Menopause and cardiometabolic diseases: What we (don't) know and why it matters.

This narrative review discusses the current understanding, knowledge gaps and challenges in expanding our knowledge of the association between menopause and the reproductive aging process and cardiometabolic disease (CMD) in women, with a focus on type 2 diabetes and cardiovascular disease. The physiological changes that occur at different stages of the reproductive life span, as well as type of menopause and timing, are factors widely associated with CMD risk; however, the underlying mechanisms remain either unclear or insufficiently studied. Decreased ovarian estrogen production and relative androgen excess around menopause onset are the most studied factors linking menopause and cardiometabolic health; nevertheless, the evidence is not persuasive and other hypotheses might explain the changes in CMD risk during menopausal transition. In this context, hormone therapy has been widely adopted in the treatment and prevention of CMD, although uncertainty regarding its cardiometabolic effects has raised the need to optimize therapeutic modalities. Mechanisms such as the "iron overload theory" and new "omics" platforms could provide new insights into potential pathways underlying the association between menopause and cardiometabolic health, such as the DNA damage response. Although it has been widely reported that environmental and lifestyle factors affect both menopause and cardiometabolic health, there is little evidence on the role of these exposures in menopause-associated CMD risk.