Metabolic effects of aromatase inhibition
Gibb, Fraser Wilson
Aromatase, a member of the cytochrome P450 superfamily, catalyses the conversion of androgens to estrogens; specifically, testosterone to estradiol and androstenedione to estrone. Aromatase is widely expressed across a range of tissues and deleterious metabolic effects are observed in both murine aromatase knock-out models and in rare human cases of aromatase deficiency. The effects of pharmacological inhibition of aromatase, as employed in the treatment of breast cancer, are not well characterised. This thesis addresses the hypothesis that aromatase inhibition, and consequent changes in sex steroid hormone action (higher androgen:estrogen ratio), results in disadvantageous changes in body composition and reduced insulin sensitivity. In a cohort study of 197 community-dwelling men, lower testosterone and SHBG concentrations were observed in those fulfilling criteria for metabolic syndrome, although no relationship with estrogens was observed. The strongest determinant of circulating estrogens was substrate androgen concentration. A case-control study of aromatase inhibitor treated breast cancer patients and age-matched controls (n=40) demonstrated decreased insulin sensitivity and increased body fat in those treated with aromatase inhibitors; serum leptin concentration and leptin mRNA transcript levels (in subcutaneous adipose tissue) were elevated in this group. In healthy male volunteers (n=17), 6 weeks of aromatase inhibition (1 mg anastrozole daily) resulted in reduced glucose disposal during a hyperinsulinaemic euglycaemic clamp study, with d2-glucose and d5-glycerol tracers. No effects upon hepatic insulin sensitivity, lipolysis or body composition were noted, although serum leptin concentration was reduced following aromatase inhibitor administration. In conclusion, aromatase inhibition is associated with increased insulin resistance and, in women, increased body fat. This may be relevant for patients receiving aromatase inhibitor therapy, where more careful monitoring of glucose tolerance may be warranted.