*Rebuttal to PREMPRO Study

Abstracts of most of the references are available for free at the National Library of Medicine

EQUINE ESTROGENS IN PREMPRO Imbalance in estrogens after intake of estrogens by oral route (as with Prempro)  
1) Powers MS, Schenkel L, Darley PE, Good WR, Balestra JC, Place VA. Pharmacokinetics and pharmacodynamics of transdermal dosage forms of 17 beta-estradiol: comparison with conventional oral estrogens used for hormone replacement. Am J Obstet Gynecol 1985 Aug 15;152(8):1099-106
2) Chetkowski RJ, Meldrum DR, Steingold KA, Randle D, Lu JK, Eggena P, Hershman JM, Alkjaersig NK, Fletcher AP, Judd HL. Biologic effects of transdermal estradiol. N Engl J Med 1986 Jun 19;314(25):1615-20

To much foreign (for humans) estrogens with Prempro  
 1) Morgan MR, Whittaker PG, Dean PD, Lenton EA, Sexton L, Cooke ID. Plasma equilin concentrations in an oophorectomized woman following ingestion of ,conjugated equine oestrogens (Premarin). Eur J Clin Invest 1979 Dec;9(6):473-4
2) Bhavnani BR, Sarda IR, Woolever CA. Radioimmunoassay of plasma equilin and estrone in postmenopausal women after the administration of premarin. J Clin Endocrinol Metab 1981 Apr;52(4):741-7
3) Utian WH, Katz M, Davey DA, Carr PJ. Effect of premenopausal castration and incremental dosages of conjugated equine estrogens on plasma follicle-stimulating hormone, luteinizing hormone, and estradiol. Am J Obstet Gynecol 1978 Oct 1;132(3):297-302  

Oral estrogens (as with Prempro) induce excessive liver plasma binding proteins production
Stumpf PG. Pharmacokinetics of estrogen. Obstet Gynecol 1990 Apr;75(4 Suppl):9S-14S; discussion 15S-17S (University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick)  

Oral estrogens (as with Prempro) reduce growth hormone activity. Transdermal estradiol does not
1) Wolthers T, Hoffman DM, Nugent AG, Duncan MW, Umpleby M, Ho KK. Oral estrogen antagonizes the metabolic actions of growth hormone in growth hormone-deficient women. Am J Physiol Endocrinol Metab 2001 Dec;281(6):E1191-6 (The Garvan Institute of Medical Research, St. Vincent's Hospital and Biomedical Mass Spectrometry Unit, University of New South Wales, Sydney, New South Wales 2010, Australia)
2) Paassilta M, Karjalainen A, Kervinen K, Savolainen MJ, Heikkinen J, Backstrom AC, Kesaniemi YA. Insulin-like growth factor binding protein-1 (IGFBP-1) and IGF-I during oral and transdermal estrogen replacement therapy: relation to lipoprotein(a) levels. Atherosclerosis 2000 Mar;149(1):157-62 (Department of Internal Medicine and Biocenter Oulu, University of Oulu, Kajaanintie 50, FIN-90220, Oulu, Finland)
3) Janssen YJ, Helmerhorst F, Frolich M, Roelfsema F. A switch from oral (2 mg/day) to transdermal (50 microg/day) 17beta-estradiol therapy increases serum insulin-like growth factor-I levels in recombinant human growth hormone (GH)-substituted women with GH deficiency. J Clin Endocrinol Metab 2000 Jan;85(1):464-7 (Department of Endocrinology and Metabolism, Leiden University Medical Center, The Netherlands)
4) Cook DM, Ludlam WH, Cook MB. Route of estrogen administration helps to determine growth hormone (GH) replacement dose in GH-deficient adults. J Clin Endocrinol Metab 1999 Nov;84(11):3956-60 (Oregon Health Sciences University, Portland 97201-3098, USA. cookd@ohsu.edu)
5) Cano A, Castelo-Branco C, Tarin JJ. Effect of menopause and different combined estradiol-progestin regimens on basal and growth hormone-releasing hormone-stimulated serum growth hormone, insulin-like growth factor-1, insulin-like growth factor binding protein (IGFBP)-1, and IGFBP-3 levels. Fertil Steril 1999 Feb;71(2):261-7 (Department of Pediatrics, Hospital Clinico Universitario-Facultad de Medicina, Valencia, Spain. antonio.cano@uv.es)
6) Bellantoni MF, Vittone J, Campfield AT, Bass KM, Harman SM, Blackman MR. Effects of oral versus transdermal estrogen on the growth hormone/insulin-like growth factor I axis in younger and older postmenopausal women: a clinical research center study. J Clin Endocrinol Metab 1996 Aug;81(8):2848-53 (Department of Medicine, Johns Hopkins Bayview Medical Center, Baltimore, Maryland 21224, USA)
7) Ho KK, Weissberger AJ. Impact of short-term estrogen administration on growth hormone secretion and action: distinct route-dependent effects on connective and bone tissue metabolism.J Bone Miner Res 1992 Jul;7(7):821-7 (Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, New South Wales, Australia)
8) Weissberger AJ, Ho KK, Lazarus L. Contrasting effects of oral and transdermal routes of estrogen replacement therapy on 24-hour growth hormone (GH) secretion, insulin-like growth factor I, and GH-binding protein in postmenopausal women. J Clin Endocrinol Metab 1991 Feb;72(2):374-81 (Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, Australia)

Transdermal estradiol is more efficient and safer than oral estrogens   
1) Balfour JA, Heel RC. Transdermal estradiol. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of menopausal complaints. Drugs 1990 Oct;40(4):561-82 (Adis Drug Information Services, Auckland, New Zealand)
2) Slater CC, Hodis HN, Mack WJ, Shoupe D, Paulson RJ, Stanczyk FZ. Markedly elevated levels of estrone sulfate after long-term oral, but not transdermal, administration of estradiol in postmenopausal women. Menopause 2001 May-Jun;8(3):200-3 (Department of Obstetrics and Gynecology, Keck School of Medicine of the University of Southern California, Los Angeles, USA)
3) Meilahn EN. Hemostatic Factors and Ischemic Heart Disease Risk Among Postmenopausal Women. J Thromb Thrombolysis 1995;1(2):125-131 (London School of Hygiene and Tropical Medicine, Department of Epidemiolgy and Population Studies)
4) Vehkavaara S, Silveira A, Hakala-Ala-Pietila T, Virkamaki A, Hovatta O, Hamsten A, Taskinen MR, Yki-Jarvinen H. Effects of oral and transdermal estrogen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women. Thromb Haemost 2001 Apr;85(4):619-25 (Department of Medicine, University of Helsinki, Finland)
5) Tikkanen MJ. The menopause and hormone replacement therapy: lipids, lipoproteins, coagulation and fibrinolytic factors. Maturitas 1996 Mar;23(2):209-16 (Department of Medicine, Helsinki University Central Hospital, Finland)
6) Lufkin EG, Ory SJ. Relative value of transdermal and oral estrogen therapy in various clinical situations. Mayo Clin Proc 1994 Feb;69(2):131-5 (Division of Endocrinology/Metabolism, Mayo Clinic Rochester, MN 55905) Lippert TH, Seeger H, Mueck AO. Estradiol metabolism during oral and transdermal estradiol replacement therapy in postmenopausal women.Horm Metab Res 1998 Sep;30(9):598-600 (Section of Clinical Pharmacology, University of Tuebigen, Germany)
7) Steingold KA, Matt DW, DeZiegler D, Sealey JE, Fratkin M, Reznikov S. Comparison of transdermal to oral estradiol administration on hormonal and hepatic parameters in women with premature ovarian failure. J Clin Endocrinol Metab 1991 Aug;73(2):275-80 (Department of Obstetrics and Gynecology, Medical College of Virginia/Virginia Commonwealth University, Richmond 23298)
8) O'Sullivan AJ, Crampton LJ, Freund J, Ho KK. The route of estrogen replacement therapy confers divergent effects on substrate oxidation and body composition in postmenopausal women. J Clin Invest 1998 Sep 1;102(5):1035-40 Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney NSW 2010, Australia.
9) Scarabin PY, Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R, Aiach M. Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. Arterioscler Thromb Vasc Biol 1997 Nov;17(11):3071-8
10) Akkad AA, Halligan AW, Abrams K, al-Azzawi F.Differing responses in blood pressure over 24 hours in normotensive women receiving oral or transdermal estrogen replacement therapy. Obstet Gynecol 1997 Jan;89(1):97-103. (Department of Obstetrics and Gynecology, Leicester University School of Medicine, England)
11) Nieto JJ, Cogswell D, Jesinger D, Hardiman P. Lipid effects of hormone replacement therapy with sequential transdermal 17-beta-estradiol and oral dydrogesterone. Obstet Gynecol 2000 Jan;95(1):111-4 (Department of Obstetrics and Gynaecology, North Middlesex Hospital and Royal Free and University College Medical School, London, United Kingdom)
12) Perera M, Sattar N, Petrie JR, Hillier C, Small M, Connell JM, Lowe GD, Lumsden MA. The effects of transdermal estradiol in combination with oral norethisterone on lipoproteins, coagulation, and endothelial markers in postmenopausal women with type 2 diabetes: a randomized, placebo-controlled study. J Clin Endocrinol Metab 2001 Mar;86(3):1140-3 (Diabetes Center, West Glasgow Hospitals National Health Service Trust, University of Glasgow, Scotland)
13) Mueck AO, Seeger H, Lippert TH. [Effect of transdermal versus oral estradiol administration on the excretion of vasoactive markers in postmenopausal women] [Article in German] Gynakol Geburtshilfliche Rundsch 2000;40(2):61-7 (Sektion Klinische Pharmakologie, Universitats-Frauenklinik, Tubingen, Deutschland)
14) Van Erpecum KJ, Van Berge Henegouwen GP, Verschoor L, Stoelwinder B, Willekens FL. Different hepatobiliary effects of oral and transdermal estradiol in postmenopausal women. Gastroenterology 1991 Feb;100(2):482-8 (Department of Gastroenterology, University Hospital Utrecht, The Netherlands)
15) Chen FP, Lee N, Soong YK, Huang KE. Comparison of transdermal and oral estrogen-progestin replacement therapy: effects on cardiovascular risk factors. Menopause 2001 Sep-Oct;8(5):347-52 (Department of Obstetrics and Gynecology, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan, Republic of China)

Conjugated estrogens (as with Prempro) increase blood coagulation Factor VII activity
Nozaki M, Ogata R, Koera K, Hashimoto K, Nakano H. Changes in coagulation factors and fibrinolytic components of postmenopausal women receiving continuous hormone replacement therapy. Climacteric 1999 Jun;2(2):124-30 (Department of Gynecology and Obstetrics, Faculty of Medicine, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan)

Decrease in tissue factor pathway inhibitor, a major inhibitor of the extrinsic coagulation pathway, and increases of C-reactive protein, a component of the acute phase    
Luyer MD, Khosla S, Owen WG, Miller VM. Prospective randomized study of effects of unopposed estrogen replacement therapy on markers of coagulation and inflammation in postmenopausal women. J Clin Endocrinol Metab 2001 Aug;86(8):3629-34 (Department of Surgery, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA)  

alpha 1-antitrypsin and plasminogen concentrations were significantly increased with higher dosage of oral estrogens
Alkjaersig N, Fletcher AP, de Ziegler D, Steingold KA, Meldrum DR, Judd HL. Blood coagulation in postmenopausal women given estrogen treatment: comparison of transdermal and oral administration. J Lab Clin Med 1988 Feb;111(2):224-8 (Geriatric Research, Education, and Clinical Center, Veterans Administration Medical Center, St. Louis, MO 63125)

 significiant decreases in antithrombin III and protein S activities  
1) Lobo RA, Bush T, Carr BR, Pickar JH. Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on plasma lipids and lipoproteins, coagulation factors, and carbohydrate metabolism. Fertil Steril 2001 Jul;76(1):13-24 (Department of Obstetrics and Gynecology, Columbia-Presbyterian Medical Center, New York, New York 10032-3784, USA. ral35@columbia.edu)
2) Bonduki CE, Lourenco DM, Baracat E, Haidar M, Noguti MA, da Motta EL, Lima GR. Effect of estrogen-progestin hormonal replacement therapy on plasma antithrombin III of postmenopausal women. Acta Obstet Gynecol Scand 1998 Mar;77(3):330-3 (Division of Endocrinological Gynecology and Climacterium, Universidade Federal de Sao Paulo, Brazil)  

The risk of venous thromboembolism was higher within the first year of oral estrogen treatment.  
Oger E, Scarabin PY. Assessment of the risk for venous thromboembolism among users of hormone replacement therapy. Drugs Aging 1999 Jan;14(1):55-61 (Department of Internal Medicine and Chest Diseases, Hopital de la Cavale Blanche, Brest, France)  

An increased risk for ischaemic stroke among postmenopausal women who use oral estrogen replacement therapy  
Oger E, Scarabin PY. [Hormone replacement therapy in menopause and the risk of cerebrovascular accident] [Article in French] Ann Endocrinol (Paris) 1999 Sep;60(3):232-41 (Departement de Medecine Interne et de Pneumologie, Hopital de la Cavale Blanche, Brest)  

Increases in matrix metalloproteinase-9 within the vessel wall could digest and weaken fibrous caps of vulnerable plaques, thus provoking thrombosis    
Zanger D, Yang BK, Ardans J, Waclawiw MA, Csako G, Wahl LM, Cannon RO 3rd. Divergent effects of hormone therapy on serum markers of inflammation in postmenopausal women with coronary artery disease on appropriate medical management. J Am Coll Cardiol 2000 Nov 15;36(6):1797-802 (Cardiology Branch and the Office of Biostatistics Research, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA)  

No effect  
Wells G, Herrington DM. The Heart and Estrogen/Progestin Replacement Study: what have we learned and what questions remain? Drugs Aging 1999 Dec;15(6):419-22 (Department of Internal Medicine/Cardiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1045, USA)   Medroxyprogesterone acetate

Blocks the beneficial  effects of estrogens on the cardiovascular system  
1) Clarkson TB. Progestogens and cardiovascular disease. A critical review. J Reprod Med 1999 Feb;44(2 Suppl):180-4 (Comparative Medicine Clinical Research Center, Wake Forest University School of Medicine, Medicine Center Boulevard, Winston-Salem, NC 27157-1040, USA)
2) Lahdenpera S, Puolakka J, Pyorala T, Luotola H, Taskinen MR. Effects of postmenopausal estrogen/progestin replacement therapy on LDL particles; comparison of transdermal and oral treatment regimens. Atherosclerosis 1996 May;122(2):153-62 (Department of Medicine, University of Helsinki, Finland) 3) Wakatsuki A, Sagara Y.Effects of continuous medroxyprogesterone acetate on lipoprotein metabolism in postmenopausal women receiving estrogen. Maturitas 1996 Aug;25(1):35-44 (Department of Obstetrics and Gynecology, Kochi Medical School, Japan)
4) Cerquetani E, Leonardo F, Pagnotta P, Galetta P, Onorati D, Fini M, Rosano GM. Anti-ischemic effect of chronic oestrogen replacement therapy alone or in combination with medroxyprogesterone acetate in different replacement schemes. Maturitas 2001 Sep 28;39(3):245-51 (Department of Internal Medicine Cardiology, San Raffaele, via Della Pisana 235, 00163, Rome, Italy)
5) Duvernoy CS, Rattenhuber J, Seifert-Klauss V, Bengel F, Meyer C, Schwaiger M. Myocardial blood flow and flow reserve in response to short-term cyclical hormone replacement therapy in postmenopausal women. J Gend Specif Med 2001;4(3):21-7, 47 (Departments of Nuclear Medicine and Gynecology, Technische Universitat Munchen, Munich, Germany)
6) Williams JK, Hall J, Anthony MS, Register TC, Reis SE, Clarkson TB. A comparison of tibolone and hormone replacement therapy on coronary artery and myocardial function in ovariectomized atherosclerotic monkeys. Menopause 2002 Jan-Feb;9(1):41-51 (the Comparative Medicine Clinical Research Center, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1040, USA. kwilliam@wfubmc.edu)
7) Mueck AO, Seeger H, Wallwiener D. Medroxyprogesterone acetate versus norethisterone: effect on estradiol-induced changes of markers for endothelial function and atherosclerotic plaque characteristics in human female coronary endothelial cell cultures. Menopause 2002 Jul;9(4):273-281 (Section of Endocrinology and Menopause, Department of Obstetrics and Gynecology, University of Tuebingen, Tuebingen, Germany)
8) Wakatsuki A, Okatani Y, Ikenoue N, Fukaya T. Effect of medroxyprogesterone acetate on endothelium-dependent vasodilation in postmenopausal women receiving estrogen. Circulation 2001 Oct 9;104(15):1773-8 (Department of Obstetrics and Gynecology, Kochi Medical School, Kochi, Japan. wakatuki@kochi-ms.ac.jp)
9) Register TC, Adams MR, Golden DL, Clarkson TB. 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 1998 Jul;18(7):1164-71 (Comparative Medicine Clinical Research Center and the Department of Comparative Medicine of the Wake Forest University School of Medicine, Winston-Salem, NC 27157-1040, USA. tregister@cpm.wfubmc.edu)
10) Miyagawa K, Rosch J, Stanczyk F, Hermsmeyer K. Medroxyprogesterone interferes with ovarian steroid protection against coronary vasospasm. Nat Med 1997 Mar;3(3):324-7 (Oregon Regional Primate Research Center, Oregon 97006, USA)
11) Adams MR, Register TC, Golden DL, Wagner JD, Williams JK. Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis. Arterioscler Thromb Vasc Biol 1997 Jan;17(1):217-21 (Comparative Medicine Clinical Research Center, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC 27157-1040, USA. madams@cpm.bgsm.edu)

Has adverse effects on cardiovascular parameters triglycerides  
Johnson JV, Davidson M, Archer D, Bachmann G. Postmenopausal uterine bleeding profiles with two forms of continuous combined hormone replacement therapy. Menopause 2002 Jan-Feb;9(1):16-22 (Department of Obstetrics and Gynecology, University of Vermont College of Medicine, Burlington, VT 05405, USA. julia.johnson@vtmednet.org)  

Adverse effect on coronary arteries, increase in arteriosclerosis (not the case with natural progesterone)  
1) Miyagawa K, Vidgoff J, Hermsmeyer K. Ca2+ release mechanism of primate drug-induced coronary vasospasm. Am J Physiol 1997 Jun;272(6 Pt 2):H2645-54 (Oregon Regional Primate Research Center, Oregon Health Sciences University, Beaverton 97006, USA)
2) Minshall RD, Stanczyk FZ, Miyagawa K, Uchida B, Axthelm M, Novy M, Hermsmeyer K. Ovarian steroid protection against coronary artery hyperreactivity in rhesus monkeys. J Clin Endocrinol Metab 1998 Feb;83(2):649-59 (Oregon Regional Primate Research Center, Portland, USA)
3) Seeger H, Wallwiener D, Mueck AO. Effect of medroxyprogesterone acetate and norethisterone on serum-stimulated and estradiol-inhibited proliferation of human coronary artery smooth muscle cells. Menopause 2001 Jan-Feb;8(1):5-9 (Department of Obstetrics and Gynecology, University of Tuebingen, Germany)

The Woman’s Health Initiative study:
Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002 Jul 17;288(3):321-33
CONTEXT: Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain.
OBJECTIVE: To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States.
DESIGN: Estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 8.5 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998.
INTERVENTIONS: Participants received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102).
MAIN OUTCOMES MEASURES: The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome. A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes. RESULTS: On May 31, 2002, after a mean of 5.2 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits. This report includes data on the major clinical outcomes through April 30, 2002. Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63) with 286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85) with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63 (0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases; hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes, 0.92 (0.74-1.14) with 331 cases. Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial and venous disease), 1.03 (0.90-1.17) for total cancer, 0.76 (0.69-0.85) for combined fractures, 0.98 (0.82-1.18) for total mortality, and 1.15 (1.03-1.28) for the global index. Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the global index was 19 per 10 000 person-years.² CONCLUSIONS: Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women. All-cause mortality was not affected during the trial. The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD.