Continuous combined conjugated equine estrogen-progestogen therapy: effects of medroxyprogesterone acetate and norethindrone acetate on bleeding patterns and endometrial histologic diagnosis

Am J Obstet Gynecol. 1992 Jul;167(1):1-7. doi: 10.1016/s0002-9378(11)91614-7.


Objectives: This study was designed to assess the incidence of amenorrhea with continuous combined therapy by using two different progestogens and to determine whether early bleeding predicts subsequent bleeding and endometrial response.

Study design: Seventy-nine postmenopausal women on sequential estrogen-progestogen treatment were switched to continuous combined estrogen-progestogen therapy comprising conjugated equine estrogens 0.625 mg daily with either norethindrone acetate 0.35 mg twice daily or medroxyprogesterone acetate 2.5 mg twice daily added continuously for 78 weeks. All bleeding was recorded, and endometrial biopsies were performed at 26 and 78 weeks.

Results: Only one third of the women who starting the study had amenorrhea by week 78, but 46 (62%) of these women had withdrawn, mainly because of chronic irregular bleeding. Endometrial atrophy was observed in the majority of biopsy specimens. The two progestogens had similar effects. Bleeding patterns were useful predictors of subsequent bleeding, but not of endometrial response.

Conclusions: Persistent irregular bleeding is common with continuous combined estrogen-progestogen therapy. Women with persistent early bleeding should probably revert to sequential treatment. Regular endometrial sampling is advised.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amenorrhea
  • Atrophy
  • Drug Therapy, Combination
  • Endometrium / pathology*
  • Estrogen Replacement Therapy / adverse effects*
  • Female
  • Humans
  • Medroxyprogesterone Acetate / administration & dosage
  • Medroxyprogesterone Acetate / adverse effects*
  • Medroxyprogesterone Acetate / therapeutic use
  • Norethindrone / administration & dosage
  • Norethindrone / adverse effects
  • Norethindrone / analogs & derivatives*
  • Norethindrone / therapeutic use
  • Norethindrone Acetate
  • Time Factors
  • Uterine Hemorrhage / chemically induced*


  • Norethindrone Acetate
  • Medroxyprogesterone Acetate
  • Norethindrone