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Thyroid Function and Serum Lipids in Older Women: A Population-based Study
Thyroid Function and Serum Lipids in Older Women: A Population-based Study Douglas C. Bauer, MD, Bruce Ettinger, MD, Warren S. Browner, MD, MPH
PURPOSE: To determine if thyroid hormone deficiency, manifested by elevated serum thyrotropin (TSH), is associated with alterations in serum lipids in an unselected population of older women. SUBJECTS AND METHODS: Population-based sampling of 279 ambulatory white women over age 65 studied at four US clinical centers, randomly selected from a cohort of 9,704 participants enrolled in the Study of Osteoporotic Fractures. A third-generation chemiluminescent TSH assay and serum lipid levels—total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides—were measured on fasting sera collected at the baseline visit. The cross-sectional relationships between TSH and lipid levels were analyzed. RESULTS: TSH was high (.5.5 mU/L) in 19 women (6.8%), and was low (#0.1 mU/L) in 10 (3.6%). After multiple adjustment, LDL-C was 17 mg/dL or 13% higher (95% confidence
interval [CI] 1%, 25%), and HDL-C was 6.5 mg/dL or 12% lower (CI 20.2%, 225%) in women with high TSH compared with those with normal TSH. The ratio of LDL-C to HDL-C was 29% greater (CI 4%, 53%) among women with elevated TSH. Although total cholesterol was 8% higher among women with high TSH, this difference was not statistically significant (CI 21%, 15%). High TSH was found in 12% of the women with the combination of high cholesterol (.240 mg/dL), high LDL-C (.160 mg/dL), and low HDL-C (,45 mg/dL); likelihood ratio 5 1.8) whereas high TSH was found in only 2.2% of women with normal lipids (likelihood ratio 5 0.3). CONCLUSION: Among older white women, high TSH is associated with deleterious changes in serum lipids, particularly HDL-C, LDL-C, and the ratio of LDL-C to HDL-C cholesterol. Women with multiple lipid abnormalities are twice as likely to have an increased TSH. Am J Med. 1998;104:546 –551. q1998 by Excerpta Medica, Inc.
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tion, most of which are clinically silent, is uncertain. Some (8 –10), but not all (11,12) cross-sectional studies have found that subclinical thyroid hypothyroidism (defined as elevated thyrotropin and normal thyroid hormone levels) is associated with deleterious changes in total cholesterol and LDL-C. Several nonrandomized intervention studies have demonstrated a reduction in total cholesterol and LDL-C among women with subclinical hypothyroidism treated with thyroid replacement (13,14), but randomized trials have not supported this finding (15–17). The relationship between thyroid function and HDL-C in older women has not been well studied, and the existing studies are conflicting (18). Furthermore, most studies of the relationship between subclinical hypothyroidism and hyperlipidemia have been conducted among select individuals with suspected thyroid dysfunction, and few studies have included large numbers of older women who are at high risk for thyroid dysfunction. To examine the relationship between abnormalities of thyroid function, as determined by thyrotropin (TSH) levels, and abnormalities of serum lipids, we studied a group of women over age 65 randomly selected from the Study of Osteoporotic Fractures, and determined if the presence of lipid abnormalities in older women could be used to predict the likelihood of detecting an elevated TSH.
yperlipidemia and thyroid abnormalities are both common disorders in older women. Population-based studies have found that a large proportion of women over age 65 have abnormal serum lipids (1), and epidemiologic studies suggest that low levels of high-density lipoprotein cholesterol (HDL-C) are strongly associated with an increased risk of coronary heart disease (2,3). Thyroid dysfunction also increases with age, particularly in women, and abnormal thyroid function tests are found in as many as 10% to 15% of independently living older women (4,5). The relationship between abnormal thyroid function and serum lipids remains controversial. Frank hypothyroidism is clearly associated with elevations of total cholesterol and low-density lipoprotein cholesterol (LDL-C) (6,7). The effect of milder abnormalities of thyroid func-
For the Study of Osteoporotic Fractures Research Group: Universities of California (San Francisco), Pittsburgh, Minnesota (Minneapolis), and Kaiser Center for Health Research, Portland, Oregon. From the Departments of Medicine and Epidemiology and Biostatistics (DCB, WSB), University of California, San Francisco, California, and the Division of Research (BE), Kaiser Permanente Medical Care Program, Oakland, California. Supported by Public Service Grant K08-AG00629 (NIA). Requests for reprints should be addressed to Douglas C. Bauer, MD, UCSF, 74 New Montgomery, Suite 600, San Francisco, California 94105. Manuscript submitted October 20, 1997 and accepted in revised form March 17, 1998. 546
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0002-9343/98/$19.00 PII S0002-9343(98)00116-8
Thyroid Function and Lipids in Older Women/Bauer et al
METHODS
Analysis
Subjects
Thyrotropin was analyzed as both a continuous and categorical variable. Results were similar using TSH or log TSH, and therefore analyses using untransformed TSH are reported. TSH levels were divided into the following categories based on accepted cutpoints for highly sensitive assays (24): #0.1 mU/L (low), .0.1 but ,5.5 mU/L (normal), and .5.5 mU/L (high). Analyses defining normal TSH as 0.5 to 5.5 mU/L gave similar results and are not reported. Serum lipids were dichotomized into low and high categories based on guidelines from the Adult Treatment Panel of the National Cholesterol Education Program (NCEP) (1). Potential confounders were selected on the basis of biologic plausibility (eg, body weight) or a strong association (P ,0.05) with TSH level (eg, age) or serum lipids (eg, estrogen use). Differences in potential confounders with low, normal, and high TSH levels were examined for statistical significance with analysis of variance (ANOVA) and chi-square tests. The relationships between thyrotropin and serum lipid levels were analyzed with linear regression models; multivariate models were constructed to adjust for potential confounders. Results are reported as percent difference in serum lipids with 95% confidence intervals (CI). All statistical analyses were performed using Statistica (StatSoft, Inc., Tulsa, Oklahoma) and SAS (SAS Institute, Inc., Cary, North Carolina).
Subjects in this cross-sectional study were participants in the Study of Osteoporotic Fractures (SOF) (19). In 1996, 9,704 white women over age 65 were recruited for SOF from population-based listings at four clinical centers. These analyses are based on a subset of 279 women randomly selected from the cohort as part of an ongoing nested case-cohort study of the biochemical predictors of osteoporosis and mortality. The final sample consisted of 74 women from Baltimore, 77 from Minneapolis, 66 from Pittsburgh, and 62 from Portland.
Measurements All SOF participants were interviewed and examined at one of the clinical centers during the baseline visit in 1986 to 1988. At that visit, detailed data about physician-diagnosed medical conditions were collected. Past use of selection medications was determined by questionnaire, and current use of medication was confirmed by examination of pill bottles by trained interviewers. Participants were asked specifically about previous diagnoses of hyperthyroidism or Grave’s disease and previous use of thyroid hormone, but use of lipid-lowering medications was not determined. Physical activity was assessed using a modified Paffenbarger survey (20), and information on health habits was collected by questionnaire. Height and weight were measured using standardized protocols (21), and a fasting serum specimen was collected from each participant and stored at 21908C. In 1994, baseline serum from 279 randomly selected participants was thawed and blindly assayed for thyrotropin and serum lipids. Thyrotropin levels were measured using a highly sensitive, third-generation chemiluminescent assay (Endocrine Science, Calabasas, California). The normal range for this assay is 0.5 to 5.5 mU/L; the minimum detection level is 0.01 mU/L. At TSH concentrations of 0.5 mU/L the intra- and interassay coefficients of variation (CV) are 4.7% and 6.3%, respectively; and at TSH concentrations of 4.5 to 5.5 mU/L the intraand interassay CVs are 12.4% and 8.5%, respectively. Previous studies have shown that TSH is highly stable in frozen serum over prolonged periods (22,23). Serum lipids were measured using standard methods (Endocrine Sciences, Calabasas, California). Total cholesterol and triglyceride were measured with enzymatic assays; the reported precision (CV) of these assays are 0.9% to 1.1% and 1.1% to 2.6%, respectively. HDL-C was assessed with an enzymatic assay after precipitation and centrifugation; the reported precision of this assay is 1.1% to 2.4%. LDL-C was calculated from standard formulas; LDL-C was considered missing when triglyceride levels exceeded 400 mg/dL (n 5 5).
RESULTS Mean (6SD) total cholesterol was 242 6 42 mg/dL, and 51% had total cholesterol levels .240 mg/dL. Mean HDL-C was 53 6 15 mg/dL (34% had levels ,45 mg/dL), mean LDL-C was 156 6 40 mg/dL (46% had levels .160 mg/dL), mean triglyceride was 165 6 85 mg/dL, and the mean LDL-C/HDL-C ratio was 3.2 6 1.8. Mean TSH (6SD) was 2.3 6 3.3 mU/L. Among the 19 women with elevated TSH (.5.5 mU/L), mean TSH was 11.2 6 8.5 mU/L (range 6.0 to 42), and 4 women had TSH values greater than 12.0 mU/L. Compared with women with normal TSH (Table 1), those with TSH .5.5 mU/L tended to weigh more, were more likely to smoke, and were less likely to drink alcohol or take estrogen, but none of these differences was statistically significant (P .0.1). TSH was strongly related to use of thyroid hormone; 90% of women with low TSH were thyroid hormone users compared with 9% of those with normal TSH and 11% of those with elevated TSH (P ,0.0001). In unadjusted analyses examining TSH as a categorical variable, higher levels of TSH were associated with higher levels of total cholesterol (Figure 1A), LDL-C (Figure 1B), and LDL-C/HDL-C ratio (Figure 1C). Although not staJune 1998
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Table 1. Characteristics of Participants TSH (mU/L) Variable
,0.1 (n 5 10)
0.1–5.5 (n 5 250)
.5.5 (n 5 19)
Age (yr 6 SD) Weight (kg 6 SD) Current smoker Current alcohol (drinks/wk 6 SD) Activity in past year (kcal/wk 6 SD) Diabetes Current thyroid use Current oral estrogen use Mean TSH (mU/L 6 SD)
75.2 6 5.8 60.0 6 7.4 0% 1.5 6 4.3 1547 6 1388 30% 90%* 0% 0.02 6 0.03
71.9 6 5.2 67.1 6 13.5 10% 1.9 6 4.4 1458 6 1689 8% 9% 13% 1.7 6 1.2
72.4 6 5.6 70.0 6 9.8 16% 1.1 6 3.2 1494 6 1559 11% 11% 6% 11.2 6 8.5*
* P ,0.05 compared with women with normal TSH (0.1–5.5 mU/L). TSH 5 thyrotropin.
tistically significant, even mild elevations of TSH (levels between 5.5 and 10 mU/L) were associated with elevated lipid levels. For example, total cholesterol and LDL-C were 262 mg/dL and 181 mg/dL, respectively, among women with TSH levels between 5.5 and 10 mU/L, compared with levels of 241 mg/dL and 155 mg/dL, respectively, among women with normal TSH values. The relationship between TSH and HDL-C was not linear, and HDL-C tended to be lower in women with either low or
high TSH (Figure 1D). There was no apparent relationship between TSH and triglycerides (data not shown). After adjustment for age, weight, estrogen use, diabetes, physical activity, and use of tobacco and alcohol, compared with women with normal TSH those with elevated TSH had significantly higher levels of LDL-C and lower levels of HDL-C (Table 2). After these adjustments, LDL-C was 17 mg/dL higher and HDL-C was 6.5 mg/dL lower among women with elevated TSH. The ratio of
Figure 1. Unadjusted serum lipid levels among older women with low (n 5 10), normal (n 5 250) and high TSH (n 5 19). 548
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Table 2. Differences in Serum Lipid Levels among Women with Low and High Thyrotropin (TSH) Compared with Those with Normal TSH, Multiply Adjusted* TSH #0.1 mU/L Mean Difference (95% CI)† Total cholesterol LDL-C HDL-C LDL-C/HDL-C ratio Triglycerides
28% (219%, 4%) 211% (227%, 6%) 29% (224%, 10%) 217% (252%, 18%) 5% (227%, 37%)
TSH .5.5 mU/L Mean Difference (95% CI)†
P Value 0.18 0.20 0.39 0.34 0.74
7% (21%, 16%) 13% (1%, 25%) 213% (225%, 20%) 29% (4%, 53%) 15% (28%, 38%)
P Value 0.08 0.03 0.04 0.03 0.21
* Adjusted for age, weight, physical activity, diabetes, current tobacco and alcohol use, and use of estrogens. † Compared with normal TSH (0.1–5.5 mU/L). CI 5 confidence interval; LDL-C 5 low-density lipoprotein cholesterol; HDL-C 5 high-density lipoprotein cholesterol.
LDL-C/HDL-C was 29% higher among women with elevated TSH. Total cholesterol and triglycerides tended to be higher among women with elevated TSH, but these differences were not statistically significant. Multivariate analyses examining TSH as a continuous variable, including undetectable levels, gave similar results. For example, each standard deviation (3.3 mU/L) increase in TSH was associated with a 3% increase in LDL-C (CI 0.0%, 6%, P 5 0.05) and a 9% increase in LDL-C/HDL-C ratio (CI 7%, 11%). Each standard deviation increase in TSH was associated with an 2% increase in total cholesterol, which approached but did not reach statistical significance (CI 20.3%, 4%; P 5 0.1). In analyses confined to women with normal TSH levels (0.1 to 5.5 mU/L); (n 5 250), there was no evidence of a significant relationship between TSH and serum lipids (data not shown). The prevalence of elevated TSH differed by lipoprotein levels (Table 3). Among all 279 women in this study, high TSH was found in 19 (6.8%). The prevalence of high TSH was 2.2% among women with normal lipids, and was considerably higher (11.8%) among women with the combination of high total cholesterol (.240 mg/dL), high LDL-C (.160 mg/dL), and low HDL-C (,45 mg/ dL). The corresponding likelihood ratios for an elevated TSH ranged from 0.3 for women with normal lipids to 1.9
among women with multiple lipoprotein abnormalities (Table 3). Thus, the odds of detecting a high TSH were 70% lower among women with normal lipids and 1.8 times greater among women with the combination of elevated total cholesterol, elevated LDL-C, and low HDL-C.
DISCUSSION In this large population-based sample of older women, we found that elevated levels of TSH were associated with deleterious effects on serum lipids, including HDL-C. A significant relationship between TSH and LDL-C, HDL-C, and the LDL-C/HDL-C ratio persisted even after adjustment for factors known to affect serum lipids, such as alcohol use, diabetes, physical activity, and estrogen use. The effect of elevated TSH was clinically significant: Compared with women with normal TSH, HDL-C levels were 13% lower and the ratio of LDL-C/HDL-C was 29% higher among women with high TSH. Based on the known relationship between HDL-C and coronary heart disease in women (1), the reduction in HDL-C associated with elevated TSH could increase the risk of atherosclerotic heart disease by as much as 26% to 39%. In vitro and in vivo studies have suggested that abnor-
Table 3. Likelihood of Lipid Abnormalities among Women with Normal and High Thyrotropin (TSH) Lipid Abnormality
High TSH (n 5 19)
Normal TSH (n 5 250)
Likelihood Ratio*
Cholesterol .240 mg/dL LDL-C .160 mg/dL HDL-C ,45 mg/dL All of the above None of the above
14 (74%) 15 (79%) 8 (42%) 6 (32%) 2 (11%)
125 (50%) 111 (44%) 83 (33%) 43 (17%) 87 (35%)
1.5 1.8 1.3 1.9 0.3
* Likelihood of abnormal lipid level among women with high TSH/likelihood of abnormal lipid level among women with normal TSH. LDL-C 5 low-density lipoprotein cholesterol; HDL-C 5 high-density lipoprotein cholesterol. June 1998
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mal thyroid function may result in alterations in serum lipids by several possible mechanisms, including reduced clearance rates of lipoproteins (25). LDL-C receptors are stimulated by thyroid hormones both in vitro (26) and in vivo (27), and variability of the LDL-C receptor genotype predicts the magnitude of hyperlipidemia associated with hypothyroidism (28). Much less is known about the effect of thyroid hormone on HDL-C levels, but hypothyroidism is associated with low levels of hepatic lipase (29). Many previous clinical studies have found that individuals with overt hypothyroidism have elevated total cholesterol and LDL-C levels (7). Some (10) but not all (9) cross-sectional studies have found a relationship between subclinical hypothyroidism and total cholesterol and LDL-C levels. Previous cross-sectional studies of thyroid dysfunction and HDL-C levels have also been conflicting; compared with individuals with normal thyroid function, HDL-C has been reported to be high (30), low (8,31), or unchanged (7,9,12,25,32) among those with biochemical evidence of hypothyroidism. Longitudinal studies of the effect of thyroid hormone replacement on HDL-C levels have also been conflicting (8,9,11–14, 25,31–36). Importantly, none of these previous studies examined the effect of abnormal TSH on HDL-C in a large sample of unselected postmenopausal women. Although the prevalence of thyroid dysfunction has been studied among individuals with abnormal lipids (36 –39), to our knowledge likelihood ratios have not been applied to these populations. We found that women with elevated LDL-C were 80% more likely to have an elevated TSH, and those with abnormal levels of total cholesterol, LDL-C, and HDL-C were 90% more likely to have high TSH. Women with normal lipids levels were much less likely to have an elevated TSH. Thus, our data suggest that measurement of TSH may be useful in women with lipid abnormalities. Few data are available regarding lipid levels among individuals with low TSH. An interesting observation from this study was the trend toward lower total cholesterol, LDL-C, HDL-C, and LDL-C/HDL-C ratio among women with low TSH, which persisted after adjustment for weight. In particular, the mechanism for the unexpected finding of low HDL-C among women with low TSH is unclear, and additional studies to confirm this finding are needed. Our study has several limitations. The sample size was limited to 279 women, and therefore the confidence intervals for many associations were wide. Lipid-lowering agents were not recorded, and therefore we could not account for their use, but it is unlikely that these medications were prescribed often when the specimens were collected (1986 to 1988) or that they were prescribed preferentially to those with or without abnormal TSH. Free thyroxine and triiodothyronine levels were not measured in this study. We did not directly assess participants for 550
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symptoms related to thyroid dysfunction and were not able to distinguish women with asymptomatic subclinical thyroid disease from those with symptomatic disease. However, we assessed thyroid function and lipids among a randomly selected group of community-dwelling older women, and our results are generalizable to a large proportion of postmenopausal women. In conclusion, we found that in older postmenopausal women with untreated abnormalities of thyroid function TSH level is related to serum lipids, specifically LDL-C and HDL-C. These lipid abnormalities, low HDL-C in particular, were of sufficient magnitude to be clinically important. These relationships persisted after adjustment for potential confounders, such as age, weight, and estrogen use. The prevalence of abnormal TSH among women with multiple lipid abnormalities was particularly high, and screening for thyroid dysfunction may be warranted in this high-risk group.
REFERENCES 1. National Cholesterol Education Program. Second Report of the Expert on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation. 1994;89:1333–1445. 2. Walsh JM, Grady D. Treatment of hyperlipidemia in women. JAMA. 1995;274:1152–1158. 3. Abbott RD, Wilson PW, Kannel WB, Castelli WP. High density lipoprotein cholesterol, total cholesterol screening, and myocardial infarction. The Framingham Study. Arteriosclerosis. 1988;8:207– 211. 4. Parle JV, Franklyn JA, Cross KW, et al. Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom. Clin Endocrinol. 1991;34:77– 83. 5. Sawin C, Geller A, Hershman J, et al. The aging thyroid. The use of thyroid hormone in older persons. JAMA. 1989;261:2653–2655. 6. Stone NJ. Secondary causes of hyperlipidemia. Med Clin North Am. 1994;78:117–141. 7. O’Brien T, Dinneen SF, O’Brien PC, Palumbo PJ. Hyperlipidemia in patients with primary and secondary hypothyroidism. Mayo Clin Proc. 1993;68:860 – 866. 8. Caron P, Calazel C, Parra HJ, et al. Decreased HDL cholesterol in subclinical hypothyroidism: the effect of L-thyroxine therapy. Clin Endocrinol (Oxf). 1990;33:519 –523. 9. Staub JJ, Althaus BU, Engler H, et al. Spectrum of subclinical and overt hypothyroidism: effect on thyrotropin, prolactin, and thyroid reserve, and metabolic impact on peripheral target tissues. Am J Med. 1992;92:631– 642. 10. Kung AW, Pang RW, Janus ED. Elevated serum lipoprotein(a) in subclinical hypothyroidism. Clin Endocrinol (Oxf). 1995;43:445– 449. 11. Bell GM, Todd WT, Forfar JC, et al. End-organ responses to thyroxine therapy in subclinical hypothyroidism. Clin Endocrinol (Oxf). 1985;22:83– 89. 12. Bogner U, Arntz HR, Peters H, Schleusener H. Subclinical hypothyroidism and hyperlipoproteinaemia: indiscriminate L-thyroxine treatment not justified. Acta Endocrinol (Copenh). 1993;128: 202–206. 13. Arem R, Patsch W. Lipoprotein and apolipoprotein levels in subclinical hypothyroidism. Effect of levothyroxine therapy. Arch Intern Med. 1990;150:2097–2100.
Thyroid Function and Lipids in Older Women/Bauer et al 14. Franklyn JA, Daykin J, Betteridge J, et al. Thyroxine replacement therapy and circulating lipid concentrations. Clin Endocrinol (Oxf). 1993;38:453– 459. 15. Nystrom E, Caidahl K, Fager G, et al. A double-blind cross-over 12-month study of L-thyroxine treatment of women with “subclinical” hypothyroidism. Clin Endocrinol. 1988;29:63–76. 16. Cooper D, Halpern R, Wood L, et al. L-thyroxine therapy in subclinical hypothyroidism. Ann Intern Med. 1984;101:18 –24. 17. Jaeschke R, Guyatt G, Gerstein H, et al. Does treatment with L-thyroxine influence health status in middle-aged and older adults with subclinical hypothyroidism? J Gen Intern Med. 1996;11:744 – 749. 18. Tanis BC, Westendorp GJ, Smelt HM. Effect of thyroid substitution on hypercholesterolaemia in patients with subclinical hypothyroidism: a reanalysis of intervention studies. Clin Endocrinol (Oxf). 1996;44:643– 649. 19. Bauer DC, Browner WS, Cauley JA, et al. Factors associated with appendicular bone mass in older women. The Study of Osteoporotic Fractures Research Group. Ann Intern Med. 1993;118:657– 665. 20. Paffenbarger RS Jr, Wing AL, Hyde RT. Physical activity as an index of heart attack risk in college alumni. Am J Epidemiol. 1978;108: 161–175. 21. Lohman TG, Roche AF, Martorell R. Anthropometric Standardization Reference Manual. 1st ed. Champaign, Ill: Human Kinetics Books; 1988. 22. Kashiwai T, Ichihara K, Tamaki H, et al. The stability of immunological and biological activity of human thyrotropin in buffer: its temperature-dependent dissociation into subunits during freezing. Scan J Clin Lab Invest. 1991;51:417– 423. 23. Stall G, Harris S, Sokoll LJ, Dawson-Hughes B. Accelerated bone loss in hypothyroid patients overtreated with l-thyroxine. Ann Intern Med. 1990;113:265–269. 24. Spencer C, Schwarzbein D, Guttler R, et al. Thyrotropin (TSH)releasing hormone stimulation test responses employing third and fourth generation TSH assays. J Clin Endocrinol Metab. 1992;76: 494 – 498. 25. Abrams JJ, Grundy SM. Cholesterol metabolism in hypothyroidism and hyperthyroidism in man. J Lipid Res. 1981;22:323–338. 26. Staels B, Van Tol A, Chan L, et al. Alterations in thyroid status modulate apolipoprotein, hepatic triglyceride lipase, and low density lipoprotein receptor in rats. Endocrinology. 1990;127:1144 – 1152. 27. Thompson GR, Soutar AK, Spengel FA, et al. Defects of receptormediated low density lipoprotein catabolism in homozygous familial hypercholesterolemia and hypothyroidism in vivo. Proc Natl Acad Sci USA. 1981;78:2591–2595. 28. Wiseman SA, Powell JT, Humphries SE, Press M. The magnitude of the hypercholesterolemia of hypothyroidism is associated with variation in the low density lipoprotein receptor gene. J Clin Endocrinol Metab. 1993;77:108 –112. 29. Valdemarsson S, Nilsson-Ehle P. Hepatic lipase and the clearing reaction: studies in euthyroid and hypothyroid subjects. Horm Metab Res. 1987;19:28 –30. 30. Muls E, Rosseneu M, Blaton V, et al. Serum lipids and apolipoproteins A-I, A-II and B in primary hypothyroidism before and during treatment. Eur J Clin Invest. 1984;14:12–15. 31. Agdeppa D, Macaron C, Mallik T, Schnuda ND. Plasma high density lipoprotein cholesterol in thyroid disease. J Clin Endocrinol Metab. 1979;49:726 –729. 32. Althaus BU, Staub JJ, Ryff-De Leche A, et al. LDL/HDL-changes in subclinical hypothyroidism: possible risk factors for coronary heart disease. Clin Endocrinol (Oxf). 1988;28:157–163. 33. Friis T, Pedersen LR. Serum lipids in hyper- and hypothyroidism before and after treatment. Clin Chim Acta. 1987;162:155–163.
34. Verdugo C, Perrot L, Ponsin G, et al. Time-course of alterations of high density lipoproteins (HDL) during thyroxine administration to hypothyroid women. Eur J Clin Invest. 1987;17:313–316. 35. Arem R, Escalante DA, Arem N, et al. Effect of L-thyroxine therapy on lipoprotein fractions in overt and subclinical hypothyroidism, with special reference to lipoprotein(a). Metabolism. 1995;44: 1559 –1563. 36. Diekman T, Lansberg PJ, Kastelein JJ, Wiersinga WM. Prevalence and correction of hypothyroidism in a large cohort of patients referred for dyslipidemia. Arch Intern Med. 1995;155:1490 –1495. 37. Glueck CJ, Lang J, Tracy T, Speirs J. The common finding of covert hypothyroidism at initial clinical evaluation for hyperlipoproteinemia. Clin Chim Acta. 1991;201:113–122. 38. Ball MJ, Griffiths D, Thorogood M. Asymptomatic hypothyroidism and hypercholesterolaemia. J R Soc Med. 1991;84:527–529. 39. Series JJ, Biggart EM, O’Reilly DS, et al. Thyroid dysfunction and hypercholesterolaemia in the general population of Glasgow, Scotland. Clin Chim Acta. 1988;172:217–221.
APPENDIX Investigators in the Study of Osteoporotic Fractures Research Group are as follows: University of California, San Francisco (Coordinating Center): S. R. Cummings (principal investigator), M. C. Nevitt (co-investigator), D. G. Seeley (project director), D. M. Black (study statistician), H. K. Genant (director, central radiology laboratory), C. Arnaud, D. Bauer, W. Browner, L. Christianson, M. Dockrell, C. Fox, S. Harvey, M. Jergas, R. Lipschutz, G. Milani, L. Palermo, R. San Valentin, K. Stone, D. Tanaka. University of Maryland: J. C. Scott (principal investigator), R. Sherwin (co-principal investigator), M. C. Hochberg (co-investigator), J. Lewis (project director), Cheryl Bailey (clinic coordinator), A. Bauer, L. Finazzo, G. Greenberg, D. Harris, B. Hohman, S. Kallenberger, E. Oliner, T. Page, A. Pettit, S. Snyder, L. Stranovsky, S. Trusty. University of Minnesota: K. Ensrud (principal investigator), R. Grimm, Jr. (co-investigator), C. Bell (project director), E. Mitson (clinic coordinator), M. Baumhover, C. Berger, S. Estill, S. Fillhouer, J. Hansen, K. Jacobson, K. Kiel, C. Linville, N. Nelson, E. Penland-Miller, J. Griffith. University of Pittsburgh: J. A. Cauley (principal investigator), L. H. Kuller (co-principal investigator), M. Vogt (co-investigator), L. Harper (project director), L. Buck (clinic coordinator), C. Bashada, A. Githens, A. McCune, D. Medve, M. Nasim, C. Newman, S. Rudovsky, N. Watson. The Kaiser Permanente Center for Health Research, Portland, Oregon: T. M. Vogt (principal investigator), W. M. Vollmer, E. Orwoll, H. Nelson, (co-investigators), J. Blank (project director), S. Craddick (clinic coordinator), R. Bright, J. Wallace, F. Heinith, K. Moore, K. Redden, C. Romero, C. Souvanlasy.
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PURPOSE: To determine if thyroid hormone deficiency, manifested by elevated serum thyrotropin (TSH), is associated with alterations in serum lipids in an unselected population of older women. SUBJECTS AND METHODS: Population-based sampling of 279 ambulatory white women over age 65 studied at four US clinical centers, randomly selected from a cohort of 9,704 participants enrolled in the Study of Osteoporotic Fractures. A third-generation chemiluminescent TSH assay and serum lipid levels—total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides—were measured on fasting sera collected at the baseline visit. The cross-sectional relationships between TSH and lipid levels were analyzed. RESULTS: TSH was high (.5.5 mU/L) in 19 women (6.8%), and was low (#0.1 mU/L) in 10 (3.6%). After multiple adjustment, LDL-C was 17 mg/dL or 13% higher (95% confidence
interval [CI] 1%, 25%), and HDL-C was 6.5 mg/dL or 12% lower (CI 20.2%, 225%) in women with high TSH compared with those with normal TSH. The ratio of LDL-C to HDL-C was 29% greater (CI 4%, 53%) among women with elevated TSH. Although total cholesterol was 8% higher among women with high TSH, this difference was not statistically significant (CI 21%, 15%). High TSH was found in 12% of the women with the combination of high cholesterol (.240 mg/dL), high LDL-C (.160 mg/dL), and low HDL-C (,45 mg/dL); likelihood ratio 5 1.8) whereas high TSH was found in only 2.2% of women with normal lipids (likelihood ratio 5 0.3). CONCLUSION: Among older white women, high TSH is associated with deleterious changes in serum lipids, particularly HDL-C, LDL-C, and the ratio of LDL-C to HDL-C cholesterol. Women with multiple lipid abnormalities are twice as likely to have an increased TSH. Am J Med. 1998;104:546 –551. q1998 by Excerpta Medica, Inc.
H
tion, most of which are clinically silent, is uncertain. Some (8 –10), but not all (11,12) cross-sectional studies have found that subclinical thyroid hypothyroidism (defined as elevated thyrotropin and normal thyroid hormone levels) is associated with deleterious changes in total cholesterol and LDL-C. Several nonrandomized intervention studies have demonstrated a reduction in total cholesterol and LDL-C among women with subclinical hypothyroidism treated with thyroid replacement (13,14), but randomized trials have not supported this finding (15–17). The relationship between thyroid function and HDL-C in older women has not been well studied, and the existing studies are conflicting (18). Furthermore, most studies of the relationship between subclinical hypothyroidism and hyperlipidemia have been conducted among select individuals with suspected thyroid dysfunction, and few studies have included large numbers of older women who are at high risk for thyroid dysfunction. To examine the relationship between abnormalities of thyroid function, as determined by thyrotropin (TSH) levels, and abnormalities of serum lipids, we studied a group of women over age 65 randomly selected from the Study of Osteoporotic Fractures, and determined if the presence of lipid abnormalities in older women could be used to predict the likelihood of detecting an elevated TSH.
yperlipidemia and thyroid abnormalities are both common disorders in older women. Population-based studies have found that a large proportion of women over age 65 have abnormal serum lipids (1), and epidemiologic studies suggest that low levels of high-density lipoprotein cholesterol (HDL-C) are strongly associated with an increased risk of coronary heart disease (2,3). Thyroid dysfunction also increases with age, particularly in women, and abnormal thyroid function tests are found in as many as 10% to 15% of independently living older women (4,5). The relationship between abnormal thyroid function and serum lipids remains controversial. Frank hypothyroidism is clearly associated with elevations of total cholesterol and low-density lipoprotein cholesterol (LDL-C) (6,7). The effect of milder abnormalities of thyroid func-
For the Study of Osteoporotic Fractures Research Group: Universities of California (San Francisco), Pittsburgh, Minnesota (Minneapolis), and Kaiser Center for Health Research, Portland, Oregon. From the Departments of Medicine and Epidemiology and Biostatistics (DCB, WSB), University of California, San Francisco, California, and the Division of Research (BE), Kaiser Permanente Medical Care Program, Oakland, California. Supported by Public Service Grant K08-AG00629 (NIA). Requests for reprints should be addressed to Douglas C. Bauer, MD, UCSF, 74 New Montgomery, Suite 600, San Francisco, California 94105. Manuscript submitted October 20, 1997 and accepted in revised form March 17, 1998. 546
q1998 by Excerpta Medica, Inc. All rights reserved.
0002-9343/98/$19.00 PII S0002-9343(98)00116-8
Thyroid Function and Lipids in Older Women/Bauer et al
METHODS
Analysis
Subjects
Thyrotropin was analyzed as both a continuous and categorical variable. Results were similar using TSH or log TSH, and therefore analyses using untransformed TSH are reported. TSH levels were divided into the following categories based on accepted cutpoints for highly sensitive assays (24): #0.1 mU/L (low), .0.1 but ,5.5 mU/L (normal), and .5.5 mU/L (high). Analyses defining normal TSH as 0.5 to 5.5 mU/L gave similar results and are not reported. Serum lipids were dichotomized into low and high categories based on guidelines from the Adult Treatment Panel of the National Cholesterol Education Program (NCEP) (1). Potential confounders were selected on the basis of biologic plausibility (eg, body weight) or a strong association (P ,0.05) with TSH level (eg, age) or serum lipids (eg, estrogen use). Differences in potential confounders with low, normal, and high TSH levels were examined for statistical significance with analysis of variance (ANOVA) and chi-square tests. The relationships between thyrotropin and serum lipid levels were analyzed with linear regression models; multivariate models were constructed to adjust for potential confounders. Results are reported as percent difference in serum lipids with 95% confidence intervals (CI). All statistical analyses were performed using Statistica (StatSoft, Inc., Tulsa, Oklahoma) and SAS (SAS Institute, Inc., Cary, North Carolina).
Subjects in this cross-sectional study were participants in the Study of Osteoporotic Fractures (SOF) (19). In 1996, 9,704 white women over age 65 were recruited for SOF from population-based listings at four clinical centers. These analyses are based on a subset of 279 women randomly selected from the cohort as part of an ongoing nested case-cohort study of the biochemical predictors of osteoporosis and mortality. The final sample consisted of 74 women from Baltimore, 77 from Minneapolis, 66 from Pittsburgh, and 62 from Portland.
Measurements All SOF participants were interviewed and examined at one of the clinical centers during the baseline visit in 1986 to 1988. At that visit, detailed data about physician-diagnosed medical conditions were collected. Past use of selection medications was determined by questionnaire, and current use of medication was confirmed by examination of pill bottles by trained interviewers. Participants were asked specifically about previous diagnoses of hyperthyroidism or Grave’s disease and previous use of thyroid hormone, but use of lipid-lowering medications was not determined. Physical activity was assessed using a modified Paffenbarger survey (20), and information on health habits was collected by questionnaire. Height and weight were measured using standardized protocols (21), and a fasting serum specimen was collected from each participant and stored at 21908C. In 1994, baseline serum from 279 randomly selected participants was thawed and blindly assayed for thyrotropin and serum lipids. Thyrotropin levels were measured using a highly sensitive, third-generation chemiluminescent assay (Endocrine Science, Calabasas, California). The normal range for this assay is 0.5 to 5.5 mU/L; the minimum detection level is 0.01 mU/L. At TSH concentrations of 0.5 mU/L the intra- and interassay coefficients of variation (CV) are 4.7% and 6.3%, respectively; and at TSH concentrations of 4.5 to 5.5 mU/L the intraand interassay CVs are 12.4% and 8.5%, respectively. Previous studies have shown that TSH is highly stable in frozen serum over prolonged periods (22,23). Serum lipids were measured using standard methods (Endocrine Sciences, Calabasas, California). Total cholesterol and triglyceride were measured with enzymatic assays; the reported precision (CV) of these assays are 0.9% to 1.1% and 1.1% to 2.6%, respectively. HDL-C was assessed with an enzymatic assay after precipitation and centrifugation; the reported precision of this assay is 1.1% to 2.4%. LDL-C was calculated from standard formulas; LDL-C was considered missing when triglyceride levels exceeded 400 mg/dL (n 5 5).
RESULTS Mean (6SD) total cholesterol was 242 6 42 mg/dL, and 51% had total cholesterol levels .240 mg/dL. Mean HDL-C was 53 6 15 mg/dL (34% had levels ,45 mg/dL), mean LDL-C was 156 6 40 mg/dL (46% had levels .160 mg/dL), mean triglyceride was 165 6 85 mg/dL, and the mean LDL-C/HDL-C ratio was 3.2 6 1.8. Mean TSH (6SD) was 2.3 6 3.3 mU/L. Among the 19 women with elevated TSH (.5.5 mU/L), mean TSH was 11.2 6 8.5 mU/L (range 6.0 to 42), and 4 women had TSH values greater than 12.0 mU/L. Compared with women with normal TSH (Table 1), those with TSH .5.5 mU/L tended to weigh more, were more likely to smoke, and were less likely to drink alcohol or take estrogen, but none of these differences was statistically significant (P .0.1). TSH was strongly related to use of thyroid hormone; 90% of women with low TSH were thyroid hormone users compared with 9% of those with normal TSH and 11% of those with elevated TSH (P ,0.0001). In unadjusted analyses examining TSH as a categorical variable, higher levels of TSH were associated with higher levels of total cholesterol (Figure 1A), LDL-C (Figure 1B), and LDL-C/HDL-C ratio (Figure 1C). Although not staJune 1998
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Table 1. Characteristics of Participants TSH (mU/L) Variable
,0.1 (n 5 10)
0.1–5.5 (n 5 250)
.5.5 (n 5 19)
Age (yr 6 SD) Weight (kg 6 SD) Current smoker Current alcohol (drinks/wk 6 SD) Activity in past year (kcal/wk 6 SD) Diabetes Current thyroid use Current oral estrogen use Mean TSH (mU/L 6 SD)
75.2 6 5.8 60.0 6 7.4 0% 1.5 6 4.3 1547 6 1388 30% 90%* 0% 0.02 6 0.03
71.9 6 5.2 67.1 6 13.5 10% 1.9 6 4.4 1458 6 1689 8% 9% 13% 1.7 6 1.2
72.4 6 5.6 70.0 6 9.8 16% 1.1 6 3.2 1494 6 1559 11% 11% 6% 11.2 6 8.5*
* P ,0.05 compared with women with normal TSH (0.1–5.5 mU/L). TSH 5 thyrotropin.
tistically significant, even mild elevations of TSH (levels between 5.5 and 10 mU/L) were associated with elevated lipid levels. For example, total cholesterol and LDL-C were 262 mg/dL and 181 mg/dL, respectively, among women with TSH levels between 5.5 and 10 mU/L, compared with levels of 241 mg/dL and 155 mg/dL, respectively, among women with normal TSH values. The relationship between TSH and HDL-C was not linear, and HDL-C tended to be lower in women with either low or
high TSH (Figure 1D). There was no apparent relationship between TSH and triglycerides (data not shown). After adjustment for age, weight, estrogen use, diabetes, physical activity, and use of tobacco and alcohol, compared with women with normal TSH those with elevated TSH had significantly higher levels of LDL-C and lower levels of HDL-C (Table 2). After these adjustments, LDL-C was 17 mg/dL higher and HDL-C was 6.5 mg/dL lower among women with elevated TSH. The ratio of
Figure 1. Unadjusted serum lipid levels among older women with low (n 5 10), normal (n 5 250) and high TSH (n 5 19). 548
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Table 2. Differences in Serum Lipid Levels among Women with Low and High Thyrotropin (TSH) Compared with Those with Normal TSH, Multiply Adjusted* TSH #0.1 mU/L Mean Difference (95% CI)† Total cholesterol LDL-C HDL-C LDL-C/HDL-C ratio Triglycerides
28% (219%, 4%) 211% (227%, 6%) 29% (224%, 10%) 217% (252%, 18%) 5% (227%, 37%)
TSH .5.5 mU/L Mean Difference (95% CI)†
P Value 0.18 0.20 0.39 0.34 0.74
7% (21%, 16%) 13% (1%, 25%) 213% (225%, 20%) 29% (4%, 53%) 15% (28%, 38%)
P Value 0.08 0.03 0.04 0.03 0.21
* Adjusted for age, weight, physical activity, diabetes, current tobacco and alcohol use, and use of estrogens. † Compared with normal TSH (0.1–5.5 mU/L). CI 5 confidence interval; LDL-C 5 low-density lipoprotein cholesterol; HDL-C 5 high-density lipoprotein cholesterol.
LDL-C/HDL-C was 29% higher among women with elevated TSH. Total cholesterol and triglycerides tended to be higher among women with elevated TSH, but these differences were not statistically significant. Multivariate analyses examining TSH as a continuous variable, including undetectable levels, gave similar results. For example, each standard deviation (3.3 mU/L) increase in TSH was associated with a 3% increase in LDL-C (CI 0.0%, 6%, P 5 0.05) and a 9% increase in LDL-C/HDL-C ratio (CI 7%, 11%). Each standard deviation increase in TSH was associated with an 2% increase in total cholesterol, which approached but did not reach statistical significance (CI 20.3%, 4%; P 5 0.1). In analyses confined to women with normal TSH levels (0.1 to 5.5 mU/L); (n 5 250), there was no evidence of a significant relationship between TSH and serum lipids (data not shown). The prevalence of elevated TSH differed by lipoprotein levels (Table 3). Among all 279 women in this study, high TSH was found in 19 (6.8%). The prevalence of high TSH was 2.2% among women with normal lipids, and was considerably higher (11.8%) among women with the combination of high total cholesterol (.240 mg/dL), high LDL-C (.160 mg/dL), and low HDL-C (,45 mg/ dL). The corresponding likelihood ratios for an elevated TSH ranged from 0.3 for women with normal lipids to 1.9
among women with multiple lipoprotein abnormalities (Table 3). Thus, the odds of detecting a high TSH were 70% lower among women with normal lipids and 1.8 times greater among women with the combination of elevated total cholesterol, elevated LDL-C, and low HDL-C.
DISCUSSION In this large population-based sample of older women, we found that elevated levels of TSH were associated with deleterious effects on serum lipids, including HDL-C. A significant relationship between TSH and LDL-C, HDL-C, and the LDL-C/HDL-C ratio persisted even after adjustment for factors known to affect serum lipids, such as alcohol use, diabetes, physical activity, and estrogen use. The effect of elevated TSH was clinically significant: Compared with women with normal TSH, HDL-C levels were 13% lower and the ratio of LDL-C/HDL-C was 29% higher among women with high TSH. Based on the known relationship between HDL-C and coronary heart disease in women (1), the reduction in HDL-C associated with elevated TSH could increase the risk of atherosclerotic heart disease by as much as 26% to 39%. In vitro and in vivo studies have suggested that abnor-
Table 3. Likelihood of Lipid Abnormalities among Women with Normal and High Thyrotropin (TSH) Lipid Abnormality
High TSH (n 5 19)
Normal TSH (n 5 250)
Likelihood Ratio*
Cholesterol .240 mg/dL LDL-C .160 mg/dL HDL-C ,45 mg/dL All of the above None of the above
14 (74%) 15 (79%) 8 (42%) 6 (32%) 2 (11%)
125 (50%) 111 (44%) 83 (33%) 43 (17%) 87 (35%)
1.5 1.8 1.3 1.9 0.3
* Likelihood of abnormal lipid level among women with high TSH/likelihood of abnormal lipid level among women with normal TSH. LDL-C 5 low-density lipoprotein cholesterol; HDL-C 5 high-density lipoprotein cholesterol. June 1998
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mal thyroid function may result in alterations in serum lipids by several possible mechanisms, including reduced clearance rates of lipoproteins (25). LDL-C receptors are stimulated by thyroid hormones both in vitro (26) and in vivo (27), and variability of the LDL-C receptor genotype predicts the magnitude of hyperlipidemia associated with hypothyroidism (28). Much less is known about the effect of thyroid hormone on HDL-C levels, but hypothyroidism is associated with low levels of hepatic lipase (29). Many previous clinical studies have found that individuals with overt hypothyroidism have elevated total cholesterol and LDL-C levels (7). Some (10) but not all (9) cross-sectional studies have found a relationship between subclinical hypothyroidism and total cholesterol and LDL-C levels. Previous cross-sectional studies of thyroid dysfunction and HDL-C levels have also been conflicting; compared with individuals with normal thyroid function, HDL-C has been reported to be high (30), low (8,31), or unchanged (7,9,12,25,32) among those with biochemical evidence of hypothyroidism. Longitudinal studies of the effect of thyroid hormone replacement on HDL-C levels have also been conflicting (8,9,11–14, 25,31–36). Importantly, none of these previous studies examined the effect of abnormal TSH on HDL-C in a large sample of unselected postmenopausal women. Although the prevalence of thyroid dysfunction has been studied among individuals with abnormal lipids (36 –39), to our knowledge likelihood ratios have not been applied to these populations. We found that women with elevated LDL-C were 80% more likely to have an elevated TSH, and those with abnormal levels of total cholesterol, LDL-C, and HDL-C were 90% more likely to have high TSH. Women with normal lipids levels were much less likely to have an elevated TSH. Thus, our data suggest that measurement of TSH may be useful in women with lipid abnormalities. Few data are available regarding lipid levels among individuals with low TSH. An interesting observation from this study was the trend toward lower total cholesterol, LDL-C, HDL-C, and LDL-C/HDL-C ratio among women with low TSH, which persisted after adjustment for weight. In particular, the mechanism for the unexpected finding of low HDL-C among women with low TSH is unclear, and additional studies to confirm this finding are needed. Our study has several limitations. The sample size was limited to 279 women, and therefore the confidence intervals for many associations were wide. Lipid-lowering agents were not recorded, and therefore we could not account for their use, but it is unlikely that these medications were prescribed often when the specimens were collected (1986 to 1988) or that they were prescribed preferentially to those with or without abnormal TSH. Free thyroxine and triiodothyronine levels were not measured in this study. We did not directly assess participants for 550
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symptoms related to thyroid dysfunction and were not able to distinguish women with asymptomatic subclinical thyroid disease from those with symptomatic disease. However, we assessed thyroid function and lipids among a randomly selected group of community-dwelling older women, and our results are generalizable to a large proportion of postmenopausal women. In conclusion, we found that in older postmenopausal women with untreated abnormalities of thyroid function TSH level is related to serum lipids, specifically LDL-C and HDL-C. These lipid abnormalities, low HDL-C in particular, were of sufficient magnitude to be clinically important. These relationships persisted after adjustment for potential confounders, such as age, weight, and estrogen use. The prevalence of abnormal TSH among women with multiple lipid abnormalities was particularly high, and screening for thyroid dysfunction may be warranted in this high-risk group.
REFERENCES 1. National Cholesterol Education Program. Second Report of the Expert on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation. 1994;89:1333–1445. 2. Walsh JM, Grady D. Treatment of hyperlipidemia in women. JAMA. 1995;274:1152–1158. 3. Abbott RD, Wilson PW, Kannel WB, Castelli WP. High density lipoprotein cholesterol, total cholesterol screening, and myocardial infarction. The Framingham Study. Arteriosclerosis. 1988;8:207– 211. 4. Parle JV, Franklyn JA, Cross KW, et al. Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom. Clin Endocrinol. 1991;34:77– 83. 5. Sawin C, Geller A, Hershman J, et al. The aging thyroid. The use of thyroid hormone in older persons. JAMA. 1989;261:2653–2655. 6. Stone NJ. Secondary causes of hyperlipidemia. Med Clin North Am. 1994;78:117–141. 7. O’Brien T, Dinneen SF, O’Brien PC, Palumbo PJ. Hyperlipidemia in patients with primary and secondary hypothyroidism. Mayo Clin Proc. 1993;68:860 – 866. 8. Caron P, Calazel C, Parra HJ, et al. Decreased HDL cholesterol in subclinical hypothyroidism: the effect of L-thyroxine therapy. Clin Endocrinol (Oxf). 1990;33:519 –523. 9. Staub JJ, Althaus BU, Engler H, et al. Spectrum of subclinical and overt hypothyroidism: effect on thyrotropin, prolactin, and thyroid reserve, and metabolic impact on peripheral target tissues. Am J Med. 1992;92:631– 642. 10. Kung AW, Pang RW, Janus ED. Elevated serum lipoprotein(a) in subclinical hypothyroidism. Clin Endocrinol (Oxf). 1995;43:445– 449. 11. Bell GM, Todd WT, Forfar JC, et al. End-organ responses to thyroxine therapy in subclinical hypothyroidism. Clin Endocrinol (Oxf). 1985;22:83– 89. 12. Bogner U, Arntz HR, Peters H, Schleusener H. Subclinical hypothyroidism and hyperlipoproteinaemia: indiscriminate L-thyroxine treatment not justified. Acta Endocrinol (Copenh). 1993;128: 202–206. 13. Arem R, Patsch W. Lipoprotein and apolipoprotein levels in subclinical hypothyroidism. Effect of levothyroxine therapy. Arch Intern Med. 1990;150:2097–2100.
Thyroid Function and Lipids in Older Women/Bauer et al 14. Franklyn JA, Daykin J, Betteridge J, et al. Thyroxine replacement therapy and circulating lipid concentrations. Clin Endocrinol (Oxf). 1993;38:453– 459. 15. Nystrom E, Caidahl K, Fager G, et al. A double-blind cross-over 12-month study of L-thyroxine treatment of women with “subclinical” hypothyroidism. Clin Endocrinol. 1988;29:63–76. 16. Cooper D, Halpern R, Wood L, et al. L-thyroxine therapy in subclinical hypothyroidism. Ann Intern Med. 1984;101:18 –24. 17. Jaeschke R, Guyatt G, Gerstein H, et al. Does treatment with L-thyroxine influence health status in middle-aged and older adults with subclinical hypothyroidism? J Gen Intern Med. 1996;11:744 – 749. 18. Tanis BC, Westendorp GJ, Smelt HM. Effect of thyroid substitution on hypercholesterolaemia in patients with subclinical hypothyroidism: a reanalysis of intervention studies. Clin Endocrinol (Oxf). 1996;44:643– 649. 19. Bauer DC, Browner WS, Cauley JA, et al. Factors associated with appendicular bone mass in older women. The Study of Osteoporotic Fractures Research Group. Ann Intern Med. 1993;118:657– 665. 20. Paffenbarger RS Jr, Wing AL, Hyde RT. Physical activity as an index of heart attack risk in college alumni. Am J Epidemiol. 1978;108: 161–175. 21. Lohman TG, Roche AF, Martorell R. Anthropometric Standardization Reference Manual. 1st ed. Champaign, Ill: Human Kinetics Books; 1988. 22. Kashiwai T, Ichihara K, Tamaki H, et al. The stability of immunological and biological activity of human thyrotropin in buffer: its temperature-dependent dissociation into subunits during freezing. Scan J Clin Lab Invest. 1991;51:417– 423. 23. Stall G, Harris S, Sokoll LJ, Dawson-Hughes B. Accelerated bone loss in hypothyroid patients overtreated with l-thyroxine. Ann Intern Med. 1990;113:265–269. 24. Spencer C, Schwarzbein D, Guttler R, et al. Thyrotropin (TSH)releasing hormone stimulation test responses employing third and fourth generation TSH assays. J Clin Endocrinol Metab. 1992;76: 494 – 498. 25. Abrams JJ, Grundy SM. Cholesterol metabolism in hypothyroidism and hyperthyroidism in man. J Lipid Res. 1981;22:323–338. 26. Staels B, Van Tol A, Chan L, et al. Alterations in thyroid status modulate apolipoprotein, hepatic triglyceride lipase, and low density lipoprotein receptor in rats. Endocrinology. 1990;127:1144 – 1152. 27. Thompson GR, Soutar AK, Spengel FA, et al. Defects of receptormediated low density lipoprotein catabolism in homozygous familial hypercholesterolemia and hypothyroidism in vivo. Proc Natl Acad Sci USA. 1981;78:2591–2595. 28. Wiseman SA, Powell JT, Humphries SE, Press M. The magnitude of the hypercholesterolemia of hypothyroidism is associated with variation in the low density lipoprotein receptor gene. J Clin Endocrinol Metab. 1993;77:108 –112. 29. Valdemarsson S, Nilsson-Ehle P. Hepatic lipase and the clearing reaction: studies in euthyroid and hypothyroid subjects. Horm Metab Res. 1987;19:28 –30. 30. Muls E, Rosseneu M, Blaton V, et al. Serum lipids and apolipoproteins A-I, A-II and B in primary hypothyroidism before and during treatment. Eur J Clin Invest. 1984;14:12–15. 31. Agdeppa D, Macaron C, Mallik T, Schnuda ND. Plasma high density lipoprotein cholesterol in thyroid disease. J Clin Endocrinol Metab. 1979;49:726 –729. 32. Althaus BU, Staub JJ, Ryff-De Leche A, et al. LDL/HDL-changes in subclinical hypothyroidism: possible risk factors for coronary heart disease. Clin Endocrinol (Oxf). 1988;28:157–163. 33. Friis T, Pedersen LR. Serum lipids in hyper- and hypothyroidism before and after treatment. Clin Chim Acta. 1987;162:155–163.
34. Verdugo C, Perrot L, Ponsin G, et al. Time-course of alterations of high density lipoproteins (HDL) during thyroxine administration to hypothyroid women. Eur J Clin Invest. 1987;17:313–316. 35. Arem R, Escalante DA, Arem N, et al. Effect of L-thyroxine therapy on lipoprotein fractions in overt and subclinical hypothyroidism, with special reference to lipoprotein(a). Metabolism. 1995;44: 1559 –1563. 36. Diekman T, Lansberg PJ, Kastelein JJ, Wiersinga WM. Prevalence and correction of hypothyroidism in a large cohort of patients referred for dyslipidemia. Arch Intern Med. 1995;155:1490 –1495. 37. Glueck CJ, Lang J, Tracy T, Speirs J. The common finding of covert hypothyroidism at initial clinical evaluation for hyperlipoproteinemia. Clin Chim Acta. 1991;201:113–122. 38. Ball MJ, Griffiths D, Thorogood M. Asymptomatic hypothyroidism and hypercholesterolaemia. J R Soc Med. 1991;84:527–529. 39. Series JJ, Biggart EM, O’Reilly DS, et al. Thyroid dysfunction and hypercholesterolaemia in the general population of Glasgow, Scotland. Clin Chim Acta. 1988;172:217–221.
APPENDIX Investigators in the Study of Osteoporotic Fractures Research Group are as follows: University of California, San Francisco (Coordinating Center): S. R. Cummings (principal investigator), M. C. Nevitt (co-investigator), D. G. Seeley (project director), D. M. Black (study statistician), H. K. Genant (director, central radiology laboratory), C. Arnaud, D. Bauer, W. Browner, L. Christianson, M. Dockrell, C. Fox, S. Harvey, M. Jergas, R. Lipschutz, G. Milani, L. Palermo, R. San Valentin, K. Stone, D. Tanaka. University of Maryland: J. C. Scott (principal investigator), R. Sherwin (co-principal investigator), M. C. Hochberg (co-investigator), J. Lewis (project director), Cheryl Bailey (clinic coordinator), A. Bauer, L. Finazzo, G. Greenberg, D. Harris, B. Hohman, S. Kallenberger, E. Oliner, T. Page, A. Pettit, S. Snyder, L. Stranovsky, S. Trusty. University of Minnesota: K. Ensrud (principal investigator), R. Grimm, Jr. (co-investigator), C. Bell (project director), E. Mitson (clinic coordinator), M. Baumhover, C. Berger, S. Estill, S. Fillhouer, J. Hansen, K. Jacobson, K. Kiel, C. Linville, N. Nelson, E. Penland-Miller, J. Griffith. University of Pittsburgh: J. A. Cauley (principal investigator), L. H. Kuller (co-principal investigator), M. Vogt (co-investigator), L. Harper (project director), L. Buck (clinic coordinator), C. Bashada, A. Githens, A. McCune, D. Medve, M. Nasim, C. Newman, S. Rudovsky, N. Watson. The Kaiser Permanente Center for Health Research, Portland, Oregon: T. M. Vogt (principal investigator), W. M. Vollmer, E. Orwoll, H. Nelson, (co-investigators), J. Blank (project director), S. Craddick (clinic coordinator), R. Bright, J. Wallace, F. Heinith, K. Moore, K. Redden, C. Romero, C. Souvanlasy.
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