Assessment of the oestrogenic activity of the contraceptive progestin levonorgestrel and its non-phenolic metabolites.
Levonorgestrel (13beta-ethyl-17alpha-ethynyl-17beta-hydroxy-4-gonen-3-one), a potent contraceptive progestin stimulates growth and proliferation of cultured breast cancer cells through a receptor-mediated mechanism, even though levonorgestrel does not bind to the oestrogen receptor (ER). To assess whether the oestrogen-like effects induced by this synthetic progestin are exerted via its metabolic conversion products, we studied the binding affinity of three A-ring levonorgestrel derivatives to the ER and their capability to transactivate an oestrogen-dependent yeast system co-transfected with the human ER gene and oestrogen responsive elements fused to a beta-galactosidase reporter vector. The results demonstrated that the 3beta,5alpha reduced levonorgestrel derivative and to a lesser extent its 3alpha isomer interact with the oestrogen receptor, with a significantly lower relative binding affinity (2.4% and 0.4%, respectively) than that of oestradiol (100%), while levonorgestrel does not. Both levonorgestrel metabolites were able to activate, in a dose-dependent manner, the beta-galactosidase reporter gene in the yeast expression system, an effect that was precluded by a steroidal antioestrogen. The oestrogenic potency of levonorgestrel metabolites was significantly lower (750-fold) than that of oestradiol. Furthermore, high doses of 3beta,5alpha levonorgestrel (2.5 mg/day/6 days) induced an increase of oestrogen-dependent progestin receptor in the anterior pituitary of castrated rats. The overall data offer a plausible explanation for the weak oestrogenic effects induced by high, non-pharmacological doses of levonorgestrel.
Santillán
R
R
Department of Reproductive Biology, National Institute of Medical Sciences and Nutrition S. Zubirán, Vasco de Quiroga 15, Mexico City, C.P. 14000, Mexico.
Pérez-Palacios
G
G
Reyes
M
M
Damián-Matsumura
P
P
García
G A
GA
Grillasca
I
I
Lemus
A E
AE
D000818:Animals; D001667:Binding, Competitive; D003271:Contraceptive Agents, Female / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D016912:Levonorgestrel / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D010903:Pituitary Gland, Anterior / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000187:drug effects / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics; D001616:beta-Galactosidase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
D003271:Contraceptive Agents, Female; D004965:Estrogen Antagonists; D004967:Estrogens; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D011993:Recombinant Fusion Proteins; D000077267:Fulvestrant; D004958:Estradiol; D016912:Levonorgestrel; D001616:beta-Galactosidase