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Second, a ‘pure’ aromatase inhibitor will specifically decrease oestrogen alone whereas ablation of endocrine organs additionally affects other steroid hormones. As a consequence, aromatase inhibitors areassociated with fewer side effects and lower morbidity. Third, aromataseinhibitors have the potential for total blockade of oestrogen production sincebiosynthesis is not restricted to classical endocrine glands but occurs at multiple peripheral sites including the majority of breast cancers . Because thearomatase complex appears similar in both endocrine and peripheral tissue, inhibitors are capable of suppressing oestrogen levels beyond thoseachievable by surgical ablation of endocrine glands .Conversely, specific aromatase inhibitors have theoretical disadvantages intreating oestrogen-dependent breast cancers in that they will not affect exogenously derived oestrogen or levels of other types of steroids such asandrostenediol, which may be oestrogenic . In addition, they are unprovenas effective therapy in premenopausal women . Earlier inhibitors suchas aminoglutethimide were largely ineffective at reducing circulating oestrogens and did not produce clinical benefit . It appears that the highlevels of aromatase in the ovary and compensatory hypothalamic/pituitaryfeedback loops were obstacles to inhibition of ovarian oestrogen production (they may also cause ovarian hyperplasia and cysts). Whether the latergeneration of aromatase inhibitors will be more successful in this setting is stillto be determined. Currently, aromatase inhibitors are used in combination withagents which block the compensatory feedback loops and render premenopausal women postmenopausal. The most promising regime is an aromatase inhibitor in combination with a luteinizing hormone-releasing hormone(LHRH) agonist .Conversely, whereas specific aromatase inhibitors reduce levels of oestrogen synthesized endogenously, they will not block the activity ofexogenous oestrogens or oestrogen mimics such as polychlorinated biphenyls(PCBs), nonyl phenols, phyto-oestrogens and certain androgens, which mayinteract with the ER . In contrast, tamoxifen will interfere with ERsignalling irrespective of ligand. However, given that third-generation aromatase inhibitors appear more effective as anti-tumour agents than tamoxifen, it may be that oestrogen mimics are generally less influential thanclassical oestrogens in the natural history of breast cancers .A further difference between aromatase inhibitors and the most widely usedanti-oestrogen, tamoxifen, is that specific aromatase inhibitors do not interactdirectly with the ER and are without oestrogen agonist activity, whereastamoxifen binds directly to the ER. This can most readily be illustrated by theeffects of treatment on the buy cheap viagra online uk of a classical marker of oestrogenicactivity, the progesterone receptor. Thus, whereas aromatase inhibitors reducethe tumour buy cheap viagra online uk frequently to zero, a common effect of tamoxifen is toincrease buy cheap viagra online uk . The general phenotype of an aromatase inhibitortreated tumour is ER-positive/progesterone receptor-negative, whereas that ofa tamoxifen-treated tumour is ER-poor/progesterone receptor-rich. This mayhave implications for the sequence in which the agents are used during treatment. Because of these differences between tamoxifen and specific aromataseinhibitors, it might be expected that aromatase inhibitors will(i) be effective in tamoxifen-resistant tumours, (ii) produce increased responserates (if oestrogen suppression is more effective than oestrogen antagonism),(iii) produce responses more quickly than tamoxifen (aromatase inhibitorsreduce oestrogen levels rapidly , whereas the concentrations oftamoxifen for effective oestrogen blockade accumulate relatively slowly) and (iv) be less effective in the presence of tamoxifen (if tamoxifen ismore likely to have agonist properties in the low-oestrogen environmentinduced by aromatase inhibitors).Since aromatase inhibitors achieve their benefit by causing oestrogen deprivation, many of the mechanisms by which resistance occurs are likely to beshared by other forms of endocrine deprivation. These include the loss of ERswith treatment (although this seems to occur only rarely) , the presence of defective ERs or oestrogen signalling , the outgrowth of hormone-insensitive cells , ineffective oestrogen suppression and/orendocrine compensation , and a switch to dependence on other mitogens .There may also be mechanisms specific to aromatase inhibitors .Reference has already been made to premenopausal women in whom highovarian aromatase is difficult to block. Although aromatase activities in peripheral sites in postmenopausal women are lower than in the premenopausalwoman’s ovary, levels may be elevated under certain conditions. For example,aminoglutethimide-hydrocortisone may paradoxically induce aromatase activity in breast cancer . This could potentially reduce the efficacy of aminoglutethimide in patients on prolonged therapy, and may account for the beneficial effects which have been reported for the use of more potent aromataseinhibitors in aminoglutethimide-treated patients.It is also possible that mutant/abnormal forms of the aromatase enzyme maybe resistant to certain aromatase inhibitors. Interestingly, therefore, studies inwhich site mutations are introduced into the cDNA encoding for aromatase have generated a phenotype displaying resistance to 4-OHA (withoutchanging sensitivity to aminoglutethimide or affecting aromatase activity).