Human Chorionic Gonadotropin (hCG) (eBook)

Laurence A. Cole (Autor)

eBook Download: PDF | EPUB

2014 | 2. Auflage
446 Seiten
Elsevier Science (Verlag)
978-0-12-800821-8 (ISBN)

Infos

Human chorionic gonadotropin (hCG) is produced during pregnancy by the embryo. It promotes progesterone production by corpus luteal cells. It also functions in pregnancy to promote angiogenesis in uterine vasculature, it immuno-blands the invading placental tissue so it is not rejected by the maternal uterine tissues, promotes the growth of the uterus in line with the growth of the fetus, promotes the differentiation of growing cytotrophoblast cells, promotes the quiescence of contractions in the uterine myometrium during the course of pregnancy, and also has function in growth and development of fetal organs. The first edition described the detailed biology, clinical chemistry, and clinical perspectives of hCG and associated molecules, and examines hCG, hyperglycosylated hCG and hCG free ß-subunit, 3 separate and independent molecules with totally sovereign physiological functions. The second edition will include coverage of the many new discoveries that have been made in the last five years: hCG analogues may be the actual driving signal of all human cancers. The editor estimates that 40% of the out of date material will be excluded and replaced with 40% of the exciting new findings. The book will also have a much clearer pregnancy and cancer focus. - It provides comprehensive information on hCG from basic science to clinical medicine - The second edition will include coverage of the many new discoveries that have been made in the last five years - Updated material with new findings in the field

Dr. Cole has served on the journal editorial board from 1994-2001 as the Editor of 'Trophoblast Disease Update'. He has written more than 100 articles on hCG structure, physiology and immunoassay and on clinical applications of hCG or hCG-related molecules. He has a 1.17 FWCI in the Medicine category of SciVal where he has published throughout the various disciplines and maintains an average of 12.6 citations per article from 2009-2014. He has experience with international, single, and institutional collaboration. Awards and recognition for Dr. Cole include the Institute for Anticancer Research, Biannual Prize for best research; American Association for Clinical Chemistry, Most Outstanding Research Contributor to Clinical Chemistry Prize; Gynecology Oncology, Outstanding Speaker Award; and International Society for Study of Trophoblastic Disease, Gold Medal for most outstanding research.

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Human chorionic gonadotropin (hCG) is produced during pregnancy by the embryo. It promotes progesterone production by corpus luteal cells. It also functions in pregnancy to promote angiogenesis in uterine vasculature, it immuno-blands the invading placental tissue so it is not rejected by the maternal uterine tissues, promotes the growth of the uterus in line with the growth of the fetus, promotes the differentiation of growing cytotrophoblast cells, promotes the quiescence of contractions in the uterine myometrium during the course of pregnancy, and also has function in growth and development of fetal organs. The first edition described the detailed biology, clinical chemistry, and clinical perspectives of hCG and associated molecules, and examines hCG, hyperglycosylated hCG and hCG free -subunit, 3 separate and independent molecules with totally sovereign physiological functions. The second edition will include coverage of the many new discoveries that have been made in the last five years: hCG analogues may be the actual driving signal of all human cancers. The editor estimates that 40% of the out of date material will be excluded and replaced with 40% of the exciting new findings. The book will also have a much clearer pregnancy and cancer focus. - It provides comprehensive information on hCG from basic science to clinical medicine- The second edition will include coverage of the many new discoveries that have been made in the last five years- Updated material with new findings in the field

Inhalt

Front Cover 1
Human Chorionic Gonadotropin (hCG) 4
Copyright Page 5
Contents 6
List of Contributors 14
About the Editors 16
Laurence A. Cole, PhD 16
Stephen A. Butler, PhD 17
Preface 18
References 19
Abbreviations 20
List of Tables 24
List of Figures 26
A. Introduction 34
1 The expanding world of hCG 36
References 39
2 History and introduction to human chorionic gonadotropin, a group of five independent growth factors 42
2.1 History 42
2.2 The pregnancy test 42
2.3 Introduction to hCG 44
References 47
B. Synthesis, Structure and Function 50
3 The molecular genetics of hCG 52
3.1 The LH/hCG gene cluster 52
3.2 Control of hCG gene expression: hCGa 54
3.3 Control of hCG gene expression: hCGß 56
3.4 Summary 61
References 61
4 Structure, synthesis, and secretion of hCG and hyperglycosylated hCG 66
4.1 Amino acid sequence of hCG 66
4.2 Carbohydrate structure of hCG 68
4.3 hCG primary structure 69
4.4 hCG secondary structure 70
4.5 hCG tertiary structure 71
4.6 hCG quaternary structure 73
4.7 Combination of hCG subunits 73
4.8 Synthesis and secretion of hCG 74
References 75
5 Three-dimensional structures of hCG and hyperglycosylated hCG 78
5.1 X-ray crystallography 78
5.2 Refining this model 79
References 82
6 Structures of hCG free a-subunit and free ß-subunit 84
6.1 Free a-subunit 84
6.2 Free ß-subunit 87
References 89
7 Glycobiology of hCG 92
7.1 Characteristic features of the sugar chains of glycoproteins 92
7.2 Biosynthetic pathways of sugar chains of glycoproteins to form characteristic features 93
7.3 The hCG sugar chains from urine of pregnant women and placenta 96
7.4 Characteristic features of the sugar chains of free a-subunit 97
7.5 Comparative studies of the N-linked sugar chains of hCG 100
7.6 Alteration induced in the O-linked sugar chains of hCG by malignant transformation of trophoblasts 103
7.7 Altered expression of GnT-IV in choriocarcinoma cells 103
7.8 Glycosylated hCG as a diagnostic marker of trophoblastic diseases 104
7.9 Functional role of the hCG sialic acid residues 106
7.10 Future prospects 108
References 111
8 Detecting hCG and hCG variants using MALDI-ToF-MS 118
References 121
9 The hCG/LH hormone receptor 124
References 127
10 TGFß-II autocrine receptor 130
References 131
C. Continuous Dissociation and Degradation 134
11 Degradation products of hCG, hyperglycosylated hCG, and free ß-subunit 136
11.1 Pure hCG preparations 138
11.2 Nicking and enzyme cleavage 139
11.3 Dissociation 141
11.4 Liver clearance 141
11.5 Degradation with pregnancy advancement 141
11.6 Degradation in cancer 143
References 146
D. Biological Function: Pregnancy 148
12 Pregnancy-1, functions during preimplantation and during blastocyst implantation 150
12.1 Preimplantation 150
12.2 Hyperglycosylated hCG function 151
12.3 Blastocyst implantation 152
12.4 Hyperglycosylated hCG the human time bomb 154
References 154
13 Pregnancy-2, maintenance of gestation 158
References 162
14 Pregnancy-3, creation and continuation of hemochorial placentation 166
References 172
15 Paradigm shift on the targets of hCG actions 174
15.1 Summary and perspectives 178
References 178
E. Biological Function: Normal Pituitary 182
16 Pituitary sulfated hCG 184
16.1 Structure of pituitary sulfated hCG 186
16.2 Biological function of pituitary sulfated hCG 186
16.3 Occurrence of pituitary sulfated hCG 188
References 193
F. Biological Function: Evolution 196
17 Evolution 198
17.1 TGFß and evolution of hCG 198
17.2 Evolution of hCG and hyperglycosylated hCG 200
17.3 hCG, hyperglycosylation, and the evolution of humans 203
17.4 Hominids and the evolution of the brain 204
17.5 hCG evolution and the development of pregnancy disorders 205
17.6 hCG and cancer 206
17.7 All tied together 209
References 209
G. Biological Function: Gestational Trophoblastic Disease 212
18 Biological functions of hyperglycosylated hCG 214
18.1 Discovery of hyperglycosylated hCG 214
18.2 Hyperglycosylated hCG, independent molecule to hCG 215
18.3 Hyperglycosylated hCG binds a TGFß receptor 217
References 217
19 Gestational trophoblastic diseases 220
19.1 Gestational trophoblastic diseases 220
19.2 Complete hydatidiform mole 220
19.3 Partial hydatidiform mole 221
19.4 Persistent or invasive hydatidiform mole 222
19.5 Gestational trophoblastic neoplasm 223
19.6 Placental site trophoblastic disease 224
19.7 Epithelioid trophoblastic disease 224
19.8 hCG and gestational trophoblastic disease 225
19.9 Hyperglycosylated hCG and gestational trophoblastic diseases 225
References 225
H. Biological Function: Cancer 228
20 Cancer-1, hCG variants as tumor markers 230
References 232
21 Cancer-2, hCG variants drive malignancies 234
References 237
22 Cancer-3, tying everything together 240
References 248
23 Expression and Biological Function of the Free ß-Subunit in Cancer: Expression and Treatment Target in Cancer 252
23.1 hCGß gene expression in cancer 255
23.2 hCGß expression in epithelial cancer 256
23.3 The biological action of hCGß on epithelial tumors 258
23.4 hCG cancer vaccines 261
23.5 Summary 265
References 265
24 hCG and breast cancer conundrum 274
References 276
I. Clinical Applications 278
25 Use of hCG in reproductive dysfunction 280
25.1 Historical overview and perspective 281
25.2 Considerations of hCG administration within clinical protocols 284
25.2.1 OI—oral agents 284
25.2.2 OI—parenteral agents with hCG 284
25.2.3 OI protocols and FSH preparations 285
25.3 Timing administration of hCG—ultrasound monitoring, progesterone patterns, and endogenous LH surge patterns 288
25.4 Risks of ovulation management with hCG 289
25.5 Efficacy of LUF syndrome 291
25.6 Considerations of hCG administration for timing IUI 294
25.7 High-order multiple pregnancies 298
References 299
26 hCG in assisted reproduction 306
26.1 The ovarian cycle and hCG use in assisted reproduction 307
26.2 The follicular phase: the role of LH 307
26.3 The periovulatory phase and the mid-cycle LH surge 308
26.4 The follicular-luteal transition 309
26.5 The luteal-placental shift 310
26.6 The potential role of hCG in implantation 310
26.7 hCG in the management of normal pregnancy 312
26.8 Hyperstimulation syndrome 313
26.9 hCG in the management of ectopic pregnancy 314
26.10 Conclusions 315
References 316
27 Illicit use of hCG in dietary programs and to promote anabolism 318
27.1 Dietary programs 318
27.2 hCG and anabolism promotion 319
27.3 hCG variants as dangerous substances 320
References 321
28 Positive hCG tests: Causes other than pregnancy 324
28.1 False-positive hCG test results 325
28.2 Pituitary hCG 328
28.3 Quiescent gestational trophoblastic disease 328
28.4 Cancer 330
28.5 Choriocarcinoma/gestational trophoblastic neoplasm 330
28.6 Munchausen’s syndrome 335
28.7 Familial hCG syndrome 335
28.8 Administering hCG 339
28.9 Managing non-pregnant individuals positive for hCG 339
References 340
J. Assays and Antibodies 344
29 Antibodies and hCG tests 346
29.1 Antibody sites on hCG 346
29.2 Radioimmunoassay 349
29.3 Laboratory immunometric assays 350
29.4 Point-of-care hCG immunoassays 350
29.5 Over-the-counter hCG immunoassays 351
29.6 Specific hCG free subunit, fragment, and carbohydrate variant assays 352
References 353
30 Problems with today’s hCG pregnancy tests 356
30.1 Automated immunometric assays 356
30.2 Problems with automated immunometric hCG assays and specificity 357
30.3 Sensitivity and specificity of point-of-care hCG immunoassays 362
30.4 Sensitivity and specificity of over-the-counter immunoassays 363
References 367
31 The future and a new generation of pregnancy tests 368
References 372
K. Test Applications and Standards 374
32 Detecting Down syndrome pregnancies and preeclampsia 376
32.1 Down syndrome screening 376
32.2 Preeclampsia screening 378
References 379
33 The biology of gestational trophoblastic neoplasms 382
33.1 Complete hydatidiform mole 382
33.2 Partial hydatidiform mole 388
33.3 Choriocarcinoma 390
33.4 Placental site trophoblastic tumor 394
References 395
34 Hyperglycosylated hCG and free ß-subunit markers of gestational trophoblastic diseases 400
34.1 Hydatidiform mole 401
34.2 Choriocarcinoma 403
34.3 Placental site trophoblastic disease 405
References 406
35 Quiescent trophoblastic disease and minimally aggressive gestational trophoblastic neoplasm 408
35.1 Quiescent gestational trophoblastic disease 408
35.2 Minimally aggressive GTN 411
References 416
36 Background hCG 418
References 420
37 hCG standards 422
37.1 First IS 422
37.2 Second IS 423
37.3 Third IS 424
37.4 IRR for hCG and related substances 425
37.5 Future prospects 427
37.6 Recombinant hCG 428
References 428
L. Methods 432
38 hCG and hyperglycosylated hCG purification and analysis from serum, urine, and culture fluids 434
38.1 Urine hCG and hyperglycosylated hCG 434
38.2 Culture fluid hCG and hyperglycosylated hCG 436
38.3 Serum hCG and hCG-H 436
38.4 Analysis 437
References 437
M. Ethics, Comments and the Future 438
39 Ethics, Texas, and politics 440
40 Summary: hCG a remarkable molecule 444
41 hCG and the future 446

Textauszug

List of Figures

Figure 3.1

A diagrammatical representation of the arrangement of genes in the LHB/CGB gene cluster on chromosome 19q13.32, where the exact positions are indicted in Kbp. The figure indicates the current gene assignments within the transcription orientation arrows, and G1 and G2 indicate the position of the snaRs.

19

Figure 3.2

Original published gene sequence of CG α indicating introns and exons (in bold black). The amino acids coded for by the italicized (bold) regions are removed during posttranslational modifications; therefore, remaining regions code for only the mature protein. Large portions of intronic regions were omitted from the published sequence, indicated by //. Data adapted from Ref.

22

Figure 3.3

ORFs of human CGA adapted from NCBI reference sequence NM_001252383.1. Entire mRNA sequence with the ORF highlighted in gray. Exons are from 1–135, 136–230, 231–323, 324–508, and 509–844.

23

Figure 3.4

A diagrammatic representation of the CGA promoter sequence based on the work of Knofler et al., with significant additions from others. In addition to the CREs, the URE is overlapped by several additional binding protein regions; such an overlap could indicate that these regions are activated by at least two different tissue-specific binding proteins.

23

Figure 3.5

CGB splice variants including both empirical and hypothetical protein sequences of splice variants from genes CGB1 and CGB2. (A) With fully spliced intron 1, splice donor site not truncated and possible ATG1 or ATG2 ORFs. From ATG1, the product for gene CGB1 would be a 132aa protein with a molecular mass of 14.0 kDa, or from ATG2 a 155aa protein with a molecular mass of 16.7 kDa; for gene CGB2 from ATG1, the predicted product would be a 132aa protein with a molecular mass of14 kDa, or from ATG2 a 163aa protein with a molecular mass of 17.4 kDa. (B) Splice variant CGB2+166 bp (from intron 1) from ATG1 may give a 60aa protein with molecular mass of 6.9 kDa. (C) Splice variant CGB1+176 bp. (D) Novel hypothetical splice variant with additional deletion within exon 1, to give exon 1A and exon 1B.

25

Figure 3.6

ORFs of CGB genes (CGB1, CGB2, CGB7, CGB, CGB5, and CGB8) showing multiple sequence alignments based on sequences adopted from NCBI database. The sequences are variable in length and show exons including mRNA from start codon to stop codon only. The asterisks indicate where CGB gene sequence differences can be seen and spaces indicate exon boundaries.

26

Figure 3.7

Multiple sequence alignments of CGB expressed proteins from all genes (CGB8, CGB5, CGB, CGB7, CGB1, and CGB2) showing sequence differences.

27

Figure 3.8

Promoter sequence of CGB5, CGB. Transcription is controlled by the SP2 and SP1 binding site between −311 and −188; this is affected positively by cAMP. Schematic drawing. Data from Ref.

28

Figure 4.1

The amino acid sequence of hCG subunits as shown by Morgan et al. The symbols N and O mark the sites of the Asn-linked N-linked and Ser-linked O-linked oligosaccharides on hCG subunits.

34

Figure 4.2

O-linked oligosaccharides on hCG and hyperglycosylated hCG. (A) Simple and (B) complex.

36

Figure 4.3

N-linked oligosaccharides on hCG and hCG-H. (A) Biantennary and (B) triantennary.

37

Figure 4.4

The cystine knot structures on hCG β-subunit.

39

Figure 4.5

The hCG β-subunit seat belt. Image shows the three-dimensional structure of hCG as shown by Lapthorn et al. Black line is β-subunit and gray line is α-subunit.

39

Figure 4.6

Serum hCG and hyperglycosylated hCG during the course of pregnancy.

42

Figure 5.1

The 3D structure of hCG as proposed by Wu et al., Lapthorn et al., and Lustbader et al. Plus and minus signs indicate sites of charged amino acids.

46

Figure 5.2

Proposed complete intact structures of hCG and hyperglycosylated hCG.

48

Figure 6.1

The N-linked oligosaccharides attached to the hCG free α-subunit.

52

Figure 6.2

Proposed structure of hCG free β-subunit oligosaccharide side chains.

55

Figure 7.1

Three subgroups of N-linked sugar chains. Structures within the solid line are the pentasaccharide core common to all N-linked sugar chains. The bars in front of the nonreducing terminal monosaccharides indicate that the sugars can be further extended by adding sugars.

60

Figure 7.2

Branching of complex sugar chains.

61

Figure 7.3

Four major core structures found in O-linked sugar chains.

61

Figure 7.4

Processing pathway in the biosynthesis of N-linked sugar chains.

62

Figure 7.5

Formation of branching structures of complex sugar chains. R and R′ represent the GlcNAc β1–4GlcNAc and the GlcNAc β1–4(Fucα 1–6)GlcNAc groups, respectively.

64

Figure 7.6

Structures of the N-linked sugar chains of hCG purified from the urine of pregnant women (A) and their desialylated forms (B).

65

Figure 7.7

Maturation of the N-linked sugar chains of hCG and of free α-subunit. S, sialic acid; G, galactose; M, mannose; F, fucose; GN, N-acetylglucosamine.

66

Figure 7.8

Biosynthesis of the abnormal biantennary sugar chains found in choriocarcinoma cells. GnT, N-acetylglucosaminyl transferase.

69

Figure 7.9

Percent molar ratio of the O-linked sugar chains with core 1 and core 2 (shown in white and black, respectively) in various urinary hCG samples.

70

Figure 7.10

Percent molar ratio of urinary hCG bound to a DSA-Sepharose column before (0) and after (e) sialidase digestion. (A) Urine samples from normal pregnant women, (B) those from patients with hydatidiform mole, (C) those from patients with invasive mole, and (D) those from patients with choriocarcinoma.

73

Figure 7.11

Schematic presentation of hCG-receptor complex. G, Gs protein; L, lectin; R, hCG receptor.

75

Figure 8.1

MALDI-ToF-MS obtained from the overlay of three spectra from the three hCG standards. Recombinant hCGβ in the peak at 23,897.76 m/z, recombinant hCG in the peak at 36,123.66 m/z, hyperglycosylated hCG (obtained from the collection described in Ref.) in the peak at 38,405.27 m/z, and hCGββ dimer seen in the peak at 47,529.76 m/z as described in Ref.

85

Figure 8.2

MALDI-ToF-MS obtained from the analysis of embryo culture fluid of a blastocyst before embryo transfer. All forms of hCG can be seen: hCGβ at 23,687.54 m/z; hCG at 36,180.49 m/z; hCG-H at 38,063.47; and hCGββ dimers at 47,988.37 m/z. Poor spectral quality is attributable to the pmol concentrations of hCG found within the embryo secretome.

86

Figure 8.3

MALDI-ToF-MS obtained from the overlay of three spectra from the three samples analyzed in this example:...

Produkt-Details

• Erscheint lt. Verlag: 2.12.2014
• Sprache: englisch
• Themenwelt: Medizinische Fachgebiete ► Innere Medizin ► Endokrinologie
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Onkologie
• Themenwelt: Studium ► 1. Studienabschnitt (Vorklinik) ► Biochemie / Molekularbiologie
• Themenwelt: Studium ► 1. Studienabschnitt (Vorklinik) ► Histologie / Embryologie
• Themenwelt: Studium ► 1. Studienabschnitt (Vorklinik) ► Physiologie
• Themenwelt: Naturwissenschaften ► Biologie
• ISBN-10: 0-12-800821-0 / 0128008210
• ISBN-13: 978-0-12-800821-8 / 9780128008218