The Excercise Timing Hypothesis

When women enter the menopause, approaching mid life, oestrogen levels start decreasing.

Now, there are a lot of symptoms that start with the lack of oestrogen and the most common way to counteract them is taking HRT. HRT stands for Hormone Replacement Therapy, and it represents a great help for women suffering heavy menopausal symptoms (or any kind of symptoms really… related to the menopause I mean). Recently I came across something called the “timing hypothesis”, which basically means the earlier on HRT the better. In other words, the earlier you start taking HRT after entering menopause, the more effective the treatment will be.

Alongside with years of medical and scientific studies on the benefits of HRT, it has also been found that a good and attractive alternative to HRT could be regular physical activity (of course not attractive for everyone). It is known though that exercise induces many of the cardiovascular health protective effects like the ones oestrogen does. Nevertheless, the research correlating the benefits of physical activity in the vascular function and cardiovascular health in menopausal women is inconsistent. This is true since whilst some studies have reported the beneficial effects of having a regular physical activity programme, some lack clear evidence for it and therefore can’t claim the same conclusions. The reason for this divergence is yet to be understood, but there are studies exploring whether there may be a timing factor also for physical training alone, independently of the HRT factor. This is what researchers have called “the exercise timing hypothesis”, in which initiation of exercise interventions as soon as possible after menopause might be more effective than initiation many years after.

HRT has been looked at for years as the ideal strategy to counteract the decline on cardiovascular health in women related to low oestrogen levels triggered by the menopause, but medical studies such as The Women’s Health initiative, described an increased risk of cardiovascular disease in women that were on HRT, being that risk accentuated in women way past the menopause.

More recent studies however, such as The Kronos Early Estrogen and Prevention Study (KEEPS) and The Early Versus Late Intervention Trial (ELITE), have clearly shown how hormone therapy might have beneficial effects on general cardiovascular health if the treatment begins within the first 6 years of starting the menopause, which the same is not true anymore in late menopausal women. This time-dependent effect correlated to treatment initiation, is referred to as “the timing hypothesis” and the mechanism underlying in this hypothesis has not yet been fully understood.

But what is the role of oestrogen in cardiovascular disease? Amongst its various roles on the female body function, oestrogen plays an important part in the cardiovascular system as well. Oestrogen contributes to the regulation of vascular tone (elasticity of the blood vessels), vascular remodelling (ability of the vessels to repair any damage) and protection against plaque formation. Interestingly, on the ELITE study cited above, they demonstrated that vascular function is maintained better in women that started HRT earlier after menopause onset, compared to the one they started at a later stage. So this is enough evidence to suggest that cardiovascular disease that may develop after the onset of the menopause, and directly related to the decline of oestrogen levels, are much more difficult to reverse or treat than preventing or delaying its development at the early stages of the menopause. That’s why this hypothesis has been stealing the stage lights recently.

But what about physical exercise? The assumption underlying this hypothesis is that oestrogen is required for the “physical training” benefits in older postmenopausal women but interestingly not in younger women. This could also suggest a direct link between muscle contraction and oestrogen receptors, however the exact cellular and molecular mechanisms behind the effects of physical training and oestrogen in women remain unclear.

There are many studies demonstrating the benefits of physical exercise in men of different age, but these lack in providing similar evidence for women, therefore more studies are needed.

When Gliemann and colleagues started studying menopausal women and exercise, they noticed that if women had been regularly exercising by the time they entered menopause, their cardiovascular systems would be benefiting more than when compared to if they had started exercising regularly later into the menopause. And the most intriguing observation: exercise training did not improve vascular function in late-postmenopausal women. This may be due to a failed responsiveness of the vasculature system beyond a certain point after entering the menopause (oestrogen levels decrease), particularly an impaired response involving endothelial cells, where it becomes progressively more difficult to reverse any existing medical condition.

In conclusion, oestrogen can act by preventing cardiovascular diseases to develop and progress. Once a women enters the menopause, she becomes progressively less protected. We can hold onto this protection only by taking measures immediately after entering menopause and being fully informed. Exercise can be a great “substitute” of HRT for all the women out there who cannot take any HRT for any reason (medical, personal). Therefore it is vital knowing that even exercise has to be started as early as possible.

By Ornella Cappellari 


J Physiol. 2019 May 11. doi: 10.1113/JP277056. [Epub ahead of print] The exercise timing hypothesis: can exercise training compensate for the reduction in blood vessel function after menopause if timed right? Gliemann L, Hellsten Y.

Grady D, Rubin SM, Petitti DB, Fox CS, Black D, Ettinger B, Ernster VL & Cummings SR (1992). Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann InternMed 117, 1016–1037.

Gliemann L, Nyberg M & Hellsten Y (2014). Nitric oxide and reactive oxygen species in limb vascular function: what is the effect of physical activity? Free Radic Res 48, 71–83.