Can endometrial protection be inferred from the bleeding pattern on combined cyclical hormone replacement therapy

Maturitas. 2000 Feb 15;34(2):155-60. doi: 10.1016/s0378-5122(99)00101-2.


Objective: To investigate the relationship between the timing of withdrawal bleeding on hormone replacement therapy and the state of the endometrium.

Design: Double-blind, prospectively randomised dose-ranging study.

Setting: Menopause clinics in the UK and the Netherlands.

Subjects: Two hundred and seventy one postmenopausal women aged 40-60.

Interventions: Administration of six 28-day treatment cycles of a continuous daily dose of 2 mg of micronised 17beta oestradiol with a randomly allocated dose of 5-20 mg of dydrogesterone added for the last 14 days of each.

Methods: Comparison of the timing of the withdrawal bleed recorded in subject-held diaries with an endometrial biopsy obtained toward the end of the last cycle.

Results: There was a trend towards later withdrawal bleeding with secretory endometrium and earlier bleeding with inactive or atrophic endometrium, but with too much overlap for this to be of clinical relevance. There were two cases of proliferative and one of hyperplastic endometrium, with no characteristic bleeding pattern.

Conclusion: Combined sequential HRT with progestogen given for 12-14 days very rarely fails to protect the endometrium. Such failures can not be detected by noting the bleeding pattern. The only suspicious pattern is non-cyclic bleeding, but this will not detect every case of hyperplasia or persistent proliferative endometrium.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Atrophy
  • Biopsy
  • Cell Division
  • Double-Blind Method
  • Dydrogesterone / administration & dosage
  • Dydrogesterone / therapeutic use
  • Endometrium / drug effects*
  • Endometrium / metabolism
  • Endometrium / pathology
  • Epithelial Cells / pathology
  • Estradiol / administration & dosage
  • Estradiol / therapeutic use
  • Female
  • Follow-Up Studies
  • Hormone Replacement Therapy / methods*
  • Humans
  • Hyperplasia
  • Medical Records
  • Middle Aged
  • Postmenopause / drug effects
  • Progesterone Congeners / administration & dosage
  • Progesterone Congeners / therapeutic use
  • Prospective Studies
  • Uterine Hemorrhage / chemically induced*


  • Progesterone Congeners
  • Estradiol
  • Dydrogesterone