Background/Aim: The cardiovascular effects of postmenopausal hormone replacement are controversially discussed. We investigated the effects of 12 months of treatment with conjugated equine estrogen and medroxyprogesterone acetate on lipoprotein(a) [Lp(a)] and other lipoproteins in Japanese postmenopausal women (PMW) with and without dyslipidemia. Methods: Forty-three normolipidemic and 17 dyslipidemic PMW [total cholesterol (TC) ≧220 mg/dl or triglyceride (TG) ≧150 mg/dl] received conjugated equine estrogen (0.625 mg) plus medroxyprogesterone acetate (2.5 mg) daily for 12 months, and the results were compared with those of 26 normolipidemic and 14 dyslipidemic subjects declining this treatment as controls. The fasting serum levels of Lp(a), TC, TG, high-density lipoprotein cholesterol, low- density lipoprotein cholesterol, apolipoprotein (Apo) AI, Apo AII, Apo B, Apo CII, and Apo E were measured in each subject at baseline and 12 months after this treatment initiation. Results: The treatment decreased Lp(a) similarly in normolipidemic and dyslipidemic PMW and decreased TC, low-density lipoprotein cholesterol, Apo CII, and Apo E and increased high-density lipoprotein cholesterol, Apo AI, and Apo AII in both groups. The therapy also significantly increased TG in normolipidemic but not dyslipidemic subjects. In controls, the levels of Lp(a) and other lipoproteins were unaltered. Conclusions: In PMW with or without dyslipidemia, improvement in Lp(a) and other lipoproteins may represent cardiovascular benefits of hormone replacement therapy. However, an elevation of the TG levels seen with the therapy warrants caution, especially in PMW without dyslipidemia.

1.
Anonymous: Lipoprotein(a). Lancet 1991;337:397–398.
2.
Scanu AM, Gunther MF: Lipoprotein(a). J Clin Invest 1990;85:1709–1715.
3.
Bostom AG, Gagnon DR, Cupples LA, Wilson PW, Jenner JL, Ordovas JM, Schaefer EJ, Castelli WP: A prospective investigation of elevated lipoprotein(a) detected by electrophoresis and cardiovascular disease in women. The Framingham Heart Study. Circulation 1994;90:1688–1695.
4.
Schaefer EJ, Lamon-Fava S, Jenner JL, McNamara JR, Ordovas JM, Davis CE, Abolafia JM, Lippel K, Levy RI: Lipoprotein(a) levels and risk of coronary heart disease in men. The lipid Research Clinics Coronary Primary Prevention Trial. JAMA 1994;271:999–1003.
5.
Wald NJ, Law M, Watt HC, Wu T, Bailey A, Johnson AM, Craig WY, Ledue TB, Haddow JE: Apolipoproteins and ischaemic heart disease: Implications for screening. Lancet 1994;343:75–79.
6.
Stevenson JC, Crook D, Godsland IF: Influence of age and menopause on serum lipids and lipoproteins in healthy women. Atherosclerosis 1993;98:83–90.
7.
Jenner JL, Ordovas JM, Lamon-Fava S, Schaefer MM, Wilson PW, Castelli WP, Schaefer EJ: Effects of age, sex, and menopausal status on plasma lipoprotein(a) levels. The Framingham Offspring Study. Circulation 1993;87:1135–1141.
8.
Brown SA, Hutchinson R, Morrisett J, Boerwinkle E, Davis CE, Gotto AM: Plasma lipid, lipoprotein cholesterol, and apoprotein distributions in selected US communities. The Atherosclerosis Risk in Communities (ARIC) Study. Arterioscler Thromb Vasc Biol 1993;13:1139–1158.
9.
Lobo RA: Lipids, clotting factors, and diabetes: Endogeneous risk factors for cardiovascular disease. Am J Obstet Gynecol 1988;158:1584–1591.
10.
Mosca L, Grundy SM, Judelson D, King K, Limacher M, Oparil S, Pasternak R, Pearson TA, Redberg RF, Smith SC Jr, Winston M, Zinberg S: Guide to Preventive Cardiology for Women. AHA/ACC Scientific Statement Consensus panel statement. Circulation 1999;99:2480–2484.
11.
Ballantyne CM: Low-density lipoproteins and risk for coronary artery disease. Am J Cardiol 1998;82:3Q–12Q.
12.
Lobo RA, Pickar JH, Wild RA, Walsh B, Hirvonen E: Metabolic impact of adding medroxyprogesterone acetate to conjugated estrogen therapy in postmenopausal women. Obstet Gynecol 1994;84:987–995.
13.
Lobo RA, Bush T, Carr BR, Pickar JH: Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on plasma lipids and lipoproteins, coagulation factors, and carbohydrate metabolism. Fertil Steril 2001:76:13–24.
14.
The Writing Group for the PEPI Trial: Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1995;273:199–208.
15.
Walsh BW, Schiff I, Rosner B, Greenberg L, Ravnikar V, Sacks FM: Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N Engl J Med 1991;325:1196–1204.
16.
Soma MR, Osnago-Gadda I, Paoletti R, Fumagalli R, Morrisett JD, Meschia M, Crosignani P: The lowering of lipoprotein(a) induced by estrogen plus progesterone replacement therapy in postmenopausal women. Arch Intern Med 1993;153:1462–1468.
17.
Haines C, Chung T, Chang A, Masarei J, Tomlinson B, Wong E: Effect of oral estradiol on Lp(a) and other lipoproteins in postmenopausal women. Arch Intern Med 1996;156:866–872.
18.
Darling GM, Johns JA, McCloud PI, Davis SR: Estrogen and progestin compared with simvastatin for hypercholesterolemia in postmenopausal women. N Engl J Med 1997;337:595–601.
19.
Sbarouni E, Kyriakides ZS, Kremastinos DT: The effect of hormone replacement therapy alone and in combination with simvastatin on plasma lipids of hypercholesterolemic postmenopausal women with coronary artery disease. J Am Coll Cardiol 1998;32:1244–1250.
20.
Soma M, Fumagalli R, Paoletti R, Meschia M, Maini MC, Crosignani P, Ghanem K, Gaubatz J, Morrisett JD: Plasma Lp(a) concentration after oestrogen and progestagen in postmenopausal women. Lancet 1991;337:612.
21.
Farish E, Rolton HA, Barnes JF, Hart DM: Lipoprotein(a) concentrations in postmenopausal women taking norethisterone. BMJ 1991;303:694.
22.
Espeland MA, Marcovina SM, Miller V, Wood PD, Wasilauskas C, Sherwin R, Schrott H, Bush TL: Effect of postmenopausal hormone therapy on lipoprotein(a) concentration. PEPI Investigators. Postmenopausal Estrogen/Progestin Interventions. Circulation 1998;97:979–986.
23.
Shlipak MG, Simon JA, Vittinghoff E, Lin F, Barrett-Connor E, Knopp RH, Levy RI, Hulley SB: Estrogen and progestin, lipoprotein(a), and the risk of recurrent coronary heart disease events after menopause. JAMA 2000;283:1845–1852.
24.
Kim CJ, Min YK, Ryu WS, Kwak JW, Ryoo UH: Effect of hormone replacement therapy on lipoprotein(a) and lipid levels in postmenopausal women: Influence of various progestogens and duration of therapy. Arch Intern Med 1996;156:1693–1700.
25.
Sacks FM, McPherson R, Walsh BW: Effect of postmenopausal estrogen replacement on plasma Lp(a) lipoprotein concentrations. Arch Intern Med 1994;154:1106–1110.
26.
Sanada M, Higashi Y, Nakagawa K, Tsuda M, Kodama I, Kimura M, Chayama K, Ohama K: Hormone replacement effects on endothelial function measured in the forearm resistance artery in normocholesterolemic and hypercholesterolemic postmenopausal women. J Clin Endocrinol Metab 2002;87:4634–4641.
27.
Somekawa Y, Umeki H, Kobayashi K, Tomura S, Aso T, Hamaguchi H: Effects of hormone replacement therapy and hepatic lipase polymorphism on serum lipid profiles in postmenopausal Japanese women. J Clin Endocrinol Metab 2002;87:4766–4770.
28.
Sumino H, Nakamura T, Ichikawa S, Kanda T, Sakamaki T, Sato K, Kobayashi I, Nagai R: Serum level of vascular endothelial growth factor is decreased by hormone replacement therapy in postmenopausal women without hypercholesterolemia. Atherosclerosis 2000;148:189–195.
29.
Sumino H, Ichikawa S, Murakami M, Nakamura T, Kanda T, Sakamaki T, Mizunuma H, Kurabayashi M: Effects of hormone replacement therapy on circulating docosahexaenoic acid and eicosapentaenoic acid levels in postmenopausal women. Endocr J 2003;50:51–59.
30.
Sumino H, Ichikawa S, Yoshida A, Murakami M, Kanda T, Mizunuma H, Sakamaki T, Kurabayashi M: Effects of hormone replacement therapy on weight, abdominal fat distribution, and lipid levels in Japanese postmenopausal women. Int J Obes Relat Metab Disord 2003;27:1044–1051.
31.
Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E: Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605–613.
32.
Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, Hsia J, Hulley S, Herd A, Khan S, Newby LK, Waters D, Vittinghoff E, Wenger N: Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/Progestin Replacement Study Follow-Up (HERS II). JAMA 2002;288:49–57.
33.
Writing Group for the Women’s Health Initiative Investigators: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321–333.
34.
Gotto AM: Triglyceride as a risk factor for coronary artery disease. Am J Cardiol 1998;82:22Q–25Q.
35.
Anonymous: Investigating Committee of Guidelines for Diagnosis and Treatment of Hyperlipidemias. J Jpn Atheroscler Soc 1997;25:1–34.
36.
Friedewald WT, Levy RI, Fredrickson DS: Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499–502.
37.
Rader D, Cain W, Zech L, Kindt M, Usher D, Brewer HB Jr: Lp(a): Plasma levels in individuals with the same apo(a) isoprotein are determined by differences in production rates. Circulation 1991;84:II–565.
38.
Mann AW, Kraft HG, Rader DJ, Schaefer JR, Zech LA, Gregg RE, Hoeg JM, Breuer HB Jr: Human in vivo catabolism of lipoprotein(a). Circulation 1989;80:II–181.
39.
Hofmann SL, Eaton DL, Brown MS, McConathy WJ, Goldstein JL, Hammer RE: Overexpression of human low density lipoprotein receptors leads to accelerated catabolism of Lp(a) lipoprotein in transgenic mice. J Clin Invest 1990;85:1542–1547.
40.
Windler E, Kovanen PT, Chao YS, Brown ML, Havel RJ, Goldstein JL: The estradiol-stimulated lipoprotein receptor of rat liver. J Biol Chem 1980;255:19464–19471.
41.
Ma PT, Yamamoto T, Goldstein JL, Brown MS: Increased mRNA for low density lipoprotein receptor in livers of rabbits treated with 17 alpha ethinyl estradiol. Proc Natl Acad Sci USA 1986;83:792–796.
42.
Inoue M, Itoh H, Ueda M, Naruko T, Kojima A, Komatsu R, Doi K, Ogawa Y, Tamura N, Takaya K, Igaki T, Yamashita J, Chun TH, Masatsugu K, Becker AE, Nakao K: Vascular endothelial growth factor (VEGF) expression in human coronary atherosclerotic lesions: Possible pathophysiological significance of VEGF in progression of atherosclerosis. Circulation 1998;98:2108–2116.
43.
Tsurumi Y, Murohara T, Krasinski K, Chen D, Witzenbichler B, Kearney M, Couffinhal T, Isner JM: Reciprocal relation between VEGF and NO in the regulation of endothelial integrity. Nat Med 1997;3:879–886.
44.
Bergstrom T, Trybala E, Spillmann D: VEGF-nitric oxide reciprocal regulation. Nat Med 1997;3:1177.
45.
Sanada M, Nakagawa H, Kodama I, Sakasita T, Ohama K: Three-year study of estrogen alone versus combined with progestin in postmenopausal women with or without hypercholesterolemia. Metabolism 2000;49:784–789.
46.
Twickler TB, Dallinga-Thie GM, de Valk HW, Schreuder PC, Jansen H, Cabezas MC, Erkelens DW: High dose of simvastatin normalizes postprandial remnant-like particle response in patients with heterozygous familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 2000;20:2422–2427.
47.
Jensen GL, Daggy B, Bensadoun A: Triacylglycerol lipase, monoacylglycerol lipase, and phospolipase activities of highly purified rat hepatic lipase. Biochim Biophys Acta 1982;710:464–470.
48.
Bensadoun A, Berryman DE: Genetics and molecular biology of hepatic lipase. Curr Opin Lipidol 1996;7:77–81.
49.
Zambon A, Austin MA, Brown BG, Hokanson JE, Brunzell JD: Effect of hepatic lipase on LDL in normal men and those with coronary artery disease. Arterioscler Thromb 1993;13:147–153.
50.
Watson TD, Caslake MJ, Freeman DJ, Griffin BA, Hinnie J, Packard CJ, Shepherd J: Determinants of LDL subfraction distribution and concentrations in young normolipidemic subjects. Arterioscler Thromb 1994;14:902–910.
51.
Kuusi T, Saarinen P, Nikkila EA: Evidence for the role of hepatic endothelial lipase in the metabolism of plasma high density lipoprotein 2 in man. Atherosclerosis 1980;36:589–593.
52.
Guerra R, Wang J, Grundy SM, Cohen JC: A hepatic lipase (LIPC) allele associated with high plasma concentrations of high density lipoprotein cholesterol. Proc Natl Acad Sci USA 1997;94:4532–4537.
53.
Zambon A, Deeb SS, Hokanson JE, Brown BG, Brunzell JD: Common variants in the promoter of the hepatic lipase gene are associated with lower levels of hepatic lipase activity, buoyant LDL, and higher HDL2 cholesterol. Arterioscler Thromb Vasc Biol 1998;18:1723–1729.
54.
Brinton EA: Oral estrogen replacement therapy in postmenopausal women selectively raises levels and production rates of lipoprotein A-I and lowers hepatic lipase activity without lowering the fractional catabolic rate. Arterioscler Thromb Vasc Biol 1996;16:431–440.
55.
Mikkola TS, Clarkson TB: Estrogen replacement therapy, atherosclerosis, and vascular function. Cardiovasc Res 2002;53:605–619.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.