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CASE STUDY

Initial Physical Exam
Height: 5 ft, 3 in
Weight: 197 lb
Body mass index (BMI):
34.8 kg/m2
Blood pressure (BP):
150/90 mm Hg
Waist circumference: 40 in
Alopecia
Cystic acne
A few hairs on chin and upper lip

Initial Laboratory Values
TC: 269 mg/dL
LDL-C: 191 mg/dL
HDL-C: 38 mg/dL
TG: 202 mg/dL
FBG: 102 mg/dL
TSH: 0.67μlU/mL
 

 


Female With Hyperlipidemia and PCOS

The following case was provided by NLEC Faculty Member Francine K. Welty, MD, PhD, Associate Professor of Medicine, Director of Preventive Cardiology and Nutrition Education, Harvard Medical School, and Director of Cardiovascular Care for Women, Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.

Disclosure Information for Dr Welty: Consultant: Pfizer Inc; Merck; Schering Plough; AstraZeneca. Speaker: Pfizer Inc; AstraZeneca.

CS, a 39-year-old female with a 6-year history of combined hyperlipidemia, was referred to a tertiary lipid clinic for treatment after developing side effects to gemfibrozil, atorvastatin, and colestipol. Her menstrual periods have been regular (28- to 32-day cycles). She reports thinning hair on her head but needing to shave hair on her abdomen. Multiple evaluations for abdominal pain included: a pelvic ultrasound at age 33, which revealed one 14-mm cyst in the right ovary; a pelvic ultrasound at age 36, which revealed multiple small cysts on the right ovary and one on the left ovary; and a pelvic computed tomography at age 38, which revealed enlarged ovaries with multiple bilateral cysts.
    Medical history is significant for hypertension for 6 years and for preeclampsia with her first pregnancy at age 22. Her father developed angina at the age of 39. She is a married homemaker and has four children.
The only medication she is currently on is felodipine 5 mg for hypertension.

Discussion
The main criterion for diagnosis of polycystic ovarian syndrome (PCOS), which affects 5%–10% of women of reproductive age,1 is evidence of hyperandrogenism, whether clinical (hirsutism, acne, or alopecia) or biochemical (elevated serum androgen levels).2-4 Androgen levels (cortisol, testosterone, DHEA-SO4, and androstenedione) were normal in our case patient. Biochemical hyperandrogenism may need to be provoked with a gonadotropin-releasing hormone agonist,5 but this is not necessary if the patient has clinical evidence. Enlarged cystic ovaries with 8 to 10 small (2-8 mm) follicles are characteristic of polycystic appearing ovaries (PAO)6 but are not necessary for the diagnosis of PCOS. Since recognizing the syndrome in normal ovulatory women, menstrual irregularity is no longer required for the diagnosis.2 PCOS is a diagnosis of exclusion after evaluation for other causes of hyperandrogenism (Cushing’s syndrome and adrenal or ovarian tumors).
    Many healthcare professionals now consider PCOS to be part of the metabolic syndrome, characterized by insulin resistance. At least half of women with PCOS are obese. Compared with women without PCOS, many women with PCOS are hyperinsulinemic and insulin resistant, independent of obesity.7,8 Elevated insulin levels directly increase luteinizing hormone-stimulated androgen secretion from the ovary9,10 and decrease circulating steroid hormone-binding globulin (SHBG) levels.11 Both of these result in higher levels of free androgens, which cause clinical manifestations of androgen excess such as hirsutism, acne, alopecia, menstrual irregularity, and amenorrhea. Insulin resistance in PCOS is secondary to a postbinding defect in signal transduction and affects metabolic actions of insulin.12 In addition, there appears to be a heritable component to beta-cell dysfunction in families of women with PCOS.13

ATP III: The Metabolic Syndrome
(Diagnosis is established when >3 risk factors are present)
*More highly correlated with metabolic RFs than ↑BMI.
†Some men develop metabolic RFs when waist is only marginally increased.
ATP III. JAMA. 2001;285:2486-2497.
.

    The most significant aspects of PCOS are not the hyperandrogenemic effects, but rather the metabolic consequences of insulin resistance, including hypertension, diabetes, and cardiovascular disease.14-15 Consistent with insulin resistance, low HDL-C and high triglyceride levels16 as well as an increase in LDL-C17,18 have been observed. Women with PCOS are at increased risk for type 2 diabetes. In a study of 122 obese women with PCOS, 35% had impaired glucose tolerance and 10% had type 2 diabetes by age 40.19
    In our case patient, the increased waist circumference, high TG (>150 mg/dL), low HDL-C (<50 mg/dL), and hypertension give the patient four characteristics of the metabolic syndrome.20 This is common in the later years of most women with PCOS and may predispose them to coronary heart disease.
    Taken together, the following studies suggest that it’s important to aggressively treat risk factors for cardiovascular disease in women with PCOS.

Among 143 women over age 60 referred for coronary angiography for assessment of chest pain or valvular disease, the women with polycystic ovaries (42% of patients) associated with low HDL-C levels, high TG levels, hirsutism, and high free testosterone had more extensive coronary disease than did the women with normal ovaries.21
Carotid artery intima-media thickness was significantly greater in 16 women with PCOS older than 40 years of age compared with the controls.22
Although no data were available to confirm a diagnosis of PCOS in this study, women with menstrual-cycle irregularity had a 25% increased risk of nonfatal MI (95% CI; 1.07-1.47) and a 67% increased risk of fatal CHD (95% CI; 1.35-2.06).23
Risk of hypertension was increased threefold and myocardial infarction up to sevenfold in women over age 30 with PCOS.24,25

    An investigation to detect insulin resistance in every hirsute woman has been recommended.26 Treatment with metformin—the most studied agent to treat insulin resistance in PCOS—decreases weight, lowers testosterone, increases SHBP, improves menstrual regularity, facilitates pregnancy, decreases PAI-1 and lipoprotein(a) levels27,28 in women with PCOS, increases levels of HDL-C, and decreases LDL-C and TG levels.29
    The National Cholesterol Education Program Third Adult Treatment Panel (ATP III) recommends at least 3 months of therapeutic lifestyle changes (TLC; diet and exercise geared toward weight loss) for patients with the metabolic syndrome.20
Our case patient followed the TLC diet and began an aerobic exercise program and lost 10 lb. Although her LDL-C increased to 244 mg/dL, on a positive note, her TG levels decreased to 174 mg/dL, her HDL-C increased to 41 mg/dL, and her glucose decreased to 93 mg/dL. Next, she will undergo a glucose tolerance test; if abnormal, metformin will be tried. Of note, she had her four children before the age of 33, when only one cyst was noted on one of her ovaries. Therefore, she had her children before she developed polycystic ovaries.

Conclusion
In any woman with signs of androgen excess, it is important to consider PCOS and insulin resistance. These women need to undergo cardiovascular risk assessment and be treated aggressively.


REFERENCES*
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2. Chang RJ. Polycystic Ovary Syndrome. New York: Marcel Dekker, Inc. 2002:361-365.
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18. Legro RS et al. Am J Med. 2001;111:607.
19. Ehrmann DA et al. Diabetes Care. 1999;22:141.
20. Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.
21. Birdsall MA et al. Ann Intern Med. 1997;126:32.
22. Guzick DS et al. Am J Obstet Gynecol. 1996;174:1224.
23. Solomon CG et al. J Clin Endocrinol Metab. 2002;87:2013.
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25. Dahlgren E et al. Acta Obstet Gynecol Scand. 1992;71:599-604.
26. Goodarzi MO et al. Fertil Steril. 2003;80:255-258.
27. Moghetti P et al. J Clin Endocrinol Metab. 2000;85:139-146.
28. Oberfield SE. J Clin Endocrinol Metab. 2000;85:3520-3525.
29. DeFronzo RA. Ann Intern Med. 1999;131:281-303.

*For complete citations, please click here.