Influence of continuous combined estradiol norethisterone acetate preparations on insulin sensitivity in postmenopausal nondiabetic women

Objective: Estrogen-progestogen replacement therapy (HRT) may be associated with deterioration of insulin sensitivity in comparison to estrogens alone , which tend to improve insulin sensitivity in postmenopausal women. Insuli n sensitivity with the use of continuous combined 17-beta estradiol/norethi sterone acetate (E-2/NETA) preparations has not been examined before in pos tmenopausal women. Design: In a double-blind randomized parallel study, we evaluated the effec t of 2 mg E-2/l mg NETA thigh dose E-2/NETA), 1 mg E-2/0.5 mg NETA (low dos e E-2/NETA), or placebo (P) on the insulin sensitivity index (S-I) in three groups (18 women/group) of postmenopausal nondiabetic women (follicle stim ulating hormone [FSH] > 40 mIU/mL, mean +/- SD) aged 56 +/- 3 years, BMI 15 +/- 4 kg/m(2), cholesterol 233 +/- 42 mg/dL, and triglycerides 87 +/- 36 m g/dL, Insulin sensitivity was measured by means of a two-step hyperinsuline mic euglycemic glucose clamp (insulin infusion rate, 0.25 and 1.0 mU/kg/min for 120 min each) at baseline and after 3 months of daily administration o f high dose E-2/NETA, low dose E-2/NETA, or P. Analysis was performed assum ing equivalence of start-end changes of insulin sensitivity among treatment groups (Anderson-Hauck test). Results: S-I was 7.7 +/- 2.9, 7.5 +/- 3.4, 6.8 +/- 2.2 at baseline and 6.3 +/- 3.0, 7.9 +/- 2.5, 7.1 +/- 3.1 mL/min/m(2) per mu U/mL 3 months after th e administration of high dose E-2/NETA, low dose E-2/NETA, and P, respectiv ely. The low dose E-2/NETA group had start-to-end changes of S-I which were equivalent to the P group (0.4 [95% confidence interval [CI] -0.8; 1.7] vs . 0.4 [-0.3; 1.0]) (p = 0.02). For the high dose E-2/NETA group, equivalenc e could not be shown with either the P (p = 0.89) or with the low dose E-2/ NETA group (p = 0.90). S-I within the high dose E-2/NETA group decreased by - .5 (95% CI -2.7; -0.2) mL/min/m(2) per mu U/mL. HbA(1c) decreased from 5 .3 +/- 0.3 to 5.1 +/- 0.3 within the high dose E-2/NETA group (p < 0.03) an d remained unchanged within the low dose E-2/NETA and P group. Fasting plas ma glucose, fasting serum insulin, and C-peptide, as well as triglycerides rind BMI were comparable among the groups at baseline and after 3 months. T otal cholesterol decreased by 12% and 8% in women treated with high dose an d low dose E-2/NETA (p < 0.02), respectively, and remained unchanged within the P group. Conclusions: These results indicate that 3 months use of a low dose continu ous E-2/NETA preparation does not change insulin sensitivity in postmenopau sal women. At high dose of E-2/NETA, a modest decrease seems possible. The effects of E-2/NETA on other parameters of carbohydrate and lipid metabolis m are neutral or favorable. (Menopause 1999;6:36-42. (C) 1999, The North Am erican Menopause Society.).