Can 19-nortestosterone derivatives be aromatized in the liver of adult humans? Are there clinical implications?

Abstract

19-nortestosterone derivatives (norethisterone, norethynodrel, tibolone) can readily be aromatized in the adult human liver. This leads to the formation of the potent estrogens ethinylestradiol from norethisterone or norethynodrel and 7 alpha-methyl-ethinylestradiol from tibolone. This may have clinical consequences, e.g. the elevated risk of venous thromboembolic disease in premenopausal women treated with high doses of norethisterone for bleeding disorders, or the elevated risk of stroke or endometrial disease in postmenopausal women treated with tibolone.

Determination and identification of estrogenic compounds generated with biosynthetic enzymes using hyphenated screening assays, high resolution mass spectrometry and off-line NMR

“…Although not frequently described, NET can be metabolized in humans to EE2 via hydroxylation of the A ring and a subsequent loss of H 2 O introducing aromaticity in the A ring. This effect was first described by Yamamoto et al [45,46], whereas Kuhl and Wiegratz recently discussed clinical implications of the formation of this potent estrogenic active metabolite in humans [47].…”

Norethisterone-induced hepatic adenomas can cause life-threatening bleeding in girls with inherited platelet disorders

“…The 19-nortestosterone derivatives are recognized by androgen receptors, to which they bind with high affinity. After oral norethisterone administration, a small proportion of the compound is rapidly converted into ethinylestradiol, and the shape of the concentration-time curve suggests that this conversion occurs in the liver (27). The oxidative introduction of double bonds into the 1-ring can be catalyzed by the hepatic cytochrome P450 enzymes, and 19-nortestosterone derivatives (norethisterone, norethynodrel, and tibolone) are readily aromatized in the normal adult liver.…”

Praxis der Hormontherapie in der Peri- und Postmenopause

“…Tibolon ist das 7α-Methyl-Derivat des Norethynodrels und damit eine Prodrug aus der Gruppe der Nortestosteronderivate, die rasch nach der Einnahme im Dünndarm und in der Leber in das 7α-Methyl-Norethisteron (MNET), das 7α-Methyl-Ethinylestradiol (MEE) sowie die schwachen Östrogene 3α-und 3β-Hydroxytibolon und zahlreiche andere Metaboliten umgewandelt wird [20]. Für das Verständnis der Wirkungen und Nebenwirkungen des kontinuierlich in einer Tages [20].…”

“…Für das Verständnis der Wirkungen und Nebenwirkungen des kontinuierlich in einer Tages [20]. Dies erklärt die signifikante Zunahme des Endometriumkarzinomrisikos durch Tibolon um 50-100% [23,24].…”

“…dosis von 2,5 mg angewandten Tibolons ist von Bedeutung, dass das MEE ein dem Ethinylestradiol vergleichbares starkes Östrogen ist, während das MNET (auch als Δ4-Isomer bezeichnet) ein schwaches Gestagen (mit nur 13% der gestagenen Wirkungsstärke von Norethisteron) mit starker androgener Aktivität (vergleichbar mit Testosteron) darstellt[20,21,22]. Daten widersprüchlich.…”