Download PDF
Horm Metab Res 2001; 33(2): 110-114
DOI: 10.1055/s-2001-12405
Original Clinical

© Georg Thieme Verlag Stuttgart · New York

Atherosclerosis in Apolipoprotein E-Deficient Mice is Decreased by the Suppression of Endogenous Sex Hormones

G. von Dehn 1 , O. von Dehn 1 , W. Völker 2 , C. Langer 1 , G. F. Weinbauer 3 , H. M. Behre 4 , E. Nieschlag 3 , G. Assmann 1,2 , A. von Eckardstein 1, 2
  • 1 Institut für Klinische Chemie und Laboratoriumsmedizin, Zentrallaboratorium, Westfälische Wilhelms-Universität Münster, Münster, Germany
  • 2 Institut für Arterioskleroseforschung an der Universität Münster, Münster, Germany
  • 3 Institut für Reproduktionsmedizin, Westfälische Wilhelms-Universität Münster, Münster, Germany
  • 4 Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe, Westfälische Wilhelms-Universität Münster, Münster, Germany
Further Information

Publication History

Publication Date:
31 December 2001 (online)

Also available at
    Permissions and Reprints

To elucidate the influence of gonadotropins, endogenous sex hormones and testosterone on atherosclerosis, 4-week-old male and female apoE-deficient mice received either 100 µg subcutaneous injections of the gonadotropin-releasing hormone (GnRH) antagonist Cetrorelix every 48 hours or a subcutaneous implantation of a permeable silastic tube with 35 mg of testosterone. Control mice received either subcutaneous injections of saline, a silastic implant with saline, or no treatment. The animals were sacrificed after eight weeks of treatment; blood was obtained by cardiac puncture and the aorta was taken out and prepared. The suppression of testosterone led to an increase in atherosclerosis in both the sinus aortae and the ascending aorta despite increases of cholesterol in male and decreases of HDL cholesterol in female mice. Treatment with testosterone led to small but significant increases of cholesterol levels and atherosclerotic lesions in male mice. Female mice showed no change in lipids and fewer atherosclerotic lesions. In conclusion, the suppression of gonadotropins appears to have a moderate anti-atherogenic effect. The effect of testosterone appears to be either neutral or opposed by gonadotropins.

Key words:

Atherosclerosis - Animal Model - Testosterone - Gonadotropin-Releasing Hormone Antagonist

References

  • 1 Lobo R A. Treatment of the postmenopausal woman: basic and clinical aspects.  New York:; Raven Press, 1994
    Google Scholar
  • 2 Kaufmann J M, Vermeulen A. Androgens in male senescence. In: Nieschlag E, Behre HM (eds). Testosterone: Action, Deficiency, Substitution. 2nd Edition.  Berlin:; Springer Verlag, 1998: 437-472
    Google Scholar
  • 3 Liu P Y, Handelsman D J. Androgen therapy in non-gonadal disease. In: Nieschlag E, Behre HM (eds). Testosterone: Action, Deficiency, Substitution. 2nd Edition.  Berlin:; Springer Verlag, 1998: 473-512
    Google Scholar
  • 4 Nieschlag E, Behre H M. Testosterone in male contraception. In: Nieschlag E, Behre HM (eds). Testosterone: Action, Deficiency, Substitution. 2nd Edition.  Berlin:; Springer Verlag, 1998: 513-528
    Google Scholar
  • 5 Schänzer W. Abuse of androgens and detection of illegal use. In: Nieschlag E, Behre HM (eds). Testosterone: Action, Deficiency, Substitution. 2nd Edition.  Berlin:; Springer Verlag, 1998: 545-566
    Google Scholar
  • 6 von Eckardstein A. Androgens, cardiovascular risk factors, and atherosclerosis. In: Nieschlag E, Behre HM (eds). Testosterone: Action, Deficiency, Substitution. 2nd Edition.  Berlin:; Springer Verlag, 1998: 229-258
    Google Scholar
  • 7 Alexandersen P, Haarbo J, Christiansen C. The relationship of natural androgens to coronary heart disease in males: a review.  Atherosclerosis. 1996;  125 1-13
    CrossrefPubMedGoogle Scholar
  • 8 Bagatell C J, Bremner W J. Androgens in men - uses and abuses.  N Engl J Med. 1996;  334 107-114
    PubMedGoogle Scholar
  • 9 Rosano G MC, Leonardo F, Pagnotta P, Pelliccia F, Panina G, Cerquetani E, della Monica P L, Bonfigli B, Volpe M, Chierchia S L. Acute anti-ischemic effect of testosterone in men with coronary artery disease.  Circulation. 1999;  99 1666-1670
    PubMedGoogle Scholar
  • 10 Larsen B A, Nordestgaard B, Stender S, Kjeldsen K. Effect of testosterone on atherogenesis in cholesterol-fed rabbits with similar plasma cholesterol levels.  Atherosclerosis. 1993;  99 79-86
    CrossrefPubMedGoogle Scholar
  • 11 Fogelberg M, Björkhem I, Diczfalusy U, Henriksson P. Stanozolol and experimental atherosclerosis: atherosclerosis development and blood lipids during anabolic steroid therapy of New Zealand white rabbits.  Scand J Clin Lab Invest. 1990;  50 693-700
    PubMedGoogle Scholar
  • 12 Alexandersen P, Haarbo J, Byrjalsen I, Lawetz H, Christiansen C. Natural androgens inhibit male atherosclerosis. A study in castrated, cholesterol-fed rabbits.  Circ Res. 1999;  84 813-819
    PubMedGoogle Scholar
  • 13 Bruck B, Brehme B, Gugel N, Hanke S, Finking G, Lutz C, Benda N, Schmahl F W, Haasis R, Hanke H. Gender-specific differences in the effects of testosterone and estrogen on the development of atherosclerosis in rabbits.  Arterioscler Thromb Vasc Biol. 1997;  17 2192-2199
    PubMedGoogle Scholar
  • 14 Adams M R, Williams J K, Kaplan J R. Effects of androgens on coronary artery atherosclerosis and atherosclerosis-related impairment of vascular responsiveness.  Arterioscler Thromb Vasc Biol. 1995;  15 562-570
    PubMedGoogle Scholar
  • 15 Toda T, Toda Y, Cho B H, Kummerow F A. Ultrastructural changes in the comb and aorta of chicks fed excess testosterone.  Atherosclerosis. 1984;  51 47-53
    PubMedGoogle Scholar
  • 16 Behre H M, Klein B, Steinmeyer E, McGregor G P, Voigt K, Nieschlag E. Effective suppression of luteinizing hormone and testosterone by single doses of the new gonadotropin-releasing hormone antagonist cetrorelix (SB-75) in normal men.  J Clin Endocrinol Metab. 1992;  75 393-398
    CrossrefPubMedGoogle Scholar
  • 17 Behre H M, Kliesch S, Pühse G, Reissmann T, Nieschlag E. High loading and low maintenance doses of a gonadotropin-releasing hormone antagonist effectively suppress serum luteinizing hormone, follicle stimulating hormone, and testosterone in normal men.  J Clin Endocrinol Metab. 1997;  82 1403-1408
    CrossrefPubMedGoogle Scholar
  • 18 Piedrahita J A, Zhang S H, Hagamann J, Oliver P M, Maeda N. Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells.  Proc Natl Acad Sci USA. 1992;  89 4471-4475
    PubMedGoogle Scholar
  • 19 Zhang S H, Reddick R L, Piedrahita J A, Maeda N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E.  Science. 1992;  258 468-471
    PubMedGoogle Scholar
  • 20 Plump A S, Smith J D, Hayek T, Aalto-Setälä K, Walsh A, Verstuyft J G, Rubin E M, Breslow J L. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells.  Cell. 1992;  71 343-353
    CrossrefPubMedGoogle Scholar
  • 21 Bourassa P AK, Milos M M, Gaynor BJ, Breslow J L, Aiello R J. Estrogen reduces atherosclerotic lesion development in apolipoprotein E deficient mice.  Proc Natl Acad Sci USA. 1996;  93 10 022-10 027
    PubMedGoogle Scholar
  • 22 Elhage R, Arnal J F, Pieraggi M -T, Duverger N, Fiévet C, Faye J C, Bayard F. 17β-estradiol prevents fatty streak formation in apolipoprotein E-deficient mice.  Arterioscler Thromb Vasc Biol. 1997;  17 2679-2684
    PubMedGoogle Scholar
  • 23 Huang Y, Langer C, Raabe M, Wiesenhütter B, Wu S, Seedorf U, Maeda N, Assmann G, von Eckardstein A. Effects of genotype and diet on cholesterol efflux into plasma and lipoproteins of normal, apolipoprotein A-I-, and apolipoprotein E-deficient mice.  Arterioscler Thromb Vasc Biol. 1997;  17 2010-2019
    PubMedGoogle Scholar
  • 24 Paigen B, Morrow A, Holmes P A, Mitchell D, Williams R A. Quantitative assessment of atherosclerotic lesions in mice.  Atherosclerosis. 1987;  68 231-240
    PubMedGoogle Scholar
  • 25 Qiao J -H, Xi P -Z, Fishbein M C, Kreuzer J, Drake T A, Demer L L, Lusis A J. Pathology of atheromous lesions in inbred and genetically engineered mice. Genetic determination of arterial calcification.  Arteriosclerosis Thromb. 1994;  14 1480-1497
    PubMedGoogle Scholar
  • 26 Paigen B, Holmes P A, Mitchell D, Albee D. Comparison of atherosclerotic lesions and HDL-lipid levels in male, female, and testosterone-treated female mice from strains C57BL/6, BALB/c, and C3H.  Atherosclerosis. 1987;  64 215-221
    PubMedGoogle Scholar
  • 27 Acton S, Rigotti A, Landschulz K T, Xu S, Hobbs H H, Krieger M. Identification of scavenger receptor SR-B1 as a high density lipoprotein receptor.  Science. 1996;  271 518-520
    CrossrefPubMedGoogle Scholar
  • 28 Kozarsky K F, Donahee M H, Rigotti A, Iqbal S N, Edelman E R, Krieger M. Overexpression of the HDL receptor SR-BI alters plasma HDL and bile cholesterol levels.  Nature. 1997;  387 414-416
    CrossrefPubMedGoogle Scholar
  • 29 Rigotti A, Trigatti B L, Penman M, Rayburn H, Herz J, Krieger M A. A targeted mutation in the murine gene encoding the high density lipoprotein (HDL) receptor scavenger receptor class B type I reveals its key role in HDL metabolism.  Proc Natl Acad Sci USA. 1997;  94 12 610-12 615
    PubMedGoogle Scholar
  • 30 Ji Y, Jian B, Wang N, Sun Y, Moya M L, Phillips M C, Rothblat G H, Swaney J B, Tall A R. Scavenger receptor BI promotes high density lipoprotein-mediated cellular cholesterol efflux.  J Biol Chem. 1997;  272 20 982-20 987
    PubMedGoogle Scholar
  • 31 Li X, Peegel H, Menon K M. In situ hybridization of high density lipoprotein (scavenger, type 1) receptor messenger ribonucleic acid (mRNA) during folliculogenesis and luteinization: evidence for mRNA expression and induction by human chorionic gonadotropin specifically in cell types that use cholesterol for steroidogenesis.  Endocrinology. 1998;  139 3043-3051
    CrossrefPubMedGoogle Scholar
  • 32 Herman S M, Robinson J TC, McCredie R J, Adams M R, Boyer M J, Celermajer D S. Androgen deprivation is associated with enhanced endothelium-dependent dilatation in adult men.  Arterioscler Thromb Vasc Biol. 1997;  17 2004-2009
    PubMedGoogle Scholar
  • 33 Chou M, Sudhir K, Hutchison S J, Ko E, Amidon T M, Collins P, Chatterjee K. Testosterone induces dilatation of canine coronary conductance and resistance arteries in vivo. .  Circulation. 1996;  94 2614-2619
    PubMedGoogle Scholar
  • 34 Yue P, Chatterjee K, Beale C, Poole-Wilson P A, Collins P. Testosterone relaxes rabbit coronary arteries and aorta.  Circulation. 1995;  91 1154-1160
    PubMedGoogle Scholar
  • 35 Hutchison S J et al. Testosterone worsens endothelial dysfunction associated with hypercholesterolemia and environmental tobacco smoke exposure in male rabbit aorta.  J Am Coll Cardiol. 1997;  29 800-807
    CrossrefPubMedGoogle Scholar

Dr. A. von Eckardstein

Institut für Klinische Chemie und Laboratoriumsmedizin
Zentrallaboratorium
Westfälische Wilhelms-Universität Münster

Albert-Schweitzer-Strasse 33
48129 Münster
Germany


Email: E-mail:vonecka@uni-muenster.de