Comparative Effects of Chlormadinone Acetate and Its 3α- and 3β-Hydroxy Metabolites on Progesterone, Androgen and Glucocorticoid Receptors

Abstract

Aim/Methods: In vitro binding tests to human receptors and in vivo functional activities in animals were used to compare the effects of the progestin chlormadinone acetate (CMA) and its 3α- and 3β-hydroxy metabolites (3α-OH-CMA and 3β-OH-CMA) on progesterone, androgen and glucocorticoid receptors. Results: CMA, 3α-OH-CMA, 3β-OH-CMA and the reference progestin R5020 bound to human progesterone receptor with Ki values of 2.5 nm, 13 nm, 6.0 nm and 4.3 nm, respectively. Binding affinities to the human androgen receptor were characterized by Ki values of 3.8 nM for CMA, 83 nM for 3α-OH-CMA, 20 nM for 3β-OH-CMA and 2.9 nM for the reference androgen methyltrienolone. The Ki values for binding to the human glucocorticoid receptor were 16 nM for CMA, 69 nM for 3α-OH-CMA, 21 nM for 3β-OH-CMA and 1.2 nM for the glucocorticoid dexamethasone. In the rabbit endometrial proliferation test CMA, 3α-OH-CMA and 3β-OH-CMA (5 and 45 μg/kg p.o. for 5 days) had similar progestomimetic activities. CMA, 3α-OH-CMA and, to a lesser extent, 3β-OH-CMA (4.64 and 21.5 mg/kg p.o. for 7 days) inhibited testosterone-stimulated growth of prostate and seminal vesicles in castrated rats showing antiandrogenic activities. Glucocorticoid properties were demonstrated for CMA and 3α-OH-CMA (21.5 and 100 mg/kg p.o. for 6 days) but not for 3β-OH-CMA as reduction in thymus and adrenal gland weights in immature rats. Conclusion: Binding assays at human receptors showed similarly high affinities of CMA with the progesterone and androgen receptors and a 5 times lower affinity with the glucocorticoid receptor. At all receptor types, CMA had the highest, 3α-OH-CMA the lowest and 3β-OH-CMA an intermediate affinity. Animal studies revealed progestomimetic and antiandrogenic activities of CMA, 3α-OH-CMA and 3β-OH-CMA and glucocorticoid activities of CMA and 3α-OH-CMA.