Regulation of Platelet Aggregation and Adenosine Triphosphate Release In Vitro by 17β-Estradiol and Medroxyprogesterone Acetate in Postmenopausal Women

J. Bar; J. Lahav; M. Hod; Z. Ben-Rafael; I. Weinberger; J. Brosens

doi:10.1055/s-0037-1614089

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2000; 84(04): 695-700
DOI: 10.1055/s-0037-1614089

Review Article

Schattauer GmbH

Regulation of Platelet Aggregation and Adenosine Triphosphate Release In Vitro by 17β-Estradiol and Medroxyprogesterone Acetate in Postmenopausal Women

J. Bar

¹From the Department of Obstetrics and Gynecology, Tel Aviv University, Tel Aviv, Israel

,

J. Lahav

²Hemostasis Laboratory, Rabin Medical Center, Beilinson Campus, Petah Tiqva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

,

M. Hod

¹From the Department of Obstetrics and Gynecology, Tel Aviv University, Tel Aviv, Israel

,

Z. Ben-Rafael

¹From the Department of Obstetrics and Gynecology, Tel Aviv University, Tel Aviv, Israel

,

I. Weinberger

²Hemostasis Laboratory, Rabin Medical Center, Beilinson Campus, Petah Tiqva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

,

J. Brosens

³Department of Reproductive Sciences and Medicine, Division of Paediatrics, Gynaecology and Obstetrics, Imperial College of Science, Technology and Medicine at Hammersmith Hospital, London, United Kingdom

› Author Affiliations

Abstract

Summary

Clinical studies have suggested that hormone replacement therapy (HRT) may reduce the risk of coronary heart disease in postmenopausal women. Although progestins are commonly added to HRT preparations for uteroprotection, the perceived beneficial cardiovascular effects of HRT are thought to be mediated predominantly by the estrogen component. Platelets play a critical role in the pathogenesis of atherosclerosis and cardiovascular disease and, hence, it is possible that the cardiovascular effects of estrogens are mediated, at least in part, through inhibition of illicit platelet activation. The aim of this study was to examine the effects of sex steroids on adenosine diphosphate (ADP)-induced platelet aggregation and adenosine triphosphate (ATP) release in vitro in postmenopausal women. In addition, the effects of antiestrogens [4-hydroxy tamoxifen (4-OHT) and ICI 182780] and antiprogestins (RU 486 and ZK 98299) were also investigated. Preincubation of platelet-rich plasma (PRP) with antiestrogens or antiprogestins did not alter subsequent platelet aggregation or ATP release in response to ADP. However, preincubation with 17β-estradiol (E2) significantly inhibited ADP-mediated platelet aggregation by a mean (±SEM) of 37% ± 6% (p = 0.02) and ATP release by 82% ± 6% (p = 0.03), an effect that was reversed by the addition of ICI 182780 or 4-OHT but not RU 486 and ZK 98299. Although the progestin medroxyprogesterone acetate (MPA) also significantly inhibited platelet aggregation (by 28% ± 5%, p = 0.02) and ATP release (by 63% ± 9%, p = 0.02), this inhibition was not reversed by the addition of antiprogestins or antiestrogens. These data show that sex steroids can modulate platelet function in vitro. Furthermore, as platelets are devoid of nuclear components, these findings indicate that estrogens may regulate platelet function through binding to a non-nuclear receptor with ligand-binding properties similar or identical to the wild-type receptor. By contrast, MPA appears to exert its effect through a mechanism that does not involve binding to the “classical” progesterone receptor.

Key words

Estrogen - progesterone - platelets - menopause - HRT

Full Text

References

References
1 American Heart Association. Heart and stroke facts. Dallas, Texas; 1992
2 US Senate Special Committee on Aging. Aging America: Trends and Projections. Washington, DC: US Department of Health and Human Services; 1988
3 Barret-Connor E. Sex differences in coronary heart disease: why are women so superior? The 1995 Ancel Keys Lecture. Circulation 1997; 95: 252-64.
4 Grodstein F, Stampfer M. The epidemiology of coronary heart disease and estrogen replacement in postmenopausal women. Prog Car Dis 1995; 38: 199-210.
5 Stampfer MJ, Colditz GA, Willett WC, Manson JE, Rosner B, Speizer FE, Hennekens CH. Postmenopausal estrogen therapy and cardiovascular disease: ten-year follow-up from the Nurses’ Health Study. N Engl J Med 1991; 325: 756-62.
6 Grady D, Rubin SM, Petitti DB, Fox CS, Black D, Ettinger B, Ernster VL, Cummings SR. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992; 117: 1016-37.
7 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: 1196-204.
8 The Writing Group for the PEPI Trial. Effects of estrogen on estrogen/ progestin regimens on heart disease risk factor in postmenopausal women The Postmenopausal Estrogen/Progestin Interventions PEPI Trial. J Am Med Assoc 1995; 273: 199-208.
9 Chae CU, Ridker PM, Manson JE. Postmenopausal hormone replacement therapy and cardiovascular disease. Thromb Haemost 1997; 78: 770-80.
10 Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med 1999; 23: 1801-11.
11 Hulley S, Grady D, Bush T, Farberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280: 605-13.
12 Mendelsohn ME, Karas RH. Estrogen and the blood vessel wall. Curr Opin Cardiol 1994; 09: 610-26.
13 Nabulsi AA, Folsom AR, White A, Patsch W, Heiss G, Wu KK, Szklo M. Association of hormone-replacement therapy with various cardiovascular risk factors in postmenopausal women The Atherosclerosis Risk in Communities Study Investigators. N Engl J Med 1993; 328: 1069-75.
14 The Writing Group for the Estradiol Clotting Factors Study. Effects on haemostasis of hormone replacement therapy with transdermal estradiol and oral sequential medroxyprogesterone acetate: a one-year, double-blind, placebo-controlled study. Thromb Haemost 1996; 75: 476-80.
15 Koh KK, Mincemoyer R, Bui MN, Csako G, Pucino F, Guetta V, Waclawiw M, Cannon 3rd RO. Effects of hormone-replacement therapy on fibrinolysis in postmenopausal women. N Engl J Med 1997; 336: 683-90.
16 Gebara OC, Mittleman MA, Sutherland P, Lipinska I, Matheney T, Xu P, Welty FK, Wilson PW, Levy D, Muller JE. et al. Association between increased estrogen status and increased fibrinolytic potential in the Framingham Offspring Study. Circulation 1995; 91: 1952-8.
17 Ross R, Glomset JA. The pathogenesis of atherosclerosis: Part 1. N Engl J Med 1976; 295: 369-77.
18 Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992; 326: 310-8.
19 Hanke H, Hanke S, Finking G, Muhic-Lohrer A, Muck AOI, Schmhal FW, Haasis R, Hombach V. Different effects of estrogen and progesterone on experimental atherosclerosis in female versus male rabbits: Quantification of cellular proliferation by bromodeoxyuridine. Circulation 1996; 94: 175-81.
20 Tsai M-J, O’Malley BW. Molecular mechanisms of action of steroid/ thyroid receptor superfamily members. Annu Rev Biochem 1994; 63: 451-86.
21 Parker MG. Steroid and related receptors. Curr Opin Cell Biol 1993; Curr Opin Cell Biol 1993; 05: 499-504.
22 Gametchu B. Glucocorticoid receptor-like antigen in lymphoma cell membranes: correlation to cell lysis. Science 1987; 236 4800 456-61.
23 Blackmore PF, Lattanzio FA. Cell surface localization of a novel nongenomic progesterone receptor on the head of human sperm. Biochem Biophys Res Commun 1991; 181 (01) 331-6.
24 Nemere I, Dormanen MC, Hammond MW, Okamura WH, Norman AW. Identification of a specific binding protein for 1 alpha, 25-dihydroxyvitamin D3 in basal-lateral membranes of chick intestinal epithelium and relationship to transcaltachia. J Biol Chem 1994; 269 (38) 23750-6.
25 Wehling M. editor. The Genomic and Non-Genomic Effects of Aldosterone. Boca Raton: CRC Press; 1995
26 Aronica SM, Mantel C, Gonin R, Marshall MS, Sarris A, Cooper S, Hague N, Zhang XF, Broxmeyer HE. Interferon-inducible protein 10 and macrophage inflammatory protein-1 alpha inhibit growth factor stimulation of Raf-1 kinase activity and protein synthesis in a human growth factor-dependent hematopoietic cell line. J Biol Chem 1995; 270 (37) 21998-2007.
27 Blackmore PF, Neulen J, Lattanzio J, Beebe SJ. Cell surface-binding sites for progesterone mediate calcium uptake in human sperm. J Biol Chem 1991; 266 (28) 18655-9659.
28 Tesarik J, Sousa M, Mendoza C. Sperm-induced calcium oscillations of human oocytes show distinct features in oocyte center and periphery. Mol Reprod Dev 1995; 41 (02) 257-63.
29 Lieberherr M, Grosse B, Kachkache M, Balsan S. Cell signaling and estrogens in female rat osteoblasts: a possible involvement of unconventional non-nuclear receptors. J Bone Miner Res 1993; 08 (11) 1365-76.
30 Le Mellay V, Grosse B, Lieberherr M. Phospholipase C beta and membrane action of calcitriol and estradiol. J Biol Chem 1997; 272 (18) 11902-7.
31 Bar J, Tepper R, Fuchs M, Pardo J, Ovadia J. The effect of replacement therapy on platelet aggregation and ATP release in postmenopausal women. Obstet Gynecol 1993; 81: 261-4.
32 Tepper R, Bar J, Goldberger S, Fuchs J, Beyth Y, Ovadia J. The effect of medroxyprogesterone acetate and clomiphene citrate on platelet function in menopausal women. Maturitas 1996; 24: 51-6.
33 Bar J, Zosmer A, Hod M, Elder MG, Sullivan MHF. The regulation of platelet aggregation in vitro by interleukin-1β and tumor necrosis factor-α: changes in pregnancy and in pre-eclampsia. Thromb Haemost 1997; 78: 1255-61.
34 Van den Berg HW, Lynch M, Martin JHJ. The relationship between affinity of progestins and antiprogestins for the progesterone receptor in breast cancer cells (ZR-PR-LT) and ability to down-regulate the receptor: evidence for heterospecific receptor modulation via the glucocorticoid receptor. Eur J Cancer 1993; 29A: 1771-5.
35 Hall JM, McDonnell DP. The estrogen receptor -isoform (ER) of the human estrogen receptor modulates ERα transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens. Endocrinology 1999; 140: 5566-78.
36 Kahmann S, Vaen L, Klein-Hitpass L. Synergistic enhancement of PRBmediated RU 486 and R 5020 agonist activities through cyclic adenosine 3’,5’-monophosphate represents a delayed primary response. Mol Endo 1998; 12: 278-89.
37 Ross R. Atherosclerosis an inflammatory disease. N Engl J Med 1999; 340: 115-26.
38 Elwood PC, Sweetnam PM. Aspirin and secondary mortality after myocardial infarction. Lancet ii 1979; 1313-5.
39 Antiplatelet Trial Lists’ Collaboration. Collaborative overview of randomized trials of anti-platelet therapy I. Prevention of death, myocardial infarction and stroke by prolonged anti-platelet therapy in various categories of patients. Br Med J 1994; 308: 81-106.
40 Mitchell HC. Effect of estrogen and progesterone on platelet adhesiveness and aggregation in rabbits. J Lab Clin Med 1974; 83: 79-89.
41 Aune B, Oian P, Omsjo I, Osterud B. Hormone replacement therapy reduces the reactivity of monocytes and platelets in whole blood. A beneficial effect on atherogenesis and thrombus formation? Am J Obstet Gynecol 1995; 173: 1816-20.
42 Kunicki TJ, Orchekowski R, Annis S, Honda Y. Variability of integrin alpha2beta1 activity on human platelets. Blood 1993; 82: 2693-703.
43 Tarantino MD, Kunicki TJ, Nugent DJ. The estrogen receptor is present in human megakaryocytes. Ann NY Acad Sci 1994; 18: 293-6.
44 Razandi M, Pedram A, Greene GL, Levin ER. Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: studies of ERalpha and ERbeta expressed in Chinese hamster ovary cells. Mol Endocrinol 1999; 13 (02) 307-19.
45 Aronica SM, Kraus WL, Katzenellenbogen BS. Estrogen action via the cAMP signaling pathway: stimulation of adenylate cyclase and cAMP-regulated gene transcription. Proc Natl Acad Sci USA 1994; 91 (18) 8517-21.
46 Habrugge M, Walter U. In: Protein kinases in blood cell function. Huang CK, Sha’afi RI. eds. CC Press; Boca Raton: 1993: 245-98.
47 Nakano Y, Ishoma T, Matsuura H, Kajiyama G, Kambe M. Effect of 17beta-estradiol on inhibition of platelet aggregation in vitro is mediated by an increase in NO synthesis. Arterioscler Thromb Vasc Biol 1998; 18 (06) 961-7.
48 Falkeborn M, Persson I, Adami H-O, Bergstrom R, Eaker E, Lithell H, Moshen R, Naassen T. The risk of acute myocardial infarctions after estrogen and estrogen-progesterone replacement. Br J Obstet Gynecol 1992; 99: 821-8.
49 Patsy BM, Heckbert SR, Atkins D, Lematire R, Koepsell TD, Wahl PW, Siscovick DS, Wagner EH. The risk of myocardial infarction associated with the combined use of estrogens and progestins in postmenopausal women. Arch Intern Med 1994; 154: 1333-9.
50 Lange CA, Richer JK, Shen T, Horwitz KB. Convergence of progesterone and epidermal growth factor signaling in breast cancer Potentiation of mitogen-activated protein kinase pathways. J Biol Chem 1998; 273 (47) 31308-16.
51 Meyer C, Schmid R, Schmieding K, Falkenstein E, Wheling M. Characterization of high affinity progesterone-binding membrane proteins by anti-peptide antiserum. Steroids 1998; 63 (02) 111-6.
52 Grazzini E, Guillon G, Mouillac B, Zingg HH. Inhibition of oxytocin receptor function by direct binding of progesterone. Nature 1998; 392 6675 509-12.