Table Of ContentHuman Chorionic Gonadotropin (hCG)
Human Chorionic
Gonadotropin (hCG)
Second Edition
Laurence A. Cole
USA hCG Reference Service,
Angel Fire, NM, USA
Stephen A. Butler
MAP Diagnostics,
BioPark, Broadwater Road,
Welwyn Garden City,
Hertfordshire, UK
AMSTERDAM(cid:129)BOSTON(cid:129)HEIDELBERG(cid:129)LONDON(cid:129)NEWYORK(cid:129)OXFORD
PARIS(cid:129)SANDIEGO(cid:129)SANFRANCISCO(cid:129)SINGAPORE(cid:129)SYDNEY(cid:129)TOKYO
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List of Contributors
Beata B. Burczynska Biomedical Sciences, Middlesex University, The Burroughs,
Hendon,London,UK
Stephen A. Butler MAP Diagnostics, BioPark, Broadwater Road, Welwyn Garden
City,Hertfordshire,UK
Francis W. Byrn Obstetrics and Gynecology, University of New Mexico,
Albuquerque,NM,USA
LaurenceA.Cole USAhCGReference Service,AngelFire,NM,USA
Robert O. Hussa Medical College of Wisconsin, Milwaukee, WI, Sunnyvale, CA,
USA
Ray K. Iles MAP Diagnostics, BioPark, Broadwater Road, Welwyn Garden City,
Hertfordshire,UK
ErvinE.Jones GeneticsandIVFInstitute,Fairfax,VA,USA
AkiraKobata TheNoguchiInstitute,Tokyo,Japan
C.V. Rao Herbert Wertheim College of Medicine, Florida International University,
Miami,FL,USA
Ulf-Ha˚kanStenman HelsinkiUniversityCentralHospital,Helsinki,Finland
About the Editors
LaurenceA.Cole,PhD,andStephenA.Butler,PhD,wrotethisbooktogether.
Laurence A. Cole, PhD
In 1971, Larry Cole began academic life studying medicine in England. A stroke in
1974 put him in a coma for 3 months and left him with amnesia and severe brain
damage. He was forced to abandon his career in medicine as a result of this brain
damage incident. After spending 1 year in the hospital, he moved to Israel in 1976,
then to the United States in 1977. He somehow was fortunate and able to “program”
the other side of his brain. He taught himself to learn and memorize science and
medicine again and, in 1978, Cole attended the Medical College of Wisconsin,
Milwaukee, to work on a PhD in Biochemistry. In 1981, Larry obtained his PhD
whilestudyingcancercellhCGwithRobertHussa,PhD.Duringthistime,Larryalso
worked with Roland Pattillo, MD, on gestational trophoblastic disease cases. In the
same year, he attended the first international symposium on gestational trophoblastic
diseasesandhasattendedall15consecutivebiannualsymposiasincethattime.
In 1983, Larry completed a postdoctoral fellowship with Raymond Ruddon,
PhD,at theUniversityofMichigan,AnnArbor, wherehecontinuedtospecializein
hCG. His experiences working with Dr. Ruddon are what inspired him to study
hCG carbohydrate structure. After his postdoctoral fellowship, Larry joined the
facultyoftheUniversityofMichigan.
In 1984, Larry took a position at Yale University, where he spent 15 years as
part of the Obstetrics and Gynecology faculty. He slowly advanced at Yale
University from Assistant Professor to Associate Professor, then to Full Professor.
While at Yale University, Larry’s research purely focused on hCG, investigating
hCG and gestational trophoblastic disease, hCG as a tumor marker, and oligosac-
charides and hCG. It was at Yale University that he studied the structure of chorio-
carcinoma hCG, which ultimately led to his discovery of hyperglycosylated hCG
andtonewdiagnosticprotocolsingestationaltrophoblasticdiseases.
In1999,LarrymovedtotheUniversityofNewMexico,Albuquerque,asatenured
FullProfessor.WhileattheUniversityofNewMexico,hestartedtheUSgovernment
CLIA-endorsed program called the USA hCG Reference Service, which globally
advises scientists who research hCG, physicians who treat gestational trophoblastic
disease, and patients with persistent low levels of hCG. With the Reference Service
xvi AbouttheEditors
came his endowment by appreciative hCG patients with false-positive test results.
In 2004, he became the Howard and Friedman Distinguished Professor of Obstetrics
andGynecology.
Today, 32 years after receiving his PhD, Dr. Cole still specializes in hCG
research. With the discovery of how hCG variants modulate cancer, Larry’s
research interest now centers on cancer biology and treatment. In 1987, Larry’s
PhD advisor, Robert Hussa, wrote the first book on hCG. It is with great dignity
that Larry follows in the footsteps of his advisor and writes this second version of
thesecondspecializedbookonhCGin2013.
Stephen A. Butler, PhD
Stephen Butler, PhD, was a Reader in Biomedical Diagnostics at the Centre for
Investigative and Diagnostic Oncology in the School of Science and Technology,
MiddlesexUniversity,London.In2014,helefthighereducationtoco-foundadiag-
nosticcompanyspecializinginprenatalscreeningcalledMAPDiagnostics.
Stephen’s first exposure to hCG came as an undergraduate in the Williamson
Laboratory for Molecular Oncology founded by Ray Iles in the Department of
Reproductive Physiology Department under Tim Chard. Stephen ran hCGβ RIAs
and IRMAs for studies into Downs Syndrome and cancer along with reverse tran-
scriptase studies on CGB gene expression. After graduating, Stephen returned to
Ray’s laboratory for his PhD on the structure/function of hCGβ in epithelial cancer
and then a fellowship at Yale with Larry Cole. Stephen moved with Larry to New
Mexico and helped set up the hCG reference service at a time when phantom hCG
was making the laboratory very busy. Stephen returned to the UK after 21/ years.
2
During this time in the USA, Stephen and Larry shared their experiences on hCG
(its variants and their structures and functions) and combined their collective evi-
dence to formulate many of the cancer hypotheses which led to the work described
in this book. This broadened the whole hCG cancer field and is a central focus of
thissecondeditionbook.
We thank Camille Sapienz for editing the grammar, punctuation, and diction of
this book. We also thank all the other authors who contributed essential chapters to
thisbook:BeataBurcznska; Francis Byrn,MD;RobertHussa, PhD;RayIles;Ervin
Jones, MD; Akira Kobata, PhD; C.V. Rao, PhD; and Ulf Stenman, PhD. Once
again,wesaythankyoutoeverybodyinvolved.
LaurenceA.ColePhD
StephenA.ButlerPhD
Preface
This book was written by twenty-first century scientists in honor of the forefathers
and pioneers of hCG research. Without them, we never would have been able to
discover the wondrous molecules that we know today. I honor and dedicate this
book to those who discovered hCG and to those who first found evidence for an
hCG-like molecule. In 1912, Bernhard Aschner at University of Vienna stimulated
the genital tract of guinea pigs with injections of water-soluble extracts of human
placenta [1]. In 1913, Otfried Fellner, a gynecologist in Vienna, induced ovulation
in immature rabbits with saline extracts of human placenta [2]. In 1919, Toyoichi
Hirose of the Osaka Medical College stimulated ovulation and normal luteal func-
tion in immature rabbits by repeated injection of human placental tissue [3]. All of
these works show that there is a clear hormonal link between the placenta and the
uterus [1(cid:1)3]. In 1927, Selamar Aschheim of the University of Berlin in Germany
and Bernhard Zondek of the Berlin-Spandau Hospital in Germany demonstrated
that pregnant women produce a gonad-stimulating substance [4].They showed that
injecting this substance subcutaneously into intact immature female mice produced
follicular maturation, luteinization, and hemorrhaging into the ovarian stroma.
These findings were confirmed by others [5,6] and the first hCG pregnancy tests
wereborn[4(cid:1)6].
Around this time, the name human chorionic gonadotropin (hCG) was con-
ceived. Chorion comes from the Latin chordata, meaning afterbirth; gonadotropin
is used because the hormone is a gonad tropic molecule acting on the ovaries and
promoting steroid production. I also dedicate this book to those 21 people who
I consider to be the pioneers of hCG research, without whom there would be little
towriteabout:
AkiraKobata,PhD TokyoUniversity,Japan.
BruceNisula,MD NationalInstitutesofHealth,Bethesda,MD.
RobertNorman,MD UniversityofAdelaide,Australia.
BruceWeintraub,MD NationalInstitutesofHealth,Bethesda,MD.
GlennBraunstein,MD Cedars-SinaiMedical,LosAngeles,CA.
IrvingBoime,PhD WashingtonUniversity,StLouis,MO.
Jean-MichelBidart,PhD InstitutGustave-Roussy,Villejuif,France.
JohnFiddes,PhD ColdSpringLaboratory,ColdSpringHarbor,NY.
JudithVaitukaitis,MD NationalInstitutesofHealth,Bethesda,MD.
KlaussMann,MD UniversityofEssen,Germany.
MarioAscoli,PhD UniversityofIowa,IowaCity,IA.
OmBahl,PhD UniversityatBuffalo,Buffalo,NY.
RobertCanfield,MD Columbia-PresbyterianHospital,NewYork,NY.
StevenBirken,PhD NationalInstitutesofHealth,Bethesda,MD.
xviii Preface
TimothyChard,MD StBartholomew’sHospital,London,UK.
MariaDufau,MD,PhD NationalInstitutesofHealth,Bethesda,MD.
UlfStenman,PhD HelsinkiUniversity,Helsinki,Finland.
WilliamOdell,MD,PhD UtahMedicalCenter,SaltLakeCity,UT.
C.V.Rao,PhD UniversityofLouisville,Louisville,KY.
RayRuddon,MD,PhD UniversityofMichigan,AnnArbor,MI.
Francis Morgan, PhD College of Physicians and Surgeons, Columbia University,
NewYork.
LaurenceA.Cole,PhD USAhCGReferenceService,AngelFire,NM,USA
Stephen A. Butler, PhD MAP Diagnostics, BioPark, Broadwater Road, Welwyn
GardenCity,Hertfordshire,UK
References
[1] Aschner B. Ueber die function der hypophyse. Pflug Arch Gest Physiol 1912;146:
1(cid:1)147.
[2] Fellner OO. Experimentelle untersuchungen uber die wirkung von gewebsextrakten
aus der plazenta und den weiblichen sexualorganen auf das genital. Arch Gynakol
1913;100:641.
[3] Hirose T. Experimentalle histologische studie zur genese corpus luteum. Mitt Med
FakultdUnivZU1919;23:63(cid:1)70.
[4] Aschheim S, Zondek B. Das Hormon des hypophysenvorderlappens: testobjekt zum
Nachweisdeshormons.KlinWochenschr1927;6:248(cid:1)52.
[5] Zondek B, Aschheim S. The Zondek(cid:1)Ascheimpregnancy test. Can Med Assoc J
1930;22:251(cid:1)3.
[6] Friedman MH, Lapham MEA. Simple, rapid procedure for the laboratory diagnosis of
earlypregnancies.AmJObstetGynecol1931;21:405(cid:1)10.
Abbreviations
αACT α-subunitactivatorelement
ActD actinomycinD
Ala alanine
Arg arginine
Asn asparagine
ATF1 activatingtranscriptionfactor1
BEP chemotherapyregimen:bleomycin,etoposide,andcisplatin
BSO bilateralsalpingo-oophorectomy
cAMP cyclicadenosinemonophosphate
CG chorionicgonadotropin
CGB chorionicgonadotropinbetagene(s)
CG-H hyperglycosylatedchorionicgonadotropin
CHO Chinesehamsterovary
CKGF cystine-knotgrowthfactor
CNS centralnervoussystem
COH controlledovarianhyperstimulation
COS controlledovarianstimulation
CRE cAMPresponseelement
CREBP cAMPresponseelementbindingprotein
CTP humanchorionicgonadotropinβ-subunitC-terminalpeptide
Cys cysteine
DSA Daturastramoniumagglutinin
DSD downstreamdomain
EDTA ethylenediaminetetra-aceticacid
EGF epidermalgrowthfactor
EMA-CO chemotherapy regimen: etoposide, methotrexate, and actinomycin D, alternating
withcyclophosphamideandonvocin(vincristine)
EMA-EP chemotherapy regimen: etoposide, methotrexate, and actinomycin D, alternating
withetoposideandcisplatin
FDA FoodandDrugAdministration(USA)
FIGO FederationInternationalofGynecologicOncology
freeα freeα-subunitofhumanchorionicgonadotropin
freeβ freeβ-subunitofhumanchorionicgonadotropin
freeβ-βCTP freeβ-subunitC-terminalpeptide
FSH follicle-stimulatinghormone
Fuc fucose
FUT fucosyltransferase
Gal galactose
GalNAc N-acetylgalactosamine
GATA DNAsequenceandDNAcoding
GlcNAc N-acetylglucosamine
xx Abbreviations
Glu glutamicacid
Gly glycine
GnRH gonadotropin-releasinghormone
GnT N-acetylglucosaminyltransferase
GTD gestationaltrophoblasticdisease
GTN gestationaltrophoblasticneoplasm
hCG humanchorionicgonadotropin
hCGα freeα-subunitofhumanchorionicgonadotropin
hCGβ freeβ-subunitofhumanchorionicgonadotropin
hCG-βCTP humanchorionicgonadotropinβ-subunitC-terminalpeptide
hCG-H hyperglycosylatedhumanchorionicgonadotropin
hCG-Hβ hyperglycosylatedhumanchorionicgonadotropinfreeβ-subunit
hCGp pituitaryhCG
His histamine
hLH humanluteinizinghormone
hMG humanmenopausalgonadotropins
ICE chemotherapyregimen:ifosamide,carboplatin,andetoposide
IFCC InternationalFederationofClinicalChemistry
Ile Isoleucine
IRP internationalreferencepreparation
IRR internationalreferencereagent
IS InternationalStandard
ISOBM InternationalAssociationofBiologicalMarkers
IU internationalunits
IUI intrauterineinsemination
IU/l internationalunitsperliter
IVF invitrofertilization
Leu leucine
LIF leukemiainhibitoryfactor
LH luteinizinghormone
LUF luteinizedunrupturedfolliclesyndrome
Lys lysine
Man mannose
MCSF macrophagecolonystimulatingfactor
Met methionine
MoM multiplesofthemedian
MCW MedicalCollegeofWisconsin
mIU milli-internationalunits
mIU/ml milli-internationalunitspermilliliter
ml milliliter
MMP metalloproteinase
Mtx methotrexate
NCBI TheNationalCenterforBiotechnologyInformation
NeuAc N-acetylneuraminicacidorsialicacid
NGF nervegrowthfactor
ng/ml nanogramspermillilter
NIH NationalInstitutesofHealth
Ob/Gyn obstetricsandgynecology
OHSS ovarianhyperstimulationsyndrome
