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
