What factor primarily affects the risk of gallstones when using HRT?

The primary factor influencing the risk of gallstones in hormone replacement therapy (HRT) is the method of administration, specifically whether the hormones are taken orally or through transdermal routes. When hormones are administered orally, they undergo first-pass metabolism in the liver, which can increase certain lipid levels and potentially heighten the risk of gallstone formation. Conversely, transdermal HRT bypasses this first-pass effect, resulting in a different metabolic response, which is associated with a lower incidence of gallstones. This mechanistic difference underscores why the method of administration is a critical consideration in assessing gallstone risk during HRT.

While other factors such as diet, duration of HRT use, and age can also have an impact on gallstone formation, they are not as directly correlated with the hormonal administration method. For example, a patient's diet may influence gallstone risk, but it does not have the same strong direct relationship with the effects of HRT as does the mode of administration. Similarly, although the duration of HRT and age may correlate with various health risks, the specific influence of the route of hormone administration on gallstone risk is distinctly significant.