From sex hormone decrease to hormonal treatment: impacts on cardiovascular risk with ageing.

The Women's Health Initiative (WHI) study revealed an unexpected increase in cardiovascular events in aged women given estrogens plus medroxyprogesterone acetate.

• The increase in CV events was observed specifically in aged women (>70 years) receiving the combination of estrogens plus the synthetic progestin medroxyprogesterone acetate (MPA).
• Estrogens alone were not harmful and were even protective in younger women (<60 years).
• The WHI study, published in 2002, was the main clinical intervention designed to evaluate the benefit/risk ratio of hormone treatment after menopause.
• The findings highlighted a double problem: the nature of the progestin used and the age at which treatment was initiated.

Natural progesterone is now preferred over synthetic progestins such as medroxyprogesterone acetate for use in hormonal treatment after menopause.

• The WHI findings pointed out the problem with the specific synthetic progestin medroxyprogesterone acetate.
• As a result, natural progesterone is currently preferred in clinical practice.
• The shift reflects concerns about the differential cardiovascular effects of synthetic versus natural progestins.

The clinical situation regarding testosterone and cardiovascular disease in men remains unclear.

• The review notes the clinical situation is 'not yet clear for testosterone and CV disease in men.'
• This uncertainty parallels the complex picture seen with estrogen therapy in women.
• The paper reviews main clinical studies conducted with androgens in terms of cardiovascular protection and the impact of age on these effects.

Both the doses and concentrations of estrogens and testosterone are important determinants of their cardiovascular effects, distinguishing physiological from pharmacological actions.

• The review analyzes the importance of doses and concentrations of estrogens and testosterone in both humans and experimental models.
• This analysis is intended to define 'relevant/physiological or pharmacological actions of sex hormones in respect to their medical modulations in practice.'
• The distinction between physiological and pharmacological concentrations is considered essential for interpreting clinical and experimental data.

Age critically modifies the cardiovascular impact of hormonal supplementation with estrogens.

• Women over 70 years showed increased CV events with estrogen plus MPA therapy.
• Women under 60 years showed protective or neutral cardiovascular effects with estrogen therapy.
• Age at initiation of hormonal treatment is identified as a key factor (the 'timing hypothesis') influencing cardiovascular outcomes.
• The age-related deterioration of artery function and structure is described as 'the first cardiovascular risk factor in men but also in women.'

Coronary and cerebral arteries are particularly prone to atheroma, and the tissues they perfuse are particularly vulnerable to ischaemia.

• The review identifies coronary and cerebral arteries as the vascular beds most susceptible to atherosclerotic disease.
• The vulnerability of perfused tissues (myocardium and brain) to ischaemia is highlighted as a key reason why cardiovascular risk in ageing is clinically significant.
• Both sexes are affected by age-related deterioration of artery function and structure.

Gender-affirming hormone therapy is reviewed as a model for understanding cardiovascular effects of sex hormones, since sex hormones are the cornerstone of gender transition care management.

• Gender-affirming hormone therapy is specifically included in the review's scope.
• Sex hormones are described as 'the cornerstone of gender transition care management.'
• This population provides additional clinical data on the cardiovascular consequences of sex hormone administration and manipulation.

The age-related decrease in sex hormones in both menopause and andropause has deleterious effects on cardiovascular health.

• Both menopause (women) and andropause (men) are identified as contributors to increased cardiovascular risk through sex hormone decline.
• The review covers mechanisms underlying cardiovascular actions of sex hormones.
• The deleterious cardiovascular effects of hormone decline are considered alongside the risks and benefits of hormonal supplementation.