Effects of tibolone or continuous combined oestradiol/norethisterone acetate on glucose and insulin metabolism.

OBJECTIVE: To determine the effects of tibolone or oestradiol (E(2) )/norethisterone acetate (NETA) hormone replacement therapy on glucose and insulin metabolism in postmenopausal women. DESIGN: Single-centre double-blind placebo-controlled randomized clinical trial. SUBJECTS/METHODS: We randomized 105 healthy postmenopausal women to tibolone 2·5 mg daily, continuous combined oral E(2) 2 mg/NETA 1 mg daily or placebo over a 2-year study. We performed intravenous glucose tolerance tests (IVGTT) with measurements of plasma glucose, insulin and C-peptide concentrations and the IVGTT glucose elimination rate, k. Mathematical modelling was performed to determine measures of insulin sensitivity, S(i) , pancreatic insulin secretion and hepatic and plasma insulin elimination. RESULTS: Tibolone decreased S(i) to 53-63% and k to 72-79% of baseline values but increased IVGTT phase 2 C-peptide concentrations 1·6-1·8-fold and pancreatic insulin secretion 2·2-2·4-fold, so overall IVGTT glucose concentrations were unaffected. Similar, but for k, significantly smaller changes in insulin and C-peptide secretion were seen with E(2) /NETA, also with no effect on overall IVGTT glucose concentrations. CONCLUSIONS: Tibolone reduces insulin sensitivity. Healthy postmenopausal women seem able to compensate for this and maintain normal postload glucose concentrations, but it may not be advisable to prescribe tibolone to women with, or at increased risk for, diabetes.

Randomized trial of effect of transdermal continuous combined hormone replacement therapy on cardiovascular risk markers.

Whether hormone replacement therapy (HRT) is beneficial for coronary heart disease (CHD) is controversial. We hypothesized that continuous combined transdermal HRT may have benefits on CHD risk markers without the potential adverse effects seen with certain other HRT regimens. Sixty apparently healthy postmenopausal women, aged 40-65 years, entered a prospective, double-blind, randomized, placebo-controlled clinical trial; 55 women completed the 6-month study. Women received either transdermal oestradiol 17beta 0.05 mg and norethisterone acetate 0.125 mg daily, or identical placebo. Circulating markers of vascular function and remodelling, forearm blood flow, lipids and lipoproteins, glucose and insulin, and haemostatic safety parameters were measured at baseline and after treatment. Compared with placebo after 6 months, HRT administration resulted in decreased E-selectin (P < 0.01), and angiotensin-converting-enzyme (ACE; P = 0.05). Cholesterol (P < 0.05), low-density lipoproteins (LDL; P < 0.05), high-density lipoprotein3 (HDL3; P < 0.05) and apolipoproteins AII (P < 0.05) and B (P < 0.05), and fasting insulin (P < 0.05) also decreased in the HRT group. Factor VII coagulation activity decreased (P < 0.01) and plasminogen activator inhibitor-1 and fibrin D-dimer increased (P < 0.05) in the HRT group, whilst prothrombin fragment 1 + 2 (P < 0.05) decreased, more so in the placebo group. There were no changes in matrix metalloproteinase (MMP)-2, or in LDL particle size. This transdermal HRT had beneficial effects on vascular function and CHD risk markers.