Polycystic Ovary Syndrome: An Overview

Journal of Pharmacy Practice 24(1) 94-101 ª The Author(s) 2011 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190010384632 http://jpp.sagepub.com

Kristin Nadine Whitaker, PharmD Candidate1

Abstract Polycystic ovary syndrome is the most common endocrine disorder in women of reproductive age. It affects 6% to 7% of the population and is characterized by hyperandrogenism and ovarian dysfunction. Women with the disorder often present with insulin resistance and obesity, making it importance for health care providers to monitor closely for signs and symptoms of metabolic syndrome and type 2 diabetes. Treatments are targeted toward improving insulin tolerance, reducing signs and symptoms of hyperandrogenism (hirsutism, anovulation, etc), restoring normal menstrual cycle function, and restoring fertility. Major treatment should include weight management through diet and exercise, regardless of body mass index and might include concurrent drug therapy. It is important that pharmacists understand the underlying pathophysiology of the disease and the available treatments, in addition to the importance of reducing risk of metabolic syndrome/type 2 diabetes, and cardiovascular disease in these patients. Keywords metformin, infertility, metabolic syndrome, clomiphene citrate, polycystic ovary syndrome

Introduction Polycystic ovary disease or polycystic ovary syndrome (PCOS) is the most commonly encountered endocrine disorder in women of reproductive age with a prevalence of 6% to 7%.1-3 Clinically, it produces a wide variety of symptoms and long-term complications and is characterized by ovarian dysfunction and hyperandrogenism that may or may not be accompanied by polycystic ovaries.1,4,5 Additionally, it has been shown to adversely affect cardiovascular, endocrine, hepatic, gastrointestinal, and psychological functioning.6-19 Polycystic ovary syndrome causes both increased anxiety and depression in women and can lead to a significant decrease in quality of life.11-14 Historically, PCOS treatment has not been curative in nature; instead treatments focus on resolution of clinical manifestations of the disease.3-5,20,21 Primary targets for treatment include, but are not limited to, restoration of ovulation and fertility, reduction in serum androgen levels, reduction or alleviation of hirsutism, improve glucose tolerance and metabolic functioning, and reduction of risk of major cardiac and endocrine complications.3-5,20,22

Epidemiology Polycystic ovary syndrome occurs at a high rate in the population of women who are of reproductive age. The exact cause of the disease is unknown but seems to be best characterized as a hyperandrogenic, anovulatory state with multiple etiologies contributing to clinical manifestation of symptoms.4 Similarly, women with a family history of the disease are also at increased risk of having the disorder.23 The major risks associated with PCOS are related to the disease process and frequent comorbid

obesity and include increased risk of diabetes mellitus, cardiovascular complications, anxiety, depression, and infertility.6-19 Women with PCOS often present with obesity and complaints of menstrual dysfunction (that may or may not be related to fertility complaints).4,6,20,22 The Rotterdam diagnostic criteria for the diagnosis of PCOS require that the patient present with two or more of the following: oligo- or anovulation, clinical and/or biochemical signs of hyperandrogenism, and polycystic ovaries (with exclusion of other etiology).5

Etiology Polycystic ovary syndrome is a disease for which the exact mechanism of pathogenesis is unknown, however, several possible mechanisms have been proposed. Insulin resistance is a common feature of PCOS and is implicated in causal relationships with major metabolic and reproductive morbidities.6 Insulin resistance can lead to increased production of insulin and resulting hyperinsulinemia may lead to increased androgen production in the adrenal glands and ovaries.4,6 However, androgens themselves might be implicated in producing or enhancing insulin resistance in women by impairing glucose utilization in muscle and adipose tissue.6 Additionally, various genetic markers for PCOS have been studied and 1

Albany College of Pharmacy and Health Sciences, Albany, New York

Corresponding Author: Kristin Nadine Whitaker Email: [email protected]

Whitaker polymorphisms of the insulin receptor have been implicated in women with PCOS as a potential cause for increasing levels of fasting insulin, contributing to insulin resistance, and the development of PCOS.6,24 Overall, the implications of insulin resistance in women with PCOS are such that there is a higher incidence of obesity and metabolic syndrome compounded by hyperandrogenism.4,6,7,20,25 A related mechanism of hormonal dysfunction in PCOS is that of malfunction in lutenizing hormone (LH) and folliclestimulating hormone (FSH) production and regulation.6,19 Normally, gonadotropin-releasing hormone (GnRH) is responsible for regulating the release of LH by way of pulsation frequency.19 As the frequency of pulse of GnRH increases, LH is preferentially produced.19 Progesterone plays an important role in regulating LH as well when increased production of progesterone by the corpus luteum slows LH production in favor of FSH production.19 Women with PCOS seem to have comparatively higher LH pulsation and elevated LH:FSH ratios, thus causing increased stimulation of theca cells in the ovaries to synthesize more androgens.6,19 The reduced impact of FSH prevents conversion of this excess androgen to estradiol, thus causing the clinical manifestations of hyperandrogenism.6,19

Review of Symptoms Polycystic ovary syndrome is often considered multifactorial in nature and women with the disease often have multisystem involvement with regard to clinical symptoms.3,4,6,20 As shown in Appendix A, symptoms are widespread and highly varied; this variation is due largely to the effects of insulin resistance and common comorbid obesity/metabolic syndrome and presence of hyperandrogenism.4,5,6-19,20 Women with PCOS have been shown to be at increased risk of developing type 2 diabetes.6,15,20,25 Metabolic symptoms linked to insulin resistance include increased waist circumference (and increased weight-to-height ratio), impaired glucose tolerance or elevated blood glucose, acanthosis nigricans, elevated insulin levels (which can lead to increased sodium and fluid retention), dyslipidemia (including elevation in triglycerides), and promotion of excess androgen production. The metabolic complications of PCOS are further complicated by the increased percentages of women who present with both PCOS and comorbid obesity— these women are at an even greater risk of developing type 2 diabetes and cardiovascular complications due to the prevalence of clinical metabolic syndrome.4,9,10,25 Although there is no direct evidence suggesting an increase in adverse cardiovascular events associated with PCOS, it should be noted that several studies have shown evidence of an increase in the prevalence of surrogate markers of cardiovascular dysfunction (like hypertension and dyslipidemia) in women with PCOS, further demonstrating the need to monitor and treat signs and symptoms of metabolic complications in order to reduce this risk.4,6,8-10 Additionally, other primary symptoms related to reproductive dysfunction including oligo- and amenorrhea,4,5 infertility,4,5 increased risk of endometrial cancer,26 and androgen excess (among other potential hormonal imbalances).

95 Anovulation and infertility are characteristics that are also interrelated to other signs of androgen excess that include hirsutism, acne, enlarged clitoris, androgenic alopecia, and decreased breast size.4,5 Complex emotional symptoms that include depression and anxiety are often noted in women with PCOS as well and have been linked to the presence of other symptoms of the disease.11-14

Diagnosis The diagnosis of PCOS is based on several criteria as demonstrated by the Rotterdam Diagnostic Criteria for PCOS.5 Patients must present with at least 2 of the following of oligoand/or anovulation, clinical and/or biochemical signs of hyperandrogenism, and polycystic ovaries. It should also be noted that a differential diagnosis is often required to eliminate other rare, but serious causes of hormonal dysfunction in women such as Cushing’s syndrome and androgen secreting tumors.4 Several physical and laboratory measures can be used to provide diagnosis of ovarian and hormonal dysfunction in women as well as provide evidence of metabolic complications of the disease.4 These include, but are not limited to evaluation for the presence of hallmark symptoms of PCOS (evidence of hyperandrogenism and insulin resistance) and laboratory testing to determine the presence of excessive androgens and potential lipid and glucose abnormalities.4 While the lipid and glucose abnormality testing is not required for diagnosis, it is an important screening tool because of the associated risk of metabolic complications in women with PCOS.4 Other examinations that are also useful in monitoring obesity are also advisable in patients with PCOS and include blood pressure, weight, and waist-to-height ratio.4,5 Screening for polycystic ovaries and ovary morphology can also be used to track problematic changes associated with ovulation and to monitor progression on ovulation-stimulating medications.4 A complete history should also be obtained for each patient that includes a detailed outline of current symptoms, medical conditions, family history of related illness, and medication utility.4,5 This allows for risk assessment in women who have a family history of diabetes, cardiovascular disease, and reproductive abnormalities and can be helpful in establishing adequate treatment regimens to reduce this risk.

Treatment Nonpharmacological Treatment Exercise and weight management have been shown to produce an array of benefits in women with PCOS that include but are not limited to a reduction in risk for type 2 diabetes, cardiovascular disease, decrease in excess androgen, and improvement in quality of life.20,22,27-34 One of the most successful treatments in managing the metabolic complications associated with PCOS is a moderate exercise regimen.27,28 Moderate weight loss, even in the absence of significant weight loss has been shown to improve lipoprotein profiles in women with PCOS27 and 3-month structured exercise programs have demonstrated

96 cardiopulmonary functional capacity improvements as well.28 This reduction in cardiovascular risk, and in offsetting the problematic metabolic changes that can lead to metabolic syndrome and type 2 diabetes in women with PCOS is important.27 Exercise of at least moderate intensity should be encouraged.27 Similarly, dietary modification to improve weight loss also has been shown to improve outcomes in women with PCOS.31-34 Short-term meal replacements and reduced caloric consumption are dietary interventions that have been effective in reducing weight in addition to bariatric surgery which has proven to reduce symptoms and clinical signs of PCOS in morbidly obese patients.31,32,34 It is recommended that women with PCOS be routinely screened for diabetes mellitus through the use of impaired glucose tolerance testing, and 2-hour glucose tolerance testing, as this will aid in monitoring for complications of PCOS and for progress in weight management.29

Pharmacological Therapy Pharmacological therapies for PCOS are directed at reducing the clinical signs and symptoms of hyperandrogenism and insulin resistance as well as in restoring normal menstrual patterns and ovulation. Though there are not currently any indicated medications for the treatment of PCOS, each of the following are treatments currently utilized in PCOS patient care and are further discussed here. Additionally, a treatment chart has been provided to outline a stepwise procedure for implementation of treatments in patients with PCOS in Appendix B. Metformin. Metformin is a biguanide and is used to improve glucose tolerance. Its primary mechanism of action is related to the increased peripheral uptake of glucose, and the associated decrease in the amount of hepatic glucose production.35 Overall, there is a reduced need for insulin in the body and in insulin production.35 As a result of this effect on glucose and insulin, metformin is useful in PCOS because of further effects of decreasing insulin production on decreased androgen production.6,36 This medication has been shown to improve glucose tolerance and metabolic status as well as in having been shown to restore ovulation and menstrual regularity both as a singular therapy and in combination with other therapies.36-45 Thiazolidinediones. Rosiglitazone and pioglitazone have been used in patients with PCOS in an effort to increase insulin sensitivity and improve menstrual regularity and ovulation.46,47 Improvements in insulin action46 as well as improvements in insulin secretion and lipoprotein levels when combined with metformin have been demonstrated with thiazolidinediones.47 Clomiphene citrate. Clomiphene citrate is a selective-estrogen reuptake modulator that is FDA indicated for the treatment of infertility. It acts as a competitive antagonist of estradiol in nuclear receptors in the hypothalamus causing an increase in the production of GnRH.48 An increase in pituitary sensitivity to GnRH follows and the overall resulting effect is an increase in FSH and LH secretion which stimulates ovarian follicular

Journal of Pharmacy Practice 24(1) development and ovulation.48 One of the major indicators of success with clomiphene citrate is the patient’s body mass index (BMI); increasing BMI has been associated with increased clomiphene citrate resistance, further demonstrating the importance of weight management in the PCOS patient population.49,50 Clomiphene citrate usage in patients with PCOS induces similar rates of pregnancy and miscarriage to that of the normal population of women and when compared to metformin, clomiphene citrate causes a higher incidence of live births with slightly greater incidence of multiple births.51,52 Medroxyprogesterone acetate. Medroxyprogesterone acetate is a synthetic progestin that is indicated to treat secondary amenorrhea. This medication suppresses the mid-cycle surge of LH, which prevents follicular maturation and ovulation. Additionally, it slows the frequency of release of GnRH and induces progestin withdrawal bleeding about 3 to 7 days after discontinuation in patients with amenorrhea, thus allowing for restoration of normalized menstrual flow in some patients.52 Additionally, medroxyprogesterone acetate has been shown to help improve insulin sensitivity in patients with PCOS.53 Drospirenone and ethinyl estradiol. Drospirenone and ethinyl estradiol is available as a combination oral contraceptive and can be used in patients with PCOS to alleviate signs and symptoms of the disease.54 Drospirenone is an analog of spironolactone and has antimineralocorticoid properties. Drospirenone can inhibit testosterone production in the body including what is produced by the ovaries and adrenal glands. In women with PCOS, this combination causes satisfactory menstrual cycle control, and improved hirsutism over time.54 Additional effects of drospirenone and ethinyl estradiol on PCOS include (1) body weight maintenance, (2) steady fat distribution ratios, (3) steady blood pressure, (4) decreased levels of LH and testosterone, and (5) decreased free androgen index.54 Spironolactone. Spironolactone is a potassium-sparing diuretic that is used in PCOS to treat the effects of excessive androgen in women.44,55-58 Spironolactone inhibits the effects of aldosterone in the distal renal tubules and acts as an androgen receptor blocker interfering with steroid synthesis. Clinically, this medication has been used in patients with PCOS to effectively reduce androgen-mediated symptoms while restoring ovulation and menstrual flow.44,55-57 Elfornithine. Elfornithine is an irreversible inhibitor or ornithine decarboxylase that blocks skin ornithine decarboxylase and reduces hair growth. This medication can be used in women with PCOS to treat excessive facial hair by reducing the rate of growth.59

Pharmacist’s Role The pharmacist’s role in treating women with PCOS is crucial for positive outcomes in the disease. First and foremost, the pharmacist must be able to recognize the common features of the disease

Whitaker and be able to relay and translate patient information and complaints into an assessment and plan. It is the role of the pharmacist to assess potential treatment failures and adverse reactions and to make appropriate recommendations for change. Treatment can be modified and monitored by the pharmacist’s recommendations to achieve important clinical goals including diabetes and

97 cardiovascular risk reduction, reduction in hyperandrogenism and related side effects, and to restore normal menstruation and fertility. The primary goal of treatment should always be to increase quality of life and satisfaction in women with PCOS, and these women should be consistently encouraged to maintain healthy eating habits and active lifestyles to help achieve treatment goals.

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Appendix A Signs and Symptoms of Polycystic Ovary Syndrome2,4,5

Head

Metabolic Symptoms

• Headache

••Obesity

• Visual disturbances

••Increased waist circumference ••Increased neck size

Cardiovascular System

••Impaired glucose tolerance

• Hypertension

••Type 2 diabetes

• Chest pain

••Gestational diabetes

• Shortness of breath

••Dyslipidemia and CVD

• Exertional dyspnea

••Increase in fatigue

• Exercise intolerance

••Temperature intolerance

• Ankle swelling Hyperandrogogenism ••Hirutism Reproductive System

••Acne

•Oligomenorrhea •

••Androgenic alopecia

• •Amenorrhea

••Male pattern baldness

• •Dysfunctional uterine bleeding

••Decreased breast size ••Enlarged clitoris

• •Infertility • •Miscarriage

Skin ••Dry skin, brittle hair and nails ••Hyperpigmentation (armpit, neck, under breasts)

Whitaker

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Appendix B Stepwise Approach to Treatment for Polycystic Ovary Syndrome4,5,20

Declaration of Conflicting Interests The author(s) declared no potential conflicts of interests with respect to the authorship and/or publication of this article.

Funding The author(s) received no financial support for the research and/or authorship of this article.

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