Article Text

Download PDFPDF
Randomised controlled trial
While hormone therapy unlikely harmful in younger postmenopausal women at low CV risk, protective effects cannot be claimed
  1. Beth L Abramson
  1. Division of Cardiology, St. Michael's Hospital, University of Toronto, Toronto, Canada
  1. Correspondence to: Beth L Abramson
    Division of Cardiology, St. Michael's Hospital, University of Toronto, 30 Bond Street Toronto, Ontario, Canada M5W 1B8; abramsonb{at}

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Commentary on: OpenUrlAbstract/FREE Full Text


The last 10 years have clarified the issues regarding postmenopausal hormone therapy (HT) and cardiovascular disease (CVD). Prior to the large, randomised women's health initiative (WHI),1 observational studies had suggested a protective cardiovascular (CV) effect. The WHI showed no benefit, and increased thromboembolic and CV events in women taking HT. The WHI findings have been challenged because of the older age of the participants.2 A ‘critical timing’ hypothesis has been suggested to try to explain how the use of HT at the onset of menopause could be cardioprotective, whereas later initiation could cause adverse events.3– ,6 This theory suggests that the prothrombotic or plaque-destabilising effects of HT in women with coronary disease may account for an initial increase in coronary artery events in older women, but that the healthy coronary arteries of younger women benefit from the effects of oestrogen.


Schierbeck and colleagues report the effect of HT on CV events in recently postmenopausal women. The trial included 1006 healthy women between the ages of 45 and 58, randomly assigned to HT or control with no placebo given. The primary endpoint was a composite of death, hospital admission for myocardial infarction or heart failure. Endpoints were assessed with a Prospectively Randomised Open with Blinded Endpoint evaluation. Patients were followed for a mean duration of 10 years on therapy, with an additional 5.7 years for a total mean duration of follow-up of 16 years.


The primary endpoint occurred in 53 women in the control group and 33 in the treated group (P=0.02). Stroke rates did not differ between groups (21 control, 19 treated) and rates of deep vein thrombosis were low and did not differ (5 control, 4 treated).

The authors conclude that the results suggest that the initiation of hormone replacement therapy in women, early after menopause significantly reduces the risk of the combined endpoint of mortality, myocardial infarction or heart failure. In addition, there was no increased risk of breast cancer or stroke.


Although the strengths of the study include the long-term follow-up and comprehensive Danish National Register data, its limitations include the fact that there was no placebo given. Some would say that this study design limitation means that it is essentially a variation on a case–control observational study.

It is surprising to see a discussion regarding lipid effects of different HT as an explanation for the study results. Lipids and other surrogate markers do not replace harder endpoints, and do not always track with mortality. This has recently been demonstrated with drugs that raise high-density lipoprotein such as niacin and cholesterylester transfer protein inhibitors. Thinking mechanistically, HT is prothrombotic and anti-inflammatory. A discussion on lipid metabolism cannot be made in isolation of these effects.

The critical timing hypothesis does not need to be invoked to explain the low event rates in younger, postmenopausal women when an epidemiological argument will suffice. Most preventive interventions have the same relative risk reduction or increase across populations but the absolute event reduction or increase is determined by the event rate in the population. Younger, perimenopausal women are at lower risk for CV events. This study was longitudinal but had low event rates. Importantly, the lack of placebo creates a design flaw that cannot be ignored.

While intriguing, the findings in the current study are in line with earlier, non-randomised cohort data. There are concerns with the authors’ suggestion that HT started early in menopause is protective as it would be a disservice to female patients to change practice patterns and guidelines based on this study. While adding to safety data in this age group, a protective effect cannot be claimed, given the study design limitations. However, this study does add reassurance to clinicians treating women with menopausal symptoms. Ultimately, this study is not strong enough to change practice guidelines on the prevention of CVD in women.


View Abstract


  • Competing interests None.