Metabolism of norethisterone and norethisterone derivatives in rat uterus,vagina, and aorta

The 19nor-progestogen norethisterone is used as a progestogen component in contraceptives and in continuous- and sequential combined hormone replaceme nt therapy (HRT) in postmenopausal women. Metabolism of norethisterone in H RT target tissues may play a role in its biological response. The aim of th is study was to investigate which steroid-metabolizing enzymes are present in rat uterus, vagina, and aorta, three HRT target tissues. Next, the abili ty of the tissues to metabolize norethisterone was assessed. Furthermore, t o investigate the effect of substituents at the 7- and 11-position, the met abolism of Org OM38 (7 alpha -methyl-norethisterone), Org 4060 (11 beta -et hyl-norethisterone), and Org 34694 (7 alpha -methyl,11-ethylidene-norethist erone) was studied. Using radiolabeled progesterone, the presence of 20 alp ha -hydroxysteroid dehydrogenase, 5 alpha -reductase, and 3 alpha -hydroxys teroid dehydrogenase activity could be demonstrated in uterus, vagina; and to a lesser extent in aorta. The combined action of the latter two enzyme a ctivities resulted in 3 alpha -OH,5 alpha -H-norethisterone as the major me tabolite of radiolabeled norethisterone in uterus (26.9%), vagina (37.1%), and aorta (1.4%). The norethisterone derivatives, however, were metabolized to a much lesser extent (1.0-7.6%). No formation of 5 alpha -reduced forms of Org 4060, Org OM38, or Org 34694 was found, while formation of minor am ounts of 3 alpha -OH-Org 4060 and 3 alpha -OH-Org OM38 could be demonstrate d in both uterus, vagina, and aorta. These findings confirm the role of 5 a lpha -reductase as a rate-limiting step in the metabolism of norethisterone derivatives and show important inhibitory effects of substituents at the 7 alpha- and 11-position of the steroid skeleton on 5 alpha -reduction.