Relation of aromatase gene polymorphism and hormone replacement therapy to serum estradiol levels, bone mineral density, and fracture risk in early postmenopausal women.
BACKGROUND
After the menopause, estrogen synthesis from androgens and androgen precursors by aromatase is the main source of circulating estrogens.


OBJECTIVE
To evaluate whether aromatase gene (CYP19)polymorphism affects circulating estradiol (E2) levels, bone mineral density (BMD), BMD change or fracture risk.


METHODS
A 5-year randomized hormone replacement therapy (HRT) trial on 331 early postmenopausal women (mean baseline age 52.7 +/- 2.3 years). The participants consisted of two treatment groups: the HRT group (n = 151) received a sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate with or without vitamin D3, 100-300 IU + 93 mg calcium as lactate/day, and the non-HRT group (n = 180) received 93 mg calcium alone or in combination with vitamin D3, 100-300 IU/day for 5 years. BMD was measured from lumbar spine and proximal femur (DXA) before and after the 5-year trial. All new symptomatic, radiographically defined fractures were recorded during the follow-up. The polymorphism (intron 4 TTTA repeat) of CYP19 was evaluated after PCR amplification of the polymorphic site. CYP19 polymorphism was divided into three repeat groups: short (length of 7 or 8 in both alleles; n = 135), long (length of 11 or higher in both alleles; n = 47), and medium (rest of the values; n = 149).


RESULTS
Of the baseline characteristics, only physical activity was associated with CYP19 polymorphism (P = 0.04) and a borderline significance was observed with previous fractures (P = 0.05). In the HRT or non-HRT groups, the 5-year serum E2 change was not associated with CYP19 polymorphism (P = 0.87 and 0.74, respectively). Further, the polymorphism did not influence the calculated annual changes of lumbar or femoral neck BMD during the 5-year follow-up in the HRT (P = 0.60 and 0.17, respectively) or non-HRT (P = 0.92 and 0.80, respectively) groups. In all, 28 women sustained 33 fractures during the follow-up. The CYP19 polymorphism was not significantly associated with fracture risk (P = 0.89 and 0.23 respectively; Cox proportional hazards model) in the HRT or non-HRT groups.


CONCLUSIONS
CYP19 polymorphism was not associated with circulating E2 levels, BMD values, or fracture risk in these early postmenopausal Finnish women. If such an association exists in women, it may become apparent in older age groups.
Salmen
Timo
T
Department of Biochemistry, Kuopio University Kuopio, Finland. salmen@hytti.uku.fi
Heikkinen
Anna-Mari
AM
Mahonen
Anitta
A
Kröger
Heikki
H
Komulainen
Marja
M
Pallonen
Heli
H
Saarikoski
Seppo
S
Honkanen
Risto
R
Mäenpää
Pekka H
PH
D001141:Aromatase / Q000235:genetics*; D015519:Bone Density / Q000187:drug effects / Q000235:genetics*; D002762:Cholecalciferol / Q000627:therapeutic use; D003534:Cyproterone / Q000627:therapeutic use; D004958:Estradiol / Q000031:analogs & derivatives* / Q000097:blood* / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D050723:Fractures, Bone / Q000453:epidemiology; D005838:Genotype; D020249:Hormone Replacement Therapy; D006801:Humans; D008875:Middle Aged; D011110:Polymorphism, Genetic; D017698:Postmenopause; D012307:Risk Factors
D002762:Cholecalciferol; D004958:Estradiol; D003534:Cyproterone; D001141:Aromatase