulin resistance is also commonly present in lean women with PCOS. In this situation fasting plasma insulin levels may be required as the clinical picture may be misleading. Other complications of PCOS include endometrial hyperplasia and carcinoma which cannot be detected or managed at primary healthcare level, and symptoms of these are a clear indicator for referral.

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Summary

Polycystic ovary syndrome (PCOS) is the most common cause of female infertility and affects 5-15% of all women. It is an endocrine disorder that causes an imbalance of a woman’s sex hormones, mainly a decrease in oestrogen and increase in androgen levels. PCOS is a complex, poorly understood syndrome that is probably genetic. Research indicates that insulin resistance plays an important role in PCOS. Symptoms of PCOS are menstrual irregularity and infertility caused by decreased oestrogen levels, and signs of raised androgens. These commonly include acne and male pattern hair growth. Symptoms of insulin resistance such as central obesity may also be present. Besides fertility problems, PCOS complications include obesity and cholesterol abnormalities. It also increases the risk of uterine cancer and of hypertension, heart disease and diabetes. In fact PCOS increases the risk of the development of the whole metabolic syndrome. The management of PCOS depends on the outcome the woman is wanting e.g. achieving pregnancy, improving cosmetic appearance and/or decreasing the risk of complications. The main focus of treatment is on managing the lifestyle of the women which is where the primary healthcare provider can play a significant role.

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Sources

1. Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Bart C.J M. Fauser, MD et al. Fertility and Sterility Vol.97, No 1, January 2012 0015-0282; American Society for Reproductive Medicine 2001.09.024. 2. Effects of myo-inositol in women with PCOS: a systemic review of randomized controlled trials. Gynecological Endocrinology, 2012; 28(7):509-515. V. Unfer, G. Carlokagno, G. Dante & F. Fachinetti 3. Inositol safety: clinical evidences. European Review for Medical and Pharmacological Sciences, 2011; 15:931-936. G. Carlomagno, V. Unfer 4. Insulin Resistance and the Polycystic Ovary Syndrome: Mechanism and Implications for Pathogenesis. Endocrine Reviews, 1997; 18(6):774-800. Andrea Dunaif, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033. 5. How to avoid missing the diagnosis of PCOS. Adam Malen MD, FRCOG; Department of Reproductive Medicine, United Leeds Teaching Hospitals 6. Polycystic Ovary Syndrome. Dr Hayley Willacy and Dr Mary Harding; 9 July 2013; www.patient.co.uk/doctor/polycystic-ovary-syndrome 7. Insulin resistance in PCOS. Endocrine, 2006 Aug;30(1):13-7. Diamanti-Kandarakis E. Endocrine Section, First Department of Medicine, Medical School University of Athens, Greece. 8. Polycystic ovary syndrome. Mayo Clinic. www.mayoclinic.com/health/polycystic-ovarysyndrome/DS00423. Accessed July 2013 9. Polycystic Ovarian Syndrome. Melissa Conrad Stoppler, MD. www.medicinenet.com. Accessed July 2013

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17.

Glossary

Acanthosis nigricans: A dark brownish or blackish discoloration of the skin related to overweight and high levels of insulin in the blood. Acanthosis nigricans is most likely to develop in the groin or armpits, or around the back of the neck. There are benign and malignant forms; the latter is most often associated with cancers of the GI tract. Amenorrhoea: The absence of menstrual periods is called amenorrhea. Primary amenorrhea is the failure to start having a period by the age of 16. Secondary amenorrhea is more common and refers to either the temporary or permanent ending of periods in a woman who has menstruated normally in the past. Many women miss a period occasionally. Amenorrhea occurs if a woman misses three or more periods in a row. The word "amenorrhea" is compounded from three Greek roots "a-", no + "men", month + "rhoia", flow = no monthly flow. Anovulatory infertility: infertility caused by the absence of ovulation Cushing syndrome: is a hormone disorder caused by high levels of cortisol in the blood. This can be caused by taking glucocorticoid drugs, or by tumours that produce cortisol or adrenocorticotropic hormone (ACTH) or CRH Endogenous 1. Biology developing or originating within an organism or part of an organism endogenous rhythms. 2. Having no apparent external cause e.g. endogenous depression Follicle Stimulating Hormone (FSH): A gonadotropic hormone of the anterior pituitary gland that stimulates the growth of follicles in the ovary and induces the formation of sperm in the testis. Gonadotropins: A hormone that stimulates the growth and activity of the gonads, especially any of several pituitary hormones that stimulate the function of the ovaries and testes Hirsutism: male pattern body hair often on upper lip, chin, around the nipples and in a line beneath the umbilicus Hyperandrogenism: a state characterized or caused by an excessive secretion of androgens by the adrenal cortex, ovaries, or testes. The clinical significance in males is negligible, so the term is used most commonly with reference to the female. The common manifestations in women are hirsutism and virilism. Hyperandrogenism is often caused by either ovarian or adrenal diseases. Hyperprolactinaemia: is the presence of abnormally-high levels of prolactin in the blood Luteinizing Hormone (LH): A hormone produced by the anterior lobe of the pituitary gland that stimulates ovulation and the development of the corpus luteum in the female and the production of testosterone by the interstitial cells of the testis in the male. Oligomenorrhoea: infrequent or very light menstruation. But physicians typically apply a narrower definition, restricting the diagnosis of oligomenorrhoea to women whose periods

25 were regularly established before they developed problems with infrequent flow. With oligomenorrhoea, menstrual periods occur at intervals of greater than 35 days, with only four to nine periods in a year. Ovarian Hyperthecosis is the development of nests of luteinized thecal cells, usually diffusely, in the ovary with the subsequent production of androgens and presentation with signs of androgen excess. Hirsutism: male pattern body hair often on upper lip, chin, around the nipples and in a line beneath the umbilicus Hyperandrogenism: a state characterized or caused by an excessive secretion of androgens by the adrenal cortex, ovaries, or testes. The clinical significance in males is negligible, so the term is used most commonly with reference to the female. The common manifestations in women are hirsutism and virilism. Hyperandrogenism is often caused by either ovarian or adrenal diseases. Virilism: The presence of male secondary sexual characteristics in a female. These could include clitomegaly, increased muscle mass, deep voice which indicate severe hyperandrogenism syndromes.