(Circulation. 1997;96:3774-3777.)
© 1997 American Heart Association, Inc.
Articles |
Premature Coronary Artery Disease Associated With a Disruptive Mutation in the Estrogen Receptor Gene in a Man
From the Cardiology Division, Department of Medicine (K.S., T.M.C., K.C.) and the Cardiovascular Research Institute (J.P.K., M.J.M., K.S., T.M.C., K.C.), University of California, San Francisco; the Division of Endocrinology, Children's Hospital Medical Center (E.P.S.) and the Division of Endocrinology, University of Cincinnati (Ohio) College of Medicine (T.C.W.); National Institutes of Environmental Health Sciences, Research Triangle Park, NC (K.S.K.); and Berlex Biosciences, Richmond, Calif (G.M.R.). Correspondence to K. Sudhir, MD, PhD, Box 0124, University of California, San Francisco, CA 94143-0124.
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Abstract |
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Background While estrogens protect against coronary artery disease in women, it is unclear whether they influence cardiovascular function in men. The present report describes coronary vascular abnormalities and the lipoprotein profile of a male patient with estrogen insensitivity caused by a disruptive mutation in the estrogen-receptor gene.
Methods and Results Stress thallium scintigraphy, echocardiography, and electron-beam computed tomography (CT) scanning of the coronary arteries and detailed lipoprotein analysis were performed. Electron-beam CT scanning of the coronary arteries showed calcium in the left anterior descending artery. Lipoprotein analysis showed relatively low levels of total (130 mg/dL), LDL (97 mg/dL), and HDL (34 mg/dL) cholesterol; apolipoprotein A-I (91.7 mg/dL;); and lipoprotein(a) (4.1 nmol/L), but normal levels of triglycerides (97 mg/dL) and pre-ß-1-HDL cholesterol (61 µg/mL).
Conclusions The absence of functional estrogen receptors may be a novel risk factor for coronary artery disease in men.
Key Words: estrogen • men • coronary disease
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Estrogens provide protection against the development of cardiovascular disease in women.1 Receptors for sex steroids have been identified in the human aorta, internal carotid, internal mammary and coronary arteries, and saphenous veins in both smooth muscle and endothelial cells.2–5 Estrogens induce coronary vasorelaxation6,7 and reportedly attenuate acetylcholine-induced vasoconstriction in atherosclerotic coronary arteries in women.8,9 Estrogen supplementation also augments flow-mediated vasodilation in the brachial artery in hypercholesterolemic postmenopausal women10 and enhances basal nitric oxide release in perimenopausal women.11 In men, although short-term administration of 17-ß estradiol does not attenuate acetylcholine-induced coronary vasoconstriction,9 preliminary reports indicate that conjugated estrogens acutely improve coronary vascular reactivity.12,13
Although it is unclear whether estrogens influence cardiovascular function in men, physiological levels of estrogen have been reported to play a role in influencing plasma levels of HDL cholesterol in men.14 Low HDL concentrations have also been reported in a man with aromatase deficiency (associated with very low estrogen concentrations)15 and in the male individual previously described with a missense mutation in both alleles of the estrogen receptor gene.16 In the male estrogen receptor knockout mouse, basal nitric oxide release is reportedly impaired in the aorta,17 suggesting that as in women, estrogen may regulate cardiovascular function in men. Here, we report the results of lipoprotein studies and noninvasive evaluation for coronary artery disease in the young man previously described with estrogen resistance resulting from a mutation in the estrogen receptor gene.16
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Methods |
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The patient is a 31-year-old man whose estrogen insensitivity is caused by a disruptive mutation in the estrogen receptor gene.16 The patient presented at 28 years of age with tall stature (204 cm, 80.3 in), normal masculinization, incomplete epiphyseal closure, and decreased bone mineral density. His serum estradiol and estrone, serum follicle-stimulating hormone, and luteinizing hormone concentrations were elevated; serum testosterone concentrations were normal. Direct sequencing of exon 2 of his estrogen receptor gene revealed a cytosine-to-thymine transition at codon 157 of both alleles, resulting in a premature stop codon and expression of a truncated nonfunctional estrogen receptor protein.16 Evaluation of the subject for coronary artery disease and lipoprotein analysis were performed as follows.
Lipoprotein Measurements
Blood was drawn after a 10-hour overnight fast. Total plasma
cholesterol and triglycerides were measured
enzymatically as described previously,18 and HDL
cholesterol was measured after polyanion precipitation. The
apolipoprotein A-I content of plasma was measured by an ELISA
technique.19 Lipoprotein(a) levels were measured
by an ELISA in which the lipoprotein(a)–associated apolipoprotein B
was quantified similarly. The plasma content of pre-ß-1 (67 kD) HDL
cholesterol was measured by isotope dilution by use of the
apolipoprotein A-I ELISA technique.19
Transthoracic Echocardiography
Two-dimensional and Doppler
echocardiographic examination of the heart and
ascending aorta was performed with a Hewlett Packard Sonos 1500
echocardiograph. A standard transthoracic
examination was performed from multiple imaging planes with the subject
recumbent in the left lateral decubitus and supine positions and
breathing quietly. Doppler interrogation of all valves was
performed.
Exercise Treadmill Testing and Myocardial Perfusion Single-Photon
Emission Computed Tomography
Exercise treadmill stress thallium scintigraphy
(Cardiolite, DuPont Scandinavia AB) myocardial perfusion single-photon
emission computed tomography was performed by use of the modified Bruce
protocol in standard fashion. Intravenous injection of 27.4
mCi of isotope was administered for the stress imaging, and 27.2 mCi
was given for rest imaging.
Electron-Beam CT Scanning
An electron-beam CT (EBCT) or "ultrafast CT" scan was
performed. In this test, a single–breath-hold ECG-gated CT scan is
performed. The EBCT scan was performed by use of an Imatron C-100 EBCT
scanner in high-resolution volume mode with a 100-month exposure time.
ECG triggering was used so that each image was obtained at the same
point in diastole, corresponding to 80% of the RR
interval. Proximal coronary artery visualization was obtained
without contrast medium injection, and at least 20 consecutive images
were obtained at 3-mm intervals beginning 1 cm below the carina and
progressing caudally to include the proximal coronary arteries.
The lesion score was calculated by multiplying the lesion area by a
density factor described by Agatston et al.20 A
total calcium score was determined by summing individual lesion scores
from each of four anatomic sites (left main, left anterior descending,
circumflex, and right coronary arteries).
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Lipoprotein Measurements
The patient is a nonsmoker. Supine blood pressure was 130/64 mm Hg. The total cholesterol and triglyceride contents of plasma were 130 and 97 mg/dL, respectively. HDL choleterol was 34 mg/dL, and VLDL cholesterol was 19 mg/dL. By calculation, the LDL cholesterol level was 77 mg/dL. The total cholesterol level was below the 5th percentile, and both the LDL and HDL cholesterol levels were at the 10th percentile for a man of the patient's age. The lipoprotein(a) associated apolipoprotein B level was 4.1 nmol/L, also below the 10th percentile. The total level of apolipoprotein A-I was 91.7 mg/dL,
68% of the mean value for adult men. The content
of pre-ß-1 HDL measured as apolipoprotein A-I was 61 µg/mL,
representing 6.7% of total apolipoprotein A-I. This value
compares to a mean of 74±43 (mean±SD) µg/mL for 146 healthy
normolipidemic individuals (6.6±3.5% of total apolipoprotein A-I)
studied by the same method.
Transthoracic Echocardiography
Cardiac chamber dimensions and function were normal, and there
were no wall motion abnormalities detected. There was no evidence of
valvular heart disease. The ascending aorta appeared normal in
morphology and dimension and was free of atherosclerotic plaque.
Exercise Stress Testing
In view of the patient's arthritis involving joints of the lower
extremities, the modified Bruce protocol was used. The patient
exercised for 9 minutes and 5 seconds, reaching a heart rate of 178 bpm
(103% of maximum predicted heart rate for age,
representing maximum workload of 10 metabolic equivalents
[METS]). There was no ECG evidence of exercise-induced
ischemia or arrhythmias. Myocardial perfusion
single-photon emission computed tomography showed no evidence of
stress-induced reversible ischemia. The left
ventricular chamber size was within normal limits. The peak
count rate was 1017 during stress imaging and 627 during rest, with a
ratio of 0.61, suggesting a significant washout effect. In view of the
normal exercise study, cardiac catheterization and
coronary angiography were not performed.
Coronary EBCT Scanning
EBCT scanning of the coronary arteries showed evidence of
coronary calcification, with a calcium score of 47 in the left
anterior descending coronary artery distribution and a score of
1 in the right coronary artery, yielding a total score of 48
(see the Figure
).
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Discussion |
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The role of endogenous estrogens in protection from cardiovascular disease in men is poorly understood; the coronary arterial and lipoprotein studies in this man with a mutation of the estrogen receptor gene provide some intriguing insights. Although an association between the presence of estrogen receptors and the absence of coronary atherosclerosis in premenopausal women has previously been suggested,4 no direct evidence of such an association has been shown in men. The present report suggests that structural abnormalities of the coronary vasculature are associated with the absence of functional estrogen receptors.
The patient demonstrates evidence of early atherosclerosis, as shown by calcium deposition in the left anterior descending coronary artery on EBCT. Although we cannot exclude the possibility that the coronary calcification observed in this patient may be a direct result of his estrogen resistance and independent of atherosclerosis, it is likely that it indicates underlying coronary artery disease for the following reasons. Coronary calcification is a process occurring within atherosclerotic plaques either as nodular masses in the lipid pool or as irregular plates in the dense collagen of advanced lesions.21 There are several connections between lipids and tissue calcification,22 and there is evidence that cholesterol occurs at the center of calcified granules of atherosclerotic plaques, suggesting that lipids may act to nucleate the calcium mineral crystals.23 The technique of EBCT is sensitive in detecting the presence of coronary calcification, which is usually otherwise subclinical, and EBCT-derived calcium scores correlate well with angiographically documented coronary artery disease. Agatston et al20 showed that subjects between the ages of 30 and 39 years had a mean score of 5±2 in the absence of coronary artery disease and a score of 132±91 (mean±SEM) when clinical coronary artery disease was present. By these criteria, our patient thus has an abnormal calcium score for his age. A recent study24 showed that a coronary calcification score of >100 predicted cardiovascular events in a cohort of 1173 asymptomatic patients in a 19-month follow-up. Thus, although our finding indicates premature coronary artery disease, this patient is not likely to be at immediate risk of a clinical event. Exercise stress testing using myocardial perfusion scintigraphy showed normal coronary perfusion, again suggesting that although atherosclerotic coronary artery disease is present in a proximal coronary artery, the lesion is not flow limiting.
The relatively low level of LDL cholesterol in this patient could be the result of diminished secretion of its precursor VLDL because estrogens increase VLDL triglyceride production25 and the estrogen receptor is expressed in liver.26 The low level of HDL cholesterol and apoliprotein A-I may also reflect the lack of estrogenic effect. Natural estrogens are responsible for the higher levels of HDL cholesterol and apoliprotein A-I observed in menstruating women than in men or postmenopausal women, and the administration of estrogens increases levels of HDL cholesterol25 and apoliprotein A-I.27 Furthermore, because androgens cause a reduction in levels of HDL,28 the action of unopposed androgens could account for the very low levels observed in this patient. It is of interest that despite the low level of total apoliprotein A-I, the levels of pre-ß-1 HDL are maintained in the normal range. In view of the role of pre-ß-1 HDL as the primary acquisitor of cholesterol in the reverse cholesterol transport pathway,29,30 a function of HDL that is of potential importance in protecting against atherogenesis may be relatively intact in this patient despite low levels of total HDL mass. The recent report of a second estrogen receptor31 might suggest that some functions of estrogen (such as effects on certain lipoproteins) could be preserved in this patient. However, it is possible that antiatherogenic functions of HDL, such as inhibition of oxidation,32 are affected.
The subject is a nonsmoker and is normotensive, and cholesterol concentrations were not elevated. Of interest, we have recently demonstrated impaired flow-mediated endothelium-dependent vasodilation in the peripheral vasculature of this individual.33 Thus, absence of a functional estrogen receptor appears to be associated with endothelial dysfunction and early atherosclerotic coronary artery disease. In conclusion, some actions of estrogen, mediated via the estrogen receptor, are likely to be protective against the development of premature vascular disease in men.
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Acknowledgments |
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We wish to acknowledge the technical assistance of Laura Kee (Outpatient Cardiology Consult Service, University of California at San Francisco [UCSF]) and Samantha Schoenhaus (Lipid Research Laboratory, Cardiovascular Research Institute, UCSF). We thank Dr Dean Keriakis (The Ohio Heart Health Center, Cincinnati) for performing the exercise stress study, Dr David King (Imatron Inc, South San Francisco, Calif) for organizing the EBCT study, and Dr Patricia M. O'Connor, MD (Cardiovascular Research Institute, UCSF) for advice and assistance with the lipid assays.
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Footnotes |
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M. Kimura, K. Sudhir, M. Jones, E. Simpson, A.-M. Jefferis, and J. P.F. Chin-Dusting Impaired Acetylcholine-Induced Release of Nitric Oxide in the Aorta of Male Aromatase-Knockout Mice: Regulation of Nitric Oxide Production by Endogenous Sex Hormones in Males Circ. Res., December 12, 2003; 93(12): 1267 - 1271. [Abstract] [Full Text] [PDF]
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L. A. Fitzpatrick Hormones and the Heart: Controversies and Conundrums J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5609 - 5610. [Full Text] [PDF]
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V. Ferrero, F. Ribichini, G. Matullo, S. Guarrera, S. Carturan, A. Vado, C. Vassanelli, A. Piazza, E. Uslenghi, and W. Wijns Estrogen Receptor-{alpha} Polymorphisms and Angiographic Outcome After Coronary Artery Stenting Arterioscler. Thromb. Vasc. Biol., December 1, 2003; 23(12): 2223 - 2228. [Abstract] [Full Text] [PDF]
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R. Lew, P. Komesaroff, M. Williams, T. Dawood, and K. Sudhir Endogenous Estrogens Influence Endothelial Function in Young Men Circ. Res., November 28, 2003; 93(11): 1127 - 1133. [Abstract] [Full Text] [PDF]
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A. M. Shearman, L. A. Cupples, S. Demissie, I. Peter, C. H. Schmid, R. H. Karas, M. E. Mendelsohn, D. E. Housman, and D. Levy Association Between Estrogen Receptor {alpha} Gene Variation and Cardiovascular Disease JAMA, November 5, 2003; 290(17): 2263 - 2270. [Abstract] [Full Text] [PDF]
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M. Muller, Y. T. van der Schouw, J. H. H. Thijssen, and D. E. Grobbee Endogenous Sex Hormones and Cardiovascular Disease in Men J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5076 - 5086. [Abstract] [Full Text] [PDF]
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 F. C. W. Wu and A. von Eckardstein Androgens and Coronary Artery Disease Endocr. Rev., April 1, 2003; 24(2): 183 - 217. [Abstract] [Full Text] [PDF]
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B. L. Herrmann, B. Saller, O. E. Janssen, P. Gocke, A. Bockisch, H. Sperling, K. Mann, and M. Broecker Impact of Estrogen Replacement Therapy in a Male with Congenital Aromatase Deficiency Caused by a Novel Mutation in the CYP19 Gene J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5476 - 5484. [Abstract] [Full Text] [PDF]
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K. J. Ho and J. K. Liao Nonnuclear Actions of Estrogen Arterioscler. Thromb. Vasc. Biol., December 1, 2002; 22(12): 1952 - 1961. [Abstract] [Full Text] [PDF]
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K. L. Chambliss and P. W. Shaul Estrogen Modulation of Endothelial Nitric Oxide Synthase Endocr. Rev., October 1, 2002; 23(5): 665 - 686. [Abstract] [Full Text] [PDF]
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L. Molero, M. Garcia-Duran, J. Diaz-Recasens, L. Rico, S. Casado, and A. Lopez-Farre Expression of estrogen receptor subtypes and neuronal nitric oxide synthase in neutrophils from women and men: Regulation by estrogen Cardiovasc Res, October 1, 2002; 56(1): 43 - 51. [Abstract] [Full Text] [PDF]
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H. Lu, T. Higashikata, A. Inazu, A. Nohara, W. Yu, M. Shimizu, and H. Mabuchi Association of Estrogen Receptor-{alpha} Gene Polymorphisms With Coronary Artery Disease in Patients With Familial Hypercholesterolemia Arterioscler. Thromb. Vasc. Biol., May 1, 2002; 22(5): 817 - 823. [Abstract] [Full Text] [PDF]
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 D. M. Herrington, T. D. Howard, G. A. Hawkins, D. M. Reboussin, J. Xu, S. L. Zheng, K. B. Brosnihan, D. A. Meyers, and E. R. Bleecker Estrogen-Receptor Polymorphisms and Effects of Estrogen Replacement on High-Density Lipoprotein Cholesterol in Women with Coronary Disease N. Engl. J. Med., March 28, 2002; 346(13): 967 - 974. [Abstract] [Full Text] [PDF]
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T. S Mikkola and T. B Clarkson Estrogen replacement therapy, atherosclerosis, and vascular function Cardiovasc Res, February 15, 2002; 53(3): 605 - 619. [Abstract] [Full Text] [PDF]
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 D. M. Herrington and K. P. Klein Genome and Hormones: Gender Differences in Physiology: Invited Review: Pharmacogenetics of estrogen replacement therapy J Appl Physiol, December 1, 2001; 91(6): 2776 - 2784. [Abstract] [Full Text] [PDF]
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P. A. Komesaroff, M. Fullerton, M. D. Esler, A. Dart, G. Jennings, and K. Sudhir Low-Dose Estrogen Supplementation Improves Vascular Function in Hypogonadal Men Hypertension, November 1, 2001; 38(5): 1011 - 1016. [Abstract] [Full Text] [PDF]
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R. K. Dubey and E. K. Jackson Genome and Hormones: Gender Differences in Physiology: Invited Review: Cardiovascular protective effects of 17{beta}-estradiol metabolites J Appl Physiol, October 1, 2001; 91(4): 1868 - 1883. [Abstract] [Full Text] [PDF]
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 M. Jankowski, G. Rachelska, W. Donghao, S. M. McCann, and J. Gutkowska Estrogen receptors activate atrial natriuretic peptide in the rat heart PNAS, September 13, 2001; (2001) 201394198. [Abstract] [Full Text] [PDF]
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 R. K. Dubey and E. K. Jackson Estrogen-induced cardiorenal protection: potential cellular, biochemical, and molecular mechanisms Am J Physiol Renal Physiol, March 1, 2001; 280(3): F365 - F388. [Abstract] [Full Text] [PDF]
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P. Zhai, T. E. Eurell, R. Cotthaus, E. H. Jeffery, J. M. Bahr, and D. R. Gross Effect of estrogen on global myocardial ischemia-reperfusion injury in female rats Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H2766 - H2775. [Abstract] [Full Text] [PDF]
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 S. Jovanovic, A. Jovanovic, W. K. Shen, and A. Terzic Low concentrations of 17{beta}-estradiol protect single cardiac cells against metabolic stress-induced Ca2+ loading J. Am. Coll. Cardiol., September 1, 2000; 36(3): 948 - 952. [Abstract] [Full Text] [PDF]
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P. Zhai, T. E. Eurell, P. S. Cooke, D. B. Lubahn, and D. R. Gross Myocardial ischemia-reperfusion injury in estrogen receptor-alpha knockout and wild-type mice Am J Physiol Heart Circ Physiol, May 1, 2000; 278(5): H1640 - H1647. [Abstract] [Full Text] [PDF]
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Estrogen: Consequences and Implications of Human Mutations in Synthesis and Action J. Clin. Endocrinol. Metab., December 1, 1999; 84(12): 4677 - 4694. [Abstract] [Full Text]
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K. Sudhir and P. A. Komesaroff Cardiovascular Actions of Estrogens in Men J. Clin. Endocrinol. Metab., October 1, 1999; 84(10): 3411 - 3415. [Full Text] [PDF]
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M. E. Mendelsohn and R. H. Karas The Protective Effects of Estrogen on the Cardiovascular System N. Engl. J. Med., June 10, 1999; 340(23): 1801 - 1811. [Full Text] [PDF]
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J. F. Couse and K. S. Korach Estrogen Receptor Null Mice: What Have We Learned and Where Will They Lead Us? Endocr. Rev., June 1, 1999; 20(3): 358 - 417. [Abstract] [Full Text]
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M. Jankowski, G. Rachelska, W. Donghao, S. M. McCann, and J. Gutkowska Estrogen receptors activate atrial natriuretic peptide in the rat heart PNAS, September 25, 2001; 98(20): 11765 - 11770. [Abstract] [Full Text] [PDF]
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