Vaginal Hormone Therapy for Urogenital and Menopausal Symptoms

ABSTRACT

Reduction of ovarian steroids at menopause leads to significant changes in the urogenital tract. These changes often worsen with time, particularly in nonsmokers, affecting up to 38% of menopausal women. Urogenital symptoms that clearly respond to estrogen therapy include atrophic vaginitis, dryness, and accompanying dyspareunia. Estrogen reduces urinary tract infections in women plagued by frequent recurrence. The sensation of urgency improves with estrogen but urge incontinence improvement is similar to that with placebo. Stress incontinence does not improve with estrogen. Until recently, vaginal therapy was reserved for local symptoms. Rings make systemic vaginal therapy acceptable and even preferred by some users. Vaginal delivery, like other parenteral therapies, bypasses the gastrointestinal tract, with less anticipated impact on lipids, globulins, clotting, and fibrinolytic factors. Evidence of a lowered risk of venous thromboembolism is reviewed. Options for estrogen therapy include native, synthetic, or biologically derived estrogens delivered by cream, gel, insert (pessary), ring, or tablet. Even the lowest dose estradiol (7.5 μg daily or 25 μg twice per week) shows evidence of systemic absorption. In long-term placebo-controlled studies, bone density was better preserved and lipid profiles were more favorable. Therefore, even these low dose therapies should be opposed by occasional progestogen to prevent endometrial carcinoma. Intermittent therapy is best given for a minimum of 12 days based on laboratory data. Less frequent dosing, although preferred by patients, likely confers a slightly increased risk of hyperplasia. No combination estrogen/progestogen vaginal product is currently available. The best dose to reduce risk of endometrial pathology adequately in the lower dose therapies will be defined not only by the dose and potency of the exogenous estrogen but by the individual is body habitus and lifestyle choices.

Urogenital - vaginal - menopause - therapy - progestogen

REFERENCES

• 1 Rymer J, Morris E P. Extracts from “clinical evidence”: menopausal symptoms.  BMJ. 2000;  321 1516-1519
• 2 Kalogeraki A, Tamiolakis D, Relakis K et al.. Cigarette smoking and vaginal atrophy in postmenopausal women.  In Vivo. 1996;  10 597-600
• 3 Iosif C S, Bekassy Z. Prevalence of genito-urinary symptoms in the late menopause.  Acta Obstet Gynecol Scand. 1984;  63 257-260
• 4 Barlow D H, Samsioe G, van Geelen J M. A study of European womens' experience of the problems of urogenital ageing and its management.  Maturitas. 1997;  27 239-247
• 5 Oldenhave A. Well-Being and Sexuality in the Climacteric: A Survey Based on 6622 Women [dissertation]. Leidshendam, United Kingdom; Excelsior 1991
• 6 Bachmann G A. Vulvovaginal complaints. In: Lobo RA Treatment of the Postmenopausal Woman: Basic and Clinical Aspects New York; Raven Press 1994: 137-142
• 7 Hargrove J T, Maxson W S, Wentz A C, Burnett L S. Menopausal hormone replacement therapy with continuous daily oral micronized estradiol and progesterone.  Obstet Gynecol. 1989;  73 606-612
• 8 Loprinzi C L, Abu-Ghazaleh S, Sloan J A et al.. Phase III randomized double-blind study to evaluate the efficacy of a polycarbophil-based vaginal moisturizer in women with breast cancer.  J Clin Oncol. 1997;  15 969-973
• 9 Bygdeman M, Swahn M L. Replens versus dienoestrol cream in the symptomatic treatment of vaginal atrophy in postmenopausal women.  Maturitas. 1996;  23 259-263
• 10 Cardozo L, Bachmann G, McClish D, Fonda D, Birgerson L. Meta-analysis of estrogen therapy in the management of urogenital atrophy in postmenopausal women: second report of the Hormones and Urogenital Therapy Committee.  Obstet Gynecol. 1998;  92 722-727
• 11 Simunic V, Banovic I, Ciglar S, Jeren L, Pavicic Baldani D, Sprem M. Local estrogen treatment in patients with urogenital symptoms.  Int J Gynaecol Obstet. 2003;  82 187-197
• 12 Molander U, Milsom I, Ekelund P, Mellstrom D. An epidemiological study of urinary incontinence and related urogenital symptoms in elderly women.  Maturitas. 1990;  12 51-60
• 13 Hu K K, Boyko E J, Scholes D et al.. Risk factors for urinary tract infections in postmenopausal women.  Arch Intern Med. 2004;  164 989-993
• 14 Robinson D, Cardozo L. The pathophysiology and management of postmenopausal urogenital oestrogen deficiency.  J Br Menopause Soc. 2001;  7 67-73
• 15 Holroyd-Leduc J M, Mehta K M, Covinsky K E. Urinary incontinence and its association with death, nursing home admission, and functional decline.  J Am Geriatr Soc. 2004;  52 712-718
• 16 Ouslander J G, Kane R L, Abrass I B. Urinary incontinence in elderly nursing home patients.  JAMA. 1982;  248 1194-1198
• 17 Diokno A C, Brock B M, Brown M B, Herzog A R. Prevalence of urinary incontinence and other urological symptoms in the noninstitutionalized elderly.  J Urol. 1986;  136 1022-1025
• 18 Youngblood V H, Tomlin E M, Davis J B. Senile urethritis in women.  J Urol. 1957;  78 150-152
• 19 Kinchen K S, Burgio K, Diokno A C, Fultz N H, Bump R, Obenchain R. Factors associated with women's decisions to seek treatment for urinary incontinence.  J Womens Health (Larchmt). 2003;  12 687-698
• 20 Kinchen K S, Long S, Orsini L, Crown W, Swindle R. A retrospective claims analysis of the direct costs of stress urinary incontinence.  Int Urogynecol J Pelvic Floor Dysfunct. 2003;  14 403-411
• 21 Fultz N H, Burgio K, Diokno A C, Kinchen K S, Obenchain R, Bump R C. Burden of stress urinary incontinence for community-dwelling women.  Am J Obstet Gynecol. 2003;  189 1275-1278
• 22 Cardozo L, Rekers H, Tapp A et al.. Oestriol in the treatment of postmenopausal urgency: a multicentre study.  Maturitas. 1993;  18 47-53
• 23 Fantl J A, Cardozo L, McClish D K. Estrogen therapy in the management of urinary incontinence in postmenopausal women: a meta-analysis. First report of the Hormones and Urogenital Therapy Committee.  Obstet Gynecol. 1994;  83 12-18
• 24 Molander U, Milsom I, Ekelund P, Mellstrom D, Eriksson O. Effect of oral oestriol on vaginal flora and cytology and urogenital symptoms in the post-menopause.  Maturitas. 1990;  12 113-120
• 25 Raz R, Stamm W E. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections.  N Engl J Med. 1993;  329 753-756
• 26 Eriksen P S, Rasmussen H. Low-dose 17 beta-estradiol vaginal tablets in the treatment of atrophic vaginitis: a double-blind placebo controlled study.  Eur J Obstet Gynecol Reprod Biol. 1992;  44 137-144
• 27 Brandberg A, Mellstrom D, Samsioe G. Low dose oral estriol treatment in elderly women with urogenital infections.  Acta Obstet Gynecol Scand Suppl. 1987;  140 33-38
• 28 Raz R, Colodner R, Rohana Y et al.. Effectiveness of estriol-containing vaginal pessaries and nitrofurantoin macrocrystal therapy in the prevention of recurrent urinary tract infection in postmenopausal women.  Clin Infect Dis. 2003;  36 1362-1368
• 29 Cardozo L, Lose G, McClish D, Versi E, de Koning Gans H. A systematic review of estrogens for recurrent urinary tract infections: third report of the hormones and urogenital therapy (HUT) committee.  Int Urogynecol J Pelvic Floor Dysfunct. 2001;  12 15-20
• 30 Fantl J A, Wyman J F, Anderson R L, Matt D W, Bump R C. Postmenopausal urinary incontinence: comparison between non-estrogen-supplemented and estrogen-supplemented women.  Obstet Gynecol. 1988;  71 823-828
• 31 Bhatia N N, Bergman A, Karram M M. Effects of estrogen on urethral function in women with urinary incontinence.  Am J Obstet Gynecol. 1989;  160 176-181
• 32 Faber P, Heidenreich J. Treatment of stress incontinence with estrogen in postmenopausal women.  Urol Int. 1977;  32 221-223
• 33 Fantl J A, Bump R C, Robinson D, McClish D K, Wyman J F. Efficacy of estrogen supplementation in the treatment of urinary incontinence. The Continence Program for Women Research Group.  Obstet Gynecol. 1996;  88 745-749
• 34 Jackson S, Shepherd A, Brookes S, Abrams P. The effect of oestrogen supplementation on post-menopausal urinary stress incontinence: a double-blind placebo-controlled trial.  Br J Obstet Gynaecol. 1999;  106 711-718
• 35 Benness C, Wise B G, Cutner A, Cardozo L D. Does low vaginal oestradiol improve frequency and urgency in postmenopausal women.  Int Urogynecol J. 1992;  3 281
• 36 Grady D, Brown J S, Vittinghoff E et al.. Postmenopausal hormones and incontinence: the Heart and Estrogen/Progestin Replacement Study.  Obstet Gynecol. 2001;  97 116-120
• 37 Zinner N R, Sterling A M, Ritter R C. Role of inner urethral softness in urinary continence.  Urology. 1980;  16 115-117
• 38 Kemmler W, Lauber D, Weineck J, Hensen J, Kalender W, Engelke K. Benefits of 2 years of intense exercise on bone density, physical fitness, and blood lipids in early postmenopausal osteopenic women: results of the Erlangen Fitness Osteoporosis Prevention Study (EFOPS).  Arch Intern Med. 2004;  164 1084-1091
• 39 Dalais F S, Rice G E, Wahlqvist M L et al.. Effects of dietary phytoestrogens in postmenopausal women.  Climacteric. 1998;  1 124-129
• 40 Chiechi L M, Putignano G, Guerra V, Schiavelli M P, Cisternino A M, Carriero C. The effect of a soy rich diet on the vaginal epithelium in postmenopause: a randomized double blind trial.  Maturitas. 2003;  45 241-246
• 41 Fugh-Berman A, Kronenberg F. Red clover (Trifolium pratense) for menopausal women: current state of knowledge.  Menopause. 2001;  8 333-337
• 42 Davis S R. Phytoestrogen therapy for menopausal symptoms?.  BMJ. 2001;  323 354-355
• 43 Schlemmer A, Jensen J, Riis B J, Christiansen C. Smoking induces increased androgen levels in early post-menopausal women.  Maturitas. 1990;  12 99-104
• 44 Ruiz E, Osorio E, Ortega E. Androgenic status in cyclic and postmenopausal women: a comparison between smokers and nonsmokers.  Biochem Int. 1992;  27 841-845
• 45 Bachmann G A, Ebert G A, Burd I D. Vulvovaginal complaints. In: Lobo RA Treatment of the Postmenopausal Woman: Basic and Clinical Aspects Philadelphia; Lippincott Williams & Wilkins 1999: 195-201
• 46 Oriba H A, Maibach H I. Vulvar transepidermal water loss (TEWL) decay curves. Effect of occlusion, delipidation, and age.  Acta Derm Venereol. 1989;  69 461-465
• 47 Bachmann G A, Nevadunsky N S. Diagnosis and treatment of atrophic vaginitis.  Am Fam Physician. 2000;  61 3090-3096
• 48 Julia J, Yacoub M, Levy G. Labial fusion causing urinary incontinence in a postmenopausal female: a case report.  Int Urogynecol J Pelvic Floor Dysfunct. 2003;  14 360-361
• 49 Henry F, Pierard-Franchimont C, Cauwenbergh G, Pierard G E. Age-related changes in facial skin contours and rheology.  J Am Geriatr Soc. 1997;  45 220-222
• 50 Schmidt J B, Binder M, Demschik G, Bieglmayer C, Reiner A. Treatment of skin aging with topical estrogens.  Int J Dermatol. 1996;  35 669-674
• 51 Hustin J, Van den Eynde J P. Cytologic evaluation of the effect of various estrogens given in postmenopause.  Acta Cytol. 1977;  21 225-228
• 52 Bergman A. Alterations in the urogenital system. In: Mishell DR Menopause: Physiology and Pharmacology Chicago; Year Book Medical Publishers 1987
• 53 Salmon U J, Walter R I, Geist S H. The use of estrogens in the treatment of dysuria and incontinence in postmenopausal women.  Am J Obstet Gynecol. 1941;  42 845-851
• 54 Marx P, Schade G, Wilbourn S, Blank S, Moyer D L, Nett R. Low-dose (0.3 mg) synthetic conjugated estrogens A is effective for managing atrophic vaginitis.  Maturitas. 2004;  47 47-54
• 55 Utian W H, Shoupe D, Bachmann G, Pinkerton J V, Pickar J H. Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate.  Fertil Steril. 2001;  75 1065-1079
• 56 Stone S C, Mickal A, Rye P H. Postmenopausal symptomatology, maturation index, and plasma estrogen levels.  Obstet Gynecol. 1975;  45 625-627
• 57 Kaufman S A. Limited relationship of maturation index to estrogen therapy for menopausal symptoms. An analysis of 200 patients.  Obstet Gynecol. 1967;  30 399-407
• 58 Notelovitz M. Urogenital atrophy and low-dose vaginal estrogen therapy. .  Menopause. 2000;  7 140-142
• 59 Caillouette J C, Sharp Jr C F, Zimmerman G J, Roy S. Vaginal pH as a marker for bacterial pathogens and menopausal status.  Am J Obstet Gynecol. 1997;  176 1270-1275
• 60 Roy S, Caillouette J C, Roy T, Faden J S. Vaginal pH is similar to follicle-stimulating hormone for menopause diagnosis.  Am J Obstet Gynecol. 2004;  190 1272-1277
• 61 Davila G W, Singh A, Karapanagiotou I et al.. Are women with urogenital atrophy symptomatic?.  Am J Obstet Gynecol. 2003;  188 382-388
• 62 Tsai C C, Semmens J P, Semmens E C, Lam C F, Lee F S. Vaginal physiology in postmenopausal women: pH value, transvaginal electropotential difference, and estimated blood flow.  South Med J. 1987;  80 987-990
• 63 Steger R, Hafez E. Age-associated changes in the vagina. In: Hafez E, Evans T Human Reproductive Medicine: The Human Vagina Amsterdam, the Netherlands; Elsevier/North-Holland Biomedical Press 1978: 95-106
• 64 Burgos M, Roig de Vargas-Linares C. Ultrastructure of the vaginal mucosa. In: Hafez E, Evans T Human Reproductive Medicine: The Human Vagina Amsterdam, the Netherlands; Elsevier/North-Holland Biomedical Press 1978: 63-93
• 65 Dennerstein L, Dudley E C, Hopper J L, Guthrie J R, Burger H G. A prospective population-based study of menopausal symptoms.  Obstet Gynecol. 2000;  96 351-358
• 66 Averette H E, Weinstein G D, Frost P. Autoradiographic analysis of cell proliferation kinetics in human genital tissues. I. Normal cervix and vagina.  Am J Obstet Gynecol. 1970;  108 8-17
• 67 Pschera H, Hjerpe A, Carlstrom K. Influence of the maturity of the vaginal epithelium upon the absorption of vaginally administered estradiol-17 beta and progesterone in postmenopausal women.  Gynecol Obstet Invest. 1989;  27 204-207
• 68 Carlstrom K, Pschera H, Lunell N O. Serum levels of oestrogens, progesterone, follicle-stimulating hormone and sex-hormone-binding globulin during simultaneous vaginal administration of 17 beta-oestradiol and progesterone in the pre- and post-menopause.  Maturitas. 1988;  10 307-316
• 69 Leiblum S, Bachmann G, Kemmann E, Colburn D, Swartzman L. Vaginal atrophy in the postmenopausal woman. The importance of sexual activity and hormones.  JAMA. 1983;  249 2195-2198
• 70 Notelovitz M. Estrogen therapy in the management of problems associated with urogenital ageing: a simple diagnostic test and the effect of the route of hormone administration.  Maturitas. 1995;  22 S31-S33
• 71 Blakeman P J, Hilton P, Bulmer J N. Oestrogen and progesterone receptor expression in the female lower urinary tract, with reference to oestrogen status.  BJU Int. 2000;  86 32-38
• 72 Belchetz P E. Hormonal treatment of postmenopausal women.  N Engl J Med. 1994;  330 1062-1071
• 73 Versi E, Cardozo L, Brincat M, Cooper D, Montgomery J, Studd J. Correlation of urethral physiology and skin collagen in postmenopausal women.  Br J Obstet Gynaecol. 1988;  95 147-152
• 74 Bergman A, Elia G, Cheung D, Perelman N, Nimni M E. Biochemical composition of collagen in continent and stress urinary incontinent women.  Gynecol Obstet Invest. 1994;  37 48-51
• 75 Stumpf W E, Sar M, Joshi S G. Estrogen target cells in the skin.  Experentia. 1974;  30 196-198
• 76 Falconer C, Ekman G, Malmstrom A, Ulmsten U. Decreased collagen synthesis in stress-incontinent women.  Obstet Gynecol. 1994;  84 583-586
• 77 Smith P. Estrogens and the urogenital tract.  Acta Obstet Gynecol Scand. 1993;  157 1-26
• 78 Levin R M, Jacobowitz D, Wein A J. Autonomic innervation of rabbit urinary bladder following estrogen administration.  Urology. 1981;  17 449-453
• 79 Hodgson B J, Dumas S, Bolling D R, Heesch C M. Effect of estrogen on sensitivity of rabbit bladder and urethra to phenylephrine.  Invest Urol. 1978;  16 67-69
• 80 Robinson D, Cardozo L D. The role of estrogens in female lower urinary tract dysfunction.  Urology. 2003;  62 45-51
• 81 Batra S, Andersson K E. Oestrogen-induced changes in muscarinic receptor density and contractile responses in the female rabbit urinary bladder.  Acta Physiol Scand. 1989;  137 135-141
• 82 Elliott R A, Castleden C M, Miodrag A, Kirwan P. The direct effects of diethylstilboestrol and nifedipine on the contractile responses of isolated human and rat detrusor muscles.  Eur J Clin Pharmacol. 1992;  43 149-155
• 83 Kronenberg F, Fugh-Berman A. Complementary and alternative medicine for menopausal symptoms: a review of randomized, controlled trials.  Ann Intern Med. 2002;  137 805-813
• 84 Nichols K C, Schenkel L, Benson H. 17 beta-estradiol for postmenopausal estrogen replacement therapy.  Obstet Gynecol Surv. 1984;  39 230-245
• 85 Antoniou G, Kalogirou D, Karakitsos P, Antoniou D, Kalogirou O, Giannikos L. Transdermal estrogen with a levonorgestrel-releasing intrauterine device for climacteric complaints versus estradiol-releasing vaginal ring with a vaginal progesterone suppository: clinical and endometrial responses.  Maturitas. 1997;  26 103-111
• 86 Laufer L R, DeFazio J L, Lu J K et al.. Estrogen replacement therapy by transdermal estradiol administration.  Am J Obstet Gynecol. 1983;  146 533-540
• 87 Shulman L P, Yankov V, Uhl K. Safety and efficacy of a continuous once-a-week 17beta-estradiol/levonorgestrel transdermal system and its effects on vasomotor symptoms and endometrial safety in postmenopausal women: the results of two multicenter, double-blind, randomized, controlled trials.  Menopause. 2002;  9 195-207
• 88 Henzl M R, Loomba P K. Transdermal delivery of sex steroids for hormone replacement therapy and contraception. A review of principles and practice.  J Reprod Med. 2003;  48 525-540
• 89 Archer D F. Percutaneous 17beta-estradiol gel for the treatment of vasomotor symptoms in postmenopausal women.  Menopause. 2003;  10 516-521
• 90 Rigg L A, Milanes B, Villanueva B, Yen S S. Efficacy of intravaginal and intranasal administration of micronized estradiol-17beta.  J Clin Endocrinol Metab. 1977;  45 1261-1264
• 91 Cicinelli E, Di Naro E, De Ziegler D et al.. Placement of the vaginal 17beta-estradiol tablets in the inner or outer one third of the vagina affects the preferential delivery of 17beta-estradiol toward the uterus or periurethral areas, thereby modifying efficacy and endometrial safety.  Am J Obstet Gynecol. 2003;  189 55-58
• 92 Speroff L. Efficacy and tolerability of a novel estradiol vaginal ring for relief of menopausal symptoms.  Obstet Gynecol. 2003;  102 823-834
• 93 Mandel F P, Geola F L, Meldrum D R et al.. Biological effects of various doses of vaginally administered conjugated equine estrogens in postmenopausal women.  J Clin Endocrinol Metab. 1983;  57 133-139
• 94 Zegura B, Keber I, Sebestjen M, Koenig W. Double blind, randomized study of estradiol replacement therapy on markers of inflammation, coagulation and fibrinolysis.  Atherosclerosis. 2003;  168 123-129
• 95 Vongpatanasin W, Tuncel M, Wang Z, Arbique D, Mehrad B, Jialal I. Differential effects of oral versus transdermal estrogen replacement therapy on C-reactive protein in postmenopausal women.  J Am Coll Cardiol. 2003;  41 1358-1363
• 96 Hemelaar M, van der Mooren M J, 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;  10 550-558
• 97 Vehkavaara S, Silveira A, Hakala-Ala-Pietila 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;  85 619-625
• 98 Post M S, van der Mooren M J, van Baal W M 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 1221-1227
• 99 Kroon U B, Silfverstolpe G, Tengborn L. The effects of transdermal estradiol and oral conjugated estrogens on haemostasis variables.  Thromb Haemost. 1994;  71 420-423
• 100 Scarabin P Y, Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R, Aiach M. Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial.  Arterioscler Thromb Vasc Biol. 1997;  17 3071-3078
• 101 Caine Y G, Bauer K A, Barzegar S et al.. Coagulation activation following estrogen administration to postmenopausal women.  Thromb Haemost. 1992;  68 392-395
• 102 Scarabin P Y, Perez Gutthann S, Garcia Rdriguez L A. Recent epidemiological studies of the association between hormone replacement therapy and venous thromboembolism. A review.  Drug Saf. 1998;  18 117-123
• 103 Scarabin P Y, Oger E, Plu-Bureau G. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk.  Lancet. 2003;  362 428-432
• 104 Rossouw J E, Anderson G L, Prentice R L 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
• 105 Anderson G L 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
• 106 Pinkerton J V, Limacher M, Assaf A R et al.. Influence of raloxifene on the efficacy of an estradiol-releasing ring for treating vaginal atrophy in postmenopausal women.  Menopause. 2003;  10 45-52
• 107 Parsons A, Merritt D, Rosen A et al.. Effect of raloxifene on the response to conjugated estrogen vaginal cream or nonhormonal moisturizers in postmenopausal vaginal atrophy.  Obstet Gynecol. 2003;  101 346-352
• 108 Naessen T, Berglund L, Ulmsten U. Bone loss in elderly women prevented by ultralow doses of parenteral 17beta-estradiol.  Am J Obstet Gynecol. 1997;  177 115-119
• 109 Prestwood K M, Kenny A M, Kleppinger A, Kulldorff M. Ultralow-dose micronized 17beta-estradiol and bone density and bone metabolism in older women: a randomized controlled trial.  JAMA. 2003;  290 1042-1048
• 110 Naessen T, Rodriguez-Macias K, Lithell H. Serum lipid profile improved by ultra-low doses of 17 beta-estradiol in elderly women.  J Clin Endocrinol Metab. 2001;  86 2757-2762
• 111 Gabrielsson J, Wallenbeck I, Birgerson L. Pharmacokinetic data on estradiol in light of the estring concept. Estradiol and estring pharmacokinetics.  Acta Obstet Gynecol Scand Suppl. 1996;  163 26-31
• 112 Henriksson L, Stjernquist M, Boquist L, Alander U, Selinus I. A comparative multicenter study of the effects of continuous low-dose estradiol released from a new vaginal ring versus estriol vaginal pessaries in postmenopausal women with symptoms and signs of urogenital atrophy.  Am J Obstet Gynecol. 1994;  171 624-632
• 113 Casper F, Petri E. Local treatment of urogenital atrophy with an estradiol-releasing vaginal ring: a comparative and a placebo-controlled multicenter study. Vaginal Ring Study Group.  Int Urogynecol J Pelvic Floor Dysfunct. 1999;  10 171-176
• 114 Lose G, Englev E. Oestradiol-releasing vaginal ring versus oestriol vaginal pessaries in the treatment of bothersome lower urinary tract symptoms.  BJOG. 2000;  107 1029-1034
• 115 Ayton R A, Darling G M, Murkies A L 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;  103 351-358
• 116 Barentsen R, van de Weijer P H, Schram J H. Continuous low dose estradiol released from a vaginal ring versus estriol vaginal cream for urogenital atrophy.  Eur J Obstet Gynecol Reprod Biol. 1997;  71 73-80
• 117 Eriksen B. A randomized, open, parallel-group study on the preventive effect of an estradiol-releasing vaginal ring (Estring) on recurrent urinary tract infections in postmenopausal women.  Am J Obstet Gynecol. 1999;  180 1072-1079
• 118 Mettler L, Olsen P G. Long-term treatment of atrophic vaginitis with low-dose oestradiol vaginal tablets.  Maturitas. 1991;  14 23-31
• 119 Rioux J E, Devlin C, Gelfand M M, Steinberg W M, Hepburn D S. 17beta-estradiol vaginal tablet versus conjugated equine estrogen vaginal cream to relieve menopausal atrophic vaginitis.  2000;  7 156-161
• 120 Manonai J, Theppisai U, Chittacharoen A. Effect and safety of 17 beta-estradiol vaginal tablet in postmenopausal women with urogenital symptoms.  J Med Assoc Thai. 2001;  84 1015-1020
• 121 Wesel S, Etienne J, Lestienne M C. Clinical, cytological and biological study of the intra-vaginal administration of oestriol (Ortho-Gynest) in post-menopausal patients.  Maturitas. 1981;  3 271-277
• 122 Rigg L A, Hermann H, Yen S S. Absorption of estrogens from vaginal creams.  N Engl J Med. 1978;  298 195-197
• 123 Heimer G M, Englund D E. Enterohepatic recirculation of oestriol studied in cholecystectomized and non-cholecystectomized menopausal women.  Ups J Med Sci. 1984;  89 107-115
• 124 Wolf H, Wandt H, Jonat W. Immunohistochemical evidence of estrogen and progesterone receptors in the female lower urinary tract and comparison with the vagina.  Gynecol Obstet Invest. 1991;  32 227-231
• 125 Pacchioni D, Revelli A, Casetta G et al.. Immunohistochemical detection of estrogen and progesterone receptors in the normal urinary bladder and in pseudomembranous trigonitis.  J Endocrinol Invest. 1992;  15 719-725
• 126 Rud T. The effects of estrogens and gestagens on the urethral pressure profile in urinary continent and stress incontinent women.  Acta Obstet Gynecol Scand. 1980;  59 265-270
• 127 Kaunitz A, Nelson A, Wysocki S, Schnare S. Frequent urination and Depo-Provera. Ask the experts.  Contracept Technol Update. 1998;  19 160-161
• 128 Paterson M E, Wade-Evans T, Sturdee D W, Thom M H, Studd J W. Endometrial disease after treatment with oestrogens and progestogens in the climacteric.  BMJ. 1980;  280 822-824
• 129 Greenblatt R B. Estrogen therapy for postmenopausal females.  N Engl J Med. 1965;  272 305-308
• 130 Nachtigall L E, Wade-Evans T, Sturdee D W, Thom M H, Studd J W. Estrogens and endometrial carcinoma [letter].  N Engl J Med. 1976;  294 848
• 131 Whitehead M I, Townsend P T, Pryse-Davies J, Ryder T A, King R J. Effects of estrogens and progestins on the biochemistry and morphology of the postmenopausal endometrium.  N Engl J Med. 1981;  305 1599-1605
• 132 Studd J WW, Thom M H, Paterson M EL, Wade-Evans T. The prevention and treatment of endometrial pathology in postmenopausal women receiving exogenous estrogens. In: Pasetto N, Paoletti R, Ambrus JL The Menopause and Postmenopause Lancaster, PA; MTP Press 1980: 127-139
• 133 Gambrell Jr R D. Cancer in the older woman: diagnosis and prevention.  Geriatrics. 1988;  43 27-36
• 134 Gambrell Jr R D, Massey F M, Castaneda T A, Ugenas A J, Ricci C A, Wright J M. Use of the progestogen challenge test to reduce the risk of endometrial cancer.  Obstet Gynecol. 1980;  55 732-738
• 135 Nachtigall L E. Clinical trial of the estradiol vaginal ring in the U.S  Maturitas. 1995;  22 S43-S47
• 136 The Writing Group for the PEPI Trial . Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial.  JAMA. 1995;  273 199-208
• 137 Suvanto-Luukkonen E, Malinen H, Sundstrom H, Penttinen J, Kauppila A. Endometrial morphology during hormone replacement therapy with estradiol gel combined to levonorgestrel-releasing intrauterine device or natural progesterone.  Acta Obstet Gynecol Scand. 1998;  77 758-763
• 138 Vilodre L C, Osorio Wender M C et al.. Endometrial response to a cyclic regimen of percutaneous 17beta-estradiol and low-dose vaginal micronized progesterone in women with mild-to-moderate hypertension.  Gynecol Endocrinol. 2003;  17 323-328
• 139 Gillet J Y, Andre G, Faguer B et al.. Induction of amenorrhea during hormone replacement therapy: optimal micronized progesterone dose. A multicenter study.  Maturitas. 1994;  19 103-115
• 140 Ross D, Pryse-Davies J, Bergeron C, Collins W P, Whitehead M I. 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;  177 937-941
• 141 Rabe T, Mueck A O, Deuringer F U, Vladescu E, Runnebaum B. Spacing-out of progestin-efficacy, tolerability and compliance of two regimens for hormonal replacement in the late postmenopause.  Gynecol Endocrinol. 1997;  11 383-392
• 142 Hirvonen E, Crona N, Wahlstrom T, Backstrom A C. Effect of an estradiol gel with monthly or quarterly progestogen on menopausal symptoms and bleeding.  Climacteric. 2000;  3 262-270
• 143 Lethaby A, Suckling J, Barlow D, Farquhar C M, Jepson R G, Roberts H. Hormone replacement therapy in postmenopausal women: endometrial hyperplasia and irregular bleeding.  Cochrane Database Syst Rev. 2004;  3 CD000402
• 144 Ettinger B, Selby J, Citron J T, Vangessel A, Ettinger V M, Hendrickson R M. Cyclic hormone replacement therapy using quarterly progestin.  Obstet Gynecol. 1994;  83 693-700
• 145 Raudaskoski T, Tapanainen J, Tomas E et al.. Intrauterine 10 microg and 20 microg levonorgestrel systems in postmenopausal women receiving oral oestrogen replacement therapy: clinical, endometrial and metabolic response.  BJOG. 2002;  109 136-144
• 146 Wren B G, McFarland K, Edwards L et al.. 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
• 147 Cooper A, Spencer C, Whitehead M I, Ross D, Barnard G J, Collins W P. Systemic absorption of progesterone from Progest cream in postmenopausal women.  Lancet. 1998;  351 1255-1256
• 148 Lewis J G, McGill H, Patton V M, Elder P A. Caution on the use of saliva measurements to monitor absorption of progesterone from transdermal creams in postmenopausal women.  Maturitas. 2002;  41 1-6
• 149 Practice Committee of the Americal Society for Reproductive Medicine . Estrogen and progestogen therapy in postmenopausal women.  Fertil Steril. 2004;  81 231-241
• 150 North American Menopause Society . Role of progestogen in hormone therapy for postmenopausal women: position statement of The North American Menopause Society.  Menopause. 2003;  10 113-132
• 151 White V E, Bennett L, Raffin S, Emmett K, Coleman M J. Use of unopposed estrogen in women with uteri: prevalence, clinical implications, and economic consequence.  Menopause. 2000;  7 123-128
• 152 Keenan N L, Franks A L, Croft J B, Scholes D, Murray E T. Vaginal estrogen creams: use patterns among a cohort of women.  J Am Geriatr Soc. 1999;  47 65-70
• 153 Parker-Pope T. Menopausal women have new options for safely taking hormone treatments.  The Wall Street Journal. Oct. 12, 2004;  D1
• 154 Utian W H, Burry K A, Archer D F et al.. Efficacy and safety of low, standard, and high dosages of an estradiol transdermal system (Esclim) compared with placebo on vasomotor symptoms in highly symptomatic menopausal patients. The Esclim Study Group.  Am J Obstet Gynecol. 1999;  181 71-79
• 155 Pickar J H, Yeh I T, Wheeler J E, Cunnane M F, Speroff L. Endometrial effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate: two-year substudy results.  Fertil Steril. 2003;  80 1234-1240
• 156 Key T J, Pike M C. The dose-effect relationship between ‘unopposed' oestrogens and endometrial mitotic rate: its central role in explaining and predicting endometrial cancer risk.  Br J Cancer. 1988;  57 205-212
• 157 Tourgeman D E, Boostanfar R, Chang L, Lu J, Stanczyk F Z, Paulson R J. Is there evidence for preferential delivery of ovarian estradiol to the endometrium?.  Fertil Steril. 2001;  75 1156-1158
• 158 Felding C, Mikkelsen A L, Clausen H V, Loft A, Larsen L G. Preoperative treatment with oestradiol in women scheduled for vaginal operation for genital prolapse. A randomised, double-blind trial.  Maturitas. 1992;  15 241-249
• 159 Gerbaldo D, Ferraiolo A, Croce S, Truini M, Capitanio G L. Endometrial morphology after 12 months of vaginal oestriol therapy in post-menopausal women.  Maturitas. 1991;  13 269-274
• 160 Weiderpass E, Baron J A, Adami H O et al.. Low-potency oestrogen and risk of endometrial cancer: a case-control study.  Lancet. 1999;  353 1824-1828
• 161 Ginsburg E S, Walsh B W, Gao X, Gleason R E, Feltmate C, Barbieri R L. The effect of acute ethanol ingestion on estrogen levels in postmenopausal women using transdermal estradiol.  J Soc Gynecol Investig. 1995;  2 26-29