Endocrine disorders associated with inappropriately high aromatase expression

Aromatase P450 (P450arom) is responsible for conversion of C19 steroids to estrogens in a number of human tissues, such as the placenta, gonads, adipose tissue, skin and the brain. Aromatase expression in human tissues is regulated by use of alternative promoters in the placenta (promoter I.1), adipose tissue (promoters I.4, I.3 and II) and gonads (promoter II). Aromatase expression is absent in the disease-free adult liver, adrenal and uterine tissues. Excessive or inappropriate aromatase expression in adipose fibroblasts and endometriosis-derived stromal cells, as well as in testicular, hepatic, adrenal and uterine tumors, is associated with abnormally high circulating estrogen levels and/or with increased local estrogen concentrations in these tissues. Whether systemically delivered or locally produced, elevated estrogen levels will in turn promote the growth of hormone-responsive tissues. We recently studied aromatase expression in testicular tumor and adipose tissue samples from prepubertal boys with gynecomastia, in hepatocellular cancer and adrenocortical tumor samples from adult men with gynecomastia, in breast adipose tissue samples proximal to breast tumors, and in endometrial cancer, leiomyoma and endometriosis tissues. Excessive aromatase activity and P450arom transcript levels were found in these tissue samples or in cultured cells derived from these tissues. In these neoplastic or non-neoplastic tissues or cells, the regulation of aromatase expression was studied in terms of alternative promoter use, both in vivo and in response to various hormonal stimuli. Our results were suggestive of a common metabolic abnormality associated with activation of a cyclic AMP-dependent signalling pathway that gives rise to transcriptional transactivation of aromatase expression via promoters I.3 and II in all of the above tissues. This article describes the common pathophysiological and molecular features of excessive aromatase expression in these disease states.