Novel methods of oestrogen deprivation for treatment of breast diseases

Abstract

SynopsisThe breast can be deprived of oestrogen by blockade of the synthesis of oestradiol or of its precursors. In postmenopausal women, oestrogen synthesis occurs almost exclusively in extraglandular tissues. Thus, liver, muscle and fat, as well as other tissues, convert precursor androgens such as androstenedione and testosterone of adrenal origin to oestrone and oestradiol through the enzyme, aromatase. Breast cancer tissue and its surrounding stroma also contain aromatase which could potentially convert a biologically important amount of androgen to oestrogen. Sulphatases are present in multiple tissues including breast and act to reform free oestrogens from their conjugated derivatives. Each of the steps outlined (i.e. precursor androgen formation, aromatase, and sulphatase), serve as potential sites of blockade of oestrogen synthesis. Aromatase can be inhibited by either suicide or competitive inhibitors. In our studies, an imidazole inhibitor of aromatase which acts competitively (i.e. CGS 16949A) is 1000-fold more potent than aminoglutethimide and ten-fold more potent than 4-hydroxyandrostenedione in vitro. In sixteen postmenopausal women, doses 500-fold less than standard doses of aminoglutethimide inhibited plasma and urinary oestrogens measured by radioimmunoassay or GLC mass spectrometry to the same extent as with aminoglutethimide. The use of sulphatase inhibitors, another means of oestrogen deprivation, may potentially be feasible. Sulphatase inhibitors are active in vitro but currently lack potency and specificity for the sulphatase in breast cancer tissue itself.In premenopausal women, the oestrogens are directly aromatised from androgens in ovarian tissues through the stimulatory influence of LH and FSH. Suppression of these gonatrophins with or without additional aromatase inhibitors provides a means of inhibiting oestrogen in premenopausal women. Aromatase inhibition, alone, will probably not be effective because of the reflex rise in LH and FSH observed. Our studies indicate effective suppression of oestradiol in premenopausal women with the GnRH superagonist analogue, Leuprolide. However, combined use of this superagonist analogue plus an aromatase inhibitor would have the advantage of blocking synthesis of oestrogen, both in ovary and in extraglandular sites.