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. 1989 Sep;84(3):802–810. doi: 10.1172/JCI114239

Effects of estrogen on low density lipoprotein metabolism in males. Short-term and long-term studies during hormonal treatment of prostatic carcinoma.

M Eriksson 1, L Berglund 1, M Rudling 1, P Henriksson 1, B Angelin 1
PMCID: PMC329722  PMID: 2760213

Abstract

To characterize the effects of estrogen treatment on the metabolism of LDL we studied six males with metastatic prostatic carcinoma before and during the initiation of therapy; a repeated study was performed in five participants after 3-6 mo of treatment. The fractional catabolic rate (FCR) of autologous 125I-LDL was calculated both from elimination curves of plasma radioactivity and from urine/plasma (U/P) radioactivity ratios. Within 1-2 d of onset of estrogen therapy a more rapid decay of plasma radioactivity occurred, and FCR measured from U/P ratios increased by 20%. Concomitantly, LDL cholesterol levels decreased by 16%. After 3-6 mo of treatment FCR determined by both techniques was almost doubled, and LDL cholesterol was reduced by 34%. This occurred despite a 29% increase in the calculated synthesis rate of LDL. Tissue culture studies demonstrated that the receptor affinity of LDL isolated from patients on long-term estrogen therapy was reduced. We conclude that a profound increase in LDL catabolism is induced through administration of pharmacological doses of estrogen in males, and hypothesize that this is the consequence of an increased expression of hepatic LDL receptors. This enhanced catabolism of LDL leaves LDL particles in plasma with lower affinity for the LDL receptor.

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Selected References

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  1. Angelin B., Raviola C. A., Innerarity T. L., Mahley R. W. Regulation of hepatic lipoprotein receptors in the dog. Rapid regulation of apolipoprotein B,E receptors, but not of apolipoprotein E receptors, by intestinal lipoproteins and bile acids. J Clin Invest. 1983 Apr;71(4):816–831. doi: 10.1172/JCI110835. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bilheimer D. W., Eisenberg S., Levy R. I. The metabolism of very low density lipoprotein proteins. I. Preliminary in vitro and in vivo observations. Biochim Biophys Acta. 1972 Feb 21;260(2):212–221. doi: 10.1016/0005-2760(72)90034-3. [DOI] [PubMed] [Google Scholar]
  3. Brown M. S., Goldstein J. L. A receptor-mediated pathway for cholesterol homeostasis. Science. 1986 Apr 4;232(4746):34–47. doi: 10.1126/science.3513311. [DOI] [PubMed] [Google Scholar]
  4. Brown M. S., Goldstein J. L. Lipoprotein receptors in the liver. Control signals for plasma cholesterol traffic. J Clin Invest. 1983 Sep;72(3):743–747. doi: 10.1172/JCI111044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brown M. S., Kovanen P. T., Goldstein J. L. Regulation of plasma cholesterol by lipoprotein receptors. Science. 1981 May 8;212(4495):628–635. doi: 10.1126/science.6261329. [DOI] [PubMed] [Google Scholar]
  6. Bulusu N. V., Lewis S. B., Das S., Clayton W. E., Jr Serum lipid changes after estrogen therapy in prostatic carcinoma. Urology. 1982 Aug;20(2):147–150. doi: 10.1016/0090-4295(82)90345-4. [DOI] [PubMed] [Google Scholar]
  7. Carlson K. Lipoprotein fractionation. J Clin Pathol Suppl (Assoc Clin Pathol) 1973;5:32–37. doi: 10.1136/jcp.s1-5.1.32. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chait A., Bierman E. L., Albers J. J. Low-density lipoprotein receptor activity in cultured human skin fibroblasts. Mechanism of insulin-induced stimulation. J Clin Invest. 1979 Nov;64(5):1309–1319. doi: 10.1172/JCI109587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chait A., Foster D., Miller D. G., Bierman E. L. Acceleration of low-density lipoprotein catabolism in man by total parenteral nutrition. Proc Soc Exp Biol Med. 1981 Oct;168(1):97–104. doi: 10.3181/00379727-168-41240. [DOI] [PubMed] [Google Scholar]
  10. Dashti N., Kelley J. L., Thayer R. H., Ontko J. A. Concurrent inductions of avian hepatic lipogenesis, plasma lipids, and plasma apolipoprotein B by estrogen. J Lipid Res. 1983 Apr;24(4):368–380. [PubMed] [Google Scholar]
  11. Deeley R. G., Tam S. P., Archer T. K. The effects of estrogen on apolipoprotein synthesis. Can J Biochem Cell Biol. 1985 Aug;63(8):882–889. doi: 10.1139/o85-109. [DOI] [PubMed] [Google Scholar]
  12. Einarsson K., Nilsell K., Leijd B., Angelin B. Influence of age on secretion of cholesterol and synthesis of bile acids by the liver. N Engl J Med. 1985 Aug 1;313(5):277–282. doi: 10.1056/NEJM198508013130501. [DOI] [PubMed] [Google Scholar]
  13. Forte T. M., Nordhausen R. W. Electron microscopy of negatively stained lipoproteins. Methods Enzymol. 1986;128:442–457. doi: 10.1016/0076-6879(86)28086-6. [DOI] [PubMed] [Google Scholar]
  14. Goldberg I. J., Le N. A., Paterniti J. R., Jr, Ginsberg H. N., Lindgren F. T., Brown W. V. Lipoprotein metabolism during acute inhibition of hepatic triglyceride lipase in the cynomolgus monkey. J Clin Invest. 1982 Dec;70(6):1184–1192. doi: 10.1172/JCI110717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Goldstein J. L., Brown M. S. Binding and degradation of low density lipoproteins by cultured human fibroblasts. Comparison of cells from a normal subject and from a patient with homozygous familial hypercholesterolemia. J Biol Chem. 1974 Aug 25;249(16):5153–5162. [PubMed] [Google Scholar]
  16. Grundy S. M., Vega G. L., Bilheimer D. W. Kinetic mechanisms determining variability in low density lipoprotein levels and rise with age. Arteriosclerosis. 1985 Nov-Dec;5(6):623–630. doi: 10.1161/01.atv.5.6.623. [DOI] [PubMed] [Google Scholar]
  17. Havel R. J. The formation of LDL: mechanisms and regulation. J Lipid Res. 1984 Dec 15;25(13):1570–1576. [PubMed] [Google Scholar]
  18. Heiss G., Tamir I., Davis C. E., Tyroler H. A., Rifkand B. M., Schonfeld G., Jacobs D., Frantz I. D., Jr Lipoprotein-cholesterol distributions in selected North American populations: the lipid research clinics program prevalence study. Circulation. 1980 Feb;61(2):302–315. doi: 10.1161/01.cir.61.2.302. [DOI] [PubMed] [Google Scholar]
  19. Henriksson P., Einarsson K., Eriksson A., Kelter U., Angelin B. Estrogen-induced gallstone formation in males. Relation to changes in serum and biliary lipids during hormonal treatment of prostatic carcinoma. J Clin Invest. 1989 Sep;84(3):811–816. doi: 10.1172/JCI114240. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Iverius P. H., Brunzell J. D. Relationship between lipoprotein lipase activity and plasma sex steroid level in obese women. J Clin Invest. 1988 Sep;82(3):1106–1112. doi: 10.1172/JCI113667. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kesaniemi Y. A., Grundy S. M. Significance of low density lipoprotein production in the regulations of plasma cholesterol level in man. J Clin Invest. 1982 Jul;70(1):13–22. doi: 10.1172/JCI110585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kuller L. H. Epidemiology of cardiovascular diseases: current perspectives. Am J Epidemiol. 1976 Oct;104(4):425–496. doi: 10.1093/oxfordjournals.aje.a112315. [DOI] [PubMed] [Google Scholar]
  23. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  24. Langer T., Strober W., Levy R. I. The metabolism of low density lipoprotein in familial type II hyperlipoproteinemia. J Clin Invest. 1972 Jun;51(6):1528–1536. doi: 10.1172/JCI106949. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. MATTHEWS C. M. The theory of tracer experiments with 131I-labelled plasma proteins. Phys Med Biol. 1957 Jul;2(1):36–53. doi: 10.1088/0031-9155/2/1/305. [DOI] [PubMed] [Google Scholar]
  26. Ma P. T., Yamamoto T., Goldstein J. L., Brown M. S. Increased mRNA for low density lipoprotein receptor in livers of rabbits treated with 17 alpha-ethinyl estradiol. Proc Natl Acad Sci U S A. 1986 Feb;83(3):792–796. doi: 10.1073/pnas.83.3.792. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Mahley R. W., Innerarity T. L. Lipoprotein receptors and cholesterol homeostasis. Biochim Biophys Acta. 1983 May 24;737(2):197–222. doi: 10.1016/0304-4157(83)90001-1. [DOI] [PubMed] [Google Scholar]
  28. Mazzone T., Foster D., Chait A. In vivo stimulation of low-density lipoprotein degradation by insulin. Diabetes. 1984 Apr;33(4):333–338. doi: 10.2337/diab.33.4.333. [DOI] [PubMed] [Google Scholar]
  29. Meddings J. B., Dietschy J. M. Regulation of plasma levels of low-density lipoprotein cholesterol: interpretation of data on low-density lipoprotein turnover in man. Circulation. 1986 Oct;74(4):805–814. doi: 10.1161/01.cir.74.4.805. [DOI] [PubMed] [Google Scholar]
  30. Nilsson-Ehle P., Garfinkel A. S., Schotz M. C. Lipolytic enzymes and plasma lipoprotein metabolism. Annu Rev Biochem. 1980;49:667–693. doi: 10.1146/annurev.bi.49.070180.003315. [DOI] [PubMed] [Google Scholar]
  31. Noble R. P. Electrophoretic separation of plasma lipoproteins in agarose gel. J Lipid Res. 1968 Nov;9(6):693–700. [PubMed] [Google Scholar]
  32. Rhoads G. G., Gulbrandsen C. L., Kagan A. Serum lipoproteins and coronary heart disease in a population study of Hawaii Japanese men. N Engl J Med. 1976 Feb 5;294(6):293–298. doi: 10.1056/NEJM197602052940601. [DOI] [PubMed] [Google Scholar]
  33. Schaefer E. J., Foster D. M., Zech L. A., Lindgren F. T., Brewer H. B., Jr, Levy R. I. The effects of estrogen administration on plasma lipoprotein metabolism in premenopausal females. J Clin Endocrinol Metab. 1983 Aug;57(2):262–267. doi: 10.1210/jcem-57-2-262. [DOI] [PubMed] [Google Scholar]
  34. Semenkovich C. F., Ostlund R. E., Jr Estrogens induce low-density lipoprotein receptor activity and decrease intracellular cholesterol in human hepatoma cell line Hep G2. Biochemistry. 1987 Aug 11;26(16):4987–4992. doi: 10.1021/bi00390a016. [DOI] [PubMed] [Google Scholar]
  35. Tam S. P., Archer T. K., Deeley R. G. Effects of estrogen on apolipoprotein secretion by the human hepatocarcinoma cell line, HepG2. J Biol Chem. 1985 Feb 10;260(3):1670–1675. [PubMed] [Google Scholar]
  36. Tikkanen M. J., Nikkilä E. A. Regulation of hepatic lipase and serum lipoproteins by sex steroids. Am Heart J. 1987 Feb;113(2 Pt 2):562–567. doi: 10.1016/0002-8703(87)90633-8. [DOI] [PubMed] [Google Scholar]
  37. Vega G. L., Grundy S. M. Mechanisms of primary hypercholesterolemia in humans. Am Heart J. 1987 Feb;113(2 Pt 2):493–502. doi: 10.1016/0002-8703(87)90620-x. [DOI] [PubMed] [Google Scholar]
  38. Wallentin L., Varenhorst E. Changes of plasma lipid metabolism in males during estrogen treatment for prostatic carcinoma. J Clin Endocrinol Metab. 1978 Sep;47(3):596–599. doi: 10.1210/jcem-47-3-596. [DOI] [PubMed] [Google Scholar]
  39. Weinstein I., Wilcox H. G., Heimberg M. Effects of high-dose ethinyl estradiol on serum concentrations and hepatic secretion of the very-low-density lipoprotein, triacylglycerol, cholesterol, and apolipoprotein A-I in the rat. Biochim Biophys Acta. 1986 May 21;876(3):450–459. doi: 10.1016/0005-2760(86)90031-7. [DOI] [PubMed] [Google Scholar]
  40. Windler E. E., Kovanen P. T., Chao Y. S., Brown M. S., Havel R. J., Goldstein J. L. The estradiol-stimulated lipoprotein receptor of rat liver. A binding site that membrane mediates the uptake of rat lipoproteins containing apoproteins B and E. J Biol Chem. 1980 Nov 10;255(21):10464–10471. [PubMed] [Google Scholar]
  41. Witztum J. L., Young S. G., Elam R. L., Carew T. E., Fisher M. Cholestyramine-induced changes in low density lipoprotein composition and metabolism. I. Studies in the guinea pig. J Lipid Res. 1985 Jan;26(1):92–103. [PubMed] [Google Scholar]

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