CLINICAL STUDY Acute estrogen exposure does not affect basal very low-density lipoprotein–triglyceride production or oxidation in postmenopausal women Lars C Gormsen 1,2 , Christian Høst 1 , Britta Eilersen Hjerrild 1 , Claus H Gravholt 1 and Søren Nielsen 1 1 Medical Department M (Endocrinology and Diabetes), Aarhus University Hospital, DK-8000 Aarhus, Denmark and 2 Department of Nuclear Medicine, Aarhus University Hospital, Skejby, DK-8200 Aarhus N, Denmark (Correspondence should be addressed to L C Gormsen; Email: lars.christian.gormsen@ki.au.dk) Abstract Context: Long-term hormone replacement therapy (HRT) with estradiol (E 2 ) is associated with an altered lipid profile including unfavorable increases in triglyceride (TG) concentrations and augmented hepatic very low-density lipoprotein (VLDL)–TG production. There are indications that this effect of estrogens may be immediate. Objective: To study the in vivo effect of a single dose of E 2 on VLDL–TG kinetics and oxidation in humans. Methods: Eight healthy, postmenopausal women were given a single dose of either placebo or E 2 (4 mg) orally. VLDL–TG kinetics was assessed by a 240-min primed-continuous infusion of ex vivo labeled [1- 14 C]triolein-labeled VLDL. Fractional and absolute VLDL–TG oxidation was determined by hyamin trapping of exhaled 14 C label. Indirect calorimetry provided measurements of lipid oxidation. Results: Administration of 4 mg of E 2 orally rapidly increased plasma E 2 concentrations from below detection threshold to premenopausal levels. Free fatty acids (FFA) and TG concentrations were unaltered. No immediate effect was observed on either VLDL–TG production (placebo versus E 2 ): 20.0G12.4 vs 24.1G10.7 mmol/min, PZ0.33; VLDL–TG oxidation: 12.3G10.9 vs 12.6 G5.6 mmol/min, PZ0.93); or VLDL–TG clearance rates: 51.4G16.8 vs 64.9G28.8 ml/min, PZ0.34). Conclusions: Short-term E 2 elevation does not affect VLDL–TG production, oxidation, or clearance in humans. We therefore propose that HRT-associated dyslipidemia has a gradual rather than immediate onset. European Journal of Endocrinology 163 421–426 Introduction Postmenopausal hormone replacement therapy (HRT) is associated with favorable changes in lipid profile including lowered levels of low-density lipoprotein (LDL) and increased high-density lipoprotein (HDL) (1). Administration of estrogens, however, may cause hypertriglyceridemia, a non-favorable effect (2) on the individual’s risk of developing cardiovascular disease. Increased concentrations of circulating triglycerides (TGs) may stem from either: i) increased hepatic production and secretion of TG rich very low-density lipoproteins (VLDLs), or ii) reduced peripheral clearance by lipoprotein lipase (LPL), hepatic lipase, direct catabolism, and/or LPL receptors (3). Whereas LPL activity is modified by estradiol (E 2 ) according to whether the enzyme is located in muscle or adipose tissue, there is now general agreement that long-term estrogen administration augments hepatic VLDL pro- duction (1) and leads to elevated TG levels. Although it is certainly possible that the TG increasing effect of estrogens may develop gradually over weeks and months, there are indications that the effect may be more immediate. Animal studies indicate that the hypertriglyceridemic effect of estrogen may have an acute onset. Thus, cultured chick hepatocytes stimulated by estrogen for 3 h secrete significantly more VLDL particles than control hepatocytes (4). Moreover, both APOB mRNA and secretion of VLDL increase following a single injection of either diethylstilbestrol (5) or E 2 (6), an effect possibly mediated by the activation of membrane-bound estrogen receptors (ERs), enabling rapid cellular signaling (7). Thus, the effect of E 2 on lipid metabolism and hence on body composition appears to be direct and mediated via ERs. These observations have led to renewed interest in adipocyte receptor subgroups, and recently, Dos Santos et al. (8) demonstrated the existence of a membrane-bound ERa. In that study, the authors demonstrated that physiological concen- trations of E 2 rapidly lead to activated p42/p44 European Journal of Endocrinology (2010) 163 421–426 ISSN 0804-4643 q 2010 European Society of Endocrinology DOI: 10.1530/EJE-10-0551 Online version via www.eje-online.org