title: Oral, more than transdermal, oestrogen therapy lowers asymmetric dimethylarginine in healthy postmenopausal women: a randomized, placebo-controlled study.
abstract: OBJECTIVE
  To compare the effects of oral and transdermal hormone therapy (HT) on asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, in postmenopausal women.
  
  
  METHODS
  In a multicentre, placebo-controlled, double-blind study, 152 hysterectomized healthy women were randomized to receive daily transdermal 17beta-oestradiol (tE2, n = 33), or oral micronized 17beta-oestradiol either unopposed (oE2, n = 37), or continuous combined with gestodene (oE2 + G, n = 33), or placebo (n = 49) for 13, 28-day treatment cycles. Plasma concentrations of ADMA, arginine and symmetric dimethylarginine (SDMA) were measured at baseline and in treatment cycles 4 and 13 with a high-performance liquid chromatography method.
  
  
  RESULTS
  After 13 cycles all active treatment groups showed a significant reduction in ADMA compared with placebo: tE2, -4.0% (95% CI: -7.5 to -0.6%); oE2, -7.7% (95% CI: -10.9 to -4.4%) and oE2 + G, -7.5% (95% CI: -10.8 to -4.3%). ancova showed a significantly larger reduction in the oral groups compared with the transdermal group (tE2 vs. oE2 and tE2 vs. oE2 + G, both P < 0.01). Oral, but not transdermal treatment, significantly reduced arginine compared with placebo. All active treatments reduced SDMA; however, this was only statistically significant in the oE2 group.
  
  
  CONCLUSIONS
  Reduction of ADMA was more pronounced after oral than after tE2 administration. Adding gestodene to oral 17beta-oestradiol did not alter the reduction of ADMA. The clinical implications of these findings remain uncertain; however, the decrease of ADMA by 17beta-oestradiol could be a key phenomenon in the modulation of nitric oxide synthesis by postmenopausal HT.
authors.affiliation: Department of Obstetrics and Gynaecology, Project Ageing Women and Institute for Cardiovascular Research-Vrije Universiteit, Amsterdam, Netherlands.
authors.forename: M O
authors.initials: MO
authors.lastname: Verhoeven
authors.forename: M
authors.initials: M
authors.lastname: Hemelaar
authors.forename: M J
authors.initials: MJ
authors.lastname: van der Mooren
authors.forename: P
authors.initials: P
authors.lastname: Kenemans
authors.forename: T
authors.initials: T
authors.lastname: Teerlink
mesh_terms: D000279:Administration, Cutaneous; D000284:Administration, Oral; D000368:Aged; D000704:Analysis of Variance; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004311:Double-Blind Method; D015914:Estrogen Replacement Therapy; D004967:Estrogens / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D007044:Hysterectomy; D008875:Middle Aged; D009652:Norpregnenes / Q000008:administration & dosage; D017698:Postmenopause / Q000097:blood*
chemical_list: D004967:Estrogens; D009652:Norpregnenes; C487735:dimethylarginine; C033273:Gestodene; D001120:Arginine