Doping in sport: 3. Metabolic conversion of oral norethisterone to urinary 19-norandrosterone

The detection of 19 norandrosterone (19-NA) in a competitor's urine sample is taken as prima facie evidence of administration of nandrolone or other 19-norsteroid but a potential problem is that administration of norethisterone, a progestogen used for menstrual disorders and for hormonal contraception, also results in the excretion of 19-NA that can exceed the laboratory reporting threshold of 2 ng/mL. The contribution of norethisterone to urinary 19-NA with and without 19-norandrostenedione, a known norethisterone tablet impurity, requires evaluation. Preparations containing, either <2 ng or 1 μg 19-norandrostenedione impurity per 5 mg of norethisterone, administered to female volunteers (n = 10) in doses comparable to those used for menstrual disorders (5 mg three times daily for 10 days), resulted in maximal 19-NA concentrations of 51 and 63 ng/mL, respectively. The maximal concentration of 19-NA, 2 h post-administration of a single 1 μg dose of 19-norandrostenedione, was 2.4 ng/mL. These results prove unequivocally that norethisterone is metabolized to 19-NA and that there is only a minor contribution from the impurity 19-norandrostenedione. Administration to women (n = 30) of a single contraceptive tablet containing norethisterone (1 mg) with one of the highest proportions of the impurity 19-norandrostenedione (∼0.5 μg, 0.05%, w/w) resulted in a urinary 19-NA concentration of 9.1 ng/mL, with a maximum concentration ratio of 19-NA to the norethisterone metabolite 3α,5β-tetrahydronorethisterone of 0.36. We provide data that should remove the need for time-consuming follow-up investigations to consider whether doping with 19-norandrogens has occurred.