What is the Origin of The Timing Hypothesis?

This hypothesis emerged from the re-analysis and subsequent interpretation of data from large-scale clinical trials, such as the Women's Health Initiative (WHI), where the average age of participants was relatively high and many years post-menopause. The realization that the age and time since hormone deficiency onset were confounding variables led researchers to propose that the benefits of HRT are highly time-dependent. It has become a cornerstone of current clinical guidelines for menopausal hormone therapy.

What is the Mechanism of The Timing Hypothesis?

The mechanism is thought to be related to the differential effects of hormones on healthy versus already-diseased tissue. Early administration of hormones, like estrogen, may exert protective, anti-inflammatory, and vasodilatory effects on a healthy endothelium, thus preventing the initiation of atherosclerotic processes. However, introducing hormones into an already damaged, unstable vascular bed with existing atherosclerotic plaque may trigger adverse events, such as plaque rupture or thrombosis, highlighting the critical nature of the therapeutic window.

The Timing Hypothesis

Meaning

The Timing Hypothesis is a critical concept in hormone replacement therapy (HRT) asserting that the initiation of HRT relative to the onset of menopause or andropause significantly influences the benefit-risk profile of the treatment. Specifically, it posits that starting hormone therapy early in the transition window, when vascular and tissue integrity is relatively preserved, confers greater cardiovascular and neurocognitive benefits. Conversely, initiating therapy many years after the onset of deficiency may be associated with increased risk, potentially due to the presence of pre-existing subclinical pathology.