Hormone replacement therapy in menopausal women: Past problems and future possibilities

Gynecological Endocrinology

Volumn 22, Issue 10, 2006, Pages 564-577

  Schmidt, John W ^a,b   Wollner, Debra ^a   Curcio, Jessica ^a   Riedlinger, June ^a   Kim, Linda S ^a  

^a Southwest College Naturopathic Med   (United States)

^b Southwest College Research Institute   (United States)

Author keywords

Bioidentical hormone replacement therapy; Hormone replacement therapy; Menopause; Review

Indexed keywords

BIEST; CONJUGATED ESTROGEN; CONJUGATED ESTROGEN PLUS MEDROXYPROGESTERONE ACETATE; ESTRADIOL; ESTRADIOL PLUS ESTRIOL; ESTRIOL; ESTROGEN; ESTROGEN RECEPTOR BETA; GESTAGEN; MEDROXYPROGESTERONE ACETATE; PLACEBO; PROGESTERONE; STEROID HORMONE;

AGING; BEHAVIOR MODIFICATION; BLOOD CLOT; BLOOD CLOTTING; BREAST CANCER; BREAST TENDERNESS; CANCER; CANCER RISK; CARCINOGENESIS; CARDIOVASCULAR DISEASE; CLINICAL TRIAL; COGNITION; COGNITIVE DEFECT; DEEP VEIN THROMBOSIS; DEMENTIA; DIZZINESS; DROWSINESS; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG DOSE REDUCTION; DRUG EFFICACY; DRUG MEGADOSE; DRUG RECEPTOR BINDING; DRUG SAFETY; DRUG WITHDRAWAL; ENDOMETRIUM CANCER; ENDOMETRIUM HYPERPLASIA; ENDOMETRIUM TUMOR; FEMALE; HEART INFARCTION; HORMONE BLOOD LEVEL; HORMONE DEPENDENCE; HORMONE METABOLISM; HORMONE SUBSTITUTION; HOT FLUSH; HUMAN; ISCHEMIC HEART DISEASE; LOW DRUG DOSE; LUNG EMBOLISM; MENOPAUSE; META ANALYSIS; MUSCULOSKELETAL DISEASE; NAUSEA; NEUROLOGIC DISEASE; OVARY CANCER; PATIENT COMPLIANCE; PRIORITY JOURNAL; REBOUND; REVIEW; RISK BENEFIT ANALYSIS; SIDE EFFECT; SINGLE DRUG DOSE; SKIN IRRITATION; SLEEP DISORDER; STROKE; SYMPTOMATOLOGY; SYSTEMATIC REVIEW; THROMBOEMBOLISM; UTERUS CANCER; VAGINA BLEEDING; VASOMOTOR DISORDER;

DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG ADMINISTRATION ROUTES; ESTRIOL; ESTROGENS, CONJUGATED (USP); FEMALE; FORECASTING; GUIDELINES; HORMONE REPLACEMENT THERAPY; HOT FLASHES; HUMANS; MENOPAUSE; PLACEBO EFFECT; PROGESTERONE; STEROIDS;

EID: 33845360291     PISSN: 09513590     EISSN: 14730766     Source Type: Journal    
DOI: 10.1080/09513590600927017     Document Type: Review

References (155)

1. Jokinen K, Rautava P, Makinen J, Ojanlatva A, Sundell J, Helenius H. Experience of climacteric symptoms among 42-46 and 52-56-year-old women. Maturitas 2003;46:199-205.
2. Coope J, Thomson JM, Poller L. Effects of 'natural oestrogen' replacement therapy on menopausal symptoms and blood clotting. Br Med J 1975;4:139-143.
3. MacLennan A, Lester S, Moore V. Oral estrogen replacement therapy versus placebo for hot flushes: a systematic review. Climacteric 2001;4:58-74.
4. Vihtamaki T, Savilahti R, Tuimala R. Why do postmenopausal women discontinue hormone replacement therapy? Maturitas 1999;33:99-105.
5. North American Menopause Society. Treatment of menopause-associated vasomotor symptoms: position statement of The North American Menopause Society. Menopause 2004;11:11-33.
6. Nelson HD. Postmenopausal estrogen for treatment of hot flashes: clinical applications. J Am Med Assoc 2004;291:1621-1625.
7. Kronenberg F. Hot flashes: epidemiology and physiology. Ann N Y Acad Sci 1990;592:52-86, discussion 123-133.
8. Harvey AG, Tang NK. Cognitive behaviour therapy for primary insomnia: can we rest yet? Sleep Med Rev 2003;7:237-262.
9. Hochberg Z, Pacak K, Chrousos GP. Endocrine withdrawal syndromes. Endocr Rev 2003;24:523-538.
10. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. J Am Med Assoc 2002;288:321-333.
11. Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, Lasser NL, Trevisan M, Black HR, Heckbert SR, Detrano R, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003;349:523-534.
12. Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, Bonds D, Brunner R, Brzyski R, Caan B, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. J Am Med Assoc 2004;291:1701-1712.
13. Anderson GL, Judd HL, Kaunitz AM, Barad DH, Beresford SA, Pettinger M, Liu J, McNeeley SG, Lopez AM. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women's Health Initiative randomized trial. J Am Med Assoc 2003;290:1739-1748.
14. Shumaker SA, Legault C, Kuller L, Rapp SR, Thal L, Lane DS, Fillit H, Stefanick ML, Hendrix SL, Lewis CE, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. J Am Med Assoc 2004;291:2947-2958.
15. Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, Hendrix SL, Jones BN 3rd, Assaf AR, Jackson RD, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. J Am Med Assoc 2003;289:2651-2662.
16. Chlebowski RT, Wactawski-Wende J, Ritenbaugh C, Hubbell FA, Ascensao J, Rodabough RJ, Rosenberg CA, Taylor VM, Harris R, Chen C, et al. Estrogen plus progestin and colorectal cancer in postmenopausal women. N Engl J Med 2004;350:991-1004.
17. Hodges RM. The effects of oral estrogen-progestin compounds on blood coagulation factors. Int J Fertil 1968;13:349-353.
18. Cali RW. Management of the climacteric and postmenopausal woman. Med Clin North Am 1972;56:789-800.
19. Tice LF. Estrogens: their function, uses and hazards. Part 2. Am Pharm 1978;18:30-33.
20. Nachtigall LE, Nachtigall RH, Nachtigall RD, Beckman EM. Estrogen replacement therapy I: a 10-year prospective study in the relationship to osteoporosis. Obstet Gynecol 1979;53:277-281.
21. Pritchard KI. Estrogen/hormone replacement therapy and the etiology of breast cancer. Recent Results Cancer Res 1998;152:22-31.
22. Hersh AL, Stefanick ML, Stafford RS. National use of postmenopausal hormone therapy: annual trends and response to recent evidence. J Am Med Assoc 2004;291:47-53.
23. Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, Hsia J, Hulley S, Herd A, Khan S, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). J Am Med Assoc 2002;288:49-57.
24. Howard BV, Kuller L, Langer R, Manson JE, Allen C, Assaf A, Cochrane BB, Larson JC, Lasser N, Rainford M, et al. Risk of cardiovascular disease by hysterectomy status, with and without oophorectomy: the Women's Health Initiative Observational Study. Circulation 2005;111:1462-1470.
25. Fremont-Smith M, Meigs JV, Graham RM, Gilbert HH. Cancer of endometrium and prolonged estrogen therapy. J Am Med Assoc 1946;131:805-808.
26. Quint BC. Changing patterns in endometrial adenocarcinoma: a study of 291 consecutive cases at a large private hospital, 1960-1973. Am J Obstet Gynecol 1975;122:498-501.
27. Anderson DG. The possible mechanisms of action of progestins on endometrial adenocarcinoma. Am J Obstet Gynecol 1972;113:195-211.
28. Gambrell RD Jr. Estrogens, progestogens and endometrial cancer. J Reprod Med 1977;18:301-306.
29. Emons G, Huschmand-Nia A, Krauss T, Hinney B. Hormone replacement therapy and endometrial cancer. Onkologie 2004;27:207-210.
30. Diamanti-Kandarakis E. Hormone replacement therapy and risk of malignancy. Curr Opin Obstet Gynecol 2004;16:73-78.
31. Wingo PA, Layde PM, Lee NC, Rubin G, Ory HW. The risk of breast cancer in postmenopausal women who have used estrogen replacement therapy. J Am Med Assoc 1987;257:209-215.
32. Kelsey JL, Gammon MD. The epidemiology of breast cancer. CA Cancer J Clin 1991;41:146-165.
33. Schairer C, Byrne C, Keyl PM, Brinton LA, Sturgeon SR, Hoover RN. Menopausal estrogen and estrogen-progestin replacement therapy and risk of breast cancer (United States). Cancer Causes Control 1994;5:491-500.
34. Steinberg KK, Smith SJ, Thacker SB, Stroup DF. Breast cancer risk and duration of estrogen use: the role of study design in meta-analysis. Epidemiology 1994;5:415-421.
35. Hulka BS. Epidemiologic analysis of breast and gynecologic cancers. Prog Clin Biol Res 1997;396:17-29.
36. Colditz GA. Relationship between estrogen levels, use of hormone replacement therapy, and breast cancer. J Natl Cancer Inst 1998;90:814-823.
37. Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer Inst 2000;92:328-332.
38. Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Feuer EJ, Thun MJ. Cancer statistics, 2005. CA Cancer J Clin 2005;55:10-30.
39. Weiss NS, Lyon JL, Krishnamurthy S, Dietert SE, Liff JM, Daling JR. Noncontraceptive estrogen use and the occurrence of ovarian cancer. J Natl Cancer Inst 1982;68:95-98.
40. Folsom AR, Anderson JP, Ross JA. Estrogen replacement therapy and ovarian cancer. Epidemiology 2004;15:100-104.
41. Rodriguez C, Calle EE, Coates RJ, Miracle-McMahill HL, Thun MJ, Heath CW Jr. Estrogen replacement therapy and fatal ovarian cancer. Am J Epidemiol 1995;141:828-835.
42. Risch HA. Estrogen replacement therapy and risk of epithelial ovarian cancer. Gynecol Oncol 1996;63:254-257.
43. Koh KK, Sakuma I. Should progestins be blamed for the failure of hormone replacement therapy to reduce cardiovascular events in randomized controlled trials? Arterioscler Thromb Vasc Biol 2004;24:1171-1179.
44. Nilsen J, Brinton RD. Divergent impact of progesterone and medroxyprogesterone acetate (Provera) on nuclear mitogen-activated protein kinase signaling. Proc Natl Acad Sci U S A 2003;100:10506-10511.
45. LeBlanc ES, Janowsky J, Chan BK, Nelson HD. Hormone replacement therapy and cognition: systematic review and meta-analysis. J Am Med Assoc 2001;285:1489-1499.
46. Maggi A, Ciana P, Belcredito S, Vegeto E. Estrogens in the nervous system: mechanisms and nonreproductive functions. Annu Rev Physiol 2004;66:291-313.
47. Yaffe K, Sawaya G, Lieberburg I, Grady D. Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. J Am Med Assoc 1998;279:688-695.
48. Henderson VW. Hormone therapy and Alzheimer's disease: benefit or harm? Expert Opin Pharmacother 2004;5:389-406.
49. Gureviciene I, Puolivali J, Pussinen R, Wang J, Tanila H, Ylinen A. Estrogen treatment alleviates NMDA-antagonist induced hippocampal LTP blockade and cognitive deficits in ovariectomized mice. Neurobiol Learn Mem 2003;79:72-80.
50. Asthana S, Craft S, Baker LD, Raskind MA, Birnbaum RS, Lofgreen CP, Veith RC, Plymate SR. Cognitive and neuroendocrine response to transdermal estrogen in postmenopausal women with Alzheimer's disease: results of a placebo-controlled, double-blind, pilot study. Psychoneuroendocrinology 1999;24:657-677.
51. Thal LJ, Thomas RG, Mulnard R, Sano M, Grundman M, Schneider L. Estrogen levels do not correlate with improvement in cognition. Arch Neurol 2003;60:209-212.
52. Grady D, Ernster VL. Hormone replacement therapy and endometrial cancer: are current regimens safe? J Natl Cancer Inst 1997;89:1088-1089.
53. Zhang QH, Huang YH, Hu YZ, Wei GZ, Han XF, Lu SY, Zhao YF. Disruption of estrogen receptor β in mice brain results in pathological alterations resembling Alzheimer disease. Acta Pharmacol Sin 2004;25:452-457.
54. de Lignieres B, Vincens M. Differential effects of exogenous oestradiol and progesterone on mood in post-menopausal women: individual dose/effect relationship. Maturitas 1982;4:67-72.
55. Crandall C. Low-dose estrogen therapy for menopausal women: a review of efficacy and safety. J Womens Health (Larchmt) 2003;12:723-747.
56. Yasui T, Uemura H, Tezuka M, Yamada M, Irahara M, Miura M, Aono T. Biological effects of hormone replacement therapy in relation to serum estradiol levels. Horm Res 2001;56:38-44.
57. Yasui T, Uemura H, Takikawa M, Irahara M. Hormone replacement therapy in postmenopausal women. J Med Invest 2003;50:136-145.
58. 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.
59. Campagnoli C, Ambroggio S, Biglia N, Sismondi P. Conjugated estrogens and breast cancer risk. Gynecol Endocrinol 1999;13(Suppl):13-19.
60. Romero M. Bioidentical hormone replacement therapy. Customizing care for perimenopausal and menopausal women. Adv Nurse Pract 2002;10:47-48, 51-52.
61. Furuhjelm M, Carlstrom K. Treatment of climacteric and postmenopausal women with 17β-oestradiol and norethisterone acetate. Acta Obstet Gynecol Scand 1977;56:351-361.
62. Francisco L. Is bio-identical hormone therapy fact or fairy tale? Nurse Pract 2003;28:39-44.
63. Boothby LA, Doering PL, Kipersztok S. Bioidentical hormone therapy: a review. Menopause 2004;11:356-367.
64. Lievertz RW. Pharmacology and pharmacokinetics of estrogens. Am J Obstet Gynecol 1987;156:1289-1293.
65. Longcope C. Estriol production and metabolism in normal women. J Steroid Biochem 1984;20:959-962.
66. Fotherby K. Bioavailability of orally administered sex steroids used in oral contraception and hormone replacement therapy. Contraception 1996;54:59-69.
67. van Haaften M, Donker GH, Haspels AA, Thijssen JH. Oestrogen concentrations in plasma, endometrium, myometrium and vagina of postmenopausal women, and effects of vaginal oestriol (E3) and oestradiol (E2) applications. J Steroid Biochem 1989;33:647-653.
68. Corson SL. A decade of experience with transdermal estrogen replacement therapy: overview of key pharmacologic and clinical findings. Int J Fertil 1993;38:79-91.
69. Franz C, Watson D, Longcope C. Estrone sulfate and dehydroepiandrosterone sulfate concentrations in normal subjects and men with cirrhosis. Steroids 1979;34:563-573.
70. Ranadive GN, Mistry JS, Damodaran K, Khosravi MJ, Diamandi A, Gimpel T, Castracane VD, Patel S, Stanczyk FZ. Rapid, convenient radioimmunoassay of estrone sulfate. Clin Chem 1998;44:244-249.
71. Standefer J. Direct radioimmunoassay for serum estriol during pregnancy. Clin Chem 1976;22:484-488.
72. Cauley JA, Gutai JP, Kuller LH, Powell JG. The relation of endogenous sex steroid hormone concentrations to serum lipid and lipoprotein levels in postmenopausal women. Am J Epidemiol 1990;132:884-894.
73. Johnston A. Estrogens - pharmacokinetics and pharmacodynamics with special reference to vaginal administration and the new estradiol formulation - Estring. Acta Obstet Gynecol Scand Suppl 1996;163:16-25.
74. Speroff L, Whitcomb RW, Kempfert NJ, Boyd RA, Paulissen JB, Rowan JP. Efficacy and local tolerance of a low-dose, 7-day matrix estradiol transdermal system in the treatment of menopausal vasomotor symptoms. Obstet Gynecol 1996;88:587-592.
75. Rich RL, Hoth LR, Geoghegan KF, Brown TA, LeMotte PK, Simons SP, Hensley P, Myszka DG. Kinetic analysis of estrogen receptor/ligand interactions. Proc Natl Acad Sci U S A 2002;99:8562-8567.
76. Ekena K, Katzenellenbogen JA, Katzenellenbogen BS. Determinants of ligand specificity of estrogen receptor-α: estrogen versus androgen discrimination. J Biol Chem 1998;273:693-699.
77. Hanstein B, Liu H, Yancisin MC, Brown M. Functional analysis of a novel estrogen receptor-β isoform. Mol Endocrinol 1999;13:129-137.
78. Mesiano S, Jaffe RB. Developmental and functional biology of the primate fetal adrenal cortex. Endocr Rev 1997;18:378-403.
79. Isgor C, Cecchi M, Kabbaj M, Akil H, Watson SJ. Estrogen receptor β in the paraventricular nucleus of hypothalamus regulates the neuroendocrine response to stress and is regulated by corticosterone. Neuroscience 2003;121:837-845.
80. Paige LA, Christensen DJ, Gron H, Norris JD, Gottlin EB, Padilla KM, Chang CY, Ballas LM, Hamilton PT, McDonnell DP, et al. Estrogen receptor (ER) modulators each induce distinct conformational changes in ERα and ERβ. Proc Natl Acad Sci U S A 1999;96:3999-4004.
81. Ruder HJ, Loriaux L, Lipsett MB. Estrone sulfate: production rate and metabolism in man. J Clin Invest 1972;51:1020-1033.
82. Powers MS, Schenkel L, Darley PE, Good WR, Balestra JC, Place VA. Pharmacokinetics and pharmacodynamics of transdermal dosage forms of 17β-estradiol: comparison with conventional oral estrogens used for hormone replacement. Am J Obstet Gynecol 1985;152:1099-1106.
83. Nelson HD. Commonly used types of postmenopausal estrogen for treatment of hot flashes: scientific review. J Am Med Assoc 2004;291:1610-1620.
84. Chaumeil JC. Micronization: a method of improving the bioavailability of poorly soluble drugs. Methods Find Exp Clin Pharmacol 1998;20:211-215.
85. Kuhnz W, Louton T, Back DJ, Michaelis K. Radioimmunological analysis of ethinylestradiol in human serum. Validation of the method and comparison with a gas chromatographic/mass spectrometric assay. Arzneimittelforschung 1993;43:16-21.
86. Englund DE, Johansson ED. Plasma levels of oestrone, oestradiol and gonadotrophins in postmenopausal women after oral and vaginal administration of conjugated equine oestrogens (Premarin). Br J Obstet Gynaecol 1978;85:957-964.
87. Ginsburg ES, Gao X, Shea BF, Barbieri RL. Half-life of estradiol in postmenopausal women. Gynecol Obstet Invest 1998;45:45-48.
88. Kuhl H. Pharmacokinetics of oestrogens and progestogens. Maturitas 1990;12:171-197.
89. Sitruk-Ware R, Bricaire C, De Lignieres B, Yaneva H, Mauvais-Jarvis P. Oral micronized progesterone. Bioavailability pharmacokinetics, pharmacological and therapeutic implications - a review. Contraception 1987;36:373-402.
90. Maxson WS, Hargrove JT. Bioavailability of oral micronized progesterone. Fertil Steril 1985;44:622-626.
91. Warren MP, Shantha S. Uses of progesterone in clinical practice. Int J Fertil Womens Med 1999;44:96-103.
92. Brussaard AB, Wossink J, Lodder JC, Kits KS. Progesterone-metabolite prevents protein kinase C-dependent modulation of γ-aminobutyric acid type A receptors in oxytocin neurons. Proc Natl Acad Sci U S A 2000;97:3625-3630.
93. Minkin MJ. Considerations in the choice of oral vs. transdermal hormone therapy: a review. J Reprod Med 2004;49:311-320.
94. Sitruk-Ware R. Percutaneous and transdermal oestrogen replacement therapy. Ann Med 1993;25:77-82.
95. O'Connell MB. Pharmacokinetic and pharmacologic variation between different estrogen products. J Clin Pharmacol 1995;35(Suppl):18S-24S.
96. Taggart W, Dandekar K, Ellman H, Notelovitz M. The effect of site of application on the transcutaneous absorption of 17-b estradiol from a transdermal delivery system (Climara). Menopause 2000;7:364-369.
97. Notelovitz M. Clinical experience with a 7-day estrogen patch: principles and practice. Gynecol Endocrinol 1998;12:248-258.
98. Lyrenas S, Carlstrom K, Backstrom T, von Schoultz B. A comparison of serum oestrogen levels after percutaneous and oral administration of oestradiol-17β. Br J Obstet Gynaecol 1981;88:181-187.
99. Friend KE, Hartman ML, Pezzoli SS, Clasey JL, Thorner MO. Both oral and transdermal estrogen increase growth hormone release in postmenopausal women - a clinical research center study. J Clin Endocrinol Metab 1996;81:2250-2256.
100. Hirvonen E, Cacciatore B, Wahlstrom T, Rita H, Wilen-Rosenqvist G. Effects of transdermal oestrogen therapy in postmenopausal women: a comparative study of an oestradiol gel and an oestradiol delivering patch. Br J Obstet Gynaecol 1997;104(Suppl):26-31.
101. Jarvinen A, Granander M, Laine T, Viitanen A. Effect of dose on the absorption of estradiol from a transdermal gel. Maturitas 2000;35:51-56.
102. Scarabin PY, Oger E, Plu-Bureau G. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet 2003;362:428-432.
103. Oger E, Alhenc-Gelas M, Lacut K, Blouch MT, Roudaut N, Kerlan V, Collet M, Abgrall JF, Aiach M, Scarabin PY, et al. Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: a randomized trial. Arterioscler Thromb Vasc Biol 2003;23:1671-1676.
104. Vooijs GP, Geurts TB. Review of the endometrial safety during intravaginal treatment with estriol. Eur J Obstet Gynecol Reprod Biol 1995;62:101-106.
105. Kao J, Hall J. Skin absorption and cutaneous first pass metabolism of topical steroids: in vitro studies with mouse skin in organ culture. J Pharmacol Exp Ther 1987;241:482-487.
106. Cicinelli E, Petruzzi D, Scorcia P, Resta L. Effects of progesterone administered by nasal spray on the human postmenopausal endometrium. Maturitas 1993;18:65-72.
107. Cicinelli E, de Ziegler D, Alfonso R, Nicoletti R, Bellavia M, Colafiglio G. Endometrial effects, bleeding control, and compliance with a new postmenopausal hormone therapy regimen based on transdermal estradiol gel and every-other-day vaginal progesterone in capsules: a 3-year pilot study. Fertil Steril 2005;83:1859-1863.
108. Chakmakjian ZH, Zachariah NY. Bioavailability of progesterone with different modes of administration. J Reprod Med 1987;32:443-448.
109. Levine H, Watson N. Comparison of the pharmacokinetics of crinone 8% administered vaginally versus Prometrium administered orally in postmenopausal women. Fertil Steril 2000;73:516-521.
110. Carey BJ, Carey AH, Patel S, Carter G, Studd JW. 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;107:722-726.
111. Hermann AC, Nafziger AN, Victory J, Kulawy R, Rocci ML Jr, Bertino JS Jr. Over-the-counter progesterone cream produces significant drug exposure compared to a Food and Drug Administration-approved oral progesterone product. J Clin Pharmacol 2005;45:614-619.
112. Leonetti HB, Wilson KJ, Anasti JN. Topical progesterone cream has an antiproliferative effect on estrogen-stimulated endometrium. Fertil Steril 2003;79:221-222.
113. Leonetti HB, Landes J, Steinberg D, Anasti JN. Transdermal progesterone cream as an alternative progestin in hormone therapy. Altern Ther Health Med 2005;11:36-38.
114. Wren BG, McFarland K, Edwards L, O'Shea P, Sufi S, Gross B, Eden JA. Effect of sequential transdermal progesterone cream on endometrium, bleeding pattern, and plasma progesterone and salivary progesterone levels in postmenopausal women. Climacteric 2000;3:155-160.
115. Giangrande PH, Kimbrel EA, Edwards DP, McDonnell DP. The opposing transcriptional activities of the two isoforms of the human progesterone receptor are due to differential cofactor binding. Mol Cell Biol 2000;20:3102-3115.
116. Richer JK, Jacobsen BM, Manning NG, Abel MG, Wolf DM, Horwitz KB. Differential gene regulation by the two progesterone receptor isoforms in human breast cancer cells. J Biol Chem 2002;277:5209-5218.
117. Smid-Koopman E, Blok LJ, Kuhne LC, Burger CW, Helmerhorst TJ, Brinkmann AO, Huikeshoven FJ. Distinct functional differences of human progesterone receptors A and B on gene expression and growth regulation in two endometrial carcinoma cell lines. J Soc Gynecol Investig 2003;10:49-57.
118. Mulac-Jericevic B, Lydon JP, DeMayo FJ, Conneely OM. Defective mammary gland morphogenesis in mice lacking the progesterone receptor B isoform. Proc Natl Acad Sci U S A 2003;100:9744-9749.
119. Mote PA, Bartow S, Tran N, Clarke CL. Loss of co-ordinate expression of progesterone receptors A and B is an early event in breast carcinogenesis. Breast Cancer Res Treat 2002;72:163-172.
120. Olive DL. Role of progesterone antagonists and new selective progesterone receptor modulators in reproductive health. Obstet Gynecol Surv 2002;57(Suppl):S55-S63.
121. Cummings JA, Brizendine L. Comparison of physical and emotional side effects of progesterone or medroxyprogesterone in early postmenopausal women. Menopause 2002;9:253-263.
122. Greendale GA, Reboussin BA, Hogan P, Barnabei VM, Shumaker S, Johnson S, Barrett-Connor E. Symptom relief and side effects of postmenopausal hormones: results from the Postmenopausal Estrogen/Progestin Interventions Trial. Obstet Gynecol 1998;92:982-988.
123. Thomas T, Rhodin J, Clark L, Garces A. Progestins initiate adverse events of menopausal estrogen therapy. Climacteric 2003;6:293-301.
124. Campagnoli C, Clavel-Chapelon F, Kaaks R, Peris C, Berrino F. Progestins and progesterone in hormone replacement therapy and the risk of breast cancer. J Steroid Biochem Mol Biol 2005;96:95-108.
125. Head KA. Estriol: safety and efficacy. Altern Med Rev 1998;3:101-113.
126. Esposito G. Estriol: a weak estrogen or a different hormone? Gynecol Endocrinol 1991;5:131-153.
127. Granberg S, Eurenius K, Lindgren R, Wilhelmsson L. The effects of oral estriol on the endometrium in postmenopausal women. Maturitas 2002;42:149-156.
128. Weiderpass E, Baron JA, Adami HO, Magnusson C, Lindgren A, Bergstrom R, Correia N, Persson I. Low-potency oestrogen and risk of endometrial cancer: a case-control study. Lancet 1999;353:1824-1828.
129. Schiff I, Tulchinsky D, Ryan KJ, Kadner S, Levitz M. Plasma estriol and its conjugates following oral and vaginal administration of estriol to postmenopausal women: correlations with gonadotropin levels. Am J Obstet Gynecol 1980;138:1137-1141.
130. Heimer GM. Estriol in the postmenopause. Acta Obstet Gynecol Scand Suppl 1987;139:1-23.
131. Fink BJ, Christensen MS. Bioavailability of oestradiol and oestriol administered orally to oophorectomized women. Maturitas 1981;3:289-294.
132. Heimer GM, Englund DE. Enterohepatic recirculation of oestriol studied in cholecystectomized and non-cholecystectomized menopausal women. Ups J Med Sci 1984;89:107-115.
133. Englund DE, Elamsson KB, Johansson ED. Bioavailability of oestriol. Acta Endocrinol (Copenh) 1982;99:136-140.
134. Ushiroyama T, Sakai M, Higashiyama T, Ikeda A, Ueki M. Estrogen replacement therapy in postmenopausal women: a study of the efficacy of estriol and changes in plasma gonadotropin levels. Gynecol Endocrinol 2001;15:74-80.
135. Foidart JM, Vervliet J, Buytaert P. Efficacy of sustained-release vaginal oestriol in alleviating urogenital and systemic climacteric complaints. Maturitas 1991;13:99-107.
136. Volpe A, Facchinetti F, Grasso A, Petraglia F, Campanini D, Genazzani AR. Benefits and risks of different hormonal replacement therapies in post-menopausal women. Maturitas 1986;8:327-334.
137. Takahashi K, Manabe A, Okada M, Kurioka H, Kanasaki H, Miyazaki K. Efficacy and safety of oral estriol for managing postmenopausal symptoms. Maturitas 2000;34:169-177.
138. Manonai J, Theppisai U. Effect of oral estriol on urogenital symptoms, vaginal cytology, and plasma hormone level in postmenopausal women. J Med Assoc Thai 2001;84:539-544.
139. Helgason S. Estrogen replacement therapy after the menopause. Estrogenicity and metabolic effects. Acta Obstet Gynecol Scand Suppl 1982;107:1-29.
140. Tzingounis VA, Aksu MF, Greenblatt RB. The significance of oestriol in the management of the post-menopause. Acta Endocrinol Suppl (Copenh) 1980;233:45-50.
141. Lindsay R, Hart DM, Maclean A, Garwood J, Clark AC, Kraszewski A. Bone loss during oestriol therapy in postmenopausal women. Maturitas 1979;1:279-285.
142. Dunn JF, Nisula BC, Rodbard D. Transport of steroid hormones: binding of 21 endogenous steroids to both testosteronebinding globulin and corticosteroid-binding globulin in human plasma. J Clin Endocrinol Metab 1981;53:58-68.
143. Voss HF. Saliva as a fluid for measurement of estriol levels. Am J Obstet Gynecol 1999;180:S226-S231.
144. Zhu Y, Bian Z, Lu P, Karas RH, Bao L, Cox D, Hodgin J, Shaul PW, Thoren P, Smithies O, et al. Abnormal vascular function and hypertension in mice deficient in estrogen receptor beta. Science 2002;295:505-508.
145. Paech K, Webb P, Kuiper GG, Nilsson S, Gustafsson J, Kushner PJ, Scanlan TS. Differential ligand activation of estrogen receptors ERα and ERβ at AP1 sites. Science 1997;277:1508-1510.
146. Liu MM, Albanese C, Anderson CM, Hilty K, Webb P, Uht RM, Price RH Jr, Pestell RG, Kushner PJ. Opposing action of estrogen receptors α and β on cyclin D1 gene expression. J Biol Chem 2002;277:24353-24360.
147. Seidlova-Wuttke D, Becker T, Christoffel V, Jarry H, Wuttke W. Silymarin is a selective estrogen receptor β (ERβ) agonist and has estrogenic effects in the metaphysis of the femur but no or antiestrogenic effects in the uterus of ovariectomized (ovx) rats. J Steroid Biochem Mol Biol 2003;86:179-188.
148. Zheng SL, Zheng W, Chang BL, Shu XO, Cai Q, Yu H, Dai Q, Xu J, Gao YT. Joint effect of estrogen receptor β sequence variants and endogenous estrogen exposure on breast cancer risk in Chinese women. Cancer Res 2003;63:7624-7629.
149. Lemon HM, Wotiz HH, Parsons L, Mozden PJ. Reduced estriol excretion in patients with breast cancer prior to endocrine therapy. J Am Med Assoc 1966;196:112-120.
150. Lemon HM. Oestriol and prevention of breast cancer. Lancet 1973;1:546-547.
151. Lemon HM. Clinical and experimental aspects of the antimammary carinogenic activity of estriol. Front Horm Res 1977;5:155-173.
152. Rajkumar L, Guzman RC, Yang J, Thordarson G, Talamantes F, Nandi S. Prevention of mammary carcinogenesis by short-term estrogen and progestin treatments. Breast Cancer Res 2004;6:R31-R37.
153. Weihua Z, Andersson S, Cheng G, Simpson ER, Warner M, Gustafsson JA. Update on estrogen signaling. FEBS Lett 2003;546:17-24.
154. Bardin A, Boulle N, Lazennec G, Vignon F, Pujol P. Loss of ERβ expression as a common step in estrogen-dependent tumor progression. Endocr Relat Cancer 2004;11:537-551.
155. Cheng J, Lee EJ, Madison LD, Lazennec G. Expression of estrogen receptor beta in prostate carcinoma cells inhibits invasion and proliferation and triggers apoptosis. FEBS Lett 2004;566:169-172.