ENDOCRINE
SURGERY
edited
by
ARTHUR
E.
SCHWARTZ, M.D., F.A.C.S.
Clinical Professor
of
Surgery
Mount Sinai School
of
Medicine, New York University
New York, New York,
U.S.A.
DEMETRIUS
PERTSEMLIDIS,
M.D., F.A.C.S.
Clinical Professor
of
Surgery
Mount Sinai School
of
Medicine, New York University
New York, New York,
U.S.A.
MICHEL
GAGNER,
M.D.,
F.A.C.S.

Professor
of
Surgery
Chiefl
Division
of
Laparoscopic Surgery
Mount Sinai School
of
Medicine, New York University
New York, New York,
USA.
MARCEL
MARCEL
DEKKER,
INC.
DEKKER
NEW
YORK
BASEL
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To
Those who learn
Those who teach
Those who hope
Those who help
For Joan, who is always there, Nancy, Susan, and Emily. Arthur E. Schwartz
For my wife Lois and my sons Alexander and David. Demetrius Pertsemlidis

For my wife France Lapointe, my three sons, Xavier, Guillaume, and Maxime, with love.
My father, Raymond Gagner, M.D., F.R.C.S.C., F.A.C.O.G., who inspired me to
pursue a career in medicine and surgery. My mother Louise Duchaine and my
three brothers, Francois, Richard, and Sebastien, for their support during
all those years of studying and training. Michel Gagner
The encouragement, advice, and expertise of Mr. Robert Siegel, Dr. Alan Freedman,
and Ms. Fran Shaller are gratefully acknowledged.
Foreword
Drs. Demetrius Pertsemlidis, Arthur E. Schwartz and
Michel Gagner have assembled a distinguished faculty
from the Mount Sinai School of Medicine in New York
and an international cadre of ‘‘who’s who’’ in endocri-
nology, to contribute to this comprehensive text.
This is much more than a book on endocrine surgery,
focused as it is on covering all aspects of endocrinology.
The text includes molecular endocrinology, pituitary,
thyroid, parathyroid, adrenal, pancreatic and GI tract
endocrine neoplasms, and concludes with an integrated
review of multiple endocrine neoplasia. The presenta-
tion deals with each organ system, with a sequential
concentration on pathology, imaging, individual syn-
dromes, and surgical managem ent in a very comprehen-
sive manner. New approaches to imaging are succinctly
summarized. Minimally invasive surgery and video-
assisted surgery are counter-balanced by aggressive
approaches to advanced disease, including organ trans-
plantation and tumor debulking.
There should be something here for everyone in-
terested in en docrine tumors, from diagnosis and lo-
calization to surgical approaches and nonsurgical

management.
While heavily weighted to the Mount Sinai faculty,
readers will find the contributions exciting, with some of
the true international leaders featured within their own
discipline. This provides a strong flavor of both stan-
dardized and alternative approaches to a series of com-
plex diseases. For me, it was a pleasure to revisit areas of
my own personal interest and I am sure other readers
will similarly enjoy the vast array of information con-
tained within this most attractive text.
In this age of increasing demands for clinical care, it
is most encouraging to see clinicians committed to such
a comprehensive and educational text.
Murray F. Brennan, M.D.
Chairman, Department of Surgery
Memorial Sloan-Kettering Cancer Center
New York, New York, U.S.A.
iv
Preface
We offer an exposition of the current status of surgical
care in the management of endocrine disorders. Endo-
crine Surgery includes a summary of present and evolv-
ing approaches to surgery of the pituitary, thy roid,
parathyroid, adrenal, and pancreas. The text is co mpre-
hensive but not exhaustive, emphasizing practical ap -
proaches. Contributors with great experience have been
encouraged to present logical differences in viewpoint,
as well as controversies and alternative approaches to
the management of problems. New diagnostic and ther-
apeutic methods are brought to the attention of the

reader. Operative techniques are presented and illus-
trated in detail.
The expanded understanding of endocrine disease,
the increasing availability of sophisticated diagnostic
methods, and the development of innovative surgical
techniques, have changed the landscape of the manage-
ment of endocrine disorders, profoundly influencing
the practice of surgical endocrinology. Diagnostic ca-
pability expands at an exponential rate. The body is
becoming virtually transparent as new x-ray imaging
methods, radioisotope scanning, and ultrasound evolve
rapidly. These techniques are presented, discussed, and
illustrated.
New developments in surgery are stunning. Intra-
operative hormone assays make it possible to confirm
success while the patient is still on the operating table.
Robotic surgery, made feasible by advanced computer
capabilities and instant communication techniques,
offers operative expertise at a great distance, and also
constitutes a huge resource for surgical training. Small
endoscopic instruments with intrinsic cameras can vi-
sualize almost any part of the body, giving surgeons
access to nearly every organ, and in addition, to virtual
spaces such as the hands, neck, retroperitoneal area,
subcutaneous and intramuscular planes. The surger y
can be executed through minimally invasive portals
while the procedure is monitored on a television screen
in real time.
Endocrine Surgery brings together the expertise of
many authorities in their fields. It provides a perspective

on present treatment and new developments. A practi-
cal summary of diagnostic methods, choices of manage-
ment, and surgical techniques is offered that we hope
will be helpful to those involved in the management of
endocrine disorders.
Arthur E. Schwartz
Demetrius Persemlidis
Michel Gagner
v
Introduction: Science, Surgery, and the Endocrine Patient
Our generation learned little about RNA and DNA in
medical school, considering it mostly irrelevant and
arcane. How this attitude has changed! As young doc-
tors we were overwhelmed by the seminal concept of
immunoassay, pioneered by Berson and Yalow, that
made it possible to determine the concentration of
virtually any biological material with exquisite accu-
racy. The watershed development of monoclonal anti-
bodies by Milstein enabled the fusion of myeloma cells,
possessing an infinite ability to multiply, to B cells that
secrete a specific antibody. This created a hybrid cell
that continually produces a chosen, identifiable, mono-
clonal antibody. Unbelievable applications of such
concepts were just beginning.
It was not until the beginning of the 1980s that
molecular biology loomed large in our minds., and not
until the 1990s that physician s realized that its relevance
to clinical practice was enormous. It was then that
seminars were organized to learn the new biology,
making it possible for physicians to read and under-

stand the many articles discussing the use of these new
techniques.
At first blush it may seem that the rapid advances in
molecular medicine have been so spectacular that by
comparison the art and scienc e of surgery have not
moved an inch. But how wrong that is! If it had been
suggested that a microscope would be useful at surgery
or tha t large openings were not nec essary for good
views, surgeons, residents, and medical students at the
time of our training would have laughed. Microsurgery
of every organ is now possible. The introduction of
endoscopic surgical approaches has been nothing but
spectacular. Endoscopes as small as 2.7 mm in diameter
offer great magnification and easy visualization in pitu-
itary surgery. Every body cavity is accessible to this
approach. Identification of sm all nerves and blood
vessels is easy. Chest-splitting incisions can be avoided
by a thoraco scopic approach to mediastinal parathy-
roid adenomas. Even virtual spaces, subcutaneous and
intermuscular planes such as the neck, retroperitneum,
and hand, can be explored endoscopically. No surgical
subspecialty has been more affected by this enormous
change than endocrine surgery.
1 MOLECULAR ENDOCRINOLOGY
Molecular endocrinology, the decoding and sequencing
of the human genome, the development of our ability to
manipulate genes, genetic engineering, and modern
clinical technology will profoundly change our way of
life. Our molecular understanding of endocrine diseases
will continue to extend our therapeutic horizons. The

study of intact organisms and cellular models is being
supplanted by molecular genetics and new technology.
Development of a large biotechnology industry,
combined with a new understanding of disease mecha-
nisms, has resulted in successful treatments for a wide
variety of diseases and holds even greater promise for
others. The use of recombinant interferon in the treat-
ment of hepatitis C and the stimulation of hematopoi-
esis by recombinant erythropoiesis in chronic renal
failure are recent examples of the biotechnological
approach. Within classical endocrinology, the develop-
ment of human growth hormone and insulin comes to
mind. The clinical use of recombinant thyrotropin
vi
(TSH) in the search for thyroid-cancer metastases,
monitoring the level of thyroglobulin to identi fy the
presence and extent of recurrent disease, as well as the
treatment of osteoporosis with recombinant parathy-
roid hormone augur an exciting and expanding horizon.
The relationship of gene abnormalities, and the possi-
bility of manipulating and altering them, offer promise
in conditions such as hemophilia, cystic fibrosis, sickle
cell anemia, Niemann-Pick disease, and others. At our
own institution, a recent example involves Fabry dis-
ease, a painful and ultimately fatal metabolic disorder in
which fatty deposits gradually clog the blood vessels of
the heart, brain, and kidneys. The cause is a deficiency of
the enzyme alpha -calactosidase A. The normal gene for
this enzyme was isolated and a method developed to
produce large quantities of the recombinant human

enzyme. Clinical trials have demonstrated the enzyme
replacement to be safe and effective.
There is evidence that schizophrenia and bipolar
disease as well as many other conditions are a function
of gene abnormalities. These deviations are certainly
complex, but the aberrant mechanisms will ultimately
be identified and ingenious methods devised for their
treatment or prevention.
2 THE MALIGNANT CELL
The discovery of genes able to drive a cell into a can-
cerous state (oncogen es) and the concept that a normal
cell may need multiple hits to activate a number of
oncogenes before becoming malignant (multiple-hit hy-
pothesis) have had an enormous impact on our under-
standing of cancer biology. But our understanding is far
from complete and has still not yet translated in a large
way into the clinical arena. The future holds g reat
promise as drugs are developed to intercept oncogene
signals and attempt to reverse the mutation s a cell may
develop. The preventive screening potential of these
observation is huge (e.g., BRCA 1 and 2 breast cancer
genes). The ability to predict diseases such as breast
cancer, medullary thyroid carcinoma in multiple endo-
crine neoplasia (MEN) patients, and other forms of
malignancy, in addition to noncancerous conditions
such as Huntington’s chorea, diabetes, and the glycoge n
storage diseases, engenders controve rsy concerning the
ethics of knowing the risk profile of patients, but offers
hope in their treatment and possible prevention.
The identification of cancer-screening proteins such

as hCG, thyroglobulin, prostrate specific antigen, and
the ovarian cancer antigens, combined with improved
scanning procedures, has resulted in a more aggressive
surgical approach to the control of cancer and its
metastases. We can anticipate that future developments
will enable the treatment of many more conditions at an
early or even incipient stage. Witness the successful
prevention of medullary carcinoma by thyroidectomy
in MEN patients with C cell hyperplasia as early as 6
years of age, made possible by the widespread applica-
tion of calcitonin immunoassays. Other conditions will
surely follow.
3 THERAPEUTIC DRUGS
The development of ingenious and poten t drugs by a
robust pharmaceutical industry is changing the pano-
rama of modern medicine. The prevention of gastric
acid secretion, control of prostatic hypertrophy, more
powerful anti-inflammatory drugs, new classes of drugs
for diabetes, monoclonal antibodies to prevent myocar-
dial thrombosis and inflamma tion, and more powerful
immunosuppressants and chemotherapeutic agents are
examples of recent success; all have reduced the number
of patients needing surgery.
In addition, large-scale epidemiological studies of
medical and surgical therapies are demonstrating that
applications that appear to be sensible at first sight may
in the end prove to have adverse effects, to wit, the
downside of female hormone replac ement therapy and
the ineffectiveness of arthroscopic surgery for osteoar-
thritis of the knee It has taken ye ars to discover that

drugs such as cortisone, thalidomide, nicotine, and
cocaine have their risks as well as benefits. Bloodletting
was employed for generations until it was shown to do
more harm than good. The concept of long-term,
controlled, double-blind studies has emerged as an
invaluable research tool to develop evidence-based
approaches.
Problems such as an effective diet for weight control
(e.g., the relative importance of fat and carbohydrates)
remain to be evaluated. Intestinal bypasses and banding
procedures for morbid obesity can now be performed
endoscopically through minimal incisions and offer
good treatment when indicated. But obesity itself is
certainly a metabolic dysfunction that will eventually
be managed by physiological means. The recognition
that the hormone PPY, originating in the small intes-
tine, switche s off the urge to eat is the forerunner of
others. An understanding of the metabolic causes of
obesity will lead to the therapy of the future.
4 ANESTHESIA
Anesthesia has progressed to a point that e xtensive
operation can be undertaken with ever-decreasing risk.
Introduction vii
Local anesthesia has had a resurgence, particularly for
minimally invasive procedures. Adjuncts such as pro-
pofol, midazolam, and fentanyl make local anesthesia
much more comfortable for the patient as well as the
surgeon. Regional nerve block can also be used effec-
tively, particularly in neck surgery. In addition, many
new and effective agents, as well as technical develop-

ments such as the pulse oximeter for the continuous
monitoring of oxygen saturation, have made anesthesia
much safer.
5 ORGAN TRANSPLANTATION
Transplantation of tissues and organs is developing at
an exciting pace: the replacement of pancreas, heart and
lungs (sometimes together), bowel, and liver and kidney
(at times combined) are becoming routine. The pioneers
of transplantation are all in debt to the development of
powerful immunosuppressants and the sophisticated
knowledge of how to use such drugs, as well as the
advances in surgical techniques of anastamoses, pros-
theses, and the use of cadaveric tissues. The concept of
delivering transplanted infused cells to treat disease is
anticipated with excitement (e.g., islet cells for diabetes
and the return of cells to the patient after gene transfer).
In addition to the technical aspects of transplanta-
tion, large organizational networks are required to
procure tissues and distribute them effectively and
equitably. These are being developed to an ever-greater
extent, and we marvel at the progress.
6 STEM CELLS AND ARTIFICIAL
ORGANS
Despite the political, religious, and ethic al aspects of
stem cells, there can be no doubt that the potential for
their therapeutic use is enormous. In endocrinology, the
replacement of hormone-secreting cells would be sem-
inal. Such possibilities are on the horizon. Whether cells
are engineered or grown from stem cells is unlikely to
matter, as long as they work long term and are not

subject to immune attack. The indentification of insulin-
secreting stem cells and dopamine-secreting stem cells
are obvious areas of hope in the management of diabe-
tes and Parkinson’s disease. More technological devel-
opment is needed, but the future is inevitable. The
success of cloning in a variety of mamm als is now well
established. If we can clone a whole animal it is likely
that we can clone individual cell supplies and organs for
each future patient. What a different world it will be
when we can grow whatever organ we each need and
replace the damage rendered by disease and age.
7 SERUM AND CELL MARKERS
OF DISEASE
The identification and sensitive measurement of a wide
variety of molecular and metabolic markers have been
other emblems of modern medicine. With increasing
frequency, the diagnosis or suspicion of disease is based
on the chemistry of a patient rather than the physical
examination. The success of parathyroid surgery can
now be confirmed intraoperatively by very rapid assays
of parathormone, taking advantage of its 3-minute
half–life. Intraoperative adrenocorticotropic hormone
confers the same advantage in surgery for Cushing’s
disease. The identification of disease markers offers
powerful future possibilities. Serum calcitonin in med-
ullary thyroid cancer, thyroglobulin in thyroid cancer,
and prostate specific antigen have been noted earlier.
More are needed.
8 IMAGING
The development of CT and MRI scanning is taken for

granted because we use them every day, but these have
been amazing advances over classical radiology. Even
the coronary arteries can now be examined by such
techniques. This approach, as well as other new nonin-
vasive methods, will certainly be ex tended to a variety of
additional sites and organs.
Isotopic scintigraphic methods that permit the iden-
tification of the anatomical site and function of primary
tumors and metastatic disease are becoming increas-
ingly useful in distinguishing benign from malignant
tumors. Molecular serum and cellular markers with
high-resolution noninvasive or invasive imaging make
it possible to diagnose and localize endocrine tumors
and nonneoplastic hypersecretory states of the adrenals
and pancreas.
Ultrasound is invaluable in the preoperative diagno-
sis of pancreatic and adrenal lesions. The intraoperative
use of ultrasound can effectively guide the surgical
excision of adrenal tumors. In addition, laparoscopic
ultrasound can successfully identify lesions deep within
the parenchyma of the pancreas, such as isl et cell ade-
nomas. Intraoperative use of ultrasound for localization
of tumors in the adrenal, pancreas, and liver during
celiotomy or laparoscopy has virtually eliminated pre-
operative angiography and transportal selective venous
sampling with their inherent risks.
The use of scintigraphy for the imaging and locating
of parathyroid tumors has become the standard of care.
PET and octreotide scans are becoming routine in the
management of a variety of malignancies.

Introductionviii
Indeed, the accuracy of imaging (CT, MRI, and
ultrasound) has advanced to the point that masses are
revealed that do not have clinical significance (‘‘inci-
dentalomas’’), with the accompanying danger of unnec-
essary surgical procedures. Does every nonpalpable
thyroid nodule require intervention? At what point
should incidental nodules in the adrenal or kidney be
removed? The parame ters to decide when intervention is
required are still being developed.
Real-time imaging using sonography and scintigra-
phy has made a great impact on everyday medicine.
Equipment has been miniaturized and the images greatly
improved. These modalities make more accurate needle
biopsies possible. They have dramat ically influenced the
information available to the surgeon, many of whom
perform the imaging themselves in their offices or at the
operating table, for example, as an aid in exploration
for parathyroid adenomas or pancreatic lesions.
9 NEEDLE BIOPSIES
Surgeons and physicians have become more aggressive
at obtaining needle aspirates from diverse sites, includ-
ing the thyroid, adrenal, breast, pancreas, lung, liver,
and even parathyroids. Nevertheless, most of these
samples continue to rely on crude morphological
descriptions of the cell types obtained. While sometimes
the diagnosis can be confirmed by immunoassay of the
aspirate or immunohistochemical assessment (e.g., val-
idation of a parathyroid adenoma by the presence of
PTH), such an appro ach in the absence of specific

cancer antigens has been limited. We badly need a
technological revolution in the examination of cell
aspirates that will utilize the molecular techniques that
are becoming available. Needle aspiration biopsies can
allow the amplifications of all the genomic and
expressed genes present in the sample. Specific amplifi-
catio n of DNA and RNA by th e polymerase chain
reaction (PCR) now permits the amplificati on of known
genes (DNA) and/or the expressed genes (RNA) present
in the samples. This approach should provide a more
scientific assessment of many biopsi es. T-cell recept ors
and many other genes have been amplified in this way
from tissue aspirates, but the diagnostic applications of
these initial attempts have yet to be exploited.
10 BIOINFORMATICS AND IMAGE
TRANSFER
Transmission of images on the Internet and robotic
surgery loom large in the foreseeable future as methods
of enormous capability. All our information is now on
the computer. We no longer have x-ray films; we just
consult the screen. Laboratory results are available
instantly. You can look up the last 500 patients with
hypercalcemia at the push of a button. Information is
available in vast quantities and with ease. What is more,
you can see all this in your home office or on your laptop
while traveling. Such changes have engendere d new
ways of investigating and managing many diseases
and have raised patient’s expectations. The information
can be made useful at remote locations. Long-distance
consultations are readily available. The performance of

surgery by robotic methods makes it possible for the
operating surgeon to be a continent away.
11 NEW SURGICAL TECHNIQUES
There have been many improvements in surgical tech-
niques, but there is little doubt that the horizon has
expanded with the mini aturization of instrumentation,
the availability of large screen displays to view surgery
as it is performed, and the expanding use of endoscopic
methods with video cameras that provide great magni-
fication. Whether it means operating on the pituitary
gland with miniature instruments under magnification
via an endoscope 3 mm or less in diameter, using
endoscopic techniques to remove a thyroid nodule, or
performing and intestinal bypass for obesity, the so-
phistication of these approaches is astounding. And
there is more to come. We have certainly not reached
the limits of miniaturization, and the promises of in situ
scanning and in situ malignant cell identification remain
to be exploited.
The endocrine glands, often small in size, are espe-
cially suited to the use of endoscopic techniques. These
glands secrete hormones that sustain our metabolism;
derangements can have devastating effects. Tumors of
the pituitary and parathyroid glands as small as several
millimeters can be responsible for severe illness.
The modest size of many endocrine tumors facilitates
removal by endoscopic approaches. Many are benign
and therefore suitable for removal by enucleation or
resection. Frequently no reconstruction is required.
Endoscopes a few millimeters in diameter are available

for these procedures and can be combined with an
operating microscope. The magnification that these
instruments offer makes the surgery easier and safer.
It is possible to employ innovative anatomical ap-
proaches such as a nasal approach to the pituitary
through the sphenoid bone or a retroperitoneal endo-
scopic approach to the adrenal tumors. Minimally
Introduction ix
invasive surgery has become the standard of care for
benign adrenal tumors and nonmalignant tumors of the
distal pancreas.
12 THE FUTURE
In early years an exploration for hyperparathyroidism
was a trying and difficult affair requiring a long and
extensive search for enlarged parathyroid glands that
might, or might not, be in their normal location. It was
not unus ual for the diagnosis to be wrong because it was
made based on clinical features that frequently over-
lapped other conditions. No biochemical confirmatory
test was available. There were many disheartening out-
comes to the surgery.
Compare that to what is at hand today. The diagno-
sis is easily established with precise accuracy by immu-
noassay of PTH. The location of the diseased gland is
now frequently known preoperatively, using scintigra-
phy, ultrasound, MRI with gadolinium, CT scanning,
or selective v enous sampling for reexplorations—a
range of choices previously unknown. The surgery is
performed through minimal incisions or even via an
endoscope. It can be performed under local anesthesia,

if desired. When an abnormal gland is excised, a rapid
parathormone assay can establish cu re while the patient
is still on the operating table.
Fear of surgery has diminished; expectations of
patients and their physicians have increased. It appears
that surgeons have mostly delivered. Progress in surgi-
cal techniques is likely to continue. Benign prostatic
hypertrop hy is now being treated with microwaves,
often removing the need for surgery. Hormone replace-
ment by tissue preservation and stem cell transplanta-
tion will eventually become a reality.
The development of robotic techniques and ad-
vanced intraoperative imaging, toget her with continu-
ing progress in miniaturization, are all in play at this
time without even considering the likely advances in
transplantation. Robotic surgery is in its infancy offer-
ing a huge potential to make quality precision surgery
available throughout the world. New computer-en-
hanced surgi cal systems, which use sensitive remote-
controlled surgical instruments, guided by a surgeon
who may be miles away at a computer keyboard, are
rapidly evolving in the field of cardiac and abdominal
surgery. Adrenalectomies and partial resections of the
pancreas have already been performed using these
devices. These systems also permit the availability of
expertise, by remote control, to use virtual reality in the
teaching of operative procedural techniques and pre-
paring new surgeons for rare situations and challenges.
The future is bright!
Terry F. Davies, M.D., F.R.C.P.

Arthur E. Schwartz, M.D., F.A. C.S.
Demetrius Pertsemlidis, M.D., F.A.C.S.
Michel Gagner, M.D., F.A.C.S., F.R.C.S.C.
Introductionx
Contents
Foreword Murray F. Brennan iv
Preface v
Introduction: Science, Surgery, and the
Endocrine Patient
vi
Terry F. Davies,
Arthur E. Schwar tz,
Demetrius Pertsemlidis,
and Michel Gagner
Contributors xv
Section I. Introduction
1. Molecular Endocrinology 1
Nicholas J. Sarlis and Loukas Gourgiotis
2. Robotic Endocrine Surgery 11
Brian P. Jacob and Michel Gagner
Section II. Brain and Lung
3. Selective Venous Sampling for Pituitary
Tumors
17
Aman B. Patel
4. Pituitary Tumors 23
Raj K. Shrivastava, Wesley A. King,
and Kalmon D. Post
5. The Neuroendocrine Lung 37
John R. Gosney

Section III. Thyroid
6. Surgery for Differentia ted Thyroid Cancer 59
Ashok Shaha and Arthur E. Schwartz
7. A Guide to the Physiology and Testing
of Thyroid Function
75
Terry F. Davies
8. Thyroid Pathology 85
Margaret Brandwein-Gensler,
Arthur E. Schwartz, and Pamela Unger
9. Hyperthyroidism 101
Terry F. Davies and Arthur E. Schwartz
10. Diagnosis and Management of Thyroid
Nodules
115
Jeffrey I. Mechanick
11. Mediastinal Goiter 133
Ashok Shaha
12. Medullary Thyroid Carcinoma 141
Lars-Erik Tisell and Ha
˚
kan Ahlman
13. Management of Papillary and Follicular
Thyroid Cancer
157
Ernest L. Mazzaferri
14. Anaplastic Thyroid Carcinoma 193
Arthur E. Schwartz and
Margaret Brandwein-Gensler
xi

15. Endoscopic Thyroid Surgery 201
Laurent Biertho and Michel Gagner
16. Video-Assisted Thyroid Surgery 209
Paolo Miccoli, Piero Berti, and
Gabriele Materazzi
Section IV. Parathyroid
17. Physiology of the Parathyroid Glands
and Pathophysiology of Primary
213
Hyperparathyroidism
John P. Bilezikian and
Shonni J. Silverberg
18. Sestamibi Scintigraphy and
Ultrasonography in Primary
Hyperparathyroidism
231
Chun Ki Kim and Richard S. Haber
19. Surgical Management of
Hyperparathyroidism
243
Arthur E. Schwartz
20. Reoperation for Primary
Hyperthyroidism
265
Daniel F. Roses
21. Parathyroid Carcinoma 279
John A. Olson, Jr.
22. Endoscopic Parathyroidectomy 289
Michel Gagner and Francesco Rubino
23. Video-Assisted Parathyroidectomy in the

Management of Patients with Primary
297
Hyperparathyroidism
Jean-Fran
c¸
ois Henry and Fre
´
de
´
ric Sebag
Section V. Adrenal
24. Adrenocortical Function and Adrenal
Insufficiency
305
J. Lester Gabrilove
25. The Sympathoadrenal System:
Its Physiology and Function
309
Laura Bertani Dziedzic and
Stanley Walter Dzi edzic
26. Surgical Pathology of the Adrenal
Glands
317
Pamela Unger
27. Ultrasonography of the Adrenal Gland 327
Hsu-Chong Yeh
28. Computed Tomography of the Adrenal
Glands
335
David S. Mendelson and

William L. Simpson, Jr.
29. Magnetic Resonance Imaging
of Endocrine Adrenal Tumors
343
Angela R. Berning and
Jeffrey P. Goldma n
30. Scintigraphic Imaging of the Adrenal
Cortex
359
Neeta Pandit-Taskar and
Samuel D. J. Yeh
31. Radionuclide Imaging of Adrenal
Medullary Tumors
369
Chun Ki Kim, Borys R. Krynyckyi,
and Josef Machac
32. Adrenal Vein Sampling 377
Harold A. Mitty
33. Cushing’s Syndromes, Adrenocortical
Carcinoma, and Estrogen- and
Androgen-Secreting Tumors
381
Moritz Wente, Guido Eibl, and
Oscar J. Hines
34. Primary Aldosteronism:
Pathophysiology, Diagnosis
and Management
401
Sotirios G. Stergiopoulos,
David J. Torpy, and

Constantine A. Stratakis
35. Adrenal Incidentalomas 411
David C. Aron and Job Kievit
36. Pheochromocytoma: Diagnosis
and Treatment
429
David S. Pertsemlidis and
Demetrius Pertsemlidis
Contentsxii
37. Techniques of Conventional Open
Adrenalectomy
451
Demetrius Pertsemlidis and
David S. Pertsemlidis
38. Laparoscopic Adrenalectomy with the
Transabdominal Lateral Approach
461
Ahmad Assalia and Michel Gagner
39. Retroperitoneoscopic Adrenalectomy 479
H. Jaap Bonjer and Bruno Sgromo
Section VI. Pancreas
40. Pathology of Pancreatic Endocrine
Neoplasia
489
Pamela Unger
41. Ultrasonography of the Pancreas 497
Hsu-Chong Yeh
42. Computed Tomography of the Pancreas 501
William L. Simpson, Jr., and
David S. Mendelson

43. Magnetic Resonance Imaging of
Neuroendocrine Pancreatic Tumors
505
Angela R. Berning and
Jeffrey P. Goldman
44. Radionuclide Imaging of the Pancreatic
Endocrine Tumors
521
Chun Ki Kim, Borys R. Krynyckyi,
and Josef Machac
45. Insulinoma 527
Per Hellman
46. Hyperinsulinism 541
Stephen E. Dolgin
47. Gastrinomas and Other Rare Pancreatic
Endocrine Tumors
547
Sydney S. Guo and Mark P. Sawicki
48. Techniques of Conventional Open
Pancreatic Surgery
565
Demetrius Pertsemlidis and
David S. Pertsemlidis
49. Laparoscopic Management of
Pancreatic Islet Cell Tumors
571
Michel Gagner, Christine A. Chu,
and William B. Inabnet
Section VII. Inherited Syndromes
50. Multiple Endocrine Neoplasia and

Other Familial Endocrine Tumor
Syndromes
583
Charles A. G. Proye and
Stephen G. Farrell
Section VIII. Gastrointestinal Tract
51. Carcinoid Tumors 613
Irvin M. Modlin, Kevin Lye, and
Mark Kidd
52. Endocrine Tumors of the
Gastrointestinal Tract
643
Maha T. Barakat, John A. Lynn,
and Stephen R. Bloom
Section IX. Treatment of Advanced Malignancy
53. Liver Transplantation for
Neuroendocrine Tumors
659
Myron E. Schwartz and
Sander S. Florm an
54. Cytoreduction of Neuroendocrine
Tumors
671
Ha
˚
kan Ahlman and Michael Olausson
55. Medical Management of Neuro-
endocrine Gastrointestinal Tumors
685
Kjell O

¨
berg and Ha
˚
kan Ahlman
Index 697
Contents xiii

Contributors
Ha
˚
kan Ahlman, M.D., Ph.D. Professor, Department
of Surgery, Sahlgrenska University Hospital, Go
¨
teborg,
Sweden
David C. Aron, M.D., M.S. Professor, Medicine and
Epidemiology and Biostatistics, Division of Clinical
and Molecular Endocrinology, Department of Medi-
cine, Case Western Reserve Unive rsity School of Medi-
cine, and Center for Quality Improvement Research,
Louis Stokes Department of Veterans Affairs Medical
Center, Cleveland, Ohio, U.S.A.
Ahmad Assalia, M.D. Division of Minimally Invasive
Surgery, Department of Surgery, Mount Sinai School
of Medicine, New York University, New York, New
York, U.S.A.
Maha T. Barakat, M.B.B.Chir., M.A., Ph.D.,
M.R.C.P. Clinical Lecturer, Division of Investigative
Science, Department of Metabolic Medicine, Imperial
College London, London, England

Angela R. Berning, M.D. Fellow in Body MRI, De-
partment of Radiology, Mount Sinai School of Medi-
cine, New York University, New York, New York,
U.S.A.
Piero Berti, M.D. Department of Surgery, University
of Pisa, Pisa, Italy
Laurent Biertho, M.D. Department of Abdominal
Surgery, Les Cliniques Saint Joseph , Liege, Belgium
John P. Bilezikian, M.D. Professor of Medicine and
Pharmacology and Chief, Division of Endocrinology,
College of Physicians and Surgeons, Columbia Univer-
sity, New York, New York, U.S.A.
Stephen R. Bloom, M.A., M.D., D.Sc., F.R.C.Path.,
F.R.C.P, F.Med.Sci. Professor of Medici ne, Division
of Investigative Science, Department of Metabolic
Medicine, Imperial College London, London , England
H. Jaap Bonjer, M.D., Ph.D. Professor, Department
of Surgery, Erasmus Medical Center, Rotterdam, The
Netherlands
Margaret Brandw ein-Gensler, M.D. Associate Profes-
sor, Department of Pathology, Mount Sinai School
of Medicine, New York University, New York, New
York, U.S.A.
Christine A. Chu, M.D. Bay Area Surgical Associates,
Inc., and John Muir/Mount Diablo Health System,
Walnut Creek, California, U.S.A.
Terry F. Davies, M.D., F.R.C.P. Florence and Theo-
dore Baumritter Professor and Director, Division of
Endocrinology, Diabetes and Bone Diseases, Depart-
ment of Medicine, Mount Sinai School of Medicine,

New York University, New York, New York, U.S.A.
Stephen E. Dolgin, M.D. Professor and Chief, Pediat-
ric Surgery, Department of Surgery, Mount Sinai
School of Medicine, New York University, New York,
New York, U.S.A.
xv
Laura Bertani Dziedzic, Ph.D. Clinical Assistant Pro-
fessor, Department of Medicine, Mount Sinai School
of Medicine, New York University, New York, New
York, U.S.A.
Stanley W alter Dziedzic, M.D., Ph.D. Clinical Assist-
ant Professor, Department of Medicine, Mount Sinai
School of Medicine, New York University, New York,
New York, U.S.A.
Guido Eibl, M.D. Associate Researcher, Division of
General Surgery, David Geffen School of Medicine at
UCLA, Los Angeles, California, U.S.A.
Stephen G. Farrell, M.B.B.S., F.R.A.C.S. Visiting
Medical Officer, Department of Surgery, University of
Melbourne, and Endocrine Surgery Unit, St. Vincent’s
Hospital, Melbourne, Aust ralia
Sander S. Florman, M.D. Assistant Professor, Depart-
ment of Surgery, Recanati/Miller Transplantation In-
stitute, Mount Sinai School of Medicine, New York
University, New York, New York, U.S.A.
J. Lester Gabrilove, M.D. Florence and Theodore
Baumritter Professor of Medicine Emeritus, Division
of Endocrinology, Diabetes and Bone Diseases, Depart-
ment of Endocrinology, Mount Sinai School of Medi-
cine, New York University, New York, New York,

U.S.A.
Michel Gagner, M.D., F.A.C.S., F.R.C.S.C. Franz W.
Sichel Professor of Surgery, Chief, Division of Laparo-
scopic Surgery, Director, Minimally In vasive Surgery
Center, Mount Sinai School of Medicine, New York
University, New York, New York, U.S.A.
Jeffrey P. Goldman, M.D. Assist ant Professor, De-
partment of Radiology, Mount Sinai School of Medi-
cine, New York University, New York, New York,
U.S.A.
John R. Gosney, D.Sc., M.D., F.R.C.Path. Consultant
Thoracic Pathologist, Honorary Reader in Thoracic
Pathology, Department of Pathology, Royal Liverpool
University Hospital, Liverpool, England
Loukas Gourgiotis, M.D. Clinical Endocrinology
Branch, National Institute of Diabetes and Digestive
and Kidney Diseases, National Institute of Health,
Bethesda, Maryland, U.S.A.
Sydney S. Guo, M.D. Resident, Department of Sur-
gery, West Los Angeles Veterans Administration Hos-
pital and David Geffen School of Medicine at UCLA,
Los Angeles, California,U.S.A.
Richard S. Haber, M.D. Associate Professor of Med-
icine, Division of Endocrinology, Diabetes and Bone
Diseases, Department of Medicine, Mount Sinai School
of Medicine, New York University, New York, New
York, U.S.A.
Per Hellman, M.D., Ph.D. Associate Professor, De-
partment of Surgery, University Hospital, Uppsala,
Sweden

Jean-Franc¸ ois Henry, M.D. Professor, Division of
General and Endocrine Surgery, Hoˆ pital de la Timone,
Marseille, France
Oscar J. Hines, M.D. Associate Pro fessor, Division of
General Surgery, David Geffen School of Medicine at
UCLA, Los Angeles, California, U.S.A.
William B. Inabnet, M.D., F.A.C.S. Assistant Profes-
sor, Division of Laparoscopic Surgery, Minimally Inva-
sive Surgery Center, Mount Sinai School of Medicine,
New York University, New York, New York, U.S.A.
Brian P. Jacob, M.D. Division of Laparoscopic Sur-
gery, Minimally Invasive Surgery Center, Mount Sinai
School of Medicine, New York University, New York,
New York, U.S.A.
Mark Kidd, Ph.D. Post-Doctoral Fellow, Department
of Surgery, Yale University School of Medicine, New
Haven, Connecticut, U.S.A.
Job Kievit, M.D., Ph.D. Associate Professor of Sur-
gery and Professor and Head of the Medical Decision
Making Unit Section, Endocrine/Head and Neck Sur-
gery, Departments of Surgery and Medical Decision
Making, Leiden University Medical Ce nter, Leiden,
The Netherlands
Chun Ki Kim, M.D. Associate Pro fessor of Radi ology,
Division of Nuclear Medicine, Mount Sinai School of
Medicine, New York University, New York, New York.
U.S.A.
Wesley A. King, M .D. Associate Professor, Depart-
ment of Neurosurgery, Mount Sinai Sc hool of Medi-
Contributorsxvi

cine, New York University, New York, New York,
U.S.A.
Borys R. Krynyckyi, M.D. Assistant Professor of Ra-
diology, Division of Nuclear Medicine, Department of
Radiology, Mount Sinai School of Medicine, New York
University, New York, New York, U.S.A.
Kevin Lye, M.D. Resident, Department of Surgery,
Yale University School of Medicine, New Haven, Con-
necticut, U.S.A.
John A. Lynn, M.S., F.R.C.S. Consultant Endocrine
Surgeon and Honorary Senior Lecturer , Department of
Surgery, Imperial College London, London, England
Josef Machac, M.D. Professor, Division of Nuclear
Medicine, Department of Radiology, Mount Sinai
School of Medicine, New York University, New York,
New York, U.S.A.
Gabriele Materazzi, M.D. Department of Surgery,
University of Pisa, Pisa, Italy
Ernest L. Mazzaferri, M.D., M.A.C.P. Emeritus Pro-
fessor and Chairman of Medicine, Department of Med-
icine, Ohio State University, Columbus, Ohio, and
Adjunct Professor of Medicine, Department of Medi-
cine, University of Florida, Gainesville, Florida, U.S.A.
Jeffrey I. Mechanick, M.D., F.A.C.P., F .A.C.E.,
F.A.C.N. Associate Clinical Professor of Medicine,
Division of Endocrinology, Diabetes and Bone Dis-
eases, Department of Medicine, Mount Sinai School
of Medicine, New York University, New York, New
York, U.S.A.
David S. Mendelson, M.D. Associate Professor, De-

partment of Radiology, Mount Sinai School of Medi-
cine, New York University, New York, New York,
U.S.A.
Paolo Miccoli, M.D. Professor, Clinical Chair, De-
partment of Surgery, University of Pisa, Pisa, Italy
Harold A. Mitty, M.D. Professor, Department of
Radiology, Mount Sinai School of Medicine, New York
University, New York, New York, U.S.A.
Irvin M. Modlin, M.D., Ph.D., F.A.C.S., F.R.C.S. Pro-
ofessor, Department of Surgery, Yal e University School
of M edicine, New Haven, Connecticut, U.S.A.
Kjell O
¨
berg, M.D., Ph.D. Professor, Department of
Endocrine Oncology, Uppsala University Hospital,
Uppsala, Sweden
Michael Olausson, M.D., Ph.D. Professor, Depart-
ment of Surgery, Sahlgrenska University Hospital,
Go
¨
teborg, Sweden
John A. Olson, Jr., M.D., Ph.D. Assistant Professor,
Department of Surgery, Duke University Medical Cen-
ter, Durham, North Carolina, U.S.A.
Neeta Pan dit-Taskar, M.D. Department of Radiol-
ogy, Memorial Sloan-Kettering Cancer Insti tute, New
York, New York, U.S.A.
Aman B. Patel, M.D. Assistant Professor, Depart-
ments of Neurosurgery and Radiology, Mount Sinai
School of Medicine, New York University, New York,

New York, U.S.A.
David S. Pertsemlidis, M.D. Assistant Clinical Pro fes-
sor, Department of Surgery, Mount Sinai School of
Medicine, New York University, New York, New York,
U.S.A.
Demetrius Pertsemlidis, M.D., F.A.C.S. Clinical Pro-
fessor, Department of Surgery, Mount Sinai School
of Medicine, New York University, New York, New
York, U.S.A.
Kalmon D. Post, M.D. Professor and Chairman, De-
partment of Neurosurgery, Mount Sinai School of
Medicine, New York University, New York, New
York, U.S.A.
Charles A. G. Proye, M.D., F.R.C.S. Ed. (Hon.) Pro-
fessor of Surgery, Department of Medicine, University
of Lille II, and Department of Endocrine Surgery,
Hoˆ pital Claude Huriez, Lille, France
Daniel F. Roses, M.D. Jules Leonard Whitehill Pro-
fessor of Surgery and Co-Director, Division of Oncol-
ogy, Department of Surgery, New York University
School of Medicine and Attending Surgeon, Tisch
Hospital, New York University Medical Center, New
York, New York, U.S.A.
Francesco Rubino, M.D. IRCAD-European Institute
of Telesurgery, Strasbourg, France
Contributors xvii
Nicholas J. Sarlis, M.D., Ph.D., F.A.C.E., F.A.C.P.
Division of Intramural Research, National Institutes
of Diabetes, Digestive and Kidney Diseases, National
Institute of Health, Bethesda, Maryland, U.S.A.

Mark P. Sawicki, M.D. Associate Professor, Depart-
ment of Surgery, West Los Angeles Veterans Adminis-
tration Hospital and David Geffen School of Medicine
at UCLA, Los Angeles, California, U.S.A.
Arthur E. Schwartz, M.D., F.A.C.S. Clinical Professor
of Surgery, Mount Sinai School of Medicine, New York
University, New York, New York, U.S.A.
Myron E. Schwartz, M.D. Professor, Department of
Surgery, Recanati/Miller Transplantation Institute,
Mount Sinai School of Medicine, New York University,
New York, New York, U.S.A.
Fre
´
de
´
ric Sebag, M.D. Division of General and Endo-
crine Sur gery, Hoˆ pital de la Timone, Marseille, France
Bruno Sgromo, M.D. Department of Surgery, Eras-
mus Medical Center, Rotterdam, The Netherlands
Ashok Shaha, M.D. F.A.C.S. Professor, Department
of Surgery, Cornell Medical School, and Attending
Surgeon, Memorial Sloan-Kettering Cancer Institute,
New York, New York, U.S.A.
Raj K. Shrivastava, M.D. Department of Neurosur-
gery, Mount Sinai School of Medicine, New York Uni-
versity, New York, New York, U.S.A.
Shonni J. Silverberg, M.D. Clinical Professor of Med-
icine, Division of Endocrinology, College of Physicians
and Surgeons, Columbia University, New York, New
York, U.S.A.

William L. Simpson, Jr., M.D. Assistant Professor,
Department of Radiology, Mount Sinai School of Med-
icine, New York University, New York, New York,
U.S.A.
Sotirios G. Stergiopoulos, M.D. Research Associate,
Unit on Genetics and Endocrinology, Developmental
Endocrinology Branch, N ationa l Institutes of Child
Health and Human Development and National Insti-
tute of Health, Bethesda, Maryland, U.S.A.
Constantine A. Stratakis, M.D., D.Sc. Section of En-
docrinology and Genetics, Developmental Endocrinol-
ogy Branch, National Institute of Child Health and
Human Development, National Institute of Health,
Bethesda, Maryland, U.S.A.
Lars-Erik Tisell, M.D., Ph.D. Retired Chief of Endo-
crine Surgery, Department of Surgery, Sahlgrenska
University Hospital, Go
¨
teborg, Sweden
David J. Torpy, M.D., M.B.B.S., Ph.D., F.R.A.C.P.
Associate Professor, Unit of Genetics and Endocrinol-
ogy, Developmental Endocrinology Branch, National
Institutes of Child Health and Human Development,
National Institute of H ealth, Bethesda, Maryland,
U.S.A.
Pamela Unger, M.D. Associate Professor, Depart-
ment of Pathology, Mount Sinai School of Medicine,
New York University, New York, New York, U.S.A.
Moritz N. Wente, M.D. Resident, Departm ent of
General Surgery, University of Heidelberg, Heidelberg,

Germany
Hsu-Chong Yeh, M .D. Department of Radiology,
Mount Sinai School of Medicine, New York University,
New York, New York, U.S.A.
Samuel D. J. Yeh, M.D. Professor, Department of
Radiology, Memorial Sloan-Kettering Cancer Insti-
tute, and Associate Professor, Weill School of Medicine,
Cornell Medical School, New York, New York, U.S.A.
Contributorsxviii
ciples. Indeed, surgical intervention is frequent ly indi-
cated for disorders, the manifestations of which stem
from specific defects at the molecular or cellular level.
Selected examples include (1) removal of hypercellular
parathyroid glands, pituitary and pancreatic tumors in
patients with multiple endocrine neoplasia type 1
(MEN1), caused by mutations in the menin gene, (2)
total thyroidectomy or adrenalectomy in patients with
MEN2 at risk for medullary thyroid cancer and pheo-
chromocytoma due to RET proto-oncogene activation,
and (3) extirpation of toxic thyroid adenomas. Addi-
tionally, the acquisition of an adequate knowledge basis
in molecular endocrinology is of cardinal importance
for the surgeon-researcher, as it can help considerably in
the design of rational basic and clinical studies. This is
exemplified by the surgical research efforts in the
domain of gene therapy for endocrine malignancies (5)
and the development of techniques for xenotransplan-
tation of pancreatic islet h-cells for the treatment of type
1 diabetes mellitus (T1DM) (6).
In this chapter, we will describe the fundamental

concepts of hormone action via their cognate receptors,
with emphasi s on the processes leading from a specific
molecular defect to a human disease phenotype.
2 MECHANISMS OF HORMONE ACTION
Horm ones exert their actions by binding to specific
receptors, which show high specificity and affinity for
their cognate ligands. A hormone can be either an
agonist—when its binding to the cognate receptor acti-
vates ‘‘downstream’’ cellular effector mechanisms—or
an antagonist—when hormone binding to the receptor
site prevents activation of the aforementioned mecha-
nisms. Of note, partial agonists also exist, i.e., a hor-
mone can act as an agonist at its specific receptor site
only in the absence of a more potent ligand, while it acts
as an antagonist in the presence of such a ligand (1).
As a general principle, the magnitude of target tissue
responses to a specific hormone signal depends on (1) the
concentration of the hormone, (2) the number of target
cells exhibiting functional receptors, and (3) the inherent
sensitivity of the target cells to hormonal stimulation.
The latter, in turn, depends mainly on the number of
functional receptors expressed, the affinity of these
receptors for the cognate ligand, and the specific post–
receptor effector mechanisms that are responsible for
transduction of the hormonal signal (7). The most com-
monly used parameter to reflect the sensitivity of a target
tissue to a given hormone is the concentration of that
hormone needed to achieve half-maximal response.
Similarly, the affinity of the receptor for a given hormone
is defined as the concentration of that hormone needed

to occupy 50% of its cognate receptors within the tissue/
cell under consideration (8). Importantly, hormones are
capable of achieving maximal physiological responses in
target tissues, even when only a small percentage of re-
ceptors a re occupied therein, e.g., the muscle uptake of
glucose stimulated by insulin becomes maximal when
only 2% of insulin receptors are occupied. The above
example denotes the principle of ‘‘spare receptors. ’’
Because of the presence of the latter in various tissues,
the concentration of a given hormone needed to produce
half-maximal responses is less than that needed to sat-
urate half of its cognate receptors (9). The above phe-
nomenology usually leads in sigmoid type curves for the
graphic description of the relationship between hor-
mone concentration and physiological effect; howeve r,
the exact position and shape of these curves are modified
by several factors, depending on the particular hormone
action system or target tissue under study (Fig. 1).
The mechanisms of hormone action can be classified
into two major categories those mediated by plasma
membrane receptors, which have a predilection for
hydrophilic hormones, and those mediated by intra-
Figure 1 Percent of maximal biological response as a
function of hormone concentration in a representative
receptor-dependent cell system. Various factors can modu-
late the level of hormonal response and move the sigmoid
dose-effect curve to the left or the right. The % receptor
occupancy as a function of hormone concentration for a
given total number of hormone receptors per cell can also be
depicted by a similar graph.

Sarlis and Gourgiotis2
cellular receptors, which have a predilection for lipo-
philic hormones. Although the vast majority of hor-
mone receptors are peptidic in nature, some plasma
membrane receptors are glycolipids (10). Many receptor
proteins can undergo posttranslational modifications
(glycosylation, phosphorylation, myristoylation, etc.)
that are occasionally extensive (11).
Mutations of specific hormone receptors have been
shown to be responsible for a variety of endocrine
diseases. Generally, there are two types of mutations (1):
1. Gain-of-function (activating) mutations, where-
by the receptor becomes constitutively active and
leads to unregulated stimulation of post–recep-
tor effector mechanisms in a ligand-independent
fashion
2. Loss-of-function (inactivating) mutations,
whereby the receptor is unable to perform its
usual function because it may be absent, unable
to bind to its ligand, or unable to activate post–
receptor effector mechanisms
Specific examples o f diseases caused by receptor-
activating or -inactivating mutations wi ll be provided
in the following sections.
2.1 Plasma Membrane Receptors
Hydrophilic (mainly peptidic) as well as a few lipophilic
hormones (e.g., melatonin and eicosanoids) exert their
action by binding to plasma membrane receptors. These
receptors share a general common structure: they have
an extracellular domain that binds to the hor mone, one

or several transmembrane domains (TMDs) (usually an
a-helix comprised of hydrophobic amino acid residues),
and an intracellular domain that is responsible for the
transduction of the hormonal signal to ‘‘downstream’’
effector mechanisms upon ligand binding. There are
three main classes of plasma membrane receptors: G-
protein–coupled (GPCRs), enzyme coupled, and ion
channel coupled (1). The features of these classes are
summarized in Table 1.
2.1.1 G-Protein–Coupled Receptors
G-protein–coupled receptors represent the largest fam-
ily of plasma membrane receptors. They are activated
by a variety of ligands of both peptidic and nonpeptidic
nature, including ‘‘classical’’ hormones, neurotransmit-
ters, growth factors, odorant molecules, and light. More
than 1% of the human genome encodes approximately
1500 different GPCRs. These receptors constitut e the
target of more than 50% of the therapeutic agents
currently in clinical use (12).
GPCRs share a common structure, as they all are
single polypeptide chains with seven a-helical TMDs
(Fig. 2) (13). Their name stems from the fact that they
interact with heterotrimeric, guanosine triphosphate
(GTP)–binding regulatory proteins, which relay signals
from the cell surface to ‘‘downstream’’ intracellular
effector mechanisms. Each G-protein consists of an
a-subunit and a hg -subunit dimer. Mammalian a-sub-
units can be categorized into four distinct classes,
depending on their amino acid sequence and presumed
evolutionary distance: (1) a

s
and a
olf
, (2) a
t1
, a
t2
, a
gust
,
Table 1 The Main Classes of Plasma Membrane Hormone Receptors
Receptor class Receptor conformation Receptor subtypes Examples
G-protein–coupled 7-transmembrane domain Numerous; depending on
subtype of Ga protein
ACTHR; FSHR; LHR; TSHR;
GHRHR; TRHR; adrenergic Rc’s
(a
1
, a
2
, h); glucagon Rcs;
Ca
2+
-sensing Rcs; V2-vasopressin Rcs
Enzyme coupled Single TMD Receptor tyrosine kinases
TK-associated receptors
Serine threonine kinases
Insulin rc; Rcs for various growth
factors
Cytokine Rcs; GHR; PRLR; leptin rc

Rcs for the TGFh superfamily
a
Ion channel–coupled Ligand-gated ion channel
complex (usually pentameric)
N/A Numerous; mainly relevant to neuro-
transmission/neuromodulation; SUR1
of endocrine interest
a
ACTH: adrenocorticotropin; FSH: follitropin; GH: growth hormone; GHRH: growth hormone–releasing hormone; GPCR: G-protein–coupled
receptor; LH: luteinizing hormone; N/A: not applicable; PRL: prolactin; Rc: receptor; RTK: receptor tyrosine kinase; STK: serine/threonine
kinase; SUR1: sulfonylurea receptor type-1; TGFh: transforming growth factor-h; TMD: transmembrane domain; TRH: thyrotropin-releasing
hormone; TSH: thyrotropin.
a
For details, please refer to text.
Molecular Endocrinology 3
a
i1
, a
i2
, a
i3
, a
0
, and a
z
, (3) a
q
, a
11
, a

14
, and a
15/16
, and (4)
a
12
and a
13
. Tissue expression varies vastly among the
above types, with some being ubiquitously expressed
(a
s
, a
i2
, a
q
, a
11
, a
12
, and a
13
) and others exhibiting
specific tissue expression (14). Similar diversity is
observed for the h- and g-subunits: there are at least
four distinct transcript variants for the h-subunit gene
and at least as many for the g-subunit (15). The type of
a-subunit defines the role of the G-protein by activating
a different effector mechanism. In the resting state, G-
proteins bind guanosine diphospate (GDP) via their a-

subunit, while the three subunits (a-, h-, and g-) are
tightly bound in a trimer configuration. Upon binding
of the ligand, GDP is dissociated from the a-subunit
and replaced by GTP, thus leading to dissoc iation of
the a-subunit from the h-andg-subunits, and the
formation of an active a-subuni t. The latter binds to
‘‘downstream’’ effectors and modulate s their actio n.
The a-subunit possesses intrinsic GTPase activity,
hydrolyzing the bound GTP to GDP, and thus render-
ing itself inactive. In that state, the a-subunit is able to
reassociate with the h- and g-subunits, rendering the
conformation of the ahg complex to its inactive state
and terminating the action of the ligand (16).
The above system has been recently shown to be
significantly more complicated, as it involves (1) RGS
proteins (regulators of G-protein signaling), which
accelerate the hydrolysis of GTP to GDP leading to
termination of the hormone signal (17), (2) receptor
phosphorylation, which rapidly attenuates early signal
transduction by receptor desensitization (18), and (3)
receptor downregulation, i.e., the reduction in the num-
ber of receptors after long-term exposure to agonistic
ligands, which occurs via decreased synthesis or
increased degradation of these receptors (18).
Both germline and somatic mutations of G-proteins
or GPCRs have been described in a variety of human
diseases (19), and their role has also been implica-
ted in carcinogenesis and cardiovascular disease.
Examples include:
1. Gain-of-function mutations (with resultant de-

fective termination of signal): pituitary, thyroid
(20), adrenal and ovarian adenomas (21,22),
McCune-Albright syndrome (23), familial male
precocious puberty (24), autosomal dominant
hypoparathyroidism (25) , and essential hyper-
tension (16)
2. Loss-of-function mutations (resulting in absent
or inactive Ga protein): pseudohypoparathy-
roidism type-Ia, pseudo-pseudohypoparathyroi-
dism (26), night blindnes s, retinitis pigmentosa
(22,27), familial hypercalcemic hypocalciuria,
and severe neonatal hyperparathyroidism (28)
2.1.2 Enzyme-Coupled Receptors
Receptors belonging to this group either have intrinsi c
enzymatic activity or are directly bound to an enzyme,
though importantly without the intervention of a sub-
membrane G-protein system. They are usually single
TMD proteins and often form dimers with each other,
either upon ligand binding or spontaneously.
Receptor Tyrosine Kinases. The ligands for these
receptors include insulin and various growth factors
(GFs) (1). They have intrinsic tyrosine kinase (TK)
activity and phosphorylate tyrosine residues. These
receptors can also undergo autophosphorylation. The
latter modification provides docking s ides for other
proteins, which become bound to the receptor and thus
activate themselves (29). Examples include the various
insulin receptor substrates (IRSs), phospholipase C-g
(PLC-g), phosphatidylinositol 3-kinase (PI3K), and the
GTPase-activating proteins (GAPs) (30–33). These

molec ules cons titute the first step of complex intra-
cellular pathways via which ligan ds exert their actions.
The relevance of this type of receptors and their
cognate ‘‘downstream’’ intracellular signaling mole-
cules for human disease cannot be overemphasized.
Figure 2 Schematic structure of the TSH receptor as a
prototype of the G–protein–coupled heptahelical transmem-
brane domain (TMD) receptors. TMDs are designated in
Latin numbers.
Sarlis and Gourgiotis4
Indeed, mutations in the insulin receptor can affect
differentially its synthesis, transport to plasma mem-
brane, capacity for insulin binding, transmembrane
signaling or its degradation, thus resulting in type A
insulin resistance. It is estimated that approximately
1% of patients with type 2 diabetes mellitus (T2DM)
may carry germline mutations of the insulin receptor
gene (14).
TK-Associated Re ceptors. The ligands for the
receptors in this group include growth hormone (GH),
prolactin (PRL), leptin, various interleukins (ILs),
EPO, granulocyte-macrophage colony-stimulating fac-
tor(GM-CSF), and granulocyte colony-stimulating
factor (type I TK-receptor subclass), as well as interfer-
ons (IFNs)-a,-h,and-g (type II receptor subclass) (34).
The structure of TK-associated receptors is similar to
that of the previous group (RTKs), with the exception
that they lack the intrinsic TK activity within their
intracellular domain. Instead, i n this case, ligand bind-
ing leads to activation of ‘‘downstream’’ intracellular

TKs. The main signalin g pathway activated by this
class of receptors is known as the ‘‘Jak-STAT path-
way,’’ which includes phosphorylation and activation
of Janus kinases (Jak). The latter subsequently phos-
phorylate and activate one of the signal transduc er
and activator of transcription (STAT) proteins, even-
tually resulting in the regu lation of transcription of
specific genes (35,36).
The clinical relevance of these receptors in endocri-
nology becomes apparent by the following: mutations
in the leptin receptor are a well-recognized, albeit rare,
cause of human obesity (37), and loss-of-function
mutations in the GH receptor gene result in Laron
dwarfism (38).
Serine/Threonine Kinase Receptors. Th e ligands
for this group of receptors are members of the trans-
forming growth factor-h (TGF-h) superfamily, which
play a significant role during embryonic development
and adult tissue homeostasis. Representative mem-
bers of this superfamily of ligands include TGF-h,
activin, bone morphogenetic proteins, several growth
and differentiation factors, and anti-Mullerian hor-
mone (39). Serine/threonine kinase (STK) receptors
consist of a single TMD with STK activity within
their intracellular part, which is activated upon
receptor dimerization. Two types (I and II) of STK
receptors have been described, the only known func-
tion of type II receptors being the activation of type
I receptors via phosphorylation (40). The ‘‘down-
stream’’ signal transduction cascade includes acti-

vation (via phosphorylation) of cytoplasmic SMAD
(À1toÀ8) proteins, which then translocate to the cell
nucleus and regulate specific gene transcription. The
acronym SMAD is derived from the initially de-
scribed members of this protein family, i.e., the C.
elegans protein SMA (‘‘small body size’’) and the
Drosophila protein MAD (‘‘mothers against decap-
entaplegic’’) (41). The STK receptor-dependent sig-
naling system is under tight control by multiple other
intracellular regulators, as this pathway is not only
relevant to transduction of selected hormonal sig-
nals, but has been also been closely implicated in the
initiation and promotion of tumorigenesis. Indeed,
loss of the cell growth inhibition induced by TGF-h
leads to tumor formation in several in vitro models
(42), while SMAD-3 inactivation in the mouse has
been shown to promote the development of meta-
static colonic carcinoma (43).
2.1.3 Ion Channel–Coupled Receptors
Ion channels control the flux of specific ions across the
plasma membrane. These channels can be either volt-
age-gated (i.e., ionic flux through them is regulated by
charge gradients across the cell membrane) or ligand-
gated (i.e., the flux is regulated by the binding of specific
ligands to the channel itself or proteins associated with
it). Members of the latter group include the nicotinic
cholinergic, g-aminobutyric acid (GABA), glutamate,
glycine, and kainic acid receptors (1).
Ion channel–coupled receptors share a common
general structure as they consist of a five-subuni t com-

plex (two a and one h, g,andy). Each subunit resembles
the GPCRs, in that it consists of an extracellular, four
transmembrane, and one short intracellular domains.
Interestingly, some of the ligand-gated ion chann el–
coupled receptors utilize G-proteins for further signal
transduction (1). No bona fide endocrine disorder has
yet been associated with defects in a ion channel-
coupled hormone receptor; however, mutations in sul-
fonylurea receptor-1 (SUR1), which in association with
the Kir6.2 complex constitutes the functional ATP-
sensitive potassium channel of the pancreatic h-cell,
have been recently linked to persistent hyperinsulinemic
hypoglycemia of infancy (44).
2.2 Intracellular Receptors
Intracellular receptors are not bound to the plasma cell
membrane; instead, they reside either in the cytoplasm
(cytoplasmic receptors, e.g., the receptors for mineralo-
corticoid and glucocorticoid hormones) or in the cell
nucleus (nuclear receptors, e.g., the receptors for pro-
gesterone and estr ogens) (45). Intracellular receptors
Molecular Endocrinology 5
bind ligands that easily penetrate the cell membrane.
The most important members of this group are the
receptors for the steroid-thyroid hormone superfamily,
which also includes compounds such as retinoids, eico-
sanoids, and the long-chain fatty acids (LCFAs) (1).
The features of the members of the above superfamily
are summarized in Table 2. All above ligands have a
profound effect on homeostasis, growth, reproduction,
and organism behavior. The effects of hormones that

bind to intracellular receptors are mediated by the
interaction of these receptors (in their liganded form)
with DNA and a wide variety of other nuclear pro-
teins, e.g., the trascription pro-initiation complex, lead-
ing to re gulation of transcription of specific target
genes (46).
Intracellular receptors have been found to share a
common structure, shown schematically in Figure 3A.
Further, certain receptor regions are highly evolution-
arily conserved among different receptor types and
subtypes. As a rule, each intracellular receptor consists
of four parts: (1) an N-terminal region that serves as
a transactivation domain [transactivation function
(TAF)-1] and controls gene transcription, (2) a cen-
tral, highly conserved, DNA-binding domain (DBD),
(3) a short ‘‘hinge’’ region, and (4) a C-terminal
ligand-binding domain (LBD), which also contains
amino acid sequences mediating receptor dimeriza-
tion, nuclear localization, and subsequent transactiva-
tion (TAF-2) (47).
Inactive [unbound to ligand (or unliganded)] cyto-
plasmic intracellular receptors exist in molecular com-
plexes with other proteins, such as heat shock
proteins (hsps) and immunophilin/p59 (48,49). Ligand
binding causes a conformational change in the recep-
tor, its disassociation from the above proteins, recep-
tor homo- or hetero-dimerization, and entrance into
the nucleus. Once inside the nucleus, the ligand-
receptor complex binds to specific DNA areas, called
hormone response elements (HREs), which are loca-

ted in the promoter regions of hormone-responsive
genes, and modulates their transcription via a com-
plex interaction with intranuclear transcription factors
(Fig. 3B) (50).
It is worth emphasizing the following points:
1. Intracellular receptors can be activated inde-
pende ntly of their ligands (possibly through
receptor phosphorylation) (51).
2. Cross-talk exists between ‘‘downstream’’ effec-
tor systems transducing signals derived from
plasma membrane receptors and intracellular
receptors (52).
3. Steroid and thyroid hormones can also exert
nongenomic (usually rapid-onset) actions (53).
Table 2 The Main Classes of Intracellular Hormone Receptors
Receptor classification Receptor Ligands hsp association
Steroid/thyroid
hormone superfamily
Type-I Rc families Glucocorticoid Rc (GR)
-a,-h types
cortisol, corticosterone, aldosterone,
progesterone, DOC
Yes
Mineralocorticoid Rc (MR) aldosterone, DOC, cortisol Yes
Progesterone Rc (PR) A- and
B-types
progesterone Yes
Androgen Rc (AR) dihydrotestosterone, testosterone,
androstenedione, DHEA
Yes

Type II Rc families Estrogen Rc (ER) -a,-h types estradiol, estrone, estriol Yes
Vitamin D Rc (VDR) 1,25 (OH)
2
-vitD
3
No
Thyroid hormone rcs (TRs)
-a,-h subfamilies
T3, T4 No
Retinoid rcs (RAR, RXR)
-a,-h,-g subfamilies
9-cis-retinoic acid, all-trans-retinoic acid No
RevErb/ROR
superfamily
PPAR family PPARs -a,-g,-y subfamilies 15D-PGJ2, PGI2, DHEA-S, LCFAs No
DHEA (-S): dihydroepiandrosterone (sulfate); DOC: deoxycorticosterone; Hsp: heat shock protein; LCFAs: long-chain fatty acids; PPAR:
peroxisome proliferator-activated receptor; PG: prostaglandin; RAR: retinoic acid receptor; RXR: retonoid-X receptor; rc: receptor; T3:
triiodothyronine; T4: thyroxine.
Sarlis and Gourgiotis6
We will offer a brief discussion of one of the sub-
classes of the intracellular receptor superfamily, the
peroxisome proliferator-activated receptors (PPARs),
primarily because of their impact in the pharma-
cological treatment of T2DM. PPARs (-a,-g, and -y)
were initially discovered as ‘‘orphan’’ receptors, i.e.,
receptors with no known ligand at that time. Subse-
quently, a variety of LCFAs and eicosanoids were
found to be endogenous ligands for this type of recep-
tors (54). Among them, PPAR-g is the most extensively
studied. PPAR-gs are abundant in adipose tissue and

skeletal muscle and have been shown to promote adipo-
genesis. The synthetic PPAR-g ligands thiazolidine-
diones (TZDs) increase insulin sensitiv ity and glucose
uptake in diabetic individuals, although the specific
target tissues of TZDs and the mechanism of decrease
in insulin resistance remain unknown (55). Finally,
PPAR-gs have been implicated in tumorigenesis: a
recent study suggested that PPAR- gshaveatumor
suppression function in human colon (56), whereas
favorable responses have been observed in men with
metastatic prostatic cancer treated with TZDs (57).
Notably, mutations of steroid hormone receptors are
responsible for a variety of human diseases. Loss-of-
function mutations in the androgen receptor are the
basis for testicular feminization or androgen insensitiv-
ity syndromes (58). Similarly, inactivating mutations of
the vitamin D receptor and thyroid receptor-h cause
vitamin D–resistant rickets type II (59) and the syn-
drome of resistance to thyroid hormone (60), respec-
tively. Qualitative and/or quantitative defects in the
glucocorticoid recep tor are associated with primary
sporadic or familial glucocorticoid resistance (61).
3 CONCLUSION
Molecular endocrinology is a continuously evolving
field. In this chapter, we have described the schemes of
hormone action and signaling in a general fashion. It is
evident that complex intricacies exist within each step of
the pathways of expression and action of hormones,
including the regulation of their secretion, modifica-
tion(s) of their molecular structure, interactions with

Figure 3 (A) Schematic representation of the structure of intracellular receptors. The following domains are identified: N-
terminal/immunogenic (containing the TAF-1 region); DNA-binding (DBD); hinge; and ligand-binding (LBD; containing the
TAF-2 region). (B) A model of transcriptional effects from the activation of the progesterone receptor (PR) as a prototype of
intracellular receptors. Ligand binding leads to PR dimerization and attachment of the resulting complex upon a hormone-
response element (in this case, PRE). This element is located within the nuclear DNA at the promoter region of a target gene. The
PR dimer–PRE complex, via a specific molecular conformation, attracts transcription factors called co-activators, leading to the
assembly and activation of basal RNA polymerase-II (RNA Pol-II) preinitiation complexes and eventually to gene transcription.
The example given pertains to a target gene promoter that contains a defined TATA box; the mechanisms at play are somewhat
different for genes with TATA-less promoters. The (+) symbol denotes activation of a molecular complex or action.
Molecular Endocrinology 7