Studies on the interaction between the estrogen and vitamin D endocrine system

Abstract

Estrogen deficiency and vitamin D deficiency play key roles in the pathogenesis of postmenopausal osteoporosis. Aim of the studies in this thesis is to extend our knowledge on the interaction between E2 and 1,25-(0H)2D3 and thereby to provide more insight into the significance of E, for 1,25-(0H)2D3 mediated processes in calcium and bone metabolism. Furthermore the significance of VDR genotypes for the biological response to 1,25-(0H)2D3 and the interaction between ERa and VDR genotypes in relation to BMD and fracture risk are studied. The first part of the thesis focuses on the effect of E2 on 1,25-(0H)2D3 mediated processes. In chapters 2 and 3 the effect of E, deficiency and E2 repletion on 1,25-(0H),D, synthesis and 1,25-(0H)2D3 mediated intestinal calcium absorption in a rat model for postmenopausal osteoporosis is described. An important bone anabolic factor is IGF-1. Both 1,25-(0H)2D3 as well as Ez have been shown to regulate IGF-I expression in vitro. Chapter 4 describes the effect of E, deficiency and E2 repletion on IGF-I levels in bone in vivo in relation to bone metabolism. The effect of E2 on bone mineralization is discussed in Chapter 5. The second part of the thesis considers the significance of VDR genotypes for the biological response to 1,25-(0H)2D3 and the interaction between ERa and VDR gene polymorphisms in relation to BMD and fracture risk. Chapter 6 describes a pilot study addressed to whether differences in rates of bone turnover between women with either extremely low or extremely high BMD can be ascribed to genetic variations of the VDR. Furthermore, the biochemical response to short-term substitution of 1,25-(0H)2D3 in both BMD groups was related to VDR gene polymorphisms. In chapter 7 functional consequences of VDR gene polymorphisms in vitro are studied. Chapter 8 discusses the association between ERa gene polymorphism and fracture risk in postmenopausal women. Moreover, the interaction between ERa gene and VDR gene polymorphisms on fracture risk is described. In chapter 9 the results are discussed and suggestions for future research are made. Finally, the main findings are summarized in Chapter 10