The challenge of comorbidity in polycystic ovary syndrome

Vol. 6, No. 3 / August 2008

PCOS

The challenge of comorbidity in polycystic ovary syndrome

KEY POINTS

PCOS diagnosis generally includes irregular or absent ovulation, elevated levels of androgenic hormones, and imaging evidence of polycystic ovaries.

Evidence exists that insulin promotes ovarian androgen production in PCOS, but the exact mechanism remains unclear.

Treatment for PCOS is directed at ameliorating hirsutism and acne, regulating the menstrual cycle, and achieving fertility when desired.

Monitoring patients with PCOS for glucose intolerance and diabetes is critical.

PonJola Coney, MD

Professor of Obstetrics and Gynecology, Virginia Commonwealth University School of Medicine, Richmond, Virginia

Dr Coney reports no commercial or financial interests or other relationships with any company that provides medically related services.

The metabolic and endocrine dysfunctions that may occur with polycystic ovary syndrome (PCOS) can be associated with future comorbidities such as diabetes, cardiovascular disease, and endometrial cancer. Although a definitive link between PCOS and these chronic illnesses has not been demonstrated, there is significant overlap in the clinical characteristics of these disorders. Consequently, the issue of identifying and measuring potential conditions that may be associated with PCOS is a priority and should be the standard of practice in its management. The context of this article is a review of the current opinions and recommendations in 2 clinical areas: diagnosis and management of PCOS and possible comorbidities.

Shifting focus in research

PCOS is the most common endocrine disorder in reproductive-aged women.¹ Over the past few decades, research and study of this enigmatic endocrinopathy has yielded significant strides in elucidating its underlying pathophysiology. Current research has turned to developing strategic pharmacologic interventions, that attempt to impact the long-term disease risks believed to be associated with this disorder. However, treatment advances have not materialized and the need remains for novel, targeted treatments or new alternatives for understanding and controlling the underlying pathology and for modifying risk factors.

A precedent in diabetes management

The management of diabetes mellitus (DM) provides a precedent for the approach to PCOS. The management goals for both disorders are to eliminate and prevent exacerbations and morbidity. Unlike DM management, which focuses primarily on tight control of peripheral blood biomarkers (blood glucose and hemoglobin A1C levels) that are predictors of long-term morbidity, no biomarkers specific to PCOS exist. Instead, for PCOS we rely on biomarkers of metabolic and endocrinologic dysfunction, that may impact long-term risk. The ultimate goal is improved long-term outcomes, comparable to the DM management paradigm.

Diagnosis of PCOS: Criteria and limitations

A pattern of abnormalities observed in a multitude of studies gives rise to the diagnosis of PCOS. An analysis of common biochemical samples is routinely performed in an effort to confirm the diagnosis.

Is There a “Metabolic Syndrome”?

Currently, there is no consensus among investigators on the approach to the metabolic syndrome.^1-3 One school of thought issues caution in labeling this cluster of abnormalities as a syndrome, arguing primarily that there is no unifying underlying pathology that causes the symptoms. This group suggests that irrespective of a metabolic syndrome, anyone with major cardiovascular disease risk factors should be evaluated for other risk factors and treated accordingly; they state that no attempt should be made to focus treatment for the syndrome.^2,3

Proponents of the metabolic syndrome label maintain that it is a true syndrome, defined as a grouping of risk factors for cardiovascular disease and/or type 2 diabetes that is likely to have more than one cause.¹ The syndrome tends to be heterogeneous across racial and ethnic populations, is more common in men than in women, and increases in prevalence with age.¹

The diagnostic criteria for the metabolic syndrome make it possible to identify individuals who are insulin resistant using routine measures that are easily obtained in an office visit. These factors appear to predict risks of cardiovascular disease and diabetes, albeit with different sensitivity.

Why not use a simple approach to identify individuals who are free of cardiovascular disease but are at an increased risk? Having such information creates an opportunity to modify that risk through early intervention.

REFERENCES

1. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement. Circulation. 2005;112:2735–2752.

2. Carnethon MR, Loria CM, Hill JO, Sidney S, Savage PJ, Liu K. Coronary artery risk development in young adults study. Risk factors for the metabolic syndrome: The Coronary Artery Risk Development in Young Adults (CARDIA) study, 1985-2001. Diabetes Care. 2004;27:2707–2715.

3. Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome: time for a critical appraisal. Joint statement from the American Diabetes Association and the European Association for the study of diabetes. Diabetologia. 2005;48:1684–1699.

In terms of PCOS, this approach is far from ideal. First, it perpetuates the confusion from researcher to clinician in the authenticity of the diagnosis of PCOS. Additionally, the heterogeneity of this disorder has not lent, to date, a reliable phenotype for unequivocal diagnostic credibility and consequent evaluation of long-term risk of morbidity and mortality.

Currently, clinical diagnosis of PCOS is based on several criteria recommended by the National Institutes of Health (NIH), the Rotterdam Group, and the Androgen Excess Society (TABLE 1).^2-5 Generally, the criteria include:

Irregular or absent ovulation
Elevated levels of androgenic hormones
Imaging evidence of polycystic ovaries (not included in NIH guidelines)

All 3 groups agree on the exclusion of related disorders of hyperandrogenemia before the diagnosis of PCOS is made final. None of these criteria take into consideration the broad implication for possible comorbidity in the PCOS patient and, hence, contribute to the dilemma of determining appropriate management for these patients.

Reappraisal of the initial recommendations by the Rotterdam Group, in association with the American Society for Reproductive Medicine, resulted in the release of updated recommendations for the diagnosis of PCOS in 2005. The revisions were made in hopes of diagnosing women who suffer the consequences of PCOS but may not demonstrate all the clinical features. The central theme of the Rotterdam Group’s 2005 recommendations is as follows: “To be diagnosed with PCOS by the Rotterdam criteria, a woman must have 2 of the following 3 manifestations: Irregular or absent ovulation, elevated levels of androgenic hormones, and/or enlarged ovaries containing at least 12 follicles each. Although the cardinal features of PCOS are hyperandrogenism and polycystic ovary morphology, no single criterion is sufficient for clinical diagnosis. Other clinical manifestations may include obesity, insulin resistance, elevated serum luteinizing hormone (LH) levels, and increased risk of type 2 diabetes, cardiovascular events, and endometrial cancer.”⁴

TABLE 1

PCOS Diagnostic Criteria

Entity	Recommended Criteria	Year
NIH/NICHHD Panel on PCOS²	• Hyperandrogenemia • Oligo-ovulation	1990
Rotterdam Group³	• Clinical and/or biochemical signs of hyperandrogenism • Oligo- or anovulation • Polycystic ovaries	2004
Rotterdam Group⁴	2 of the following 3 factors: • Irregular or absent ovulation • Elevated levels of androgenic hormones • Enlarged ovaries containing at least 12 follicles each	2005
Androgen Excess Society⁵	4 features that comprise the 9 PCOS phenotypes: • Hirsutism • Hyperandrogenemia • Oligoanovulation • Polycystic ovaries	2006
NIH/NICHHD, National Institutes of Health/National Institute of Child Health and Human Development; PCOS, polycystic ovary syndrome.

Baseline comorbidities in PCOS

The frequent presence of factors such as insulin resistance and hyperinsulinemia, metabolic syndrome, and obesity in PCOS have been predicted to place these patients at high risk of diabetes, cardiovascular disease, and endometrial cancer. These comorbidities occupy a central feature of the diagnosis and management of PCOS, although an increase in risk of these disorders due to PCOS remains unproven. Additionally, the prevalent combination of PCOS and obesity pose challenges for successful pregnancy.

Insulin resistance and hyperinsulinemia

Insulin resistance and hyperinsulinemia are often (but not always) increased in patients with PCOS.^6,7 However, not all women with insulin resistance and hyperinsulinemia develop PCOS, nor are all women with PCOS insulin resistant and hyperinsulinemic. Ongoing research seeks to clarify the role of insulin in PCOS. PCOS is known to be a function of insulin resistance, and insulin resistance is prevalent in the pathophysiology of PCOS. Increased testosterone secretion by ovaries with at least normal insulin sensitivity is seen secondary to higher circulating insulin levels in these patients. Evidence exists that insulin promotes ovarian androgen production in PCOS, but the exact mechanism remains unclear.⁷ Further evidence for the central role of insulin comes from observations that treatment with metformin is effective in PCOS.^8,9

As reported by Dunaif et al, women with PCOS have significant insulin resistance that is independent of obesity, changes in body composition, and impairment of glucose tolerance.⁶ Insulin resistance is independent of the “metabolic syndrome” that is often described in PCOS. It is not a disease unto itself, but it is an abnormality that increases the risk of dyslipidemia, hypertension, and diabetes mellitus, with equivalent risk of subsequent coronary heart disease.^10,11 Therefore, insulin resistance is a treatable precursor of diabetes and, possibly, cardiovascular disease.

Consequently, the chance of developing several closely related abnormalities and associated clinical syndromes might be greatly increased in PCOS patients who have insulin resistance and/or hyperinsulinemia.¹⁰

Metabolic syndrome

The term “metabolic syndrome” describes a cluster of metabolic risk factors for cardiovascular disease and diabetes.^10-12 The risk factors are dyslipidemia, elevated blood pressure, elevated plasma glucose, abdominal obesity, and associated prothrombotic and proinflammatory states (TABLE 2).^13,14

The presence of this syndrome is reportedly observed in up to 20% of patients with PCOS.¹⁵ The metabolic syndrome is accompanied by a 2-fold increased risk of cardiovascular disease and a 5- to 10-fold increased risk of type 2 diabetes.^16,17 Clinicians should be aware of the metabolic syndrome, screen for it, and treat it aggressively (TABLE 3).¹⁸ Interventions of dietary, behavioral, and lifestyle modifications have been shown to decrease progression to full-blown diabetes and decrease the lifelong risk of cardiovascular disease.^19,20 In this case scenario, early interventions should provide the greatest benefit to patients.

TABLE 2

Diagnostic Criteria for the Metabolic Syndrome

WHO (1999)	NCEP ATP III (2001)
Insulin resistance,^a as identified by 1 of the following: • Hyperinsulinemia (fasting insulin level ≥75th percentile) • Type 2 diabetes • Impaired fasting glucose • Impaired glucose	3 or more of the following: • Waist circumference ≥88 cm (for women) Triglycerides ≥150 mg/dL • HDL <50 mg/dL (for women) • Blood pressure ≥130/85 mm Hg and/or pharmacologic treatment • Fasting plasma glucose ≥110 mg/dL
Plus 2 or more of the following: • Blood pressure ≥140/90 mm Hg • Triglycerides ≥150 mg/dL • HDL <39 mg/dL (for women) • BMI >30 kg/m² and/or waist-hip ratio >0.85 (for women) • Urinary albumin-creatinine ratio >30 mg/g
BMI, body mass index; HDL, high-density lipoprotein; NCEP ATP, National Cholesterol Education Program-Adult Treatment Panel; WHO, World Health Organization.
^aClamp-assessed glucose uptake < 25th percentile
WHO. Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications: Report of a WHO Consulation. Geneva, Switzerland: WHO; 1999. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2467.

TABLE 3

Insulin Resistance Syndrome: Diagnostic Criteria^a

Risk Factor

• BMI ≥25 kg/m²
• Triglycerides ≥150 mg/dL
• Blood pressure ≥130/85 mm Hg
• 2-hr post 75 g glucose challenge >140 mg/dL
• Fasting glucose: 110-126 mg/dL

BMI, body mass index; ^a American Association of Clinical Endocrinologists Consensus Conference. Bloomgarden ZT. Diabetes Care. 2003;26:1297-1303.

Endometrial cancer

Several studies support an association between PCOS and an increased risk or incidence of endometrial cancer, but no definitive link between the 2 has been found.^21,22 This perception is derived from the known mechanism of chronic anovulation and/or continuous estrogen stimulation of the endometrium unopposed by progesterone, a major risk factor for endometrial cancer.

The role of obesity, hyperinsulinemia, and hyperandrogenemia in endometrial cancer is unclear. It is standard practice to prescribe hormonal treatment to reduce this risk, in the form of combination hormonal contraceptive agents (pills, patches, rings) or cyclic progesterone therapy.

Obesity and infertility

Women with PCOS and infertility pose significant challenges. Obesity is very common among patients with PCOS and adversely affects ovulation. Because of the resistance of obesity to pharmacologic ovulation induction, such treatment often fails. In addition, the miscarriage and prematurity rates are high.

Managing PCOS and comorbidities

For a patient with suspected PCOS, the first important step is an accurate diagnosis. Once diagnosed, evaluation for abdominal obesity, triglycerides, high-density lipoproteins, hypertension, and fasting and 2-hour glucose tolerance should be performed.^23,24

Treatment is directed at ameliorating hirsutism and acne, regulating the menstrual cycle, and achieving fertility when desired. Use of combination hormonal contraceptives is the mainstay of treatment for reduction of hyperandrogenemia and regulation of menstrual cycles in PCOS patients not desiring fertility. Counseling is critical in the management of PCOS patients to make them aware of the potential for harboring serious disease long term.

For the obese patient seeking pregnancy, counseling about lifestyle modifications is also an important management strategy. Patients should understand that achieving weight reduction will facilitate ovulation induction and reduce overall complications of pregnancy for the mother and fetus. Ovulation induction is the primary therapy for patients seeking pregnancy. First-line therapy should include clomiphene citrate, followed by exogenous gonadotropins; in vitro fertilization is a last resort.

Monitoring patients with PCOS for glucose intolerance and diabetes is critical.^23,24 It has been demonstrated that hyperinsulinemia may be a key component in the pathogenesis of PCOS, so insulin sensitizers have been considered in the routine management of PCOS. Insulin resistance is a treatable precursor of diabetes and, potentially, of cardiovascular disease as well. However, evidence for nonglycemic benefits is insufficient to recommend insulin sensitizers routinely in the management of PCOS. Therefore, use of metformin in PCOS should be restricted to cases of glucose intolerance. Whether administered to obese or lean subjects with type 2 diabetes, metformin appears to reduce fasting glucose concentrations, as well as improve oral glucose tolerance with a modest reduction of plasma insulin levels.^11,25 It does not improve insulin-mediated glucose disposal by muscle and adipose tissue.^11,25

Looking toward the future

The current approaches to the diagnosis and management of the PCOS patient are far from ideal. Diagnostic criteria for initial screening fall woefully short in providing a method to identify patients who will benefit most from intensive surveillance and intervention.

There remains an essential need to find relevant biomarkers for PCOS. An ideal biomarker would identify a specific biologic state that is relevant to this disease process, provide additional information beyond what is known from conventional clinical factors, and account for a large proportion of the risk associated with PCOS. Such a biomarker would be most useful in PCOS for identification of at-risk individuals, surveillance of events that precede the condition, diagnosis, and prognosis. There is still much research to be done toward definition and clarification of PCOS, comorbidity, and risks to health.

REFERENCES

1. Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab. 2004;89:2745–2749.