Polycystic Ovary Syndrome

A Guide to Clinical Management

Adam H. Balen, Gerard Conway, Roy Homburg, Richard Legro, Adam H. Balen, Gerard Conway, Roy Homburg, Richard Legro

• Publisher: CRC Press
• Year: 2005
• eBook ISBN: 9781135402099
• Topic: Medicine
• Subtopic: Endocrinology & Metabolism

Clearly presented and thoroughly up to date, this important text provides an overview of current knowledge of the polycystic ovary syndrome (PCOS) - its etiology, pathology, and the implications for effective medical management. In contrast with existing titles, this book focuses on the difficulty in making an accurate diagnosis and the conseq

Chapter 1
Introduction and overview

Many believe polycystic ovary syndrome (PCOS) to be a condition of our time. Certainly PCOS is the most common endocrine disturbance to affect women and it appears that its prevalence is on the increase. There is considerable heterogeneity of symptoms and signs among women with PCOS, and for an individual these may change over time. The extreme end of the spectrum, once known as the Stein-Leventhal syndrome, encompasses the combination of hyperandrogenism (hirsutism, acne, alopecia and elevated serum testosterone concentrations), severe menstrual disturbance (amenorrhea or oligomenorrhea) and obesity. We now appreciate that polycystic ovaries may exist without clinical signs of the syndrome. PCOS is familial, and various aspects of the syndrome may be differentially inherited. There are a number of interlinking factors that affect expression of PCOS. A gain in weight is associated with a worsening of symptoms while weight loss will ameliorate the endocrine and metabolic profile and symptomatology. Normal ovarian function relies upon the selection of a follicle, which responds to an appropriate signal (follicle stimulating hormone) in order to grow, become ‘dominant’ and ovulate. This mechanism is disturbed in women with PCOS, resulting in multiple small cysts, most of which contain potentially viable oocytes but within dysfunctional follicles.

In recent times there has been a significant change in lifestyle in many parts of the world, with most people experiencing a more sedentary existence combined with an abundance of food. This has resulted in the modern epidemic of obesity and consequent hyperinsulinemia—a situation which in women may precipitate expression of PCOS, while in men presentation is often with cardiovascular disease and type 2 diabetes in later life. Elevated serum concentrations of insulin are more common in both lean and obese women with PCOS than in weight-matched controls. Indeed it is hyperinsulinemia that appears to be the key to the pathogenesis of the syndrome, as insulin stimulates androgen secretion by the ovarian stroma and appears to affect the normal development of ovarian follicles, both by the adverse effects of androgens on follicular growth, and possibly also by suppressing apoptosis and permitting the survival of follicles otherwise destined to disappear.

Women with polycystic ovaries may experience a range of the clinical and biochemical features that define PCOS. These features include menstrual cycle disturbances, obesity, hirsutism, acne, and abnormalities of biochemical profiles including elevated serum concentrations of luteinizing hormone (LH), testosterone, androstenedione, and insulin. Presentation of the syndrome is so varied that one, all, or any combination of the above features may be present in association with an ultrasound picture of polycystic ovaries.

In this book we aim to provide a practical appraisal of our current understanding of PCOS. We shall discuss in detail the diagnosis of PCOS, with reference to ultrasonography and endocrine assessment (Chapter 2). We shall expand upon the assessment of hyperinsulinemia and its short-term and long-term health consequences (Chapters 4, 6, 7 and 8). Women who are obese, and also many slim women with PCOS, will have insulin resistance and elevated serum concentrations of insulin (usually <30 mU/l fasting). We suggest that a 75 g oral glucose tolerance test (GTT) be performed in women with PCOS and a body mass index (BMI) >30 kg/m², with an assessment of the fasting and two-hour glucose concentration. It has been suggested that South Asian women should have an assessment of glucose tolerance if their BMI is greater than 25 kg/m² because of the greater risk of insulin resistance at a lower BMI than seen in the Caucasian population.

The epidemiology of PCOS has received increasing attention in recent times, with respect both to prevalence in the general population and racial differences (Chapter 3). The highest reported prevalence of PCO has been 52% amongst South Asian immigrants in Britain, of whom 49.1% had menstrual irregularity.¹ Rodin and coworkers (1998) demonstrated that South Asian women with PCO had a comparable degree of insulin resistance to controls with established type 2 diabetes mellitus.¹ Generally, there has been a paucity of data on the prevalence of PCOS among women of South Asian origin, both among migrant and native groups. Type 2 diabetes and insulin resistance have a high prevalence among indigenous populations in South Asia, with a rising prevalence among women. Insulin resistance and hyperinsulinemia are common antecedents of type 2 diabetes, with a high prevalence in South Asians. Type 2 diabetes also has a familial basis, inherited as a complex genetic trait that interacts with environmental factors, chiefly nutrition, commencing from fetal life. We have already found that South Asians with anovular PCOS have greater insulin resistance and more severe symptoms of the syndrome than anovular Caucasians with PCOS.² Furthermore, we have found that women from South Asia living in the UK appear to express symptoms at an earlier age than their Caucasian British counterparts.

Obesity and metabolic abnormalities are recognized risk factors for the development of ischemic heart disease (IHD) in the general population, and these are also recognized features of PCOS. The questions are whether women with PCOS are at an increased risk of IHD, and whether this will occur at an earlier age than in women with normal ovaries. The basis for the idea that women with PCOS are at greater risk for cardiovascular disease is that these women are more insulin resistant than weight-matched controls and that the metabolic disturbances associated with insulin resistance are known to increase cardiovascular risk in other populations (Chapter 8).

Insulin resistance is defined as a diminution in the biological responses to a given level of insulin. In the presence of an adequate pancreatic reserve, normal circulating glucose levels are maintained at higher serum insulin concentrations. In the general population, cardiovascular risk factors include insulin resistance, obesity, glucose intolerance, hypertension, and dyslipidemia.

Insulin sensitivity varies depending upon menstrual pattern. Women with PCOS who are oligomenorrheic are more likely to be insulin resistant than those with regular cycles—irrespective of their BMI. Insulin resistance is restricted to the extra-splanchnic actions of insulin on glucose dispersal. The liver is not affected (hence the fall in sex hormone binding globulin (SHBG) and high-density lipoprotein (HDL)), neither is the ovary (hence the menstrual problems and hypersecretion of androgens) nor the skin (hence the development of acanthosis nigricans). The insulin resistance causes compensatory hypersecretion of insulin, particularly in response to glucose, so euglycemia is usually maintained at the expense of hyperinsulinemia.

Simple obesity is associated with greater deposition of gluteo-femoral fat while central obesity involves greater truncal abdominal fat distribution. Obesity is observed in 35–60% of women with PCOS. Hyperandrogenism is associated with a preponderance of fat localized to truncal abdominal sites. Women with PCOS have a greater truncal abdominal fat distribution as demonstrated by a higher waist:hip ratio. The central distribution of fat is independent of BMI and associated with higher plasma insulin and triglyceride concentrations, and reduced HDL cholesterol concentrations. Thus, examining the surrogate risk factors for cardiovascular disease, there is evidence that insulin resistance, central obesity and hyperandrogenemia are features of PCOS and have an adverse effect on lipid metabolism. Women with PCOS have been shown to have dyslipidemia, with reduced HDL cholesterol and elevated serum triglyceride concentrations, along with elevated serum plasminogen activator inhibitor-l concentrations. The evidence is thus mounting that women with PCOS may have an increased risk of developing cardiovascular disease and diabetes later in life, which has important implications in their management. However, Pierpoint and coworkers reported the mortality rate in 1,028 women diagnosed as having PCOS between 1930 and 1979.³ The standard mortality rate both overall and for cardiovascular disease was not higher in the women with PCOS compared with the national mortality rates in women, although the observed proportion of women with diabetes as a contributory or underlying factor leading to death was significantly higher than expected (odds ratio 3.6, 95% confidence interval (Cl) 1.5–8.4). Thus, despite surrogate markers for cardiovascular disease, in this study no increased rate of death from cardiovascular disease could be demonstrated. An overview of the epidemiology of insulin resistance in PCOS is provided in Chapter 8.

Other long-term consequences of PCOS arise from chronic exposure to increased serum concentrations of estrogen, often unopposed by the post-ovulatory secretion of progesterone by the corpus luteum. Patients with PCOS are therefore not estrogen deficient and those with amenorrhea are at risk not of osteoporosis but rather of endometrial hyperplasia and adenocarcinoma and there may be an association also with breast cancer (Chapter 9). Cycle control and regular withdrawal bleeding is achieved with the oral contraceptive pill, which has the additional beneficial effect of suppressing serum testosterone concentrations and hence improving hirsutism and acne. Dianette^® and Yasmin^®, containing the anti-androgens cyproterone acetate and drosperinone respectively, are commonly recommended.

The symptoms of PCOS may cause significant distress and are dealt with in turn (hirsutism— Chapter 10; acne—Chapter 11; menstrual disturbance—Chapter 12 and infertility—Chapter 13). Little attention has been paid to the effect that PCOS has on the quality of life of the woman. The psychological stress experienced by sufferers of obesity, menstrual disturbance, infertility and hirsutism has been studied separately, yet the overall effects of PCOS and the changing spectrum of the condition necessitates especial attention (Chapter 6). Treatment options for hirsutism include cosmetic and medical therapies (Chapter 10). As drug therapies may take six to nine months or longer before any improvement of hirsutism is perceived, physical treatments including electrolysis, laser therapy, waxing and bleaching may be helpful while waiting for medical treatments to work.

The management of the PCOS is symptom orientated. Whilst obesity worsens the symptoms, the metabolic scenario can conspire against weight loss. Diet and exercise are key to symptom control and weight loss improves the endocrine profile, and the likelihood of ovulation and a healthy pregnancy. Much has been written about diet and PCOS. The right diet for an individual is one that is practical, sustainable and compatible with her lifestyle. It is sensible to keep carbohydrate content down and to avoid fatty foods (Chapter 7). It is often helpful to refer to a dietitian. Anti-obesity drugs may help with weight loss. Metformin may lead to improvements with insulin resistance and may aid some women with weight loss, combined with a healthy diet and exercise program.

For women with infertility, ovulation can be induced with the anti-estrogens, clomifene citrate or tamoxifen. While clomifene is successful in inducing ovulation in over 80% of women, pregnancy only occurs in about 40%. Clomifene citrate should only be prescribed in a setting where ultrasound monitoring is available (and performed) in order to minimize the 10% risk of multiple pregnancy and to ensure that ovulation is taking place (Chapter 13). Recently attention has turned to the use of aromatase inhibitors and further research is ongoing. The therapeutic options for patients with anovulatory infertility who are resistant to anti-estrogens are either parenteral gonadotrophin therapy, or laparoscopic ovarian diathermy. Because the polycystic ovary is very sensitive to stimulation by exogenous hormones, it is very important to start with very low doses of gonadotrophins and follicular development must be carefully monitored by ultrasound scans. The advent of transvaginal ultrasonography has enabled the multiple pregnancy rate to be reduced to approximately 5% because of its higher resolution and clearer view of the developing follicles. Cumulative conception and livebirth rates after 6 months may be 62% and 54%, respectively, and after 12 months 73% and 62%, respectively.⁴ Close monitoring should enable treatment to be suspended if three or more mature follicles develop, as the risk of multiple pregnancy obviously increases.

Women with PCOS are also at increased risk of developing ovarian hyperstimulation syndrome (OHSS). This occurs if too many follicles (>10 mm) are stimulated, and results in abdominal distension, discomfort, nausea, vomiting and sometimes difficulty in breathing. The mechanism for OHSS is thought to be secondary to activation of the ovarian renin-angiotensin pathway and excessive secretion of vascular endothelial growth factor (VEGF). The ascites, pleural and pericardial effusions exacerbate this serious condition and the resultant hemoconcentration can lead to thromboembolism. The situation worsens if a pregnancy has resulted from the treatment, as human chorionic gonadotropin (hCG) from the placenta further stimulates the ovaries. Hospitalization is sometimes necessary in order for intravenous fluids and heparin to be given to prevent dehydration and thromboembolism. Although OHSS is rare it is potentially fatal and should be avoidable with appropriate monitoring of gonadotropin therapy.

Ovarian diathermy is free of the risks of multiple pregnancy and ovarian hyperstimulation, and does not require intensive ultrasound monitoring. Laparoscopic ovarian diathermy has taken the place of wedge resection of the ovaries (which resulted in extensive peri-ovarian and tubal adhesions), and it appears to be as effective as routine gonadotrophin therapy in the treatment of clomifene-insensitive PCOS.

A number of pharmacological agents have been used to amplify the physiological effect of weight loss, notably insulin-lowering agents such as metformin. This biguanide inhibits the production of hepatic glucose and enhances the sensitivity of peripheral tissue to insulin, thereby decreasing insulin secretion. It has been shown that metformin ameliorates hyperandrogenism and abnormalities of gonadotropin secretion in women with PCOS and can restore menstrual cyclicity and fertility.⁵

In summary, PCOS is a heterogeneous, familial condition. Ovarian dysfunction leads to the main signs and symptoms and the ovary is influenced by external factors in particular the gonadotropins, insulin and other growth factors, which are dependent upon both genetic and environmental influences. There are longterm risks of developing diabetes and possibly cardiovascular disease. Therapy to date has been symptomatic but by our improved understanding of the pathogenesis, treatment options are becoming available that strike more at the heart of the syndrome.

Key point

• PCOS is the most common endocrine rine disorder in women (prevalence 15–20%).
• PCOS is a heterogeneous condition. Diagnosis is made by the ultrasound detection of polycystic ovaries and one or more of a combination of symptoms and signs (hyperandrogenism (acne, hirsutism, alopecia), obesity, menstrual cycle disturbance (oligo-/amanorrhea)) and biochemical abnormalities (hyperseeretion of testosterona, luteinizing hormone and insulin).
• Management is symptom orientated.
• If obese, weight loss improves symptoms and endocrinology and should be encouraged. A glucose tolerance test should be performed if the BMl is >30 kg/m².
• Menstrual cycle control is achieved by cyclical oral contraceptives or progestogens,
• Ovulation induction may be difficult and require progression through various treatments which should be monitored carefully to prevent multiple pregnancy.
• Hyperandrogenism is usually managed with Dianette^®, containing ethinylestradiol in combination with cyproterone acetate, A new combined oral contraceptive pill, Yasmin^® may also be of benefit. Alternatives include spironolactone. Flutamide and finasteride are not routinely prescribed because of potential adverse effects. Reliable contraception is required.
• Insulin-sensitizing agents (e.g. metformin) are showing early promise but require further long-term evaluation and should only be prescribed by endocrinologists/reproductive endocrinologists.

Indications for referral to a reproductive medicine specialist

• Serum testosterone >5 nmol/l (to exclude other causes of androgen excess, e.g. tumors, late onset congenital adrenal hyperplasia, Cushing’s syndrome)
• Infertility
• Rapid onset hirsutism (to exclude androgen-secreting tumors)
• Glucose intolerance/diabetes
• Amenorrhea of mor...

Table of contents

• Cover Page
• Title Page
• Copyright Page
• Foreword
• Preface
• Chapter 1: Introduction and overview
• Chapter 2: Defining the polycystic ovary syndrome
• Chapter 3: Epidemiology of polycystic ovary syndrome
• Chapter 4: The pathophysiology of polycystic ovary syndrome
• Chapter 5: The genetics of polycystic ovary syndrome
• Chapter 6: Body image and quality of life with polycystic ovary syndrome
• Chapter 7: The effects of obesity and diet
• Chapter 8: Long-term sequelae of polycystic ovary syndrome: diabetes and cardiovascular disease
• Chapter 9: Long-term sequelae of polycystic ovary syndrome: gynecological cancer
• Chapter 10: Disorders of the pilosebaceous unit: hirsutism and androgenic alopecia
• Chapter 11: Acne
• Chapter 12: Menstrual disturbances
• Chapter 13: The management of infertility associated with polycystic ovary syndrome
• Chapter 14: Polycystic ovary syndrome, pregnancy and miscarriage
• Chapter 15: The management of women in the climateric and menopause who have a diagnosis of polycystic ovary syndrome
• Appendix 1: Ultrasound assessment of the polycystic ovary: technical considerations
• Appendix 2: Polycystic ovary syndrome history sheet
• Appendix 3: Support groups and web sites
• Appendix 4: Further reading