The growth of some cancers of the breast is stimulated or maintained by oestrogens. Treatment of breast cancer thought to be hormonally responsive (i.e., oestrogen and/or progesterone receptor-positive or receptor unknown) has included a variety of efforts to decrease oestrogen levels (ovariectomy, adrenalectomy, hypophysectomy) or inhibit oestrogen effects (anti-oestrogens and progestational agents). These interventions lead to decreased tumour mass or delayed progression of tumour growth in some women.
In postmenopausal women, oestrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens (primarily androstenedione and testosterone) to oestrone and oestradiol. The suppression of oestrogen biosynthesis in peripheral tissues and in the cancer tissue itself can, therefore, be achieved by specifically inhibiting the aromatase enzyme.
Letrozole is a non-steroidal competitive inhibitor of the aromatase enzyme system; it inhibits the conversion of androgens to oestrogens. In adult non-tumour- and tumour-bearing female animals, letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum luteinizing hormone (LH), and causing the regression of oestrogen-dependent tumours. In contrast to ovariectomy, treatment with letrozole does not lead to an increase in serum follicle-stimulating hormone (FSH). Letrozole selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis.
Letrozole inhibits the aromatase enzyme by competitively binding to the haem of the cytochrome (CY) P450 subunit of the enzyme, resulting in a reduction of oestrogen biosynthesis in all tissues. Treatment of women with letrozole significantly lowers serum oestrone, oestradiol and oestrone sulphate and has not been shown to significantly affect adrenal corticosteroid synthesis, aldosterone synthesis or the synthesis of thyroid hormones.
In postmenopausal patients with advanced breast cancer, daily doses of 0.1–5 mg letrozole suppress plasma concentrations of oestradiol, oestrone and oestrone sulphate by 75–95% from the baseline, with maximal suppression achieved within 2–3 days. Suppression is dose-related, with doses of 0.5 mg and higher giving many values of oestrone and oestrone sulphate that were below the limit of detection in the assays. Oestrogen suppression was maintained throughout the treatment in all patients treated at 0.5 mg or higher.
Letrozole is highly specific in inhibiting aromatase activity. There is no impairment of adrenal steroidogenesis. No clinically relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxy-progesterone, adrenocorticotropic hormone (ACTH) or in plasma renin activity among postmenopausal patients treated with a daily dose of letrozole 0.1–5 mg. The ACTH stimulation test performed after 6 and 12 weeks of treatment with daily doses of 0.1, 0.25, 0.5, 1, 2.5 and 5 mg did not indicate any attenuation of aldosterone or cortisol production. Glucocorticoid or mineralocorticoid supplementation is, therefore, not necessary.
No changes were noted in plasma concentrations of androgens (androstenedione and testosterone) among healthy postmenopausal women after 0.1, 0.5 and 2.5 mg single doses of letrozole or in plasma concentrations of androstenedione among postmenopausal patients treated with daily doses of 0.1–5 mg. This indicates that the blockade of oestrogen biosynthesis does not lead to the accumulation of androgenic precursors. Letrozole did not affect the plasma levels of LH and FSH or the thyroid function, as evaluated by the thyroid stimulating hormone (TSH) levels, T3 uptake and T4 levels.