Pharmacology of estradiol valerate/dienogest

Abstract

The particular features of the pharmacology of a new continuous regimen for hormone replacement therapy containing 2 mg estradiol valerate (E2V) and 2 mg dienogest (DNG) (Climodien, Schering AG, Berlin, Germany) depend largely on its progestogenic component. Dienogest has the essential properties of an effective progestogen, so that it protects against endometrial proliferation and remarkably does not counteract the effects of estrogens. It is a derivative of 19-nortestosterone, but, instead of having an alkyl group at position C17, it has a cyanomethyl group, which endows it with a unique pharmaceutical profile. Its pharmacokinetics make it suitable for oral administration, without accumulation following repeat dosing. The strength of its effect on the endometrium is reflected by the fact that its progestogenic potency (ovulation dose/transformation dose) is about four times greater than that of any other progestogen. It does not bind to sex hormone binding globulin (SHBG), a feature that helps to keep free serum levels of dienogest high and free testosterone levels low. The low antiestrogenicity of dienogest has been well demonstrated in studies of estrogen-related parameters, such as SHBG levels and vasodilatation markers (cyclic guanosine monophosphate, 5-hydroxylindole acetic acid). Receptor binding studies show similar antiandrogenic effects for dienogest and cyproterone acetate, although the Hershberger test of clinical androgenicity suggests that dienogest is not as strongly antiandrogenic as cyproterone acetate, but is more antiandrogenic than chlormadinone acetate or drospirenone. In summary, E2V/DNG is well suited as an effective hormone replacement therapy, with the potential for good bleeding patterns and low androgenicity, owing to its formulation with a progestogenic component that is highly endometriotropic, has low antiestrogenicity and exhibits considerable antiandrogenicity.