Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:217-221
© 1997 American Heart Association, Inc.
Articles |
Medroxyprogesterone Acetate Antagonizes Inhibitory Effects of Conjugated Equine Estrogens on Coronary Artery Atherosclerosis
the Comparative Medicine Clinical Research Center, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC.
Correspondence to Michael R. Adams, DVM, Dept of Comparative Medicine, Bowman Gray School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1040. E-mail madams@cpm.bgsm.edu.
Although estrogen replacement therapy is associated with reduced risk of coronary heart disease and reduced extent of coronary artery atherosclerosis, the effects of combined (estrogen plus progestin) hormone-replacement therapy are uncertain. Some observational data indicate that users of combined hormone replacement consisting of continuously administered oral conjugated equine estrogens (CEE) and oral sequentially administered (7 to 14 days per month) medroxyprogesterone acetate (MPA) experience a reduction in risk similar to that of users of CEE alone. However, the effects of combined, continuously administered CEE plus MPA (a prescribing pattern that has gained favor) on the risk of coronary heart disease or atherosclerosis are not known. We studied the effects of CEE (monkey equivalent of 0.625 mg/d) and MPA (monkey equivalent of 2.5 mg/d), administered separately or in combination, on the extent of coronary artery atherosclerosis (average plaque size) in surgically postmenopausal cynomolgus monkeys fed atherogenic diets and treated with these hormones for 30 months. Treatment with CEE alone resulted in atherosclerosis extent that was reduced 72% relative to untreated (estrogen-deficient) controls (P<.004). Atherosclerosis extent in animals treated with CEE plus MPA or MPA alone did not differ from that of untreated controls. Although treatment had marked effects on plasma lipoprotein patterns, statistical adjustment for variation in plasma lipoproteins did not alter the between-group relationships in atherosclerotic plaque size, suggesting that these factors do not explain substantially the atheroprotective effect of estrogen or the MPA-associated antagonism. Although the mechanism(s) remains unclear, we conclude that oral CEE inhibits the initiation and progression of coronary artery atherosclerosis and that continuously administered oral MPA antagonizes this atheroprotective effect.
Key Words: coronary artery atherosclerosis • cynomolgus monkeys • estrogen • medroxyprogesterone acetate • women's health
This article has been cited by other articles:
 |
|
 |
|
  X.-D. Fu, M. Flamini, A. M. Sanchez, L. Goglia, M. S. Giretti, A. R. Genazzani, and T. Simoncini Progestogens regulate endothelial actin cytoskeleton and cell movement via the actin-binding protein moesin Mol. Hum. Reprod., April 1, 2008; 14(4): 225 - 234. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Meendering, B. N. Torgrimson, N. P. Miller, P. F. Kaplan, and C. T. Minson Estrogen, medroxyprogesterone acetate, endothelial function, and biomarkers of cardiovascular risk in young women Am J Physiol Heart Circ Physiol, April 1, 2008; 294(4): H1630 - H1637. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Schumacher, R. Guennoun, A. Ghoumari, C. Massaad, F. Robert, M. El-Etr, Y. Akwa, K. Rajkowski, and E.-E. Baulieu Novel Perspectives for Progesterone in Hormone Replacement Therapy, with Special Reference to the Nervous System Endocr. Rev., June 1, 2007; 28(4): 387 - 439. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 The ESHRE Capri Workshop Group Hormones and cardiovascular health in women Hum. Reprod. Update, September 1, 2006; 12(5): 483 - 497. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Ouyang, E. D. Michos, and R. H. Karas Hormone Replacement Therapy and the Cardiovascular System: Lessons Learned and Unanswered Questions J. Am. Coll. Cardiol., May 2, 2006; 47(9): 1741 - 1753. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Wassmann, S. Wassmann, and G. Nickenig Progesterone Antagonizes the Vasoprotective Effect of Estrogen on Antioxidant Enzyme Expression and Function Circ. Res., November 11, 2005; 97(10): 1046 - 1054. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. G. Mishra, R. K. Hermsmeyer, K. Miyagawa, P. Sarrel, B. Uchida, F. Z. Stanczyk, K. A. Burry, D. R. Illingworth, and F. J. Nordt Medroxyprogesterone Acetate and Dihydrotestosterone Induce Coronary Hyperreactivity in Intact Male Rhesus Monkeys J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3706 - 3714. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Hermenegildo, P.J. Oviedo, M.C. Garcia-Martinez, M.A. Garcia-Perez, J.J. Tarin, and A. Cano Progestogens stimulate prostacyclin production by human endothelial cells Hum. Reprod., June 1, 2005; 20(6): 1554 - 1561. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. C. Register, J. A. Cann, J. R. Kaplan, J. K. Williams, M. R. Adams, T. M. Morgan, M. S. Anthony, R. M. Blair, J. D. Wagner, and T. B. Clarkson Effects of Soy Isoflavones and Conjugated Equine Estrogens on Inflammatory Markers in Atherosclerotic, Ovariectomized Monkeys J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1734 - 1740. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. V. Nair, D. Waters, W. Rogers, G. J. Kowalchuk, T. D. Stuckey, and D. M. Herrington Pulse Pressure and Coronary Atherosclerosis Progression in Postmenopausal Women Hypertension, January 1, 2005; 45(1): 53 - 57. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Adams, J. K. Williams, J. R. Kaplan, K. K. Koh, and I. Sakuma Estrogens, Progestins, and Atherosclerosis Arterioscler. Thromb. Vasc. Biol., November 1, 2004; 24(11): e190 - e191. [Full Text] [PDF]
|
|
|
|
|
|
K. K. Koh and I. Sakuma Should Progestins Be Blamed for the Failure of Hormone Replacement Therapy to Reduce Cardiovascular Events in Randomized Controlled Trials? Arterioscler. Thromb. Vasc. Biol., July 1, 2004; 24(7): 1171 - 1179. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Duvernoy, J. Martin, K. Briesmiester, A. Bargardi, O. Muzik, and L. Mosca Myocardial Blood Flow and Flow Reserve in Response to Hormone Therapy in Postmenopausal Women with Risk Factors for Coronary Disease J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2783 - 2788. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. K. Hermsmeyer, R. G. Mishra, D. Pavcnik, B. Uchida, M. K. Axthelm, F. Z. Stanczyk, K. A. Burry, D. R. Illingworth, J. C. Kaski, and F. J. Nordt Prevention of Coronary Hyperreactivity in Preatherogenic Menopausal Rhesus Monkeys by Transdermal Progesterone Arterioscler. Thromb. Vasc. Biol., May 1, 2004; 24(5): 955 - 961. [Abstract] [Full Text]
|
|
|
|
|
|
R. K. Dubey, D. G. Gillespie, M. Grogli, H. J. Kloosterboer, and B. Imthurn Tibolone and Its Metabolites Induce Antimitogenesis in Human Coronary Artery Smooth Muscle Cells: Role of Estrogen, Progesterone, and Androgen Receptors J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 852 - 859. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. M. Greenwood and R. Parasuraman Normal Genetic Variation, Cognition, and Aging Behav Cogn Neurosci Rev, December 1, 2003; 2(4): 278 - 306. [Abstract] [PDF]
|
|
|
|
|
|
L. A. Fitzpatrick Hormones and the Heart: Controversies and Conundrums J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5609 - 5610. [Full Text] [PDF]
|
|
|
|
 |
|
 H. N. Hodis, W. J. Mack, S. P. Azen, R. A. Lobo, D. Shoupe, P. R. Mahrer, D. P. Faxon, L. Cashin-Hemphill, M. E. Sanmarco, W. J. French, et al. Hormone Therapy and the Progression of Coronary-Artery Atherosclerosis in Postmenopausal Women N. Engl. J. Med., August 7, 2003; 349(6): 535 - 545. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Krajewski, T. W. Abel, M. L. Voytko, and N. E. Rance Ovarian Steroids Differentially Modulate the Gene Expression of Gonadotropin-Releasing Hormone Neuronal Subtypes in the Ovariectomized Cynomolgus Monkey J. Clin. Endocrinol. Metab., February 1, 2003; 88(2): 655 - 662. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. H. Kuller Hormone Replacement Therapy and Risk of Cardiovascular Disease: Implications of the Results of the Women's Health Initiative Arterioscler. Thromb. Vasc. Biol., January 1, 2003; 23(1): 11 - 16. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. B. Hodgin and N. Maeda Minireview: Estrogen and Mouse Models of Atherosclerosis Endocrinology, December 1, 2002; 143(12): 4495 - 4501. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. B. Clarkson, M. S. Anthony, T. S. Mikkola, and R. W. St Clair Comparison of Tibolone and Conjugated Equine Estrogens Effects on Carotid Artery Atherosclerosis of Postmenopausal Monkeys Stroke, November 1, 2002; 33(11): 2700 - 2703. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. McNeill, C. Zhang, F. Z. Stanczyk, S. P. Duckles, and D. N. Krause Estrogen Increases Endothelial Nitric Oxide Synthase via Estrogen Receptors in Rat Cerebral Blood Vessels: Effect Preserved After Concurrent Treatment With Medroxyprogesterone Acetate or Progesterone Stroke, June 1, 2002; 33(6): 1685 - 1691. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 H. N. Hodis, W. J. Mack, R. A. Lobo, D. Shoupe, A. Sevanian, P. R. Mahrer, R. H. Selzer, C.-r. Liu, C.-h. Liu, S. P. Azen, et al. Estrogen in the Prevention of Atherosclerosis: A Randomized, Double-Blind, Placebo-Controlled Trial Ann Intern Med, December 4, 2001; 135(11): 939 - 953. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. C. Register, C. S. Carlson, and M. R. Adams Serum YKL-40 Is Associated with Osteoarthritis and Atherosclerosis in Nonhuman Primates Clin. Chem., December 1, 2001; 47(12): 2159 - 2161. [Full Text] [PDF]
|
|
|
|
|
|
T. B. Clarkson, M. S. Anthony, and J. D. Wagner A Comparison of Tibolone and Conjugated Equine Estrogens Effects on Coronary Artery Atherosclerosis and Bone Density of Postmenopausal Monkeys J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5396 - 5404. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Wakatsuki, Y. Okatani, N. Ikenoue, and T. Fukaya Effect of Medroxyprogesterone Acetate on Endothelium-Dependent Vasodilation in Postmenopausal Women Receiving Estrogen Circulation, October 9, 2001; 104(15): 1773 - 1778. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F Al-Azzawi The menopause and its treatment in perspective Postgrad. Med. J., May 1, 2001; 77(907): 292 - 304. [Full Text]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
M. Otsuki, H. Saito, X. Xu, S. Sumitani, H. Kouhara, T. Kishimoto, and S. Kasayama Progesterone, but Not Medroxyprogesterone, Inhibits Vascular Cell Adhesion Molecule-1 Expression in Human Vascular Endothelial Cells Arterioscler. Thromb. Vasc. Biol., February 1, 2001; 21(2): 243 - 248. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Angerer, S. Stork, W. Kothny, P. Schmitt, and C. von Schacky Effect of Oral Postmenopausal Hormone Replacement on Progression of Atherosclerosis : A Randomized, Controlled Trial Arterioscler. Thromb. Vasc. Biol., February 1, 2001; 21(2): 262 - 268. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. B. Clarkson, M. S. Anthony, and T. M. Morgan Inhibition of Postmenopausal Atherosclerosis Progression: A Comparison of the Effects of Conjugated Equine Estrogens and Soy Phytoestrogens J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 41 - 47. [Abstract] [Full Text]
|
|
|
|
 |
|
 M. Seed, R. H Sands, M. McLaren, G. Kirk, and D. Darko The effect of hormone replacement therapy and route of administration on selected cardiovascular risk factors in post-menopausal women Fam. Pract., December 1, 2000; 17(6): 497 - 507. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Angerer, W. Kothny, S. Stork, and C. von Schacky Hormone replacement therapy and distensibility of carotid arteries in postmenopausal women: a randomized, controlled trial J. Am. Coll. Cardiol., November 15, 2000; 36(6): 1789 - 1796. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Mosca The Role of Hormone Replacement Therapy in the Prevention of Postmenopausal Heart Disease Arch Intern Med, August 14, 2000; 160(15): 2263 - 2272. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. A. Greaves, M. D. Wilson, L. L. Rudel, J. K. Williams, and J. D. Wagner Consumption of Soy Protein Reduces Cholesterol Absorption Compared to Casein Protein Alone or Supplemented with an Isoflavone Extract or Conjugated Equine Estrogen in Ovariectomized Cynomolgus Monkeys J. Nutr., April 1, 2000; 130(4): 820 - 826. [Abstract] [Full Text]
|
|
|
|
 |
|
 X. Zhu, B. Bonet, H. Gillenwater, and R. H. Knopp Opposing Effects of Estrogen and Progestins on LDL Oxidation and Vascular Wall Cytotoxicity: Implications for Atherogenesis Experimental Biology and Medicine, December 1, 1999; 222(3): 214 - 221. [Abstract] [Full Text]
|
|
|
|
|
|
D. M. Herrington The HERS Trial Results: Paradigms Lost? Ann Intern Med, September 21, 1999; 131(6): 463 - 466. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. J. Anderson Assessment and treatment of endothelial dysfunction in humans J. Am. Coll. Cardiol., September 1, 1999; 34(3): 631 - 638. [Full Text] [PDF]
|
|
|
|
|
|
U. Brehme, B. Bruck, N. Gugel, M. Wehrmann, S. Hanke, G. Finking, F. W. Schmahl, and H. Hanke Aortic Plaque Size and Endometrial Response in Cholesterol-Fed Rabbits Treated With Estrogen Plus Continuous or Sequential Progestin Arterioscler. Thromb. Vasc. Biol., August 1, 1999; 19(8): 1930 - 1937. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. J. Teede, Y.-L. Liang, L. M. Shiel, J. J. McNeil, and B. P. McGrath Hormone replacement therapy in postmenopausal women protects against smoking-induced changes in vascular structure and function J. Am. Coll. Cardiol., July 1, 1999; 34(1): 131 - 137. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. W. Abel, M. L. Voytko, and N. E. Rance The Effects of Hormone Replacement Therapy on Hypothalamic Neuropeptide Gene Expression in a Primate Model of Menopause J. Clin. Endocrinol. Metab., June 1, 1999; 84(6): 2111 - 2118. [Abstract] [Full Text]
|
|
|
|
 |
|
 D. C. Schwenke, J. D. Wagner, and M. R. Adams In vitro lipid peroxidation of LDL from postmenopausal cynomolgus macaques treated with female hormones J. Lipid Res., February 1, 1999; 40(2): 235 - 244. [Abstract] [Full Text]
|
|
|
|
|
|
S. Oparil Hormones and Vasoprotection Hypertension, January 1, 1999; 33(1): 170 - 176. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Zandberg, J. L. M. Peters, P. N. M. Demacker, M. J. Smit, E. G. de Reeder, and D. G. Meuleman Tibolone Prevents Atherosclerotic Lesion Formation in Cholesterol-Fed, Ovariectomized Rabbits Arterioscler. Thromb. Vasc. Biol., December 1, 1998; 18(12): 1844 - 1854. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Hulley, D. Grady, T. Bush, C. Furberg, D. Herrington, B. Riggs, E. Vittinghoff, and for the Heart and Estrogen/progestin Replacement S Randomized Trial of Estrogen Plus Progestin for Secondary Prevention of Coronary Heart Disease in Postmenopausal Women JAMA, August 19, 1998; 280(7): 605 - 613. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. B. Clarkson and M. S. Anthony Lack of Effect of Raloxifene on Coronary Atherosclerosis of Postmenopausal Monkeys--Authors' Response J. Clin. Endocrinol. Metab., August 1, 1998; 83(8): 3002 - 3004. [Full Text]
|
|
|
|
 |
|
 G. I. Gorodeski, T. Yang, M. N. Levy, J. Goldfarb, and W. H. Utian Modulation of Coronary Vascular Resistance in Female Rabbits by Estrogen and Progesterone Reproductive Sciences, July 1, 1998; 5(4): 197 - 202. [Abstract] [PDF]
|
|
|
|
|
|
T. C. Register, M. R. Adams, D. L. Golden, and T. B. Clarkson Conjugated Equine Estrogens Alone, but Not in Combination With Medroxyprogesterone Acetate, Inhibit Aortic Connective Tissue Remodeling After Plasma Lipid Lowering in Female Monkeys Arterioscler. Thromb. Vasc. Biol., July 1, 1998; 18(7): 1164 - 1171. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Alexandersen, J. Haarbo, I. Sandholdt, M. Shalmi, H. Lawaetz, and C. Christiansen Norethindrone Acetate Enhances the Antiatherogenic Effect of 17ß-Estradiol : A Secondary Prevention Study of Aortic Atherosclerosis in Ovariectomized Cholesterol-Fed Rabbits Arterioscler. Thromb. Vasc. Biol., June 1, 1998; 18(6): 902 - 907. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Nekooeian and C. C. Y. Pang Estrogen restores role of basal nitric oxide in control of vascular tone in rats with chronic heart failure Am J Physiol Heart Circ Physiol, June 1, 1998; 274(6): H2094 - H2099. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. B. Clarkson, M. S. Anthony, and C. P. Jerome Lack of Effect of Raloxifene on Coronary Artery Atherosclerosis of Postmenopausal Monkeys J. Clin. Endocrinol. Metab., March 1, 1998; 83(3): 721 - 726. [Abstract] [Full Text]
|
|
|
|
|
|
J. D. Wagner, M. J. Thomas, J. K. Williams, L. Zhang, K. A. Greaves, and W. T. Cefalu Insulin Sensitivity and Cardiovascular Risk Factors in Ovariectomized Monkeys with Estradiol Alone or Combined with Nomegestrol Acetate J. Clin. Endocrinol. Metab., March 1, 1998; 83(3): 896 - 901. [Abstract] [Full Text]
|
|
|
|
|
|
E. A. Enas and K. Orth-Gomer Lipoprotein(a) as a Determinant of Coronary Heart Disease in Young Women: A Stronger Risk Factor Than Diabetes? • Response Circulation, January 27, 1998; 97(3): 293 - 295. [Full Text]
|
|
|
|
|
|
R. H. Knopp and X. Zhu Multiple Beneficial Effects of Estrogen on Lipoprotein Metabolism J. Clin. Endocrinol. Metab., December 1, 1997; 82(12): 3952 - 3954. [Full Text] [PDF]
|
|
|
|
|
|
L. Mosca, J. E. Manson, S. E. Sutherland, R. D. Langer, T. Manolio, E. Barrett-Connor, and E. Barrett-Connor Cardiovascular Disease in Women : A Statement for Healthcare Professionals From the American Heart Association Circulation, October 7, 1997; 96(7): 2468 - 2482. [Full Text]
|
|
|
|
|
|
J. D. Wagner, D. C. Schwenke, L. Zhang, D. Applebaum-Bowden, J. D. Bagdade, and M. R. Adams Effects of Short-term Hormone Replacement Therapies on Low-Density Lipoprotein Metabolism in Cynomolgus Monkeys Arterioscler. Thromb. Vasc. Biol., June 1, 1997; 17(6): 1128 - 1134. [Abstract] [Full Text]
|
|