Advances in Therapy

, Volume 25, Issue 6, pp 525–551 | Cite as

Rationale for low-dose systemic hormone replacement therapy and review of estradiol 0.5 mg/NETA 0.1 mg



The menopausal transition is associated with several symptoms, for which both non-pharmacological and pharmacological measures are available to provide relief. However, present knowledge indicates that the former is not highly effective, and that the latter, in terms of systemic oestrogen and progestogen-based hormone replacement therapy (HRT), although being effective (e.g. on vasomotor symptoms, bleeding control, bone mineral density, vaginal atrophy and quality of life), can be associated with some caveats. Amongst these are an increased risk for coronary heart disease, breast cancer, venous thromboembolism and stroke.

In recent years, literature has indicated a dose dependency for HRT on some of the caveats, hence authorities (Food and Drug Administration, and the European Medicines Agency) and menopause societies (International Menopause Society and North American Menopause Society) now recommend that women deemed in need of HRT should receive the lowest possible dose without compromising the effect of symptom relief. Estradiol 0.5 mg/norethisterone acetate (NETA) 0.1 mg, despite being a lower dose than conventional hormones, is a compound, among a few other low-dose options, that can be used in such therapy. As a first-line oral option, it has demonstrated its effectiveness (which seems comparable to other compounds), with high tolerability and, apparently, no safety concerns, in a 6-month study. Further long-term clinical trials and observational studies are mandatory in order to capture any potential harm as well as to elucidate this compound’s full potential.

Following a thorough literature search using PubMed and MEDLINE from the earliest publication dates through to January 2008, including results from various types of clinical trials and statements on HRT, we review the rationale for these recommendations. We also review the effects and safety of a novel ‘ultra-low-dose’ oral continuous combined HRT tablet, estradiol 0.5 mg/NETA 0.1 mg.


cardiovascular HRT mammographic density menopause NETA oestrogen pharmacological treatment progestogen randomised controlled trials review 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    United Common Database. Available at: Accessed 10 January 2008.
  2. 2.
    Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321–333.PubMedGoogle Scholar
  3. 3.
    Topal NB, Ayhan S, Topal U, Bilgin T. Effects of hormone replacement therapy regimens on mammographic breast density: the role of progestins. J Obstet Gynaecol Res. 2006;32:305–308.PubMedGoogle Scholar
  4. 4.
    Bremnes Y, Ursin G, Bjurstam N, Lund E, Gram IT. Different types of postmenopausal hormone therapy and mammographic density in Norwegian women. Int J Cancer. 2007;120:880–884.PubMedGoogle Scholar
  5. 5.
    Jick H, Derby LE, Myers MW, Vasilakis C, Newton KM. Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens. Lancet. 1996;348:981–983.PubMedGoogle Scholar
  6. 6.
    Wu O. Postmenopausal hormone replacement therapy and venous thromboembolism. Gend Med. 2005;2(suppl 1):S18–S27.PubMedGoogle Scholar
  7. 7.
    Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet. 1996;348:977–980.PubMedGoogle Scholar
  8. 8.
    Grodstein F, Manson JE, Colditz GA, Willett WC, Speizer FE, Stampfer MJ. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med. 2000;133:933–941.PubMedGoogle Scholar
  9. 9.
    Burger H, Archer D, Barlow D, et al. Practical recommendations for hormone replacement therapy in the peri-and postmenopause. Climacteric. 2004;7:210–216.PubMedGoogle Scholar
  10. 10.
    Pedersen SH, Pedersen NG, Dalsgaard T, Lund CO, Nilas L, Ottesen B. Different cerebrovascular effects of medroxyprogesterone acetate and norethisterone acetate in the New Zealand white rabbit. Climacteric. 2004;7:12–22.PubMedGoogle Scholar
  11. 11.
    European Medicines Agency. CHMP guideline on clinical investigations of medicinal products for hormone replacement therapy of oestrogen deficiency symptoms in postmenopausal women. Document ref: EMEA/CHMP/021/97 rev 1. London: EMEA; 13 October 2005. Available at: Scholar
  12. 12.
    Food and Drug Administration. Guidance for industry. Estrogen and estrogen/progestin drug products to treat vasomotor symptoms and vulvar and vaginal atrophy symptoms. Recommendations for clinical evaluation. Rockville, MD: US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER); January 2003.Google Scholar
  13. 13.
    Board of the International Menopause Society. IMS updated recommendations on postmenopausal hormone therapy. Climacteric. 2007;10:181–194.Google Scholar
  14. 14.
    North American Menopause Society. Estrogen and progestogen use in peri-and postmenopausal women: March 2007 position statement of the North American Menopause Society. Menopause. 2007;14:168–182.Google Scholar
  15. 15.
    Santoro N. The menopause transition: an update. Hum Reprod Update. 2002;8:155–160.PubMedGoogle Scholar
  16. 16.
    Rödström K, Bengtsson C, Lissner L, Björkelund C. Reproducibility of selfreported menopause age at the 24-year follow-up of a population study of women in Gøteborg, Sweden. Menopause. 2005;12:275–280.PubMedGoogle Scholar
  17. 17.
    Bengtsson C, Lindquist O, Redvall L. Menstrual status and menopausal age of middle-aged Swedish women. A population study of women in Gøteborg 1968–69 and 1974–75. Acta Obstet Gynecol Scand. 1981;60:269–275.PubMedGoogle Scholar
  18. 18.
    Hammar M, Berg G, Fåhraeus L, Larsson-Cohn U. Climacteric symptoms in an unselected sample of Swedish women. Maturitas. 1984;6:345–350.PubMedGoogle Scholar
  19. 19.
    Stearns V, Ullmer López JF, Smith Y, Isaacs C, Hayes D. Hot flushes. Lancet. 2002;360:1851–1861.PubMedGoogle Scholar
  20. 20.
    Maartens LW, Leusink GL, Knottnerus JA, Smeets CG, Pop VJ. Climacteric complaints in the community. Fam Pract. 2001;18:189–194.PubMedGoogle Scholar
  21. 21.
    Bromberger JT, Meyer PM, Kravitz HM, et al. Psychologic distress and natural menopause: a multiethnic community study. Am J Public Health. 2001;91:1435–1442.PubMedGoogle Scholar
  22. 22.
    Lipton RB, Goadsby P, Silberstein SD. Classification and epidemiology of headache. Clin Cornerstone. 1999;1:1–10.PubMedGoogle Scholar
  23. 23.
    Freeman EW, Sammel MD, Lin H, et al. Symptoms associated with menopausal transition and reproductive hormones in midlife women. Obstet Gynecol. 2007;110:230–240.PubMedGoogle Scholar
  24. 24.
    Woods NF, Smith-DiJulio K, Percival DB, Tao EY, Taylor HJ, Mitchell ES. Symptoms during the menopausal transition and early postmenopause and their relation to endocrine levels over time: observations from the Seattle Midlife Women’s Health Study. J Womens Health. 2007;16:667–677.Google Scholar
  25. 25.
    Dennerstein L, Dudley EC, Hopper JL, Guthrie JR, Burger HG. A prospective population-based study of menopausal symptoms. Obstet Gynecol. 2000;96:351–358.PubMedGoogle Scholar
  26. 26.
    Dennerstein L, Dudley E, Burger H. Are changes in sexual functioning during midlife due to aging or menopause? Fertil Steril. 2001;76:456–460.PubMedGoogle Scholar
  27. 27.
    Lindau ST, Schumm LP, Laumann EO, Levinson W, O’Muircheartaigh CA, Waite LJ. A study of sexuality and health among older adults in the United States. N Engl J Med. 2007;357:762–774.PubMedGoogle Scholar
  28. 28.
    Avis NE, Kaufert PA, Lock M, McKinlay SM, Vass K. The evolution of menopausal symptoms. Baillieres Clin Endocrinol Metab. 1993;7:17–32.PubMedGoogle Scholar
  29. 29.
    Kumari M, Stafford M, Marmot M. The menopausal transition was associated in a prospective study with decreased health functioning in women who report menopausal symptoms. J Clin Epidemiol. 2005;58:719–727.PubMedGoogle Scholar
  30. 30.
    Hardy R, Kuh D. Change in psychological and vasomotor symptom reporting during the menopause. Soc Sci Med. 2002;55:1975–1988.PubMedGoogle Scholar
  31. 31.
    Marmot MG, Stansfeld S, Patel C, et al. Health inequalities among British civil servants: the Whitehall II study. Lancet. 1991;337:1387–1393.PubMedGoogle Scholar
  32. 32.
    Daly E, Gray A, Barlow D, McPherson K, Roche M, Vessey M. Measuring the impact of menopausal symptoms on quality of life. BMJ. 1993;307:836–840.PubMedGoogle Scholar
  33. 33.
    Berg G, Gottwall T, Hammar M, Lindgren R, Gottgall T. Climacteric symptoms among women aged 60–62 in Linkøping, Sweden, in 1986. Maturitas. 1988;10:193–199.PubMedGoogle Scholar
  34. 34.
    Rödström K, Bengtsson C, Lissner L, Milsom I, Sundh V, Björkelund C. A longitudinal study of the treatment of hot flushes: the population study of women in Gothenburg during a quarter of a century. Menopause. 2002;9:156–161.PubMedGoogle Scholar
  35. 35.
    Staropoli CA, Flaws JA, Bush TL, Moulton AW. Predictors of menopausal hot flashes. J Womens Health. 1998;7:1149–1155.PubMedGoogle Scholar
  36. 36.
    Whiteman MK, Staropoli CA, Langenberg PW, McCarter RJ, Kjerulff KH, Flaws JA. Smoking, body mass, and hot flashes in midlife women. Obstet Gynecol. 2003;101:264–272.PubMedGoogle Scholar
  37. 37.
    Li C, Samsioe G, Borgfeldt C, Lidfeldt J, Agardh CD, Nerbrand C. Menopause-related symptoms: what are the background factors? A prospective population-based cohort study of Swedish women (the Women’s Health in Lund Area study). Am J Obstet Gynecol. 2003;189:1646–1653.PubMedGoogle Scholar
  38. 38.
    Freedman RR. Hot flash trends and mechanisms. Menopause. 2002;9:151–152.PubMedGoogle Scholar
  39. 39.
    Leal M, Diaz J, Serrano E, Abellan J, Carbonell LF. Hormone replacement therapy for oxidative stress in postmenopausal women with hot flushes. Obstet Gynecol. 2000;95:804–809.PubMedGoogle Scholar
  40. 40.
    Ginsburg J, Hardiman P, O’Reilly B. Peripheral blood flow in menopausal women who have hot flushes and in those who do not. BMJ. 1989;298:1488–1490.PubMedGoogle Scholar
  41. 41.
    Oldenhave A, Jaszmann LJ, Haspels AA, Everaerd WT. Impact of climacteric on well-being. A survey based on 5213 women 39 to 60 years old. Am J Obstet Gynecol. 1993;168:772–780.PubMedGoogle Scholar
  42. 42.
    Iosif C, Bekassy Z. Prevalence of genitourinary symptoms in the late menopause. Acta Obstet Gynecol Scand. 1984;63:257–260.PubMedCrossRefGoogle Scholar
  43. 43.
    Siris ES, Miller PD, Barrett-Connor E, et al. Identification and fracture outcomes of undiagnosed low bone mineral density in postmenopausal women: results from the National Osteoporosis Risk Assessment. JAMA. 2001;286:2815–2822.PubMedGoogle Scholar
  44. 44.
    Welty FK, Lee KS, Lew NS, Nasca M, Zhou JR. The association between soy nut consumption and decreased menopausal symptoms. J Womens Health. 2007;16:361–369.Google Scholar
  45. 45.
    Lethaby A, Brown J, Marjoribanks J, Kronenberg F, Roberts H, Eden J. Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst Rev. 2007;(4):CD001395.Google Scholar
  46. 46.
    Grady D. Management of menopausal symptoms. N Engl J Med. 2006;355:2338–2347.PubMedGoogle Scholar
  47. 47.
    Hammar M, Berg G, Lindgren R. Does physical exercise influence the frequency of postmenopausal hot flushes? Acta Obstet Gynecol Scand. 1990;69:409–412.PubMedGoogle Scholar
  48. 48.
    Daley A, Macarthur C, Mutrie N, Stokes-Lampard H. Exercise for vasomotor menopausal symptoms. Cochrane Database Syst Rev. 2007(4):CD006108.Google Scholar
  49. 49.
    Nelson HD, Vesco KK, Haney E, et al. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA. 2006;295:2057–2071.PubMedGoogle Scholar
  50. 50.
    Speroff L, Gass M, Constantine G, et al. Efficacy and tolerability of desvenlafaxine succinate treatment for menopausal vasomotor symptoms: a randomized controlled trial. Obstet Gynecol. 2008;111:77–87.PubMedGoogle Scholar
  51. 51.
    Rymer JM. The effects of tibolone. Gynecol Endocrinol. 1998;12:213–220.PubMedGoogle Scholar
  52. 52.
    Swegle JM, Kelly MW. Tibolone: a unique version of hormone replacement therapy. Ann Pharmacother. 2004;38:874–881.PubMedGoogle Scholar
  53. 53.
    De Lignieres B, Basdevant A, Thomas G, et al. Biological effects of estradiol-17 in postmenopausal women: oral versus percutaneous administration. J Clin Endocrinol Metab. 1986;62:536–541.PubMedCrossRefGoogle Scholar
  54. 54.
    O’Connell MB. Pharmacokinetic and pharmacologic variation between different estrogen products. J Clin Pharmacol. 1995;35(suppl):S18–S24.Google Scholar
  55. 55.
    Stanczyk FZ, Shoupe D, Nunez V, Macias-Gonzales P, Vijod MA, Lobo RA. A randomized comparison of nonoral estradiol delivery in postmenopausal women. Am J Obstet Gynecol. 1998;159:1540–1546.Google Scholar
  56. 56.
    Frenkel Y, Kopernik G, Lazer S, et al. Acceptability and skin reactions to transdermal estrogen replacement therapy in relation to climate. Maturitas. 1994;20:31–36.PubMedGoogle Scholar
  57. 57.
    The Transdermal HRT Investigators Group. A randomized study to compare the effectiveness, tolerability and acceptability of two different transdermal estradiol replacement therapies. Int J Fertil Menopausal Stud. 1993;38:5–11.Google Scholar
  58. 58.
    Mosekilde L, Beck-Nielsen H, Sørensen OH, et al. Hormonal replacement therapy reduces forearm fracture incidence in recent postmenopausal women-results of the Danish Osteoporosis Prevention Study. Maturitas. 2000;36:181–193.PubMedGoogle Scholar
  59. 59.
    Christiansen C, Christensen MS, McNair P, Hagen C, Stocklund KE, Transbøl I. Prevention of early postmenopausal bone loss: controlled 2-year study in 315 normal females. Eur J Clin Invest. 1980;10:273–279.PubMedGoogle Scholar
  60. 60.
    Lindsay R, Gallagher JC, Kleerekoper M, Pickar JH. Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early postmenopausal women. JAMA. 2002;287:2668–2676.PubMedGoogle Scholar
  61. 61.
    Ettinger B, Ensrud KE, Wallace R, et al. Effects of ultralow-dose transdermal estradiol on bone mineral density: a randomized clinical trial. Obstet Gynecol. 2004;104:443–451.PubMedGoogle Scholar
  62. 62.
    Gambacciani M, Cappagli B, Ciaponi M, Pepe A, Vacca F, Genazzani AR. Ultra low-dose hormone replacement therapy and bone protection in postmenopausal women. Maturitas. 2008;59:2–6.PubMedGoogle Scholar
  63. 63.
    Gambacciani M, Ciaponi M, Cappagli B, et al. A longitudinal evaluation of the effect of two doses of tibolone on bone density and metabolism in early postmenopausal women. Gynecol Endocrinol. 2004;18:9–16.PubMedGoogle Scholar
  64. 64.
    Prestwood KM, Kenny AM, Unson C, Kulldorff M. The effect of low dose micronized 17ss-estradiol on bone turnover, sex hormone levels, and side effects in older women: a randomized, double blind, placebo-controlled study. J Clin Endocrinol Metab. 2000;85:4462–4469.PubMedGoogle Scholar
  65. 65.
    Salminen HS, Sääf ME, Johansson SE, Ringertz H, Strender LE. The effect of transvaginal estradiol on bone in aged women: a randomised controlled trial. Maturitas. 2007;57:370–381.PubMedGoogle Scholar
  66. 66.
    Nathorst-Böös J, Hammar M. Effect on sexual life — a comparison between tibolone and a continuous estradiol-norethisterone acetate regimen. Maturitas. 1997;26:15–20.PubMedGoogle Scholar
  67. 67.
    Simon JA, Bouchard C, Waldbaum A, et al. Low dose of transdermal estradiol gel for treatment of symptomatic postmenopausal women: a randomized controlled trial. Obstet Gynecol. 2007;109:588–596.PubMedGoogle Scholar
  68. 68.
    The North American Menopause Society. The role of local vaginal estrogen for treatment of vaginal atrophy in postmenopausal women: 2007 position statement of The North American Menopause Society. Menopause. 2007;14:357–369.Google Scholar
  69. 69.
    Bachmann G, Lobo RA, Gut R, Nachtigall L, Notelovitz M. Efficacy of low-dose estradiol vaginal tablets in the treatment of atrophic vaginitis: a randomized controlled trial. Obstet Gynecol. 2008;111:67–76.PubMedGoogle Scholar
  70. 70.
    Gambacciani M, Ciaponi M, Cappagli B, et al. Effects of low-dose, continuous combined estradiol and noretisterone acetate on menopausal quality of life in early postmenopausal women. Maturitas. 2003;44:157–163.PubMedGoogle Scholar
  71. 71.
    Schneider HPG. The view of the International Menopause Society on the Women’s Health Initiative. Climacteric. 2002;5:211–216.PubMedGoogle Scholar
  72. 72.
    Naftolin F, Schneider HP, Sturdee D, et al. Guidelines for hormone treatment of women in the menopausal transition and beyond. Climacteric. 2004;7:333–337.PubMedGoogle Scholar
  73. 73.
    Hilditch JR, Lewis J, Ross AH, et al. A comparison of the effects of oral copjugated equine estrogen and transdermal estradiol-17beta combined with an oral progestin on quality of life in postmenopausal women. Maturitas. 1996;24:177–184.PubMedGoogle Scholar
  74. 74.
    Zethraeus N, Johannesson M, Henriksson P, Strand RT. The impact of hormone replacement therapy on quality of life and willingness to pay. Br J Obstet Gynaecol. 1997;104:1191–1195.PubMedGoogle Scholar
  75. 75.
    Lethaby A, Hogervorst E, Richards M, Yesufu A, Yaffe K. Hormone replacement therapy for cognitive function in postmenopausal women. Cochrane Database Syst Rev. 2008;(1):CD003122.Google Scholar
  76. 76.
    Kanaya AM, Herrington D, Vittinghoff E, et al. Glycemic effects of postmenopausal hormone therapy: the heart and estrogen/progestin replacement study — a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2003;138:1–9.PubMedGoogle Scholar
  77. 77.
    Margolis KL, Bonds DE, Rodabough RJ, et al. Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women’s Health Initiative Hormone Trial. Diabetologia. 2004;47:1175–1187.PubMedGoogle Scholar
  78. 78.
    Ferrara A, Karter AJ, Ackerson LM, Liu JY, Selby JV. Hormone replacement therapy is associated with better glycemic control in women with type 2 diabetes: the Northern California Kaiser Permanente Diabetes Registry. Diabetes Care. 2001;24:1144–1150.PubMedGoogle Scholar
  79. 79.
    Ziel HK, Finkle WD. Increased risk of endometrial carcinoma among users of conjugated estrogens. N Engl J Med. 1975;293:1167–1170.PubMedGoogle Scholar
  80. 80.
    Manson JE, Martin KA. Postmenopausal hormone-replacement therapy. N Engl J Med. 2001;345:34–40.PubMedGoogle Scholar
  81. 81.
    Weiderpass E, Baron JA, Adami HO, et al. Low-potency oestrogen and risk of endometrial cancer: a case-control study. Lancet. 1999;353:1824–1828.PubMedGoogle Scholar
  82. 82.
    King RJ, Whitehead MI. Assessment of the potency of orally administered progestins in women. Fertil Steril. 1986;46:1062–1066.PubMedGoogle Scholar
  83. 83.
    Kurman RJ, Félix JC, Archer DF, Nanavati N, Arce J, Moyer DL. Norethindrone acetate and estradiol-induced endometrial hyperplasia. Obstet Gynecol. 2000;96:373–379.PubMedGoogle Scholar
  84. 84.
    Sturdee DW, Ulrich LG, Barlow DH, et al. The endometrial response to sequential and continuous combined oestrogen-progestogen replacement therapy. BJOG. 2000;107:1392–1400.PubMedGoogle Scholar
  85. 85.
    Riis BJ, Lehmann HJ, Christiansen C. Norethisterone acetate in combination with estrogen: effects on the skeleton and other organs. A review. Am J Obstet Gynecol. 2002;187:1101–1116.PubMedGoogle Scholar
  86. 86.
    Dietel M, Lewis MA, Shapiro S. Hormone replacement therapy: pathobiological aspects of hormone-sensitive cancers in women relevant to epidemiological studies on HRT: a mini-review. Hum Reprod. 2005;20:2052–2060.PubMedGoogle Scholar
  87. 87.
    Machens K, Schmidt-Gollwitzer K. Issues to debate on the Women’s Health Initiative (WHI) study. Hormone replacement therapy: an epidemiological dilemma? Hum Reprod. 2003;18:1992–1999.PubMedGoogle Scholar
  88. 88.
    McDonough PG. The randomized world is not without its imperfections: reflections on the Women’s Health Initiative study. Fertil Steril. 2002;78:951–956.PubMedGoogle Scholar
  89. 89.
    Shapiro S. Risks of estrogen plus progestin therapy: a sensitivity analysis of findings in the Women’s Health Initiative randomized controlled trial. Climacteric. 2003;6:302–310.PubMedGoogle Scholar
  90. 90.
    Clark JH. A critique of Women’s Health Initiative studies (2002–2006). Nucl Recept Signal. 2006;4:e023.PubMedGoogle Scholar
  91. 91.
    Shapiro S. Risk of cardiovascular disease in relation to the use of combined postmenopausal hormone therapy: detection bias and resolution of discrepant findings in two Women’s Health Initiative studies. Climacteric. 2006;9:416–420.PubMedGoogle Scholar
  92. 92.
    Løkkegaard E, Lidegaard O, Møller LN, Agger C, Andreasen AH, Jørgensen T. Hormone replacement therapy in Denmark, 1995–2004. Acta Obstet Gynecol Scand. 2007;86:1342–1351.PubMedGoogle Scholar
  93. 93.
    Tiihonen MJ, Heikkinen AM, Ahonen RS. Do Finnish women using hormone replacement therapy need more information about risks? Pharm World Sci. 2007;29:635–640.PubMedGoogle Scholar
  94. 94.
    French LM, Smith MA, Holtrop JS, Holmes-Rovner M. Hormone therapy after the Women’s Health Initiative: a qualitative study. BMC Fam Pract. 2006;7:61.PubMedGoogle Scholar
  95. 95.
    Pedersen AT, Iversen OE, Løkkegaard E, et al. Impact of recent studies on attitudes and use of hormone therapy among Scandinavian gynaecologists. Acta Obstet Gynecol Scand. 2007;86:1490–1495.PubMedGoogle Scholar
  96. 96.
    Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297:1465–1477.PubMedGoogle Scholar
  97. 97.
    Manson JE, Allison MA, Rossouw JE, et al. Estrogen therapy and coronaryartery calcification. N Engl J Med. 2007;356:2591–2602.PubMedGoogle Scholar
  98. 98.
    Grodstein F, Manson JE, Stampfer MJ. Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. J Womens Health. 2006;15:35–44.Google Scholar
  99. 99.
    Salpeter SR, Walsh JME, Greyber E, Salpeter EE. Brief report: coronary heart disease events associated with hormone therapy in younger and older women. a meta-analysis. J Gen Intern Med. 2006;21:363–266.PubMedGoogle Scholar
  100. 100.
    Alexandersen P, Tankó LB, Bagger YZ, Qin G, Christiansen C. The long-term impact of 2–3 years of hormone replacement therapy on cardiovascular mortality and atherosclerosis in healthy women. Climacteric. 2006;9:108–118.PubMedGoogle Scholar
  101. 101.
    Salpeter SR, Walsh JME, Greyber E, Ormiston TM, Salpeter EE. Mortality associated with hormone replacement therapy in younger and older women. a meta-analysis. J Gen Intern Med. 2004;19:791–804.PubMedGoogle Scholar
  102. 102.
    Mikkola TS, Clarkson TB. Estrogen replacement therapy, atherosclerosis, and vascular function. Cardiovasc Res. 2002;53:605–619.PubMedGoogle Scholar
  103. 103.
    Deroo BJ, Korach KS. Estrogen receptors and human disease. J Clin Invest. 2006;116:561–570.PubMedGoogle Scholar
  104. 104.
    Henttonen AT, Kortelainen ML, Kunnas TA, Nikkari ST. Estrogen receptor-1 genotype is related to coronary intima thickness in young to middle-aged women. Scand J Clin Lab Invest. 2007;67:380–386.PubMedGoogle Scholar
  105. 105.
    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.PubMedGoogle Scholar
  106. 106.
    Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet. 1997;350:1047–1059.Google Scholar
  107. 107.
    Espié M, Daures JP, Chevallier T, Mares P, Micheletti MC, De-Reilhac P. Breast cancer incidence and hormone replacement therapy: results from the MISSION study, prospective phase. Gynecol Endocrinol. 2007;23:391–397.PubMedGoogle Scholar
  108. 108.
    Durna EM, Heller GZ, Leader LR, Sjoblom P, Eden JA, Wren BG. Breast cancer in premenopausal women: recurrence and survival rates and relationship to hormone replacement therapy. Climacteric. 2004;7:284–291.PubMedGoogle Scholar
  109. 109.
    Verheul HA, Coelingh-Bennink HJ, Kenemans P, et al. Effects of estrogens and hormone replacement therapy on breast cancer risk and on efficacy of breast cancer therapies. Maturitas. 2000;36:1–17.PubMedGoogle Scholar
  110. 110.
    Schuetz F, Diel IJ, Pueschel M, et al. Reduced incidence of distant metastases and lower mortality in 1072 patients with breast cancer with a history of hormone replacement therapy. Am J Obstet Gynecol. 2007;196:342.e1–e9.Google Scholar
  111. 111.
    Tamimi RM, Byrne C, Colditz GA, Hankinson SE. Endogenous hormone levels, mammographic density, and subsequent risk of breast cancer in postmenopausal women. J Natl Cancer Inst. 2007;99:1178–1187.PubMedGoogle Scholar
  112. 112.
    Ettinger B. Personal perspective on lowdosage estrogen therapy for postmenopausal women. Menopause. 1999;6:273–276.PubMedGoogle Scholar
  113. 113.
    Erel CT, Elter K, Akman C, et al. Mammographic changes in women receiving tibolone therapy. Fertil Steril. 1998;69:870–875.PubMedGoogle Scholar
  114. 114.
    Egarter C, Eppel W, Vogel S, Wolf G. A pilot study of hormone replacement therapy with tibolone in women with mastopathic breasts. Maturitas. 2001;40:165–171.PubMedGoogle Scholar
  115. 115.
    Colacurci N, Mele D, De-Franciscis P, Costa V, Fortunato N, De-Seta L. Effects of tibolone on the breast. Eur J Obstet Gynecol Reprod Biol. 1998;80:235–238.PubMedGoogle Scholar
  116. 116.
    Lundström E, Christow A, Kersemaekers W, et al. Effects of tibolone and continuous combined hormone replacement therapy on mammographic breast density. Am J Obstet Gynecol. 2002;186:717–722.PubMedGoogle Scholar
  117. 117.
    Beral V. Million Women Study Collaborators. Breast cancer and hormonereplacement therapy in the Million Women Study. Lancet. 2003;362:419–427.PubMedGoogle Scholar
  118. 118.
    Velthuis-Te Wierik EJ, Hendricks PT, Martinez C. Preferential prescribing of tibolone and combined estrogen plus progestogen therapy in postmenopausal women. Menopause. 2007;14:518–527.PubMedGoogle Scholar
  119. 119.
    Kubista E, Kenemans P, Foidart JM, et al. Safety of tibolone in the treatment of vasomotor symptoms in breast cancer patients — design and baseline data ‘LIBERATE’ trial. Breast. 2007;16(suppl 2):182–189.Google Scholar
  120. 120.
    International klimakteriestudie with breast cancer patients terminated prematurely [press release; in Swedish]. Gothenburg, Sweden: Organon Schering-Plough; 21 May 2007. Available at: Accessed 10 January 2008.
  121. 121.
    Scarabin PY, Oger E, Plu-Bureau G. EStrogen and THromboEmbolism Risk Study Group. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet. 2003;362:428–432.PubMedGoogle Scholar
  122. 122.
    Simon JA, Hsia J, Cauley JA, et al. Postmenopausal hormone therapy and risk of stroke: the Heart and Estrogen-Progestin Replacement Study (HERS). Circulation. 2001;103:638–642.PubMedGoogle Scholar
  123. 123.
    Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI. A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med. 2001;345:1243–1249.PubMedGoogle Scholar
  124. 124.
    Notelovitz M, Lenihan JP, McDermott M, Kerber IJ, Nanavati N, Arce J. Initial 17beta-estradiol dose for treating vasomotor symptoms. Obstet Gynecol. 2000;95:726–731.PubMedGoogle Scholar
  125. 125.
    Kenny AM, Kleppinger A, Wang Y, Prestwood KM. Effects of ultra-low-dose estrogen therapy on muscle and physical function in older women. J Am Geriatr Soc. 2005;53:1973–1977.PubMedGoogle Scholar
  126. 126.
    Gambacciani M, Genazzani AR. Hormone replacement therapy: the benefits in tailoring the regimen and dose. Maturitas. 2001;40:195–201.PubMedGoogle Scholar
  127. 127.
    6th IMS Workshop web site. Available at: Accessed 10 December 2007.
  128. 128.
    Activella physician insert. Princeton, NJ: Novo Nordisk Inc; 2006. Available at: Accessed 10 January 2008.
  129. 129.
    Activelle Produktresume [in Swedish]. Bagsværd, Denmark: Novo Nordisk A/S; 2007. Available at: Accessed 10 January 2008.
  130. 130.
    Panay N, Ylikorkala O, Archer DF, Gut R, Lang E. Ultra-low-dose estradiol and norethisterone acetate: effective menopausal symptom relief. Climacteric. 2007;10:120–131.PubMedGoogle Scholar
  131. 131.
    Sturdee DW, Archer DF, Rakov V, Lang E. CHOICE Study investigators. Ultra low-dose continuous combined estradiol and norethisterone acetate: improved bleeding profile in postmenopausal women. Climacteric. 2008;11:63–73.PubMedGoogle Scholar
  132. 132.
    Lundström E, Bygdeson M, Svane G, Azavedo E, von-Schoultz B. Neutral effect of ultra-low-dose continuous combined estradiol and norethisterone acetate on mammographic breast density. Climacteric. 2007;10:249–256.PubMedGoogle Scholar
  133. 133.
    Hammar M, Christau S, Nathorst B, Rud T, Garre K. 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;105:904–911.PubMedGoogle Scholar
  134. 134.
    Hammar ML, van de Weijer P, Franke HR, et al. Tibolone and low-dose continuous combined hormone treatment: vaginal bleeding pattern, efficacy and tolerability. BJOG. 2007;114:1522–1529.PubMedGoogle Scholar
  135. 135.
    Junkermann H, von-Holst T, Lang E, Rakov V. Influence of different HRT regimens on mammographic density. Maturitas. 2005;50:105–110.PubMedGoogle Scholar
  136. 136.
    Rozenberg S, Caubel P, Lim PC. Constant estrogen, intermittent progestogen vs. continuous combined hormone replacement therapy: tolerability and effect on vasomotor symptoms. Int J Gynaecol Obstet. 2001;72:235–243.PubMedGoogle Scholar
  137. 137.
    Bruhat M, Rudolf K, Vaheri R, Kainulainen P, Timonen U, Viitanen A. Effective bleeding control and symptom relief by lower dose regimens of continuous combined hormone replacement therapy: a randomized comparative dose-ranging study. Maturitas. 2001;40:259–271.PubMedGoogle Scholar
  138. 138.
    Endrikat J, Graeser T, Mellinger U, Ertan K, Holz C. A multicenter, prospective, randomized, double-blind, placebo-controlled study to investigate the efficacy of a continuous-combined hormone therapy preparation containing 1mg estradiol valerate/2mg dienogest on hot flushes in postmenopausal women. Maturitas. 2007;58:201–207.PubMedGoogle Scholar
  139. 139.
    Conner P, Svane G, Azavedo E, et al. Mammographic breast density, hormones, and growth factors during continuous combined hormone therapy. Fertil Steril. 2004;81:1617–1623.PubMedGoogle Scholar
  140. 140.
    Mattsson LA, Skouby S, Rees M, et al. Efficacy and tolerability of continuous combined hormone replacement therapy in early postmenopausal women. Menopause Int. 2007;13:124–131.PubMedGoogle Scholar
  141. 141.
    Lee BS, Kang BM, Yoon BK, Choi H, Park HM, Kim JG. Efficacy and tolerability of estradiol 1 mg and drospirenone 2 mg in postmenopausal Korean women: a double-blind, randomized, placebocontrolled, multicenter study. Maturitas. 2007;57:361–369.PubMedGoogle Scholar
  142. 142.
    Utian WH, Shoupe D, Bachmann G, Pinkerton JV, Pickar J. Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Fertil Steril. 2001;75:1065–1079.PubMedGoogle Scholar
  143. 143.
    Archer DF, Dorin M, Lewis V, Schneider DL, Pickar JH. Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on endometrial bleeding. Fertil Steril. 2001;75:1080–1087.PubMedGoogle Scholar
  144. 144.
    Pickar JH, Yeh I, Wheeler JE, Cunnane MF, Speroff L. Endometrial effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Fertil Steril. 2001;76:25–31.PubMedGoogle Scholar

Copyright information

© Springer Healthcare Communications 2008

Authors and Affiliations

  1. 1.Medical departmentAsker and Baerum HospitalRudNorway
  2. 2.Department of GynaecologyUllevål University HospitalOsloNorway

Personalised recommendations