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Lipid Profiles in Women With 45,X vs 46,XX Primary Ovarian Failure
To the Editor: The increased prevalence of coronary heart disease (CHD) in women with monosomy X (Turner syndrome) has been attributed to their premature ovarian failure, which causes loss of estrogen effect and excess adiposity.1-2 However, the longstanding view of estrogen as a cardioprotective agent responsible for the relative protection from CHD enjoyed by women compared with men has recently been challenged.3 To investigate the possibility that haploinsufficiency for X-chromosome genes, rather than gonadal insufficiency, contributes to the increased CHD risk in monosomy X, we compared fasting lipid profile, glucose and insulin levels, and body composition in young, nonobese women with Turner syndrome and in 46,XX women with premature ovarian failure.
Methods
Women were recruited mainly through notices on the National Institute of Child Health Web site. The criteria for inclusion in our institutional review board–approved studies on premature ovarian failure and Turner syndrome have been described previously.4-5 Participants were 33 women with Turner syndrome and 35 women with premature ovarian failure. Exclusion criteria included diabetes mellitus, age younger than 18 years or older than 50 years, body mass index (BMI) greater than 30 or less than 19 (calculated as weight in kilograms divided by the square of height in meters), use of antilipid medications, and ingestion of more than 3 drinks of alcohol per week. All women discontinued estrogen use at least 2 weeks prior to the study and were in good general health. All were euthyroid, based on initial clinical and laboratory evaluations. Most participants were sedentary; there were no athletes or exceptionally fit individuals. Lipid profiles and levels of glucose and insulin were measured after a 12-hour overnight fast.
Results
The groups were similar in age and BMI; however, levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C) (direct), non–high-density lipoprotein cholesterol (HDL-C), and triglycerides were all significantly higher in women with Turner syndrome compared with women with 46,XX premature ovarian failure (Table 1). Only 2 of 35 women with premature ovarian failure had a fasting total cholesterol level greater than 240 mg/dL (6.2 mmol/L), compared with 12 of 33 women with Turner syndrome. The ratio of total cholesterol to HDL-C was 3.3 (95% confidence interval, 3.1-3.6) in participants with Turner syndrome and 2.8 (95% confidence interval, 2.6-3.0) in those with premature ovarian failure (P = .004). Total percent body fat and truncal fat, determined by dual X-ray absorptiometry,5 and fasting insulin sensitivity, determined by the QUICKI (Quantitative Insulin Sensitivity Check Index) analysis,6 were similar in both groups (Table 1).
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Table. Metabolic Parameters in Women With Turner Syndrome and Premature Ovarian Failure*
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Comment
We found that healthy, young, nonobese women with Turner syndrome exhibit an atherogenic lipid profile compared with 46,XX women of the same age and body composition with premature ovarian failure. Since advancing age is associated with decreasing levels of HDL-C and increasing levels of LDL-C, this unfavorable lipid profile may contribute to the excess mortality in women with Turner syndrome.1 Interestingly, in contrast to the obesity-related "metabolic syndrome," insulin sensitivity measured by fasting levels of insulin and glucose appears to be normal in these young women with Turner syndrome. Because the 2 groups in this study are similar in gonadal status, adiposity, and lifestyle factors influencing lipid metabolism, the atherogenic lipid profile in Turner syndrome may be caused by haploinsufficiency for as-yet unknown X-chromosome gene(s). Given that a number of X-chromosome genes escape inactivation yet do not have a Y-chromosome homologue,7 some of these genes may contribute to the the more favorable lipid profiles of healthy 46,XX women compared with men.
Acknowledgment: We thank Lawrence Nelson, MD, for allowing us access to his sample of patients with premature ovarian failure, and Vien Vanderhoof for helping organize the data. We are grateful to the nurses and staff of the National Institutes of Health Clinical Center for supporting our work.
Margaret Cooley, BA;
Vladimir Bakalov, MD;
Carolyn A. Bondy, MD
National Institute of Child Health and Human Development
National Institutes of Health
Bethesda, Md
1. Gravholt CH, Juul S, Naeraa RW, Hansen J. Morbidity in Turner syndrome. J Clin Epidemiol. 1998;51:147-158.
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2. Elsheikh M, Conway GS. The impact of obesity on cardiovascular risk factors in Turner's syndrome. Clin Endocrinol (Oxf). 1998;49:447-450.
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3. Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349:523-534.
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4. Bakalov VK, Vanderhoof VH, Bondy CA, Nelson LM. Adrenal antibodies detect asymptomatic auto-immune adrenal insufficiency in young women with spontaneous premature ovarian failure. Hum Reprod. 2002;17:2096-2100.
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5. Bakalov V, Chen M, Baron J, et al. Bone mineral density and fractures in Turner syndrome. Am J Med. 2003;115:259-264.
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6. Katz A, Nambi SS, Mather K, et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab. 2000;85:2402-2410.
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7. Brown CJ, Greally JM. A stain upon the silence: genes escaping X inactivation. Trends Genet. 2003;19:432-438.
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Letters Section Editor: Stephen J. Lurie, MD, PhD, Senior Editor.
JAMA. 2003;290:2127-2128.
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