Aristotle University of Thessaloniki

83 Pages·2017·0.62 MB·English

Aristotle University of Thessaloniki
Faculty of Health Sciences
School of Medicine

Hypovitaminosis D in women with endometriosis: a systematic review

A thesis submitted in fulfillment of the requirements
for the degree of
Master of Science in Medical Research Methodology
by

Vasiliki Venetsanaki

Thessaloniki, November 2017
Hypovitaminosis D in women with endometriosis: a systematic review

A MSc thesis submitted in fulfillment
of the requirements for the degree of
Master of Science in Medical Research Methodology
at

The Faculty of Health Sciences
School of Medicine
Aristotle University of Thessaloniki
by

Vasiliki Venetsanaki

Supervisor: Associate Professor Dimitrios G. Goulis

Thessaloniki, November 2017
Word count: 9.611
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Supervisor: Associate Professor Dimitrios G. Goulis
Member of the examining committee: Professor Dimitrios Vavilis
Member of the examining committee: Professor Grigorios Grimbizis
Date of Submission: 25/11/2017
Conflict of Interest/Funding Source: None declared

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Acknowledgements

This work was completed in 2016-2017 at the School of Health Sciences, Faculty of Medicine of
the Aristotle University of Thessaloniki.
I would like to thank the members of the examining committee, professor Dimitrios Vavilis and
professor Grigorios Grimbizis for the time they invested in this project.
I owe my deepest gratitude to my supervising professor Dimitrios G. Goulis for suggesting this
topic. As both the field of reproductive endocrinology and the conduct of systematic review were
new to me, I would not have successfully completed it without his guidance and qualitative
feedback.
On a personal note, I would like to thank my family, colleagues and friends for their continuous
support and encouragement throughout this strenuous journey.

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Contents
Abbreviations ................................................................................................................................................ 6
List of Tables ................................................................................................................................................ 8
Abstract ......................................................................................................................................................... 9
Chapter 1 : Endometriosis ........................................................................................................................... 11
Epidemiology and Risk Factors .............................................................................................................. 11
Symptoms ............................................................................................................................................... 12
Infertility ................................................................................................................................................. 12
Classification Systems ............................................................................................................................ 12
Pathogenesis of Endometriosis ............................................................................................................... 13
I. Retrograde Menstruation ........................................................................................................... 13
II. Coelomic Metaplasia ................................................................................................................. 13
III. Induction Theory ....................................................................................................................... 14
V. Vascular and Lymphatic Spread ................................................................................................ 14
VI. Other Predisposing Factors ........................................................................................................ 14
Treatment ................................................................................................................................................ 15
Chapter 2 : Vitamin D ................................................................................................................................. 17
Introduction ............................................................................................................................................. 17
Vitamin D Metabolism ........................................................................................................................... 17
Hypovitaminosis D: Assays, Definition and Dietary Reference Intakes ................................................ 17
Etiology of Hypovitaminosis D .............................................................................................................. 18
Diseases Associated with Lack of Vitamin D ......................................................................................... 18
I. Skeletal Diseases ....................................................................................................................... 18
II. Extra-skeletal Diseases .............................................................................................................. 20
Chapter 3 : Vitamin D and Endometriosis .................................................................................................. 22
The Role Of Vitamin D Binding Protein ................................................................................................ 22
The Role of Vitamin D Receptor ............................................................................................................ 24
The Role of 1-α-hydroxylase, Calcitriol and Cholecalciferol ................................................................. 26
Conclusion .............................................................................................................................................. 28
Chapter 4 : Systematic Review ................................................................................................................... 29
Background ............................................................................................................................................. 29
Objective ................................................................................................................................................. 29
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Formulation of Clinical Question ........................................................................................................... 30
Study Selection ....................................................................................................................................... 30
Study Eligibility Criteria ......................................................................................................................... 31
Search Strategy ....................................................................................................................................... 32
Data Extraction ....................................................................................................................................... 34
Search Results ......................................................................................................................................... 34
Excluded Studies ..................................................................................................................................... 34
Systematic Review Results ..................................................................................................................... 36
Study Characteristics .......................................................................................................................... 36
Population Characteristics................................................................................................................... 39
Endometriosis ..................................................................................................................................... 42
Serum Vitamin D levels ...................................................................................................................... 43
Findings of Included Studies............................................................................................................... 45
Critical Analysis...................................................................................................................................... 50
General Considerations ....................................................................................................................... 50
Quality Assessment ............................................................................................................................. 50
Discussion ........................................................................................................................................... 57
Chapter 5 : Conclusion ................................................................................................................................ 59
References ................................................................................................................................................... 60
APPENDIX ................................................................................................................................................. 69

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Abbreviations
DES Diethylstilbestrol
r-ASRM Revised American society for reproductive medicine
EFI Endometriosis fertility index
MMP-3 Matrix metalloproteinase-3
ICAM-1 Intracellular adhesion molecule 1
TNF-α Tumor necrosis factor alpha
TGF-β Transforming growth factor beta
IL Interleukin
VEGF Vascular endothelial growth factor
17β-HSD 17β-hydroxysteroid dehydrogenase
GnRH Gonadotropin-releasing hormone
VDR Vitamin D receptor
UV Ultraviolet
7-DHC 7-dehydrocholesterol
(h)VDBP (Human) vitamin D binding protein
CPBA Competitive protein binding assay
RIA Radioimmunoassay
HPLC High performance liquid chromatography
RDA Recommended dietary allowances
HAART Highly active antiretroviral therapy
VDR-RXR Vitamin D receptor-retinoic acid x-receptor
FGF-23 Fibroblast growth factor 23
RANKL Receptor activator nuclear factor-κB ligand
PTH Parathyroid hormone
PCOS Polycystic ovary syndrome
MAF Macrophage activating factor
2D-PAGE Two-dimensional polyacrylamide gel electrophoresis
ELISA Enzyme-linked immunosorbent assay
NR Nuclear receptor
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DRIP Vitamin D receptor interacting protein
VDRE Vitamin D response element
NF Nuclear factor
NHS II Nurses’ health study II
BMI Body mass index
FFQ Food frequency questionnaire
VAS Visual analog scale
OR Odds ratio
CI Confidence interval

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List of Tables

Table 1 The r-ASRM Classification - point distribution ............................................................................ 13
Table 2 Studies investigating the association of DBP and endometriosis .................................................. 24
Table 3 Studies investigating the association of VDR and endometriosis .................................................. 26
Table 4 Other studies investigating the association of vitamin D and endometriosis ................................. 27
Table 5 Clinical Question in PICO Format ................................................................................................. 30
Table 6 Summary of absolute inclusion and exclusion criteria .................................................................. 31
Table 7 Search terms included .................................................................................................................... 32
Table 8 Summary characteristics of excluded studies ................................................................................ 35
Table 9 Design of included studies ............................................................................................................. 37
Table 10 Population characteristics among studies .................................................................................... 40
Table 11 Endometriosis-related evidence among studies ........................................................................... 42
Table 12 Determination of serum 25-hydroxyvitamin D levels ................................................................. 43
Table 13 Summary of findings of included studies .................................................................................... 47
Table 14 Newcastle-Ottawa Quality Assessment Scale for case-control studies ....................................... 53
Table 15 Newcastle-Ottawa Quality Assessment Scale for cohort study ................................................... 54
Table 16 Summary of study quality ............................................................................................................ 56

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Abstract

Background: A unified theory regarding the pathogenesis of endometriosis remains unavailable.
The implication of vitamin D in the development of endometriosis was firstly supported by the
expression of the vitamin D receptor, vitamin D binding protein and 1-α hydroxylase in ectopic
endometrium, suggesting that vitamin D has a role in the development of endometriosis. Also,
previous studies have suggested that calcitriol and cholecalciferol can reduce endometriotic
lesions possibly by modulating the inflammatory processes involved. However, results from
studies performed on humans to determine serum 25-hydroxyvitamin D concentrations in
women with endometriosis have not been conclusive.
Aim: The aim of this systematic review was to identify all studies performed in humans that
investigate an association between vitamin D levels and endometriosis and determine whether
women with endometriosis have a higher prevalence of vitamin D insufficiency or deficiency
compared to women without the disease.
Methods: A systematic literature search was conducted from November 2016 to April 2017 to
identify studies that investigate an association between serum vitamin D levels and
endometriosis. The electronic databases PubMed, Scopus, Cochrane Database of Systematic
Reviews and Web of Science were searched as well as grey literature. Quality assessment of
included observational studies was completed using the Newcastle-Ottawa scale. As high quality
studies were defined those awarded with 8-9 stars and as moderate quality those with 6-7 stars.
Results: Full-text evaluation of 8 studies was conducted. Four studies met the inclusion criteria
and were included in the systematic review. A cohort study was awarded 8 stars, two case-
control studies were awarded 7 stars and another case-control study 4 stars. The reported results
between studies were contradictory; two studies concluded that there is an association between
low vitamin D concentrations and endometriosis. On the other hand, one study suggested that
women with endometriosis have higher vitamin D concentrations and another found no
difference between groups.
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