The Adverse Effects of Estrogen and Selective Estrogen Receptor Modulators on Hemostasis and Thrombosis

 

 Buy Article Permissions and Reprints

Abstract

Agonists of the estrogen receptor include estrogens and selective estrogen receptor modulators (SERMs). Both types of compounds increase the risk for thrombosis in the arterial and the venous tree. The magnitude of the effect is influenced by potency, which depends on the type of compound and the dose. The particulars of the process change in each territory. Atherosclerosis, which creates local inflammatory conditions, may favor thrombogenesis in arteries. A direct effect of estrogen agonists is also well endorsed at both arteries, as suggested from data with high-estrogenic contraceptives, and veins. Dose reduction has been proved to be an effective strategy, but there is debate on whether additional benefit may be attained beyond a certain threshold. Hormone therapy and SERMs exhibit a lower potency estrogenic profile, but are mainly used by older women, who have a baseline increased thrombogenic risk. When used as sole agents, estrogens substantially reduce the increased risk (venous thrombosis) or may even be neutral (coronary disease). SERMs exhibit a neutral profile for coronary disease and possibly for stroke but not for venous thrombosis.

• References

• 1 Roger VL, Go AS, Lloyd-Jones DM , et al. Executive summary: heart disease and stroke statistics—2012 update: a report from the American Heart Association. Circulation 2012; 125 (1) 188-197
  CrossrefPubMedGoogle Scholar
• 2 Lobo RA. Menopause and stroke and the effects of hormonal therapy. Climacteric 2007; 10 (Suppl. 02) 27-31
  PubMedGoogle Scholar
• 3 White RH. The epidemiology of venous thromboembolism. Circulation 2003; 107 (23) (Suppl. 01) I4-I8
  PubMedGoogle Scholar
• 4 Oger E. Incidence of venous thromboembolism: a community-based study in Western France. EPI-GETBP Study Group. Groupe d'Etude de la Thrombose de Bretagne Occidentale. Thromb Haemost 2000; 83 (5) 657-660
  Article in Thieme ConnectPubMedGoogle Scholar
• 5 de Gooyer ME, Deckers GH, Schoonen WG, Verheul HA, Kloosterboer HJ. Receptor profiling and endocrine interactions of tibolone. Steroids 2003; 68 (1) 21-30
  CrossrefPubMedGoogle Scholar
• 6 Cano A, Hermenegildo C. Modulation of the oestrogen receptor: a process with distinct susceptible steps. Hum Reprod Update 2000; 6 (3) 207-211
  CrossrefPubMedGoogle Scholar
• 7 Blanco-Molina MA, Lozano M, Cano A, Cristobal I, Pallardo LP, Lete I. Progestin-only contraception and venous thromboembolism. Thromb Res 2012; 129 (5) e257-e262
  CrossrefPubMedGoogle Scholar
• 8 Tchaikovski SN, Rosing J. Mechanisms of estrogen-induced venous thromboembolism. Thromb Res 2010; 126 (1) 5-11
  CrossrefPubMedGoogle Scholar
• 9 Odlind V, Milsom I, Persson I, Victor A. Can changes in sex hormone binding globulin predict the risk of venous thromboembolism with combined oral contraceptive pills?. Acta Obstet Gynecol Scand 2002; 81 (6) 482-490
  PubMedGoogle Scholar
• 10 Raps M, Helmerhorst F, Fleischer K , et al. Sex hormone-binding globulin as a marker for the thrombotic risk of hormonal contraceptives. J Thromb Haemost 2012; 10 (6) 992-997 DOI: 10.1111/j.1538-7836.2012.04720.
  CrossrefPubMedGoogle Scholar
• 11 Cano A, Hermenegildo C, Oviedo P, Tarín JJ. The risk for cardiovascular disease in women: from estrogens to selective estrogen receptor modulators. Front Biosci 2007; 12: 49-68
  CrossrefPubMedGoogle Scholar
• 12 Jayachandran M, Miller VM. Human platelets contain estrogen receptor alpha, caveolin-1 and estrogen receptor associated proteins. Platelets 2003; 14 (2) 75-81
  CrossrefPubMedGoogle Scholar
• 13 Miller VM, Jayachandran M, Hashimoto K, Heit JA, Owen WG. Estrogen, inflammation, and platelet phenotype. Gend Med 2008; 5 (suppl A) S91-S102
  CrossrefPubMedGoogle Scholar
• 14 García-Martínez MC, Labiós M, Hermenegildo C, Tarín JJ, O'Connor E, Cano A. The effect of hormone replacement therapy on Ca²⁺ mobilization and P-selectin (CD62P) expression in platelets examined under flow cytometry. Blood Coagul Fibrinolysis 2004; 15 (1) 1-8
  CrossrefPubMedGoogle Scholar
• 15 Boudoulas KD, Montague CR, Goldschmidt-Clermont PJ, Cooke GE. Estradiol increases platelet aggregation in Pl(A1/A1) individuals. Am Heart J 2006; 152 (1) 136-139
  CrossrefPubMedGoogle Scholar
• 16 Dobrydneva Y, Weatherman RV, Trebley JP , et al. Tamoxifen stimulates calcium entry into human platelets. J Cardiovasc Pharmacol 2007; 50 (4) 380-390
  CrossrefPubMedGoogle Scholar
• 17 Shah VP, Chegini HA, Vishneski SR, Weatherman RV, Blackmore PF, Dobrydneva Y. Tamoxifen promotes superoxide production in platelets by activation of PI3-kinase and NADPH oxidase pathways. Thromb Res 2012; 129 (1) 36-42
  CrossrefPubMedGoogle Scholar
• 18 Nayak MK, Singh SK, Roy A, Prakash V, Kumar A, Dash D. Anti-thrombotic effects of selective estrogen receptor modulator tamoxifen. Thromb Haemost 2011; 106 (4) 624-635
  Article in Thieme ConnectPubMedGoogle Scholar
• 19 Chang Y, Lee JJ, Chen WF, Chou DS, Huang SY, Sheu JR. A novel role for tamoxifen in the inhibition of human platelets. Transl Res 2011; 157 (2) 81-91
  CrossrefPubMedGoogle Scholar
• 20 Cano A, Hermenegildo C, Oviedo P, Tarín JJ. Selective estrogen receptor modulators and risk for coronary heart disease. Climacteric 2007; 10 (2) 97-111
  PubMedGoogle Scholar
• 21 Vogelvang TE, van der Mooren MJ, Mijatovic V. Hormone replacement therapy, selective estrogen receptor modulators, and tissue-specific compounds: cardiovascular effects and clinical implications. Treat Endocrinol 2004; 3 (2) 105-115
  CrossrefPubMedGoogle Scholar
• 22 Bertina RM. Elevated clotting factor levels and venous thrombosis. Pathophysiol Haemost Thromb 2003/ 2004; 33 (5–6) 395-400
  PubMedGoogle Scholar
• 23 Cano A, Van Baal WM. The mechanisms of thrombotic risk induced by hormone replacement therapy. Maturitas 2001; 40 (1) 17-38
  CrossrefPubMedGoogle Scholar
• 24 Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA 1993; 90 (3) 1004-1008
  CrossrefPubMedGoogle Scholar
• 25 Tans G, Bouma BN, Büller HR, Rosing J. Changes of hemostatic variables during oral contraceptive use. Semin Vasc Med 2003; 3 (1) 61-68
  Article in Thieme ConnectPubMedGoogle Scholar
• 26 Eilertsen AL, Liestøl S, Mowinckel MC, Hemker HC, Sandset PM. Differential impact of conventional and low-dose oral hormone therapy (HT), tibolone and raloxifene on functionality of the activated protein C system. Thromb Haemost 2007; 97 (6) 938-943
  PubMedGoogle Scholar
• 27 Fair DS, Marlar RA, Levin EG. Human endothelial cells synthesize protein S. Blood 1986; 67 (4) 1168-1171
  PubMedGoogle Scholar
• 28 Lupu C, Zhu H, Popescu NI, Wren JD, Lupu F. Novel protein ADTRP regulates TFPI expression and function in human endothelial cells in normal conditions and in response to androgen. Blood 2011; 118 (16) 4463-4471
  CrossrefPubMedGoogle Scholar
• 29 Dahm AE, Iversen N, Birkenes B, Ree AH, Sandset PM. Estrogens, selective estrogen receptor modulators, and a selective estrogen receptor down-regulator inhibit endothelial production of tissue factor pathway inhibitor 1. BMC Cardiovasc Disord 2006; 6: 40
  CrossrefPubMedGoogle Scholar
• 30 Rossouw JE, Anderson GL, Prentice RL , et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002; 288 (3) 321-333
  CrossrefPubMedGoogle Scholar
• 31 Rossouw JE, Prentice RL, Manson JE , et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007; 297 (13) 1465-1477
  CrossrefPubMedGoogle Scholar
• 32 Mishell Jr DR. Oral contraception: past, present, and future perspectives. Int J Fertil 1992; 37 (Suppl. 01) 7-18
  PubMedGoogle Scholar
• 33 Curtis KM, Chrisman CE, Peterson HB. WHO Programme for Mapping Best Practices in Reproductive Health. Contraception for women in selected circumstances. Obstet Gynecol 2002; 99 (6) 1100-1112
  CrossrefPubMedGoogle Scholar
• 34 Petitti DB. Clinical practice. Combination estrogen-progestin oral contraceptives. N Engl J Med 2003; 349 (15) 1443-1450
  CrossrefPubMedGoogle Scholar
• 35 Khader YS, Rice J, John L, Abueita O. Oral contraceptives use and the risk of myocardial infarction: a meta-analysis. Contraception 2003; 68 (1) 11-17
  CrossrefPubMedGoogle Scholar
• 36 Baillargeon JP, McClish DK, Essah PA, Nestler JE. Association between the current use of low-dose oral contraceptives and cardiovascular arterial disease: a meta-analysis. J Clin Endocrinol Metab 2005; 90 (7) 3863-3870
  CrossrefPubMedGoogle Scholar
• 37 Margolis KL, Adami HO, Luo J, Ye W, Weiderpass E. A prospective study of oral contraceptive use and risk of myocardial infarction among Swedish women. Fertil Steril 2007; 88 (2) 310-316
  CrossrefPubMedGoogle Scholar
• 38 Petitti DB, Sidney S, Bernstein A, Wolf S, Quesenberry C, Ziel HK. Stroke in users of low-dose oral contraceptives. N Engl J Med 1996; 335 (1) 8-15
  CrossrefPubMedGoogle Scholar
• 39 Schwartz SM, Siscovick DS, Longstreth Jr WT , et al. Use of low-dose oral contraceptives and stroke in young women. Ann Intern Med 1997; 127 (8 pt 1) 596-603
  CrossrefPubMedGoogle Scholar
• 40 Siritho S, Thrift AG, McNeil JJ , et al. Risk of ischemic stroke among users of the oral contraceptive pill: the Melbourne Risk Factor Study (MERFS) Group. Stroke 2003; 34 (7) 1575-1580
  CrossrefPubMedGoogle Scholar
• 41 Anderson GL, Limacher M, Assaf AR , et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004; 291 (14) 1701-1712
  CrossrefPubMedGoogle Scholar
• 42 LaCroix AZ, Chlebowski RT, Manson JE , et al. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA 2011; 305 (13) 1305-1314
  CrossrefPubMedGoogle Scholar
• 43 Bath PM, Gray LJ. Association between hormone replacement therapy and subsequent stroke: a meta-analysis. BMJ 2005; 330 (7487) 342
  CrossrefPubMedGoogle Scholar
• 44 Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI. A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med 2001; 345 (17) 1243-1249
  CrossrefPubMedGoogle Scholar
• 45 Simon JA, Hsia J, Cauley JA , et al. Postmenopausal hormone therapy and risk of stroke: the Heart and Estrogen-progestin Replacement Study (HERS). Circulation 2001; 103 (5) 638-642
  CrossrefPubMedGoogle Scholar
• 46 Cummings SR, Ettinger B, Delmas PD , et al. The effects of tibolone in older postmenopausal women. N Engl J Med 2008; 359 (7) 697-708
  CrossrefPubMedGoogle Scholar
• 47 Barrett-Connor E, Mosca L, Collins P , et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 2006; 355 (2) 125-137
  CrossrefPubMedGoogle Scholar
• 48 Fisher B, Costantino JP, Wickerham DL , et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998; 90 (18) 1371-1388
  CrossrefPubMedGoogle Scholar
• 49 Vogel VG, Costantino JP, Wickerham DL , et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 2006; 295 (23) 2727-2741
  CrossrefPubMedGoogle Scholar
• 50 Bushnell CD, Goldstein LB. Risk of ischemic stroke with tamoxifen treatment for breast cancer: a meta-analysis. Neurology 2004; 63 (7) 1230-1233
  CrossrefPubMedGoogle Scholar
• 51 Silverman SL, Christiansen C, Genant HK , et al. Efficacy of bazedoxifene in reducing new vertebral fracture risk in postmenopausal women with osteoporosis: results from a 3-year, randomized, placebo-, and active-controlled clinical trial. J Bone Miner Res 2008; 23 (12) 1923-1934
  CrossrefPubMedGoogle Scholar
• 52 de Villiers TJ, Chines AA, Palacios S , et al. Safety and tolerability of bazedoxifene in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled phase 3 trial. Osteoporos Int 2011; 22 (2) 567-576
  CrossrefPubMedGoogle Scholar
• 53 Cummings SR, Ensrud K, Delmas PD , et al. Lasofoxifene in postmenopausal women with osteoporosis. N Engl J Med 2010; 362 (8) 686-696
  CrossrefPubMedGoogle Scholar
• 54 Zhou WB, Ding Q, Chen L, Liu XA, Wang S. Toremifene is an effective and safe alternative to tamoxifen in adjuvant endocrine therapy for breast cancer: results of four randomized trials. Breast Cancer Res Treat 2011; 128 (3) 625-631
  CrossrefPubMedGoogle Scholar
• 55 Jordan WM. Pulmonary embolism. Lancet 1961; 2: 1146-1147
  PubMedGoogle Scholar
• 56 Thorogood M, Mann J, Murphy M, Vessey M. Risk factors for fatal venous thromboembolism in young women: a case-control study. Int J Epidemiol 1992; 21 (1) 48-52
  CrossrefPubMedGoogle Scholar
• 57 Vandenbroucke JP, Koster T, Briët E, Reitsma PH, Bertina RM, Rosendaal FR. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994; 344 (8935) 1453-1457
  CrossrefPubMedGoogle Scholar
• 58 World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. Lancet 1995; 346 (8990) 1575-1582
  PubMedGoogle Scholar
• 59 Farmer RD, Lawrenson RA, Thompson CR, Kennedy JG, Hambleton IR. Population-based study of risk of venous thromboembolism associated with various oral contraceptives. Lancet 1997; 349 (9045) 83-88
  CrossrefPubMedGoogle Scholar
• 60 Lidegaard Ø, Løkkegaard E, Svendsen AL, Agger C. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ 2009; 339: 2890
  CrossrefPubMedGoogle Scholar
• 61 Vessey M, Mant D, Smith A, Yeates D. Oral contraceptives and venous thromboembolism: findings in a large prospective study. Br Med J (Clin Res Ed) 1986; 292 (6519) 526
  CrossrefPubMedGoogle Scholar
• 62 Gerstman BB, Piper JM, Tomita DK, Ferguson WJ, Stadel BV, Lundin FE. Oral contraceptive estrogen dose and the risk of deep venous thromboembolic disease. Am J Epidemiol 1991; 133 (1) 32-37
  PubMedGoogle Scholar
• 63 Bloemenkamp KW, Rosendaal FR, Helmerhorst FM, Büller HR, Vandenbroucke JP. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a third-generation progestagen. Lancet 1995; 346 (8990) 1593-1596
  CrossrefPubMedGoogle Scholar
• 64 Lidegaard Ø, Nielsen LH, Skovlund CW, Skjeldestad FE, Løkkegaard E. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9. BMJ 2011; 343: d6423
  CrossrefPubMedGoogle Scholar
• 65 van den Heuvel MW, van Bragt AJ, Alnabawy AK, Kaptein MC. Comparison of ethinylestradiol pharmacokinetics in three hormonal contraceptive formulations: the vaginal ring, the transdermal patch and an oral contraceptive. Contraception 2005; 72 (3) 168-174
  CrossrefPubMedGoogle Scholar
• 66 Cole JA, Norman H, Doherty M, Walker AM. Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users. Obstet Gynecol 2007; 109 (2 pt 1) 339-346
  CrossrefPubMedGoogle Scholar
• 67 Dore DD, Norman H, Loughlin J, Seeger JD. Extended case-control study results on thromboembolic outcomes among transdermal contraceptive users. Contraception 2010; 81 (5) 408-413
  CrossrefPubMedGoogle Scholar
• 68 Jick SS, Kaye JA, Russmann S, Jick H. Risk of nonfatal venous thromboembolism in women using a contraceptive transdermal patch and oral contraceptives containing norgestimate and 35 microg of ethinyl estradiol. Contraception 2006; 73 (3) 223-228
  CrossrefPubMedGoogle Scholar
• 69 Jick SS, Hagberg KW, Hernandez RK, Kaye JA. Postmarketing study of ORTHO EVRA and levonorgestrel oral contraceptives containing hormonal contraceptives with 30 mcg of ethinyl estradiol in relation to nonfatal venous thromboembolism. Contraception 2010; 81 (1) 16-21
  CrossrefPubMedGoogle Scholar
• 70 Bjarnadóttir RI, Tuppurainen M, Killick SR. Comparison of cycle control with a combined contraceptive vaginal ring and oral levonorgestrel/ethinyl estradiol. Am J Obstet Gynecol 2002; 186 (3) 389-395
  CrossrefPubMedGoogle Scholar
• 71 Oddsson K, Leifels-Fischer B, de Melo NR , et al. Efficacy and safety of a contraceptive vaginal ring (NuvaRing) compared with a combined oral contraceptive: a 1-year randomized trial. Contraception 2005; 71 (3) 176-182
  CrossrefPubMedGoogle Scholar
• 72 Ahrendt HJ, Nisand I, Bastianelli C , et al. Efficacy, acceptability and tolerability of the combined contraceptive ring, NuvaRing, compared with an oral contraceptive containing 30 microg of ethinyl estradiol and 3.  mg of drospirenone. Contraception 2006; 74 (6) 451-457
  CrossrefPubMedGoogle Scholar
• 73 Kolacki C, Rocco V. The combined vaginal contraceptive ring, Nuvaring, and cerebral venous sinus thrombosis: a case report and review of the literature. J Emerg Med 2012; 42 (4) 413-416
  CrossrefPubMedGoogle Scholar
• 74 Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996; 348 (9033) 977-980
  CrossrefPubMedGoogle Scholar
• 75 Jick H, Derby LE, Myers MW, Vasilakis C, Newton KM. Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens. Lancet 1996; 348 (9033) 981-983
  CrossrefPubMedGoogle Scholar
• 76 Grodstein F, Stampfer MJ, Goldhaber SZ , et al. Prospective study of exogenous hormones and risk of pulmonary embolism in women. Lancet 1996; 348 (9033) 983-987
  CrossrefPubMedGoogle Scholar
• 77 Pérez Gutthann S, García Rodríguez LA, Castellsague J, Duque Oliart A. Hormone replacement therapy and risk of venous thromboembolism: population based case-control study. BMJ 1997; 314 (7083) 796-800
  CrossrefPubMedGoogle Scholar
• 78 Varas-Lorenzo C, García-Rodríguez LA, Cattaruzzi C, Troncon MG, Agostinis L, Perez-Gutthann S. Hormone replacement therapy and the risk of hospitalization for venous thromboembolism: a population-based study in southern Europe. Am J Epidemiol 1998; 147 (4) 387-390
  CrossrefPubMedGoogle Scholar
• 79 Høibraaten E, Abdelnoor M, Sandset PM. Hormone replacement therapy with estradiol and risk of venous thromboembolism—a population-based case-control study. Thromb Haemost 1999; 82 (4) 1218-1221
  PubMedGoogle Scholar
• 80 Smith NL, Heckbert SR, Lemaitre RN , et al. Esterified estrogens and conjugated equine estrogens and the risk of venous thrombosis. JAMA 2004; 292 (13) 1581-1587
  CrossrefPubMedGoogle Scholar
• 81 Cushman M, Kuller LH, Prentice R , et al. Estrogen plus progestin and risk of venous thrombosis. JAMA 2004; 292 (13) 1573-1580
  CrossrefPubMedGoogle Scholar
• 82 Grady D, Wenger NK, Herrington D , et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/progestin Replacement Study. Ann Intern Med 2000; 132 (9) 689-696
  PubMedGoogle Scholar
• 83 Scarabin PY, Oger E, Plu-Bureau G. Estrogen and Thromboembolism Risk Study Group. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet 2003; 362 (9382) 428-432
  CrossrefPubMedGoogle Scholar
• 84 Canonico M, Oger E, Plu-Bureau G , et al. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation 2007; 115 (7) 840-845
  CrossrefPubMedGoogle Scholar
• 85 Straczek C, Oger E, Yon de Jonage-Canonico MB , et al. Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration. Circulation 2005; 112 (22) 3495-3500
  CrossrefPubMedGoogle Scholar
• 86 Canonico M, Oger E, Conard J , et al. Obesity and risk of venous thromboembolism among postmenopausal women: differential impact of hormone therapy by route of estrogen administration. The ESTHER Study. J Thromb Haemost 2006; 4 (6) 1259-1265
  CrossrefPubMedGoogle Scholar
• 87 Canonico M, Plu-Bureau G, Lowe GD, Scarabin PY. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ 2008; 336 (7655) 1227-1231
  CrossrefPubMedGoogle Scholar
• 88 Renoux C, Dell'Aniello S, Suissa S. Hormone replacement therapy and the risk of venous thromboembolism: a population-based study. J Thromb Haemost 2010; 8 (5) 979-986
  PubMedGoogle Scholar
• 89 Canonico M, Fournier A, Carcaillon L , et al. Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism: results from the E3N cohort study. Arterioscler Thromb Vasc Biol 2010; 30 (2) 340-345
  CrossrefPubMedGoogle Scholar
• 90 Canonico M, Plu-Bureau G, Scarabin PY. Progestogens and venous thromboembolism among postmenopausal women using hormone therapy. Maturitas 2011; 70 (4) 354-360
  CrossrefPubMedGoogle Scholar
• 91 Cuzick J, Powles T, Veronesi U , et al. Overview of the main outcomes in breast-cancer prevention trials. Lancet 2003; 361 (9354) 296-300
  CrossrefPubMedGoogle Scholar
• 92 Delmas PD, Ensrud KE, Adachi JD , et al. Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial. J Clin Endocrinol Metab 2002; 87 (8) 3609-3617
  CrossrefPubMedGoogle Scholar
• 93 Martino S, Cauley JA, Barrett-Connor E , et al. Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Natl Cancer Inst 2004; 96 (23) 1751-1761
  CrossrefPubMedGoogle Scholar
• 94 Adomaityte J, Farooq M, Qayyum R. Effect of raloxifene therapy on venous thromboembolism in postmenopausal women. A meta-analysis. Thromb Haemost 2008; 99 (2) 338-342
  PubMedGoogle Scholar
• 95 Taylor HS, Ohleth K. Using bazedoxifene plus conjugated estrogens for treating postmenopausal women: a comprehensive review. Menopause 2012; 19 (4) 479-485
  CrossrefPubMedGoogle Scholar
• 96 Ensrud K, LaCroix A, Thompson JR , et al. Lasofoxifene and cardiovascular events in postmenopausal women with osteoporosis: five-year results from the Postmenopausal Evaluation and Risk Reduction with Lasofoxifene (PEARL) trial. Circulation 2010; 122 (17) 1716-1724
  CrossrefPubMedGoogle Scholar
• 97 Lee VY, Liu DT, Li CL, , Hoi-Fan, Lam DS. Central retinal vein occlusion associated with clomiphene-induced ovulation. Fertil Steril 2008; 90 (5) 2011.e11-2011.e12
  PubMedGoogle Scholar
• 98 Viola MI, Meyer D, Kruger T. Association between clomiphene citrate and visual disturbances with special emphasis on central retinal vein occlusion: a review. Gynecol Obstet Invest 2011; 71 (2) 73-76
  CrossrefPubMedGoogle Scholar