The Effect of Perimenopausal Transdermal Estradiol and Micronized Progesterone on Markers of Risk for Arterial Disease

J Clin Endocrinol Metab. 2020 May 1;105(5):e2050-e2060. doi: 10.1210/clinem/dgz262.


Background: The arterial effects of hormone therapy remain controversial. This study tested the effects of transdermal estradiol plus intermittent micronized progesterone (TE + IMP) in healthy perimenopausal and early postmenopausal women on several mechanisms involved in the pathophysiology of arterial disease.

Methods: Healthy perimenopausal and early postmenopausal women, ages 45 to 60 years, were enrolled in this randomized, double-blind, placebo-controlled trial. Women were randomized to receive TE (0.1 mg/day) + IMP (200 mg/day for 12 days) or identical placebo patches and pills for 12 months. Outcomes included: change in stress reactivity composite z-score (combining inflammatory, cortisol, and hemodynamic responses to a standardized psychological laboratory stressor); flow-mediated dilation (FMD) of the brachial artery (an index of vascular endothelial function); baroreflex sensitivity; and metabolic risk (presence of the metabolic syndrome or insulin resistance), all assessed at baseline and at months 6 and 12.

Results: Of 172 women enrolled, those assigned to TE + IMP tended to have higher resting baroreflex sensitivity than those assigned to placebo across the 6- and 12-month visits. Although treatment groups did not differ in terms of the other prespecified outcomes, a significant treatment-by-age interaction was found for FMD and stress reactivity such that an age-related decrease in FMD and increase in stress reactivity were seen among women assigned to placebo but not those assigned to TE + IMP. Women on TE + IMP also had lower resting diastolic blood pressure, lower levels of low-density lipoprotein cholesterol, and higher baroreflex sensitivity during stress testing.

Conclusions: TE + IMP tended to improve cardiac autonomic control and prevented age-related changes in stress reactivity and endothelial function among healthy perimenopausal and early postmenopausal women.

Trial registration: NCT01308814.

Keywords: baroreceptor sensitivity; early postmenopause; flow mediated dilation; intermittent micronized progesterone; menopause transition; metabolic risk; stress reactivity; transdermal estradiol.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Cutaneous
  • Biomarkers / blood*
  • Double-Blind Method
  • Drug Therapy, Combination
  • Estradiol / administration & dosage*
  • Estradiol / adverse effects
  • Estrogen Replacement Therapy / adverse effects
  • Estrogen Replacement Therapy / methods
  • Female
  • Humans
  • Middle Aged
  • Perimenopause / blood
  • Perimenopause / drug effects*
  • Placebos
  • Progesterone / administration & dosage*
  • Progesterone / adverse effects
  • Risk Factors
  • Transdermal Patch
  • Treatment Outcome
  • Vascular Diseases / blood*
  • Vascular Diseases / chemically induced
  • Vascular Diseases / epidemiology


  • Biomarkers
  • Placebos
  • Progesterone
  • Estradiol

Associated data