Sat, 26 Jul 2008 00:09:14 BST CiteULike: omalbams Eriksson http://www.citeulike.org/user/omalbam/author/Eriksson CiteULike.org en-gb Copyright © 2004-2008 citeulike.org http://www.citeulike.org/user/omalbam/article/2294245 <i>J Clin Endocrinol Metab, Vol. 91, No. 12. (December 2006), pp. 5029-5037.</i><br /><br />CONTEXT: SHBG regulates free sex steroid levels, which in turn regulate skeletal homeostasis. Twin studies have demonstrated that genetic factors largely account for interindividual variation in SHBG levels. Glucuronidated androgen metabolites have been proposed as markers of androgenic activity. OBJECTIVE: Our objective was to investigate whether polymorphisms in the SHBG gene promoter [(TAAAA)(n) microsatellite and rs1799941 single-nucleotide polymorphism] are associated with serum levels of SHBG, sex steroids, or bone mineral density (BMD) in men. DESIGN AND STUDY SUBJECTS: We conducted a population-based study of two cohorts of Swedish men: elderly men (MrOS Sweden; n congruent with 3000; average age, 75.4 yr) and young adult men (GOOD study; n = 1068; average age, 18.9 yr). MAIN OUTCOME MEASURES: We measured serum levels of SHBG, testosterone, estradiol, dihydrotestosterone, 5alpha-androstane-3alpha,17beta-diol glucuronides, androsterone glucuronide, and BMD determined by dual-energy x-ray absorptiometry. RESULTS: In both cohorts, (TAAAA)(n) and rs1799941 genotypes were associated with serum levels of SHBG (P < 0.001), dihydrotestosterone (P < 0.05), and 5alpha-androstane-3alpha,17beta-diol glucuronides (P < 0.05). In the elderly men, they were also associated with testosterone and BMD at all hip bone sites. The genotype associated with high levels of SHBG was also associated with high BMD. Interestingly, male mice overexpressing human SHBG had increased cortical bone mineral content in the femur, suggesting that elevated SHBG levels may cause increased bone mass. CONCLUSIONS: Our findings demonstrate that polymorphisms in the SHBG promoter predict serum levels of SHBG, androgens, and glucuronidated androgen metabolites, and hip BMD in men. SHBG gene promoter polymorphisms in men are associated with serum sex hormone-binding globulin, androgen and androgen metabolite levels, and hip bone mineral density. AL Eriksson M Lorentzon D Mellström L Vandenput C Swanson N Andersson GL Hammond J Jakobsson A Rane ES Orwoll O Ljunggren O Johnell F Labrie SH Windahl C Ohlsson doi:10.1210/jc.2006-0679 J Clin Endocrinol Metab, Vol. 91, No. 12. (December 2006), pp. 5029-5037. 2008-01-27T02:17:52-00:00 2006 J Clin Endocrinol Metab 0021-972X 91 12 5029 5037 androgen bmd malegonadal metabolism molecular shbg http://www.citeulike.org/user/omalbam/article/2209604 <i>N Engl J Med, Vol. 357, No. 21. (22 November 2007), pp. 2109-2122.</i><br /><br />BACKGROUND: Inhibition of cholesteryl ester transfer protein (CETP) has been shown to have a substantial effect on plasma lipoprotein levels. We investigated whether torcetrapib, a potent CETP inhibitor, might reduce major cardiovascular events. The trial was terminated prematurely because of an increased risk of death and cardiac events in patients receiving torcetrapib. METHODS: We conducted a randomized, double-blind study involving 15,067 patients at high cardiovascular risk. The patients received either torcetrapib plus atorvastatin or atorvastatin alone. The primary outcome was the time to the first major cardiovascular event, which was defined as death from coronary heart disease, nonfatal myocardial infarction, stroke, or hospitalization for unstable angina. RESULTS: At 12 months in patients who received torcetrapib, there was an increase of 72.1% in high-density lipoprotein cholesterol and a decrease of 24.9% in low-density lipoprotein cholesterol, as compared with baseline (P<0.001 for both comparisons), in addition to an increase of 5.4 mm Hg in systolic blood pressure, a decrease in serum potassium, and increases in serum sodium, bicarbonate, and aldosterone (P<0.001 for all comparisons). There was also an increased risk of cardiovascular events (hazard ratio, 1.25; 95% confidence interval [CI], 1.09 to 1.44; P=0.001) and death from any cause (hazard ratio, 1.58; 95% CI, 1.14 to 2.19; P=0.006). Post hoc analyses showed an increased risk of death in patients treated with torcetrapib whose reduction in potassium or increase in bicarbonate was greater than the median change. CONCLUSIONS: Torcetrapib therapy resulted in an increased risk of mortality and morbidity of unknown mechanism. Although there was evidence of an off-target effect of torcetrapib, we cannot rule out adverse effects related to CETP inhibition. (ClinicalTrials.gov number, NCT00134264 [ClinicalTrials.gov].). Effects of torcetrapib in patients at high risk for coronary events. PJ Barter M Caulfield M Eriksson SM Grundy JJ Kastelein M Komajda J Lopez-Sendon L Mosca JC Tardif DD Waters CL Shear JH Revkin KA Buhr MR Fisher AR Tall B Brewer doi:10.1056/NEJMoa0706628 N Engl J Med, Vol. 357, No. 21. (22 November 2007), pp. 2109-2122. 2008-01-09T04:07:55-00:00 2007 N Engl J Med 1533-4406 357 21 2109 2122 chd hplp sideffects therapy