Antiandrogenic activity of norgestimate in a human androgen-dependent stable-transfected cell line

Acne occurs from an overstimulation of the sebaceous glands by high levels of androgens or because sebaceous glands are hypersensitive to normal levels of testosterone. In women with moderate acne, norgestimate (NG) in association with ethinyl estradiol (EE) is acknowledged as an effective treatment; this is related to the effect of oral contraceptives on androgen production and transport. However, the antiandrogenic properties of NG itself have been poorly studied.

The present work was undertaken to find out whether NG and its derivative, 17-deacetylnorgestimate (dNG), present antiandrogen activity. First, we studied the effect of NG and dNG on the intracellular localization of green fluorescent protein (GFP)-labeled androgen receptor (AR). Then, we compared the AR activity of NG and dNG with that of cyproterone acetate (CPA), a gold-standard antiandrogenic compound, by investigating competitive binding, antagonist activity and transactivation level of AR.

NG and dNG decreased GFP-AR nuclear translocation, revealing their antiandrogenic property, as for CPA. In the whole cell competition assay performed in a human cell line stably expressing an AR-responsive luminescent reporter gene (PALM cells) with (3)H-labeled R1881 as tracer, NG and dNG were slightly stronger competitors than the antiandrogen CPA. Half-maximal inhibition (K(i)) of (3)H-labeled R1881 (10(-9) M) binding occurred at 4.2 +/- 0.5 x 10(-8) M of NG, 3.4 +/- 0.4 x 10(-8) M of dNG and 6.6 +/- 0.8 x 10(-8) M of CPA. Comparison of antagonist activities of NG, dNG and CPA on AR transactivation levels showed that NG, dNG and CPA inhibited androgen-induced luciferase activity in PALM cells. We observed slight and similar inhibition with 6 x 10(-8) M respectively of NG, dNG and CPA. For the three compounds, the best inhibitory effect was found at 3 x 10(-7) M: 24% for NG and dNG vs. 47% for CPA. The antiandrogenic activity of NG and dNG was found to be 50% that of CPA.

In a human androgen-dependent stable-transfected cell line, a useful tool for studying AR transcriptional activity and its subnuclear localization in the presence of androgens and antiandrogens, we demonstrated that NG and dNG have antiandrogenic properties that could partly explain the efficacy of NG in association with EE for the treatment of moderate acne in women.