Aus der Klinik für Gynäkologie und Geburtshilfe der medizinischen Fakultät der
Charité – Universitätsmedizin Berlin

DISSERTATION

Effects of Insulin Sensitizing Drug Metformin on Clinical Features, Endocrine and Metabolic Profiles in Obese Women with Polycystic Ovary Syndrome: A Randomized, Double Blind, Placebo-Controlled Sixteen Weeks Trial

Zur Erlangung des akademischen Grades
Doctor medicinae (Dr. med.)

vorgelegt der Medizinischen Fakultät
der Charité – Universitätsmedizin Berlin

von

Elena   Steinheim  
(geb. Ibragimova)
aus Ufa  

Dekan: Prof. Dr. med. Martin Paul

Gutachter:
1. Prof. Dr. med. W. Lichtenegger
2. Prof. Dr. med. H. Alexander
3. Priv-Doz. Dr. med. R. Sudik

Datum der Promotion: 29.06.2006.

Table of contents

• 1 INTRODUCTION
  • 1.1  Polycystic Ovary Syndrome
  • 1.2 Presentation
  • 1.3 Polycystic Ovaries 
  • 1.4 Pathogenesis Of PCOS 
  • 1.5 Long-Term Disease Risks
  • 1.6 Management of PCOS
  • 1.7 Aim Of The Trial
• 2 SUBJECTS AND METHODS
  • 2.1  Patients 
  • 2.2 Study Design
  • 2.3 Methods 
  • 2.4 Free Androgen Index
  • 2.5 Questionnaires
  • 2.6 Dietary Composition
  • 2.7 Metformin Treatment
  • 2.8 Randomization 
  • 2.9 Statistical Analysis 
• 3 RESULTS 
  • 3.1  Recruitment And Pretreatment Assessments
  • 3.2 Treatment Compliance
  • 3.3 Conception During Treatment
  • 3.4 Anthropometric Assessments
  • 3.5 Endocrine Assessments 
  • 3.6 Menstrual Cycle
  • 3.7 Subgroup Analysis
  • 3.8 Correlation Analysis
  • 3.9 Menstrual Cycle
• 4 DISCUSSION
  • 4.1  Body Weight And Body Mass Index
  • 4.2 Body Fat Distribution and Waist-Hip Ratio
  • 4.3 Reproductive Hormones 
  • 4.4 Insulin And Glucose Metabolism 
  • 4.5 Insulin Like Growth Factor-I 
  • 4.6 Leptin
  • 4.7 Lipids
  • 4.8 Menstrual Abnormalities 
  • 4.9 Metformin and Pregnancy Rates
• 5 SUMMARY 
  • 5.1  English Version
  • 5.2 Deutsche Version
• 6. REFERENCES
• 7.LIST OF ABBREVIATIONS 
• 8.DECLARATION
• 9.ACKNOWLEDGMENTS 
• 10. PUBLICATIONS
• 11. ATTACHMENT

Tables

• Table 1: Clinical characteristics of PCOS women recruited in the trial
• Table 2: Criteria for the diagnosis of diabetes mellitus
• Table 3: Characteristics of the patients randomized to receive placebo or metformin
• Table 4: BMI measurements before and after treatment
• Table 5: Waist and hip measurements before and after metformin or placebo treatment
• Table 6: Sex hormones and SHBG blood concentrations in PCOS women before and after placebo or metformin treatment
• Table 7: Levels of glucose, insulin, Hb1Ac, leptin and IGF-I levels in PCOS women before and after placebo or metformin treatment.
• Table 8: Serum cholesterol and triglycerids concentrations in placebo- and metformin-treated women with PCOS before and after treatment.
• Table 9: Menstrual cycle in metformin-treated women with PCOS before and after treatment, n=19
• Table 10: Menstrual cycle in placebo-treated women with PCOS before and after treatment, n=18
• Table 11: Menstrual cycle in amenorrheic patients with PCOS treated with placebo or metformin.
• Table 12: Main baseline characteristics of metformin-treated patients divided into responders and nonresponders according to efficacy of treatment of menstrual disturbances
• Table 13: Endocrine and metabolic parameters in women with PCOS before and after metformin treatment. Subgroup analysis
• Table 14: Menstrual cycle in women with PCOS before and after metformin treatment, subgroup analysis
• Table 15: Menstrual disfunction and insulin resistance.
• Table 16: Symptome  
• Table 17: Krankheiten
• Table 18: Familiärer Hintergrund
• Table 19: Visitenplan (Übersicht)

Images

• Figure I: Transvaginal ultrasound of the polycystic ovary
• Figure II: Box plot
• Figure III: Chart of patients progressing through the trial of placebo or metformin treatment.
• Figure IV: Box plot of BMI in women with PCOS before and after metformin treatment.
• Figure V: Box plot of BMI in women with PCOS before and after placebo treatment.
• Figure VI: Box plot of free testosterone levels in women with PCOS before and after metformin or placebo treatment.
• Figure VII: Box plot of LH/FSH ratio in women with PCOS before and after metformin or placebo treatment.
• Figure VIII: SHBG plasma concentrations in women with PCOS before and after metformin or placebo treatment.
• Figure IX: Fasting glucose levels in women with PCOS before and after metformin or placebo treatment.
• Figure X: Fasting insulin concentrations in women with PCOS before and after placebo treatment.
• Figure XI: Fasting insulin concentrations in women with PCOS before and after metformin treatment.
• Figure XII: 2-hours postprandial insulin concentrations in women with PCOS before and after metformin or placebo treatment.
• Figure XIII: Area Under The Curve insulin (AUC insulin) in metformin-treated women with PCOS before and after treatment.
• Figure XIV. Area Under The Curve insulin in placebo-treated women with PCOS before and after treatment
• Figure XV. IGF-I plasma concentrations in women with PCOS before and after metformin or placebo treatment
• Figure XVI. HDL-cholesterol concentrations in women with PCOS before and after metformin or placebo treatment.
• Figure XVII. Menstrual cycle in women with PCOS before metformin or placebo treatment.
• Figure XVIII. Menstrual cycle in women with PCOS after metformin or placebo treatment.
• Figure XIX. Correlation between BMI and leptin concentrations in women with PCOS, r=0.53; n=46
• Figure XX. Correlation between Free Androgen Index (FAI) and AUC insulin, n=46
• Figure XXI. Correlation between HDL total cholesterol and fasting insulin in women with PCOS, n=46
• Figure XXII. Correlation between total cholesterol and 2 hour insulin  in women with PCOS, n=46
• Figure XXIII. Correlation between changes in IGF-I levels and AUC insulin in the   metformin-treated group, n=19
• Figure XXIV. Correlation between changes in IGF-I and HDL cholesterol levels in the metformin-treated group, n=19