New evidence regarding hormone replacement therapies is urgently required. Transdermal postmenopausal hormone therapy differs from oral hormone therapy in risks and benefits
[en] Controversies about the safety of different postmenopausal hormone therapies (HTs) started 30 years ago and reached a peak in 2003 after the publication of the results from the Women Health Initiative (WHI) trial and the Million Women Study (MWS) [Writing group for the women's health initiative investigations. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002;288:321–33; Million women study collaborators. Breast cancer and hormone-replacement therapy in the million women study. Lancet 2003;362:419–27]. The single HT formulation used in the WHI trial for non hysterectomized women—an association of oral conjugated equine estrogens (CEE–0.625 mg/day) and a synthetic progestin, medroxyprogesterone acetate (MPA–2.5 mg/day)—increases the risks of venous thromboembolism, cardiovascular disease, stroke and breast cancer. The MWS, an observational study, showed an increased breast cancer risk in users of estrogens combined with either medroxyprogesterone acetate (MPA), norethisterone, or norgestrel. It is unclear and questionable to what extent these results might be extrapolated to other HRT regimens, that differ in their doses, compositions and administration routes, and that were not assessed in the WHI trial and the MWS. Significant results were achieved with the publication of the WHI estrogen-only arm study [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;291:1701–1712] in which hormone therapy was reserved to women who had carried out hysterectomy. What emerged from this study will allow us to have some important argument to develop.
Disciplines :
Reproductive medicine (gynecology, andrology, obstetrics)
Author, co-author :
Modena, M. G.
Sismondi, P.
Mueck, A. O.
Kuttenn, F.
De Lignieres, B.
Verhaeghe, J.
Foidart, Jean-Michel ; Université de Liège - ULiège > Département des sciences cliniques > Gynécologie - Obstétrique - Labo de biologie des tumeurs et du développement
Caufriez, A.
Genazzani, A. R.
Language :
English
Title :
New evidence regarding hormone replacement therapies is urgently required. Transdermal postmenopausal hormone therapy differs from oral hormone therapy in risks and benefits
Publication date :
2005
Journal title :
Maturitas
ISSN :
0378-5122
eISSN :
1873-4111
Publisher :
Elsevier North Holland Biomedical Press, Limerick, Ireland
Risks and benefits of estrogen plus progestin in healthy postmenopausal women (2002) JAMA, 288, pp. 321-333
Women Studet Al.laborators, M., Breast cancer and hormone-replacement therapy in the million women study (2003) Lancet, 362, pp. 419-427
Anderson, G.L., Limacher, M., Assaf, A.R., Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The women's health initiative randomized controlled trial (2004) JAMA, 291, pp. 1701-1712
European Agency for the Evaluation of Medicinal Products. EMEA Public Statement on Recent Publications Regarding Hormone Replacement Therapy, , http://www.emea.eu.intdec.2003
Crandall, C., Low-dose estrogen therapy for menopausal women: A review of efficacy and safety (2003) J Women's Health, 12, pp. 723-747
Hulley, S., Grady, D., Bush, T., Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women (1998) JAMA, 280, pp. 605-613
Grady, D., Herrington, D., Bittner, V., Cardiovascular disease outcomes during 6.8 years of hormone therapy (HERS II) (2002) JAMA, 288, pp. 49-57
Hulley, S., Furberg, C., Barrett-Connor, E., Noncardiovascular disease outcomes during 6.8 years of hormone therapy heart and estrogen/progestin replacement study follow-up (HERS II) (2002) JAMA, 288, pp. 58-66
Hoibraaten, E., Qvigstad, E., Arnesen, H., Increased risk of recurrent venous thromboembolism during hormone replacement therapy results of the randomized, double-blind, placebo-controlled estrogen in venous thromboembolism trial (2000) Thromb Haemost, 84, pp. 961-967
Viscoli, C.M., Brass, L.M., Kernan, W.N., A clinical trial of estrogen replacement therapy after ischemic stroke (2001) N Eng J Med, 345, pp. 1243-1249
Beral, V., Banks, E., Reeves, G., Evidence from randomised trials on the long-term effects of hormone replacement therapy (2002) Lancet, 360, pp. 942-944
Collaborative, Group on hormonal factors in breast cancer breast cancer and hormone replacement therapy: Collaborative reanalysis of data from 51 epidemiologic studies of 52705 women with breast cancer and 108411 women without breast cancer (1997) Lancet, 350, pp. 1047-1059
Geller, M.L., Chlebowski, R.T., HT and breast cancer risk (2003) Sex Reprod Menopause, 1, pp. 5-9
Utian, W.H., Gass, M.L.S., Sullivan, J.M., A decision tree for the use of estrogen replacement therapy or hormone replacement therapy in postmenopausal women: Consensus opinion of the North American menopause society (2000) Menopause, 7, pp. 76-86
Barrett-Connor, E., An epidemiologist looks at hormones and heart disease in women (2003) J Clin Endocrinol Metab, 88, pp. 4031-4042
Caine, Y.G., Bauer, K.A., Barzegar, S., Coagulation activation following estrogen administration to postmenopausal women (1992) Thromb Haemostas, 68, pp. 392-395
Nabulsi, A.A., Folsom, A.R., White, A., Association of hormone replacement therapy with various cardiovascular risk factors in postmenopausal women (1993) N Engl J Med, 328, pp. 1069-1075
Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women (1995) JAMA, 273, pp. 199-208
Petitti, D., Hormone replacement therapy for prevention (2002) JAMA, 288, pp. 99-101
Fletcher, S., Colditz, G., Failure of estrogen plus progestin therapy for prevention (2002) JAMA, 288, pp. 366-368
De Lignieres, B., Mauvais-Jarvis, P., Postmenopausal hormonal therapy (1976) Ovarian Endocrinology, pp. 578-592. , R. Scholler SEPE Paris
Holst, J., Cajander, S., Carlstrom, K., A comparison of liver protein induction in postmenopausal women during oral and percutaneous oestrogen replacement therapy (1983) Br J Obstet Gynaecol, 90, pp. 355-360
De Lignieres, B., The case for a non-plasma lipoprotein etiology of reduced vascular risk in estrogen replacement therapy (1993) Curr Opin Obstet Gynecol, 5, pp. 389-395
De Lignieres, B., Basdevant, A., Thomas, G., Biological effects of estradiol-17 beta in postmenopausal women: Oral versus transdermal administration (1986) J Clin Endocrinol Metab, 62, pp. 536-541
Moorjani, S., Dupont, A., Labrie, F., Changes in plasma lipoprotein and apolipoprotein composition in relation to oral vesrsus transdermal administration of estrogens (1991) J Clin Endocrinol Metab, 73, pp. 373-379
Scarabin, P.Y., Alhenc-Gelas, M., Plu-Bureau, G., Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women (1997) Arterioscler Thromb Vasc Biol, 17, pp. 3071-3078
Godsland, I.F., Effects of postmenopausal hormone replacement therapy on lipid, lipoprotein, and apolipoprotein (a) concentrations: Analysis of studies published from 1974-2000 (2001) Fertil Steril, 75, pp. 898-915
Wakatsuki, A., Okatani, Y., Ikenoue, N., Different effects of oral conjugated equine estrogen and transdermal estrogen replacement on size and oxidative susceptibility of low-density lipoprotein particles in postmenopausal women (2002) Circulation, 106, pp. 1771-1776
Venkov, C.D., Rankin, A.B., Douglas, E., Identification of authentic estrogen receptor in cultured endothelial cells. a potential mechanism for steroid hormone regulation of endothelial function (1996) Circulation, 94, pp. 727-733
Kim-Schulze, S., McGowan, K., Hubchak, S.C., Expression of an estrogen receptor by human coronary artery and umbilical vein endothelial cells (1996) Circulation, 94, pp. 1402-1407
Alvarez, R.J., Gips, S.J., Moldovan, N., 17b-estradiol inhibits apoptosis of endothelial cells (1997) Biochem Biophys Res Communic, 237, pp. 372-381
Iwakura, A., Luedemann, C., Shasrty, S., Estrogen-mediated, endothelial nitric oxide synthase-dependent mobilization of bone marrow-derived endothelial progenitor cells contributes to reendothelialization after arterial injury (2003) Circulation, 108, pp. 3115-3121
Simoncini, T., Genazzani, A.R., Direct vascular effects of estrogens and selective estrogen receptor modulators (2000) Curr Opin Obstet Gynecol, 12, pp. 181-187
Simoncini, T., Hafezi-Moghadam, A., Brazil, D., Ley, K., Chin, W.W., Liao, J.K., Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase (2000) Nature, 407, pp. 538-541
Simoncini, T., Genazzani, A.R., Non-genomic actions of sex steroid hormones (2003) Eur J Endocrinol, 148, pp. 281-292
Vazquez, F., Rodriguez-Manzanesque, J.C., Lydon, J.P., Progesterone regulates proliferation of endothelial cells (1999) J Biol Chem, 274, pp. 2185-2192
Miyagawa, K., Rosch, J., Stanczyk, F., Hermsmeyer, K., Medroxyprogesterone interferes with ovarian steroid protection against coronary vasospasm (1997) Nat Med, 3, pp. 324-327
Cheng, W., Lau, O.D., Abumrad, N.A., Two antiatherogenic effects of progesterone on human macrophages
Inhibition of cholesteryl ester synthesis and block of its enhancement by glucocorticoids (1999) J Clin Endocrinol Metab, 84, pp. 265-271
Otsuki, M., Saito, H., Xu, X., Progesterone, but not medroxyprogesterone, inhibits vascular cell adhesion molecule-1 expression in human vascular endothelial cells (2001) Arterioscler Thromb Vasc Biol, 21, pp. 243-248
Xing, D., Miller, A., Novak, L., Estradiol and progestins differentially modulate leukocyte infiltration after vascular injury (2004) Circulation, 109, pp. 234-241
Simoncini, T., Mannella, P., Fornari, L., Caruso, A., Varone, G., Genazzani, A.R., In vitro effects of progesterone and progestins on vascular cells (2003) Steroids, 68, pp. 831-836
Vehkavaara, S., Silveira, A., Hakala-Ala-Pietila, T., Effects of oral and transdermal estrogen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women (2001) Thromb Haemost, 85, pp. 619-625
Decensi, A., Omodei, U., Robertson, C., Effect of transdermal estradiol and oral conjugated estrogen on C-reactive protein in retinoid-placebo trial in healthy women (2002) Circulation, 106, pp. 1224-1228
Modena, M.G., Bursi, F., Fantini, G., Effects of hormone replacement therapy on C-reactive protein levels in healthy postmenopausal women: Comparison between oral and transdermal administration of estrogen (2002) Am J Med, 113, pp. 331-334
Vongpatanasin, W., Tuncel, M., Wang, Z., Differential effects of oral versus transdermal estrogen replacement therapy on C-reactive protein in postmenopausal women (2003) J Am Coll Cardiol, 41, pp. 1358-1363
Clarke, S.C., Kelleher, J., Lloyd-Jones, A study of hormone replacement therapy in postmenopausal women with ischaemic heart disease: The Papworth HRT atherosclerosis study (2002) Br J Obstet Gynecol, 109, pp. 1056-1062
Grodstein, F., Clarkson, T.B., Manson, J.E., Understanding the divergent data on postmenopausal hormone therapy (2003) N Engl J Med, 348, pp. 645-650
Hoibraaten, E., Qvigstad, E., Andersen, T.O., The effects of hormone replacement therapy (HRT) on hemostatic variables in women with previous venous thromboembolism: Results from a randomized, double-blind, clinical trial (2001) Thromb Haemost, 85, pp. 775-781
Scarabin, P.Y., Oger, E., Plu-Bureau, G., Differential association of oral and transdermal oestrogen replacement therapy with venous thromboembolism risk (2003) Lancet, 362, pp. 428-432
Conard, J., Samama, M., Basdevant, A., Differential at III response to oral and parenteral administration of 17-beta estradiol (1983) Thromb Haemost, 49, p. 245
De Visser, M.C., Rosendaal, F.R., Bertina, R.M., A reduced sensitivity for activated protein C in the absence of factor V Leiden increases the risk of venous thrombosis (1999) Blood, 93, pp. 1271-1276
Tans, G., Van Hylckama Vlieg, A., Thomassen, M.C., Activated protein C resistance determined with a thrombin generation-based test predicts for venous thrombosis in men and women (2003) Br J Haematol, 122, pp. 465-470
Rosing, J., Middeldorp, S., Curvers, J., Low-dose oral contraceptives and acquired resistance to activated protein C: A randomised cross-over study (1999) Lancet, 354, pp. 2036-2040
Hoibraaten, E., Mowinckel, M.C., De Ronde, H., Bertina, R.M., Sandset, P.M., Hormone replacement therapy and acquired resistance to activated protein C: Results of a randomized, double-blind, placebo-controlled trial (2001) Br J Haematol, 115, pp. 415-420
Post, M.S., Christella, M., Thomassen, L.G., Effect of oral and transdermal estrogen replacement therapy on hemostatic variables associated with venous thrombosis: A randomized, placebo-controlled study in postmenopausal women (2003) Arterioscler Thromb Vasc Biol, 23, pp. 1116-1121
Oger, E., Alhenc-Gelas, M., Lacut, K., Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: A randomised trial (2003) Arterioscler Thromb Vasc Biol, 23, pp. 1671-1676
Rossouw, J.E., Hormones for coronary disease-full circle (2002) Lancet, 360, pp. 1996-1997
Kuller, L.H., Hormone replacement therapy and risk of cardiovascular disease: Implications of the results of the Women's Health Initiative (2003) Arterioscler Thromb Vasc Biol, 23, pp. 11-16
Manson, J.E., Hsia, J., Johnson, K.C., Estrogen plus progestin and the risk of coronary heart disease (2003) N Engl J Med, 349, pp. 523-533
Shlipak, M.G., Chaput, L.A., Vittinghoff, E., Lipid changes on hormone therapy and coronary heart disease events in the heart and estrogen/progestin replacement study (HERS) (2003) Am Heart J, 146, pp. 870-875
De Lignieres, B., De Vathaire, F., Le, M.G., Kuttenn, F., Traitements hormonaux substitutifs de la ménopause et risque cardiovasculaire: Les spécificités françaises (2003) Mt-Med Ther, 9, pp. 38-45
Sykes, D.H., Arveiler, D., Salters, C.P., Psychosocial risk factors for heart disease in France and Northern Ireland: The prospective epidemiological study of myocardial infarction (PRIME) trial (2002) Int J Epidemiol, 31, pp. 1094-1097
Chelbowski, R.T., Hendrix, S.L., Langer, R.D., Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women. the women's health initiative randomized trial (2003) JAMA, 289, pp. 3243-3253
Jordan, C., Jeng, M., Catherino, W., The estrogenic activity of synthetic progestin used in oral contraception (1993) Cancer, 71, pp. 1501-1505
Coldham, N.G., James, V.H.T., A possible mechanism for increase breast cell proliferation by progestins through increased reductive 17b-hydroxysteroid dehydrogenase activity (1990) Int J Cancer, 45, pp. 174-178
Malet, C., Spritzer, P., Guillaumin, D., Kuttenn, F., Progesterone effect on cell growth, ultrastructural aspect and estradiol receptors of normal human breast epithelial cells in culture (2000) J Steroid Biochem, 73, pp. 171-181
(2000) NTP Board of Scientific Counselors Report on Carcinogens Background Document for Steroidal Estrogens, , US Deparment of Health and Human Services. 13-14 December
Lippert, C., Seeger, H., Mueck, A.O., Lippert, T.H., The effects of A-ring and D-ring metabolites of estradiol on the proliferation of vascular endothelial cells (2000) Life Sci, 67, pp. 1653-1658
Lippert, C., Seeger, H., Mueck, A.O., The effect of endogenous estradiol metabolites on the proliferation of human breast cancer cells (2003) Life Sci, 72, pp. 877-883
Lippert, T.H., Seeger, H., Mueck, A.O., Estradiol metabolism during oral and transdermal estradiol replacement therapy in the postmenopause (1998) Horm Metab Res, 30, pp. 598-600
Mueck, A.O., Seeger, H., Lippert, T.H., Estradiol metabolism and malignant disease (2002) Maturitas, 43, pp. 1-10
Mueck, A.O., Seeger, H., Smoking, estradiol metabolism and hormone replacement therapy (2003) Drug Res, 53, pp. 1-11
Yancik, R., Wesley, M., Ries, L., Effect of age and comorbidity in postmenopausal breast cancer patients aged 55 years and older (2001) JAMA, 285, pp. 885-892
Gunnarsson, C., Olsson, B.M., Stal, O., Abnormal expression of 17b-hydroxysteroid dehydrogenase in breast cancer predicts late recurrence (2001) Cancer Res, 61, pp. 8448-8451
Breast cancer and hormone replacement therapy: Collaborative reanalysis of data from 51 epidemiologic studies of 52705 women with breast cancer and 108411 women without breast cancer (1997) Lancet, 350, pp. 1047-1059
Beral, B., Banks, E., Reeves, G., Use of HRT and the subsequent risk of cancer (1999) J Epidemiol Biostat, 4, pp. 191-200
Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women (2003) J Natl Cancer Inst, 95, pp. 212-218
Pollow, K., Boquoi, E., Baumann, J., Comparison of the in vitro conversion of estradiol-17b to estrone of normal and neoplastic human breast (1977) Mol Cell Endocrinol, 6, pp. 333-348
Fournier, S., Kuttenn, F., De Cicco, F., Baudot, N., Malet, C., Mauvais-Jarvis, P., Estradiol 17 beta-hydroxysteroid dehydrogenase activity in human breast fibroadenomas (1982) J Clin Endocrinol Metab, 55, pp. 428-433
Barrat, J., De Lignieres, B., Marpeau, L., Effet in vivo de l'administration locale de progesterone sur l'activité mitotique des galactophores humains (1990) J Gynecol Obstet Biol Reprod, 19, pp. 269-274
Chang, K.J., Fournier, S., Lee, T.T.Y., Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo (1995) Fertil Steril, 63, pp. 785-791
Plu-Bureau, G., Le, M.G., Thalabard, J.C., Percutaneous progesterone use and risk of breast cancer: Results from a French cohort study of premenopausal women with benign breast disease (1999) Cancer Detect Prev, 23, pp. 290-296
McGonigle, K.F., Huggins, G.R., Oral contraceptives and breast disease (1991) Fertil Steril, 56, pp. 799-819
Petitti, D.B., Clinical practice combination estrogen-progestin oral contraceptives (2004) N Engl J Med, 349, pp. 1443-1450
Dumeaux, V., Alsaker, E., Lund, E., Breast cancer and specific types of oral contraceptives: A large Norwegian cohort study (2003) Int J Cancer, 105, pp. 844-850
O'Brien, S.N., Anandjiwala, J., Price, T.M., Differences in the estrogen content of breast adipose tissue in women by menopausal status and hormone use (1997) Obstet Gynecol, 90, pp. 244-248
De Lignieres, B., De Vathaire, F., Fournier, S., Combined hormone replacement therapy and risk of breast cancer in a French cohort study of 3175 women (2002) Climacteric, 5, pp. 332-340
Stahlberg, C., Tonnes Pedersen, A., Lynge, E., Hormone replacement therapy and risk of breast cancer: The role of progestins (2003) Acta Obstet Gynecol Scand, 82, pp. 335-344
Mueck, A.O., Seeger, H., Wallwiener, D., Comparison of the proliferative effect of estradiol and conjugated equine estrogens on human breast cancer cells and impact of continuous combined progestin addition (2003) Climacteric, 6, pp. 221-227
Groshong, S.D., Owen, G.I., Grimison, B., Biphasic regulation of breast cancer cell growth by progesterone: Role of the cyclin-dependent kinase inhibitors, p21 and p27 (1997) Mol Endocrinol, 11, pp. 1593-1607
Musgrove, E., Hunter, L., Lee, C., Cyclin D1 overexpression induces progestin resistance in T-47D breast cancer cells despite p27 (Kip1) association with cyclin E-Cdk2 (2001) J Biol Chem, 276, pp. 47675-47683
Formby, B., Wiley, T.S., Bcl-2, survivin and variant CD44v7-v10 are downregulated and p53 is upregulated in breast cancer cells by progesterone: Inhibition of cell growth and induction of apoptosis (1999) Mol Cell Biochem, 202, pp. 53-61
Gompel, A., Somaï, S., Chaouat, M., Hormonal regulation of apoptosis in breast cells and tissues (2000) Streroids, 65, pp. 593-598
Ory, K., Lebeau, J., Levalois, C., Apoptosis inhibition mediated by medroxyprogesterone acetate treatment of breast cancer cell lines (2001) Breast Cancer Res Treat, 68, pp. 187-198
Hofseth, L.J., Raafat, A.M., Osuchi, J.R., Hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone acetate is associated with increased epithelial proliferation in the normal postmenopausal breast (1999) J Clin Endocrinol Metab, 84, pp. 4559-4565
Foidart, J.M., Colin, C., Denoo, X., Estradiol and progesterone regulate the proliferation of human breast epithelial cells (1998) Fertil Steril, 69, pp. 963-969
Fournier, A., Berrino, F., Riboli, E., Avenel, V., Clavel-Chapelon, F., Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort (2005) Int J Cancer, 114 (3), pp. 448-454
Rabbani, L.E., Seminario, N.A., Sciacca, R.R., Chen, H.J., Giardina, E.G., Oral conjugated equine estrogen increases plasma von Willebrand factor in postmenopausal women (2002) J Am Coll Cardiol, 40 (11), pp. 1991-1999