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Nunmii Iiiiiiiiiiiiiiiiiiiii Iinhimu nun mi i ii iiiiiiiiiiiiiiiiiii i in hi mu 2807400684 CQRTICQTRQTHII RELEASI1G FACTOR II PREGIAICI Thesis submitted for the degree of Doctor of Medicine in the Faculty of Medicine of the University of London, 1989. BY CHARLES DAVID ALEXANDER WOLFE MB BS MRCOG Division of Obstetrics and Gynaecology, United Medical and Dental School (St Thomas's Campus) London. MEDICAL LIBRARY, ROYAL FREE HOSPITAL HAMPSTEAD - 1 - ProQuest Number: U548982 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest U548982 Published by ProQuest LLC(2018). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C ode Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 0 ^ 7 , 0 ABSTRACT Using a "two-site" immunoradiometric assay Corticotrophin Releasing Factor (CRF) has been measured in maternal plasma and elevated levels observed in the third trimester of pregnancy. The dilution curve of this CRF paralleled the IRKA standard curve. This CRF-like material eluted on reverse phase high pressure liquid chromatography with a retention time identical to that of synthetic CRF and had equipotent bioactivity with the synthetic peptide. Third trimester maternal plasma contains a carrier substance for CRF with a molecular weight in the region of 40,000. The binding capacity of the carrier is not saturated but most of the CRF in late gestational plasma is bound. In a group of 72 pregnant women CRF levels rose from a median of 20 pg/ml at 28 weeks to 1320 pg/ml at 40 weeks and 1732 pg/ml during labour. There was a strong correlation (r=0.81,P < 0.001) between gestational age and CRF levels. The rate of rise of CRF (pg/ml) per week was associated with weight gain <r= 0.36, P < 0.05) but with no other obstetric variable. There was an association between umbilical cord and maternal plasma CRF levels (r= 0.54, P < 0.01). CRF levels were elevated after accidental antepartum haemorrhage at 28 weeks (P < 0.03). In twin pregnancies maternal CRF levels were significantly raised throughout the third trimester (28-32 weeks, P < 0.01; 34-36 weeks, P < 0.001). In cases of pregnancy induced -2- hypertension (28 weeks, P < 0.001; 32-36 weeks, P < 0.001 and 38-40 weeks, P < 0.01), preterm labour and premature rupture of the membranes (28 weeks, P < 0.004; 30-32 weeks, P < 0.002 and 34-36 weeks, P <0.001), CRF levels were significantly raised. Maternal plasma CRF levels did not correlate with total cortisol levels and did not display diurnal variation. Short term variation in plasma CRF levels had a Coefficient of Variation (CV) of 5.3 ± 0.52 pg/ml and the effect of posture had a CV of 7.1 ± 0.52 pg/ml. During and between uterine contractions in labour the CV was 4.5 ± 1.4 pg/ml and postpartum the half life of CRF was estimated at 65 minutes. -3- ACCTQWLEDGEME1TS The infectious enthusiasm, intellectual stimulation, encouragement and profound scientific ethic of Professor Kortyn Jones,Dsc has prepared me not only for this thesis, but for all that I attempt in my future career. He is sadly missed as mentor and friend. I am Indebted for the continual guidance and enlightenment of Drs Campbell and Linton with whom the majority of collaboration was made. I am muut grateful to Professor Lowry for supervision and the use of laboratory space. Without the financial support of St Thomas's Hospital Endowments Committee and the facilities made available to me in the Division of Gynaecology by Professor Taylor this project would not have been possible. The thesis would never have been in its present form without the hard work of Swatee Patel in the Division of Community Medicine. I wish to thank all my clinical colleagues at StThomas's for allowing access to the pregnant mothers and to the midwifery staff for their continued support. I am especially indebted to Dr Anderson, Sister Carabelli and Mr Quartero for all their help. Finally to my parents, Antony and Richard for their unfailing encouragement and tolerance. - 4 - I1DEI EASE. Abstract 2 Acknowledgements 4 List of Figures 8 List of Tables 11 Major Publications 12 Outline of Thesis 13 chapter i Characterisation of placental and aaternal plasma CortlcQtrophin Releasing factor. 1.1. Corticotrophln Releasing Factor(CRF) 1.1.1.The nature of CRF 14 1.1.2.Evidence for CRFs 14 1.1.3.VP & other CRFs 15 1.1.4.The CRF molecule 18 1.1.5.Heural pathways for CRF 18 1.1.6.Mechanism of action of CRF and VP 19 1.1.7.Biological actions of CRF 20 1.1.8.Other CHS effects of CRF 22 1.1.9.Distribution of CRF outside the brain 22 1.2. The Hypothalamic-Pituitary Adrenal Axis 1.2.1.Adrenocorticotrophic hormone (ACTH) 26 1.2.2.ACTH related peptides 26 1.2.3.Glucocorticoids Regulation 27 1.2.4.Factors controlling the HPA axis 27 1.3. HPA Axis During Pregnancy 28 1.3.1.ACTH 29 1.3.2.Cortisol Binding Globulin (CBG) 29 1.3.3.Total Cortisol 30 1.3.4.Cortisol metabolism 32 1.4. The Fetal HPA Axis 1.4.1.CRF 33 1.4.2.ACTH 34 1.4.3.Cortisol & Cortisone 34 1.5. Placental Peptides Resembling Hypothalamic and Pituitary Peptides 1.5.1.ACTH 36 1.5.2.Other POMC Related Peptides 38 1.5.3.Prolactin 39 1.5.4.Follicle Stimulating Hormone (FSH) 39 1.5.5.Luteinising Hormone (LH) and Growth Hormone (GH) 39 1.5.6.Thyroid Stimulating Hormone (TSH) 39 1.5.7.Hypothalamic Releasing Hormones of the Placenta 40 1.5.8.CRF 41 1.6 Direct Measurement of Maternal Elasjoa CRE by "TWQ-Site". Immunoradlometrlc Assay. 1.6.1.Immunoradiometrlc assay for CRF 44 - 5 - I1DEI ctd. i. Antibodies 44 11. Iodination 45 ill. Standards 45 Iv. Assay Procedure 45 v. Plasma Collection 46 1.6.2. 1. Immunoadsorption of plasma CRF 47 11. High Pressure Liquid Chromatography (HPLC) 48 1.6.3. Corticotrophin Releasing Activity of the Extract 48 1.6.4. Results 48 i. Assay Characteristics 46 il. CRF in Plasma 50 ill. HPLC 52 iv. Bioassay 52 1.6.5. Discussion 52 CHAPTER 2. EVIDENCE FOR A SPECIFIC CARRIER SPBSTAJCB FOR CRF II LATE GBSIATIQIAI MATERIAL PLASHA, 2.1.Introduction 57 2.2.Plasma Collection and Treatment 57 2.3.Column Chromatography 58 2.4.Bioassay 58 2.5.Results 59 2.6.Discussion 63 CHAPTER 3. MATERIAL h UMBILICAL CORD PLASHA CRF II 1DRMAL PREGIAJCY 3.1. Introduction 69 3.1.1.Placental Steroids & Proteins. 69 3.2. Materials and Methods 3.2.1.Plasma Collection 73 3.2.2.Demographic Data 74 3.2.3.Statistics 74 3.2.4.CRF Radioimmunoassay <RIA) 75 3.2.5.CRF IRMA 78 3.3. Results 3.3.1.CRF RIA 80 3.3.2.CRF IRMA 80 3.4. Discussion 90 CHAPTER 4. MATERTAL PLASMA CRF LEVELS II AB1DRMAL PREGMATCY STATES 4.1. Introduction 100 4.2. Material & Methods 102 4.3. Results 104 4.3.1.Hydatidiform Mole 104 4.3.2.Twin Pregnancy 104 4.3.3.Diabet i c Pregnancy 104 4.3.4.Antepartum Haemorrhage 107 4.3.5.Polyhydramnios 107 4.3.6.Pregnancy Induced Hypertension 107 4.3.7.Preterm Labour 107 4.3.8.Low Birthweight Infants 107 4.3.9.Intrauterine Death 109 4.4. Discussion 109 - 6 - IMPEL ctd. CHAPTER 5. MATERIAL HPA AXIS STUDIES 5.1. Introduction 116 5.2. Materials & Methods 116 5.2.1.Subjects 116 5.2.2.Cortisol Assay 118 5.2.3.CBG Assay 118 5.2.4.Urinary Free Cortisol Assay 118 5.3. Results 118 5.3.1.Total Cortisol 118 5.3.2.CBG 119 5.3.3.Diurnal Variation 123 5.4. Discussion 123 CHAPTER 6. VARIABILITY OF MATERIAL PLASMA CRF 6.1. Introduction 125 6.2. Materials & Methods 125 6.3. Results 126 6.4. Discussion 126 APPEIDICBS 1. Antenatal record sheet 132 2. Antenatal and labour data entry sheets for the computer 133 3. CRF antenatal values in 72 normal subjects 136 4. CRF rank order analysis 139 5. CRF 6lope estimates. 141 6. CRF labour values 144 7. Rank order of CRF values in labour. 145 REFERENCES 146 - 7 - LIST OF FIGURES PAGE 1. The proposed structure of human pre-pro-CRF. 17 2. The primary structure of human CRF. 17 3. The hypothalamic-Pituitary Adrenal Axis. 25 4. Processing of ACTH/fl-LPH precursor in the anterior lobe of the pituitary. 25 5. CRF IRMA. 43 6. Isolated pituitary cell column perfusion apparatus. Perfusion buffer or test substance was pumped through two heating colls at 37°C, past a debubbler, over the cell column and to the fraction collector. 43 7. CRF 'two-site* IRMA standard curve in heat-treated human plasma containing enzyme inhibitors (•) and in dilutions of plasma from a normal male < m ) and from a woman who was 39 weeks pregnant <o). The data points are the means of duplicate determinations. 49 8. HPLC of CRF IRMA activity of extracts of maternal plasma (•) pooled normal plasma containing synthetic CRF (A ) and human brain extract (A ) on ultrapore RPSC.
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