来曲唑-芳香化酶抑制剂.ppt

The role of estradiol gaining and maintaining bone mass closing of the epiphyses the feedback on gonadotropin secretion Estrogen excess premature closure of the epiphyses gynecomastia low gonadotropin low testosterone levels. Aromatase Aromatase, also known as estrogen synthetase, is the key enzyme in estrogen biosynthesis. The enzyme, localized in the endoplasmic reticulum of the estrogen-producing cell, is encoded by the?CYP19A1?gene，which is localized on chromosome 15 and comprises nine exons， the start codon for translation is located on exon 2. CYP19 gene Men with estrogen deficiency caused by a mutation in the CYP19 gene suffer from： low bone mineral density (BMD) unfused epiphyses, high gonadotropin high testosterone levels . Aromatase activity gonads placenta brain fat tissue muscle hair bone vascular tissue Estradiol production direct testicular secretion conversion of testicular androgens peripheral conversion of adrenal androgens Mechanism Nonsteroidal enzyme inhibitors such as anastrozole and letrozole inhibit enzyme activity by binding with the heme iron of the enzyme. Incomplete efficacy Although aromatase inhibition by anastrozole and letrozole is reported to be close to 100%, administration of these inhibitors to men will not suppress plasma estradiol levels completely. In men third-generation aromatase inhibitors will decrease the mean plasma estradiol/testosterone ratio by 77% . Cause of incomplete efficacy Aromatase is less suppressed in the testis compared to adipose and muscle tissue. Advantage It prevents excessive reduction of estrogen levels in men and the possible associated adverse effects. In postmenopausal women with breast carcinoma, long-term use of potent aromatase inhibitors reduces circulating estradiol levels by 88% and is associated with adverse effects on bone. Effect Lowering estradiol levels, by administering an aromatase inhibitor such as letrozole, i