Involvement of G-463A MPO gene polymorphism in the response of postmenopausal women to hormone therapy.
OBJECTIVE
The aims of this work were to determine (1) the effects of estrogen plus progestogen therapy (EPT) and raloxifene on oxidative stress and cardiovascular risk biomarkers in postmenopausal women and (2) the involvement of the functional G-463A polymorphism of the myeloperoxidase (MPO) gene in the therapy responses.


METHODS
Postmenopausal women (45-55 y old) were assigned to three groups receiving (1) EPT (continuous 50 μg transdermal estradiol daily and 200 mg/d micronized progesterone orally the first 14 d of each month; n = 21), (2) raloxifene (60 mg daily; n = 17), and (3) no treatment (control; n = 21). Blood and urine samples were taken before and after 6 months of therapy. Measurements were serum lipid profile, C-reactive intercellular adhesion molecule 1 (ICAM-1), α-tocopherol, γ-tocopherol, uric acid, total antioxidant activity (TAA), malondialdehyde, and urinary 1,4-dihydroxynonane-mercapturic acid (the major urinary 4-hydroxynonenal metabolite). The G-463A MPO polymorphism was analyzed by polymerase chain reaction and restriction fragment length polymorphism.


RESULTS
EPT significantly decreased TAA and the levels of ICAM-1, not modifying other cardiovascular risk or oxidative stress markers. The raloxifene and control groups experienced no modifications in oxidative stress or endothelial dysfunction markers. The MPO genotype specifically influenced the outcomes in the EPT group. Thus, TAA decreased significantly in GG (high-expression genotype) homozygotes, whereas ICAM-1 levels were reduced in A allele carriers.


CONCLUSIONS
EPT exerted a negative action on the serum oxidant/antioxidant balance in the MPO GG homozygotes and a positive effect on the ICAM-1 endothelial dysfunction marker in carriers of the low-expression A allele. This observation provides evidence of the importance of this polymorphism in the response to EPT.
Department of Physiology, Medicine and Dentistry School, University of the Basque Country, Leioa, Spain.
Ainhoa Ruiz
AR
del Agua
Igor
I
Aurrekoetxea
Miguel Angel
MA
Elorriaga
Fernando
F
Rodriguez
Françoise
F
Guéraud
M Begoña
MB
Ruiz-Larrea
José Ignacio
JI
Ruiz-Sanz
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000652:urine; D000975:Antioxidants / Q000032:analysis; D004958:Estradiol / Q000627:therapeutic use*; D005260:Female; D020249:Hormone Replacement Therapy / Q000379:methods*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D008055:Lipids / Q000097:blood; D008315:Malondialdehyde / Q000097:blood; D008875:Middle Aged; D009195:Peroxidase / Q000235:genetics*; D011110:Polymorphism, Genetic; D017698:Postmenopause / Q000187:drug effects* / Q000235:genetics; D011374:Progesterone / Q000627:therapeutic use*; D020849:Raloxifene Hydrochloride / Q000627:therapeutic use; D020845:Selective Estrogen Receptor Modulators / Q000627:therapeutic use; D014527:Uric Acid / Q000097:blood; D024502:alpha-Tocopherol / Q000097:blood
C501116:1,4-dihydroxynonene mercapturic acid; D000975:Antioxidants; D008055:Lipids; D020845:Selective Estrogen Receptor Modulators; D018799:Intercellular Adhesion Molecule-1; D014527:Uric Acid; D020849:Raloxifene Hydrochloride; D011374:Progesterone; D004958:Estradiol; D008315:Malondialdehyde; D009195:Peroxidase; D024502:alpha-Tocopherol; D000111:Acetylcysteine