Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age.1 It is characterized by menstrual and ovulatory abnormalities, excess androgens and often the presence of cystic ovaries.2 Despite its relative commonality, PCOS can be considered a daunting diagnosis for providers as well as patients. Due to complications of the syndrome, particularly infertility and associated comorbidities, the recognition and appropriate management of PCOS should be of concern to every NP and PA who treats women who have not reached menopause.
Background
Approximately 5% to 10% of women throughout the world are affected by PCOS.3 The syndrome is the most common cause of infertility and androgen excess, and it typically is associated with some form of ovulatory dysfunction, hyperandrogenism and polycystic-appearing ovaries.4,5 In addition to the clinical findings, patients with PCOS are at increased risk for developing serious comorbidities including diabetes mellitus, cardiovascular disease and metabolic syndrome.2
PCOS is considered a diagnosis of exclusion, and clinicians must have a working knowledge of potential differential diagnoses in order to properly identify the syndrome.3 Provider competency results in a more timely diagnosis and ensures proper patient management.
Etiology
The underlying etiology of PCOS is unknown, but strong evidence supports the possibility of a genetic component in disease development. Familial clustering of the disorder and noted inheritance of hyperandrogenemia and hyperinsulinemia (common findings in PCOS) strongly indicate a possible hereditary influence. Environmental risk factors such as obesity may also play a role, supporting the hypothesis that genetics and environment may be interconnected.3,5
Pathogenesis
Most women with PCOS have an abnormality in gonadotropin stimulation that results in an increase in the ratio of luteinizing hormone to follicle-stimulating hormone (LH:FSH ratio), a characteristic laboratory finding in PCOS.3,6 As a consequence of this increase, the ovaries produce excessive testosterone that leads to the clinical manifestations of hyperandrogenism.
The gonadotropin abnormality causes the affected woman to produce a weakened form of estrogen, resulting in positive feedback-induced LH production. This increased LH stimulation contributes to the development of cysts, anovulation and ovarian theca cell hyperplasia. Hyperplasia stimulates further androgen production, which perpetuates the situation.3 In women with PCOS, the obesity that often results from excessive androgenesis effectively decreases levels of sex-binding hormones, allowing more of them to circulate freely.7 Essentially, the syndrome and its manifestations arise from a cascade of uncontrolled hormonal irregularities.
If these hormonal imbalances are not treated, ovulatory abnormalities such as infertility, menstrual variations and manifestations of hyperandrogenism such as hirsutism develop. Additionally, affected women are at increased risk for developing endometrial cancer as a direct result of unopposed estrogen stimulation.3
Clinical Presentation
It is important for NPs and PAs to have a proficient understanding of the common signs, symptoms and presentations of PCOS. Because the condition is so common in women of reproductive age, patients with PCOS are likely to present to family practice, pediatric, women's health or endocrinology settings at any time.
The clinical picture of PCOS can vary dramatically from patient to patient. A majority of the manifestations are a direct result of the underlying hyperandrogenism. One of the most common features of PCOS is hirsutism (excessive hair on the face, chin and pubis), and it occurs in approximately 50% of cases.3 In addition to hirsutism, patients may present with male-pattern alopecia or acne.7 These signs of virilization occur in approximately 20% of affected patients.3
Menstrual and ovulatory irregularities are other common manifestations of PCOS. Patients typically present for evaluation of oligomenorrhea or amenorrhea (50% of cases), abnormal uterine bleeding (30%) or inability to become pregnant.3 Infertility is one of the hallmark findings of PCOS, and it is one of the most distressing symptoms for the patient.7 It results from sporadic or inadequate ovulation. Menstrual abnormalities may often be overlooked, since patients with PCOS have usually experienced irregular bleeding since puberty and they have come to consider their inconsistent patterns normal.7 NPs and PAs can avoid this oversight by taking a good menstrual history and evaluating patients who have clinical signs of an irregular bleeding cycle.
Polycystic ovaries may be present in patients with PCOS. Despite what the name of the condition implies, this is not always the case. In approximately 25% of women with the disease, the ovaries do not exhibit a characteristic polycystic appearance on ultrasound.7 In fact, polycystic ovaries are a relatively common ultrasound finding in all women of reproductive age.8
Therefore, the presence of cysts is not an absolute requirement for diagnosis and clinicians should initiate further work-up regardless of ultrasound findings if the clinical picture produces a high index of suspicion for PCOS.
Approximately half of patients with PCOS are obese. Obesity poses a health threat and should be of major concern to healthcare providers. In women who are obese, sex hormone-binding globulins are decreased and more sex hormones are allowed to freely circulate, leading to clinical manifestations. Furthermore, obesity is associated with both hyperlipidemia and insulin resistance, conditions that compound the patient's already increased clinical risk for cardiovascular disease and type 2 diabetes.
Insulin resistance is another common clinical feature of PCOS. This condition exacerbates androgen excess, negatively affects ovulation and increases diabetes risk.7 NPs and PAs should monitor lipid, insulin and blood sugar levels in patients with PCOS, since all may be elevated in the presence of the syndrome or its comorbid states.
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Assessment and Differential
Three entities have published diagnostic criteria for PCOS: the National Institutes of Health, the Androgen Excess and PCOS Society and the Rotterdam Consensus (Table 1).1,9,10 Regardless of which criteria are followed, exclusion of possible related disorders is imperative, making PCOS a diagnosis of exclusion. Some of the most common conditions considered in a diagnostic work-up include nonclassical congenital adrenal hyperplasia (NCAH), Cushing syndrome, thyroid disorders and hyperprolactinemia.1
NCAH is an autosomal recessive disorder that often presents with hirsutism, acne and menstrual irregularities.1 NCAH results from a deficiency of 21 hydroxylase, an enzyme in the adrenal cortex.2
To differentiate it from PCOS, obtain a measurement of the serum 17-hydroxyprogesterone level. The level is elevated (> 2 ng/mL) only in NCAH. Measurement of gonadotropin levels can also help distinguish PCOS from NCAH. For instance, levels of FSH are normal to low with PCOS, while LH levels are generally moderately elevated. With NCAH, both the FSH and LH levels are normal.11
In addition to NCAH, other less likely causes of androgen excess, such as Cushing syndrome, should be ruled out. This can be done through the measurement of serum cortisol levels. Conditions that could potentially lead to ovulatory dysfunction, such as thyroid disorders or hyperprolactinemia, should be considered and ruled out during a proper work-up. Measuring thyroid-stimulating hormone (TSH) and prolactin (PRL) levels can accomplish this goal.1,2
After feasible alternatives to PCOS have been explored, clinicians may choose to incorporate imaging studies such as ultrasound into the diagnostic workup. If cysts are present, ultrasound of the ovaries shows the characteristic "string of pearls" sign.12 However, the presence of cysts does not necessarily denote a diagnosis of PCOS. This finding is present in approximately 25% of healthy women.8
In summary, correctly diagnosing PCOS is an involved and methodical process. In addition to following accepted diagnostic criteria, clinicians must consider and definitively rule out disorders in the differential. This requires knowledge and understanding of the various processes that may cause similar symptoms, as well as the laboratory tests used to assess for them.
Associated Comorbidities
PCOS is associated with an increased risk for several serious comorbidities, most notably type 2 diabetes, cardiovascular disease (CVD) and metabolic syndrome. As previously mentioned, three common features of PCOS include hyperinsulinemia, glucose intolerance and obesity. The presence of these manifestations leads to an estimated two to five times greater increased risk for developing type 2 diabetes when compared to women without the condition.2 Patients diagnosed with PCOS should be evaluated for the potential presence of diabetes. A 2-hour oral glucose tolerance test or fasting glucose test can be performed for this diagnostic purpose.1
Cardiovascular disease is another commonly encountered comorbidity associated with PCOS. Patients with the syndrome often have many risk factors for CVD, including obesity, dyslipidemia, hypertension, glucose intolerance and diabetes.13
Any new or established patient with PCOS should be routinely screened for the presence of CVD. This can be done by obtaining a lipid profile and a fasting glucose level and by calculating the patient's body mass index.1,2
Finally, many women with PCOS also meet diagnostic criteria for metabolic syndrome: central obesity, hypertriglyceridemia, low HDL levels, hypertension and glucose intolerance or diabetes. Patients with metabolic syndrome are at an even higher risk for developing both diabetes mellitus and CVD.13 Every effort should be made to screen all patients with PCOS for each of these criteria and to adjust treatment regimens accordingly to reduce this risk.
Treatment
No cure for PCOS has been identified, so the condition should be treated symptomatically. Ideally, a unique treatment plan for each woman should be created and tailored to her particular symptomatology and personal wishes.14
Options are available for women with oligo-ovulation, anovulation or infertility who desire to become pregnant. The first-line treatment for inducing ovulation is clomiphene citrate, an anti-estrogen drug.2 By increasing the availability of FSH, clomiphene induces ovulation in approximately 75% to 80% of patients.15
An alternative to clomiphene for the purpose of ovulation induction is the use of the oral hypoglycemic drug metformin. Metformin can produce an increase in both menstrual cyclicity and ovulation rates. It is believed that reducing insulin levels along with altering insulin's effect on ovarian androgen synthesis and theca cell proliferation allows a return to an ovulatory state.
In addition to metformin's ovulation effects, the drug has other positive therapeutic potential. It has significant effects on glucose intolerance and hyperinsulinemia and can thus help reduce a patient's risk for type 2 diabetes. Metformin may also help patients lose weight, which can have positive effects on many obesity-induced symptoms.
Furthermore, metformin has the ability to reduce circulating androgen levels by inhibiting ovarian gluconeogenesis and androgen synthesis.15,16 Due to metformin's multifaceted therapeutic profile and ability to target multiple symptoms of PCOS, NPs and PAs may consider using the drug as first-line therapy.
Women with PCOS who experience menstrual irregularities and do not wish to conceive can manage symptoms using oral contraceptives (OCs). Combination low-dose OCs are a common first-line treatment and can be used for long-term management.2
Prescribing OCs for a patient who does not wish to conceive serves multiple purposes. It manages various manifestations of the condition and it offers endometrial protection from unopposed estrogen stimulation. In particular, this protection lowers the patient's risk for developing endometrial cancer in the future.
In addition to regulating a patient's menstrual cycle and providing contraception, these drugs can also play a role in the treatment of androgen excess. By suppressing LH secretion and increasing synthesis of sex hormone binding globulins, OCs effectively lower androgen levels and provide relief from hirsutism and acne.16 Clinical decision making about an OC depends on the symptoms the patient is experiencing and her desire to conceive.
Aside from pharmacologic therapy, clinicians should encourage incorporation of lifestyle changes such as weight loss through diet and exercise as an integral part of the treatment regimen. Obesity is overwhelmingly common with PCOS, and being overweight can worsen symptoms and impart higher risk for the development of serious comorbid conditions.
Weight reduction can improve reproductive symptoms, androgen excess symptoms, insulin resistance and metabolic abnormalities.17 For instance, it is possible that with weight reduction alone, patients can potentially resume regular ovulation and thus improve infertility.6 Furthermore, diet and exercise can significantly lower a patient's risk for developing diabetes and cardiovascular disease.2,17
It is important for NPs and PAs to realize the overwhelmingly positive effects of lifestyle management on almost all aspects of PCOS. Adequate time should be spent counseling, encouraging and supporting patients to adopt these changes for the benefit of their overall health.
Multifaceted Condition
PCOS is a multifaceted and complex health condition that requires adequate understanding in order to provide proper management.
NPs and PAs responsible for the care of women in their reproductive years should familiarize themselves with the clinical picture of PCOS. Correctly identifying, diagnosing and treating the condition can provide significant relief for the patient. Most importantly, continued management of the patient will help lower her risk of developing serious comorbidities and thus improve her quality of life for years to come. â–
References
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3. McPhee SJ, Papadakis M. Polycystic ovarian syndrome. In: Current Medical Diagnosis and Treatment 2010. 49th ed. McGraw-Hill Medical; 2009: 690.
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13. Lorenz LB, Wild RA. Polycystic ovarian syndrome: an evidence-based approach to evaluation and management of diabetes and cardiovascular risks for today's clinician. Clin Obstet Gynecol. 2007;50(1):226-243.
14. Legro RS. Polycystic ovary syndrome: current and future treatment paradigms. Amer J Obstet Gyn. 1998;179(6):S101-S108.
15. Badawy A, Elnashar A. Treatment options for polycystic ovary syndrome. Int J Womens Health. 2011;3:25-35.
16. Dronavalli S, Ehrmann DA. Pharmacologic therapy of polycystic ovary syndrome. Clin Obstet Gynecol. 2007;50(1):244-254.
17. Hoeger KM. Obesity and lifestyle management in polycystic ovary syndrome. Clin Obstet Gynecol. 2007;50(1):277-294.