ABSTRACT

The basic work for this PhD dissertation was carried out at the Center for Clinical and Basic Research, Ballerup (2000-2002) and during my one year scholarship granted by the University of Aarhus (2004-2005). The thesis consists of three published or accepted articles and one submitted manuscript currently in peer review.

The aim was to study whether some women responded differently than others in plasma lipids and bone mineral density (BMD) during treatment with estrogen ± progestin hormone therapy (HT), and whether selected polymorphisms of the estrogen receptor (ER) genes influenced the HT response. Additionally, potential associations between body fat distribution, serum lipids, fasting glucose, BMD of spine and arm, prevalence of vertebral fractures and annual rate of bone loss with the ER gene polymorphisms were investigated.

The total study population comprised 1098 postmenopausal Danish women, who were examined twice with a mean follow-up period of 11.4 years. Genomic DNA was amplified by PCR followed by cleavage with PvuII and XbaI restriction enzymes for the ER α polymorphism and the AluI restriction enzyme for the ER β polymorphism. Body composition, fat distribution and BMD were determined by dual energy X-ray absorptiometry. Vertebral fractures and plasma lipid measurements were obtained using standard methods.

Baseline plasma lipids, BMD, prevalence of spinal fractures, and response to HT were not significantly associated with polymorphisms in the ER genes. However, the AluI polymorphism of ER β was significantly associated with bone loss from the distal forearm in women, who had never received HT.

Body composition and fat distribution were significantly associated with the PvuII polymorphism of ER α . Thus, women with at least one mutant P-allele had significantly more central fat (1 kg difference), a lower percentage of lean tissue mass, and the most unfavourable ratios of central-to-peripheral fat. In addition, a gene-environmental interaction between smoking and the PvuII polymorphism was observed.

In a large Caucasian population of postmenopausal women, body composition and fat distribution variables were influenced by the PvuII polymorphism in the ER α gene, thereby partly accounting for the genetic determinants of anthropometrics.

The selected ER polymorphisms were not associated with BMD or lipid profile at baseline or with the responses to HT in bone and lipids; but the ER β genotype modulated bone loss from the distal forearm in non-treated women.

Further studies are needed to determine the clinical relevance of the observed associations between the PvuII polymorphism of ER α with body composition, as well as the clinical importance of ER β polymorphism in bone loss and risk of osteoporotic fractures.