Hormonal replacement regimens and bleeding

34 Suppl 1 (2000) S17 – S23 www.elsevier.com/locate/maturitas

Hormonal replacement regimens and bleeding Martina Do¨ren * Department of Family Planning, King’s College Hospital, Denmark Hill, London, SE5 9RS, UK

Abstract Hormone replacement therapy may increase the quality of life of postmenopausal women. Any regimen need to offer long-term endometrial safety. It is a standard to consider the co-administration of a sequential progestogen when estrogen replacement should be initiated in non-hysterectomized women. It is almost impossible to decide which combination of an estrogen and a progestogen seems to be optimal as individual tolerance of HRT may very well limit acceptability despite metabolic benefits and proven endometrial safety of a given combination. Several combinations of oral and transdermal estradiol or conjugated equine estrogens, oral progestogens, transdermal norethisterone acetate and levonorgestrel, and intrauterine levonorgestrel may achieve endometrial safety. It is noteworthy that there is no uniform correlation between the timing of onset of bleeding induced by any sequential estrogen and progestogen replacement and a certain pattern of histology. Therefore, although it is likely, there is no absolute reassurance that regular bleeding on or after day 11 of progestogen administration rules out abnormal histopathology. Transvaginal sonography seems not to be of pivotal importance to screen asymptomatic women on replacement therapy for detection of serious abnormal endometrial findings such as hyperplasia and endometrial cancer. Continuous combined hormone replacement therapy or the use of tibolone may be an alternative in postmenopausal women, who do not want any uterine bleedings after menopause. However, spottings or bleedings most often occur at the beginning of treatment. Vaginal administration of estriol and estradiol for urogenital symptoms of estrogen deficiency may stimulate the endometrium unintentionally. Available data suggest that use of oral estriol may be associated with endometrial hyperplasia and endometrial carcinoma relatively more often compared to sequential HRT. Raloxifene, a benzothiophene derivative acting as a selective estrogen receptor modulator approved for prevention of vertebral osteoporosis, rarely causes uterine bleeding. There is no ideal therapy available to suit women looking for a permanently bleed-free hormonal replacement therapy today. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Hormone replacement therapy; Quality of life; Endometrial safety

1. Introduction

* Tel.: +44-171-3463421; fax: +41-171-3463196. E-mail address: martina – [email protected] Do¨ren)

(M.

Hormone replacement therapy (HRT) may substantially increase the quality of life of postmenopausal women. Nevertheless, even in the presence of clear-cut benefits such as prophylaxis against postmenopausal osteoporosis, many

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M. Do¨ren / Maturitas 34 (2000) S17–S23

women are reluctant to use long-term HRT. It is a well-known fact that the motivation of women to continue HRT diminishes substantially over time irrespective of the type of estrogen and progestogen, route of administration, and regimen. The cessation of menses is an event belonging to every woman’s life. Many women do not consider bleedings after the menopausal transition in conjunction with HRT to be ‘natural’ or ‘normal’. The absence of monthly withdrawal bleedings after menopause seems to be appreciated by a majority of women as reflected by several assessments of mostly caucasian women [1 – 8]. It is possible that the high rate of acceptance of uterine bleedings among menopausal women enrolled in a clinical trial assessing two sequential estrogen and progestogen replacement therapies with induction of withdrawal bleedings [9] may be due to selection factors. Apart from this, the increased likelihood of having breast cancer diagnosed after long-term therapy [10], is a most significant concern for postmenopausal patients considering HRT. Any hormonal replacement needs to offer endometrial safety. The overall likelihood to develop an endometrial carcinoma for a 50-year-old caucasian women is 2.6%, the median age of diagnosis is 68 years [11]. Apart from endometrial cancer, the incidence of hyperplasia is estimated to occur in some 5% of postmenopausal women without administration of HRT. The concept of endometrial safety is most often related to the regular induction of regular shedding of transformed endometrial tissue stimulated by exogenous estrogens by a sequential progestogen. Progestogens should be given for 10 – 14 days per cycle. Various compounds, classified either as 17a-progesterone or 19-nortestosterone and originally developed for contraception, and natural progesterone are in clinical use; their metabolic effects may vary substantially [12]. Whether a small excess risk of endometrial cancer despite progestogen coadministration of at least 10 days exists in long-term users [13] may be due to inadequate continuation of the recommended dose and duration of the progestogen [14] and the inclusion of women with long-term use of unop-

posed estrogen prior to the use of opposed regimens. The results of the largest yet performed published population-based case-control study including women mostly using conjugated equine estrogens (CEE) suggest that sequential use of a progestogen in 88% of all HRT users 10 mg medroxyprogesterone acetate (MPA) for 10 days does not increase a woman’s underlying risk of endometrial cancer [15]. Other treatment modalities such as continuous combined HRT try to achieve endometrial atrophy or avoid endometrial stimulation. This regimen was not demonstrated to increase the pre-existent, underlying risk of endometrial cancer in postmenopausal women [15]. We do not know why some postmenopausal women on various types of continuous combined HRT may experience amenorrhea and others irregular spotting and bleeding and why women bleed or may not bleed in the presence of an atrophic endometrium [16]. Certainly local factors involved in the regulation of endometrial stimulation and maintenance of endometrial quiescence are poorly understood [17,18]. Any irregular, unscheduled bleeding irrespective of the individual treatment modality should therefore raise concerns. The majority of endometrial cancer presents with postmenopausal bleeding, a term which should be restricted to women not using HRT. Fortunately, only a minority of cases of postmenopausal bleedings are due to cancer.

2. Sequential HRT It is a standard to consider the co-administration of a sequential progestogen when estrogen replacement should be initiated in non-hysterectomized women. A growing variety of progestogens is approved for clinical use. It is almost impossible to decide which combination of an estrogen and a progestogen seems to be optimal as individual tolerance of HRT may very well limit acceptability despite metabolic benefits and proven endometrial safety transformation of a stimulated endometrium into secretory phase of a given combination. A growing number of combinations of oral and transdermal estradiol or con-

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jugated equine estrogens and progestogens including progesterone, transdermal norethisterone acetate and levonorgestrel, and intrauterine levonorgestrel achieve endometrial safety. For example, looking at long-term studies, a combination of, i.e. transdermal estradiol 100 mg per day and sequential MPA 10 mg per day added on cycle days 13–25 each month results in a predictable cyclic bleeding pattern with the onset of withdrawal bleeding on cycle day 27 – 28 and lasts on average 5 days in the majority of women studied for 2 years [19]. Abnormal biopsy results were restricted to one case of simple hyperplasia in this sample of 30 postmenopausal women. A combination of estradiol 2 mg and sequential dydrogesterone 10 mg per day for 14 days each month is another alternative to provide predictable withdrawal bleeding [20]. Dydrogesterone is a progestogen similar to natural progesterone. If it is administered in the second half of the cycle, a period-like withdrawal bleeding of 5 days duration is to be expected; most women will start within the last 2 days of co-administration of dydrogesterone. Approximately 86% of postmenopausal women in this 1-year study had cyclic withdrawal bleedings, which apparently exceeds the percentage achieved in large-scale studies involving other sequential therapies [21]. Dydrogesterone achieved secretory transformation of the endometrium in more than 86% of all women studied. Proliferative en-

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dometrium was observed in only 0.2% of cases, endometrial abnormalities were exceptionally rare and restricted to simple hyperplasia. Two thirds of the patients who finished the trial (78%) did not report intermittent bleeding or spotting within the study period, apparently only two of 188 patients treated discontinued HRT because of bleeding disturbances. However, due to differences in reporting and classifications of bleedings comparisons between studies are most difficult. If dydrogesterone is administered at the very beginning of a cycle together with estradiol [22], the duration of bleeding at the end of the combination phase is less as demonstrated in a small sample of women treated for 2 years (Table 1). It is noteworthy that there is no uniform correlation between the timing of onset of bleeding induced by any sequential estrogen and progestogen replacement and a certain pattern of histology [23]. Therefore, although it is likely, there is no absolute reassurance that regular bleeding on or after day 11 of progestogen administration indicates a healthy endometrium as previously thought [24]. Unfortunately, transvaginal sonography seems not to be of pivotal importance to screen asymptomatic women on sequential or continuous combined replacement for detection of serious abnormal endometrial findings such as hyperplasia and endometrial cancer [25].

Table 1 Estradiol and sequential dydrogesterone — bleeding patterna Regimen A E2 2 mg/day, days 1–28+dydrogesterone 10 mg/day, day 15–28 day for 1 year (n=188) Withdrawal bleeding Duration 5.59 1.8 days Cycle 2 5.19 1.9 days Cycle 12 Onset of bleeding Day of combined phase 13.79 3.1 Cycle 2 14.09 3.1 Cycle 12 a

Modified after 20 (A) and 22 (B).

Regimen B E2 2 mg/day, days 1–28 + dydrogesterone 10 mg/day, days 1–14 for 2 years (n = 27) 2.3 91.8 days 1.5 9 1.1 days 12.3 9 2.5 13.7 9 1.8

Cycle 2 Cycle 24 Cycle 2 Cycle 24

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Table 2 Recent long-term continuous combined HRT regimens — occurence of uterine bleedingd Estrogen (mg/day)

1 -year-trials CEE 0.625 mg Estrone sulfate 1.25 mg

Transdermal E 50 mg Estradiol valerate 2 mg Estradiol 1 mg Estradiol 2 mg Estradiol gel 1.5 mg

2 -year-trial Estrone sulfate 1.25 mg

Progestogen (mg/day)

na

Patients with bleeding (%) at a given timeb

MPA 2.5 mg MPA 5 mg MPA 2.5 mg MPA 5 mg MPA 10 mg NETA 0.17 mg NETA 0.35 mg NETA 0.7 mg NETA 0.25 mg NETA 0.5 mg NETA 1 mg LNG-IUD P 100 mg Vaginal P 100 mg (n= 7) or 200 mg (n= 12)

340 338 190 189 189 154 158 116 19 20 21 20 21

40.4 52.6 20 12.2 14.2 22.2 19.1 35 14 6 0 20 33

MPA 2.5 mg MPA 5 mg MPA 10 mg

19

47

10 11 11

25 30 13

Authors

[31]c Month 12 ‘‘ ‘‘ During 1 year ‘‘ Months 7–12 Month 12 ‘‘ ‘‘

[32] [33]c [34]c

[35]

[36] After 2 years ‘‘ ‘‘

[37]

a

Initial number of enrolled patients. Note the considerable differences in reporting: ref. [31] provided observed frequencies of bleeding for patients with amenorrhoea for at least cycles 7–13. c Ref. [31,33,34]: other study regimens not shown. d E, estradiol; NETA, norethisterone acetate; LNG-IUD, levonorgestrel-containing intrauterine device. b

3. Alternatives

3.1. Continuous combined HRT There are considerable differences in patients adherence, achievement of amenorrhoea and endometrial histopathology as assessed in mainly short-term trials of continuous combined HRT [26,27]. The adherence over time varies between studies [28–30]. Various combinations of estrogens and progestogens have been evaluated, all are associated with spottings or bleedings in a small to a substantial minority of patients most often at the beginning of treatment ([26,31 – 37]; Table 2) with reported amenorrhoea rates not

always adjusted for decreasing rates of adherence and thus difficult to compare. The pivotal question of endometrial safety has been raised as there is no regular withdrawal of the progestogen to allow for shedding of the proliferated and transformed endometrium. In addition, the continuous use of a progestogen may produce continuous down-regulation of endometrial progesterone receptors, the clinical significance of which is uncertain. One large-scale, prospective, randomised long-term trial [38] and the results of the largest yet performed published population-based casecontrol study [15] do not suggest an increased risk of endometrial cancer in women using continuous combined HRT. Clinical experience shows that

M. Do¨ren / Maturitas 34 (2000) S17–S23

endometrial cancer may occur in women using any type of HRT and related substances such as tibolone [39–41] despite (endometrial) surveillance of therapy. A modification of continuous combined HRT with both the estrogen and the progestogen compound administered for 25 consecutive days out of a 30 day cycle [42] was suggested to maintain amenorrhoea with interrupted progestogen exposure.

3.2. Local estrogen and progestogen administration Vaginal administration of estriol and estradiol to treat urogenital symptoms of estrogen deficiency may stimulate the endometrium unintentionally. One observational study of postmenopausal women undergoing transvaginal sonography for determination of endometrial thickness prior dilatation and curettage because of bleeding, and a nationwide population-based case-control study, both of which were conducted in Sweden, suggest that use of oral estriol given at doses of 1–2 mg per day may be associated with an increased risk of endometrial hyperplasia and cancer [43,44]. Intrauterine release of levonorgestrel may be a promising alternative for endometrial protection in particular in women with side-effects to HRT thought to be related to the progestogen [45].

3.3. Long cycle therapy A progestogen used less than monthly has been advocated to increase adherence of women otherwise likely to stop HRT because of side effects attributed to the progestogen and the occurrence of monthly withdrawal bleeding. Quarterly use of both MPA 5 and 10 mg daily for 14 days in conjunction with CEE 0.625 mg daily resulted in 1.5% cases of abnormal biopsies including atypical hyperplasia [46]. Another regimen consisting of estradiol valerate 2 mg given continuously for 84 days and combined with MPA 20 mg daily for 14 days every three months did not result in hyperplasia in a 2-year study with high compliance [47]. However, compared to sequential and continuous combined regimens, there are consid-

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erably less data available to evaluate these regimens, one of which was reported to increase the risk of endometrial hyperplasia, atypia, and cancer only after long-term exposure [48].

3.4. Tibolone This synthetic steroid may provide yet another alternative for women to maintain postmenopausal amenorrhoea. It is structurally related to norethisterone and norethynodrel and shows weak progestogenic, estrogenic, and androgenic properties. Apart from the relief of climacteric symptoms and protection of bone loss the use of tibolone was associated with maintenance of amenorrhoea in 66–70% of adherent women in randomised clinical trials [49,34].

3.5. Selecti6e estrogen receptor modulators Raloxifene is a compound derived from a benzothiophene series of antiestrogens. It may be classified as a selective estrogen receptor modulator on the basis of investigations in which prevention of bone loss and decrease of serum cholesterol was not accompanied by endometrial stimulation [50]. Reported results of randomised trials indicate that raloxifene does not cause endometrial thickening and, more importantly, uterine bleeding in postmenopausal women compared with placebo [51]. In conclusion, various sequential estrogen and progestin replacement therapies are available, some of which achieve predictable, cyclic bleeding mimicking the premenopausal situation. There are no ideal replacement therapies or treatments with related substances available to suit all women looking for a permanently bleed-free hormonal replacement therapy today. References [1] Hahn RC, Nachtigall RD, Davies TC. Compliance difficulties with progestin supplemented estrogen replacement therapy. J Fam Pract 1984;18:411 – 4. [2] Hemminki E, Brambilla DJ, McKinlay SM, Posner JG. Use of estrogens among middle-aged Massachussetts women. DICP 1991;25:418 – 23.

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M. Do¨ren / Maturitas 34 (2000) S17–S23

[3] Wren B, Brown L. Compliance with hormone replacement therapy. Maturitas 1991;13:17–21. [4] Ravnikar VA. Compliance with hormone therapy: are women receiving the full impact of hormone replacement therapy preventive health benefits? Womens Health Issues 1992;2:75 – 80. [5] Wallace WA, Price VH, Elliott CA, MacPherson MBA, Scott BW. Hormone replacement therapy acceptability to Nottingham postmenopausal women with a risk factor for osteoporosis. J Royal Soc Med 1992;83:699–701. [6] Ryan PJ, Harrison R, Blake GM, Fogelman I. Compliance with hormone replacement therapy (HRT) after screening for post menopausal osteoporosis. Br J Obstet Gynaecol 1992;99:325–8. [7] Barentsen R, Groeneveld FPMJ, Bareman FP, Hoes AW, Dokter HJ, Drogendijk AC. Women’s opinion on withdrawal bleeding with hormone replacement therapy. Eur J Obstet Gynecol Repr Biol 1993;51:203–7. [8] Cano A. Compliance to hormone replacement therapy in menopausal women controlled in a third level academic centre. Maturitas 1995;20:91–9. [9] van der Weijer PHM, Barentsen R, Kenemans P. Women’s expectations and acceptance of cyclic induced HRT bleeds. Maturitas 1998;30:257–63. [10] Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52 705 women with breast cancer and 108 411 women without breast cancer, Lancet 1997;350:1047–59. [11] Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Int Med 1992;117:1016–37. [12] Do¨ren M, Samsioe G. Metabolic effects of progestins in the replacement therapy of postmenopausal women. Israel J Obstet Gynecol 1998;9:36–46. [13] Beresford SAA, Weiss NS, Voigt LF, McKnight B. Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestogen therapy in postmenopausal women. Lancet 1997;349:458–61. [14] Barrett-Connor E, Grady D. Hormone replacement therapy, heart disease, and other considerations. Annu Rev Public Health 1998;19:55–72. [15] Pike MC, Peters RK, Cozen W, et al. Estrogen–progestin replacement therapy and endometrial cancer. J Natl Cancer Inst 1997;89:1110–6. [16] Smith SK. Bleeding from an atrophic endometrium. In: Wren BG, editor. Progress in the Management of the Menopause. Lancaster: Parthenon Publishing Group, 1997:241 – 5. [17] Casper RF. Regulation of estrogen/progestogen receptors in the endometrium. Int J Fertil 1996;41:16–21. [18] Rees M, Hague S, Oehler MK, Bicknell R. Regulation of endometrial angiogenesis. Climacteric 1999;2:52–8. [19] Clisham PR, Cedars MI, Greendale G, Fu YS, Gambone J, Judd HL. Long-term transdermal estradiol therapy: effects on endometrial histology and bleeding patterns. Obstet Gynecol 1992;79:196–201.

[20] Ferenczy A, Gelfand MM. Endometrial histology and bleeding patterns in post-menopausal women taking sequential, combined estradiol and dydrogesterone. Maturitas 1997;26:219 – 26. [21] Archer DF, Pickar JH, Bottiglioni F, for the Menopause Study Group. Bleeding patterns in postmenopausal women taking continuous combined or sequential regimens of conjugated estrogens with medroxyprogesterone acetate. Obstet Gynecol 1994;83:686 – 92. [22] van der Mooren MJ, Hanselaar AGJM, Borm GF, Rolland R. Changes in the withdrawal bleeding pattern and endometrial histology during 17b-estradiol-dydrogesterone therapy in postmenopausal women: a 2 year prospective study. Maturitas 1995;20:175 – 80. [23] Sturdee DW, Barlow DH, Ulrich LG, et al. Is the timing of withdrawal bleeding a guide to endometrial safety during sequential oestrogen-progestagen replacement therapy? Lancet 1994;344:979 – 82. [24] Padwick ML, Pryse-Davies J, Whitehead MI. A simple method for determining the optimal dosage of progestin in postmenopausal women. N Engl J Med 1986;315:930 – 4. [25] Langer RD, Pierce JJ, O’Hanlan KA et al., for the Postmenopausal Estrogen/Progestin Interventions Trial. Transvaginal ultrasonography compared with endometrial biopsies for the detection of endometrial disease: postmenopausal estrogen/progestin interventions trial, New Engl J Med 1997;337:1792– 8. [26] Udoff L, Langenberg P, Adashi EY. Combined continuous hormone replacement therapy: a critical review. Obstet Gynecol 1995;86:306 – 16. [27] Do¨ren M, Schneider HPG. The impact of different HRT regimens on compliance. Int J Fertil 1996;41:S362 – 71. [28] 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. [29] Komulainen M, Kro¨ger H, Tuppurainen MT, et al. HRT and vit D in prevention of non-vertebral fractures in postmenopausal women; a 5-year randomized trial. Maturitas 1998;31:45 – 54. [30] Hart DM, Farish E, Fletcher CD, et al. Long-term effects of continuous combined HRT on bone turnover and lipid metabolism in postmenopausal women. Osteoporos Int 1998;8:326 – 32. [31] Woodruff JD, Pickar JH, for the Menopause Study Group. Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (premarin) with medroxyprogesterone acetate or conjugated estrogens alone, Am J Obstet Gynecol 1994;170:1213– 23. [32] Nand SL, Webster MA, Baber R, O’Connor V, for the Ogen/Provera Study Group. Bleeding pattern and endometrial changes during continuous combined hormone replacement therapy, Obstet Gynecol 1998;91:678 – 84. [33] Rozenberg S, Ylikorkala O, Arrenbrecht S. Comparison of continuous and sequential transdermal progestogen

M. Do¨ren / Maturitas 34 (2000) S17–S23

[34]

[35]

[36]

[37]

[38]

[39]

[40]

[41]

with sequential oral progestogen in postmenopausal women using continuous transdermal estrogen: vasomotor symptoms, bleeding patterns, and serum lipids. Int J Fertil 1997;2(Suppl.):376–87. Al-Azzawi F, Wahab M, Habiba M, Akkad A, Mason T. Continuous combined hormone replacement therapy compared with tibolone. Obstet Gynecol 1999;93:258–64. Stadberg E, Mattson L-A, , Uvebrant M. 17b-estradiol and norethisterone acetate in low doses as continuous combined replacement therapy. Maturitas 1996;23:31–9. Suvanto-Luukonen E, Sundstro¨m H, Penttinen J, La¨a¨ra¨ E, Pramila S, Kauppila A. Percutaneous estradiol gel with an intrauterine device or natural progesterone in hormone replacement therapy. Maturitas 1997;26:211–7. Nand SL, Webster MA, Wren BG. Continuous combined piperazine oestrone sulphate and medroxyprogesterone acetate hormone replacement therapy-a study of bleeding pattern, endometrial response, serum lipid and bone density changes. Aust NZ J Obstet Gynaecol 1995;35:92–6. Hulley S, Grady D, Bush T et al., for the Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605–13. Do¨ren M, Schneider HPG. Long-term compliance of continuous combined estrogen and progestogen replacement in postmenopausal women. Maturitas 1996;25:99– 105. Gambrell RD. Strategies to reduce the incidence of endometrial cancer in postmenopausal women. Am J Obstet Gynecol 1997;177:1196–207. van Dadelszen P, Gillmer MDG, Gray MD, et al. Endometrial hyperplasia and adenocarcinoma during tibolone (Livial®) therapy. Br J Obstet Gynaecol 1994;101:158 – 61.

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[42] Darj E, Nilsson, Axelsson O, Hellberg D. Clinical and endometrial effects of oestradiol and progesterone in post-menopausal women. Maturitas 1991;13:109 – 15. [43] Granberg S, Ylo¨stalo P, Wikland M, Karlsson B. Endometrial sonographic and histological findings in women with and without hormonal replacement therapy suffering from postmenopausal bleeding. Maturitas 1997;27:35 – 40. [44] Weiderpass E, Baron JA, Adami H-O, et al. Low-potency oestrogen and risk of endometrial cancer: a case control study. Lancet 1999;353:1824– 8. [45] Andersson K, Mattson L-A, , Rybo G, Stadberg E. Intrauterine release of levonorgestrel — a new way of adding progestogen in hormone replacement therapy. Obstet Gynecol 1992;79:963 – 7. [46] Ettinger B, Selby J, Citron JT, Vangessel A, Ettinger VM, Hendrickson MR. Cyclic hormone replacement therapy using quarterly progestin. Obstet Gynecol 1994;83:693 – 700. [47] Hirvonen E, Salmi T, Puolakka J, et al. Can progestin be limited to every third month only in postmenopausal women taking estrogen? Maturitas 1995;21:39 – 44. [48] Cerin A, , Heldaas K, Moeller B for the Scandinavian Long Cycle Study Group. New Engl J Med 1996;334:668 – 9 (Letter). [49] Hammar M, Christau S, Nathorst-Bo¨o¨s 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. Br J Obstet Gynaecol 1998;105:904 – 11. [50] Delmas PD, Bjarnason NH, Mitlak BH, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. New Engl J Med 1997;337:1641– 7. [51] Davies GC, Huster WJ, Lu Y, Plouffe L, Lakshmanan M. Adverse events reported by postmenopausal women in controlled trials with raloxifene. Obstet Gynecol 1999;93:558 – 65.

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