Cardiac Death Risk in Relation to the Age at Initiation or the Progestin Component of Hormone Therapies

J Clin Endocrinol Metab. 2016 Jul;101(7):2794-801. doi: 10.1210/jc.2015-4149. Epub 2016 May 12.


Context: The "window of opportunity hypothesis" refers to data indicating that conjugated equine estrogen alone or in combination with medroxyprogesterone acetate, if initiated before 60 years of age, protects the heart but endangers it if initiated later (Women's Health Initiative study). Less is known about the "window of opportunity hypothesis" with natural estradiol alone (ET) or with various progestins in combination with estradiol (EPT).

Objective: We related the death risk from coronary heart disease (CHD) in users of ET or EPT to the age at the initiation of therapy and to the progestin component of EPT. Design, Patients, Interventions, and Main Outcome Measures: Altogether, 498 105 women had used ET or EPT containing medroxyprogesterone acetate, norethisterone acetate, dydrogesterone, other progestins, or tibolone during 3.7 million person-years during 1994-2009. Women were followed from the therapy initiation to death, or to the end of year 2009. The risk of CHD death in hormone users was compared with that in the age-matched background population using standardized mortality ratio with 95% confidence intervals.

Results: Age younger than 60 rather than older than 60 years at the initiation of ET (standardized mortality ratio, 0.53; 95% confidence interval, 0.47-0.59 vs 0.76; 0.71-0.82), EPT with norethisterone acetate (0.45; 0.41-0.49 vs 0.74; 0.67-0.81), or tibolone (0.35; 0.26-0.47 vs 1.01; 0.67-1.46) therapy lasting for less than 5 years was associated with significantly greater decreases in the CHD death risk. A similar tendency was also seen for other EPT groups and for longer use. In all hormone users, the CHD death risk was smaller the earlier the use of ET or EPT had started (P < .05); this phenomenon was unrelated to the progestin component of EPT.

Conclusions: Estradiol-based hormone therapies are accompanied with larger CHD mortality risk reductions the earlier the therapies are initiated. The progestin component of EPT does not modify this "timing effect."

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Case-Control Studies
  • Coronary Disease / mortality*
  • Estradiol / administration & dosage
  • Estradiol / adverse effects
  • Estrogen Replacement Therapy / adverse effects*
  • Estrogen Replacement Therapy / statistics & numerical data
  • Estrogens, Conjugated (USP) / administration & dosage
  • Female
  • Humans
  • Medroxyprogesterone Acetate / administration & dosage
  • Medroxyprogesterone Acetate / adverse effects
  • Middle Aged
  • Progestins / administration & dosage*
  • Progestins / adverse effects
  • Risk Factors
  • Time Factors


  • Estrogens, Conjugated (USP)
  • Progestins
  • Estradiol
  • Medroxyprogesterone Acetate