Correspondence

Adverse Endometrial Effects of Long-Cycle Estrogen and Progestogen Replacement Therapy

N Engl J Med 1996; 334:668-669March 7, 1996

Article

To the Editor:

Treatment with unopposed estrogen is known to increase the risk of endometrial hyperplasia, atypia, and carcinoma, and therefore the administration of a progestogen during hormone-replacement therapy is recommended.1,2 The addition of a progestogen may cause unwanted monthly bleeding, changes in mood, and other side effects.3 To improve compliance during hormone-replacement therapy, various long-cycle regimens of progestogen therapy are used in clinical practice. However, there are few controlled studies of the safety of such treatment as regards the endometrium, and only one study has been carried out for more than two years.4,5 We present here preliminary data from the Scandinavian LongCycle Study, which was recently discontinued because of the unsatisfactory safety profile of the long-cycle hormone-replacement regimen.

The Scandinavian LongCycle Study was an open, randomized, multicenter trial conducted in Denmark, Norway, and Sweden of 240 women 45 to 65 years old who had been postmenopausal for at least one year (mean [±SD] age, 52±4 years). Half the women received hormone-replacement therapy with an extended cycle of 84 days: 2 mg of estradiol for 68 days, 2 mg of estradiol plus 1 mg of norethindrone for 10 days, and 1 mg of estradiol for 6 days. The remaining women received 2 mg of estradiol for 12 days, 2 mg of estradiol plus 1 mg of norethindrone for 10 days, and 1 mg of estradiol for 6 days (Trisequens, Novo Nordisk, Copenhagen, Denmark). The base-line characteristics of the groups did not differ significantly. Endometrial-biopsy specimens were obtained before treatment and every 12 months during treatment. The planned duration of the study was five years.

Over the course of two to three years of treatment, simple endometrial hyperplasia developed in eight women in the long-cycle group, complex endometrial hyperplasia in six (one also had atypia), and endometrial cancer in one, whereas in the monthly-cycle group simple endometrial hypoplasia and complex hyperplasia developed in one woman each. The atypia was diagnosed after one year of treatment, and the cancer after three years; previous biopsy specimens from both women were normal. The annual incidence of conversion to hyperplasia, atypia, or cancer is shown in Table 1Table 1Yearly Incidence of Endometrial Hyperplasia (Simple or Complex), Atypia, and Cancer in Postmenopausal Women Treated with Two Different Estrogen–Progestogen Regimens.. In all, the incidence of endometrial hyperplasia, atypia, and cancer after three years of treatment was significantly higher in the long-cycle group (P = 0.004 by an exact Kruskal–Wallis test).

These results indicate that long-cycle treatment to replace estrogen and progestogens increases the risk of endometrial hyperplasia, and eventually that of atypia and cancer, as compared with conventional therapy using a monthly cycle. Therefore, careful monitoring is mandatory during any long-cycle regimen.

Åsta Cerin, M.D.
Karolinska Hospital, S-171 76 Stockholm, Sweden

Knut Heldaas, M.D.
Telemark Central Hospital, N-3900 Porsgrunn, Norway

Birger Moeller, M.D., Ph.D.
Odense Hospital, DK-5000 Odense, Denmark

for the Scandinavian LongCycle Study Group

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Citing Articles (17)

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   Susan Furness, Helen Roberts, Jane Marjoribanks, Anne Lethaby, Martha Hickey, Cindy Farquhar, Susan Furness. 2009. Hormone therapy in postmenopausal women and risk of endometrial hyperplasia. .
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   Zoltan Magyar, Eniko Berkes, Zsolt Csapo, Zoltan Papp. (2007) Effect of hormone replacement therapy on postmenopausal endometrial bleeding. Pathology & Oncology Research 13:4, 351-359
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   Zoltán Magyar, Zsolt Csapó, Zoltán Papp. (2007) A postmenopausalis hormonpótló kezelés hatása a változókorban jelentkező vérzészavarra. Orvosi Hetilap 148:31, 1451-1459
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   Albrecht W.E. Popp, Christine Bodmer, Christoph Senn, Gaby Fuchs, Marius E. Kraenzlin, H. Wyss, Martin H. Birkhaeuser, Kurt Lippuner. (2006) Prevention of postmenopausal bone loss with long-cycle hormone replacement therapy. Maturitas 53:2, 191-200
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   2006. Estrogens. , 1253-1274.
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   Sue Furness, Helen Roberts, Jane Marjoribanks, Anne Lethaby, Martha Hickey, Cindy Farquhar, Sue Furness. 2004. Hormone therapy in postmenopausal women and risk of endometrial hyperplasia. .
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   Piero Sismondi, Nicoletta Biglia. (2004) HRT and gynaecologic cancer after WHI: old stuff or new doubts?. Maturitas 48:1, 13-18
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   Marius Jan van der Mooren, Peter Kenemans. (2004) Postmenopausal Hormone Therapy. Drugs 64:8, 821-836
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    Piero Sismondi, Nicoletta Biglia, Maurizia Giai, Riccardo Ponzone, Riccardo Roagna, Luca Sgro, Carlo Campagnoli. (1999) HRT, breast and endometrial cancers: strategies and intervention options. Maturitas 32:3, 131-139
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    R.Don Gambrell. (1997) Strategies to reduce the incidence of endometrial cancer in postmenopausal women. American Journal of Obstetrics and Gynecology 177:5, 1196-1207
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    Marius J. van der Mooren, Pierre N.M. Demacker, Henk J. Blom, Yolanda B. de Rijke, Rune Rolland. (1997) The effect of sequential three-monthly hormone replacement therapy on several cardiovascular risk estimators in postmenopausal women. Fertility and Sterility 67:1, 67-73
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