High-dose synthetic progestogens inhibit foam and smooth muscle cell proliferation and atherosclerotic plaque formation in aortas of rabbits fed a hypercholesterolemic diet

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      Female rabbits on a hypercholesterolemic atherogenic diet were treated with high doses of the synthetic progestogens norethisterone and medroxyprogesterone acetate in order to clarify the effect and possibly some of the mechanism of action of these hormones on diet-induced atherogenesis. We employed morphometric studies to determine the surface area of the rabbit aorta occupied by and the maximum thickness of lipid plaques. Autoradiography with tritiated thymidine was performed to demonstrate the effect of the progestogens on cell proliferation, which plays a key role in atherogenesis. Medroxyprogesterone acetate-treated and, above all, norethisterone-treated animals exhibit a more marked reduction of atherosclerosis than control rabbits fed the same diet. Our results suggest that both progestogens we used inhibit the development of atherosclerosis mainly by blocking the proliferation of smooth muscle cells in the tunica media and the cell population of the plaque.


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        • McGill Jr., H.C.
        • Stern M.P.
        Sex and Atherosclerosis.
        in: Version 5 Edition. Atherosclerosis Review. Vol. 4. Raven Press, New York1979: 157-235
        • Kannel W.B.
        • Hjortland M.C.
        • McNamara P.M.
        • Gordon T.
        Menopause and risk of cardiovascular disease: the Framingham study.
        Ann. Intern. Med. 1976; 85: 447
        • Johansson S.
        • Vedin A.
        • Wilhelmsson C.
        Myocardial infarction in women.
        Epidemiol. Rev. 1983; 5: 67
        • Bengtsson C.
        Ischemic heart disease in women.
        Acta Med. Scand. 1973; 549: 75
        • Barr D.P.
        Some chemical factors in the pathogenesis of atherosclerosis.
        Circulation. 1953; 8: 641
        • Russ E.M.
        • Eder H.A.
        • Barr D.P.
        Influence of gonadal hormones on protein-lipid relationships in human plasma.
        Am. J. Med. 1955; 15: 4
        • Furman R.H.
        • Howard R.P.
        • Norcia L.N.
        • Keaty E.C.
        The influence of androgens, estrogens and related steroids on serum lipids and lipoproteins. Observations in hypogonadal and normal human subjects.
        Am. J. Med. 1958; 24: 80
        • Coronary Drug Project Research Group
        the Coronary Drug Project — initial findings leading to modifications of its research protocol.
        JAMA. 1970; 214: 1303
        • Coronary Drug Project Research Group]
        The Coronary Drug Project — findings leading to discontinuation of the 2.5 mg/day estrogen group.
        JAMA. 1973; 226: 652
        • Byar D.P.
        The Veterans Administration Cooperative Urological Research Group's studies of cancer of the prostate.
        Cancer. 1973; 32: 1126
        • Realini J.P.
        • Goldzieher J.W.
        Oral contraceptives and cardiovascular disease: a critique of the epidemiologic studies.
        Am. J. Obstet. Gynecol. 1985; 152: 729
        • Porter J.B.
        • Hunter J.R.
        • Jick H.
        • Stergachis A.
        Oral contraceptives and non fatal vascular disease.
        Obstet. Gynecol. 1985; 66: 1
        • Collaborative Group for the Study of Stroke in Young Women
        Oral contraception and increased risk of cerebral ischemia and thrombosis.
        New Engl. J. Med. 1973; 288: 871
        • Collaborative Group for the Study of Stroke in Young Women
        Oral contraceptives and stroke in young women: associate risk factors.
        JAMA. 1975; 231: 718
        • Petitti D.B.
        • Wingerd J.
        Use of oral contraceptives, cigarette smoking, and risk of subarachnoid haemorrhage.
        Lancet. 1978; 2: 234
        • Thorogood M.
        • Adam S.A.
        • Mann J.I.
        Fatal subarachnoid hemorrhage in young women: role of oral contraceptives.
        Br. Med. J. 1981; 283: 762
        • Mann J.I.
        Progestogens in cardiovascular disease: an introduction to the epidemiologic data.
        Am. J. Obstet. Gynecol. 1982; 142: 752
        • Kay C.R.
        Progestogens and arterial disease. Evidence from the Royal College of General Practitioners' study.
        Am. J. Obstet. Gynecol. 1982; 142: 762
        • Fotherby K.
        Oral contraceptives, lipids and cardiovascular disease.
        Contraception. 1985; 31: 367
        • Meade T.W.
        • Greenberg G.
        • Thompson S.G.
        Progestogens and cardiovascular reaction associated with oral contraceptives and a comparison of the safety of 50- and 30-μg oestrogen preparations.
        Br. Med. J. 1980; 280: 1157
        • Hubbard S.M.
        • Seipp C.A.
        Administration of cancer treatments: practical guide for physicians and oncology nurses.
        in: De Vita Jr., V.T. Hellman S. Rosenberg S.A. Cancer: Principles and Practice of Oncology. J.B. Lippincott Company, Philadelphia, PA1985: 2189-2222
        • Meade T.W.
        Effects of progestogens on the cardiovascular system.
        Am. J. Obstet. Gynecol. 1982; 142: 776
        • Plunkett E.R.
        Contraceptive steroids, age, and the cardiovascular system.
        Am. J. Obstet. Gynecol. 1982; 142: 747
        • Bradley D.D.
        • Wingerd J.
        • Petitti D.B.
        • Pellegrin S.
        Serum high-density-lipoprotein cholesterol in women using oral contraceptives, estrogens and progestins.
        N. Engl. J. Med. 1978; 299: 17
        • Tikkanen M.J.
        • Nikkilä E.A.
        • Kuusi T.
        • Sipinen S.
        Different effect of two progestins on plasma high density lipoprotein (HDL2) and postheparin plasma hepatic lipase activity.
        Atherosclerosis. 1981; 40: 365
        • Crona N.
        • Enk L.
        • Mattsson L.-A.
        • Samsioe G.
        • Silfverstolpe G.
        Progestogens and lipid metabolism.
        Maturitas. 1986; 8: 141
        • Gaspard U.J.
        Metabolic effects of oral contraceptives.
        Am. J. Obstet. Gynecol. 1987; 157: 1029
        • Fotherby K.
        Oral contraceptives, lipids and cardiovascular disease.
        Contraception. 1985; 31: 367
        • Hirvonen E.
        • Malkonen M.
        • Mannen V.
        Effects of different progestogens on lipoproteins during postmenopausal replacement therapy.
        N. Engl. J. Med. 1981; 304: 560
        • Tikkanen M.J.
        • Kuusi T.
        • Nikkilä E.A.
        • Sipinen S.
        Post-menopausal hormone replacement therapy: effects of progestogens on serum lipids and lipoproteins. A review.
        Maturitas. 1986; 8: 7
        • Neumann F.
        The physiological action of progesterone and the pharmacological effects of progestogens. A short review.
        Postgrad. Med. J. 1978; 54: 11
        • Brenner P.F.
        The pharmacology of progestogens.
        J. Reprod. Med. 1982; 27: 490
        • Gore I.
        • Iwanaga Y.
        • Gore H.
        Inhibition of dietary atherosclerosis in rabbits by norethynodrel.
        J. Atheroscler. Res. 1967; 7: 361
        • Al-Shebib T.H.
        • Al Zubaidy A.J.
        • Al-Hashimi A.S.
        Experimental study of the effects on rabbits of the injectable contraceptive medroxyprogesterone acetate, cholesterol feeding and drug-atherogenic diet combination.
        Lab. Anim. 1982; 16: 78
        • Fischer G.M.
        • Cherian K.
        • Swain M.L.
        Increased synthesis of aortic collagen and elastin in experimental atherosclerosis. Inhibition by contraceptive steroids.
        Atherosclerosis. 1983; 39: 463
        • Fischer G.M.
        • Swain M.L.
        Effects of estradiol and progesterone on the increased synthesis of collagen in atherosclerotic rabbit aortas.
        Atherosclerosis. 1985; 54: 177
        • Fischer G.M.
        • Bashey R.I.
        • Rosenbaum H.
        • Lyttle C.R.
        A possible mechanism in arterial wall for mediation of sex difference in atherosclerosis.
        Exp. Mol. Pathol. 1985; 43: 288
        • Ross R.
        • Glomset J.
        The pathogenesis of atherosclerosis.
        N. Engl. J. Med. 1976; 295: 369
        • Cavallero C.
        • Di Tondo U.
        • Mingazzini P.L.
        • Pesando P.C.
        • Spagnoli L.G.
        Cell proliferation in the atherosclerotic lesions of cholesterol-fed rabbits. Part 2. Histological, ultrastructural and radioautographic observations on epinephrine-treated rabbits.
        Atherosclerosis. 1973; 17: 49
        • Spagnoli L.G.
        • Villaschi S.
        • Neri L.
        • Palmieri G.
        • Taurino M.
        • Faraglia V.
        • Fiorani P.
        Autoradiographic studies of the smooth muscle cells in human arteries.
        Paroi Arterielle/Arterial Wall. 1981; 7: 107
        • Villaschi S.
        • Spagnoli L.G.
        Autoradiographic and ultrastructural studies on the human fibro-atheromatous plaque.
        Atherosclerosis. 1983; 48: 95
        • Spagnoli L.G.
        • Villaschi S.
        • Palmieri G.
        • Mauriello A.
        Foam cells in the development of human atheroma: a morphological and autoradiographic approach.
        Wien. Klin. Wochenschr. 1984; 96: 412
        • Karovsky M.J.
        A formaldehyde-glutaraldehyde fixative of high osmolarity forms in electron microscopy.
        J. Cell Biol. 1965; 27: 137
        • Lillie R.D.
        Histopathologic Technic and Practical Histochemistry.
        in: McGraw-Hill Book Company, New York1965: 454-462
        • Folch J.
        • Lees M.
        • Sloane S.G.H.
        A simple method for the isolation and purification of total lipids from animal tissue. 1957; 226: 497
        • Van Gent C.M.
        • van der Voort H.A.
        • de Bruyn A.M.
        • Klein F.
        Cholesterol determination. A comparative study of methods with special reference to enzymatic procedure.
        Clin. Chim. Acta. 1977; 75: 243
        • Bucolo G.
        • McCroskey R.
        • Whittaker N.
        Lipase-triggered kinetic assay of serum tryglicerides.
        Clin. Chem. 1975; 21: 424
        • Nordqvist S.
        The synthesis of DNA and RNA in normal human endometrium in short-term incubation in vitro and its response to oestradiol and progesterone.
        J. Endocrinol. 1970; 48: 17
        • Ronnemaa T.
        • Jarvelainen H.
        • Lehtonen A.
        • Gronroos M.
        • Marniemi J.
        • Rautio A.
        Growth of human aortic smooth muscle cells cultured with human serum is retarded when serum lipids are lowered by medroxyprogesterone.
        Atherosclerosis. 1987; 67: 223
        • Goldstein J.L.
        • Faust J.R.
        • Dygos J.N.
        • Chorvat R.J.
        • Brown M.S.
        Inhibition of cholesteryl ester formation in human fibroblasts by an analogue of 7-ketocholesterol and by progesterone.
        in: Version 5 Edition. Proc. Natl. Acad. Sci. USA. 75. 1978: 1877
        • Brown M.S.
        • Ho Y.K.
        • Goldstein J.L.
        The cholesteryl ester cycle in macrophage foam cells. Continual hydrolysis and re-esterification of cytoplasmic cholesteryl esters.
        J. Biol. Chem. 1980; 18: 9344
        • Miller N.E.
        • La Ville A.
        • Crook D.
        Direct evidence that reverse cholesterol transport is mediated by high-density lipoprotein in rabbit.
        Nature. 1985; 307: 109