Endocrine Abstracts

Models of estrogen insufficiency have revealed new and unexpected roles for estrogens in both males and females. These models include knockouts of aromatase in mice (the ArKO mouse) as well as of the estrogen receptors (ERKO mice). There are also a number of individuals with natural mutations in the aromatase gene, as well as one man with a mutation in the ERa receptor. Some of these roles of estrogens apply equally to males and females and do not relate to reproduction, for example, the bone, vascular, and metabolic syndrome phenotypes. In terms of the latter, ArKO mice develop a phenotype of increased intra-abdominal adipose accumulation, hyperinsulinemia, hyperleptinemia, decreased physical activity and decreased glucose utilization. In addition, the males develop a striking sexually dimorphic hepatic steatosis. These symptoms are reversed by estradiol administration. Male ArKO mice also show a loss of neurons in the arcuate nucleus and medial pre-optic areas of the hypothalamus which is characterized by increased apoptosis of tyrosine hydroxylase expression neurons. This is not present in female mice. Men with aromatase deficiency develop a similar phenotype of dysfunctional energy homeostasis with type 2 diabetes, truncal obesity, acanthosis nigricans and hepatic steatosis. As with the mice, these symptoms are reversed by estrogen administration. Thus it is apparent that estrogen deficiency caused by lack of a functional aromatase gene results in a fully developed metabolic syndrome. It is concluded that estrogen has many roles which are similar to those of leptin in both mice and men