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Meta-Analysis
. 2012 Aug 15;2012(8):CD000402.
doi: 10.1002/14651858.CD000402.pub4.

Hormone therapy in postmenopausal women and risk of endometrial hyperplasia

Susan Furness  1 , Helen Roberts, Jane Marjoribanks, Anne Lethaby
Affiliations
Meta-Analysis

Hormone therapy in postmenopausal women and risk of endometrial hyperplasia

Susan Furness et al. Cochrane Database Syst Rev. .

Abstract

Background: Reduced circulating estrogen levels around the time of the menopause can induce unacceptable symptoms that affect the health and well-being of women. Hormone therapy (both unopposed estrogen and estrogen/progestogen combinations) is an effective treatment for these symptoms, but is associated with risk of harms. Guidelines recommend that hormone therapy be given at the lowest effective dose and treatment should be reviewed regularly. The aim of this review is to identify the minimum dose(s) of progestogen required to be added to estrogen so that the rate of endometrial hyperplasia is not increased compared to placebo.

Objectives: The objective of this review is to assess which hormone therapy regimens provide effective protection against the development of endometrial hyperplasia or carcinoma.

Search methods: We searched the Cochrane Menstrual Disorders and Subfertility Group trials register (searched January 2012), The Cochrane Library (Issue 1, 2012), MEDLINE (1966 to January 2012), EMBASE (1980 to January 2012), Current Contents (1993 to May 2008), Biological Abstracts (1969 to 2008), Social Sciences Index (1980 to May 2008), PsycINFO (1972 to January 2012) and CINAHL (1982 to May 2008). Attempts were made to identify trials from citation lists of reviews and studies retrieved, and drug companies were contacted for unpublished data.

Selection criteria: Randomised comparisons of unopposed estrogen therapy, combined continuous estrogen-progestogen therapy, sequential estrogen-progestogen therapy with each other or placebo, administered over a minimum period of 12 months. Incidence of endometrial hyperplasia/carcinoma assessed by a biopsy at the end of treatment was a required outcome. Data on adherence to therapy, rates of additional interventions, and withdrawals owing to adverse events were also extracted.

Data collection and analysis: In this update, 46 studies were included. Odds ratios (ORs) were calculated for dichotomous outcomes. The small numbers of studies in each comparison and the clinical heterogeneity precluded meta-analysis for many outcomes.

Main results: Unopposed estrogen is associated with increased risk of endometrial hyperplasia at all doses, and durations of therapy between one and three years. For women with a uterus the risk of endometrial hyperplasia with hormone therapy comprising low-dose estrogen continuously combined with a minimum of 1 mg norethisterone acetate (NETA) or 1.5 mg medroxyprogesterone acetate (MPA) is not significantly different from placebo at two years (1 mg NETA: OR 0.04; 95% confidence interval (CI) 0 to 2.8; 1.5 mg MPA: no hyperplasia events).

Authors' conclusions: Hormone therapy for postmenopausal women with an intact uterus should comprise both estrogen and progestogen to reduce the risk of endometrial hyperplasia.

PubMed Disclaimer

Conflict of interest statement

There was no conflict of interest.

Figures

1
1
Summary of risk of bias: review authors' judgements about each 'Risk of bias' domain for each included study (Characteristics of included studies/risk of bias section, for details).
2
2
Risk of bias graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies.
1.1
1.1. Analysis
Comparison 1 Unopposed estrogen versus placebo, Outcome 1 Endometrial hyperplasia at 1 year.
1.2
1.2. Analysis
Comparison 1 Unopposed estrogen versus placebo, Outcome 2 Cumulative endometrial hyperplasia at 18‐24 months.
1.3
1.3. Analysis
Comparison 1 Unopposed estrogen versus placebo, Outcome 3 Cumulative endometrial hyperplasia at 3 years.
1.4
1.4. Analysis
Comparison 1 Unopposed estrogen versus placebo, Outcome 4 Endometrial cancer 2‐3 years.
1.5
1.5. Analysis
Comparison 1 Unopposed estrogen versus placebo, Outcome 5 Adherence to therapy at 1 year.
1.6
1.6. Analysis
Comparison 1 Unopposed estrogen versus placebo, Outcome 6 Additional investigations (unscheduled biopsy).
1.7
1.7. Analysis
Comparison 1 Unopposed estrogen versus placebo, Outcome 7 Withdrawals because of adverse events.
2.1
2.1. Analysis
Comparison 2 Estrogen (E) + progestogen (continuous) vs placebo, Outcome 1 Endometrial hyperplasia at 1 year.
2.2
2.2. Analysis
Comparison 2 Estrogen (E) + progestogen (continuous) vs placebo, Outcome 2 Cumulative endometrial hyperplasia at 2 years.
2.3
2.3. Analysis
Comparison 2 Estrogen (E) + progestogen (continuous) vs placebo, Outcome 3 Endometrial hyperplasia at 3 years.
2.4
2.4. Analysis
Comparison 2 Estrogen (E) + progestogen (continuous) vs placebo, Outcome 4 Cumulative endometrial cancer at 2 years.
2.5
2.5. Analysis
Comparison 2 Estrogen (E) + progestogen (continuous) vs placebo, Outcome 5 Cumulative endometrial cancer at 3 years.
2.6
2.6. Analysis
Comparison 2 Estrogen (E) + progestogen (continuous) vs placebo, Outcome 6 Cumulative endometrial cancer at 5+ years.
2.7
2.7. Analysis
Comparison 2 Estrogen (E) + progestogen (continuous) vs placebo, Outcome 7 Adherence to therapy.
2.8
2.8. Analysis
Comparison 2 Estrogen (E) + progestogen (continuous) vs placebo, Outcome 8 Additional investigations (unscheduled biopsy).
2.9
2.9. Analysis
Comparison 2 Estrogen (E) + progestogen (continuous) vs placebo, Outcome 9 Withdrawals because of adverse events.
3.1
3.1. Analysis
Comparison 3 Estrogen (E) + progestogen (sequential) vs placebo, Outcome 1 Endometrial hyperplasia at 1 year.
3.2
3.2. Analysis
Comparison 3 Estrogen (E) + progestogen (sequential) vs placebo, Outcome 2 Cumulative endometrial hyperplasia at 2 years.
3.3
3.3. Analysis
Comparison 3 Estrogen (E) + progestogen (sequential) vs placebo, Outcome 3 Cumulative endometrial hyperplasia at 3 years.
3.4
3.4. Analysis
Comparison 3 Estrogen (E) + progestogen (sequential) vs placebo, Outcome 4 Cumulative endometrial cancer at 2 years.
3.5
3.5. Analysis
Comparison 3 Estrogen (E) + progestogen (sequential) vs placebo, Outcome 5 Cumulative endometrial cancer at 3 years.
3.6
3.6. Analysis
Comparison 3 Estrogen (E) + progestogen (sequential) vs placebo, Outcome 6 Additional investigations (unscheduled biopsy).
3.7
3.7. Analysis
Comparison 3 Estrogen (E) + progestogen (sequential) vs placebo, Outcome 7 Withdrawal because of adverse events.
4.1
4.1. Analysis
Comparison 4 Unopposed estrogen (E) vs E+P (continuous), Outcome 1 Endometrial hyperplasia at 1 year.
4.2
4.2. Analysis
Comparison 4 Unopposed estrogen (E) vs E+P (continuous), Outcome 2 Cumulative endometrial hyperplasia at 2 years.
4.3
4.3. Analysis
Comparison 4 Unopposed estrogen (E) vs E+P (continuous), Outcome 3 Cumulative endometrial hyperplasia at 3 years.
4.4
4.4. Analysis
Comparison 4 Unopposed estrogen (E) vs E+P (continuous), Outcome 4 Endometrial cancer at 1 year.
4.5
4.5. Analysis
Comparison 4 Unopposed estrogen (E) vs E+P (continuous), Outcome 5 Endometrial cancer at 3 years.
4.6
4.6. Analysis
Comparison 4 Unopposed estrogen (E) vs E+P (continuous), Outcome 6 Adherence to therapy.
4.7
4.7. Analysis
Comparison 4 Unopposed estrogen (E) vs E+P (continuous), Outcome 7 Additional investigations (unscheduled biopsy).
4.8
4.8. Analysis
Comparison 4 Unopposed estrogen (E) vs E+P (continuous), Outcome 8 Withdrawal because of adverse events.
5.1
5.1. Analysis
Comparison 5 Unopposed estrogen (E) vs E+P (sequential), Outcome 1 Endometrial hyperplasia at 1 year.
5.2
5.2. Analysis
Comparison 5 Unopposed estrogen (E) vs E+P (sequential), Outcome 2 Cumulative endometrial hyperplasia at 2 years.
5.3
5.3. Analysis
Comparison 5 Unopposed estrogen (E) vs E+P (sequential), Outcome 3 Cumulative endometrial hyperplasia at 3 years.
5.4
5.4. Analysis
Comparison 5 Unopposed estrogen (E) vs E+P (sequential), Outcome 4 Endometrial cancer at 1 year.
5.5
5.5. Analysis
Comparison 5 Unopposed estrogen (E) vs E+P (sequential), Outcome 5 Endometrial cancer at 3 years.
5.6
5.6. Analysis
Comparison 5 Unopposed estrogen (E) vs E+P (sequential), Outcome 6 Adherence to therapy.
5.7
5.7. Analysis
Comparison 5 Unopposed estrogen (E) vs E+P (sequential), Outcome 7 Additional investigations (endometrial biopsy).
5.8
5.8. Analysis
Comparison 5 Unopposed estrogen (E) vs E+P (sequential), Outcome 8 Withdrawal owing to adverse events.
6.1
6.1. Analysis
Comparison 6 E+P (continuous) vs E+P (sequential), Outcome 1 Endometrial hyperplasia at 1 year.
6.2
6.2. Analysis
Comparison 6 E+P (continuous) vs E+P (sequential), Outcome 2 Cumulative endometrial hyperplasia at 2 years.
6.3
6.3. Analysis
Comparison 6 E+P (continuous) vs E+P (sequential), Outcome 3 Cumulative endometrial hyperplasia at 3 years.
6.4
6.4. Analysis
Comparison 6 E+P (continuous) vs E+P (sequential), Outcome 4 Endometrial cancer at 1 year.
6.5
6.5. Analysis
Comparison 6 E+P (continuous) vs E+P (sequential), Outcome 5 Cumulative endometrial cancer at 2 years.
6.6
6.6. Analysis
Comparison 6 E+P (continuous) vs E+P (sequential), Outcome 6 Cumulative endometrial cancer at 3 years.
6.7
6.7. Analysis
Comparison 6 E+P (continuous) vs E+P (sequential), Outcome 7 Adherence to therapy.
6.8
6.8. Analysis
Comparison 6 E+P (continuous) vs E+P (sequential), Outcome 8 Additional Investigations.
6.9
6.9. Analysis
Comparison 6 E+P (continuous) vs E+P (sequential), Outcome 9 Withdrawal owing to adverse events.
7.1
7.1. Analysis
Comparison 7 Continuous combined E+P (dose comparisons), Outcome 1 Endometrial hyperplasia at 1 year.
7.2
7.2. Analysis
Comparison 7 Continuous combined E+P (dose comparisons), Outcome 2 Cumulative endometrial hyperplasia at 2 years.
7.3
7.3. Analysis
Comparison 7 Continuous combined E+P (dose comparisons), Outcome 3 Endometrial cancer at 1 year.
7.4
7.4. Analysis
Comparison 7 Continuous combined E+P (dose comparisons), Outcome 4 Withdrawal owing to adverse events.
8.1
8.1. Analysis
Comparison 8 Sequential E+P (dose/regimen comparisons), Outcome 1 Endometrial hyperplasia at 1 year.
8.2
8.2. Analysis
Comparison 8 Sequential E+P (dose/regimen comparisons), Outcome 2 Cumulative endometrial hyperplasia at 2 years.
8.3
8.3. Analysis
Comparison 8 Sequential E+P (dose/regimen comparisons), Outcome 3 Cumulative endometrial hyperplasia at 3 years.
8.4
8.4. Analysis
Comparison 8 Sequential E+P (dose/regimen comparisons), Outcome 4 Endometrial cancer at 1 year.
8.5
8.5. Analysis
Comparison 8 Sequential E+P (dose/regimen comparisons), Outcome 5 Cumulative endometrial cancer at 2 years.
8.6
8.6. Analysis
Comparison 8 Sequential E+P (dose/regimen comparisons), Outcome 6 Cumulative endometrial cancer at 3 years.
8.7
8.7. Analysis
Comparison 8 Sequential E+P (dose/regimen comparisons), Outcome 7 Adherence to therapy.
8.8
8.8. Analysis
Comparison 8 Sequential E+P (dose/regimen comparisons), Outcome 8 Additional investigations.
8.9
8.9. Analysis
Comparison 8 Sequential E+P (dose/regimen comparisons), Outcome 9 Withdrawals because of adverse events.
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References

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    1. Espeland MA, Bush TL, Mebane‐Sims I, Stefanick ML, Johnson S, Sherwin R, et al. Rationale, design, and conduct of the PEPI Trial. Controlled Clinical Trials 1995;16:3S‐19S. - PubMed
    1. Johnson S, Mebane‐Sims I, Hogan PE, Stoy DB. Recruitment of postmenopausal women in the PEPI Trial. Controlled Clinical Trials 1995;16:20S‐35S. - PubMed
    1. Lindenfield E, Langer R. Bleeding patterns of the hormone replacement therapies in postmenopausal estrogen and progestin interventions trial. Obstetrics and Gynecology 2002;100:853‐63. - PubMed
Portman 2003 {published data only}
    1. Portman DJ, Shumel BS, Symons JP. Hormone replacement therapy (HRT) with 1 mg norethindrone acetate (NA) / 5 mcg ethinyl estradiol (EE) (FemHRT) provides greater protection against breakthrough bleeding versus 0.625 mg combined equine estrogens (CEE) / 2.5 mg medroxyprogesterone (MPA) (Prempro). The 3rd World Congress on Controversies in Obstetrics, Gynecology & Infertility. 2002:82.
    1. Portman DJ, Symons JP, Wilborn W, Kempfert NJ. A randomised, double‐blind, placebo‐controlled, multicenter study that assessed the endometrial effects of norethindrone acetate plus ethinyl estradiol versus ethinyl estradiol alone. American Journal of Obstetrics & Gynecology 2003;188(2):334‐42. - PubMed
Prestwood 2003 {published data only}
    1. Prestwood KM, Kenny AM, Kleppinger A, Kulldorff M. Ultra‐low‐dose micronized 17beta‐estradiol and bone density and bone metabolism in older women: a randomized controlled trial. JAMA 2003;290(8):1042‐8. - PubMed
Rees 2004 {published data only}
    1. Rees MCP, Kuhl H, Engelstein M, Mattila L, Maenpaa J, Mustonen M. Endometrial safety and tolerability of triphasic sequential hormone replacement estradiol valerate/medroxyprogesterone acetate therapy regimen. Climacteric 2004;7(1):23‐32. - PubMed
Rozenberg 2001 {published data only}
    1. Rozenberg S, Caubel P, Lim PC. Constant estrogen, intermittent progestogen vs continuous combined hormone replacement: tolerability and effect on vasomotor symptoms. International Journal of Gynecology and Obstetrics 2001;72:235‐43. - PubMed
    1. Rozenberg S, Lim P. One‐year efficacy and safety of Prefect, a pulsed progestogen, constant estrogen hormone replacement therapy regimen. European Journal of Obstetrics, Gynecology, & Reproductive Biology 1999;86(Suppl):S18‐9.
    1. Ylikorkala O, Lim P, Caubel P. Effects on serum lipid profiles of continuous 17beta‐estradiol, intermittent norgestimate regimens versus continuous combined 17beta‐estradiol/norethisterone acetate hormone replacement therapy. Clinical Therapeutics 2000; Vol. 22, issue 5:622‐36. - PubMed
    1. Ylikorkala O, Wahlstrom T, Caubel P, Lane R. Intermittent progestin administration as part of hormone replacement therapy: long‐term comparison between estradiol 1 mg combined with intermittent norgestimate and estradiol 2 mg combined with constant norethisterone acetate. Acta Obstetricia et Gynecologica Scandinavica 2002;81:654‐9. - PubMed
Scandinavia 1996 {published and unpublished data}
    1. Bjarnason K, Cerin A, Lingren R, Weber T. Adverse endometrial effects during long cycle hormone replacement therapy. Maturitas 1999;32:161‐70. - PubMed
    1. Cerin A, Heldaas K, Moeller B for the Scandinavian Long Cycle Study Group. Adverse endometrial effects of long‐cycle estrogen and progestogen replacement therapy (letter). New England of Journal of Medicine 1996;334(10):668‐9. - PubMed
    1. Cerin A, Hjarnason K, Heldaas K, Thomsen HK, Boeller B. Adverse endometrial effects during long cycle hormone replacement therapy. Proceedings of the 8th International Congress on the Menopause, 1996, Nov 3‐7. Sydney, Australia, 1996:48.
Sporrong 1988 {published data only}
    1. Sporrong T, Hellgren M, Samsioe G, Mattsson LA. Comparison of four continuously administered progestogen plus oestradiol combinations for climacteric complaints. British Journal of Obstetrics and Gynaecology 1988;95(10):1042‐8. - PubMed
    1. Sporrong T, Samsioe G, Larsen S, Mattsson LA. A novel statistical approach to analysis of bleeding patterns during continuous hormone replacement therapy. Maturitas 1989;11(3):209‐15. - PubMed
Stadberg 1996 {published data only}
    1. Stadberg E, Mattsson LA, Uvebrant M. 17 beta‐estradiol and norethisterone acetate in low doses as continuous combined hormone replacement therapy. Maturitas 1996;23(1):31‐9. - PubMed
van de Weijer 1999 {published data only}
    1. Weijer PH, Scholten PC, Mooren MJ, Barentsen R, Kenemans P. Bleeding patterns and endometrial histology during administration of low‐dose estradiol sequentially combined with dydrogesterone. Climacteric 1999;2(2):101‐9. - PubMed
Warming 2004 {published data only}
    1. Warming L, Ravn P, Nielsen T, Christiansen C. Safety and efficacy of drospirinone used in a continuous combination with 17beta‐estradiol for prevention of postmenopausal osteoporosis. Climacteric 2004;7(1):103‐11. - PubMed
WHI 2002 {published data only}
    1. Anderson GL, Judd HL, Kaunitz AM, Barad DH, Beresford SAA, Pettinger M, et al. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women's Health Initiative randomized trial.[see comment]. JAMA 2003; Vol. 290, issue 13:1739‐48. - PubMed
    1. Barnabei VM, Cochrane BB, Aragaki AK, Nygaard I, Williams RS, McGovern PG, et al. Menopausal symptoms and treatment‐related effects of estrogen and progestin in the Women's Health Initiative. Obstetrics & Gynecology 2005;105(5 Pt 1):1063‐73. - PubMed
    1. Writing group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002;288:321‐33. - PubMed
Williams 1994 {published data only}
    1. Williams DB, Voigt BJ, Fu YS, Schoenfeld MJ, Judd HL. Assessment of less than monthly progestin therapy in postmenopausal women given estrogen replacement. Obstetrics & Gynecology 1994;84(5):787‐93. - PubMed
Wu 2002 {published data only}
    1. Wu Y, Liu J, Xing S, Xu R, Zhang Z, Wang Y. Comparative study on two different dosages of conjugated equine estrogen continuously combined with medroxyprogesterone in prevention of postmenopausal osteoporosis. Chinese Journal of Obstetrics & Gynecology 2002;37(5):267‐70. - PubMed
    1. Xing S, Wu Y, Liu J, Xu R, Zhang Z, Wang Y. A comparison of two different dosages of conjugated equine estrogen in continuous combined hormone replacement therapy with progestin. Chinese Medical Journal 2003;116(4):584‐7. - PubMed
Yildirim 2006 {published data only}
    1. Yildirim G, Tugrul S, Uslu H, Pekin O, Eren S. Effects of two different regimens of continuous hormone replacement therapy on endometrial histopathology and postmenopausal uterine bleeding. Archives of Gynecology & Obstetrics 2006;273(5):268‐73. - PubMed

References to studies excluded from this review

Aoki 1990 {published data only}
    1. Aoki T, Asai T. Assessment of oestrogen replacement therapy with conjugated oestrogens by histological evaluation of the endometrium in 205 women. Proceedings of the 6th International Congress on the Menopause, Bangkok, Thailand, 1990, Oct 29‐Nov 3. Bangkok, Thailand, 1990:151.
Archer 1999 {published data only}
    1. Archer D, Dorin M, Heine W, Nanavati N, Arce J. Uterine bleeding in postmenopausal women on continuous therapy with estradiol and norethindrone acetate. Obstetrics and Gynecology 1999;94:323‐9. - PubMed
Archer 2001 {published data only}
    1. Archer D, Dorin M, Lewis V, Schneider D, Pickar J. Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on endometrial bleeding. Fertility & Sterility 2001;75(6):1080‐7. - PubMed
Arrenbrecht 2004 {published data only}
    1. Arrenbrecht S, Caubel P, Garnero P, Felsenberg D, Vogel N, Coenders A, et al. The effect of continuous oestradiol with intermittent norgestimate on bone mineral density and bone turnover in post‐menopausal women. Maturitas 2004;48(3):197‐207. - PubMed
Bergeron 2010 {published data only}
    1. Bergeron C, Nogales FF, Rechberger T, Tatarchjuk T, Zipfel L. Ultra low dose continuous combined hormone replacement therapy with 0.5mg 17beta ‐oestradiol and 2.5mg dydrogesterone: protection of the endometrium and amenorrhoea rate. Maturitas 2010; Vol. 66, issue 2:201‐5. - PubMed
Blumel 1994 {published data only}
    1. Blumel JE, Roncagliolo ME, Gramegna G, Vasquez R, Estartus A, Tacla X, et al. Double‐blind study of the effect of continuous therapy with estradiol valerate and medroxyprogesterone acetate on menopausal symptoms, lipid profile and endometrial thickness [Estudio doble ciego del efecto sobre la sintomatologia menopausica, el perfil lipidico y el grosor endometrial de una terapia continua de valerato de estradiol mas acetato de medroxiprogesterona]. Revista Chilena Obstetricia y Ginecologia 1994;59(5):354‐60. - PubMed
Byrjalsen 1992a {published data only}
    1. Byrjalsen I, Thormann L, Riis BJ, Christiansen. Secretory endometrial protein PP14 in serum from post‐menopausal women receiving continuous combined oestradiol‐cyproterone acetate: correlation with serum hormone concentrations and bleeding patterns. Maturitas 1992;15:39‐46. - PubMed
Byrjalsen 1992b {published data only}
    1. Byrjalsen I, Thormann L, Meinecke B, Riis BJ, Christiansen C. Serum placental protein 14 (PP14) reflects endometrial status during hormone replacement therapy. Human Reproduction 1992; Vol. 7, issue 8:1042‐7. - PubMed
Campbell 1977 {published data only}
    1. Campbell S, Whitehead M. Oestrogen therapy and the menopausal syndrome. Clinics in Obstetrics and Gynaecology 1977;4(1):31‐47. - PubMed
Campodonico 1996 {published data only}
    1. Campodonico I, Valdivia I. Bleeding pattern in two combined continuous hormone replacement therapy (HRT) regimes in climacteric women. Proceedings of the 8th International Congress on the Menopause, 1996, Nov 3‐7. Sydney, Australia, 1996:191.
Chen 1999 {published data only}
    1. Chen FP, Teng LF. Effects of cyclic continuous and sequential post‐menopausal hormone replacement therapy on uterine bleeding and climacteric symptoms. Human Reproduction 1999;14:246.
Christensen 1982 {published data only}
    1. Christensen MS, Hagen C, Christiansen C, Transbol I. Dose‐response evaluation of cyclic estrogen/gestagen in postmenopausal women: placebo‐controlled trial of its gynaecologic and metabolic actions. American Journal of Obstetrics & Gynecology 1982;144(8):873‐9. - PubMed
Endrikat 2007 {published data only}
    1. Endrikat J, Graeser T, Mellinger U, Ertan K, Holz C, Endrikat J, et al. A multicenter, prospective, randomized, double‐blind, placebo‐controlled study to investigate the efficacy of a continuous‐combined hormone therapy preparation containing 1mg estradiol valerate/2mg dienogest on hot flushes in postmenopausal women. Maturitas 2007; Vol. 58, issue 2:201‐7. - PubMed
Granberg 2002 {published data only}
    1. Granberg S, Eurenius K, Lindgren R, Wilhelmsson L. The effects of oral estriol on the endometrium in postmenopausal women. Maturitas 2002;42:149‐56. - PubMed
Gulhan 2004 {published data only}
    1. Gulhan S, Dilek S. The effect of different postmenopausal hormone replacement treatment protocols on endometrial thickness. Gulhane Medical Journal 2004;46(3):205‐8.
Hagen 1982 {published data only}
    1. Hagen C, Christensen MS, 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 Gynecologica Scandinavica 1982;61:237‐41. - PubMed
Heytmanek 1990 {published data only}
    1. Heytmanek G. Continuous hormone replacement therapy with oestradiol valerate alone and in combination with cyproterone acetate: clinical and endometrial findings. Proceedings of the 6th International Congress on the Menopause, Bangkok, Thailand, 1990, Oct 29‐Nov 3. Bangkok, Thailand, 1990:86.
Istre 1996 {published data only}
    1. Istre O, Holm Nielsen P, Bourne T, Forman A. Hormone replacement therapy after transcervical resection of the endometrium. Proceedings of the 8th International Congress on the Menopause, 1996, Nov 3‐7. Sidney, Australia, 1996:100. - PubMed
    1. Istre O, Holm‐Nielsen P, Bourne T, Forman A. Hormone replacement therapy after transcervical resection of the endometrium. Obstetrics & Gynecology 1996;88(5):767‐70. - PubMed
Jaisamrarn 2002 {published data only}
    1. Jaisamrarn S, Sitravarin N, Taechakrichana K, Panyakamlert K, Limpapayom K. Bleeding patterns in menopausal women taking HRT. Climacteric 2002;F‐13‐03:75.
Jirapinyo 2003 {published data only}
    1. Jirapinyo M, Theppisai U, Manonai J, Suchartwatnachai C, Jorgensen LN. Effect of combined oral estrogen/progestogen preparation (Kliogest) on bone mineral density, plasma lipids and postmenopausal symptoms in HRT‐naive Thai women. Acta Obstetricia et Gynecologica Scandinavica 2003;82(9):857‐66. - PubMed
Kazerooni 2004 {published data only}
    1. Kazerooni T, Zolghadri J. The comparison of bleeding patterns with high‐dose and low‐dose hormone replacement therapy in postmenopausal women. Gynecological Endocrinology 2004;19(2):64‐8. - PubMed
Keil 2002 {published data only}
    1. Holst TH, Keil D, Lang E. Comparison of the incidence of irregular bleeding during treatment with a low dose continuous combined or sequential hormone replacement therapy. The 1st scientific meeting of the Asia‐Pacific Menopause Federation. 2002; Vol. 02‐05:61.
Limpaphayom 2000 {published data only}
    1. Limpaphayom K, Bunyavejchevin S. Clinical effects of 17 beta‐estradiol and norethisterone acetate in postmenopausal Thai women. Journal of the Medical Association of Thailand 2000;83:407‐15. - PubMed
Liu 2005 {published data only}
    1. Liu JH, Muse KN. The effects of progestins on bone density and bone metabolism in postmenopausal women: a randomized controlled trial. American Journal of Obstetrics & Gynecololgy 2005;192(4):1316‐24. - PubMed
Luciano 1988 {published data only}
    1. Luciano A, Turksoy N, Carleo J, Hendrix J. Clinical and metabolic responses of menopausal women to sequential versus continuous estrogen and progestin replacement therapy. Obstetrics and Gynecology 1988;71:39‐43. - PubMed
Marslew 1991 {published data only}
    1. Marslew U, Riis BJ, Christiansen C. Desogestrel in hormone replacement therapy: long‐term effects on bone, calcium and lipid metabolism, climacteric symptoms, and bleeding. European Journal of Clinical Investigation 1991;21:601‐7. - PubMed
Marslew 1992 {published data only}
    1. Marslew 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. Obstetrics and Gynecology 1992;79:202‐10. - PubMed
    1. Marslew U, Riis BJ, Christiansen C. Bleeding patterns during continuous combined estrogen‐progestogen therapy. American Journal of Obstetrics & Gynecology 1991;164(5 Pt 1):1163‐8. - PubMed
Mizunuma 1997 {published data only}
    1. Mizunuma H, Okano H, Soda M, Kagami I, Miyamoto S, Tokizawa T, et al. Prevention of postmenopausal bone loss with minimal uterine bleeding using low dose continuous estrogen/progestin therapy: a 2‐year prospective study. Maturitas 1997;27:69‐76. - PubMed
Morabito 2004 {published data only}
    1. Crisafulli A, Marini H, Bitto A, Altavilla D, Squadrito G, Romeo A, et al. Effects of genistein on hot flushes in early postmenopausal women: a randomized, double‐blind EPT‐ and placebo‐controlled study. Menopause 2004;11(4):400‐4. - PubMed
    1. Morabito N, Crisafulli A, Vergara C, Gaudio A, Lasco A, Frisina N, et al. Effects of genistein and hormone‐replacement therapy on bone loss in early postmenopausal women: a randomized double‐blind placebo‐controlled study. Journal of Bone & Mineral Research 2002;17(10):1904‐12. - PubMed
Nachtigall 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
Odmark 2001 {published data only}
    1. Odmark I, Jonsson B, Backstrom T. Bleeding patterns in postmenopausal women using two types of continuous combined hormone replacement therapy. Gynecological Endocrinology 2000;14(Suppl 2):128.
    1. Odmark IS, Jonsson B, Backstrom T. Bleeding patterns in postmenopausal women using continuous combination hormone replacement therapy with conjugated estrogen and medroxyprogesterone acetate or with 17B‐estradiol and norethindrone acetate. American Journal of Obstetrics and Gynecology 2001;184(6):1131‐8. - PubMed
Pickar 2003a {published data only}
    1. Pickar J, Yeh IT, Cunnane M, Archer D. Impact of conjugated estrogens (CE)/trimegestone (TMG) on endometrial hyperplasia and bleeding profiles in a double‐blind, randomized, placebo‐controlled study. Fertility & Sterility 2003;80(Suppl 3):18.
Pinto 2003 {published data only}
    1. Pinto A, Binder E, Kohrt W, Bronder D, Williams D. Effects of trimonthly progestin administration on the endometrium in elderly postmenopausal women who receive hormone replacement therapy: a pilot study. American Journal of Obstetrics and Gynecology 2003;189:11‐5. - PubMed
Popp 2006 {published data only}
    1. Popp AWE, Bodmer C, Senn C, Fuchs G, Kraenzlin ME, Wyss H, et al. Prevention of postmenopausal bone loss with long‐cycle hormone replacement therapy. Maturitas 2006;53(2):191‐200. - PubMed
Schiff 1982 {published data only}
    1. Schiff I, Sela HK, Cramer D, Tulchinsky D, Ryan KJ. Endometrial hyperplasia in women on cyclic or continuous estrogen regimens. Fertility & Sterility 1982;37(1):79‐82. - PubMed
Simon 2001 {published data only}
    1. Simon J, Symons J. Unscheduled bleeding during initiation of continuous combined hormone replacement therapy:a direct comparison of two combinations of norethindrone acetate and ethinyl estradiol to medroxyprogesterone acetate and conjugated equine estrogens. Menopause 2001;8:321‐6. - PubMed
Simon 2003 {published data only}
    1. Simon J, Liu J, Speroff L, Speroff L, Shumel B, Symons J. Reduced vaginal bleeding in postmenopausal women who receive combined norethindrone acetate and low‐dose ethinyl estradiol therapy versus combined conjugated equine estrogens and medroxyprogesterone acetate therapy. American Journal of Obstetrics & Gynecology 2003;188:92‐9. - PubMed
Steiner 2007 {published data only}
    1. Steiner AZ, Xiang M. Unopposed estradiol therapy in postmenopausal women: results from two randomized trials. Obstetrics & Gynecology 2007;109(3):581‐7. - PubMed
Stevenson 2001 {published data only}
    1. Stevenson JC, Teter P, Lees B. 17beta‐Estradiol (1 mg/day) continuously combined with dydrogesterone (5, 10 or 20 mg/day) increases bone mineral density in postmenopausal women. Maturitas 2001;38(2):197‐203. - PubMed
Stevenson 2010 {published data only}
    1. Stevenson Jc DGKEPT. Oral ultra‐low dose continuous combined hormone replacement therapy with 0.5 mg 17[beta]‐oestradiol and 2.5 mg dydrogesterone for the treatment of vasomotor symptoms: results from a double‐blind, controlled study. Maturitas 2010; Vol. 67, issue 3:227‐32. - PubMed
Sturdee 1996 {published data only}
    1. Sturdee DW. Bleeding patterns and endometrial histology with sequential HRT. Proceedings of the 8th International Congress on the Menopause, 1996, Nov 3‐7. Sidney, Australia, 1996:S36.
Sturdee 2000 {published data only}
    1. Sturdee DW, Ulrich LG, Barlow DH, Wells M, Campbell MJ, Vessey MP, et al. The endometrial response to sequential and continuous combined oestrogen‐progestogen replacement therapy. British Journal of Obstetrics and Gynecology 2000;11:1392‐400. - PubMed
Sturdee 2008 {published data only}
    1. Sturdee DW ADFRVLECSI. Ultra‐low‐dose continuous combined estradiol and norethisterone acetate: improved bleeding profile in postmenopausal women. Climacteric : the journal of the International Menopause Society 2008; Vol. 11, issue 1:63‐73. - PubMed
Symons 2000 {published data only}
    1. Symons J, Kempfert N, Speroff L. Vaginal bleeding in postmenopausal women taking low dose norethindrone acetate and ethinyl estradiol combinations. Obstetrics & Gynecology 2000;96:366‐72. - PubMed
Symons 2002 {published data only}
    1. Symons J. Comparative effect of norethindrone acetate/ethinyl estradiol and 0.625 mg conjugated estrogen/2.5 mg medroxyprogesterone acetate on bleeding control: early results from a randomized placebo controlled trial.. Obstetrics & Gynecology 2002;Suppl:84.
Ulla Timonen 2002 {published data only}
    1. Ulla Timonen R, Heikkinen R, Vaheri P, Kainulainen P. Bleeding control, endometrial safety and adherence to continuous combined HRT after 5 years. Climacteric 2002;P‐07‐21:146.
Utian 2002 {published data only}
    1. Utian W, Leonard T, Davis A, Vega R. Efficacy and safety study of a new synthetic 10‐component, modified release conjugated estrogens (CE) tablet for treatment of vasomotor symptoms in postmenopausal women. Fertility & Sterility 2002;78(3 Suppl 1):S159.
van der Mooren 1996 {published data only}
    1. Mooren MJ, Hanselaar A, Schiff Ch PT, Girardin C. Sequential three‐monthly versus monthly HRT: a prospective double‐blind randomised study. Proceedings of the 8th International Congress on the Menopause, 1996, Nov 3‐7. Sidney, Australia, 1996:47.
van de Weijer 2002 {published data only}
    1. Weijer P. Long‐term data on endometrial safety and bleeding control with a continuous combined HRT regimen. Climacteric. 10th World Congress on Menopause 2002;5(Suppl 1):210.
Veerus 2008 {published data only}
    1. Veerus P, Fischer K, Hovi SL, Karro H, Rahu M, Hemminki E. Symptom reporting and quality of life in the Estonian Postmenopausal Hormone Therapy Trial. BMC Women's Health 2008;26(8):5. - PMC - 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;6:327‐34. - PubMed
Von Holst 2002 {published data only}
    1. Holst T, Lang E, Winkler U, Keil D. Bleeding patterns in peri and postmenopausal women taking a continuous combined regimen of estradiol with norethisterone acetate or a conventional sequential regimen of conjugated equine estrogens with medrogestone. Maturitas 2002;43(4):265‐75. - PubMed
Wahab 2002 {published data only}
    1. Wahab M, Thompson J, Whitehead M, Al‐Azzawi F. The effect of a change in the dose of trimegestone on the pattern of bleeding in estrogen‐treated post‐menopausal women: 6 month extension of a dose‐ranging study. Human Reproduction 2002;17(5):1386‐90. - PubMed
Wang 2006 {published data only}
    1. Wang SH, Lin SQ, Gui QF, Jin MJ, Jiang Y. Profiles of irregular bleeding induced by low‐dose hormone therapy and Chinese formulated herb products. Acta Academiae Medicinae Sinicae 2006;28(2):256‐61. - PubMed
Warming 2004a {published data only}
    1. Warming L, Ravn P, Spielman D, Delmas P, Christiansen C. Trimegestone in a low‐dose, continuous‐combined hormone therapy regimen prevents bone loss in osteopenic postmenopausal women. Menopause 2004;11(3):337‐42. - PubMed
Webster 1996 {published data only}
    1. Webster M. Combination continuous therapy ‐ what is the optimal MPA dose? Effect on bleeding profiles and endometrial histology. Proceedings of the 8th International Congress on the Menopause, 1996, Nov 3‐7. Sidney, Australia, 1996:27.
Weinstein 1990 {published data only}
    1. Weinstein LB. Evaluation of a continuous combined low‐dose regimen of estrogen‐progestin for treatment of the menopausal patient. American Journal of Obstetrics & Gynecology 1990;162(6):1534‐9. - PubMed
Wells 2002 {published data only}
    1. Wells M, Sturdee D, Barlow D, Ulrich L, O'Brien K, Campbell M, et al. Effect on endometrium of long term treatment with continuous combined oestrogen‐progestogen replacement therapy: follow up study. British Medical Journal 2002;325:1‐5. - PMC - PubMed
Williams 1990 {published data only}
    1. Williams SR, Frenchek B, Speroff T, Speroff L. A study of combined continuous ethinyl estradiol and norethindrone acetate for postmenopausal hormone replacement. American Journal of Obstetrics and Gynecology 1990;162:438‐46. - PubMed
Yang 2001 {published data only}
    1. Yang TS, Liang WH, Chang SP, Yuan CC. Effects of period free hormone replacement therapy in postmenopausal women in Taiwan. Chinese Medical Journal (Taipei) 2001;65:23‐8. - PubMed

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