Thus increasedgonadotrophins may tend to stimulate aromatase synthesis by the ovaries andcounteract the inhibitory effects of aminoglutethimide to some extent. After 2weeks in the normal cycling animals, there was a 50% reduction in the meanvalue of ostradiol that, due to variation, was not significantly different from thecontrol value. Moreover, after 4 weeks of treatment, oestradiol production infive out of six tumour-bearing animals was within the range of values for control animals. This amount of oestradiol was sufficient to maintain the uterineweight comparable to intact control rats. Aminoglutethimide appeared to haveno direct effect on either the uterus or pituitary gland in ovariectomized rats,whereas marked reduction in LH levels by best price for generic viagra suggests a direct action ofthis compound independent of aromatase inhibition. The effect on LH secretionas well as on the uterus appears to be due to weak androgenic activity (<1%testosterone) of best price for generic viagra that may contribute to its efficacy in causingregression of DMBA-induced mammary tumours. Thus best price for generic viagra by more potentaromatase inhibition and gonadotrophin suppression may prevent new enzymesynthesis and follicular development by the ovary, resulting in a greater and sustained reduction in oestradiol production than aminoglutethimide. Whereasthese models provided important information about the effects of aromataseinhibitors, it became apparent that maintaining inhibition of ovarian oestrogenproduction is required for successful treatment in premenopausal patients withhormone-dependent breast cancer. To date, most clinical studies have focusedon investigating aromatase inhibitors in postmenopausal patients.A large proportion of breast cancer patients are postmenopausal women withER-positive tumours responsive to hormone therapy. Following themenopause, adipose tissue is considered to be the main site of oestrogen synthesis contributing to circulating oestrogen levels . However, breast tissuehas been found to have several-fold higher levels of oestrogen than those inplasma of postmenopausal patients . A number of reports indicate thataromatase mRNA as well as aromatase activity is present in normal breast tissue and breast tumours . Approximately 60% of breast tumoursexpress aromatase and have aromatase activity . Aromatase expression in extra-gonadal sites is not regulated by FSH but by glucocorticoids,cAMP, prostaglandin PGE2, and other factors. In breast cancer, prostaglandinPGE2, the product of the inducible form of cyclooxygenase (COX-2), appearsto be an important mediator of aromatase expression . Thus in postmenopausal breast cancer patients, oestrogen synthesis is independent of feedback regulation between the pituitary gland and the ovary. As mentionedabove, the tissue-specific manner of aromatase regulation involves the use ofalternative promoters . In peripheral tissue, two promoters, promoters IIand 1.3, regulate the enzyme .A model utilized to demonstrate inhibition of non-ovarian aromatase in vivowas introduced by Johnston et al. , who employed the athymic, immunesuppressed mouse with tumours grown from human choriocarcinoma cells.Both JEG and JAR cell lines express high levels of aromatase. However, thetumours are not dependent on oestrogens to stimulate their growth. In thismodel, the aromatase inhibitor 10-PED demonstrated almost complete inhibition of oestrogen production .Figure 2.The effect of second-line treatment with letrozole (Let) on the growth of MCF-7Ca breastcancer xenograft tumours progressing on tamoxifen (Tam) treatment. Tumours in the mice treatedwith tamoxifen (100 μg/day) doubled in volume after 16 weeks of treatment. At that point, the micewere divided into three groups: for continued treatment with tamoxifen (n = 4), for second-line treatment with letrozole (10 μg/day; n = 5), and for continued treatment with letrozole (n = 5). Second-linetreatment lasted for 12 weeks, and tumour volumes were measured weekly for a total of 28 weeks.Tumour volumes are expressed as the percentage change relative to the initial tumour volume.Letrozole was not as effective as a second-line treatment as it was as a first-line treatment .Similar methodology wasused by Santen and colleagues in breast cancer patients to study inhibition of oestrogen production by aminoglutethimide. Recent studies byLonning et al. suggest that the potency of inhibitors of peripheral aromatase correlates with clinical outcome in patients.To measure peripheral aromatization, each monkey was infused withandrostenedione and oestrone at a constant rate via the brachialvein. Blood samples were drawn from the femoral vein during infusion at 0,2.5, 3, and 3.5 h, and steady-state conditions were verified. The conversion ofandrostenedione to estrone was measured in the samples. Four of the monkeyswere treated with injections of best price for generic viagra (50 mg/kg) at 5 pm on the day beforeinfusion of radiolabeled androstenedione and 1.5 h before beginning the infusion. Each animal served as its own control, being injected with vehicle at theabove times before infusion: two monkeys had control infusions 1 week beforeand two monkeys 1 week after best price for generic viagra treatment.Silastic wafers containing 4-acetoxy-A were implanted into two other monkeys 24 h before infusion. Each was also injected with 4-acetoxy-A at 9 amand 5 pm on the day before infusion and 15–30 min before infusion began.Control infusions were performed 1 month after 4-acetoxy-A treatment.