ENDOCRINE CHANGES WITH THE AROMATASE INHIBITOR FADROZOLE HYDROCHLORIDE IN BREAST-CANCER

Fadrozole hydrochloride is a potent aromatase inhibitor with proven cl inical effectiveness. However, its optimal dose and its effects on ser um aldosterone levels/electrolyte balance have been disputed. To resol ve these issues, a double-blind randomised endocrine study of three do ses of fadrozole hydrochloride [0.5 mg twice daily (bd); 1.0 mg bd; 2. 0 mg bd] was conducted in 80 (68 evaluable) postmenopausal patients wi th advanced breast cancer over a period of 3 months. There were substa ntial falls in the serum levels of oestradiol, oestrone and oestrone s ulphate. For oestrone only, there was a significant effect of dose (on -treatment means: 0.5 mg, 38.0 pmol/l; 1.0 mg, 25.0 pmol/l; 2.0 mg, 23 .9 pmol/l). All oestrogens showed a similar pattern in relation to tim e, with the 3-month mean being higher than those at 1 and 2 months, an d this was significant for oestradiol (P = 0.012). There was an indica tion that complete suppression of oestrdiol and oestrone ws not mainta ined throughout the 12-h dosing period, but the data and its interpret ation are complicated by a minor diurnal rhythm in these parameters. T here were significant increases in 17-hydroxyprogesterone and androste nedione which may be due to a block of 11 beta-hydroxylase. There was a statistically non-significant fall in aldosterone levels (P = 0.06) during treatment (median pretreatment, 446 pmol/l; median decrease, 12 5 pmol/l). However the concurrent significant fall in the plasma sodiu m:potassium ratio indicated that changes in aldosterone secretion did occur. None of these effects on adrenal pathways was of a degree which is likely to have clinically relevant consequences. It is concluded t hat fadrozole hydrochloride achieves near maximal suppression of oestr ogens at 1 mg bd, and that its effects on aldosterone synthesis are un likely to be of clinical significance.