Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2004 Oct 18;2004(4):CD002978.
doi: 10.1002/14651858.CD002978.pub2.

Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes

A H Maclennan  1 , J L Broadbent, S Lester, V Moore
Affiliations
Meta-Analysis

Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes

A H Maclennan et al. Cochrane Database Syst Rev. .

Abstract

Background: Hot flushes and night sweats are common symptoms experienced by menopausal women. Hormone therapy (HT), containing oestrogens alone or oestrogens together with progestogens in a cyclic or continuous regimen, is often recommended for their alleviation.

Objectives: To examine the effect of oral HT compared to placebo on these vasomotor symptoms and the risk of early onset side-effects.

Search strategy: We searched the Cochrane Menstrual Disorders Group and Subfertility Group trials register (searched May 2002). This register is based on regular searches of MEDLINE, EMBASE, CINAHL, the Cochrane Central Register of Controlled Trials (CENTRAL), PsycINFO, the handsearching of 20 relevant journals and conference proceedings, and searches of several key grey literature sources. We also contacted all relevant pharmaceutical companies, The Journal of the International Menopause Society and Climacteric.

Selection criteria: Double-blind, randomised, placebo-controlled trials of oral HT for at least three months duration.

Data collection and analysis: Study quality and outcome data were assessed independently. Random effects models were considered appropriate due to the variety of trial methodologies. The meta-analyses were explored for sensitivity to trial quality and therapy duration. Symptom frequency and severity were assessed separately, together with withdrawals and side-effects. Frequency data were analysed using the Weighted Mean Difference (WMD) between treatment and placebo outcomes. For severity data, odds ratios were estimated from the proportional odds model. From 115 references originally identified, 24 trials meeting the selection criteria were included in the review. Study participants totaled 3,329. Trial duration ranged from three months to three years.

Main results: There was a significant reduction in the weekly hot flush frequency for HT compared to placebo (WMD -17.92, 95% CI -22.86 to -12.99). This was equivalent to a 75% reduction in frequency (95% CI 64.3 to 82.3) for HT relative to placebo. Symptom severity was also significantly reduced compared to placebo (OR 0.13, 95% CI 0.07 to 0.23). Withdrawal for lack of efficacy occurred significantly more often on placebo therapy (OR 10.51, 95% CI 5.00 to 22.09). Withdrawal for adverse events, commonly breast tenderness, oedema, joint pain and psychological symptoms, was not significantly increased (OR 1.25, 95% CI 0.83 to 1.90), although the occurrence of any adverse events was significantly increased for HT (OR 1.41, 95% CI 1.00 to 1.99). In women who were randomised to placebo treatment, a 57.7% (95% CI 45.1 to 67.7) reduction in hot flushes was observed between baseline and end of study.

Reviewers' conclusions: Oral HT is highly effective in alleviating hot flushes and night sweats. Therapies purported to reduce such symptoms must be assessed in blinded trials against a placebo or a validated therapy because of the large placebo effect seen in well conducted randomised controlled trials, and also because during menopause symptoms may fluctuate and after menopause symptoms often decline. Withdrawals due to side-effects were only marginally increased in the HT groups despite the inability to tailor HT in these fixed dose trials. Comparisons of hormonal doses, product types or regimens require analysis of trials with these specific "within study" comparisons.

PubMed Disclaimer

Conflict of interest statement

Alastair MacLennan is the Co‐Editor‐in‐Chief of Climacteric, the Journal of the International Menopause Society. He has been the recipient of research grants awarded by various pharmaceutical companies for clinical trials of new products and epidemiological studies on menopause and grants for educational videos on menopause.

Update of

References

References to studies included in this review

Archer 1992 {published data only}
    1. Archer DR, Fischer LA, Rich D, Schade GH, Schwartz S, Wittoff H, et al. Estrace vs Premarin for treatment of menopausal symptoms: dosage comparison study. Advances in Therapy 1992;9(1):21‐31.
Baerug 1998 {published and unpublished data}
    1. Baerug U, Winge T, Nordland G, Faber‐Swensson E, Heldaas K, Norling B, et al. Do combinations of 1 mg estradiol and low doses of NETA effectively control menopausal symptoms?. Climacteric 1998;1:219‐28. - PubMed
Baumgardner 1978 {published data only}
    1. Baumgardner SB, Condrea H, Daane TA, Dorsey JH, Jurow HN, Shively JP, et al. Replacement estrogen therapy for menopausal vasomotor flushes. Comparison of Quinestrol and conjugated estrogens. Obstetrics and Gynecology 1978;51(4):445‐52. [MEDLINE: ] - PubMed
Bech 1998 {published data only}
    1. Bech P, Munk‐Jensen N, Obel EB, Ulrich LG, Eiken P, Pors Nielsen S. Combined versus sequential hormonal replacement therapy: a double‐blind, placebo‐controlled study on quality of life‐related outcome measures. Psychotherapy and Psychosomatics 1998;67:259‐65. [MEDLINE: ] - PubMed
    1. Obel EB, Munk‐Jensen N, Svenstrup B, Bennett P, Micic S, Henrik‐Nielsen R, et al. A two‐year double‐blind controlled study of the clinical effect of combined and sequential postmenopausal replacement therapy and steroid metabolism during treatment. Maturitas 1993;16:13‐21. [MEDLINE: ] - PubMed
Blumel 1994 {published and unpublished data}
    1. Blumel JE, Roncagliolo ME, Gramegna G, Vasquez R, Estartus AT. Double blind method of the effect of menopause symptoms, lipid profile, and endometrial thickness of continuous therapy with estradiol valerate and medroxyprogesterone acetate [Estudio doble ciego del efecto sobre la sintomatologia menopausica, et perfil lipidico y el grosor endometrial de una terapia continua de valerato de estradiol mas acetato de medroxiprogesterona]. Revista Chilena de Obstetricia y Ginecologia 1994;59(5):354‐60. - PubMed
Campbell 1976 {published data only}
    1. Campbell S. Double blind psychometric studies on the effects of natural estrogens on post‐menopausal women. In: Campbell S editor(s). The Management of the Menopause and Post Menopausal Years. Lancaster: MTP, 1976.
    1. Campbell S, Whitehead M. Oestrogen therapy and the menopausal syndrome. Clinics in Obstetrics and Gynecology 1977;4(1):31‐46. [MEDLINE: ] - PubMed
Chung 1996 {published and unpublished data}
    1. Chung TKH, Yip SK, Lam P, Chang AMZ, Haines CJ. A randomized, double‐blind, placebo‐controlled, crossover study on the effect of oral oestradiol on acute menopausal symptoms. Maturitas 1996;25:115‐23. [MEDLINE: ] - PubMed
Conard 1995 {published and unpublished data}
    1. Conard J, Basdevant A, Thomas J‐L, Ochsenbein E, Denis C, Guyene TT, et al. Cardiovascular risk factors and combined estrogen‐progestin replacement therapy: a placebo‐controlled study with nomegestrol acetate and estradiol. Fertility and Sterility 1995;64(5):957‐62. [MEDLINE: ] - PubMed
Coope 1975 {published and unpublished data}
    1. Coope J. Double blind cross‐over study of estrogen replacement therapy. In: Campbell S editor(s). The Management of the Menopause and Post‐Menopausal Years. Lancaster: MTP, 1976.
    1. Coope J, Thomson JM, Poller L. Effects of "natural oestrogen" replacement therapy on menopausal symptoms and blood clotting. British Medical Journal 1975;4(5989):139‐43. [MEDLINE: ] - PMC - PubMed
Coope 1981 {published and unpublished data}
    1. Coope J. Is oestrogen therapy effective in the treatment of menopausal depression?. Journal of the Royal College of General Practitioners 1981;31(224):134‐40. [MEDLINE: ] - PMC - PubMed
    1. Poller L, Coope J. A double‐blind cross‐over study of piperazine oestrone sulphate and placebo with coagulation studies. British Journal of Obstetrics and Gynaecology 1980;87(8):718‐25. [MEDLINE: ] - PubMed
Davidsen 1974 {published data only}
    1. Davidsen PCB, Secher HJ, Pedersen GT, Christennnsen N. Cyclical therapy with oestradiol valerale/norgestrel at the menopause. Report of a double‐blind investigation [Sekvensterapi med ostradiolvalerat/norgestrel i klimakteriet]. Ugeskrift for Laeger 1974;136:1805‐8. - PubMed
Dennerstein 1978 {published data only}
    1. Dennerstein L, Burrows GD, Hyman GJ, Sharpe K. Hormone therapy and affect. Maturitas 1979;1(4):247‐59. [MEDLINE: ] - PubMed
    1. Dennerstein L, Fotherby K, Burrows GD, Senior J, Wood C. Hormone replacement therapy at the menopause. Double blind controlled study of women's preferences. Australian and New Zealand Journal of Obstetrics and Gynaecology 1978;18:139‐43.
    1. Dennerstein LL, Burrows GD, Hyman G. Menopausal hot flushes: a double blind comparison of placebo, ethinyl oestradiol and norgestrel. British Journal of Obstetrics and Gynaecology 1978;85(11):852‐6. [MEDLINE: ] - PubMed
Derman 1995 {published data only}
    1. Derman RJ, Dawood MY, Stone S. Quality of life during sequential hormone replacement therapy ‐ a placebo controlled study. Internationa Journal of Fertility and Menopausal Studies 1995;40(2):73‐8. [MEDLINE: ] - PubMed
Hagen 1982 {published data only}
    1. Christiansen C, Christensen MS, McNair P, Hagen C, Stocklund K, Transbol IB. Prevention of early postmenopausal bone loss: controlled 2‐year study in 315 normal females. European Journal of Clinical Investigation 1980;10(4):273‐9. [MEDLINE: ] - PubMed
    1. Hagen C, Christensen M, Christiansen C, Stocklund K‐E, Transbol I. Effects of two years' estrogen‐gestagen replacement on climacteric symptoms and gonadotropins in the early postmenopausal period. Acta Obstetrica et Gyanecologica Scandinavica 1982;61(3):237‐41. [MEDLINE: ] - PubMed
Jensen J 1983 {published data only}
    1. Christensen M, Hagen C, Christiansen C, Transbol I. Dose‐response evaluation of cyclic estrogen/gestagen in postmenopausal women: Placebo‐controlled trial of its gynecologic and metabolic actions. American Journal of Obstetrics and Gynecology 1982;144(8):873‐9. [MEDLINE: ] - PubMed
    1. Jensen J, Christiansen C. Dose‐response and withdrawal effects on climacteric symptoms after hormonal replacement therapy. A placebo‐controlled therapeutic trial. Maturitas 1983;5:125‐33. [MEDLINE: ] - PubMed
Jensen P 1987 {published data only}
    1. Christiansen C, Nilas L, Riis BJ, Rodbro P, Deftos L. Uncoupling of bone formation and resorption by combined osetrogen and progestagen therapy in postmenopausal osteoporosis. Lancet 1985;2:800‐1. [MEDLINE: ] - PubMed
    1. Jensen J, Riis BJ, Christiansen C. Cyproterone acetate, an alternative progestogen in postmenopausl hormone replacement therapy? Effects on serum lipids and lipoproteins. British Journal of Obstetrics and Gynaecology 1987;94:136‐41. - PubMed
    1. Jensen PB, Jensen J, Riis BJ, Rodbro P, Strom V, Christiansen C. Climacteric symptoms after oral and percutaneous hormone replacement therapy. Maturitas 1987;9(3):207‐15. [MEDLINE: ] - PubMed
Marslew 1992 {published data only}
    1. Marlsew U, Overgaard K, Riis BJ, Christiansen C. Two new combinations of estrogen and progestogen for prevention of postmenopausal bone loss: long‐term effects on bone, calcium and lipid metabolism, climacteric symptoms and bleeding. Obsterics and Gynecology 1992;79(2):202‐9. [MEDLINE: ] - PubMed
    1. Marslew U, Riis B, Christiansen C. Progestogens: therapeutic and adverse effects in early post‐menopausal women. Maturitas 1991;13(1):7‐16. [MEDLINE: ] - PubMed
Martin 1971 {published data only}
    1. Martin PL, Burnier AM, Segre EJ, Huix FJ. Graded sequential therapy in the menopause: a double‐blind study. American Journal of Obstetrics and Gynecology 1971;111(2):178‐6. - PubMed
Notelovitz 2000a {published and unpublished data}
    1. Notelovitz M, Arce JC, Nanavate N, Huang WC. One milligram 17 beta‐estradiol is the optimal dose for treatment of moderate to severe vasomotor symptoms: a dose‐response study (Abstract P‐3, ninth annual NAMS meeting). Menopause. 1998; Vol. 5:251.
    1. Notelovitz M, Lenihan JP, McDermott M, Kerber IJ, Nanavati N, Arce J‐C. Initial 17b‐estradiol dose for treating vasomotor symptoms. Obstetrics and Gynecology 2000;95(5):726‐31. - PubMed
Paterson 1982a {published and unpublished data}
    1. Paterson ME. A randomised, double‐blind, cross‐over study into the effect of sequential mestranol and norethisterone on climacteric symptoms and biochemical parameters. Maturitas 1982;4(2):83‐94. [MEDLINE: ] - PubMed
PEPI 1998 {published and unpublished data}
    1. Espeland MA, Bush TL, Mebane‐Sims I, Stefanick ML, Johnson S, Sherwin R et al. PEPI Trial Investigators. Rationale, design and conduct of the PEPI trial. Postmenopausal Estrogen/Progestin Interventions. Controlled Clinical Trials 1995;16(4 Suppl):3S‐19S. [MEDLINE: ] - PubMed
    1. Greendale GA, Reboussin BA, Hogan P, Barnabel VM, Shumaker S, Johnson S, et al. Symptom relief and side effects of postmenopausal hormones: results from the Postmenopausal Estrogen/Progestin Inverventions Trial. Obsterics and Gynecology 1998;92(6):982‐8. [MEDLINE: ] - PubMed
    1. Miller VT, Byington RL, Espeland MA, Langer R, Marcus R, et al. Baseline characteristics of the PEPI participants. Postmenopausal Estrogen/Progestin Interventions. Controlled Clinical Trials 1995;16(4 Suppl):54S‐65S. [MEDLINE: ] - PubMed
    1. The Writing Group for the PEPI Trial. Effects of estrogenor estrogen/progestin regimes on heart disease risk factors in postmenopausal women. JAMA: Journal of the American Medical Association 1995;273:199‐208. [MEDLINE: ] - PubMed
Symons 2000 Study 1 {published and unpublished data}
    1. Symons J, Kempfert N, Speroff L for the FemHRT Study investigators. Vaginal bleeding in postmenopausal women taking low‐dose norethindrone acetate and ethinyl estradiol combinations. Obstetrics and Gynecology 2000;96(3):366‐72. - PubMed
Symons 2000 Study 2 {published and unpublished data}
    1. Symons J, Kempfert N, Speroff L for the FemHRT Study investigators. Vaginal bleeding in postmenopausal women taking low‐dose norethindrone acetate and ethinyl estradiol combinations. Obstetrics and Gynecology 2000;96(3):366‐72. - PubMed
Viklylaeva 1997 {published and unpublished data}
    1. Vikhlyaeva EM, Zaidiieva YaZ, Lobova TA, Shishkina AV, Larsen S. Trisequens in perimenopausal women with climacteric syndrome: a randomised double‐blind trial. Acta Obstetrica et Gynecologica Scandanavica. 1997; Vol. 76, issue 167S:58 (abstract P86.19).

References to studies excluded from this review

Agnusdei 1995 {published data only}
    1. Agnusdei A, Gennari C, Bufalino L. Prevention of early postmenopausal bone loss using low doses of conjugated estrogens and the non‐hormonal, bone‐active drug Iprilflavone. Osteoporosis International 1995;5(6):462‐6. [MEDLINE: ] - PubMed
Al‐Azzawi 1999 {published data only}
    1. Al‐Azzawi F, Wahab M, Habiba M, Akkad A, Mason T. Continuous combined hormone replacement therapy compared with tibolone. Obsterics and Gynecology 1999;93(2):258‐64. [MEDLINE: ] - PubMed
Archer 1999 {published data only}
    1. Archer DF, Furst K, Tipping D, Dain MP, Vandepol C. A randomized comparison of continuous combined transdermal delivery of estradiol‐norethindrone acetate and estradiol alone for menopause. CombiPatch Study Group. Obsterics and Gynecology 1999;94(4):498‐503. [MEDLINE: ] - PubMed
Aslaksen 1982 {published data only}
    1. Aslaksen K, Frankendal B. Effect of oral medroxyprogesterone acetate on menopausal symptoms in patients with endometrial carcinoma. Acta Obstetrica et Gyanecologica Scandinavica 1982;61(5):423‐8. [MEDLINE: ] - PubMed
Aylward 1974 {published data only}
    1. Aylward M, Holly F, Parker RJ. An evaluation of clinical response to piperazine oestrone sulphate ('Harmogen') in menopausal patients. Current Medical Research and Opinion 1974;2(7):417‐23. [MEDLINE: ] - PubMed
Bakke 1965 {published data only}
    1. Bakke JL. A double‐blind study of a progestin‐estrogen combination in the management of the menopause. Pacific Medicine & Surgery 1965;May‐June:200‐5.
Barret‐Connor 1999 {published data only}
    1. Barrett‐Connor E, Young R, Notelovitz M, Sullivan J, Wiita B, Yan HM, et al. A two‐year, double‐blind comparison of estrogen‐androgen and conjugated estrogens in surgically menopausal women. Effects on bone mineral density, symptoms and lipid profile. Journal of Reproductive Medicine 1999;44(12):1012‐20. [MEDLINE: ] - PubMed
Blahey 1953 {published data only}
    1. Blahey PR. Double‐blind and prolonged constant quinestrol therapy in the menopausal patient. Current Therapeutic Research, Clinical & Experimental 1969;11(12):755‐62. [MEDLINE: ] - PubMed
Blatt 1953 {published data only}
    1. Blatt MH, Wiesbader H, Kupperman HS. Vitamin E and climacteric syndrome. A.M.A. Archives of Internal Medicine 1953:792‐9. - PubMed
Cano 1999 {published data only}
    1. Cano A, Tarin JJ, Duenas JL. Two‐year prospective, randomized trial comparing an innovative twice‐a week progestin regimen with a continuous combined regimen as postmenopausal therapy. Fertility and Sterility 1999;71(1):129‐36. [MEDLINE: ] - PubMed
CHART 1996 {published data only}
    1. Speroff L, Rowan J, Symons J, Genant H, Wilborn W. The comparative effect on bone density, endometrium, and lipids of continuous hormones as replacement therapy (CHART study). A randomized controlled trial. JAMA: Journal of the American Medical Association 1996;276(17):1397‐404. [MEDLINE: ] - PubMed
Cheng 1993 {published data only}
    1. Cheng GJ, Liu JL, Zhang Q, Fan W, Ye HF, Wang ZQ, et al. Nylestriol replacement therapy in postmenopausal women. A three‐year prospective study. Chinese Medical Journal 1993;106(12):911‐6. - PubMed
Cooper 1974 {published data only}
    1. Cooper W, Marnie M, Daw E. A clinical trial of piperazine oestrone sulphate (Harmogen) in the treatment of menopausal symptoms. Current Medical Research and Opinion 1974;2(5):260‐3. [MEDLINE: ] - PubMed
Crona 1988 {published data only}
    1. Crona N, Samsioe G, Lindberg UB, Silfverstolpe G. Treatment of climacteric complaints with Org OD 14: a comparative study with oestradiol valerate and placebo. Maturitas 1988;9(4):303‐8. [MEDLINE: ] - PubMed
Dennerstein 1980 {published data only}
    1. Dennerstein L, Fotherby K, Burrows GD, Laby B, Wood C. Plasma levels of ethinyl oestradiol and norgestrel during hormone replacement therapy. Maturitas 1980;2(2):147‐54. [MEDLINE: ] - PubMed
Ditkoff 1991 {published data only}
    1. Ditkoff EC, Crary WG, Cristo M, Lobo RA. Estrogen improves psychological function in asymptomatic postmenopausal women. Obsterics and Gynecology 1991;78(6):991‐5. [MEDLINE: ] - PubMed
Fedor‐Freybergh 1977 {published data only}
    1. Fedor‐Freybergh P. The influence of oestrogens on the wellbeing and mental performance in climacteric and postmenopausal women. Acta Obstetrica et Gyanecologica Scandinavica 1977;64(Suppl):1‐91. [MEDLINE: ] - PubMed
Fritsch 1997 {published data only}
    1. Fritsch H, Fritsch W, Julius U, Rehak E, Wieczorek A, Hanefeld M. Postmenopausal hormone substitution and its effects on the climacteric syndrome, body weight and blood pressure. Zentralblatt fur Gynakologie 1997;119(3):128‐32. [MEDLINE: ] - PubMed
Furuhjelm 1976 {published data only}
    1. Furuhjelm M, Fedor‐Freybergh P. The influence of estrogens on the psyche in climacteric and post‐menopausal women. 1st International Congress on the Menopause. La Grande Motte, France. 1976:84‐93.
Furuhjelm 1984 {published data only}
    1. Furuhjelm M, Karlgren E, Carlstrom K. The effect of estrogen therapy on somatic and psychical symptoms in postmenopausal women. Acta Obstetrica et Gyanecologica Scandinavica 1984;63:655‐61. - PubMed
Geola 1980 {published data only}
    1. Geola FL, Frumar AM, Tataryn IV, Lu KH, Hershman JM, Eggena P, Sambhi MP, Judd HL. Biological effects of various doses of conjugated equine estrogens in postmenopausal women. Journal of Clinical Endocrinology and Metabolism 1980;51(3):620‐5. [MEDLINE: ] - PubMed
Greenblatt 1959 {published data only}
    1. Greenblatt RB, Barfield WE, Garner JF, Calk GL, Harrod JP. Evaluation of an estrogen, androgen, estrogen‐androgen combination, and a placebo in the treatment of the menopause. Journal of Clinical Endocrinology 1950;10:1547‐58. - PubMed
Hailes 1981 {published data only}
    1. Hailes JD, Nelson JB, Schneider M, Rennie GC, Burger HG. Conjugated equine oestrogen versus placebo in the management of menopausal symptoms. Medical Journal of Australia 1981;2(7):340‐2. [MEDLINE: ] - PubMed
Hammar 1998 {published data only}
    1. Hammer M, Christau S, Nathorst‐Boos J, 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. British Journal of Obstetrics and Gynaecology 1998;105(8):904‐1. [MEDLINE: ] - PubMed
Hammar 1999 {published data only}
    1. Hammar M, Ekblad S, Lonnberg B, Berg G, Lindgren R, Wyon Y. Postmenopausal women without previous or current vasomotor symptoms do not flush after abruptly abandoning estrogen replacement therapy. Maturitas 1999;31(2):117‐22. [MEDLINE: ] - PubMed
Hovic 1989 {published data only}
    1. Hovik P, Sundsbak HP, Gaasemyr M, Sandvik L. Comparison of continuous and sequential oestrogen‐progestogen treatment in women with climacteric symptoms. Maturitas 1989;11(1):75‐82. [MEDLINE: ] - PubMed
Jarvinen 1971 {published data only}
    1. Jarvinen PA, Kokkonen J, Ryhanen P. Oestriol succinate in the treatment of climacteric women (a double‐blind trial). Acta Obstetricia et Gynecologica Scandinavica 1971;Supplement 50:26. - PubMed
Jones 1977 {published data only}
    1. Jones MM, Marshall DH, Nordin BEC. Quantitation of menopausal symptomatology and its response to ethinyl oestradiol and piperazine oestrone sulphate. Current Medical Research and Opinion 1977;4(Suppl 3):12‐20.
Khoo 1998 {published data only}
    1. Khoo SK, Coglan MJ, Wright GR, DeVoss KN, Battistutta D. Hormone therapy in women in the menopause transition. Randomised, double‐blind, placebo‐controlled trial of effects on body weight, blood pressure, lipoprotein levels, antithrombin III activity, and the endometrium. Medical Journal of Australia 1998;268(5):216‐20. [MEDLINE: ] - PubMed
Kirkham 1991 {published data only}
    1. Kirkham C, Hahn PM, Vugt DA, Carmichael JA, Reid RL. A randomized, double‐blind, placebo‐ controlled, cross‐over trial to assess the side effects of medroxyprogesterone acetate in hormone replacement therapy.. Obsterics and Gynecology 1991;78(1):93‐7. [MEDLINE: ] - PubMed
Klaiber 1996 {published data only}
    1. Klaiber EL, Broverman DM, Vogel W, Peterson L, Snyder MB. Individual differences in changes in mood and platelet monoamine oxidase (MAO) activity during hormonal replacement therapy in menopausal women. Psychoneuroendocrinology 1996;21(7):575‐92. [MEDLINE: ] - PubMed
Kupperman 1953 {published data only}
    1. Kupperman HS, Blatt MHG, Wiesbader H, Filler W. Comparative clinical evaluation of estrogenic preparations by the menopausal amd amenorrheal indices. Journal of Clinical Endocrinology 1953;13:688‐703. - PubMed
Lagrelius 1986 {published data only}
    1. Lagrelius A, Fredricsson B, Hirt M, Weintraub L. Clinical experience with a low‐dose combination of estradiol valerate and levonorgestrel. Double‐blind comparative study between SH D 386 F and Cyclabil. Effects on symptoms, lipids and endometrial condition. Acta Obstetricia et Gynecologica Scandinavica ‐ Supplement 1986;134:97‐101. [MEDLINE: ] - PubMed
Leonetti 1999 {published data only}
    1. Leonetti HB, Longo S, Anasti JN. Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss. Obsterics and Gynecology 1999;94(2):225‐8. [MEDLINE: ] - PubMed
Lind 1979 {published data only}
    1. Lind T, Cameron EC, Hunter WM, Leon C, Moran PF, Oxley A, et al. A prospective, controlled trial of six forms of hormone replacement therapy given to postmenopausal women. British Journal of Obstetrics and Gynaecology 1979;86(Suppl 3):1‐29. [MEDLINE: ] - PubMed
Martin 1972 {published data only}
    1. Martin PL, Burnier AM, Greaney MO. Oral menopausal therapy using 17‐ micronized estradiol. A preliminary study of effectiveness, tolerance and patient preference. Obsterics and Gynecology 1972;39(5):771‐4. [MEDLINE: ] - PubMed
Mattsson 1999 Study1 {published data only}
    1. Mattsson LA. Clinical experience with continuous combined transdermal hormone replacement therapy. Menopause 1999;6(1):25‐9.
Mattsson 1999 Study2 {published data only}
    1. Mattsson LA. Clinical experience with continuous combined transdermal hormone replacement therapy. Menopause 1999;6(1):25‐9.
Morrison 1980 {published data only}
    1. Morrison JC, Martin DC, Blair RA, Anderson GD, Kincheloe BW, Bates GW, et al. The use of medroxyprogesterone acetate for relief of climacteric symptoms. American Journal of Obstetrics and Gynecology 1980;138(1):99‐104. [MEDLINE: ] - PubMed
Myers 1990 {published data only}
    1. Myers LS, Dixen J, Morrissette D, Carmichael M, Davidson JM. Effects of estrogen, androgen, and progestin on sexual psychophysiology and behavior in postmenopausal women. Journal of Clinical Endocrinology and Metabolism 1990;70(4):1124‐31. [MEDLINE: ] - PubMed
Nand 1998 {published data only}
    1. Nand SL, Webster MA, Baber R, Heller GZ. Ogen/Provera Study Group. Menopausal symptom control and side‐effects on continuous estrone sulfate and three doses of medroxyprogesterone acetate. Climacteric 1998;1:211‐8. - PubMed
    1. Nand SL, Wren BG. Continuous oestrone sulphate and medroxyprogesterone acetate hormone replacement therapy ‐ a study of bone density over 2 years. Proceedings of the 8th International Congress on the Menopause. Sydney, Australia, November 1996:Abstract S17.
Natchigall 1979 {published data only}
    1. Nachtigall LE, Nachtigall RH, Nachtigall RD, Beckman EM. Estrogen replacement therapy II: a prospective study in the relationship to carcinoma and cardiovascular and metabolic problems. Obstetrics and Gynecology 1979;54(1):74‐9. - PubMed
Nordin 1980 {published data only}
    1. Nordin BEC, Jones MM, Crilly RG, Marshall DH, Brooke R. A placebo‐controlled trial of ethinyl oestradiol and norethisterone in climacteric women. Maturitas 1980;2(3):247‐51. [MEDLINE: ] - PubMed
Notelovitz 2000b {published data only}
    1. Notelovitz M, Cassel D, Hille D, Furst KW, Dain MP, VandePol C, et al. Efficacy of continuous sequential transdermal estradiol and norethindrone acetate in relieving vasomotor symptoms associated with menopause. American Journal of Obstetrics and Gynecology 2000;182(1 Pt 1):7‐12. [MEDLINE: ] - PubMed
Paterson 1982b {published data only}
    1. Paterson ME. A randomized double‐blind cross‐over trial into the effect of norethisterone on climacteric symptoms and biochemical profiles. British Journal of Obstetrics and Gynaecology 1982;89(6):464‐72. [MEDLINE: ] - PubMed
Pattison 1989 {published data only}
    1. Pattison NS, Uptin T, Knox B, France J. Transdermal oestrogen for postmenopausal women: a double blind crossover comparative study with ethinyl oestradiol. Australian and New Zealand Journal of Obstetrics and Gynaecology 1989;29(1):62‐5. [MEDLINE: ] - PubMed
Place 1985 {published data only}
    1. Place VA, Powers M, Darley PE, Schenkel L, Good WR. A double‐blind comparative study of Estraderm and Premarin in the amelioration of postmenopausal symptoms. American Journal of Obstetrics and Gynecology 1985;152(8):1092‐9. [MEDLINE: ] - PubMed
Polo‐Kantola 1998 {published data only}
    1. Polo‐Kantola P, Erkkola R, Helenius H, Irjala K, Polo O. When does estrogen replacement therapy improve sleep quality?. American Journal of Obstetrics and Gynecology 1998;178(5):1002‐9. [MEDLINE: ] - PubMed
    1. Polo‐Kantola P, Portin R, Polo O, Helenius H, Irjala K, Erkkola R. The effect of short‐term estrogen replacement therapy on cognition: a randomized, double‐blind, cross‐over trial in postmenopausal women. Obstetrics and Gynecology 1998;91(3):459‐66. [MEDLINE: ] - PubMed
Pratt 1937 {published data only}
    1. Pratt JP, Thomas WL. The endocrine treatment of menopausal phenomena. JAMA: Journal of the American Medical Association 1937;109:1875‐80.
Rauramo 1975 {published data only}
    1. Rauramo L, Lagerspetz K, Engblom P, Punnonen R. The effect of castration and peroral estrogen therapy on some psychological functions. Frontiers of Hormone Research 1975;3:94‐104. - PubMed
Rohr 1999 {published data only}
    1. Rohr UD, Nauert C, Stehle B. 17beta‐estradiol delivered by three different matrix patches 50 microg/day: a three way cross‐over study in 21 postmenopausal women. Maturitas 1999;33(1):45‐58. [MEDLINE: ] - PubMed
Saarikoski 1981 {published data only}
    1. Saarikoski S, Niemela A, Jokela H, Pystynen P. Effect of oestriol succinate on serum lipids. Maturitas 1981;3(3‐4):235‐9. [MEDLINE: ] - PubMed
Schiff 1979 {published data only}
    1. Regestein QR, Schiff I, Tulchinsky D, Ryan K. Relationships among estrogen‐induced psychophysiological changes in hypogonadal women. Psychosomatic Medicine 1981;43(2):147‐55. [MEDLINE: ] - PubMed
    1. Schiff I, Regestein Q, Tulchinsky D, Ryan KJ. Effects of estrogens on sleep and psychological state of hypogonadal women. JAMA: Journal of the American Medical Association 1979;242(22):2405‐7. [MEDLINE: ] - PubMed
Schubert 1977 {published data only}
    1. Schubert L, Sansa G, Nencioni T, Polvani F, Pruneri C, Sostero M, et al. The use of cyclofenil in menopausal women. Acta Europaea Fertilitatis 1977;8(1):83‐110. [MEDLINE: ] - PubMed
Shargil 1985 {published data only}
    1. Shargil AA. Hormone replacement therapy in perimenopausal women with a triphasic contraceptive compound: a three‐year prospective study. International Journal of Fertility 1985;30(1):15‐28. [MEDLINE: ] - PubMed
Sheffrey 1969 {published data only}
    1. Sheffery JB, Wilson TA, Walsh JC. Double‐blind, cross‐over study comparing chlordiazepoxide, conjugated estrogens, combined chlordiazepoxide and conjugated estrogens, and placebo in the treatment of the menopause. Medical Annals of the District of Columbia 1969;38(8):433‐6. - PubMed
Sherwin 1989 {published data only}
    1. Sherwin BB, Gelfand MM. A prospective one‐year study of estrogen and progestin in postmenopausal women: effects on clinical symptoms and lipoprotein lipids. Obsterics and Gynecology 1989;73(5 Pt 1):759‐66. [MEDLINE: ] - PubMed
Spencer 1999 {published data only}
    1. Spencer C, Crook D, Ross D, Cooper A, Whitehead M, Stevenson J. A randomised comparison of the effects of oral versus transdermal 17beta‐oestradiol, each combined with sequential oral norethisterone acetate, on serum lipoprotein levels. British Journal of Obstetrics and Gynaecology 1999;106(9):948‐53. [MEDLINE: ] - PubMed
Strickler 1977 {published data only}
    1. Strickler RC, Borth R, Cecutti A, Cookson BA, Harper JA, Potvin R, et al. The role of oestrogen replacement in the climacteric syndrome. Psychological Medicine 1977;7(4):631‐9. [MEDLINE: ] - PubMed
    1. Strickler RC, Borth R, Woodlever CA. The climacteric syndrome: an estrogen replacement dilemma. Canadian Medical Association Journal 1977;116(6):586‐7. [MEDLINE: ] - PMC - PubMed
    1. Strickler RC, Woolever CA. Estrogen replacement therapy in peri‐ and postmenopausal women. Gynecologic and Obstetric Investigation. 1976; Vol. 7:105‐6.
Studd 1995 {published data only}
    1. Studd JW, MacCarthy K, Zamblera D, Dain MP. Efficacy and safety of Menorest (50 mikrog/day) compared to Premarin 0.625 mg in the treatment of menopausal symptoms and the prevention of bone loss, in menopausal women. A single‐center, comparative, randomized, double‐blind, double‐dummy study. Scandinavian Journal of Rheumatology Supplement 1996;103:89‐90. [MEDLINE: ] - PubMed
    1. Studd JW, McCarthy K, Zamblera D, Burger HG, Silberberg S, Wren B, et al. Efficacy and tolerance of Menorest compared to Premarin in the treatment of postmenopausal women. A randomised, multicentre, double‐blind, double‐dummy study. Maturitas 1995;22(2):105‐14. [MEDLINE: ] - PubMed
Sulak 1999 {published data only}
    1. Corson SL, Richart RM, Caubel P, Lim P. Effect of a unique constant‐estrogen, pulsed‐progestin hormone replacement therapy containing 17beta‐estradiol and norgestimate on endometrial histology. International Journal of Fertility & Womens Medicine 1999;44(6):279‐85. [MEDLINE: ] - PubMed
    1. Sulak PJ, Caubel P, Lane R. Efficacy and safety of a constant‐estrogen, pulsed‐progestin regimen in hormone replacement therapy. International Journal of Fertility & Womens Medicine 1999;44(6):286‐96. [MEDLINE: ] - PubMed
Taga 1999 {published data only}
    1. Taga M, Tanaka K, Honjo H, Miyake A, Aono T, Ohoshima K, et al. The efficacy of several doses of oral 17b‐estradiol for the treatment of vasomotor symptoms in Japanese women. International Menopause Society, Conference Poster, Yokohama Japan. 1999.
Thomson 1976 {published data only}
    1. Thomson J. Double blind study on the effect of oestrogen on sleep, anxiety and depression in perimenopausal women: Preliminary results. Proceedings of the Royal Society of Medicine 1976;68:829‐30. - PMC - PubMed
Utian 1971 {published data only}
    1. Utian WH. The mental tonic effect of oestrogens administered to oophorectomized females. South African Medical Journal 1972;46(3):1079‐82. [MEDLINE: ] - PubMed
    1. Utian WH. The true clinical features of postmenopause and oophorectomy and their response to oestrogen therapy. South African Medical Journal 1971;46:732‐7. - PubMed
Volpe 1986 {published data only}
    1. 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;84(4):327‐34. [MEDLINE: ] - PubMed

References to studies awaiting assessment

Ferguson 1981 {published data only}
    1. Ferguson MM, Carter J, Boyle P, Hart D M, Lindsay R. Oral complaints related to climacteric symptoms in oophorectomized women. Journal of the Royal Society of Medicine 1981;74:492‐8. - PMC - PubMed
Hackman 1977 {published and unpublished data}
    1. Hackman BW, Galbraith D. Six month pilot study of oestrogen replacement therapy with piperazine oestrone sulphate and its effect on memory. Current Medical Research and Opinion 1977;4(3):21‐28. - PubMed
Notelovitz 1990 {published data only}
    1. Notelovitz M, Katz‐Karp S, Jennings D, Lancaster J, Green EM, Stroll BS, et al. Effect of cyclic estrone sulfate treatment on lipid profiles of postmenopausal women with elevated cholesterol levels. Obsterics and Gynecology 1990;76(1):65‐70. [MEDLINE: ] - PubMed
Notelovitz 1998b {published data only}
    1. Notelovitz M, Arce J‐C, Nanavati M, Huang WC. Norethindrone acetate at 0.5mg dose adds to the efficacy of 1mg 17 beta estradiol on vasomotor symptom relief (Abstract P‐2, ninth annual meeting of NAMS). Menopause. 1998; Vol. 5:250.
Rebar 2000 {published data only}
    1. Rebar RW, Trabal J, Mortola J. Low‐dose esterified estrogens (0.3 mg/day): long term and short‐term effects on menopausal symptoms and quality of life in postmenopausal women. Climacteric 2000;3:1‐7. - PubMed
Simon 1999 {published data only}
    1. Simon J, Klaiber E, Wiita B, Bowen A, Yang HM. Differential effects of estrogen‐androgen and estrogen‐only therapy on vasomotor symptoms, gonadotropin secretion, and endogenous androgen bioavailability in postmenopausal women. Menopause 1999;6(2):138‐46. [MEDLINE: ] - PubMed
Studd 1999 {published data only}
    1. Studd J, Pornel B, Marton I, Bringer J, Varin C, Tsouderos Y, et al. Efficacy and acceptability of intranasal 17b‐oestradiol for menopausal symptoms: randomised dose‐response study. Lancet 1999;353:1574‐8. - PubMed

Additional references

Baujat 1999
    1. Baujat B, Mahe C, Guerin S, Pignon J‐P. Detection of outlying and influential trials: a graphical method to explore heterogeneity in meta‐analysis. VII Cochrane Colloquium. The best evidence for health care: the role of the Cochrane Collaboration. Rome, October 5‐9, 1999.
Freedman 1995
    1. Freedman RR, Norton D, Woodward S, Cornelissen G. Core body temperature and circadian rhythm of hot flashes in menopausal women. Journal of Clinical Endocrinology and Metabolism 1995;80(8):2354‐8. [MEDLINE: ] - PubMed
Helton 1977
    1. Helton ED, Goldzieher JW. Pharmacokinetics of ethynyl estrogens: a review. Contraception 1981;15(3):255‐84. [MEDLINE: ] - PubMed
Lethaby 2004
    1. Lethaby A, Suckling J, Barlow D, Farquhar CM, Jepson RG, Roberts H. Hormone replacement therapy in postmenopausal women: endometrial hyperplasia and irregular bleeding. Cochrane Database of Systematic Reviews 2004, Issue 3. - PubMed
MacLennan 1993
    1. MacLennan AH, MacLennan A, Wenzel S, Chambers H, Eckert K. Continuous low‐dose oestrogen and progestogen hormone replacement therapy: a randomised trial. Medical Journal of Australia 1993;159(2):102‐6. [MEDLINE: ] - PubMed
Mohyi 1997
    1. Mohyi D, Tabassi K, Simon J. Differential diagnosis of hot flashes. Maturitas 1997;27(3):203‐14. [MEDLINE: ] - PubMed
Nachtigall 1999
    1. Nachtigall LE, Nachtigall LB. The effects of isoflavones derived from red clover on vasomotor symptoms and endometrial thickness. Proceedings of the Ninth International Menopause Society World Congress on the Menopause. Climacteric. 1999; Vol. 2 Suppl 1:128.
Norman 1999
    1. Norman RJ, Flight IHK, Rees MCP. Oestrogen and progestogen hormone replacement therapy for peri‐menopausal and post‐menopausal women: weight and body fat distribution. Cochrane Database of Systematic Reviews 1999, Issue 1. - PubMed
Porter 1996
    1. Porter M, Penney GC, Russell D, Russell E, Templeton A. A population based survey of women's experience of the menopause. British Journal of Obstetrics and Gynaecology 1996;103(10):1025‐8. [MEDLINE: ] - PubMed
Sturdee 1988
    1. Sturdee D, Brincat M. The hot flush. In: Studd JWW, Whitehead MI editor(s). The Menopause. London: Blackwell Scientific, 1988.
Sturdee 2003
    1. Sturdee DW, MacLennan AH. HT or HRT that is the question? Time to change the terminology of hormone therapy. Climacteric 2003;6(1):1. - PubMed
Suckling 2004
    1. Suckling J, Lethaby A, Kennedy R. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database of Systematic Reviews 2004, Issue 3.
Thompson 1999
    1. Thompson SG, Sharp S. Explaining heterogeneity in meta‐analysis: a comparison of methods. Statistics in Medicine 1999;18:2693‐708. [MEDLINE: ] - PubMed
WHI 2002
    1. Writing group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA: Journal of the American Medical Association 2002;288:321‐33. - PubMed
WHI 2004
    1. The Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. The Women's Health Initiative Randomised Controlled Trial. JAMA: Journal of the American Medical Association 2004;294:1701‐12. - PubMed
Whitehead 1999a
    1. Whitehead A, Bailey AJ, Elbourne D. Combining summaries of binary outcomes with continuous outcomes in a meta‐analysis. Journal of Biopharmaceutical Statistics 1999;9(1):1‐16. [MEDLINE: ] - PubMed
Whitehead 1999b
    1. Whitehead A. Personal Communication 1999.

LinkOut - more resources