Textbook of Men’s Health and Aging 2nd Edition ppt

Textbook of Men’s
Health and Aging
2
nd
Edition
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Textbook of Men’s
Health and Aging
2
nd
Edition
Editors in Chief
Bruno Lunenfeld MD FRCOG FACOG [Hon]
Professor Emeritus, Reproductive Endocrinology,
Bar-Ilan University, Ramat Gan
Israel
Louis JG Gooren
MD
Professor, Vrjie Universiteit Medical Center,
Amsterdam, The Netherlands
Alvaro Morales
MD
Queen’s University General Hospital,
Kingston, Ontario, Canada
John E Morley
MB MCh
St Louis University,
St Louis, MO, USA
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© 2007 Informa UK Ltd
First published in the United Kingdom in 2007 by Informa Healthcare, Telephone House, 69-77 Paul Street, London EC2A 4LQ.
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Lunenfeld Prelims.qxd 8/23/2007 5:46 PM Page iv
Foreword
This a long road knows no turning (Sophokles: Ajax)
In the “sleepwalkers” (1964) Arthur Koestler
remarks that “I mistrust the word progress and much
prefer the word evolution simply because progress,
by definition, can never go wrong, whereas evolu-
tion constantly does and so does the evolution of
the ideas. Indeed, it is fascinating to observe
throughout history the evolution of quite a few “rul-
ing” ideas , moving from gradual acceptance, to
popularization, vulgarization, overextension, col-
lapse and disappearance. At the height of their
importance, some of them are so generally accepted,
that they become the spirit of the time (the famous
“Zeitgeist” in German) with all of its societal conse-
quences, masterfully characterized by Virginia
Woolf (1929) saying that “what is amusing now had

to be taken in desperate earnest once”. Other ideas
may show a markedly different evolution; as Jean
Monnet (1978) emphasized in his Mémoires, “When
an idea corresponds to the necessity of an epoch , it
ceases to belong to those who invented it and it
becomes stronger than those who are in charge of
it”. In fact, such an idea may become stronger than
political power by developing into the common
property of humankind ; it may deeply influence the
spiritual content of an entire era and may resist the
historical forces of destruction for a long time. In a
few, rare , cases a new idea becomes exceptionally
strong, when – in addition – it is generated as a
response to powerful historical challenges by some
new realities. The ageing of populations presents
such a challenge. It is a fundamentally new and
unique problem in our history, with no previous
analogies. Hence, people and their governments
have not had yet enough time (and/or courage?) to
consider the necessary - and in part fundamental –
socioeconomical and political adjustments needed
to meet one of the greatest challenges of the 21st
century, which will profoundly affect many aspects
of our life, social institutions and perhaps even eth-
ical values. The Population division of the United
Nations Secretariat estimates that last year (2006)
some 11% of the global population (688 million
persons) were aged 60 years or more and 13% of
these persons were aged 80 years and over. The sex
ratio of those aged 60 and over was 82 men for 100

women and among those aged 80 years and more it
was 55 men for 100 women. Life expectancy at the
age of 60 was 17 years for men and 21 years for
women. The Population division projects that by
the year 2050 , 22% of the world population (or
almost 2 billion people) will be aged 60 years and
over and that 20% of these 2 billion persons will be
aged 80 years or more. The United Nations also
point out that, by the year 2050 – for the first time
in our history – the population of persons older than
60 years will be larger than the population of chil-
dren (0 to 14 years of age). Humankind is growing
rapidly and it is ageing very rapidly… Fortunately,
scientific knowledge is growing even more rapidly .
In 1830, Alfred Tennyson still could say with some
justification that “Science moves, but slowly slowly,
creeping on from point to point ”. However, by the
mid-fiftees of the 20th century it was recognized,
that science progresses in proportion to the mass of
knowledge that is left to it by preceding generations,
that is under the most ordinary circumstances in
geometrical proportion (F.Engels, 1963). The same
year Derek John de Solla Price has put this progress
in a proper perspective: “Using any reasonable defi-
nition of a scientist, we can say that between 80 and
90 per cent of all scientists that have ever lived are
alive now. Now depending on what one measures
and how, the crude size of science in manpower or
in publications tends to double within a period of
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Foreword
vi
10 to 15 years”. This was 44 years ago and nowadays
it is often said that today the amount of new infor-
mation tends to double every 6 to 7 years…. And
when the amount of new information increases so
rapidly, the perimeter between the known and
unknown also increases and opens new avenues
for fruitful investigation. If I am allowed to quote
another forword written more than 400 years ago, in
the Preface to De La Sagesse, Pierre Charron
remarks that “La vraye science et le vray étude de
l´homme c´est l´homme” (The true science and study
of mankind is
man). This will particularly be true in the world of
tomorrow, where the octagenarian populations will
grow most rapidly of all groups and lot of new infor-
mation will be required on their pathophysiology
and optimal medical care.It is said, that Leonardo
da Vinci was the last scientist in history, who still
could grasp the entire body of knowledge of his
epoch. I doubt very much that there exists any med-
ical scientist today, who could claim to grasp all
medical knowledge, or eventhat of any major disci-
pline, the Study of the Ageing Male being no
exception. It is sufficient to look at a few of the
almost 60 excellent articles of the present textbook
to be convinced. Science is organized knowledge, said
Herbert Spencer; therefore, a textbook will always
represent an important contribution to the body of

contemporary knowledge, particularly, when it
contains so many carefully selected articles, as the
present textbook. In fact, when the perimeter
between the known and unknown rapidly increases,
it inevitably results in increasing specialisation and
in the establishment of new disciplines. The estab-
lishment of a new discipline for the Study of the
Ageing Male slightly more than a decade ago, was
considered then by some medical scientists as a
courageous innovation with a somewhat uncertain
future. Few, if any of them would doubt today that
this discipline has come to stay and for a long time,
since more and more evidence is forthcoming to
indicate that many aspects of ageing are gender spe-
cific, like the localisation of certain receptors in dif-
ferent tissues or the functions of the blood-brain
barrier. Therefore, an in-depth study of the various
aspects of gender specificity is likely to lead to
improved diagnostic and therapeutic methods for
ageing populations. Therefore, as Shakespeare says
“What is past is prologue”. Last, but not least, I feel
that the scientific community ought to be grateful
to theeditors and contributors of this Textbook.
Their effort should remind us that the acquisition,
critical evaluation, systematisation and dissemina-
tion of positive knowledge are the only human
activities which are truly cumulative and progres-
sive (George Sarton, 1930, paraphrased).
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Preface & Acknowledgments

Text to come
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Contents
Introduction 1
History of research on the aging male – selected aspects 1
Micheal Oettel, Sergio Musitelli & Dirk Schultheiss
Section I: Biology of aging 11
1. The biology of gender differences in animal models of aging 13
HJ Armbrecht
2. The biologic basis for longevity differences between men & women 23
Rafi T Kevorkian & Oscar A Cepeda
3. The biology of the aging brain 31
Xi Chen & Shirley Shidu Yan
4. The blood-brain barrier: age & gender differences 39
William A Banks
Section II: Diagnostics & Primary Assessment 47
5. Aging men – The challenge ahead 49
Bruno Lunenfeld
6. Screening of the aging male 63
Louis JG Gooren, Alvaro Morales & Bruno Lunenfeld
7. Laboratory tests in the endocrine evaluation of aging males 97
Michael John Wheeler
Section III: The Genitourinary System 111
8. Genitourinary System: an introduction 113
Claude C. Schulman
9. Benign prostatic hyperplasia 115
Simon RJ Bott & Roger S Kirby
10. Prostate cancer 131
Michaël Peyromaure, Vincent Ravery & Laurent Boccon-Gibod

11. Erectile dysfunction in the aging male 147
Andrea Gallina, Alberto Briganti, Andrea Salonia, Federico Dehò,
Giuseppe Zanni, Pierre I Karahiewiz & Francesco Montorsi
12. Infertility in the aging male 161
Wolfgang Weidner, Thorsten Diemer & Martin Bergmann
13. Urinary incontinence 167
Adrian Wagg
14. Testicular cancer 183
Axel Heidenreich
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Section IV: Sexual Dysfunction 205
15. Treatment of erectile dysfunction in the elderly 207
Kok Bin Lim & Gerald B Brock
16. Assessment of the aging man with sexual dysfunction 229
Sidney Glina
Section V: Endocrine System 239
17. Endocrinology of the aging male: an overview 241
John E Morley
18. Androgen deficiency and its management in elderly men 245
Louis JG Gooren & Bruno Lunenfeld
19. Growth hormone and aging in men 265
Marc R Blackman
20. The Thyroid 273
Mary H Samuels & Jerome M Hershman
Section VI: Aging and Body Composition 281
21. Aging testosterone, and body composition 283
Alex Vermeulen
22. Growth hormone & body composition in the aging male 289
Fred Sattler
23. Androgens & lean body mass in the aging male 307

Melinda Sheffield-Moore, Shanon Casperson & Randall J Urban
24. Visceral obesity, androgens and the risks of cardiovascular disease 313
Louis JG Gooren
Section VII: Nutrition, Digestion and Metabolism 327
25. Nutrition in older men 329
David R Thomas
26. Obesity in middle-aged men 345
Richard YT Chen & Gary A Wittert
27. Diabetes in the elderly male: nutritional aspects 355
John E Morley
28. Lipids through the ages 363
Margaret-Mary G Wilson
29. Insulin resistance syndrome in older people 373
Angela Marie Abbatecola & Giuseppe Paolisso
30. Free radicals and vitamins 391
Seema Joshi
31. Resistance exercise 405
Charles P Lambert
32. Constipation & diarrhoea 421
Syed H Tariq
33. Macrovascular complications in the elderly diabetic 431
Nikiforos Ballian, Mahmoud Malas, and Dariush Elahi
34. Upper gastrointestinal complaints 443
Christopher K Rayner & Michael Horowitz
Contents
x
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Section VIII: Cardiovascular and Respiratory System 463
35. Atherosclerotic risk assessment of androgen therapy in aging men 465
David Crook

36. Male aging: changes in metabolic, inflammatory, and endothelial
indices of cardiovascular risk 473
Ian F Godsland
37. Androgens: Studies in animal models of atherosclerosis 487
Peter Alexandersen
38. Androgens and blood pressure in men 501
Guy Lloyd
39. Androgens and arterial disease 511
Carolyn M Webb & Peter Collins
40. Androgenic influences on ventilation and ventilatory responses to
oxygen and carbon dioxide during wakefulness and sleep 517
Christopher P Cardozo
41. The role of androgens in respiratory function 521
Ann M Spungen
Section IX: Central Nervous System and Psyche 529
42. Changes in libido/sex life 531
Syed H Tariq
43. Depression 539
Margaret-Mary G Wilson
44. Testosterone, depression and cognitive function 551
John E Morley
45. Modern antidepressants 561
Margaret-Mary G Wilson
46. Sleep disorders 575
Hosam K Kamel
47. Cognitive changes in aging 683
Syed H Tariq & John E Morley
Section X: Skeletal System 609
48. Bone loss and osteoporotic fracture occurrence in aging men 611
Steven Boonen & Dirk Vanderschueren

Section XI: Sensory Organs 619
49. Aging and the eye 621
Ali R Djalilian & Hamid R Djalilian
50. Aging and inner ear dysfunction 631
Emiro Caicedo, Diego Preciado, George Harris & Frank Ondrey
51. Smell and taste 645
Weiru Shao & Frank Ondrey
Section XII: Skin and Hair 659
52. Healthy skin aging 661
Walter Krause
xi
Contents
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53. Skin disease caused by changes in the immune system and infection 677
Isaak Effendy and Karen Kuschela
54. Skin changes caused by venous diseases 691
Eberhard Rabe & F Pannier
55. Aging of Hair 697
Ralph Trüeb & Rolf Hoffmann
Epilogue 709
56. Hormone treatment and preventative strategies in aging men:
whom to treat, when to treat and how to treat 711
Louis JG Gooren, Alvaro Morales & Bruno Lunenfeld
Index 731
Contents
xii
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Angela Marie Abbatecola
Department of Geriatric Medicine
and Metabolic Diseases

Il University of Naples
Italy
Peter Alexandersen, MD
Center for Clinical & Basic Research
Vejle, Denmark
HJ Armbrecht PhD
Professor of Biochemistry &
Molecular Biology
Geriatric Research, Education &
Clinical Center
St. Louis VA Medical Center
St. Louis, MO, USA &
St. Louis University
School of Medicine, MO
USA
Nikiforos Ballian
Johns Hopkins University
School of Medicine
USA
William A Banks, MD
GRECC, VA Medical Center
St. Louis & Division of Geriatric,
Department of Internal Medicine
St. Louis University School of Medicine, MO
USA
Martin Bergmann
Institut fur Veterinär-Anatomie
Histologie und Embryologie
der Justus-Liebig-Universität Giessen
Germany

Marc R Blackman, MD
National Center for Complementary &
Alternative Medicine
National Institutes of Health
Bethesda, MD
USA
Laurent Boccon-Gibod, MD PhD
Professor
CHU BICHAT
University of Paris VII, Paris
France
Steven Boonen, MD PhD
Leuven University Center for Metabolic Bone Diseases
Katholieke Universiteit Leuven
Belgium
Simon RJ Bott,
FRCS
Trustees of the London Clinic Ltd
London
UK
Alberto Briganti
Department of Urology
Vita-Salute University
Milan
Italy
Gerald B Brock
MD FRCSC
St. Joseph's Health Centre
London
Canada

Emiro Caicedo,
MD
University of Minnesota
Minneapolis, MN
USA
Contributors
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Christopher P Cardozo MD
VA Medical Center
Bronx, NY, USA and
Associate Professor of Medicine
Mount Sinai School of Medicine
New York, NY
USA
Shanon Casperson, DTR
Oscar A Cepeda, MD
Fellow, Division of Geriatric Medicine
Department of Internal Medicine
St. Louis University School
of Medicine & GRECC VA Medical Center
St. Louis, MO
USA
Richard YT Chen
Associate Consultant (Endocrinology)
Department of Medicine
Changi General Hospital
Singapore
Xi Chen, MD PhD
Department of Neurology
St. Louis University School of Medicine &

St Louis VA Medical Center, MO
USA
Peter Collins MD FRCP FESC
National Heart & Lung Institute
London
UK
David Crook, PhD
St. Bartholomew’s & Royal London School of Medicine
London
UK
Federico Dehò
Department of Urology
Vita-Salute University
Milan
Italy
Thorsten Diemer
Poliklnik für Urologie und Kinderurologie
Zentrum für Chirurgie, Anästhesiologie
und Urologie, Universitätsklinikum
Giessen und Marburg GmbH
Standort Giessen
Justus-Liebig-Universität Giessen
Germany
Ali R Djalilian, MD
National Eye & Health Institute
Bethesda, MD
USA
Hamid R Djalilian, MD
UCI Medical Center
University of California

Irvine, CA, USA
Isaak Effendy MD
Department of Dermatology
Municipal Hospital of Bielefeld
Germany
Dariush Elahi, MD
Johns Hopkins University
School of Medicine
USA
Andrea Gallina
Department of Urology
Vita-Salute University
Milan
Italy
Spas V Getov
Academic F2 SHO in Stroke Medicine
Brighton and Sussex University Hospitals
UK
Sidney Glina, MD PhD
Head of Department of Urology
Hospital Ipiranga, and Director of Instituto H Ellis
São Paulo
Brazil
Contributors
xiv
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Ian F Godsland, PhD
Faculty of Medicine
Imperial College London
St Mary’s Hospital

London
UK
George Harris, BS
Axel Heidenreich, MD
Klinikum der Philipps-
Universitat Marburg
Germany
Jerome M Hershman, MD
West Los Angeles VA Medical Center
Los Angeles, CA
USA
Rolf Hoffmann,
MD
Dermaticum
Freiburg
Germany
Michael Horowitz
University of Adelaide
Department of Medicine
Royal Adelaide Hospital
Australia
Seema Joshi, MD
St. Louis University Medical Center
St. Louis, MO
USA
Hosam K Kamel
MD MPH
Director, Geriatrics &
Extended Care
St. Joseph’s Mercy Health Center

Hot Springs National Park, Arkansas
USA
Pierre I Karakiewiz
Cancer Prognostics &
Health Outcomes Unit
University of Montreal, Quebec
Canada
Rafi T Kevorkian,
MD
Assistant Professor
Division of Geriatic Medicine,
Department of Internal Medicine
St. Louis University School of Medicine &
GRECC VA Medical Center
St. Louis, MO
USA
Roger S Kirby MA MD FRCS (UROL) FEBU
Professor, the Prostate Centre
London
UK
Walter Krause, MD
Philipps University Marburg
Medical Center
Marburg
Germany
Karen Kuschela
Department of Dermatology
Municipal Hospital of Biekfeld
Biekfeld
Germany

Charles P Lambert PhD
Assistant Professor
University of Arkansas for
Medical Sciences
Little Rock, AR
USA
Richard W Lee
Academic F2 SHO in Stroke Medicine
Brighton and Sussex University
Hospitals
UK
Kok Bin Lim
Singapore General Hospital
Singapore
Guy Lloyd,
MD FRCP
East Sussex NHS Trust
UK
xv
Contributors
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Mahmoud Malas
Johns Hopkins University
School of Medicine
USA
Francesco Montorsi, MD
Professor
Department of Urology
Vita-Salute University
Milan, Italy

John E Morley MB BCH
Divison of Geriatric Medicine
St Louis University School of Medicine,
MO, USA and VA GRECC
Medical Center, St Louis, MO
USA
Sergio Musitelli
Michael Oettel
Frank Ondrey MD PhD
University of Minnesota School of Medicine
Minneapolis, MN
USA
Feliztas Pannier
Dermatology Clinic and Polyclinic
Rheinischen Friedrich Wilhelms
Universitat
Bonn
Germany
Giuseppe Paolisso, MD
Department of Geriatric Medicine and
Metabolic Diseases
Il University of Naples
Italy
Michaël Peyromaure, MD
Service d'Urologie
Hospital Cochin
Paris
France
Diego Preciado, MD PhD
Assistant Professor

George Washington University School of Medicine
Children's National Medical Center, DC
USA
Eberhard Rabe
Professor of Dermatology
Klinik und Poliklinik für Dermatologie
University of Bonn
Germany
C Rajkumar
Chair in Geriatrics and Stroke Medicine
Brighton and Sussex Medical School
UK
Vincent Ravery, MD PhD
Professor
Hospital Bicat
Paris, France
Christopher K Rayner
University of Adelaide
Department of Medicine
Royal Adelaide Hospital
Australia
Andrea Salonia,
MD
Department of Urology
Vita-Salute University
Milan, Italy
Mary H Samuels, MD
Oregon Health and Science University
Portland, Oregon
USA

Fred Sattler, MD
Professor of Medicine & Biokinesiology
Keck School of Medicine
University of Southern California
Los Angeles, CA
USA
Contributors
xvi
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Claude C. Schulman, MD
University Clinics Brussels
Belgium
Weiru Shao, MD
Director, Division of Otology & Neurotology
Tufts- New England Medical Center
Boston, MA
USA
Melinda Sheffield-Moore, PhD
Associate Professor
University of Texas Medical Branch
Galveston, TX
USA
Shirley Shidu Yan, MD
Department of Pathology
College of Physicians & Surgeons
Columbia University
New York
USA
Ann M Spungen, PhD
Associate Professor of Medicine

and Rehabilitation Medicine
Mount Sihai School of Medicine
New York, NY, USA, and
Co-chair VA cooperative Study
VA Medical Center
Brunx, NY
USA
Syed H Tariq, MD FACP
Assistant Professor of Medicine
Division of Geriatic Medicine
St. Louis University Medical Center
St Louis, MO, USA & GRECC Veterans Affairs
Medical Center
St. Louis, MO
USA
David R Thomas, MD FACP AGSF
Division of Geriatric Medicine
St. Louis University Health Sciences Center
St. Louis, MO
USA
Ralph Trüeb, MD
Department of Dermatology
University of Zurich
Switzerland
Randall J Urban, MD
Professor
University of Texas Medical Branch
Galveston, TX
USA
Dirk Vanderschueren, MD PhD

Katholieke Universiteit Leuven
Belgium
Alex Vermeulen, MD
Professor Emeritus
University Hospital Ghent
Belgium
Adrian Wagg, FRCP
Senior Lecturer in Geriatric Medicine
University College London Hospital
UK
Carolyn M Webb PhD
Wolfgang Weidner, MD
Direktor der Klinik und Poliklnik
für Urologie und Kinderurologie
Zentrum für Chirurgie
Anästhesiologie und Urologie
Universitätsklinikum Giessen und
Marburg GmbH
Standort Giessen
Justus-Liebig-Universität Giessen
Germany
Michael John Wheeler
Professor
Department of Chemical Pathology
Guy’s & St. Thomas Foundation Trust
St. Thomas Hospital
London
UK
xvii
Contributors

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Contributors
xviii
Margaret-Mary G Wilson, MD MRCP
Division of Geriatric Medicine
St. Louis University
St. Louis, MO
USA
Gary A Wittert
Mortlock Professor of Medicine and Head
Department of Medicine
University of Adelaide
Royal Adelaide Hospital
Australia
Giuseppe Zanni
Department of Urology
Vita-Salute University
Milan
Italy
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1
INTRODUCTION
History of research on the
aging male – selected aspects
Michael Oettel, Sergio Musitelli, and Dirk Schultheiss
Doubtless, in all periods of the history of mankind
the possibility of prolonging the life of the man
including the preservation of his masculinity has
claimed more attention than the treatment and/or
cure of, e.g., specific infectious, cardiovascular,

mental, or tumor diseases. This interest was also
often greater than the impetus to find new ways for
the treatment of women’s diseases – at least in patri-
archal periods. In early primitive civilizations,
erotic matters including those of aging males were
of prime importance and became an integral part of
life. According to Hippocrates, old men suffer from
difficulty in breathing, catarrh accompanied by
coughing, strangury, difficult micturition, pains at
the joints, kidney diseases, dizziness, apoplexy,
cachexia, pruritus of the whole body, sleeplessness,
watery discharges from the bowels, eyes and nostrils,
dullness of sight, cataract, and hardness of hearing.
1
The history of research on elderly men’s health
reflects most parts of the broad cultural history and,
therefore, an attempt to press this field into only
one chapter of a textbook is at the beginning an act
of despair. Additionally, the story of the ‘fountain of
youth’ for males is also the story of wrong ways,
blind alleys, hasty speculations, and of charla-
tanism. Christian Wilhelm Hufeland (1762–1836)
characterized the unsuccessful attempts to prolong
life simply as ‘gerontokomic’. Furthermore, describ-
ing our object in ancient times we are often unable
to distinguish between historic facts, mysticisms,
and mythologic or religious interpretations.
Here we can discuss and reflect only selected
historic aspects pronouncing the endocrinologic back-
ground of hypogonadism and testosterone therapy. For

more historic details, see references 1 to 14.
Obviously, the highly sophisticated molecular
pharmacology of androgen action substantially
improved our knowledge of the molecular biology of
endogenous signal systems in the second half of the
last century. Nevertheless, there is still a certain sus-
picion in some quarters about androgen therapy.
Why should that be so? A look at the history of
testosterone therapy in aging men shows remark-
able scientific achievements, but often, however,
also a great deal of speculation and many dubious
practices. Already John Hunter (1728–1793) per-
formed testicular transplantation experiments while
studying tissue transplantation techniques in 1767
and, almost a century later, Arnold Berthold
(1801–1863) linked the physiologic and behavioral
changes of castration to a substance secreted by
the testes. He wrote in 1849
15
‘Da nun aber an
fremden Stellen transplantierte Hoden mit ihren
ursprünglichen Nerven nicht mehr in Verbindung
stehen können, und da es, …, keine specifischen, der
Secretion vorstehenden Nerven giebt, so folgt, dass
der fragliche Consensus durch das productive
Verhältnis der Hoden, d.h. durch deren Einwirkung
auf das Blut, und dann durch entsprechende
Einwirkung des Blutes auf den allgemeinen
Organismus überhaupt, …, bedingt wird.’ Summarizing
transplanted testes affect behavioral and sexual

Lunenfeld Introduction.qxd 8/23/2007 4:48 PM Page 1
characteristics by secreting a substance into the
blood stream.
Aging as an endocrine disorder?
The earliest contribution of modern medicine to
the understanding of the clinical features of a disor-
der related to the beginning of aging was the article
‘On the climacteric disease’ by Sir Henry Halford,
which was read at the Royal College of Physicians
in London in 1813:
16
… ‘I will venture to question,
whether it be not, in truth, a disease rather than a
mere declension of strength and decay of the nat-
ural powers.’ He seems to be the first to connect the
term climacteric with the symptoms observed in
some men between the ages of 50 and 75:
‘Sometimes the disorder comes on so gradually and
insensibly, that the patient is hardly aware of its
commencement. He perceives that he is sooner
tired than usual, and that he is thinner than he was;
but yet he has nothing material to complain of. In
process of time his appetite becomes seriously
impaired: his nights are sleepless, or if he gets sleep,
he is not refreshed by it. His face becomes visibly
extenuated, or perhaps acquires a bloated look. His
tongue is white, and he suspects that he has fever.’
Halford pointed out that this disease had been over-
looked so far: ‘We find it generally complicated with
other complaints, assuming their character, and

accompanying them in their course, and perhaps
this may be the reason why we do not find the cli-
macteric disease described in books of nosology as a
distinct and particular distemper.’ Interestingly,
concerning the etiology of this climacteric disease,
he drew no connection to the testes: ‘It is not very
improbable that this important change in the con-
dition of the constitution is connected with a defi-
ciency in the energy of the brain itself, and an
irregular supply of the nervous influence to the
heart.’ The therapeutic options were rather limited.
‘In fact, I have nothing to offer with confidence, in
that view, beyond a caution that the symptoms of
the disease be not met by too active a treatment.’
And, after suggesting ‘local evacuations’ and ‘warm
purgatives’, Halford came to the conclusion: ‘For
the rest, “the patient must minister to himself ”.’
‘To be able to contemplate with complacency
either issue of a disorder which the great Author of
our being may, in his kindness, have intended as a
warning to us to prepare for a better existence, is of
prodigious advantage to recovery, as well as to comfort,
and the retrospect of a well-spent life is a cordial of
infinitely more efficacy than all resources of the med-
ical art.’ And this was just the opinion of the
90-year-old Cephalus at the very beginning of the
dialogue ‘The Republic’ of Plato (428–348 BC).
For unknown reasons, the term climacteric was
not used again in relation to the aging male for
more than 100 years, although the problem in gen-

eral was discussed by other scientists, as demon-
strated, for example, in the studies of Charles
Edouard Brown-Séquard (see below). The French
physician Maurice de Fleury reactivated the topic in
1909 with his contribution ‘Sur le retour d’àge de
l’homme,’ a condition detected in males ‘de quar-
ante et quelques années.’
17
In addition to the clini-
cal symptoms, he found significant changes in the
genital organs of women. The thyroid gland was the
main cause of the disease in men: ‘Pourtant, il est
une autre glande à secretion interne qui me paraît
jouer un role dans la genèse de ce faux retour d’àge:
je veux parler de la thyroid’.
In July 1910, Archibald Church, professor of ner-
vous and mental diseases in Chicago, Illinois, USA,
published his article on ‘Nervous and mental distur-
bances of the male climacteric’, not citing any of the
above-mentioned works.
18
On the other hand, he
gave a detailed review of the literature dealing with
the issue of certain symptoms that might occur in a
‘monthly rhythm in men’, e.g. variations in weight
and temperature, frequency of nocturnal emissions,
hemorrhoidal flux, or attacks of cardiac asthma. He
even refers to the earlier ‘Selected papers on hysteria’
of Sigmund Freud, who wrote ‘There are men who
show a climacterium like woman, and merge into an

anxiety neurosis at the time when their potency
diminishes.’ Church continues with his own descrip-
tion of symptoms observed over 10 years at the ‘invo-
lutional or climacteric period’ of his patients between
the ages of 50 and 65: ‘the particular interest of my
subject does not pertain to the insanities, but to
minor psychoses and neurotic disturbances. These,
one and all, however, have mental background.’
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In October 1910, the German physician Kurt
Mendel
19
and, in response to Mendel’s article,
Bernard Hollander
20
from England both published
articles entitled ‘Die Wechseljahre des Mannes
(Climacterium virile),’ claiming that they were also
aware of this clinical entity and had treated patients
over the last decade. Mendel’s father, a well-known
university professor of neurology, had already used
the term when dealing with such in his lectures.
Although Mendel and Hollander approached the
problem from the point of view of neurologists, they
both agreed that the involution of the testes is the
main pathomechanism responsible for the climac-
teric disease that can then be influenced by other
factors:

19
‘Sehe ich somit die Hypofunktion der
Keimdrüsen als Grundursache des beschriebenen
Krankheitsbildes an, so können daneben aber andere
Momente in Betracht kommen, die als mitwirkende
Faktoren bei Auslösung und Entwicklung des
Leidens anzusprechen sind.’ Despite organotherapy
with ‘Spermin’ and unspecific treatments like cold
showers and faradization of the body, Mendel sug-
gested psychotherapy as the preferable and most
successful therapeutic modality. Furthermore, he
discussed some forensic aspects of the climacteric in
males. As is the case with women, a higher rate of
criminal acts – mainly consisting of insults towards
others – is to be expected in the sixth decade of
man’s life and this circumstance should be kept in
mind by medical experts who are asked for their
professional opinion in court.
In 1916, the dermatologist and sexologist Max
Marcuse from Berlin drew a connection between
the ‘climacterium virile’ and some urosexual distur-
bances or changes of the prostate making his work
of special interest to urologists.
21
In most of his
patients he detected an involuted small and soft
prostate, a status he called ‘Prostata-Atonie’. In sev-
eral cases, he successfully applied either organother-
apy with ‘Testikulin’, ‘Testogan’ and ‘Hormin’, or
faradization of the prostate.

Two examples of comprehensive monographies
on the topic written in German are ‘Über den Mann
von 50 Jahren’ by FK Wenckebach
22
in 1915 and
‘Die Wechseljahre des Mannes’ by A Hoche
23
in
1928. According to Hoche, in the sixth decade of
life a deep decline in psychic and physical fitness
occurs in men. In this period, for example, poets,
writers, and musicians have passed their zenith. Well
known exceptions are Joseph Haydn, who composed
the ‘The Creation’ with 66 and ‘The Seasons’ at 68
years of age, and Konrad Ferdinand Meyer and
Theodor Fontane, who in their sixth and seventh
decades respectively reached the top of their artistic
work. Hoche concluded that a true male climacteric
doesn’t exist, but men aged between 40 and 60 years
show many typical natural as well as pathologic
changes, which need mainly psychologic or psychi-
atric care. According to Diepgen (cited by Hoche
23
)
the term ‘Wechseljahre’ (changing years for turn of
life) is exemplified in German literature in the 17th
and 18th centuries.
August Werner from St Louis, USA, re-introduced
the term male climacteric (from the Greek for ‘rung
of a ladder’) in the late 1930s and today his name is

still associated with it by most authors. In 1939,
Werner suggested the following theoretic back-
ground for this clinical condition:
24
‘it seems reason-
able to believe that many if not all men pass
through a climacteric period somewhat similar to
that of women, usually in a less severe but perhaps
more prolonged form … . The endocrine dysfunc-
tion, plus the imbalance of equilibrium between the
two divisions of the autonomic nervous system,
with evidence at times of disturbance in psychic
centres, is the climacteric. The true climacteric is
due primarily to decline of function of the sex
glands. Decline of sex function is not limited to
women but is also a heritage of all men.’
25,26
Testosterone and the aging male
Throughout history, many concepts have been sug-
gested and practiced to achieve eternal youth,
longevity, and rejuvenation. To point out only one
example, one might think of the biblical case
(Kings, III, 1, 3 ff) of King David, who was old in
years and showed a significant loss of ‘heat’.
A young virgin was chosen to compensate this
deficit: … ‘and let her lie in thy bosom, that my lord
the king may get heat’. As the name of this virgin
was Abhisag the Sunamite, the method of bringing
an aged man in close contact with a young woman
3

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was, henceforth, called ‘sunamitism’ and this idea
was kept up among many others until recent cen-
turies and is still an attractive option of machismo
for the future of mankind.
27
Tales and myths about aphrodisiacs and rejuvena-
tion extracts from testicular tissue or blood were
reported from ancient times up to the present. As
early as 140 BC Suçruta of India advocated the
ingestion of testis tissue for the cure of impotence. A
vague foreshadow of the endocrine function of the
testis was speculated by Aretaeus of Cappadocia
(2nd to 3rd century AD) and more vigorously in
1775 by de Bordeu. They proposed that each organ
of the body produced a substance, which was
secreted into the blood to regulate bodily function.
28
With the birth of modern endocrinology in the
19th century, the testes and, later, their identified
hormonal product testosterone increasingly
attracted the interest of scientists who were investi-
gating the aging process. The first considerations
regarding the relationship between hormone pro-
duction and the aging process stemmed from the
French neurologist Charles Edouard Brown-Séquard
(1817–94), the son of a Philadelphia seaman, giving
rise to the field of organotherapy. In 1869 he sug-
gested injecting semen into the blood of old men in

order to increase mental and physical strength and
performed the first animal experiments 6 years later.
His famous self-experiment at the age of 72 with
several subcutaneous injections of a mixture of
blood from the testicular veins, semen, and juice
extracted from crushed testicles of young and vigor-
ous dogs and guinea pigs in 1889 was one of the first
milestones for androgen therapy in the aging male.
He reported an increase in his physical and mental
abilities, a better stream of urine and the relief of
constipation. Brown-Séquard had inspired physi-
cians around the world to investigate the nature of
this compound, and by the end 1889 over 12 000
physicians were administering this new ‘elixir of
life’.
29
Nevertheless, Brown-Séquard’s ‘pharmaceu-
tic’ prescription must have been equivalent to a
placebo.
27,30,31
The following passage on ‘seminal
losses’, a condition Brown-Séquard also called ‘sper-
matic anemia’, and which was generally better
known as ‘spermatorrhoea’, reveals the limited
understanding of testicular endocrinology at that
time:
30
‘Besides, it is well known that seminal losses,
arising from any cause, produce a mental and phys-
ical debility which is in proportion to their fre-

quency. These facts and many others have led to the
generally admitted view that in the seminal fluid, as
secreted by the testicles, a substance or several sub-
stances exist which, entering the blood by resorp-
tion, have a most essential use in giving strength to
the nervous system and to other parts.’ Arthur
Biedl,
32
the author of the first textbook on internal
secretory organs in 1910 categorically states that:
‘The date of birth of “the science of internal secre-
tion” is that memorable meeting of the Société de
Biologie of Paris of June 1
st
1889, where Brown-
Séquard, then 72 years of age reported on his exper-
iments undertaken to prove his hypothesis by means
of subcutaneous injections of testicular juice into
himself.’
In 1902, Ancel and Bouin in France ligated the
ductus deferens in rabbits and noted atrophy of the
seminal epithelium. However, the Leydig cells
remained unchanged, and many of the animals
appeared to have increased sexual activity.
33
This
paved the way for Eugen Steinach (1861–1944) in
Vienna. This physiologist started conducting experi-
ments with testicular transplantation in animals at
the turn of the century in order to study the sexual

differentiation and the hormonal function of the
gonads. In this theory of ‘autoplastic’ treatment of
aging, he postulated an increased incretory hor-
monal production following the cessation of the
secretory output of the gonads after surgical ligation
of the seminal ducts.
34
The basic idea was that liga-
ture of the spermatic ducts leads to an atrophy of the
seminal epithelium and (hopefully) to hypertrophy
of the Leydig cells. The first operation was per-
formed in 1918 and resulted in a worldwide vasoli-
gation boom over the next two decades. Steinach
nicely summarized the results of his scientific life in
his late biography:
35
‘It has frequently been said that
a man is as old as his blood vessels. One may have
greater justification for saying that a man is as old as
his endocrine glands.’
Early in his career, the Russian Serge Voronoff
(1866–1951), working in Paris and elsewhere, dis-
cussed the life expectancy and signs of aging in
castrates. He was one of the first to transplant
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testicular tissue from a monkey into a human testi-
cle in 1920. He later became the world’s leading sur-
geon to transplant testicular tissue from ape to

man.
36
But AS Parkes remembered as follows: ‘This
attractive idea was naturally exploited in dubious
ways, and early in the period under review Voronoff,
working in Algiers, became notorious for his so-
called rejuvenation experiments on man and farm
animals. His claims were such that an international
deputation visited his establishment in Algiers in
1927 to make a critical review of the work. The
report of the British contingent to the Ministry of
Agriculture was very cautious.’
37
At the same time, several American surgeons per-
formed testicular transplantations (or rather: implan-
tations), such as Victor D Lespinasse, Robert T
Morris, Leo L Stanley, John R Brinkley, and George
F Lydston.
38
Victor Lespinasse, Professor of
Genitourinary Surgery at North-Western University,
treated impotence by oral glandular extracts. When
this failed, Lespinasse grafted slices of human testi-
cles taken from fresh cadavers into the rectus mus-
cle of impotent men. He believed that most cases
of impotence in middle-aged men were caused by
a failure of hormone secretion, and reported posi-
tive results after several weeks, athough these were
transient.
39

Leo Stanley, a physician working at the San
Quentin Prison in California, performed 1000 tes-
ticular substance implantations into 656 prisoners
under his care. Unlike Lespinasse, Stanley used the
testicles of goats, rams, boars, or deer. He cut the
testicles into strips of such a size that he could put
them into a pressure syringe for injection under the
skin of the abdomen. He reported a marked
improvement in impotence.
40
A rejuvenation boom took place in the early
1920s with both vasoligation and testis implanta-
tion, which were performed by many doctors in
Europe and America.
4,27
The Swiss genito-urinary
surgeon Paul Niehans (1882–1971) claimed to have
performed more than 50 000 ‘cellular therapy’ treat-
ments. He envisioned the replacement of organ
transplantation by the injection of viable cells.
4,41
All these hormonal approaches to rejuvenation
were made before the discovery of testosterone or
the supply of suitable androgen products by the
pharmaceutic industry. Is it true, that they are
all completely out of date now? Machluf and
co-workers
42
reported on the microencapsulation of
Leydig cells as a system for testosterone supplemen-

tation in the future. And could stem cell technology
be the modern version of ‘organotherapy’ or ‘cellular
therapy’?
The identification and chemical synthesis of
testosterone and other steroid hormones was
achieved in the 1930s.
43
This was a ‘condition sine
qua non’ for the further development of modern
endocrinology and the basis for a rational therapy
with sexual hormones. Only with the introduction
of high-quality testosterone preparations did it
become possible to provide a scientific basis for
androgen therapy.
As defined traditionally, an androgen is a sub-
stance that stimulates the growth of the male repro-
ductive tract. It is important to realize that this is a
biologic and not a chemical definition. Nonetheless,
the most potent androgens are steroids. It has been
proved to be a difficult challenge in steroid chem-
istry to isolate, characterize, and synthesize the male
hormones.
44
Pezard, in 1912, reported that aqueous extract of
pig testes maintained the comb and wattles of the
capon.
28
18 years later, Gallagher and Koch devel-
oped the response in the capon into a quantitative
assay procedure, which was adopted with minor

modifications by most laboratories as the standard
assay procedure for male hormone activity.
45
As early as 1927, Lemuel Clyde McGee
46
demon-
strated the isolation of a biologically active extract
of the lipid fraction of bull testicles. In 1933
McCullagh and co-workers
47
reported in a very ele-
gant paper, using the chick comb assay for measuring
androgenic activity, that extracts from blood, urine, or
spinal fluid of men are useful for the treatment of male
hypogonadism. The authors called the substance
which is produced in the testes ‘Androtin’. The mag-
nitude of the problem faced by steroid chemists has
been illustrated by the fact that labor-intensive
extracts from up to 100 g of testes were required for a
positive result in the so-called chick comb bioassay.
2,48
It is not surprising, therefore, that 15 mg of the first
known androgen – androsterone – was isolated under
the leadership of Adolf Butenandt, at the age of 28
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years, 15 000–25 000 liters of policemen’s urine in
1931.
49,50

The name of this relatively weak urinary
5α-reduced androgen comes from ‘andro’ = male,
‘ster’ = sterol, and ‘one’ = ketone. The chemical syn-
thesis of androsterone was performed by Leopold
Ruzicka and co-workers 3 years later.
51
The Japanese
workers Ogata and Hirano,
52
not sufficiently
acknowledged by the Europeans and Americans,
found in 1934 that the androgen from the urine
(Butenandt’s androsterone) was not identical with
the androgen extracted from boar testes. The andro-
genic properties of this crystal hormone were more
active than any of the testicular preparations previ-
ously reported. One year later, Karoly David,
Elizabeth Dingemanse, Janos Freud, and Ernst
Laqueur
53
reported the isolation of testosterone, the
main secretory product from the testes and the main
androgen in the blood, from several tonnes of bull
testes. The term ‘testosterone’, coined by this Dutch
group, combines ‘testo’ = testes, ‘ster’ = sterol, and
‘one’ = ketone. In the same year, the chemical syn-
thesis of testosterone was published by three groups
from Germany, the Netherlands, and Switzerland,
led by Adolf Butenandt,
54

Ernst Laqueur,
53
and
Leopold Ruzicka.
55
Ruzicka and Butenandt were
offered the 1939 Nobel Prize for chemistry for their
work, but Butenandt was forced by the Nazi govern-
ment to decline the honor.
Adolf Butenandt wrote in 1941:
56
‘Die heute syn-
thetisch zubereiteten Hormone sind den natürlichen
Wirkstoffen nicht nur ähnlich, sondern mit ihnen …
identisch; sie stellen demnach keine Kunstprodukte
dar im Sinne körperfremder Pharmaka mit hor-
monartiger Wirkung, sondern natürliche, kör-
pereigene Wirkstoffe. Daher bedeutet die Behandlung
eines Kranken mit den heute von der pharmazeutis-
chen Industrie dargebotenen Hormonen eine
Therapie auf natürlicher Basis.’ [The hormones syn-
thesized today are not only similar to the naturally
occurring drug substances, but are identical with …
them; they are therefore not artificial products in the
sense of exogenous pharmaceuticals with hormone-
like action, but rather natural, endogenous substances.
Thus, the treatment of a patient with the hormones
now offered by the pharmaceutical industry means
a treatment on a natural basis.] Is this point of
view still applicable today? Is the administration of

testosterone to men an effective natural form of
treatment without serious side effects? This question
will be answered by some of the authors of this
textbook.
Heller and Myers
57
demonstrated that climac-
teric symptoms of men could be reversed by testos-
terone propionate therapy. They utilized a quasi-
placebo trial to demonstrate this effect. Using the
rat ovary-weight assay the authors demonstrated
elevated gonadotropin concentrations in the urine
of climacteric men.
In 1946 Werner
25
presented detailed results of the
evaluation of 273 climacteric male patients. The
most prominent symptoms were nervousness,
decreased potency, decreased libido, irritability,
fatigue, depression, memory problems, sleep distur-
bances, numbness, tingling, and hot flushes. Of these
patients, 177 were treated with intramuscular testos-
terone propionate injections, only four of whom did
not benefit from the treatment. Werner’s summary is
convincing: ‘Men are subject to the hypogonadal or
climacteric syndrome, just are woman, when there is
decrease of function or a function of the sexual
glands. Testosterone propionate is as effective in
relieving the subjective symptoms of this syndrome
in men as estrogen is in relieving the symptoms of

similar origin in women. Sex hormones should not be
administered to men and women of climacteric age
with the idea of stimulating increased sexual potency;
if this is the object of treatment, disappointment will
result in the great majority of instances.’
One of the earliest long-term experiences with
testosterone therapy came from the writer Ernest
Hemingway. He took testosterone for the last decade
of his life, providing us with one of the longest
patient histories for testosterone administration.
58
In the first years after testosterone became avail-
able, an overgenerous application of this new thera-
peutic option to the problem of the ‘climacteric in
the aging male’, was hinted at by an editorial in the
Journal of the American Medical Association in 1942:
59
‘Recently many reports have appeared in medical
journals claiming that a climacteric occurs in middle
aged men. Brochures circulated by pharmaceutical
manufacturers depict the woeful course of aging
man. None too subtly these brochures recommend
that male hormonal substance, like a veritable elixir
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