Contents of HRT and mechanisms of action.

Formulation of HRT preparations has changed very significantly over the last few decades. The problems of unopposed oestrogens are now well recognised. Addition of progestins may overcome these problems in some target tissues. However, there is clear evidence for differential effects of both steroids in different target tissues. It is also vital to be clear on the dose-response to each steroid in each target tissue. Steroids given orally may undergo different metabolism from those given transdermally or subcutaneously. This can mean that, even given dose for dose, there can still be differences in the regulation of, for example, lipid profiles, depending on delivery route. The situation is further complicated by the discovery that there is more than one receptor for each steroid. Steroid receptors are members of the super-family of nuclear receptors. Steroid enters the cell, binds and activates empty receptors, inducing dimerisation and acquisition of high affinity for specific sequences of nucleotides within the hormone-response elements (HRE) of the target genes. Hormone-receptor complex interacts with the HRE to modulate transcription of the gene. The different receptors for each steroid (e.g. oestrogen receptors alpha and beta) help promote the differential responses in different target tissues. Analysis of the overall responses to HRT requires a knowledge of the dose and specificity of each steroid within the formulation, together with an understanding of how each steroid regulates the activities of each sub-group of receptors in each target tissue, allowing for the appropriate metabolism of the primary steroids. Additionally, there will be variations among different individuals.