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Whereas there have been dissenting opinions about whether total bodyaromatization and plasma oestrogen levels reflect what is happening in tissues,interestingly these biochemical findings are consistent with clinical observations. Thus randomized studies comparing the firstand second-generationcompounds aminoglutethimide, formestane and fadrozole, either to megestrolacetate or tamoxifen in metastatic disease, reveal no clinical superiority for anyof these compounds compared to conventional treatment . In contrast,as will be reviewed elsewhere in this volume, the novel, more potent, thirdgeneration compounds provided clinical superiority.All values were determined by the same assay at the Academic Department of Biochemistry, RoyalMarsden Hospital, London, UK (head: Professor M. Dowsett) and the viagra for sale without a prescription Cancer Research Groupat the Haukeland University Hospital in Bergen, Norway (head: Professor P.E. Lonning).Abbreviations: od, once daily; bid, twice daily; qid, four times daily; w, weekly; 2w, every 2 weeks.Accordingly, the assessment of total body aromatization with use of tracer techniques estimates thesum of oestrogens produced in the peripheral tissues and should be consideredas a surrogate marker for non-glandular oestrogen production.A different issue relates to local oestrogen synthesis within the tumour tissue. Interestingly, there is a substantial variation in oestrogen levels betweendifferent tumours. This probably reflects differences regarding expression ofthe aromatase enzyme, although differences with respect to local oestrogenmetabolism may be relevant as well . Whereas only one aromatasegene has been identified, this contains at least 10 different promoters . Thepromoters II, I.3 and I.7 are particularly active in viagra for sale without a prescription cancer tissue .Notably, these promoter regions are stimulated by different growth factors andinterleukins known to be synthesized in viagra for sale without a prescription tumours, probably contributingto the high local oestrogen concentrations observed in some human breasttumours . It is noteworthy that tissue oestrogen concentrations seem to bemuch higher in oestrogen receptor-positive compared to -negative tumours. Beside aromatase, several other enzyme systems (see for references)are involved in oestrogen synthesis and conversion in postmenopausal women,such as steroid sulphatase, oestrogen sulphotransferase and 17s-hydroxysteroid dehydrogenase type 1 and 2.Whereas the influence of aromatase inhibitors on tissue oestrogen levels hasbeen evaluated in several studies , each study involved a limitednumber of patients only. An overview has recently been published .Concerning the third-generation aromatase inhibitors, significantly decreasedtissue oestrogen levels in viagra for sale without a prescription tissue samples have been found during treatment with anastrozole and letrozole . Data about the influence ofexemestane on tissue oestrogen levels are currently not available.Third generation aromatase inhibitors (anastrozole, letrozole and exemestane)differ to previous compounds with respect to their biochemical efficacy. Whilein general there is a good consistency between in vitro and in vivo effects,notable there may be important differences, as illustrated by comparing fadrozole and letrozole. This is due to the fact that in vivo effects also depend onlocal tissue and total body drug disposition. Whether the lack of cross-resistance between non-steroidal and steroidal compounds may be explainedby differential effects on the aromatase enzyme (enzyme inactivation versusenzyme inhibition) or by other factors, like slight androgen side-effects of thesteroidal compounds , remains an open question.Oestrogen is the major stimulus driving the growth of hormone-dependentviagra for sale without a prescription cancer, and most forms of endocrine therapy are directed towardsinhibiting, ablating or interfering with oestrogen activity. In young adultwomen, the ovary is the main source of oestrogen synthesis; after a cascade ofbiochemical steps, the conversion of androgen precursors (testosterone andandrostenedione) into the corresponding oestrogens (oestradiol and oestrone,respectively) ultimately occurs, specifically mediated by the enzyme aromatase. As ovarian function declines with the onset of the menopause, the relative proportion of oestrogens synthesized in extragonadal sites increases, andeventually non-ovarian oestrogens (mainly oestrone) predominate in the circulation. Enzymatic conversion of androgenic precursors (testosterone andandrostenedione), secreted by the adrenals, generates oestradiol and oestronein peripheral tissues. Aromatase, the enzyme responsible for this conversion, ismainly present in adipose tissue, liver, placenta, muscle, skin and brain.Aromatase activity has also been identified in the epithelial and stromal components of the breast. Therefore, local synthesis of oestrogens may contributeto viagra for sale without a prescription cancer growth in postmenopausal women. At the tissue level, complexparacrine and autocrine crosstalk plays an instrumental role in normal breastphysiology, but is also crucial for the promotion and development of a cancer.Tumour cells may also be able to produce hormones or growth factors, whicheither can cause promotion of proliferation or modulate the local environment.During the 1960s, successful medical approaches were developed with pharmacological doses of steroids (oestrogens, progestins and androgens) and laterantioestrogens, selective oestrogen receptor modulators (SERMs) and aromatase inhibitors, which have now rendered obsolete major endocrine-ablativesurgery.