Glycaemic control and hormone replacement therapy - Implications of the Postmenopausal Estrogen/Progestogen Intervention (PEPI) Study

Despite evidence that supports the beneficial effects of postmenopausal hor mone replacement therapy (HRT), concerns remain about its possible adverse effects. However, entry into the postmenopausal state is associated with ma ny characteristics of the insulin resistance syndrome, including increased cardiovascular morbidity and mortality, accretion of generalised and viscer al adiposity and insulin resistance. Studies carried out in postmenopausal women have revealed that an increase in visceral obesity is associated with an increase in androgenicity that, in turn, is associated with type 2 (non -insulin-dependent) diabetes mellitus. Short term studies of HRT containing conjugated estrogens (CEE) and medroxyprogesterone (MPA) have shown preven tion of the accretion of visceral fat. However, longer term studies using o ther techniques suggest that these effects may be evanescent, A few trials suggest that oral estrogen therapy reduces postmenopausal insulin resistanc e, as suggested by reductions in fasting insulin and glucose levels and an increase in glucose metabolism rates, whereas most studies do not show an a dverse effect upon carbohydrate metabolism. MPA may decrease these benefici al effects. Transdermal estrogen is essentially neutral with regard to insu lin sensitivity and oral estradiol (17 beta -estradiol) may also be neutral or enhance sensitivity. Different progestogens vary in their effects upon carbohydrate metabolism. The Postmenopausal Estrogen/Progestogen Intervention (PEPI) Study was a pro spective, 3-year, randomised trial in 875 women that compared placebo, unop posed CEE, CEE plus continuous MPA, CEE plus cyclical MPA, and CEE plus cyc lical micronised progesterone. Fasting insulin and glucose levels decreased significantly by 16.1% and 0.122 mmol/L, respectively, in all drug treatme nt groups. However, after a 75g glucose load, glucose levels at 2 hours inc reased by 0.33 mmol/L in the active treatment groups without a correspondin g increase in insulin levels. No beneficial effects on waist/hip ratio coul d be demonstrated. Data from the PEPI trial also suggested that the maximum benefit regarding carbohydrate metabolism was achieved in patients who wer e the most hyperglycaemic and hyperinsulinaemic at the start of therapy. It can be concluded, therefore, that HRT has few, if any, harmful effects o n carbohydrate metabolism and that it may be of benefit in women in modifyi ng the long term complications of the postmenopausal state.