Clinical Evaluation of Polycystic Ovary Syndrome (PCOS)
The history should include a detailed inquiry about growth and sexual development, menarche, and menstrual pattern, as well as information to exclude other potential causes of oligomenorrhea, hirsutism, acne, and infertility. Physical findings of acanthosis nigricans and a hyperpigmented area on the nape of the neck or other areas such as the axillae or groin are suggestive of insulin resistance. Measurements of blood pressure, body mass index (BMI), and waist circumference must be made. Defining the extent of hirsutism and the degree of acne or alopecia is also essential.
Laboratory Assessment of Possible PCOS
No consensus exists among endocrinologists about the battery of laboratory tests that must be ordered in the assessment of women for PCOS. The following are the most commonly ordered laboratory tests, which are meant both to confirm the clinical diagnosis of PCOS and to evaluate for glucose intolerance and cardiovascular risk. Studies should be performed early in the morning, with the patient in a fasting state, and, in women with regular menses, sometime between days 5 and 9 of the menstrual cycle.
- Several determinations of total and free testosterone levels or a free androgen index performed by a competent laboratory will help assess the status of androgens.
- Serum levels of luteinizing hormone and follicle-stimulating hormone can be determined. An increased ratio of luteinizing hormone to follicle-stimulating hormone >2 is found in 60 to 70% of women with PCOS and is more likely to occur in nonobese than in obese women.
- Measurement of serum sex hormone-binding globulin may reveal decreased levels in patients with PCOS.
- Measurements of serum prolactin, dehydroepiandrosterone sulfate, and 17alpha-hydroxyprogesterone will provide useful information.
- A lipid profile can be obtained, including serum high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol and triglycerides.
- Plasma insulin may be measured; clinicians should remember that methodologic inconsistencies occur and that insulin levels are not necessary for the diagnosis of the insulin resistance syndrome (IRS).
- The American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE) recommend screening for diabetes by age 30 years in all patients with PCOS, including obese and nonobese women. The risk for diabetes is further heightened by a family history of diabetes, a personal history of gestational diabetes, and obesity, sedentary behavior, and ethnicity. Determination of a blood glucose level after challenge with a 75-gram load of glucose may be performed. The usefulness of measuring insulin levels at baseline and 2 hours after administration of glucose is under study. Under some circumstances, earlier testing before the age of 30 years may be indicated. Because type 2 diabetes mellitus (T2DM) evolves over time, women with PCOS who initially test negative for diabetes should be periodically reassessed throughout their lifetime.
- Pelvic ultrasonography, although nonspecific, affords a pretreatment view of the ovaries. The effect of treatment of PCOS can be monitored, in part, by noting ovarian size, follicle number, endometrial lining, and possible development of benign ovarian dermoids or other neoplasms (incidence of approximately 5 to 10%). The finding of morphologic evidence of polycystic ovaries on pelvic ultrasonography in 23% of apparently normal women limits its specificity in the diagnosis of PCOS. Several other endocrine pathologic conditions may mimic the ovarian morphologic appearance in PCOS. Thus, a history of oligomenorrhea and evidence of ovarian hyperandrogenism are key elements in defining PCOS.
Summary and Synthesis of Data on Cardiovascular Risk
In summary, several lines of evidence strongly support the concept that women with PCOS are at high risk for cardiovascular and metabolic disease.
- The prevalences of both T2DM, a myocardial infarction-equivalent state, and impaired glucose tolerance (IGT), a condition associated with increased cardiovascular risk, are substantially increased in patients with PCOS. Accordingly, AACE and ACE recommend screening for diabetes in all patients with PCOS by age 30 years.
- Multiple recognized cardiovascular risk factors are present in excess in women with PCOS (often several simultaneously). The result is a higher-than-usual prevalence of the Adult Treatment Panel III- and AACE-defined metabolic insulin resistance syndrome (IRS) in patients with PCOS.
- Imaging studies in women with PCOS have uniformly identified a higher prevalence of anatomic and functional abnormalities indicative of existing underlying cardiovascular disease or dysfunction in comparison with findings in age-matched control subjects.
These observations are remarkable for their abundance, uniformity, and consistency, and they predict an increased risk for adverse cardiovascular events in patients with PCOS. To date, however, no prospective longitudinal study has assessed cardiovascular outcomes specifically in women with PCOS. Nonetheless, it is notable that a prospective large-scale study of women with oligomenorrhea who underwent follow-up for 1-1/2 decades reported a 2-fold increased risk for fatal myocardial infarction in this population. Most likely, a large proportion of these women had PCOS. Hence, this study provides indirect confirmation of increased adverse cardiovascular outcomes in patients with PCOS.
Despite the absence of prospective longitudinal studies, retrospective epidemiologic studies have been performed to assess cardiovascular outcomes in PCOS. Unfortunately, these studies have been of variable quality, and they have differed from one another with respect to diagnostic criteria, anthropometric and phenotypic characteristics, duration of follow-up, therapeutic intervention with bilateral wedge resection of the ovaries, and other factors. Nonetheless, most of these studies have confirmed an increased risk for adverse cardiovascular outcomes in patients with PCOS.
Collectively, the foregoing substantive evidence indicates that women with PCOS are at high risk for cardiovascular disease (CVD). Even in the absence of definitive outcome studies, the evidence supports a strong recommendation that women with PCOS should undergo comprehensive evaluation for recognized cardiovascular risk factors and receive appropriate treatment based on findings.
Treatment of PCOS
Well-defined published data indicate a high risk for development of T2DM and CVD in women with PCOS. In view of the lack of protective effect of female sex on CVD risk in patients with diabetes, the associated risks of CVD are magnified in women with diabetes who have PCOS. Clearly, this situation means that PCOS is a general health disorder of young women, with potential for reversal of some of the associated risk with early diagnosis and treatment. Lifestyle modification with weight loss and exercise, avoidance of tobacco, correction of lipid abnormalities, and use of metformin may be of value. Metformin therapy not only reduces hyperinsulinism and improves steroidogenic dysfunction but also is helpful in achieving better regularity of menses and fertility potential. Thiazolidinediones have also been shown to decrease androgen levels, improve ovulation, and reduce progression to overt T2DM in patients with PCOS and IGT.
In view of the potential for and actual presence of numerous cardiovascular and metabolic risk factors in most women with PCOS, the role of the clinical endocrinologist is essential in the following:
- Early recognition of the syndrome.
- Lifestyle modification, with emphasis on the need for controlled eating patterns and regular aerobic exercise. Encouragement should be offered by an empathic physician, who will monitor the patient carefully during the course of treatment.
- Measurement of glucose (and possibly insulin levels). An oral glucose challenge may be considered, particularly in obese women with PCOS and those with a family history of T2DM.
- Detection and treatment of lipid abnormalities, with dietary measures first and then use of appropriate medications, such as a statin, fibrate, niacin, or ezetimibe (or some combination of these agents), as necessary.
- Careful attention to and treatment of blood pressure abnormalities.
- Measurement of atherogenic markers (C-reactive protein [CRP], fibrinogen, and possibly homocysteine).
- Consideration of metformin therapy as the initial intervention in most women with PCOS, particularly in those who are overweight or obese. Metformin improves many metabolic abnormalities in PCOS and may improve menstrual cyclicity and the potential for pregnancy. Of note, metformin has not been approved by the US Food and Drug Administration for use in PCOS, although abundant medical literature supports its efficacy.
- The use of a nonandrogenic oral contraceptive agent and an antiandrogen such as spironolactone for the skin manifestations of PCOS. The presence of hair thinning requires the maximal dose of spironolactone in conjunction with an oral contraceptive agent. Ancillary use of electrolysis and laser therapy may also be helpful.
- The use of thiazolidinediones in patients with impaired glucose tolerance or frank diabetes. The use of these agents to improve hyperandrogenism and ovulation is considered only investigational at this time. Thiazolidinediones are category C drugs; their use is contraindicated during pregnancy.
