Pharmacology of estrogens and progestogens: influence of different routes of administration

References

• Steingold KA, Laufer L, Chetkowski RJ, et al. Treatment of hot flashes with transdermal estradiol administration. J Clin Endocrinol Metab 1985;61:627–32
   PubMed Web of Science ®Google Scholar
• Ray S, Rastogi R, Kumar A. Current status of estrogen receptors. Progr Drug Res 2002;59:201–32
   PubMedGoogle Scholar
• Hall JM, McDonnell DP. The estrogen receptor β-isoform (ERβ) 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
   PubMed Web of Science ®Google Scholar
• Weihua Z, Andersson S, Cheng G, et al. Update on estrogen signalling. FEBS Lett 2003;546:17–24
   PubMed Web of Science ®Google Scholar
• Albertazzi P, Purdie DW. The life and times of the estrogen receptors: an interim report. Climacteric 2001;4:194–202
   PubMedGoogle Scholar
• Gebhart JB, Rickard DJ, Barrett TJ, et al. Expression of estrogen receptor isoforms α and β messenger RNA in vaginal tissue of premenopausal and postmenopausal women. Am J Obstet Gynecol 2001;185:1325–31
   PubMed Web of Science ®Google Scholar
• Pedersen SB, Bruun JM, Hube F, et al. Demonstration of estrogen receptor subtypes α and β in human adipose tissue: influence of adipose cell differentiation and fat depot localization. Mol Cell Endocrinol 2001;182:27–37
   PubMed Web of Science ®Google Scholar
• Thronton MJ, Taylor AH, Mulligan K, et al. The distribution of estrogen receptor β is distinct to that of estrogen receptor α and the androgen receptor in human skin and the pilosebaceous unit. J Invest Dermatol Symp Proc 2003;8:100–3
   PubMed Web of Science ®Google Scholar
• Kuiper GGJM, Carlsson B, Grandien K, et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors α and β. Endocrinology 1997;138:863–70
   PubMed Web of Science ®Google Scholar
• Lee SK, Choi HS, Song MR, et al. Estrogen receptor, a common interaction partner for a subset of nuclear receptors. Mol Endocrinol 1998;12:1184–92
   PubMed Web of Science ®Google Scholar
• Vignon F, Gompel A, Siromachkova M, et al. Effects of pulsed or continuous estradiol administration on proliferation of normal and tumoral human breast cells (Abstract). Menopause 1999;6:362
   Google Scholar
• Mashchak CA, Lobo RA, Dozono-Takano R, et al. Comparison of pharmacodynamic properties of various estrogen formulations. Am J Obstet Gynecol 1982;144:511–18
   PubMed Web of Science ®Google Scholar
• Helgason S. Estrogen replacement therapy after the menopause. Acta Obstet Gynecol Scand 1982;Suppl 107:1–29
   Google Scholar
• Lobo RA, Nguyen HN, Eggena P, et al. Biologic effects of equilin sulfate in postmenopausal women. Fertil Steril 1988;49:234–8
   PubMed Web of Science ®Google Scholar
• Bhavnani BR, Cecutti A. Metabolic clearance rate of equilin sulfate and its conversion to plasma equilin, conjugated and unconjugated equilenin, 17β-dihydroequilin, and 17β-dihydroequilenin in normal postmenopausal women and men under steady state conditions. J Clin Endocrinol Metab 1993;77:1269–74
   PubMed Web of Science ®Google Scholar
• Bhavnani BR. Pharmacology of conjugated estrogens. Menopause Rev 2000;5/3–4:45–68
   Google Scholar
• Bhavnani BR. Estrogens and menopause: pharmacology of conjugated equine estrogens and their potential role in the prevention of neurodegenerative diseases such as Alzheimer’s. J Steroid Biochem Mol Biol 2003;85:473–82
   PubMed Web of Science ®Google Scholar
• Kuhl H. Pharmacology of estradiol and estriol. Menopause Rev 2000;5/3–4:23–44
   Google Scholar
• Zhu BT, Conney AH. Functional role of estrogen metabolism in target cells. Carcino genesis 1998;19:1–27
   PubMed Web of Science ®Google Scholar
• Martucci C, Fishman J. Uterine estrogen receptor binding of catecholestrogens and of estetrol (1,3,5(10)-estratriene-3,15a,16a,17btetrol). Steroids 1976;27:325–33
   PubMed Web of Science ®Google Scholar
• Fishman J, Martucci CP. New concepts of estrogenic activity: the role of metabolites in the expression of hormone action. In Pasetto N, Paoletti R, Ambrus JL, eds. The Menopause and Postmenopause. Lancaster: MTP Press, 1980;43–52
   Google Scholar
• Kuhnz W, Gansau C, Mahler M. Pharmacokinetics of estradiol, free and total estrone, in young women following single intravenous and oral administration of 17β-estradiol. Drug Res 1993;43:966–73
   PubMed Web of Science ®Google Scholar
• Nachtigall LE, Raju U, Banerjee S, et al. Serum estradiol-binding profiles in postmenopausal women undergoing three common estrogen replacement therapies: association with sex hormone-binding globulin, estradiol, and estrone levels. Menopause 2000;7:243–50
   PubMed Web of Science ®Google Scholar
• Kuhl H. Pharmacokinetics of estrogens and progestogens. Maturitas 1990;12:171–97
   PubMed Web of Science ®Google Scholar
• Dunn JF, Nisula BC, Rodbard D. Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma. J Clin Endocrinol Metab 1981;53:58–68
   PubMed Web of Science ®Google Scholar
• Wiegerinck MAHM, Poortman J, Donker TH, et al. In vivo uptake and subcellular distribution of tritium labelled estrogens in human endometrium, myometrium, and vagina. J Clin Endocrinol Metab 1983;56:76–86
   PubMed Web of Science ®Google Scholar
• Back DJ, Breckenridge AM, MacIver M, et al. The gut wall metabolism of ethinyloestradiol and its contribution to the pre-systemic metabolism of ethinyloestradiol in humans. Br J Clin Pharmacol 1982;13:325–30
   PubMed Web of Science ®Google Scholar
• Verheugen C, Pardridge WM, Judd HL, et al. Differential permeability and liver vascular beds to estrogens and estrogen conjugates. J Clin Endocrinol Metab 1984;59:1128–32
   PubMed Web of Science ®Google Scholar
• Steingold KA, Cefalu W, Pardridge W, et al. Enhanced extraction of estrogens used for replacement therapy. J Clin Endocrinol Metab 1986;62:761–6
   PubMed Web of Science ®Google Scholar
• Aedo AR, Landgren BM, Diczfalusy E. Pharmacokinetics and biotransformation of orally administered oestrone sulphate and oestradiol valerate in postmenopausal women. Maturitas 1990;12:333–43
   PubMed Web of Science ®Google Scholar
• Stadberg E, Westlund P, Landgren BM, et al. Bioavailability of norethisterone acetate alone and in combination with estradiol administered in single or multiple oral doses to post-menopausal women. Maturitas 1999;33:59–69
   PubMed Web of Science ®Google Scholar
• Zdravkovic M, Müller M, Larsen S, et al. Bioequivalence and relative bioavailability of three estradiol and norethisterone acetate-containing hormone replacement therapy tablets. Int J Clin Pharmacol Ther 2001;39:41–6
   PubMed Web of Science ®Google Scholar
• Järvinen A, Kainulainen P, Nissilä M, et al. Pharmacokinetics of estradiol valerate and medroxyprogesterone acetate in different age groups of postmenopausal women. Maturitas 2004;47:209–17
   PubMed Web of Science ®Google Scholar
• Kraemer GR, Kraemer RR, Ogden BW, et al. Variability of serum estrogens among postmenopausal women treated with the same transdermal estrogen therapy and the effect on androgens and sex hormone blinding globulin. Fertil Steril 2003;79:534–42
   PubMed Web of Science ®Google Scholar
• Reginster JY, Albert A, Deroisy R, et al. Plasma estradiol concentrations and pharmacokinetics following transdermal application of Menorest 50 or Systen /Evorel) 50. Maturitas 1997;27:179–86
   PubMed Web of Science ®Google Scholar
• Rohr UD, Ehrly AM, Kuhl H. Plasma profiles of transdermal 17β-estradiol delivered by two different matrix patches. Drug Res 1997;47:761–7
   PubMed Web of Science ®Google Scholar
• Buch A, Shen L, Kelly S, et al. Steady state bioavailability of estradiol from two matrix transdermal delivery systems, Alora and Climara. Menopause 1998;5:107–12
   PubMed Web of Science ®Google Scholar
• Baracat E, Haidar M, Castelo A, et al. Comparative bioavailability study of once-a-week matrix versus a twice-a-week reservoir transdermal estradiol delivery systems in post-menopausal women. Maturitas 1996;23:285–91
   PubMed Web of Science ®Google Scholar
• Setnikar I, Rovati LC, Thebault JJ, et al. Pharmacokinetics of estradiol and of estrone during application of three strengths of an estradiol transdermal patch with active matrix. Drug Res 1997;47:859–65
   Web of Science ®Google Scholar
• Hossain M, Quebe-Fehling E, Sergejew T, et al. Dose proportionality of four doses of an estradiol transdermal system, Estradot. Maturitas 2003;46:173–85
   PubMed Web of Science ®Google Scholar
• Scott RT, Ross B, Anderson C, et al. Pharmacokinetics of percutaneous estradiol: a crossover study using a gel and a transdermal system in comparison with oral micronized estradiol. Obstet Gynecol 1991;77:758–64
   PubMed Web of Science ®Google Scholar
• Järvinen A, Nykänen S, Paasiniemi L. Absorption and bioavailability of oestradiol from a gel, a patch and a tablet. Maturitas 1999;32:103–13
   PubMed Web of Science ®Google Scholar
• Place VA, Powers M, Darley PE, et al. A double-blind comparative study of Estraderm and Premarin in the amelioration of postmenopausal symptoms. Am J Obstet Gynecol 1985;152:1092–9
   PubMed Web of Science ®Google Scholar
• Yasui T, Uemura H, Tezuka M, et al. Biological effects of hormone replacement therapy in relation to serum estradiol levels. Horm Res 2001;56:38–44
   PubMed Web of Science ®Google Scholar
• Archer DF, for the EstroGel Study Group. Percutaneous 17β-estradiol gel for the treatment of vasomotor symptoms in postmenopausal women. Menopause 2003;10:516–21
   PubMed Web of Science ®Google Scholar
• Cauley JA, Robbins J, Chen Z, et al. The Women’s Health Initiative Randomized Trial. Effects of estrogen plus progestin on risk of fracture and bone mineral density. JAMA 2003;290:1729–38
   PubMed Web of Science ®Google Scholar
• Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy post-menopausal women: principal results from the Women’s Health Initiative randomised controlled trial. JAMA 2002;288:321–33
   PubMed Web of Science ®Google Scholar
• The Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. The Women’s Health Initiative Randomized Controlled Trial. JAMA 2004;291:1701–12
   PubMed Web of Science ®Google Scholar
• Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in post-menopausal women. JAMA 1998;280:605–52
   PubMed Web of Science ®Google Scholar
• Byington RP, Furberg CD, Herrington DM, et al. Effect of estrogen plus progestin on progression of carotid atherosclerosis in postmenopausal women with heart diesease, HERS B-mode substudy. Arterioscler Thromb Vasc Biol 2002;22:1692–7
   PubMed Web of Science ®Google Scholar
• Herrington DM, Reboussin DM, Brosnihan KB, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 2000;343:522–9
   PubMed Web of Science ®Google Scholar
• Angerer P, Störk S, Kothny W, et al. Effect of oral postmenopausal hormone replacement on progression of atherosclerosis. A randomized, controlled trial. Arterioscler Thromb Vasc Biol 2001;21:262–8
   PubMed Web of Science ®Google Scholar
• Clarke SC, Kelleher J, Lloyd-Jones H, et al. A study of hormone replacement therapy in postmenopausal women with ischaemic heart disease: the Papworth HRT Atherosclerosis Study. Br J Obstet Gynaecol 2002;109:1056–62
   Google Scholar
• Manson JAE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003;349:523–34
   PubMed Web of Science ®Google Scholar
• Losordo DW, Kearney M, Kim EA, et al. Variable expression of the estrogen receptor in normal and atherosclerotic coronary arteries of premenopausal women. Circulation 1994;89:1501–10
   PubMed Web of Science ®Google Scholar
• Post WS, Goldschmidt-Clermont PJ, Wolhide CC. Methylation of the estrogen receptor gene is associated with aging and atherosclerosis in the cardiovascular system. Cardiovasc Res 1999;43:985–91
   PubMed Web of Science ®Google Scholar
• Hodis HN, Mack WJ, Lobo RA, et al. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;135:939–53
   PubMed Web of Science ®Google Scholar
• Espeland MA, Applegate W, Furberg CD, et al. Estrogen replacement therapy and progression of intimal-medial thickness in the carotid arteries of postmenopausal women. Am J Epidemiol 1995;142:1011–9
   PubMed Web of Science ®Google Scholar
• Mihmanli V, Mihmanli I, Atakir K, et al. Carotid intima-media thickness in surgical menopause: women who received HRT versus who did not. Maturitas 2002;42:37–43
   PubMed Web of Science ®Google Scholar
• Grodstein F, Manson JAE, Colditz GA, et al. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med 2000;133:933–41
   PubMed Web of Science ®Google Scholar
• Westendorp ICD, in’t Veld BA, Grobbee DE, et al. Hormone replacement therapy and peripheral arterial disease. Arch Intern Med 2000;160:2498–502
   PubMed Web of Science ®Google Scholar
• Westendorp ICD, in’t Veld BA, Bots ML, et al. Hormone replacement therapy and intima-media thickness of the common carotid artery. The Rotterdam study. Stroke 1999;30:2562–7
   PubMed Web of Science ®Google Scholar
• Clarkson TB. The new conundrum: do estrogens have any cardiovascular benefits? Int J Fertil 2002;47:61–8
   Google Scholar
• Varas-Lorenzo C, Garcia-Rodriguez LA, Perez-Guthann S, et al. Hormone replacement therapy and incidence of acute myocardial infarction. A population-based nested case-control study. Circulation 2000;101:2572–8
   PubMed Web of Science ®Google Scholar
• Le Gal G, Gourlet V, Hogrel P, et al. Hormone replacement therapy use is associated with a lower occurrence of carotid atherosclerotic plaques but not with intima-media thickness progression among postmenopausal women. The vascular aging (EVA) study. Atherosclerosis 2003;166:163–70
   PubMed Web of Science ®Google Scholar
• Miller J, Chan BKS, Nelson HD. Postmenopausal estrogen replacement and risk for venous thromboembolism: a systematic review and meta-analysis for the US Preventive Services Task Force Ann Intern Med 2002;136:680–90
   Google Scholar
• Scarabin PY, Oger E, Plu-Bureau G. Differential association of oral and transdrmal oestrogen-replacement therapy with venous thromboembolism risk. Lancet 2003;362:428–32
   PubMed Web of Science ®Google Scholar
• Daly E, Vessey MP, Hawkins MM, et al. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996;348:977–80
   PubMed Web of Science ®Google Scholar
• Guthann SP, Garcia Rodriguez LA, Castellsague J, et al. Hormone replacement therapy and risk of venous thromboembolism: population based case-control study. BMJ 1997;314:796–800
   PubMed Web of Science ®Google Scholar
• Crook D. The metabolic consequences of treating postmenopausal women with non-oral hormone replacement therapy. Br J Obstet Gynaecol 1997;104(Suppl 16):4–13
   PubMedGoogle Scholar
• Uhler ML, Marks JW, Voigt BJ, et al. Comparison of the impact of transdermal versus oral estrogens on biliary markers of gallstone formation in postmenopausal women. J Clin Endocrinol Metab 1998;83:410–14
   PubMed Web of Science ®Google Scholar
• Vehkavaara S, Silveira A, Hakala-Ala-Pietilä T, et al. 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;85:619–25
   PubMed Web of Science ®Google Scholar
• Marque V, Alhenc-Gelas M, Plu-Bureau G, et al. The effects of transdermal and oral estrogen/ progesterone regimens on free and total protein S in postmenopausal women. Thromb Haemost 2001;86:713–14
   PubMed Web of Science ®Google Scholar
• Lowe GDO, Upton MN, Rumley A, et al. Different effects of oral and transdermal hormone replacement therapies on factor IX, APC resistance, t-PA, PAI and C-reactive protein. Thromb Haemost 2001;86:550–6
   PubMed Web of Science ®Google Scholar
• Rabbani LE, Seminario NA, Sciacca RR, et al. Oral conjugated equine estrogen increases plasma von Willebrand factor in postmenopausal women. J Am Coll Cardiol 2002;40:1991–9
   PubMed Web of Science ®Google Scholar
• Post MS, Thomassen CLGD, van der Mooren MJ, et al. Effect of oral and transdermal estrogen replacement therapy on hemostatic variables associated with venous thrombosis. Arterioscler Thromb Vasc Biol 2003;23:1116–21
   PubMed Web of Science ®Google Scholar
• Post MS, van der Mooren MJ, van Baal WM, et al. Effects of low-dose oral and transdermal estrogen replacement therapy on hemostatic factors in healthy postmenopausal women: a randomized placebo-controlled study. Am J Obstet Gynecol 2003;189:1221–7
   PubMed Web of Science ®Google Scholar
• Meade TW. Hormone replacement therapy and haemostatic function. Thromb Haemost 1997;78:765–9
   PubMed Web of Science ®Google Scholar
• Oger E, Alhenc-Gelas M, Lacut K, et al. Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women. Arterioscler Thromb Vasc Biol 2003;23:1671–6
   PubMed Web of Science ®Google Scholar
• Crook D, Cust MP, Gangar KF, et al. Comparison of transdermal and oral estrogenprogestin replacement therapy: effects on serum lipids and lipoproteins. Am J Obstet Gynecol 1992;166:950–5
   PubMed Web of Science ®Google Scholar
• Hemelaar M, van der Mooren MJ, Mijatovic V, et al. Oral, more than transdermal, estrogen therapy improves lipids and lipoprotein(a) in postmenopausal women: a randomized, placebo-controlled study. Menopause 2003;10:550–8
   PubMed Web of Science ®Google Scholar
• Godsland IF. Effects of postmenopausal hormone rplacement therapy on lipid, lipoprotein, and apolipoprotein(a) concentrations: analysis of studies published from 1974–2000. Fertil Steril 2001;75:898–915
   PubMed Web of Science ®Google Scholar
• Walsh BW, Li H, Sacks FM. Effects of postmenopausal hormone replacement with oral and transdermal estrogen on high density lipoprotein metabolism. J Lipid Res 1994;35:2083–93
   PubMed Web of Science ®Google Scholar
• de Lignieres B, Basdevant A, Thomas G, et al. Biological effects of estradiol-17β in postmenopausal women: oral versus percutaneous administration. J Clin Endocrinol Metab 1986;62:536–41
   PubMed Web of Science ®Google Scholar
• Shulman LP. Effects of progestins in different hormone replacement therapy formulations on estrogen-induced lipid changes in postmenopausal women. Am J Cardiol 2002;89(Suppl):47E–55E
   PubMedGoogle Scholar
• Szekacs B, Vajo Z, Acs N, et al. Hormone replacement therapy reduces mean 24-hour blood pressure and its variability in postmenopausal women with treated hypertension. Menopause 2000;7:31–5
   PubMed Web of Science ®Google Scholar
• Modena MG, Molinari R, Muia N, et al. Double-blind randomized placebo-controlled study of transdermal estrogen replacement therapy on hypertensive postmenopausal women. Am J Hypertens 1999;12:1000–8
   PubMed Web of Science ®Google Scholar
• Spencer CP, Godsland IF, Cooper AJ, et al. Effects of oral and transdermal 17β-estradiol with cyclical oral norethindrone acetate on insulin sensitivity, secretion, and elimination in postmenopausal women. Metabolism 2000;49:742–7
   PubMed Web of Science ®Google Scholar
• Siseles NO, Benencia H, Mesch V, et al. Once and twice a week transdermal estradiol delivery systems: clinical efficacy and plasma estrogen levels. Climacteric 1998;1:196–201
   PubMedGoogle Scholar
• Nugent AG, Leung KC, Sullivan D, et al. Modulation by progestogens of the effects of oestrogen on hepatic endocrine function in postmenopausal women. Clin Endocrinol 2003;59:690–8
   PubMed Web of Science ®Google Scholar
• Geola FL, Frumar AM, Tataryn IV, et al. Biological effects of various doses of conjugated equine estrogens in postmenopausal women. J Clin Endocrinol Metab 1980;51:620–5
   PubMed Web of Science ®Google Scholar
• Rocha Fidalgo dos Reis CM, de Melo NR, Souza Meirelles E, et al. Body composition, visceral fat distribution and fat oxidation in postmenopausal women using oral or transdermal oestrogen. Maturitas 2003;46:59–68
   PubMed Web of Science ®Google Scholar
• Heald A, Selby PL, White A, et al. Progestins abrogate estrogen-induced changes in the insulin-like growth factor axis. Am J Obstet Gynecol 2000;183:593–600
   PubMed Web of Science ®Google Scholar
• Cano A, Castelo-Branco C, Tarin JJ. Effect of menopause and different combined estradiolprogestin 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;71:261–7
   PubMed Web of Science ®Google Scholar
• O’Sullivan AJ, Freund J, Ho KKY. Route of estrogen replacement confers divergent effects on energy metabolism and body composition in postmenopausal women. J Clin Invest 1998;102:1035–40
   PubMed Web of Science ®Google Scholar
• Blümel JE, Castelo-Branco C, Leal T, et al. Effects of transdermal estrogens on endothelial function in postmenopausal women with coronary disease. Climacteric 2003;6:38–44
   PubMed Web of Science ®Google Scholar
• Cicinelli E, Ignarro LJ, Lograno M, et al. Acute effects of transdermal estradiol administration on plasma levels of nitric oxide in postmenopausal women. Fertil Steril 1997;67:63–6
   PubMed Web of Science ®Google Scholar
• Cicinelli E, Ignarro LJ, Schönauer LM, et al. Effects of short-term transdermal estradiol administration on plasma levels of nitric oxide in postmenopausal women. Fertil Steril 1998;69:58–61
   PubMed Web of Science ®Google Scholar
• Cicinelli E, Ignarro LJ, Matteo MG, et al. Effects of estrogen replacement therapy on plasma levels of nitric oxide in postmenopausal women. Am J Obstet Gynecol 1999;180:334–9
   PubMed Web of Science ®Google Scholar
• Mikkola T, Viinikka L, Ylikorkala O. Administration of transdermal estrogen without progestin increases the capacity of plasma and serum to stimulate prostacyclin production in human vascular endothelial cells. Fertil Steril 2000;73:72–4
   PubMed Web of Science ®Google Scholar
• Wilcox JG, Hatch IE, Gentzschein E, et al. Endothelin levels decrease after oral and nonoral estrogen in postmenopausal women with increased cardiovascular risk factors. Fertil Steril 1997;67:273–7
   PubMed Web of Science ®Google Scholar
• Wakatsuki A, Okatani Y, Ikenoue N, et al. Different effects of oral conjugated equine estrogen and transdermal estrogen replacement therapy on size and oxidative susceptibility of low-density lipoprotein particles in post-menopausal women. Circulation 2002;106:1771–6
   PubMed Web of Science ®Google Scholar
• Zanger D, Yang BK, Ardans J, et al. 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;36:1797–802
   PubMed Web of Science ®Google Scholar
• Wakatsuki A, Ikenoue N, Shinohara K, et al. Different effects of oral and transdermal estrogen replacement therapy on matrix metalloproteinase and their inhibitor in post-menopausal women. Arterioscl Thromb Vasc Biol 2003;23:1948–9
   PubMed Web of Science ®Google Scholar
• Vongpatanasin W, Tuncel M, Wang Z, et al. Differential effects of oral versus transdermal estrogen replacement therapy on C-reactive protein in postmenopausal women. J Am Coll Cardiol 2003;41:1358–63
   PubMed Web of Science ®Google Scholar
• Post MS, van der Mooren MJ, Stehouwer CDA, et al. Effects of transdermal and oral oestrogen replacement therapy on C-reactive protein levels in postmenopausal women: a randomised, placebo-controlled trial. Thromb Haemost 2002;88:605–10
   PubMed Web of Science ®Google Scholar
• Zegura B, Keber I, Sebestjen M, et al. Double blind, randomized study of estradiol replacement therapy on markers of inflammation, coagulation and fibrinolysis. Atherosclerosis 2003;168:123–9
   PubMed Web of Science ®Google Scholar
• Strandberg TE, Ylikorkala O, Tikkanen MJ. Differing effects of oral and transdermal hormone replacement therapy on cardiovascular risk factors in healthy postmenopausal women. Am J Cardiol 2003;92:212–14
   PubMed Web of Science ®Google Scholar
• Decensi A, Omodei U, Robertson C, et al. Effect of transdermal estradiol and oral conjugated estrogen on C-reactive protein in retinoid-placebo trial in healthy women. Circulation 2002;106:1224–8
   PubMed Web of Science ®Google Scholar
• Yilmazer M, Fenkci V, Fenkci S, et al. Hormone replacement therapy, C-reactive protein, and fibrinogen in healthy postmenopausal women. Maturitas 2003;46:245–53
   PubMed Web of Science ®Google Scholar
• Lacut K, Oger E, Le Gal G, et al. Differential effects of oral and transdermal postmenopausal estrogen replacement therapies on C-reactive protein. Thromb Haemost 2003;90:124–31
   PubMed Web of Science ®Google Scholar
• 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 culture. Menopause 2002;9:273–81
   PubMed Web of Science ®Google Scholar
• Koh KK, Cardillo C, Bui MN, et al. Vascular effects of estrogen and cholesterol-lowering therapies in hypercholesterolemic post-menopausal women. Circulation 1999;99:354–60
   PubMed Web of Science ®Google Scholar
• Wattanakumtornkul S, Pinto AB, Williams DB. Intranasal hormone replacement therapy. Menopause 2003;10:88–98
   PubMed Web of Science ®Google Scholar
• Sakane T, Akisuki M, Yamashita S, et al. The transport of a drug to the cerebrospinal fluid directly from the nasal cavity: the relation to the lipophilicity of the drug. Chem Pharm Bull 1991;39:2456–8
   PubMed Web of Science ®Google Scholar
• Devissaguet JP, Brion N, L’Hote O, et al. Pulsed estrogen therapy: pharmacokinetics of intranasal 17-beta-estradiol (S21400) in post-menopausal women and comparison with oral and transdermal formulations. Eur J Drug Metab Pharmacokin 1999;24:265–71
   PubMed Web of Science ®Google Scholar
• Studd J, Pomel B, Marton I, et al. Efficacy and acceptability of intranasal 17β-oestradiol for menopausal symptoms: randomised dose-response study. Lancet 1999;353:1574–8
   PubMed Web of Science ®Google Scholar
• Lopes P, Rozenberg S, de Graaf J, et al. Aerodiol versus the transdermal route: perspectives for patient preference. Maturitas 2001;38(Suppl 1):S31–9
   PubMedGoogle Scholar
• Panay N, Toth K, Pelissier C, et al. Dose-ranging studies of a novel intranasal estrogen replacement therapy. Maturitas 2001;38(Suppl 1):S15–22
   PubMedGoogle Scholar
• Delmas PD, Marianowski L, de Castro Perez A, et al. Prevention of postmenopausal bone loss by pulsed estrogen therapy: comparison with transdermal route. Maturitas 2004;48:85–96
   PubMed Web of Science ®Google Scholar
• Mattsson LA. Safety and tolerability of pulsed estrogen therapy: key factors for an improved compliance. Climacteric 2002;5(Suppl 2):40–5
   PubMedGoogle Scholar
• Lopes P, Merkus H, Nauman J, et al. Randomized comparison of intranasal and transdermal estradiol. Obstet Gynecol 2000;96:906–12
   PubMed Web of Science ®Google Scholar
• Price TM, Blauer KL, Hansen M, et al. Single-dose pharmacokinetics of sublingual versus oral administration of micronized 17β-estradiol. Obstet Gynecol 1997;89:340–5
   PubMed Web of Science ®Google Scholar
• Zhang H, Zhang J, Streisand JB. Oral mucosal drug delivery. Clinical pharmacokinetics and therapeutic applications. Clin Pharmacokinet 2002;41:661–80
   PubMed Web of Science ®Google Scholar
• Wren BG, Day RO, McLachlan AJ, et al. Pharmacokinetics of estradiol, progesterone, testosterone and dehydroepiandrosterone after transbuccal administration to postmenopausal women. Climacteric 2003;6:104–11
   PubMed Web of Science ®Google Scholar
• Pines A, Averbuch M, Fisman EZ, et al. The acute effects of sublingual 17β-estradiol on the cardiovascular system. Maturitas 1999;33:81–5
   PubMed Web of Science ®Google Scholar
• Ahokas A, Kaukoranta J, Wahlbeck K, et al. Estrogen deficiency in severe postpartum depression: successful treatment with sublingual physiologic 17β-estradiol: a preliminary study. J Clin Psychiatry 2001;62:332–6
   PubMed Web of Science ®Google Scholar
• Gass MS, Rebar RW, Cuffie-Jackson, et al. A short study in the treatment of hot flashes with buccal administration of 17β -estradiol. Maturitas 2004;49:140–7
   PubMed Web of Science ®Google Scholar
• Rigg LA, Hermann H, Yen SSC. Absorption of estrogens from vaginal creams. N Engl J Med 1978;298:195–7
   PubMed Web of Science ®Google Scholar
• Nash HA, Alvarez-Sanchez F, Mishell DR, et al. Estradiol-delivering vaginal rings for hormone replacement therapy. Am J Obstet Gynecol 1999;181:1400–6
   PubMed Web of Science ®Google Scholar
• Nash HA, Brache V, Alvarez-Sanchez F, et al. Estradiol delivery by vaginal rings: potential for hormone replacement therapy. Maturitas 1997;26:27–33
   PubMed Web of Science ®Google Scholar
• Farish E, Barnes JF, Rankin M, et al. Effects on climacteric symptoms, bone and lipoprotein metabolism of hormone replacement therapy delivered by estradiol-releasing intravaginal rings: a pilot study. Climacteric 2003;6:211–20
   PubMed Web of Science ®Google Scholar
• Nilsson K, Heimer G. Low-dose oestradiol in the treatment of urogenital oestrogen deficiency – a pharmacokinetic and pharmacodynamic study. Maturitas 1992;15:121–7
   PubMed Web of Science ®Google Scholar
• Johnston A. Estrogens – pharmacokinetics and pharmacodynamics with special reference to vaginal administration and the new estradiol formulation – Estring. Acta Obstet Gynecol Scand 1996;75(Suppl 163):16–25
   Google Scholar
• Gabrielsson J, Wallenbeck I, Larsson G, et al. New kinetic data on estradiol in light of the estring concept. Maturitas 1995:22(Suppl): S35–9
   PubMedGoogle Scholar
• Hall G, Blombäck M, Landgren BM, et al. Effects of vaginally administered high estradiol doses on hormonal pharmacokinetics and hemostasis in postmenopausal women. Fertil Steril 2002;78:1172–7
   PubMed Web of Science ®Google Scholar
• Simunic V, Banovic I, Ciglar S, et al. Local estrogen treatment in patients with urogenital symptoms. Int J Gynecol Obstet 2003;82:187–97
   PubMed Web of Science ®Google Scholar
• Dugal R, Hesla K, Sordal T, et al. Comparison of usefulness of estradiol vaginal tablets and estriol vagitories for treatment of vaginal atrophy. Acta Obstet Gynecol Scand 2000;79:293–7
   PubMed Web of Science ®Google Scholar
• Mattson LA, Cullberg G, Eriksson O, et al. Vaginal administration of low-dose oestradiol – effects on the endometrium and vaginal cytology. Maturitas 1989;11:217–22
   PubMed Web of Science ®Google Scholar
• Lose G, Englev E. Oestradiol-releasing vaginal ring versus oestriol vaginal pessaries in the treatment of bothersome lower urinary tract symptoms. Br J Obstet Gynaecol 2000;107:1029–34
   Google Scholar
• Ayton RA, Darling GM, Murkies AL, et al. A comparative study of safety and efficacy of continuous low dose oestradiol released from a vaginal ring compared with conjugated equine oestrogen vaginal cream in the treatment of postmenopausal urogenital atrophy. Br J Obstet Gynaecol 1996;103:351–8
   PubMedGoogle Scholar
• Stanczyk FZ, Shoupe D, Nunez V, et al. A randomized comparison of nonoral estradiol delivery in postmenopausal women. Am J Obstet Gynecol 1988;159:1540–6
   PubMed Web of Science ®Google Scholar
• Owen EJ, Siddle NC, McGarrigle HT, et al. 25 mg oestradiol implants – the dosage of first choice for subcutaneous oestrogen replacement therapy? Br J Obstet Gynaecol 1992;99:671–5
   Google Scholar
• Studd JWW, Holland EF, Leather AT, et al. The dose-response of percutaneous oestradiol implants on the skeletons of postmenopausal women. Br J Obstet Gynaecol 1994;101:787–91
   PubMedGoogle Scholar
• Barlow DH, Abdalla HI, Roberts ADG, et al. Long-term hormone implant therapy – hormonal and clinical effects. Obstet Gynecol 1986;67:321–5
   PubMed Web of Science ®Google Scholar
• Notelovitz M, Johnston M, Smith S, et al. Metabolic and hormonal effects of 25 mg and 50 mg 17b-estradiol implants in surgically menopausal women. Obstet Gynecol 1987;70:749–54
   PubMed Web of Science ®Google Scholar
• Pereda CA, Hannon RA, Naylor KE, et al. The impact of subcutaneous oestradiol implants on biochemical markers of bone turnover and bone mineral density in postmenopausal women. Br J Obstet Gynaecol 2002;109:812–20
   Google Scholar
• Farish E, Fletcher CD, Hart DM, et al. The effects of hormone implants on serum lipoproteins and steroid hormones in bilaterally oophorectomised women. Acta Endocrinol 1984;106:116–20
   PubMedGoogle Scholar
• Gangar K, Cust M, Whitehead MI. Symptoms of oestrogen deficiency associated with supra-physiological plasma oestradiol concentrations in women with oestradiol implants. BMJ 1989;299:601–2
   PubMed Web of Science ®Google Scholar
• Pirwany IR, Sattar N, Greer IA, et al. Supraphysiological concentrations of estradiol in menopausal women given repeated implant therapy do not adversely affect lipid profiles. Hum Reprod 2002;17:825–9
   PubMed Web of Science ®Google Scholar
• Düsterberg B, Nishino Y. Pharmacokinetics and pharmacological features of oestradiol valerate. Maturitas 1982;4:315–24
   PubMed Web of Science ®Google Scholar
• Oriowo MA, Landgren BM, Stensröm B, et al. A comparison of the pharmacokinetic properties of three estradiol esters. Contraception 1980;21:415–24
   PubMed Web of Science ®Google Scholar
• Washburn SA, Honore EK, Cline JM, et al. Effects of 17α-dihydroequilenin sulfate on atherosclerotic male and female rhesus monkeys. Am J Obstet Gynecol 1996;175:341–51
   PubMed Web of Science ®Google Scholar
• Stern MD. Pharmacology of conjugated estrogens. Maturitas 1982;4:333–9
   PubMed Web of Science ®Google Scholar
• Bhavnani BR, Woolever CA. Interaction of ring B unsaturated estrogens with estrogen receptors of human endometrium and rat uterus. Steroids 1991;56:201–9
   PubMed Web of Science ®Google Scholar
• The Writing Group for the PEPI Trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. JAMA 1996;275:370–5
   PubMed Web of Science ®Google Scholar
• Troy SM, Hicks DR, Parker VD, et al. Differences in pharmacokinetics and comparative bioavailability between Premarin® and Estratab® in healthy postmenopausal women. Curr Ther Res 1994;55:359–72
   Web of Science ®Google Scholar
• Mandel FP, Geola FL, Meldrum DR, et al. Biological effects of various doses of vaginally administered conjugated equine estrogens in postmenopausal women. J Clin Endocrinol Metab 1983;57:133–9
   PubMed Web of Science ®Google Scholar
• Lacelin GCL, McGarrigle HHG. A comparison of saliva, plasma unconjugated and plasma total oestriol levels throughout normal pregnancy. Br J Obstet Gynaecol 1984;91:1203–9
   PubMedGoogle Scholar
• Melamed M, Castano E, Notides AC, et al. Molecular and kinetic basis for the mixed agonist/antagonist activity of estriol. Mol Endocrinol 1997;11:1868–78
   PubMed Web of Science ®Google Scholar
• Weichman BM, Notides AC. Estrogen receptor activation and the dissociation kinetics of estradiol, estriol and estrone. Endocrinology 1980;106:434–9
   PubMed Web of Science ®Google Scholar
• Anderson JN, Peck EJ, Clark JH. Estrogen-induced uterine responses and growth: relationship to receptor estrogen binding by uterine nuclei. Endocrinology 1975;96:160–7
   PubMed Web of Science ®Google Scholar
• Englund DE, Heimer G, Johansson EDB. Influence of food on oestriol blood levels. Maturitas 1984;6:71–5
   PubMed Web of Science ®Google Scholar
• Heimer GM. Estriol in the postmenopause. Acta Obstet Gynecol Scand 1987;Suppl 139:1–23
   Google Scholar
• Weiderpass E, Baron JA, Adami HO, et al. Low-potency oestrogen and risk of endometrial cancer: a case-control study. Lancet 1999;353:1824–8
   PubMed Web of Science ®Google Scholar
• Schiff I, Wentworth B, Koos B, et al. Effect of estriol administration on the hypogonadal woman. Fertil Steril 1978;30:278–82
   PubMed Web of Science ®Google Scholar
• Heimer GM, Englund DE. Enterohepatic recirculation of estriol: inhibition by activated charcoal. Acta Endocrinol 1986;113:93–5
   PubMedGoogle Scholar
• Rauramo L, Punnonen R, Kaihola HL, et al. Serum oestriol, oestrone and oestradiol concentrations during oral oestriol succinate treatment in ovarectomized women. Maturitas 1978;1:71–8
   PubMedGoogle Scholar
• Volpe A, Facchinetti F, Grasso A, et al. Benefits and risks of different hormonal replacement therapies in post-menopausal women. Maturitas 1986;8:327–34
   PubMed Web of Science ®Google Scholar
• Takahashi K, Manabe A, Okada M, et al. Efficacy and safety of oral estriol for managing postmenopausal symptoms. Maturitas 2000;34:169–77
   PubMed Web of Science ®Google Scholar
• Molander U, Milson I, Ekelund P, et al. Effect of oral oestriol on vaginal flora and cytology and urogenital symptoms in the post-meno-pause. Maturitas 1990;12:113–20
   PubMed Web of Science ®Google Scholar
• Cardozo L, Rekers H, Tapp A, et al. Oestriol in the treatment of postmenopausal urgency: a multicentre study. Maturitas 1993;18:47–53
   PubMed Web of Science ®Google Scholar
• Punnonen R. Effect of castration and peroral estrogen therapy on the skin. Acta Obstet Gynecol Scand 1972;Suppl 21:7–44
   Google Scholar
• Lindsay R, Hart DM, Maclean A, et al. Bone loss during oestriol therapy in postmenopausal women. Maturitas 1979;1:279–85
   PubMed Web of Science ®Google Scholar
• Michaelsson K, Baron JA, Farahmand BY, et al. Use of low potency estrogens does not reduce the risk of hip fracture. Bone 2002;30:613–18
   PubMed Web of Science ®Google Scholar
• Schiff I, Tulchinsky D, Ryan KJ, et al. Plasma estriol and its conjugates following oral and vaginal administration of estriol to postmenopausal women: correlations with gonadotropin levels. Am J Obstet Gynecol 1980;138:1137–41
   PubMed Web of Science ®Google Scholar
• Bottiglione F, Volpe A, Esposito G, et al. Transvaginal estriol administration in postmenopausal women: a double blind comparative study of two different doses. Maturitas 1995;22:227–32
   PubMed Web of Science ®Google Scholar
• Vooijs GP, Geurts TB. Review of the endome-trial safety during intravaginal treatment with estriol. Eur J Obstet Gynecol Reprod Biol 1995;62:101–6
   PubMed Web of Science ®Google Scholar
• Mattson LA, Cullberg G. A clinical evaluation of treatment with estriol vaginal cream versus suppository in postmenopausal women. Acta Obstet Gynecol Scand 1983;62:397–401
   PubMed Web of Science ®Google Scholar
• Guengerich FP. Inhibition of oral contraceptive steroid-metabolizinmg enzymes by steroids and drugs. Am J Obstet Gynecol 1990;163:2159–63
   PubMed Web of Science ®Google Scholar
• Ortiz de Montellano PR, Kunze KL. Self-catalyzed inactivation of hepatic cytochrome P-450 by ethynyl substrates. J Biol Chem 1980;255:5578–85
   PubMed Web of Science ®Google Scholar
• Metzler M. Metabolism of stilbene estrogens and steroidal estrogens in relation to carcinogenicity. Arch Toxicol 1984;55:104–9
   PubMed Web of Science ®Google Scholar
• Aten RF, Eisenfeld AJ. Estradiol is less potent than ethinyl estradiol for in vivo translocation of the mammalian liver estrogen receptor to the nucleus. Endocrinology 1982;111:1292–8
   PubMed Web of Science ®Google Scholar
• Mandel FP, Geola FL, Lu JKH, et al. Biologic effects of various doses of ethinyl estradiol in postmenopausal women. Obstet Gynecol 1982;59:673–9
   PubMed Web of Science ®Google Scholar
• Lindberg UB, Crona N, Stigendal L, et al. A comparison between effects of estradiol vale-rate and low dose ethinyl estradiol on haemostasis parameters. Thromb Haemost 1989;61:65–9
   PubMed Web of Science ®Google Scholar
• Lindberg UB, Enk L, Crona N, et al. A comparison of the effects of ethinyl estradiol and estradiol valerate on serum and lipoprotein lipids. Maturitas 1988;10:343–52
   PubMed Web of Science ®Google Scholar
• Gurpide E, Marks C. Influence of endometrial 17β-hydroxysteroid dehydrogenase activity on the binding of estradiol to receptors. J Clin Endocrinol Metab 1981;52:252–5
   PubMed Web of Science ®Google Scholar
• Brosens IA, Pijnenborg R. Comparative study of the estrogenic effect of ethinylestradiol and mestranol on the endometrium. Contraception 1976;14:679–85
   PubMed Web of Science ®Google Scholar
• Suparto IH, Williams K, Cline M, et al. Contrasting effects of two hormone replacement therapies on the cardiovascular and mammary gland outcomes in surgically post-menopausal monkeys. Am J Obstet Gynecol 2003;188:1132–40
   PubMed Web of Science ®Google Scholar
• Boyd RA, Zegarac EA, Eldon MA. The effect of food on the bioavailability of norethindrone and ethinyl estradiol from norethindrone acetate/ethinyl estradiol tablets intended for continuous hormone replacement therapy. J Clin Pharmacol 2003;43:52–8
   PubMed Web of Science ®Google Scholar
• Jung-Hoffmann C, Fitzner M, Kuhl H. Oral contraceptives containing 20 or 30 mg ethinylestradiol and 150 mg desogestrel: pharmacokinetics and pharmacodynamic parameters. Horm Res 1991;36:238–46
   PubMed Web of Science ®Google Scholar
• Jones MM, Pearlman B, Marshall DH, et al. Dose-dependent response of FSH, flushes and urinary calcium to oestrogen. Maturitas 1982;4:285–90
   PubMed Web of Science ®Google Scholar
• Speroff L, Symons J, Kempfert N, et al. The effect of varying low-dose combinations of norethindrone acetate and ethinyl estradiol (femhrt) on the frequency and intensity of vasomotor symptoms. Menopause 2000;6:383–90
   Google Scholar
• Williams SR, Frenchek B, Speroff T, et al. A study of combined continuous ethinyl estradiol and norethindrone acetate for postmenopausal hormone replacement. Am J Obstet Gynecol 1990;162:438–46
   PubMed Web of Science ®Google Scholar
• Simon JA, Liu JH, Speroff L, et al. Reduced vaginal bleeding in postmenopausal women who receive combined norethindrone acetate and low-dose ethinyl estradiol therapy versus combined conjugated equine estrogens and medroxyprogesterone acetate therapy. Am J Obstet Gynecol 2003;188:92–9
   PubMed Web of Science ®Google Scholar
• Horsman A, Jones M, Francis R, et al. The effect of estrogen dose on postmeno-pausal bone loss. N Engl J Med 1983;309:1405–7
   PubMed Web of Science ®Google Scholar
• Harvey PJ, Wing LM, Savage J, et al. The effects of different types and doses of oestrogen replacement therapy on clinic and ambulatory blood pressure and the renin-angiotensin system in normotensive postmenopausal women. J Hypertens 1999;17:405–11
   PubMed Web of Science ®Google Scholar
• Back DJ, Grimmer SFM, Rogers S, et al. Comparative pharmacokinetics of levonorgestrel and ethinyloestradiol following intravenous, oral and vaginal administration. Contraception 1987;36:471–9
   PubMed Web of Science ®Google Scholar
• Timmer CJ, Mulders TMT. Pharmacokinetics of etonogestrel and ethinylestradiol released from a combined contraceptive vaginal ring. Clin Pharmacokinet 2000;39:233–42
   PubMed Web of Science ®Google Scholar
• Goebelsmann U, Mahchak CA, Mishell DR. Comparison of hepatic impact of oral and vaginal administration of ethinyl estradiol. Am J Obstet Gynecol 1985;151:868–77
   PubMed Web of Science ®Google Scholar
• Giangrande PH, McDonnell DP. The A and B isoforms of the human progesterone receptor: two functionally different transcription factors encoded by a single gene. Recent Progr Horm Res 1999;54:291–313
   PubMedGoogle Scholar
• Kuhl H. Pharmacology of progestogens. Basic aspects – progesterone derivatives. Menopause Rev 2001;6:9–16
   Google Scholar
• Cline JM, Soderqvist G, von Schoultz E, et al. Effects of hormone replacement therapy on the mammary gland of surgically postmenopausal cynomolgus macaques. Am J Obstet Gynecol 1996;174:93–100
   PubMed Web of Science ®Google Scholar
• Beier S, Düsterberg B, El Etreby MF, et al. Toxicology of hormonal fertility-regulating agents. In Benagiano G, Diczfalusy E, eds. Endocrine Mechanisms in Fertility Regulation. New York: Raven Press, 1983;261–346
   Google Scholar
• Kuhnz W, Heuner A, Hümpel M, et al. In vivo conversion of norethisterone and norethisterone acetate to ethinyl estradiol in postmenopausal women. Contraception 1997;56:379–85
   PubMed Web of Science ®Google Scholar
• Kuhl H. Comparative pharmacology of newer progestogens. Drugs 1996;51:188–215
   PubMed Web of Science ®Google Scholar
• Ortiz de Montellano PR. Suicide substrates for drug metabolising enzymes: mechanisms and biological consequences. Progr Drug Metab 1988;11:99–148
   Google Scholar
• Guengerich FP. Mechanism-based inactivation of human liver microsomal cytochrome P-450 IIIA4 by gestodene. Chem Res Toxicol 1990;3:363–71
   PubMed Web of Science ®Google Scholar
• Kuhl H, Jung-Hoffmann C, Storch A, Fitzner M, Rühl E. New aspects on the mechanism of action of contraceptive steroids – recent pharmacokinetic studies of low dose formulations. Adv Contracept 1991;7(Suppl 3):149–63
   Google Scholar
• Kim-Björklund T, Landgren BM, Hamberger L. Is the contraceptive effect of 300 μg norethisterone mainly peripheral or central? Contraception 1992;45:57–66
   Google Scholar
• Neumann F. The physiological action of progesterone and the pharmacological effects of progestogens – a short review. Postgrad Med J 1978;54(Suppl):11–24
   PubMedGoogle Scholar
• Neumann F, Elger W, Nishino Y, Steinbeck H. Probleme der Dosisfindung: Sexualhormone. Drug Res 1977;27:296–318
   Google Scholar
• Levine H, Watson N. Comparison of the pharmacokinetics of Crinone 8% administered vaginally versus Prometrium administered orally in postmenopausal women. Fertil Steril 2000;73:516–21
   PubMed Web of Science ®Google Scholar
• Arafat ES, Hargrove JT, Maxson WS, et al. Sedative and hypnotic effects of oral administration of micronized progesterone may be mediated through its metabolites. Am J Obstet Gynecol 1988;159:1203–9
   PubMed Web of Science ®Google Scholar
• Nahoul K, Dehennin L, Jondet M, et al. Profiles of plasma estrogens, progesterone and their metabolites after oral or vaginal administration of estradiol or progesterone. Maturitas 1993;16:185–202
   PubMed Web of Science ®Google Scholar
• Lane G, Siddle NC, Ryder TA, et al. Dose dependent effects of oral progesterone on the oestrogenised postmenopausal endometrium. BMJ 1983;287:1241–5
   PubMed Web of Science ®Google Scholar
• Pelissier C, Maroni M, Yaneva H, et al. Chlormadinone acetate versus micronized progesterone in the sequential combined hormone replacement therapy of the menopause. Maturitas 2001;40:85–94
   PubMed Web of Science ®Google Scholar
• Moyer D, de Lignieres B, Driguez P, et al. Prevention of endometrial hyperplasia by progesterone during long-term estradiol replacement: influence of bleeding pattern and secretory changes. Fertil Steril 1993;59:992–7
   PubMed Web of Science ®Google Scholar
• Gillet JY, Andre B, Faguer B, et al. Induction of amenorrhea during hormone replacement therapy: optimal micronized progesterone dose. A multicenter study. Maturitas 1994;19:103–15
   PubMed Web of Science ®Google Scholar
• The Wrting Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAMA 1995;273:199–208
   PubMed Web of Science ®Google Scholar
• Rylance PB, Brincat M, Lafferty K, et al. Natural progesterone and antihypertensive action. BMJ 1985;290:13–14
   PubMed Web of Science ®Google Scholar
• Freeman EW, Weinstock L, Rickels K, et al. A placebo-controlled study of effects of oral progesterone on performance and mood. Br J Clin Pharmacol 1992;33:293–8
   PubMed Web of Science ®Google Scholar
• Miles RA, Paulson RJ, Lobo RA, et al. Pharmacokinetics and endometrial tissue levels of progesterone after administration by intramuscular and vaginal routes: a comparative study. Fertil Steril 1994;62:485–90
   PubMed Web of Science ®Google Scholar
• Bulletti C, de Ziegler D, Flamigni C, et al. Targeted drug delivery in gynaecology: the first uterine pass effect. Hum Reprod 1997;12:1073–9
   PubMed Web of Science ®Google Scholar
• Kleinstein J, Schlegelmilch R, Mazur D, et al. Pharmacokinetic comparison of progesterone capsules with a progesterone gel after vaginal administration. Drug Res 2002;52:615–21
   PubMed Web of Science ®Google Scholar
• de Lignieres B, Dennerstein L, Backstrom T. Influence of route of administration on progesterone metabolism. Maturitas 1995;21:251–7
   PubMed Web of Science ®Google Scholar
• Fanchin R, de Ziegler D, Bergeron C, et al. Transvaginal administration of progesterone. Obstet Gynecol 1997;90:396–401
   PubMed Web of Science ®Google Scholar
• Ross D, Cooper AJ, Pryse-Davies J, et al. Randomized, double-blind, dose-ranging study of the endometrial effects of a vaginal progesterone gel in estrogen-treated postmenopausal women. Am J Obstet Gynecol 1997;177:937–41
   PubMed Web of Science ®Google Scholar
• Cicinelli E, Ragno G, Cagnazzo I, et al. Nasally-administered progesterone: comparison of ointment and spray formulation. Maturitas 1991;13:313–17
   PubMed Web of Science ®Google Scholar
• Ottoson UB, Carlström K, Damber JE, et al. Serum levels of progesterone and some of its metabolites including deoxycorticosterone after oral and parenteral administration. Br J Obstet Gynaecol 1984;91:1111–19
   PubMedGoogle Scholar
• Wren BG. Progesterone creams: do they work? Climacteric 2003;6:184–7
   PubMed Web of Science ®Google Scholar
• Carey BJ, Carey AH, Sanjaykumar P, et al. A study to evaluate serum and urinary hormone levels following short and long term administration of two regimens of progesterone cream in postmenopausal women. Br J Obstet Gynaecol 2000;107:722–6
   Google Scholar
• Wren BG, Champion SM, Zoa Manga R, et al. Transdermal progesterone and its effect on vasomotor symptoms, blood lipid levels, bone metabolic markers, moods, and quality of life for postmenopausal women. Menopause 2003;10:13–18
   PubMed Web of Science ®Google Scholar
• Leonetti HB, Longo S, Anasti JN. Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss. Obstet Gynecol 1999;94:225–8
   PubMed Web of Science ®Google Scholar
• Leonnetti HB, Wilson KJ, Anasti JN. Topical progesterone cream has an antiproliferative effect on estrogen stimulated endometriums. Fertil Steril 2003;79:221–2
   PubMed Web of Science ®Google Scholar
• Herkert O, Kuhl H, Sandow J, Busse R, SchiniKerth VB. Sex steroids used in hormonal treatment increase vascular procoagulant activity by inducing thrombin receptor (PAR-1) expression. Role of glucocorticoid receptor. Circulation 2001;104:2826–31
   PubMed Web of Science ®Google Scholar
• Rozenbaum H. Pharmacology of progesterone and related compounds: dydrogesterone and norpregnane derivatives. Menopause Rev 2001;6:17–28
   Google Scholar
• Golbs S, Nicolov R, Zimmermann T. Pharmacology of nortestosterone derivatives. Menopause Rev 2001;6:29–44
   Google Scholar
• Fotherby K, Caldwell ADS. New progestogens in oral contraception. Contraception 1994;49:1–32
   PubMed Web of Science ®Google Scholar
• Losert W, Casals-Stenzel J, Buse M, et al. Progestogens with antimineralocorticoid activity. Drug Res 1985;35:459–71
   PubMed Web of Science ®Google Scholar
• Schoonen WGEJ, Deckers GH, de Gooijer ME, et al. Hormonal properties of norethisterone, 7alpha-methyl-norethisterone and their derivatives. J Steroid Biochem Mol Biol 2000;74:213–22
   PubMed Web of Science ®Google Scholar
• Wahab M, Al-Azzawi F. Trimegestone: expanding therapeutic choices for the treatment of the menopause. Expert Opin Invest Drugs 2001;10:1737–44
   PubMed Web of Science ®Google Scholar
• Kumar N, Koide SS, Tsong YY, et al. Nestor-one: a progestin with a unique pharmacological profile. Steroids 2000;65 :629–36
   PubMed Web of Science ®Google Scholar
• Philibert D, Bouchoux F, Degryse M, et al. The pharmacological profile of a novel norpregnane progestin (trimegestone). Gynecol Endocrinol 1999;13:316–26
   PubMed Web of Science ®Google Scholar
• Tikkanen MJ, Kuusi T, Nikkilä EA, et al. Postmenopausal hormone replacement therapy: effects of progestogens on serum lipids and lipoproteins. A review. Maturitas 1986;8:7–17
   PubMed Web of Science ®Google Scholar
• Erlik Y, Meldrum DR, Lagasse LD, et al. Effect of megestrol acetate on flushing and bone metabolism in postmenopausal women. Maturitas 1981;3:167–72
   PubMed Web of Science ®Google Scholar
• Sporrong T, Hellgren M, Samsioe G, et al. Metabolic effects of continuous estradiol-progestin therapy in postmenopausal women. Obstet Gynecol 1989;73:754–8
   PubMed Web of Science ®Google Scholar
• Gallegos AJ, Gonzalez-Diddi M, Merino G, et al. Tissue localization of radioactive chlormadinone acetate and progesterone in the human. Contraception 1970;1:151–61
   Google Scholar
• Curran MP, Wagstaff AJ. Ethinylestradiol/ chlormadinone acetate. Drugs 2004;64:751–60
   PubMed Web of Science ®Google Scholar
• Kuhl H. Chemie und Pharmakologie von Chlormadinonacetat. In Loch EG, Schramm G, eds. Chlormadinonacetat bei Androgenisierungserscheinungen. Stuttgart: Schattauer, 1995:1–24
   Google Scholar
• Alwers R, Urdinola J, Onatra W, et al. Changes in normal lipid profile of menopausal women with combined hormone replacement therapy. Comparative clinical trial of two hormonal combinations. Maturitas 1999;32:41–50
   PubMed Web of Science ®Google Scholar
• Ojasoo T. Multivariate preclinical evaluation of progestins. Menopause 1995;2:97–107
   Web of Science ®Google Scholar
• Pollow K, Juchem M, Elger W, et al. Dihydrospirorenone (ZK30595), a novel synthetic progestagen – characterization of binding to different receptor proteins. Contraception 1992;46:561–74
   PubMed Web of Science ®Google Scholar
• Kontula K, Paavonen T, Luukkainen T, et al. Binding of progestins to the glucocorticoid receptor. Correlation to their glucocorticoid-like effects on in vitro functions of human mononuclear leukocytes. Biochem Pharmacol 1983;32:1511–18
   PubMed Web of Science ®Google Scholar
• Phillips AA. Comparison of the potencies and activities of progestogens used in contraceptives. Contraception 1987;36:181–92
   PubMed Web of Science ®Google Scholar
• Tausk M, de Visser J. Pharmacology of orally active progestational compounds: animal studies. In Tausk M, ed. Pharmacology of the Endocrine System and Related Drugs: Progesterone, Progestational Drugs and Antifertility Agents. Oxford: Pergamon Press, II: 35–216
   Google Scholar
• Ferenczy A, Gelfand MM, van de Weijer PHM, et al. Endometrial safety and bleeding patterns during a 2-year study of 1 or 2 mg 17β-estradiol combined with sequential 5–20 mg dydrogesterone. Climacteric 2002;5:26–35
   PubMed Web of Science ®Google Scholar
• Pornel B, Chevallier O, Netelenbos JC. Oral 17β-estradiol (1 mg) continuously combined with dydrogesterone improves the serum lipid profile of postmenopausal women. Menopause 2002;9:171–8
   PubMed Web of Science ®Google Scholar
• Sitruk-Ware R, Sundaram K. Pharmacology of new progestogens: the 19-norprogesterone derivatives. In Sitruk-Ware R, Mishell DR, eds. Progestins and Antiprogestins in Clinical Practice. New York: Marcel Dekker, 2000;7:153–61
   Google Scholar
• Meuwissen JHJM, Beijers-De Bie L, Vihtamaki T, et al. A 1-year comparison of the efficacy and clinical tolerance in postmenopausal women of two hormone replacement therapies containing estradiol in combination with either norgestrel or trimegestone. Gynecol Endocrinol 2001;15:349–58
   PubMed Web of Science ®Google Scholar
• Al-Azzawi F, Wahab M, Thompson J, et al. Acceptability and patterns of endometrial bleeding in estradiol-based HRT regimens: a comparative study of cyclical sequential combinations of trimegestone or norethisterone acetate. Climacteric 2001;4:343–54
   PubMedGoogle Scholar
• Basdevant A, Pelissier C, Conard J, et al. Effects of nomegestrol acetate (5 mg/d) on hormonal, metabolic and hemostatic parameters in premenopausal women. Contraception 1991;44:599–605
   PubMed Web of Science ®Google Scholar
• Paris J, Thevenot R, Bonnet P, et al. The pharmacological profile of TX066 (17a-acteoxy-6-methyl-19-nor-4,6-pregna-diene-3,20-dione), a new oral progestative. Drug Res 1983;33:710–15
   Web of Science ®Google Scholar
• Noe G, Salvatierra A, Heikinheimo O, et al. Pharmacokinetics and bioavailability of ST1433 administered by different routes. Contraception 1993;48:548–56
   PubMed Web of Science ®Google Scholar
• Haukkamaa M, Laurikka-Routti M, Heikinheimo O. Transdermal absorption of the progestin ST-1435: therapeutic serum steroid concentrations and high excretion of the steroid in saliva. Contraception 1991;44:269–76
   PubMed Web of Science ®Google Scholar
• Saperstein S, Edgren RA, Jung D, et al. Pharmacokinetics of norethindrone: effect of particle size. Contraception 1989;40:731–40
   PubMed Web of Science ®Google Scholar
• Braseltone WE, Lin TJ, Ellegood JO, et al. Accumulation of norethindrone and individual metabolites in human plasma during short- and long-term administration of a contraceptive dosage. Am J Obstet Gynecol 1979;133:154–60
   PubMed Web of Science ®Google Scholar
• Klehr-Bathmann I, Kuhl H. Formation of ethinylestradiol in postmenopausal women during continuous treatment with a combination of estradiol, estriol and norethisterone acetate. Maturitas 1995;21:245–50
   PubMed Web of Science ®Google Scholar
• Wiseman LR, McTavish D. Transdermal estradiol/norethisterone. A review of its pharmacological properties and clinical use in postmenopausal women. Drugs Aging 1994;4:238–56
   PubMed Web of Science ®Google Scholar
• Archer DF, Furst K, Tipping D, et al. A randomised comparison of continuous combined transdermal delivery of estradiol–norethindrone acetate and estradiol alone for menopause. Obstet Gynecol 1999;94:498–503
   PubMed Web of Science ®Google Scholar
• Brynhildsen J, Hammar M. Low dose transdermal estradiol/norethisterone acetate treatment over 2 years does not cause endometrial proliferation in postmenopausal women. Menopause 2002;9:137–44
   PubMed Web of Science ®Google Scholar
• Mattson LA, Bohnet HG, Gredmark T, et al. Continuous, combined hormone replacemen: randomized comparison of transdermal and oral preparations. Obstet Gynecol 1999;94:61–5
   PubMed Web of Science ®Google Scholar
• Rubinacci A, Peruzzi E, Bacchi Modena A, et al. Effect of low-dose transdermal E2/NETA on the reduction of postmenopausal bone loss in women. Menopause 2003;10:241–9
   PubMed Web of Science ®Google Scholar
• Notelovitz M, Cassel D, Hille D, et al. Efficacy of continuous sequential transdermal estradiol and norethindrone acetate in relieving vasomotor symptoms associated with meno-pause. Am J Obstet Gynecol 2000;182:7–12
   PubMed Web of Science ®Google Scholar
• Rozenberg S, Ylikorkala O, Arrenbrecht S. Comparison of continuous and sequential transdermal progestogen with sequential oral progestogen in postmenopausal women using continuous transdermal estrogen: vasomotor symptoms, bleeding patterns, and serum lipids. Int J Fertil 1997;42(Suppl 2):376–871
   Google Scholar
• Lindgren R, Risberg B, Hammar M, et al. Endometrial effects of transdermal estradiol/ norethisterone acetate. Maturitas 1992;15:71–8
   PubMed Web of Science ®Google Scholar
• Kuhnz W, Al-Yacoub G, Fuhrmeister A. Pharmacokinetics of levonorgestrel in 12 women who received a single oral dose of 0.15 mg levonorgestrel and, after a wash-out phase, the same dose during one treatment cycle. Contraception 1992;46:443–54
   PubMed Web of Science ®Google Scholar
• Kuhnz W, Staks T, Jütting G. Pharmacokinetics of levonorgestrel and ethinylestradiol in 14 women during three months of treatment with a tri-step combination oral contraceptive: serum protein binding of levonorgestrel and influence of treatment on free and total testosterone levels in the serum. Contraception 1994;50:563–79
   PubMed Web of Science ®Google Scholar
• Endrikat J, Blode H, Gerlinger C, et al. A pharmacokinetic study with a low-dose oral contraceptive containing 20 μg ethinylestradiol plus 100 μg levonorgestrel. Eur J Contracept Reprod Health Care 2002;7:79–90
   PubMed Web of Science ®Google Scholar
• Raudaskoski T, Tapanainen J, Tomas E, et al. Intrauterine 10 μg and 20 μg levonorgestrel systems in postmenopausal women receiving oral oestrogen replacement therapy: clinical, endometrial and metabolic response. Br J Obstet Gynaecol 2002;109:136–44
   Google Scholar
• Wildemeersch D, Schacht E, Wildemeersch P. Performance and acceptability of intrauterine release of levonorgestrel with a miniature delivery system for hormonal substitution therapy, contraception and treatment in peri and postmenopausal women. Maturitas 2003;44:237–45
   PubMed Web of Science ®Google Scholar
• Varila E, Wahlström T, Rauramo I. A 5-year follow-up study on the use of a levonorgestrel intrauterine system in women receiving hormone replacement therapy. Fertil Steril 2001;76:969–73
   PubMed Web of Science ®Google Scholar
• Riphagen FE. Intrauterine application of prges-tins in hormone replacement therapy: a review. Climacteric 2000;3:199–211
   PubMedGoogle Scholar
• von Holst T, Salbach B. Efficacy of a new 7-day transdermal sequential estradiol/levonorgestrel patch in women. Maturitas 2002;41:231–42
   PubMed Web of Science ®Google Scholar
• Sturdee DW, van de Weijer P, von Holst T, et al. Endometrial safety of a transdermal sequential estradiol–levonorgestrel combination. Climacteric 2002;5:170–7
   PubMed Web of Science ®Google Scholar
• van de Weijer PHM, Sturdee DW, von Holst T. Estradiol and levonorgestrel: effects on bleeding pattern when administered in a sequential combined regimen with a new transdermal patch. Climacteric 2002;5:36–44
   PubMed Web of Science ®Google Scholar
• Paoletti AM, Pilloni M, Orru M, et al. Efficacy and safety of oral and transdermal hormonal replacement treatment containing levonorgestrel. Maturitas 2002;42:137–47
   PubMed Web of Science ®Google Scholar
• Shulman LP, Yankov V, Uhl K. Safety and efficacy of a continuous once-a-week 17bestradiol/levonorgestrel transdermal system and its effects on vasomotor symptoms and endometrial safety in postmenopausal women: the results of two multicenter, double-blind, randomised, controlled trials. Menopause 2002;3:195–207
   Google Scholar
• Hammond GL, Abrams LS, Creasy GW, et al. Serum distribution of the major metabolites of norgestimate in relation to its pharmacological properties. Contraception 2003;67:93–9
   PubMed Web of Science ®Google Scholar
• Kuhnz W, Blode H, Mahler M. Systemic availability of levonorgestrel after single oral administration of a norgestimate-containing combination oral contraceptive to 12 young women. Contraception 1994;49:255–63
   PubMed Web of Science ®Google Scholar
• Curran MP, Wagstaff AJ. Estradiol and norgestimate. A review of their combined use as hormone replacement therapy in postmenopausal women. Drugs Aging 2001;18:863–85
   PubMed Web of Science ®Google Scholar
• Timmer CJ, Verheul HAM, Doorstam DP. Pharmacokinetics of tibolone in early and late postmenopausal women. Br J Clin Pharmacol 2002;54:101–6
   PubMed Web of Science ®Google Scholar
• de Gooyer ME, Deckers GH, Schoonen WGEJ, et al. Receptor profiling and endocrine interactions of tibolone. Steroids 2003;68:21–30
   PubMed Web of Science ®Google Scholar
• Tang B, Markiewicz L, Kloosterboer HJ, et al. Human endometrial 3β-hydroxysteroid dehydrogenase can locally reduce intrinsic estrogenic/progestagenic activity ratios of a steroidal drug (Org OD 14). J Steroid Biochem Molec Biol 1993;45:345–51
   PubMed Web of Science ®Google Scholar
• Dören M, Rübig A, Coelingh Bennink HJT, et al. Impact on uterine bleeding and endometrial thickness: tibolone compared with continuous combined estradiol and norethisterone acetate replacement therapy. Menopause 1999;6:299–306
   PubMed Web of Science ®Google Scholar
• Perez-Medina T, Bajo-Arenas J, Haya J, et al. Tibolone and risk of endometrial polyps: a prospective, comparative study with hormone therapy. Menopause 2003;10:534–7
   PubMed Web of Science ®Google Scholar
• Hammar M, Christau S, Nathorst-Böös J, et al. A double-blind, randomised trial comparing the effects of tibolone and continuous combined hormone replacement therapy in postmenopausal women with menopausal symptoms. Br J Obstet Gynaecol 1998;105:904–11
   PubMedGoogle Scholar
• Valdivia I, Campodonico I, Tapia A, et al. Effects of tibolone and continuous combined hormone therapy on mammographic breast density and breast histochemical markers in postmenopausal women. Fertil Steril 2004;81:617–23
   PubMed Web of Science ®Google Scholar
• Nathoorst-Böös J, Hammar M. Effect on sexual life – a comparison between tibolone and a continuous estradiol–norethisterone acetate regimen. Maturitas 1997;26:15–20
   PubMed Web of Science ®Google Scholar
• Winkler UH, Altkemper R, Kwee B, et al. Effects of tibolone and continuous combined hormone replacement therapy on parameters in the clotting cascade: a multicenter, double-blind, randomized study. Fertil Steril 2000;74:10–19
   PubMed Web of Science ®Google Scholar
• Al-Azzawi F, Wahab M, Habiba M, et al. Continuous combined hormone replacement therapy compared with tibolone. Obstet Gynecol 1999;93:258–64
   PubMed Web of Science ®Google Scholar
• Modelska K, Cummings S. Tibolone for post-menopausal women: systematic review of randomised trials. J Clin Endocrinol Metab 2002;87:16–23
   PubMed Web of Science ®Google Scholar
• Wiegratz I, Sänger N, Kuhl H. Formation of 7alpha-methyl-ethinyl estradiol during treatment with tibolone. Menopause 2000;9:293–5
   Web of Science ®Google Scholar
• Bodine PVN, Harris HA, Lyttle CR, et al. Estrogenic effects of 7α-methyl-17α-ethynylestradiol: a newly discovered tibolone metabolite. Steroids 2002;67:681–6
   PubMed Web of Science ®Google Scholar
• de Gooyer ME, Oppers-Tiemissen HM, Leysen D, et al. Tibolone is not converted by human aromatase to 7α-methyl-17α-ethynylestradiol (7α-MEE): analyses with sensitive bioassays for estrogens and androgens with LC-MSMS. Steroids 2003;68:235–43
   PubMed Web of Science ®Google Scholar
• Thompson RM, Horning EC. Aromatization of the A-ring of norethynodrel, a steroidal oral contraceptive, during trimethylsilylation. Steroids Lipids Res 1973;4:135–42
   PubMedGoogle Scholar
• Yamamoto T, Yoshiji S, Yasuda J, et al. Aromatization of norethisterone to ethynylestradiol in human adult liver. Endocrinol Jpn 1986;33:527–31
   PubMedGoogle Scholar
• Urabe M, Yamamoto T, Yoshiji S, et al. Aromatization of norethindrone to ethynylestradiol in human adult liver. Steroids 1987;50:607–8
   Google Scholar
• World Health Organization Task Force on Oral Contraceptives. A multicentre comparative study of serum lipids and lipoproteins in four groups of oral combined contraceptive users and a control group of IUD users. Contraception 1988;38:605–29
   PubMed Web of Science ®Google Scholar
• Oelkers W, Berger V, Bolik A, et al. Dihydrospirorenone, a new progestogen with antimineralocorticoid activity: effects on ovulation, electrolyte excretion, and the renin–aldosterone system in normal women. J Clin Endocrinol Metab 1991;73:837–42
   PubMed Web of Science ®Google Scholar
• Krattenmacher R. Drospirenone: pharmacology and pharmacokinetics of a unique progestogen. Contraception 2000;62:29–38
   PubMed Web of Science ®Google Scholar
• Rübig A. Drospirenone: a new cardiovascular-active progestin with antialdosterone and anti-androgenic properties. Climacteric 2003;6(Suppl 3):49–54
   PubMedGoogle Scholar
• Burger H. Hormone replacement therapy in the post-Women’s Health Initiative era. Climacteric 2003;6(Suppl 2):11–36
   PubMedGoogle Scholar
• Schiff I. The effects of progestins on vasomotor flushes. J Reprod Med 1982;27(Suppl):498–502
   PubMedGoogle Scholar
• Abdalla HI, McKay Hart D, Lindsay R, et al. Prevention of bone mineral loss in postmenopausal women by norethisterone. Obstet Gynecol 1985;66:789–92
   PubMed Web of Science ®Google Scholar
• Moore RA. Livial: a review of clinical studies. Br J Obstet Gynaecol 1999;106(Suppl 19):1–21
   PubMedGoogle Scholar
• Thijssen JHH. Overview on the effects of progestins on bone. Maturitas 2003;46(Suupl 1):S77–S87
   PubMedGoogle Scholar
• Gruber DM, Sator MO, Joura EA, et al. Topical cyproterone acetate treatment in women with acne. Arch Dermatol 1998;134:459–63
   PubMed Web of Science ®Google Scholar
• Adams RM, Burdick KH. An antiandrogen delta I chlormadinone acetate in acne: lack of effect topically. Acta Dermatovener 1970;50:479–80
   PubMedGoogle Scholar
• Björn I, Bixo M, Strandberg K, et al. Negative mood changes during hormone replacement therapy: a comparison between two pro-gestogens. Am J Obstet Gynecol 2000;183:1419–26
   PubMed Web of Science ®Google Scholar
• Sherwin BB. The impact of different doses of estrogen and progestin on mood and sexual behavior in postmenopausal women. J Clin Endocrinol Metab 1991;72:336–43
   PubMed Web of Science ®Google Scholar
• Björn I, Sundström-Poromaa I, Bixo M, et al. Increase of estrogen dose deteriorates mood during progestin phase in sequential hormonal therapy. J Clin Endocrinol Metab 2003;88:2026–30
   PubMed Web of Science ®Google Scholar
• Modelska K, Cummings S. Female sexual dysfunction in postmenopausal women: systematic review of placebo-controlled trials. Am J Obstet Gynecol 2003;188:286–93
   PubMed Web of Science ®Google Scholar
• Whitehead MI, Hillard TC, Crook D. The role and use of progestogens. Obstet Gynecol 1990;75:59S–76S
   Web of Science ®Google Scholar
• Menard S, Casalini P, Agresti R, et al. Proliferation of breast carcinoma during menstrual phases. Lancet 1998;352:148–9
   PubMed Web of Science ®Google Scholar
• Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women. JAMA 2003;289:3243–53
   PubMed Web of Science ®Google Scholar
• Adams MR, Register TC, Golden DL, et al. Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis. Arterioscler Thromb Vasc Biol 1997;17:217–21
   PubMed Web of Science ®Google Scholar
• Williams JK, Honore EK, Washburn SA, et al. Effects of hormone replacement therapy on reactivity of atherosclerotic arteries in cynomolgus monkeys. J Am Coll Cardiol 1994;24:1757–61
   PubMed Web of Science ®Google Scholar
• Clarkson TB, Anthony MS, Wagner JD. A comparison of tibolone and conjugated equine estrogens effects on coronary artery atherosclerosis and bone density of postmenopausal monkeys. J Clin Endocrinol Metab 2001;86:5396–404
   PubMed Web of Science ®Google Scholar
• Adams MR, Clarkson TB, Shively CA, et al. Oral contraceptives, lipoproteins, and atherosclerosis. Am J Obstet Gynecol 1990;163:1388–93
   PubMed Web of Science ®Google Scholar
• Punnonen RH, Jokela HA, Dastidar PS, et al. Combined oestrogen–progestin replacement therapy prevents atherosclerosis in postmenopausal women. Maturitas 1995;21:179–87
   PubMed Web of Science ®Google Scholar
• Kuhl H. Effects of progestogens on haemostasis. Maturitas 1996;24:1–19
   PubMed Web of Science ®Google Scholar
• Kluft C, de Maat MPM, Heinemann LAJ, et al. Importance of levonorgestrel dose in oral contraceptives for effects on coagulation. Lancet 1999;354:832–3
   PubMed Web of Science ®Google Scholar