class="bi x0 y0 w0 h1"
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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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

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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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

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

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

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

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 &

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

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

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

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

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

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

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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

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

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.

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

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-

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
Textbook of health in aging men
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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

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-

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
5
History of research on the aging male – selected aspects
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years, 15 000–25 000 liters of policemen’s urine in
1931.
49,50

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

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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