The Timing Hypothesis remains a valid explanation of differential cardioprotective effects of menopausal hormone treatment.

OBJECTIVE

Randomized clinical trials (RCTs) using delayed hormone treatment (HT) have failed to validate the reduction in cardiovascular disease-associated events found in observational studies of early menopausal HT (MHT). The Timing Hypothesis--effects of differences between the chronologic age/length of postmenopause of study participants--continues to be questioned as an explanation for the discrepant outcomes. We reviewed evidence regarding the basis of the hypothesis and its suitability to explain differences in outcomes between MHT and HT trials.

METHODS

Literature review.

RESULTS

Reports of laboratory, animal, and human clinical studies support the differential effect of HT on normal versus diseased vessels. Age and time since menopause have been related to the extent of vascular disease in women.

CONCLUSIONS

There is ample evidence of the validity of the Timing Hypothesis as an entity and as an explanation of the different outcomes of observational studies and RCTs. The available delayed HT RCT data do not rule out the validity of the Timing Hypothesis or protection by MHT against cardiovascular events. Cardiovascular disease remains the single largest cause of death in women, and research on its prevention by MHT should be the highest national priority.