Estrogen biosynthesis in adipose: regulation by paracrine and autocrine mechanisms

E R Simpson, S E Bulun, J E Nichols and Y Zhao

Cecil H. and Ida Green Center for Reproductive Biology Sciences, and the Departments of Obstetrics/Gynecology and Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA
(Requests for offprints should be addressed to E R Simpson, Green Center for Reproductive Biology Sciences, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235-9051, USA)

Abstract

Estrogen biosynthesis is catalyzed by an enzyme known as aromatase P450 (1-4) (P450arom, the product of the CYP19 gene (5)). CYP19 is a member of the P450 superfamily of genes which currently contains over 300 members in some 36 gene families (5). Typically, these enzymes catalyze the insertion of oxygen atoms derived from molecular oxygen into organic molecules to form hydroxyl groups. In the case of P450arom, three such attacks by molecular oxygen give rise to loss of the C19 angular methyl group of the steroid substrate as formic acid, with concomitant aromatization of the A-ring to give the phenolic A-ring characteristic of estrogens (6).

Estrogen biosynthesis in humans occurs in a number of tissue sites of expression including the granulosa cells and corpus luteum of the ovary (7,8), the Leydig cells of the testis (9), the syncytiotrophoblast of the placenta, various sites in the brain including the hypothalamus, amygdala, and hippocampus (10,11), as well as adipose tissue (12). The significance of adipose tissue as a source of estrogens was first recognized some twenty years ago by MacDonald, Siiteri, and their colleagues (13-16) who determined the fractional conversion of circulating androstenedione to estrone in male and female human subjects. They found that not only was there a striking increase with obesity, suggesting that most of the extragonadal conversion occurred in adipose tissue, but also that there was an equally striking increase with age for any given body weight.

Journal of Endocrinology

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