Adverse endometrial effects during long cycle hormone replacement therapy. Scandinavian Long Cycle Study Group

Maturitas. 1999 Aug 16;32(3):161-70. doi: 10.1016/s0378-5122(99)00033-x.


Objectives: Treatment with unopposed estrogen is known to increase the risk of endometrial hyperplasia, atypia, and carcinoma, and therefore the administration of a progestin during hormone replacement therapy (HRT) is recommended. The addition of a progestin may cause unwanted side effects. Progestin administration of various durations are therefore used in HRT.

Study design: Data were obtained about endometrial histopathology, bleeding interval and compliance in 240 early postmenopausal women receiving HRT with a progestin administered for 10 days during 12 week or 4 week cycles of estrogen administration. These regimens were studied for as long as 4 years. The daily estrogen given was 17beta-estradiol 2 mg per day which was reduced to 1 mg day during the last 6 days of each cycle. The progestin used was norethindrone acetate, given at a dose of 1 mg per day.

Results: The incidence of endometrial hyperplastic changes, i.e. simple or complex hyperplasia, atypia or cancer, was significantly higher in the 12 weeks cycle than in the monthly cycle group (P = 0.003), with an overall annual incidence of 5.6% in the 12 weeks cycle group and 1% in the monthly cycle group. One case of atypical hyperplasia and one case of endometrial adenocarcinoma was observed in the long cycle group. Long cycle treatment produced more irregular bleeding pattern. Accordingly, the rate of drop-out due to bleeding was significantly higher in the long cycle group (P<0.01).

Conclusion: We conclude that the long cycle HRT modality investigated did not improve compliance and may increase the risk of endometrial hyperplasia and eventually cancer compared to conventional HRT with a monthly cycle. Caution using long cycle HRT regimens is advisable, and careful monitoring of the endometrium during treatment is recommended.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • Biopsy
  • Endometrial Hyperplasia / chemically induced*
  • Endometrial Hyperplasia / epidemiology
  • Estradiol / adverse effects*
  • Estradiol / therapeutic use
  • Female
  • Hormone Replacement Therapy / adverse effects*
  • Humans
  • Incidence
  • Middle Aged
  • Norethindrone / adverse effects
  • Norethindrone / analogs & derivatives*
  • Norethindrone / therapeutic use
  • Norethindrone Acetate
  • Postmenopause
  • Risk Factors
  • Time Factors


  • Estradiol
  • Norethindrone Acetate
  • Norethindrone