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Essentials of Men's Health
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Essentials
of Men's Health
EDITOR-IN-CHIEF:
Shalender Bhasin, MB, BS

Professor of Medicine, Harvard Medical School
Director, Research Program in Men’s Health: Aging and Metabolism
Director, Boston Claude D. Pepper Older Americans Independence Center
Brigham and Womens Hospital
Boston, Massachusetts
ASSOCIATE EDITORS:
Michael P. O’Leary, MD, MPH

Professor of Surgery, Harvard Medical School
Senior Urologic Surgeon, Director of Men’s Health
Brigham and Women’s Hospital
Shehzad S. Basaria, MD
Associate Professor of Medicine
Associate Director, Research Program in Men’s Health: Aging and Metabolism
Brigham and Women’s Hospital, Harvard Medical School
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Contents
Contributors......................................................... ix SECTION 2
Preface.............................................................. xiii A Tailored Approach to the Diagnostic
Evaluation of Men's Health
SECTION 1
Pathophysiologic Basis of the Male CHAPTER 6
Reproductive Disorders A Rational Approach to the Physical
Examination of Men for the Evaluation
CHAPTER 1 of Male Reproductive Disorders........................ 67
The Pathophysiological Basis of Androgen Farah Daneshvar and Bradley D. Anawalt
Disorders in Men..................................................3
llpo Huhtaniemi CHAPTER 7
Laboratory Evaluation of Men with
CHAPTER 2 Reproductive Disorders in the Primary
Pathophysiology of Erectile Dysfunction .......... 21 Care Setting........................................................ 75
Chirag N. Dave, Arthur L. Burnett, and Amin S. Herati Maria A. Yialamas
CHAPTER 3 CHAPTER 8
The Pathophysiology of Male Infertility..............29 The Effective Use of the Electronic Health
Ramy Abou Ghayda and Martin Kathrins Record, Internet Resources, and Patient
Education Materials in Clinical Practice ........... 83
CHAPTER 4 Ramy Abou Ghayda, Anna Goldman, and Martin Kathrins
Reproductive Disorders Associated
with Aging...........................................................37 SECTION 3
Shalender Bhasin
Androgen Disorders
CHAPTER 5
CHAPTER 9
Genetics of Male Reproductive Deficiency........53
Diagnosis and Treatment of Androgen
Rena Xu, Cigdem Tanrikut, and Robert Oates
Deficiency Syndromes in Men........................... 95
Frances J. Hayes
vi Contents
CHAPTER 10 SECTION 6
Gynecomastia.................................................. 109
Urologic Disorders in Primary Care
Thiago Gagliano-Juca and Shehzad Basaria
CHAPTER 11 CHAPTER 17
Disordered Sleep and Reproductive Genitourinary Disorders in Primary Care........ 205
Dysfunction ..................................................... 121 Katherine M. Rodriguez, Zachary Dao, Alexander W. Pastuszak,
Fiona Yuen, Amy James, Jeanne Wallace, and Peter Y. Liu and Mohit Khera
SECTION 4 CHAPTER 18
Lower Urinary Tract Symptoms Secondary to
Sexual Dysfunction in Men
Benign Prostatic Hyperplasia.......................... 221
Joseph Mahon and Kevin T. McVary
CHAPTER 12
Evaluation and Management of Erectile
CHAPTER 19
Dysfunction ..................................................... 135
Diagnoses and Management of Chronic
Alan W. Shindel and Tom F. Lue
Pelvic Pain in Men........................................... 237
Iryna M. Crescenze and J. Quentin Clemens
CHAPTER 13
What a Sex Therapist Wants You to Know
CHAPTER 20
About Treating Men with Sexual Disorders 151
Screening for Prostate Cancer........................ 253
Michael A. Perelman
Manuel Ozambela Jr. and Mark A. Preston
SECTION 5
SECTION 7
Fertility Regulation and Infertility
Sexually Transmitted Diseases,
Mental Health Problems,
CHAPTER 14 and High Risk Behaviors in Young Men
The Evaluation of the Infertile Man................. 167
Ramy Abou Ghayda, Shalender Bhasin, and Martin Kathrins
CHAPTER 21
Detection, Prevention,
CHAPTER 15
and Treatment of Sexually Transmitted
Assisted Reproductive Technologies
Infections in Men............................................. 267
for Male Infertility............................................. 181
Kevin L. Ard and Sigal Yawetz
Martin Kathrins, Ramy Abou Ghayda, and Elena Yanushpolsky
CHAPTER 22
CHAPTER 16
The Use of Body-Appearance and
Contraceptive Options for Single Men
Performance-Enhancing Drugs
and Men in Stable Relationships.................... 193
and Body Image Disorders in Men.................. 279
Christina Wang and Ronald S. Swerdloff
Gen Kanayama and Harrison G. Pope Jr.
Contents vii
CHAPTER 23
SECTION 9
Management of Eating Disorders, Body
Reproductive Issues in the Care of Men
Image Disorders and Appearance- and
performance-Enhancing Drugs Use in with Cancers
Young Men...................................................... 293
Trevor C. Griffen and Tom Hildebrandt
CHAPTER 26
Health Issues Among Survivors of Testicular
SECTION 8 Cancer and Infertile Men................................. 339
Transgender Health Angel Elenkov, Stefan Arver and Aleksander Giwercman
CHAPTER 27
CHAPTER 24 Management of Complications Related to
Integrated Care of the Transgender and the Treatment of Localized Prostate Cancer 349
Gender Nonbinary Person ............................. 309 Ramy Abou Ghayda and Michael O'Leary
Anna Goldman and Ole-Petter R. Hamnvik
CHAPTER 28
CHAPTER 25 Fertility and Reproductive Health of
Optimizing the Use of Gender-Affirming Long-Term Cancer Survivors.......................... 363
Therapies......................................................... 325 Robert E. Brannigan
Jason A. Park and Joshua D. Safer
Index................................................................. 379
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Contributors
Bradley D. Anawalt, MD Brigham and Women’s Hospital

Professor of Medicine Boston, Massachusetts
Vice Chairman of Department of Medicine Robert E. Brannigan, MD
University of Washington Professor of Urology, Northwestern
Chief of Medicine University, Feinberg School of Medicine
University of Washington Medical Center Vice Chair of Clinical Urology
Seattle, Washington Head, Division of Male Reproductive Surgery and
Kevin L. Ard, MD, MPH Men’s Health
Director, Sexual Health Clinic Director, Andrology Fellowship
Division of Infectious Diseases Assistant Director of Student Affairs
Massachusetts General Hospital Northwestern Memorial Hospital
Instructor in Medicine Chicago, Illinois
Harvard Medical School Arthur L. Burnett, MD MBA FACS
Boston, Massachusetts Patrick C. Walsh Distinguished Professor
Stefan Arver, MD, PhD of Urology, Oncology
Associate Professor Department of Urology, The Johns
Department of Medicine Hopkins University School of Medicine
Huddinge Karolinska Institutet The James Buchanan Brady Urological Institute
Director ANOVA Andrology, Sexual Medicine The Johns Hopkins Hospital
Transmedicine Baltimore, Maryland
Karolinska University Hospital J. Quentin Clemens, MD
Stockholm, Sweden Edward J. McGuire Professor
Associate Chair for Research
Shehzad Basaria, MD
Department of Urology
Associate Professor of Medicine
University of Michigan
Associate Director, Research Program in Men’s
Ann Arbor, Michigan
Health: Aging and Metabolism
Brigham and Womens Hospital, Harvard Medical School Iryna M. Crescenze, MD
Boston, Massachusetts Assistant Professor of Urology
The Ohio State University
Shalender Bhasin, MB, BS
Columbus, Ohio
Professor of Medicine
Harvard Medical School Farah Daneshvar, DO
Director, Research Program in Men’s Health: Aging Clinical Instructor
and Metabolism Division of Endocrinology
Director, Boston Claude D. Pepper Older Americans University of Michigan, School of Medicine
Independence Center Ann Arbor, Michigan
ix
x Contributors
Zachary Dao, BS Ole-Petter R. Hamnvik, MB, BCh, BAO, MMSc,

Baylor College of Medicine MRCPI
Houston, Texas Assistant Professor in Medicine
Harvard Medical School
Chirag N. Dave, MD Program Director
Fellow Endocrinology Fellowship
Department of Urology Brigham and Womens Hospital
Johns Hopkins University School of Medicine Division of Endocrinology, Diabetes and
Baltimore, Maryland Hypertension
Angel Elenkov, MD, PhD
Molecular Reproductive Medicine, Department of Frances J. Hayes, MB, BCh, BAO, FRCPI
Translational Medicine Associate Professor of Medicine
Lund University and Reproductive Medicine Centre Harvard Medical School
Skane University Hospital Associate Clinical Chief of Endocrinology, Massachu
Malmo, Sweden setts General Hospital
Thiago Gagliano-Juca, MD, PhD
Research Fellow, Research Program in Men’s Health: Amin S. Herati, MD
Aging and Metabolism Assistant Professor
Brigham and Womens Hospital Department of Urology
Harvard Medical School Johns Hopkins University School of Medicine
Boston, Massachusetts Baltimore, Maryland
Ramy Abou Ghayda, MD, MPH Tom Hildebrandt, PsyD
Assistant Professor Associate Professor of Psychiatry and Chief
Harvard Medical School Division of Eating and Weight Disorders Department
Center for Infertility and Reproductive Surgery of Psychiatry
Division of Urology, Brigham and Womens Hospital Icahn School of Medicine at Mount Sinai
Boston, Massachusetts New York City, New York
Aleksander Giwercman, MD
Professor, Molecular Reproductive Medicine, Ilpo Huhtaniemi, MD, PhD, FMedSci
Department of Translational Medicine Professor Emeritus of Reproductive Endocrinology
Lund University and Reproductive Medicine Centre Imperial College London
Skane University Hospital, 214 28 London, United Kingdom
Malmo, Sweden Professor Emeritus of Physiology
University of Turku
Anna Goldman, MD Turku, Finland
Instructor in Medicine
Harvard Medical School Amy James, BSc
Associate Program Director Research Nutritionist
Endocrinology Fellowship Harbor UCLA Medical Center and The Lundquist
Brigham and Womens Hospital Institute
Division of Endocrinology, Diabetes and Hypertension Torrance, California
Gen Kanayama, MD, PhD
Trevor C. Griffen, MD, PhD Associate Director, Substance Abuse Research
Resident Physician Biological Psychiatry Laboratory, McLean Hospital
Department of Psychiatry Belmont, Massachusetts
Icahn School of Medicine at Mount Sinai Harvard Medical School
New York City, New York Boston, Massachusetts
Contributors xi
Martin Kathrins, MD Manuel Ozambela Jr., MD

Assistant Professor of Surgery, Harvard Medical School Resident
Division of Urology Division of Urology, Brigham and
Brigham and Womens Hospital Womens Hospital
Boston, Massachusetts Clinical Fellow
Mohit Khera, MD, MBA, MPH
Professor of Urology
Scott Department of Urology Jason A. Park, SM
Baylor College of Medicine Medical Student
Houston, Texas Boston University School of Medicine
Peter Y. Liu, MBBS (Hons I), FRACP, PhD Boston Medical Center
Professor of Medicine in Residence Boston, Massachusetts
David Geffen School of Medicine at UCLA
Alexander W. Pastuszak, MD, PhD
Division of Endocrinology and Metabolism
Assistant Professor
Harbor UCLA Medical Center and The Lundquist
Division of Urology, Department of Surgery
Institute
University of Utah School of Medicine
Torrance, California
Salt Lake City, Utah
Tom F. Lue, MD, ScD (Hon)
Michael A. Perelman, PhD
Professor and Vice Chair of Urology
Co-Director, Human Sexuality ProgramClinical
Emil Tanagho Endowed Chair in Clinical Urology
Professor Emeritus of Psychology in Psychiatry,
Reproductive Medicine and UrologyWeill Cornell
University of California
Medicine
San Francisco, California
NewYork-PresbyterianFounder and ChairmanMAP
Joseph Mahon, MD Education & Research Foundation, Inc.
Fellow in Male Health and Reconstruction New York, New York
Department of Urology, Stritch School of Medicine
Loyola University Medical Center Harrison G. Pope Jr., MD
Maywood, Illinois Director, Biological Psychiatry Laboratory, McLean
Hospital
Kevin T. Me Vary, MD-FACS
Belmont, Massachusetts
Director of the Center for Male Health
Professor of Psychiatry, Harvard Medical School
Professor of Urology
Stritch School of Medicine Mark A. Preston, MD, MPH
Loyola University Medical Center Assistant Professor of Surgery
Maywood, Illionois Harvard Medical School
Michael O’Leary, MD, MPH Associate Surgeon
Professor of Surgery, Harvard Medical School Division of Urology, Brigham and
Senior Urologic Surgeon, Director of Men’s Health Womens Hospital
Brigham and Womens Hospital Surgical Oncology, Dana Farber Cancer Institute
Boston, Massachusetts Boston, Massachusetts
Robert Oates, MD, FACS Katherine M. Rodriguez, MD

Professor of Urology Brady Department of Urology
Boston University School of Medicine Johns Hopkins School of Medicine
Boston, Massachusetts Baltimore, Maryland
xii Contributors
Joshua D. Safer, MD, FACP, FACE Division of Endocrinology, Department of Medicine,

Professor of Medicine, Icahn School of Medicine at Harbor-UCLA Medical Center
Mount Sinai Torrance, California
Executive Director, Center for Transgender Medicine
Rena Xu, MD
and Surgery
Resident Physician
Mount Sinai Health System
New York, New York
Massachusetts General Hospital
Alan W. Shindel, MD, MAS Boston, Massachusetts
Associate Professor of Urology
Elena Yanushpolsky, MD
Assistant Professor, Harvard Medical School
University of California
Center for Infertility and Reproductive Surgery
San Francisco, California
Ronald S. Swerdloff, MD Boston, Massachusetts
Professor of Medicine
Sigal Yawetz, MD
Assistant Professor of Medicine
Senior Investigator
Los Angeles Biomedical Research Institute
Director, Ryan White Program for HIV
Division of Endocrinology, Department of Medicine,
in Women and Youth
Harbor-UCLA Medical Center
Division of Infectious Diseases
Torrance, California
Cigdem Tanrikut, MD, FACS Boston, Massachusetts
Reproductive Urologist
Maria A. Yialamas, MD
Shady Grove Fertility
Assistant Professor of Medicine, Harvard Medical
Georgetown University School of Medicine
School
Washington, DC
Associate Program Director, Internal Medicine
Jeanne Wallace, MD, MPH Residency
Clinical Professor of Medicine Brigham and Womens Hospital
David Geffen School of Medicine at UCLA Boston, Massachusetts
Division of Sleep Medicine, Olive View-UCLA Med
Fiona Yuen, MD
ical Center
Senior Research Fellow
Sylmar, California
Harbor UCLA Medical Center and The Lundquist
Christina Wang, MD Institute
Professor of Medicine Torrance, California
Associate Director of the Clinical and Transla
tional Science Institute at Los Angeles Biomedical
Research Institute
Preface
Essentials of Mens Health is unique in being the first clinics have long existed for women, but men’s health
comprehensive textbook on men’s health that is centers have emerged only recently as a novel prac
directed primarily at practicing clinicians—primary tice model. In a reflection of the growing attention
care providers, family physicians, internists, endocri on issues related to men’s health, men’s health clinics
nologists, andrologists, and urologists—who care for have mushroomed all over the country. Although the
men with these problems. The textbook emphasizes major threats to men’s health have not changed—heart
an evidence-based approach to disease management, disease, cancer, and unintentional injury continue to
integrated models of patient-centric treatment, and a dominate the list of major medical causes of morbid
pathophysiological basis of major men’s health prob ity and mortality in men—the men who attend men’s
lems; it offers useful guidance on optimizing workflow, health clinics do so largely for sexual, reproductive,
includes many patient education tools and resources, and urological health concerns involving common
and its management strategies are well aligned with conditions, such as androgen deficiency syndromes,
recent trends in health care delivery. The textbook has age-related decline in testosterone levels, sexual dys
been authored by internationally recognized experts function, muscle dysmorphia and anabolic-andro
in the content areas. genic steroid use, lower urinary tract symptoms, and
The emergence of men’s health as a distinct dis medical complications of cancer treatment, which are
cipline within internal medicine is founded on the the focus of this textbook.
wide consensus that men and women differ across For much of human history, societal views of repro
their lifespan in their susceptibility to disease, in the ductive health and human sexuality were dictated by
clinical manifestations of the disease, and in their religious dogma, and issues of sexual health or uro
response to treatment. Furthermore, men and women genital problems were rarely discussed in public. The
weigh the health consequences of illness differently discovery of Viagra and the appearance of Senator
and have different motivations for seeking care. Men Bob Dole in Viagra advertisements helped remove
and women experience different types of disparities the stigma from genitourinary and sexual problems
in access to health care services and in the manner and have made it easier for men to discuss and seek
in which health care is delivered to them because of a treatment for their sexual, reproductive, and urogen
complex array of socioeconomic and cultural factors. ital problems. The growing interest in men’s health
Attitudinal and institutional barriers to accessing care; is also reflected in the extraordinary increase in pre
fear and embarrassment due to the perception that it scription sales of testosterone and products for erectile
is not manly to seek medical help; and reticence on the dysfunction, such as Viagra. As our population ages
part of male patients and physicians to discuss issues and greater focus is placed on a holistic approach to
related to sexuality, urogenital tract problems, drug men’s health, there is a clear need for all practicing
use, body image, and aging have heightened the need clinicians, but particularly primary care physicians,
for a textbook tailored to address the issues that are who are on the frontlines, to have a clear understand
specific to men’s health. ing of the issues affecting men’s health, including their
A confluence of historical factors has rendered sexual, reproductive, and genitourinary health. As
such a textbook timely. Gender-specific integrated a reflection of the growing societal interest in men’s
xiii
xiv Preface
health, there are over 100 lay books on this topic on and find themselves inadequately prepared to care
Amazons website, but these books are written as self for these patients. Recognizing this unmet need, sev
help books for the lay public. eral professional organizations, such as the Ameri
The book is contemporary and comprehensive in can Urological Association, the American Society of
its coverage of topics related to men’s health, includ Men’s Health, and the American Society of Andrology,
ing androgen disorders, various types of sexual dys have deemed the development of curriculum in men’s
function, reproductive problems associated with aging health a national priority. Essentials of Mens Health
in men, sexually transmitted diseases and high-risk was developed to fulfill this mandate and address an
behaviors in men, body image disorders and the use of unmet need in medical education.
appearance- and performance-enhancing substances,
infertility, contraception, reproductive problems
among cancer survivors, and urological problems in Shalender Bhasin, MB, BS
primary care practice. The section on transgender Editor-in-Chief
health offers guidance on integrated care of trans Professor of Medicine, Harvard Medical School
gender people and optimization of gender-affirming Director, Research Program in Men’s Health:
therapies. Aging and Metabolism
The coverage of these topics that are specific to Director, Boston Claude D. Pepper Older
men’s health in textbooks of internal medicine and Americans Independence Center
in medical school curricula has remained limited in Brigham and Women’s Hospital
spite of the high prevalence of these conditions and Boston, Massachusetts
their known impact on overall health, well-being, and sbhasin@bwh.harvard.edu
quality of life. Primary care providers and internists
receive little training in managing these problems
Pathophysiologic Basis
of the Male Reproductive
Disorders
The Pathophysiological
Basis of Androgen
Disorders in Men
llpo Huhtaniemi
INTRODUCTION hypogonadism are mutations of genes functional at

the HPT axis (organic hypogonadism), consequences
Testicular production of male sex hormones (andro of nonendocrine systemic illness, or the influence of
gens) starts in the fetal period and continues until the exogenous/lifestyle factors (functional hypogonad
end of life. Androgens are quintessential for the struc ism). We will first review the normal processes of tes
tural and functional differentiation and maturation ticular androgen production, action, and regulation
of all aspects of the male phenotype. Testosterone (T) by the HPT axis. We then review the pathophysiologi
is the most important androgen; some of its actions cal basis of the various diseases and disorders that can
require its conversion to 5a-dihydrotestosterone disturb androgen synthesis or action.
(DHT) mainly in peripheral androgen target organs. In
addition, some actions of T, such as on the bone, brain,
and sexual desire, require its conversion to the active
THE HPT AXIS
estrogen, estradiol (E2). Normal testicular androgen The HPT axis forms the backbone of endocrine reg
production is critically dependent on regulatory input ulation of the testis. This regulatory circuit contains
from the hypothalamic-pituitary level through the hierarchical cascades of feed-forward and feedback
action of luteinizing hormone (LH) and fine-tuning regulatory events (Fig. 1-1). According to the classi
by a plethora of other hormones and intratesticular cal concept, specific hypothalamic nuclei synthesize
paracrine signals. Androgen actions in the testis and the decapeptide gonadotropin-releasing hormone
other organs are mediated by the androgen receptor (GnRH).1 The axon terminals of GnRH neurons in
(AR), a ligand-activated nuclear transcription factor. median eminence release the peptide into the hypoph
The pivotal regulatory unit in androgen production yseal portal circulation, where it is transported to the
is the hypothalamic-pituitary-testicular (HPT) axis, anterior pituitary gland to stimulate in gonadotropin
where feed-forward and feedback actions between the cells the synthesis and release of luteinizing hormone
hypothalamus, pituitary, and testes maintain the phys (LH) and follicle-stimulating hormone (FSH).1 LH
iological androgen homeostasis. Disturbances of this and FSH reach the testes through the peripheral cir
balance, leading to hypogonadism, may occur at any culation and exert their stimulatory effects on Leydig
level of the HPT axis and in AR function. The patho and Sertoli cells, respectively.
physiological basis of androgen disorders is localized The negative feedback effects of testicular hor
somewhere in the cascade of androgen regulation —> mones on gonadotropin secretion at the hypotha
production —> action, either intrinsic to the HPT func lamic-pituitary level maintain the functional balance
tion or as a consequence of primarily nonendocrine of the regulatory circuit (Fig. 1-1). Testicular T, pri
conditions or external influences. Typical causes for marily after conversion to E2, inhibits LH secretion
3
4 Essentials of Men's Health
^-aminobutyric acid), and neuropeptides (e.g., neu

ropeptide Y, galanin-like peptide, opioid peptides,
and orexins). GnRH neurons also receive signals
from glial cells, including neurotrophic factors and
glutamate, which participate in the timing of puberty
and pulsatile GnRH secretion. They fine-tune the
pulsatile GnRH secretion into the hypophysial portal
circulation, which is vital for its stimulatory action
on the pituitary gonadotropin.
GnRH neurons are regulated by the neuromodu-
latory peptide kisspeptin, encoded by the KISSI gene
(Fig. I-l).5 Some kisspeptin neurons co-express neu
rokinin B and dynorphin; thus, they are termed kis-
speptin-neurokinin B-dynorphin (KNDy) neurons.
The KNDy neurons are localized in the hypothala
mus in the infundibular nucleus and in the rostral
preoptic area, whereas neurons in the preoptic area
FIGURE 1-1. The hypothalamic-pituitary-testicular (HPT) axis. only express kisspeptin.6 Kisspeptin and GnRH neu
The main hormones functioning in the HPT axis are depicted, rons have close anatomic proximity and cell contacts,
including the effects of kisspeptin on GnRH secretion, GnRH on enabling kisspeptin to evoke GnRH secretory pulses.
LH and FSH secretion, and their effects on testicular function,
Kisspeptin activates a G protein-coupled receptor
followed by negative feedback effects of testicular sex steroids
and inhibin. GnRH, gonadotropin-releasing hormone; KiSSIR, (GPCR) KISSIR (formerly called GPR54) in GnRH
kisspeptin receptor; LH, luteinizing hormone; FSH, follicle- neurons, thereby stimulating GnRH expression and
stimulating hormone; R, receptor. secretion.5 Because estrogen receptor a is expressed
in the kisspeptin neurons but not in the GnRH neu
rons, the negative feedback action of sex steroids on
at the level of the hypothalamus and pituitary, while GnRH secretion is indirect through the inhibition of
inhibin B, the product of the Sertoli cell, suppresses kisspeptin production.5,7
FSH secretion at the pituitary.
GnRH and GnRH Pulse Generator The larger pro
The Hypothalamic Level peptide encoded by the GnRH gene is cleaved into
the 24-amino acid signal peptide, the GnRH deca
GnRH Neurons The hypothalamus, the most proxi
peptide, and the 56-amino acid GnRH-associated
mal level of the HPT axis, is an area in the base of the
peptide with unknown function.8 These peptides are
brain containing numerous discrete nuclei specialized
secreted in median eminence from the GnRH neuron
to synthesize and secrete neuroendocrine hormones.2
terminals to the hypophysial portal circulation in 1 to
In humans, GnRH neuronal cell bodies are primar
2-min pulses of varying amplitude, at a frequency of
ily located in the anterior hypothalamus and in the
one pulse every 1 to 2 h. The exact nature and location
periventricular and tuberal regions.3 GnRH is consid
of the GnRH pulse generator remain important unan
ered the master switch in the regulatory interactions
swered questions in GnRH neurobiology, but recent
between the brain and reproduction, that drives the
research indicates that kisspeptin neurons in the
function of the downstream HPT elements.4
hypothalamic arcuate nucleus may be the anatomic
Regulation of GnRH Neurons An array of hypotha site of the pulse generator.9
lamic hormones and neurotransmitters is involved
in the maturation, regulation, and fine-tuning of
The Anterior Pituitary Gland
GnRH neuronal function.4 They include classical
neurotransmitters (e.g., norepinephrine), excitatory GnRH Action In the anterior pituitary, GnRH
and inhibitory amino acids (e.g., glutamate and binds to its high-affinity receptor (GnRHR) on the
Chapter 1 THE PATHOPHYSIOLOGICAL BASIS OF ANDROGEN DISORDERS IN MEN 5
gonadotropin cells. The GnRHR is a GPCR, and evokes the morning and a trough in the evening. There is also
the Ca2+/diacyl glycerol/protein kinase C/mitogen- good synchrony between serum LH and T pulses.
activated protein kinase second messenger signaling
cascade.10 GnRH secretion must be pulsatile for a stimu
The Testis
latory effect on gonadotropins; tonic GnRHR activation
(e.g., upon GnRH agonist treatment) causes GnRHR Trophic Stimulation of Testicular Function LH and
desensitization by blocking the signal transduction and FSH bind in the testis to their cognate receptors, LH
suppressing gonadotropin synthesis and release. After a to LH/chorionic gonadotropin receptor (LHCGR)
GnRH pulse, the secretory peaks of LH are more distinct in Leydig cells and FSH to FSH receptor (FSHR) in
than those of FSH because of the shorter circulatory Sertoli cells. Both gonadotropin receptors reside
half-life of the former. The pulsatility of serum gonad on the plasma membrane and belong to the class A
otropins reflects the mode of GnRH action, but it is not GPCRs.14,15 Their functional domains are (1) the extra
essential at the gonadal level, as continuous treatment cellular domain with distinctive leucine-rich repeats
with gonadotropin can maintain testicular function. forming the primary ligand binding site, (2), the short
hinge-region with a role in determining specificity of
Gonadotropins LH and FSH, with molecular masses the hormone binding, (3) the transmembrane domain
of 30 kDa and 35 kDa, respectively, along with thy whose conformational change after ligand binding
roid-stimulating hormone (TSH) and human cho transfers the gonadotropin signal across the plasma
rionic gonadotropin (hCG), belong to the family of membrane, and (4) the intracellular tail that partici
glycoprotein hormones. Most gonadotropin produce pates in the termination of signaling through receptor
both LH and FSH, and only a minority of cells are desensitization (by phosphorylation) and downregu
monohormonal. The partial dissociation of the secre lation (by internalization).
tory profiles of LH and FSH is due to differential LH The main second messenger system involved in the
and FSH responses to the different patterns of pul signaling of both gonadotropin receptors is the ade
satile release of GnRH, with high-frequency GnRH nylyl cyclase/cAMP/protein kinase A cascade,14,15 but
secretory pulses favoring LH release.11 other signaling mechanisms also are involved, espe
LH and FSH are composed of a common a-subunit cially at higher hormone and receptor concentrations.
that is noncovalently coupled to the hormone-specific
P-subunit to form a heterodimer. The common Functional Compartments of the Mature Testis The
ot-subunit has two, LHp has one, and FSHp has two two functions of the adult testis are to produce sex
N-linked carbohydrate side chains.12 The carbohy hormones and sperm. Leydig cells in the interstitial
drate termini of LH are heavily sulfated (50%), while tissue are the site of androgen synthesis under LH
in FSH they are mainly sialylated. The differences in stimulation. Spermatogenic cells are harbored in sem
glycosylation explain the longer half-life of FSH in iniferous tubules within and between the large, met-
circulation as compared to LH (3 to 4 h vs. 20 min). abolically active Sertoli cells. The latter are regulated
In addition, a specific hepatic receptor for sulfated by the endocrine action of FSH and by the paracrine
glycoproteins accelerates the elimination of LH from action of T from the Leydig cells. T and FSH stimula
circulation.13 There is considerable microheteroge tion is vital for the maintenance of Sertoli cell metab
neity (isoforms) in the carbohydrate residues of the olism, which provides paracrine stimuli and nutrients
circulating gonadotropin molecules.12 The isoforms for “nursing” the spermatogenic cells. The peptide
vary in bioactivity, and their relative proportions are hormone inhibin B is a Sertoli cell product; it has
apparently hormonally regulated, but the physiologi paracrine functions within the testis, and its hormonal
cal significance of this variability remains uncertain. function is to mediate the testicular negative feedback
The circhoral (every 1 to 2 h) release of GnRH on FSH secretion. The seminiferous tubules are cir
pulses from the hypothalamus is superimposed with cumscribed by a layer of peritubular myoid cells,
the episodic ultradian (24-h interval) activity of which promote sperm movement with their smooth
GnRH release. The result is the circadian rhythmicity muscle-like activity. Besides Leydig cells, the intertu
of LH pulses from the pituitary, with peak activity in bular (interstitial) space harbors various immune cells
(e.g., macrophages), fibroblasts, and blood and lym as intermediates (Fig. 1-2B). This “backdoor” pathway
phatic vessels. of DHT formation, using androsterone produced by
the placenta as a substrate, may play an active role in
Testicular Steroid Production and Secretion Ley the masculinization of male fetal genitals.18,19
dig cells are the testicular site of steroid hormone The testes produce 6 to 7 mg of T daily. In adult
production, particularly T. All steroid hormones men, about 95% of T originates from the testes and
are metabolic products of cholesterol, which can the rest from peripheral metabolism of adrenal andro
originate from a number of sources, including de genic precursors. In addition to T, the human testes
novo synthesis, intracellular stores of cholesterol store and secrete intermediates and metabolites of the
esters, circulating lipoprotein-bound cholesterol, androgen synthetic pathway (Table 1-1, Fig. 1-2B),
and plasma membrane.16 An array of steroidogenic particularly as sulfate conjugates,20,21 which apparently
enzymes regulates the conversion of cholesterol to represent storage and secretory forms with no bioac
T (Fig. 1-2A). The enzymes are either cytochrome tivity of their own.
P450s (CYP) or hydroxysteroid dehydrogenases The secretion of steroids from Leydig cells is con
(HSD). sidered a passive process due to their lipid solubility
Steroid synthesis starts with the transfer of choles and easy transit through cell membranes. T and the
terol from the outer to the inner mitochondrial mem sulfate conjugates of T—pregnenolone, dehydroepi
brane in a rapid LH-regulated fashion. The transfer androsterone, and 5-androstene-3(3,17(3-diol—are the
is augmented by a protein complex containing the quantitatively most abundant steroids in the human
steroidogenic acute regulatory protein (StAR) and testis (Table 1-1). T concentration in the testis tissue
the 18-kDa translocator protein (TSPO).17 The first is over 100-fold higher than in the peripheral circu
and rate-limiting step of steroid biosynthesis in mito lation. The intratesticular T has been considered nec
chondria is the conversion of cholesterol to pregnen essary for spermatogenesis, although its importance
olone, catalyzed by the CYP cholesterol side-chain has recently been challenged by animal experiments
cleavage enzyme (CYP11A1, P450scc) and auxiliary where full spermatogenesis was evoked in hypogo-
electron-transferring proteins. The next steps occur in nadal mice by T doses that only reached about 2% of
the smooth endoplasmic reticulum, including the con normal intratesticular T.22 The intratesticular T con
version of pregnenolone via 17-hydroxypregnenolone centration may be high only because the testis is the
to dehydroepiandrosterone by 17a-hydroxylase/17- site of T production.
20-lyase (CYP17A1, P450cl7), then to 5-androstene- There is a diurnal variation in testicular steroid
3(3,17(3-diol by 17(3-hydroxysteroid dehydrogenase secretion, which follows a similar variation in cir
type 3 (17(3HSD3), and finally to T by 3(3- culating LH levels. The synchrony between secre
hydroxysteroid dehydrogenase type 2 (3|3HSD2). This tory pulses of T and those of LH is less consistent,
sequence of conversions (called the A5 pathway) apparently due to the sluggish response of human
is preferred in the human testis. The A4 pathway testicular steroidogenesis to gonadotropin stimula
involving the initial conversion from pregnenolone to tion (only up to 30% to 50%)23 and to the buffering
progesterone by 3(3HSD2 dominates in rodents. The effect of steroid hormone binding to plasma trans
most important steroidogenic end product in the tes port proteins.24
tis is T, but about 0.5% of T is converted by aromatase Only about 2% of serum T is free, while 44% is
(CYP19A1) to E2 and by the steroid 5a-reductase bound to sex hormone-binding globulin (SHBG)
type 2 (SRD5A2) to DHT in peripheral androgen tar and 54% to albumin and other transport proteins.24
get tissues (prostate, genital skin, hair follicles). The plasma level of SHBG is under endocrine regu
An alternative pathway, also referred to as the lation; it is increased by estrogen and with aging, and
backdoor pathway, was recently discovered for DHT is reduced by androgens and obesity. If function of the
synthesis, which bypasses T as a precursor.18 In this HPT axis is normal, changes in SHBG levels do not
pathway, DHT is produced from progesterone via 5a- alter the androgen milieu, as the free testosterone con
dihydroprogesterone, allopregnanolone, 17-hydroxy- centrations are maintained in the normal range as a
allopregnanolone, androsterone, and androstanediol result of feedback regulation.
(A) (7) P450 Cholesterol side chain

cleavage
(5) P450 17-Hydroxylase/17,20 lyase
CH3 (J) 3(3-Hydroxysteroid

Cholesterol
q Dehydrogenase type 2
170-Hydroxysteroid
Dehydrogenase type 3
(5) Aromatase
(?) 5a-Reductasetype 2
Androstene-30,170-diol Testosterone
(B) Cholesterol
I CYP11A1
▼ , HSD3B2 SRD5A1
Pregnenolone ---------- ——----> Progesterone — ——-------- > 5ot-DHP
1 CYP17A1 I CYP17A1 I AKR1C2/4
POR POR (Red)
17-OH-Pregnenolone 17-OH-Progesterone Allopregnanolone
I
I CYP17A1 I CYP17A1
V POR/b5 V POR
AKR1C2/4
Androstenedione ______ DHEA 17-OH-DHP 17-OH-Allopregnanolone
I CYP17A1
HSD17B3 HSD17B2 HSD17B3 HSD17B2
POR
Testosterone Androstenediol Androsterone
HSD17B3
SRD5A2
AKR1C2RoDH (Ox)
5cx-DHT Androstanediol
Classical pathway Alternative/backdoor pathway
FIGURE 1 -2. A. The key steroid metabolic steps in the testis leading to formation of T, 5a-DHT, and E2. The A5 pathway (blue arrows)
is used by the human testis, and the A4 pathway (red arrows) is more important in rodents. The same enzyme with a dual function,
P450 17-hydroxylase/17,20-lyase (CYP17A1), catalyzes both 17-hydroxylation and D-ring side chain cleavage in pregnenolone and
progesterone. Apart from the interconversion of 17-keto and 17-hydroxy steroids, all other reactions in the steroid metabolic pathway are
irreversible. B.The"classical"(blue background) and alternative/backdoor (pink background) pathways of 5a-DHT synthesis.The factors
functional in the classic pathway are CYP11A1 (cholesterol side-chain cleavage enzyme, P450scc), CYP17A1 (17a-hydroxylase/17,20-
lyase, P450c17), HSD3B2 (3[3-hydroxysteroid dehydrogenase, type 2), HSD17B3 (170-HSD3 [17(3-hydroxysteroid dehydrogenase, type
3]), and 5a-reductase, type 2 (5a-reductase 2, encoded by SRD5A2).The alternative/backdoor pathway uses the following additional
enzymes: 5cv-reductase, type 1 (5ct-reductase 1, encoded by SRD5A1), AKR1C2 3 (3a-reductase, type 3), and possibly AKR1C4
(3a-reductase, type 1) and RoDH (3-hydroxyepimerase, encoded by HSD17B6). The trivial names and abbreviations of the steroids
are 17-hydroxy-dihydroprogesterone (17OH-DHP), 5a-pregnane-17a-hydroxy-3-20-dione; 17-hydroxy-allopregnanolone (17OH-allo),
5a-pregnane-3a,17a-dihydroxy-20-one; 5a-di hydro prog esterone (5a-DHP), 5a-pregnane-3,20-dione; and allopregnanolone,
3a-hydroxy-5a-pregnan-20-one. From Ref. 67, with permission.
TABLE 1-1. The Mean Testicular, Spermatic Vein, and Peripheral Vein Concentrations (in nmol/L) of the Key
Testicular Steroids in Man20,21
STEROID TESTIS SPERMATIC VEIN PERIPHERAL VEIN
Pregnenolone sulfate 2600 430 90
Progesterone 130 23 0.8
17-Hydroxyprogesterone 690 45 3.2
Dehydroepiandrosterone 680 35 8.2
Dehydroepiandrosterone sulfate 2000 1400 1000
5-Androstene-3(3,17(3-diol 820 590 500
Androstenedione 740 45 2.5
Testosterone 2600 720 20
Testosterone sulfate 1400 150 13
5o-Dihydrotestosterone 50 14 1.5
Estradiol 15 0.4 0.1
Hormonal Regulation of Spermatogenesis Sper T treatment provides a successful means of male con
matogenesis is regulated by the hormonal action of traception.26 If such men receive LH or hCG injec
FSH and paracrine action of testicular T, supplemented tions, their spermatogenesis recovers qualitatively, due
by other endocrine, paracrine, and autocrine factors, to the restoration of intratesticular T levels,27 although
as well as nutrients. The crucial role of LH-stimulated in the absence of FSH, the sperm counts remain about
T production in spermatogenesis is well recognized, 50% suppressed. These findings suggest that T action
but the role of FSH remains somewhat unclear. It is alone is sufficient for the reinitiation of spermatogen
apparent that the regulatory requirements are dif esis, but full quantitative recovery may also require
ferent at puberty for the initiation of spermatogene FSH. Indeed, addition of FSH to the treatment of these
sis, its subsequent maintenance, and its reinitiation men fully restored spermatogenesis.
after transient suppression in adult life. Testosterone
alone may be insufficient to drive spermatogenesis to Feedback Regulation of Gonadotropins The func
completion in the immature testis. After prepubertal tional balance of the HPT axis is maintained through
hypophysectomy in experimental animals, LH alone the feedback action of T and E2, as well as inhibin B,
only partially reverses germ cell loss. In contrast, full at the hypothalamic-pituitary level1; inhibin B spe
spermatogenesis can be initiated in various gonado cifically inhibits FSH synthesis and secretion at the
tropin-deficient adult animal models by T treatment pituitary level. Unlike the menstrual cycle in females,
alone (see Ref. 22). In men with postpubertal gonado the function of the male HPT axis is tonic and regu
tropin deficiency, prolonged hCG treatment alone can lated only by negative feedback from the gonad at the
initiate spermatogenesis without FSH.25 hypothalamic-pituitary level. In the hypothalamus,
Treatment with T suppresses LH and FSH secre T on its own, but more importantly after conversion
tion via negative feedback, which reciprocally leads to E2, suppresses GnRH secretion indirectly by sup
to marked suppression of intratesticular T, while pressing the activity of kisspeptin neurons, which then
maintaining peripheral androgen actions. This leads results in the suppression of GnRH and gonadotropin
to suppression of spermatogenesis to the extent that secretion.
Although testicular steroids also regulate FSH, it of activin, a pituitary paracrine factor that stimulates
is mainly regulated at the pituitary level by the Ser FSH synthesis.
toli cell peptide hormone inhibin B,28 the only type
of inhibin present in the male serum. FSH stimu
ANDROGEN ACTION
lates Sertoli cell inhibin B production, thus form
ing the other side of a classical feedback regulatory All T actions within and outside the testis are mediated
loop. Inhibin also has complex intratesticular para/ by the same AR (NR3C4) (Fig. 1-3), a ligand-activated
autocrine functions. Serum inhibin B levels correlate nuclear transcription factor belonging to the group
negatively with FSH levels and positively with sperm of steroid nuclear receptors.31 The human AR gene is
production and testis volume. It is low in patients located on chromosome X; hence, the male has only one
with impaired spermatogenesis, idiopathic azoosper copy of the gene. This, together with the fact that loss
mia, Klinefelter syndrome, and cryptorchidism.29 of androgen action is not essential for human survival,
Pituitary gonadotropin are the site of inhibin action may explain the large number of known AR mutations.32
through the inhibin co-receptor beta glycan.30 The AR actions induce the male-type sexual differenti
inhibitory action of inhibin B on FSH secretion is ation and maturation in fetal life and during puberty.
explained by its inhibition of the stimulatory effects In adult men, androgens maintain spermatogenesis
FIGURE 1-3. The classical and non-classical T signaling mechanisms of androgen action. In the classical pathway (left) T crosses the
plasma membrane and binds to androgen receptor (AR). A conformational change in AR releases it from heat shock proteins (HSP).
AR therafter translocates to the nucleus, where it binds to target gene androgen response elements, recruits co-regulator proteins,
and regulates gene expression. In the non-classical pathway (right), T stimulation transiently localizes AR to the plasma membrane,
followed by AR interaction with and activating SRC tyrosine kinase. The latter can alter numerous physiological processes, including
the phosphorylation and activation of the epidermal growth factor (EGF) receptor that in turn activates the mitogen-activated protein
(MAP) kinase cascade (RAF, MEK, and ERK). Further signaling through p90RSK kinase results in phosphorylation of the CAMP-response
element binding protein (CREB) transcription factor and increased transcription of CREB-regulated genes.
TABLE 1 -2. The Physiological Actions of Androgens repeats, whose lengths affect the activity of AR. AR
has 4 functional domains31: the N-terminal domain
• Androgenic actions (NTD) is the binding region of transactivating co-reg-
• Differentiation of the male sexual organs
ulators; the C-terminal ligand binding domain (LBD)
• Secondary sex characteristics
contains a structural pocket that binds the androgen
• Growth of male sex organs
• Testis
molecule; the DNA-binding domain (DBD) has 2
• Epididymis Q-helixes arranged into 2 zinc finger domains, which
• Seminal vesicle participate in dimerization and DNA binding of the
• Prostate activated AR; and the hinge region contains the AR
• Penis nuclear localization and export signals, as well as heat
• Scrotum shock protein association of the inactive AR molecule.
• Pubic hair LBD interacts with NTD to stabilize the transcription
• Axillary hair ally active AR dimer.
• Facial hair Androgen binding to the receptor takes place in
• Regulation of spermatogenesis
the cytoplasm (Fig. 1-3), whereby the chaperon heat
• Male-type hair distribution and balding
shock proteins are released and the receptor becomes
• Feedback regulation of gonadotropin secretion
Psychological actions
phosphorylated and dimerized and translocates to
• Cognitive functions the nucleus. There it binds to the regulatory elements
• Libido and potency of androgen target genes, initiating the formation of
• Sexual behavior a large multiprotein complex of co-regulators, which
Aggression either activate or suppress target genes that encode
Other actions proteins and noncoding RNAs, including regulatory
• Growth spurt at puberty microRNA species.31,33 The human genome contains
• Epiphyseal closure tens of thousands of AR binding sites in thousands
• Growth of larynx of AR target genes. Their collection in a specific cell
• Thickening of vocal cords
type is termed cistrome, and they display cell-spe
• Effects on blood lipids
cific features with little overlap, which together with
• Muscle mass
• Distribution of adipose tissue
a cell-specific array of AR collaborating transcription
• Hematopoiesis factors and co-regulators, explain how the same event
• Thickening of skin of androgen binding to AR can exert the diverse bio
• Function of sebaceous gland logical responses in different target cells.33
• Effects on immune system The “classical” genomic steroid hormone action
described earlier through modulation of gene expres
sion requires minutes to hours to occur. There is also
and sexual behavior and exert additional effects in a a rapid “nonclassical” or “nongenomic” (seconds to
variety of nonreproductive organs (Table 1-2). AR is minutes) mechanism of androgen action (Fig. 1-3)
ubiquitously expressed in almost all tissues, with the whereby cytoplasmic or cell membrane-bound AR
highest level in the male reproductive tissues and directly activates kinase signaling cascades (e.g., SRC/
the brain, where it regulates male sexual behavior.31 ERK/CREB).34 Another candidate mediator for rapid
Androgens regulate the immune system, bone health, androgen action has been proposed to be the GPCR
and hematopoiesis and exert anabolic effects on the GPRC6A, activated by multiple ligands, including T.35
muscles.
AR has 8 exons; its promoter region lacks TATA PATHOPHYSIOLOGY OF ANDROGEN
and CCAAT elements but contains Spl, NfftB, and
PRODUCTION AND ACTION
c-MYC binding sites.30,32 Its expression is regulated by
androgens in a tissue- and cell-specific fashion. AR Pathophysiological changes in androgen disorders can
encodes a 110-kDa protein of 919 amino acid residues. occur at each level of the regulation production —>
It has 2 polymorphic (polyglutamine and polyglycine) action cascade. Secondary hypogonadism results from
GnRH neuron development and/or migration:
Hypothalamic-pituitary development:
ANOS1 (KAL1), NSMF, FGFR1, FGF8, FGF17, IL 17RD, DUSP6, SPRY4,
NR0B1 (DAX1), NR5A1, SRA1, HESX-1,
GLCE, FLRT3, KLB, PROK2, PROKR2, HS6ST1, CHD7, WDR11, SEMA3A,
LHX3,PROP-1, SOX2, TC3, TAC3R,LEP, LEPR
SEMA3E, TUBB3, SOX10, OTUD4, FEZF1, RNF216, POLS3A, POLR3B,
NROB1
PNPLA6, STUB1, DMXL2, IGSF10, SMCHD1, CCDC141, FEZF1
Testicular regulation and function
LHCGR 17bHSD2
STAR SRD5A2
CYP11A1 AKR1C2
CYP17A1 AKR1C4
3bHSD2 AR
FIGURE 1 -4. Genes functional along the hypothalamic-pituitary-testicular axis whose inactivating mutations can result in secondary
(hypothalamus and pituitary) or primary (testis) suppression of androgen (T and/or DHT) production.
insufficient gonadotropin production due to distur Disorders at the Hypothalamic-Pituitary Level

bances at the hypothalamic-pituitary level, while (Fig. 1-4)
primary hypogonadism is due to failure of the tes
The highest well-defined level in the regulation of
tis itself to produce T or sperm. Whereas androgen
gonadotropin secretion is the function of the KNDy
deficiency usually results in deficient spermatogen
neurons and their hormonal product kisspeptin. Muta
esis (fertile eunuch syndrome is the only exception),
tions of the kisspeptin (KISSI) or its receptor KISS1R
defective spermatogenesis can occur in the presence
genes have been described in humans.36 Both cause
of apparently normal androgen production. Androgen
a similar phenotype of isolated hypogonadotropic
deficiency can be either congenital (e.g., mutations of
hypogonadism (HH). The pathogenesis is in line with
key genes of the HPT axis) or acquired, organic (e.g.,
the now well-established crucial role of kisspeptin in
a pituitary tumor or hemochromatosis), or func
regulating GnRH neuronal secretory function.
tional (e.g., due to a nonstructural condition, such
The next level concerns the development and func
as an eating disorder, acute illness, or drug effect).
tion of GnRH neurons, subdivided into cases with and
In many cases, the etiology of testicular dysfunction
without normal olfaction. The embryonal origin of
remains unknown (e.g., in men with idiopathic oligo/
GnRH neurons is in the olfactory placode of the dorsal
azoospermia).
region of the nasal cavity. An array of genes directs tubular hypoplasia and reduced spermatogenesis.
the migration of GnRH neurons along the olfactory Pubertal maturation of these men can be induced with
nerves to the hypothalamus. If GnRH neurons are T or hCG treatment, but spermatogenesis responds
unable to reach the hypothalamus, they cannot secrete poorly. Interestingly, one patient40 has been described
GnRH into the hypothalamic portal circulation to with normal spermatogenesis in the absence of LH.
stimulate gonadotropin release. This explains why He apparently had sufficient T production to sup
hypogonadism in individuals with disturbed GnRH port spermatogenesis, perhaps augmented by elevated
neuron migration is often associated with disturbed FSH levels. The same may occur in the rare cases of
olfaction (termed Kallmann syndrome). Another form Pasqualini syndrome (fertile eunuch syndrome),
of HH is normoosmic, where GnRH neuronal migra where men with very low T can have spermatogen
tion is not affected. Today, over 30 genes are known esis. An LHCGR knockout mouse combined with
whose mutations interfere with the GnRH neuronal transgenic expression of constitutively active FSHR in
migration or action, resulting in HH with or without Sertoli cells has demonstrated that strong FSH action
reduced olfaction; these genes explain the molecular without T can maintain spermatogenesis.41 Hence,
pathogenesis of about 50% of such conditions.37 They spermatogenesis in the absence of LH could be a com
can be subdivided into those disturbing GnRH neuro bined effect of marginal testicular T production and
nal migration, function of the GnRH pulse generator, high FSH stimulation.
anatomic development of the hypothalamic-pituitary Men with an inactivating FSHB mutation (reviewed
region, and hypogonadism associated with obesity or in Ref. 39) are azoospermic despite normal T.
neurodegenerative syndromes (Fig. 1-4).37
The next level is the pituitary gland, where HH can
Disorders at the Gonadal Level (Fig. 1 -4)
be caused by mutations encoding the GnRH receptor
(GNRHR) or the gonadotropin subunits (CGA, LHB, Disorders of Gonadotropin Action Because LHC-
FSHB). Multiple mutations in GNRHR have been GR-stimulated Leydig cell androgen production is
described, and their phenotypes are variable depend essential for masculinization, inactivating LHCGR
ing on the severity of receptor inactivation, from partial mutations typically disrupt sexual differentiation
to complete gonadotropin deficiency with associated and development from fetal life through adulthood,
hypogonadism, though with normal olfaction.38 thus forming an etiological subclass of 46,XY dis
The mutations described earlier result in the lack of orders of sexual development (DSD).38 In partial
spontaneous puberty, but depending on the mutated LHCGR inactivation, the phenotype includes hypo
gene, other congenital anomalies may exist. Because spadias and/or micropenis (Leydig cell hypoplasia,
hCG stimulates fetal testicular T production, male LCH type 2), and upon complete receptor inacti
sexual differentiation in HH is not disturbed, despite vation, there is complete male-to-female sex rever
an inability to produce gonadotropins in utero. sal (LCH type 1) with near-total lack of male-type
Mutations in the gonadotropin subunit genes sexual differentiation in utero and at puberty. The
(CGA, LHB, FSHB) are very rare, apparently because phenotype resembles the androgen insensitivity syn
of compromised reproduction (reviewed in Ref. 39). drome (see Sec. “Disorders of Androgen Action”),
No germline mutations of CGA have been described, but notably lacks pubertal breast development,
most likely because pregnancy in the absence of func which in the latter occurs through T-derived E2.
tional CGA, and hence of hCG, would be impossible. The testes in complete LHCGR inactivation have
Men with an inactivating LHB mutation are normally no mature Leydig cells, which explains the lack of
masculinized at birth, because hCG provides the T production.
stimulus for fetal testicular T production. Second Activating LHCGR mutations are associated with
ary sexual characteristics do not develop at puberty early-onset male-limited precocious puberty, also
without LH-stimulated Leydig cell T production, and termed “testotoxicosis.”38
spermatogenesis fails (with one exception, see below). Several inactivating mutations have been detected
These men have undetectable LH, low T, and normal in FSHR, most of them in women with hypergonad
to low AMH and E2 levels. The testes are small with otropic hypogonadism.39 Five men with complete
inactivating FSHR mutation have been described; they The next step in androgen synthesis—conversion
had normal masculinization at puberty and features of cholesterol to pregnenolone in the mitochon
of mild hypogonadism as adults.42 Their testes were drial inner membrane—is blocked by a mutation in
mildly or severely reduced in size, all had abnormal CYP11A1. The phenotype and hormone values of
semen analyses but none was azoospermic, and 2 of affected individuals are similar to those of patients with
the men had fathered 2 children each. As expected, StAR mutation but without the adrenal hyperplasia.44
they had high FSH, low inhibin-B, normal or slightly The survival of individuals with StAR and CYP11A1
elevated LH, and normal T. The mild phenotype of mutations until birth is not fully understood, as their
FSHR inactivation was unexpected because of the placenta does not produce progesterone.
assumed role of FSH in spermatogenesis, particularly Mutations of CYP17A1 with its dual activity of
during its pubertal initiation. It appears that FSH is catalyzing 17a—hydroxylation and D-ring side chain
largely needed to improve the quality and quantity cleavage by Cl7,20 lyase reaction (from pregnenolone
of spermatogenesis. Subsequent experiments on Fshr to dehydroepiandrosterone) usually inactivates both
or Fshb knockout mice produced similar phenotypes enzyme reactions. A subgroup of CYP17A1 muta
(reviewed in Ref. 43); the animals were fertile, but their tions only lacks the lyase activity, when only andro
testes were reduced in size and their spermatogene gen, but not glucocorticoid, synthesis is hampered.
sis was qualitatively and quantitatively suppressed. It Men with both types of mutations are undervirilized
remains an enigma why the azoospermic phenotype at birth and need T replacement therapy and genital
of the men with FSHB mutation (see Sec. “Disorders surgery to repair hypospadias. The reactions catalyzed
at the Hypothalami-Pituitary Level”) differs from the by CYP17A1 need NADH for electron transfer and
milder phenotype of human FSHR mutations and cog NADPH cytochrome P450 reductase (POR) and b5
nate knockout mouse models. as co-factors; mutations of these co-factors can also
cause a Cl7,20 lyase deficiency-like phenotype.
Disorders of Androgen Production The genetic Of the two 30HSD genes, type 2 is expressed in the
defects of androgen synthesis can be caused by muta testis, and its deficiency in boys causes 46,XY SDS with
tions in multiple enzymes and regulatory co-factors in varying degrees of undermasculinizaton.44 Mullerian
the androgen biosynthetic pathway.44 Depending upon structures are absent because of normal anti-Mullerian
the severity of androgen deficiency, 46,XY males with hormone production by fetal Sertoli cells, and testic
defects in the T biosynthetic pathway may present ular descent is variably impaired. Some androgen is
with variable DSDs. Milder forms may be associated produced because of activity of type 1 3[3HSD, and
with failure of pubertal development or hypogonad fertility is possible in less severely affected males.
ism in adulthood. Patients with 3|3HSD type 2 deficiency require lifelong
Mutations of the StAR protein catalyzing the glucocorticoid and mineralocorticoid therapy, and T
transfer of cholesterol from the outer to the inner replacement is needed for pubertal masculinization.
mitochondrial membrane cause lipoid adrenal hyper The mutations of 17/3HSD do not affect adrenal
plasia characterized by adrenal glucocorticoid and function but present exclusively with testicular disor
mineralocorticoid insufficiency and 46,XY DSD due ders and are limited to males. Of the multiple 17/3HSD
to failure of masculinization of external genitalia genes in the human genome, only the deficiency of
because of impaired T synthesis.44 The StAR muta type 3, expressed exclusively in the testis, causes dis
tions have a 2-fold effect: the lack of androgen syn ease, resulting in a 46,XY DSD because of the lack
thesis and destruction of Leydig cells by cholesterol of T synthesis. Affected XY males have complete or
accumulation. No hormonal replacement therapy can near-complete female external genitalia as newborns,
amend the sex-reversed phenotype of XY individuals and their phenotype is very close to that of 5a-reduc-
because the condition is diagnosed only after birth tase deficiency or partial androgen insensitivity due
and after the critical period of male genital differen to an AR mutation. Wolffian derivatives, including
tiation has passed. Hence, these patients are usually epididymides, vasa deferentia, seminal vesicles, and
gonadectomized to prevent malignant transformation ejaculatory ducts, are present, suggesting that alter
of the cryptorchid testes and raised as females. native 17(3HSDs or DHT formed by the backdoor
pathways contribute to some androgenic activity. has occurred. Breasts and female adiposity develop at
Mullerian structures have involuted, and the testes puberty; likewise, the growth spurt is normal because
are often partially undescended. The patients often of normal function of the estrogen formed from T.
present as females with progressive virilization, poor Pubic and axillary hair is absent or sparse as a sign
breast development, and amenorrhea because of the of missing androgen action. CAIS women are taller
action of peripherally produced androgens and their than average because of the effect of the Y chromo
estrogen metabolites. some. The estimated prevalence of CAIS is 1:20,400
Of the 3 steroid 5a-reductase isoforms convert to 1:99,100 in genetic males, and >500 individual
ing T to DHT in androgen target tissues, inactivating mutations have been described as a cause of androgen
mutation of type 2 causes a disorder of male sexual insensitivity.32,45
differentiation with consequent ambiguous genitalia.44 The phenotype of PAIS, depending on the residual
Mutations in enzymes involved in the recently dis AR activity, ranges from severe undermasculinization
covered “backdoor pathway” of DHT formation (see with femalelike external genitalia to male genitalia. The
Sec. “Testicular Steroid Production and Secretion”) typical phenotype includes micropenis, severe hypo
may present as a rare cause of DSD due to defective spadias, and bifid scrotum with or without cryptorchi
DHT action in fetal life. Undervirilization has been dism. Subjects with the mildest form mild androgen
described when there are simultaneous mutations in insensitivity syndrome (MAIS) usually have normal
both of the two alfa-keto-reductases, AKR1C2 and male development with possible isolated micropenis,
AKR1C4, participating in the backdoor DHT forma gynecomastia at puberty, and infertility in adulthood.
tion.18,19 The disorder follows sex-limited recessive AR also displays polymorphisms in the length of the
genetics, consistent with the essential role for andro polyglutamine (CAG) and polyglycine (GGN) tracts in
gens only in male reproductive biology. The obser its N-terminal domain, which influence AR activity.46
vation that human males with both SRD5A2 and Long CAG repeats reduce receptor activity and are
AKR1C2/4 deficiency present with ambiguous geni associated with genital abnormalities, variable effects
talia suggests that both pathways of DHT synthesis are on serum T, and male infertility. Shorter CAG repeats
needed for normal male fetal masculinization. may increase the risk of prostate cancer. Extremely
long CAG repeats are seen in Kennedy disease (spinal
Disorders of Androgen Action The disturbance in and bulbar muscular atrophy), probably by AR aggre
androgen action, usually termed androgen insen gating to the cell nucleus. The AR CAG repeat may
sitivity syndrome (AIS), is caused by inactivating play an important role in the overall androgenicity of
mutations in AR leading to androgen resistance.45 an individual, although the feedback regulation of the
Depending on the degree of AR inactivation, the phe HPT axis may also compensate for the reduced activity
notype of patients with AR mutations may vary sub- of AR with long CAG repeats with increased T levels.47
stantially.31,32,44 Most complete androgen insensitivity The GGN polymorphism in AR has a small and likely
syndrome (CAIS) cases are due to inactivating AR clinically insignificant effect on T levels and fertility.46
mutation, but in partial androgen insensitivity syn
drome (PAIS) AR mutation has been found in <30%
Androgen Disorders Caused by Diseases
of the cases. CAIS presents as primary amenorrhea in
Outside the HPT Axis
an adult woman, but testes may be found earlier in the
inguinal region during hernia repair. There may also Numerous congenital and acquired disorders not pri
be a family history (X-linked recessive) or mismatch marily affecting the HPT axis can indirectly suppress
between fetal sexing by ultrasound and presence of a Y HPT function and androgen production (see Chaps. 4
chromosome SRY marker in a newborn with a female and 9). Causes of isolated failure in spermatogenesis
phenotype. Because the fetal testes produce AMH (e.g., obstructive azoospermia and FSH deficiency)
normally, the Mullerian ductal derivatives (including will not be reviewed here. These conditions can be
a uterus) are absent. The gonads are located in the primary (hypergonadotropic), affecting the testes;
lower abdomen or inguinal canal because only the secondary (hypogonadotropic), affecting the hypo
INSL3-dependent transabdominal passage of testes thalamic-pituitary function; or both.
Disorders Causing Primary Hypogonadism Several cell damage is often compensated for by elevated LH.
congenital or developmental conditions compromise The mechanisms for the damage include decreased
the function of testicular parenchyma, including sup basal and LH-stimulated Leydig cell signal transduc
pressed capacity to produce T (see Chap. 9). Some of tion and inhibition of the RORa signaling pathway,
them are due to chromosomal anomalies, with the where inhibition of this clock gene suppresses ste
best known among them being Klinefelter syndrome roidogenic enzyme expression. Cranial irradiation
(47,XXY).48 After puberty, patients develop hypergo may lead to gonadotropin deficiency and secondary
nadotropic hypogonadism with Leydig cell hyperpla hypogonadism.
sia and degeneration and hyalinization of seminiferous Cancer chemotherapy has major effects on testicu
tubules. Transcriptome analyses have revealed dis lar function.53 It may either affect the testis directly or
turbed maturation of Sertoli and Leydig cells in the through actions at the hypothalamic-pituitary level.
testes of patients with Klinefelter syndrome.49 Spermatogenesis is more sensitive to the toxic effects
Down syndrome (chromosome 21 trisomy) is of chemotherapeutic agents than T production, and
associated with mild hypergonadotropic hypo only high doses lead to serious Leydig cell damage;
gonadism and germ cell hypoplasia.50 A similar mild damage can be compensated for by elevated LH.
reproductive phenotype with hypergonadotropic It is possible that Leydig cell dysfunction in these cases
hypogonadism and Leydig cell hypoplasia is found is a consequence of the germinal cell damage, and it
in Noonan syndrome (disrupted RAS-MAPK signal often recovers following chemotherapy.
ing pathway).51 Several drugs interfere with T production, metab
Other conditions with variable primary hypogo olism, or action. They include the cholesterol-lowering
nadism include maldescended testes and bilateral con medications (statins and HMG-CoA reductase inhib
genital anorchia. Acquired causes of primary testicular itors), because they lower the level of the mandatory
failure include surgical castration, testicular torsion, or substrate for androgen production. However, the
testicular trauma. Orchitis, usually caused by mumps small suppression in serum T brought about by them
virus, brings about atrophy of Leydig cells and germi is unlikely of clinical significance.54 Steroid synthesis
nal epithelium. Varicoceles are common among healthy inhibitors (aminoglutethimide, ketoconazole), by virtue
men and are usually an incidental finding on scro of their mechanisms of action, bring about substantial
tal examination—their clinical significance remains suppression of T production. Spironolactone inhibits
unclear. The detrimental effect of large varicoceles on several steroidogenic enzymes and also functions as an
spermatogenesis and decreased Leydig cell function AR antagonist. Chronic glucocorticoid treatment sup
is assumed to result from the associated poor venous presses T production by combined inhibition of gonad
drainage and increase in testicular temperature. At the otropin secretion and testicular steroidogenesis. It was
molecular level, varicocele has been shown to decrease recently demonstrated that ibuprofen reduces Leydig
testicular DNA polymerase activity and increase cell cell sensitivity to LH stimulation, inducing a condition
apoptosis and reactive oxygen species (ROS), all of reminiscent of compensated hypogonadism with a nor
which have detrimental effects on testicular function. mal T and increased LH/T ratio.55 Hypothetically, the
Hypogonadism in men with HIV infection is likely use of cyclooxygenase (COX) inhibitor-type pain kill
multifactorial and related to comorbidities, chronic ers may amplify the borderline impairment of Leydig
inflammation, illicit drugs, and changes in body compo cell function (e.g., with aging) and accelerate the transit
sition.52 The testicular effect is probably caused by direct from compensated to real hypogonadism. Withdrawal
inhibitory actions of tumor necrosis factor alpha (TNF from prolonged abuse of anabolic-androgenic steroids
alpha) and interleukin-1 (IL-1) that are upregulated in typically causes secondary hypogonadism. Alcohol
HIV infection. However, normal or suppressed gonad abuse brings about primary damage of testis tissue,
otropin concentrations indicating secondary hypogo including Leydig cells.
nadism are more common in HIV-infected men. T production decreases during aging, but it seldom
Although spermatogenic cells are more sensitive to reaches clearly hypogonadal levels.56,57 The decrease
radiation than Leydig cells, the latter may also expe usually occurs as a combined consequence of aging,
rience damage from high doses,53 and mild Leydig obesity, and comorbidities and often expresses a
mixture of primary and secondary hypogonadism. deposits in pituitary gonadotropin leading to sup
However, the component caused purely by chronolog pressed LH and FSH secretion, but testicular damage
ical aging seems to be a primary decrease of Leydig due to iron deposition has also been described.
cell capacity to produce T.56 Both acute and chronic systemic illness and chronic
Hypogonadism in myotonic dystrophy 1 and 2, organ failure affect androgen production at multiple
caused by a CTG repeat expansion in the DMPK gene levels of the HPT axis, and the causative factor may
in the former and a CCTG repeat in the CNBP gene in be the illness itself or its treatment (e.g. opioids).61
the latter, is usually of the primary type and associated The associated hypogonadism is usually multifac
with testicular atrophy, myotonia, loss of muscle mass, torial due to weight loss, stress, inflammation, spe
and visceral obesity.58 cific medications, and infection that influence the
Primary gonadal dysfunction is common in men HPT function at multiple levels. One mechanism in
with chronic and end-stage kidney disease. Serum T acute illness is the inhibitory role of proinflamma-
concentrations are also low in chronic obstructive pul tory cytokines (IL1, IL6, TNFa) at the testicular and
monary disease, which is aggravated by glucocorticoid hypothalamic levels.
treatment. The pathogenetic mechanism may involve
Effects of Lifestyle and Environment Diet and exercise
a direct inhibitory effect of hypoxia on testicular func
can influence HPT function. Fasting-induced suppres
tion. In rheumatoid arthritis, serum T concentration is
sion of the HPT axis is caused by reduced hypothalamic
consistently suppressed, but both elevated and normal/
GnRH release.62 Although more common in females,
suppressed gonadotropin levels have been reported.
anorexia nervosa, with consequent HH, also occurs in
males. Reduced leptin and kisspeptin levels contribute
Disorders Causing Secondary Hypogonadism Sev to the disruption of GnRH pulse generator function.
eral complex genetic syndromes cause secondary Similar effects can be observed in men during excessive
hypogonadism. These include the Bardet-Biedl and physical training, which suppresses gonadotropin lev
Prader-Willi syndromes, which are characterized by els, at least partly, through GnRH suppression by the
obesity, metabolic syndrome, HH, and other congen stress-associated increase of cortisol.63 T suppression is
ital anomalies.59 particularly common in athletes who overtrain.
Acquired causes of HH include pituitary and hypo Overweight and obesity are common lifestyle factors
thalamic tumors, granulomatous and infiltrative dis with negative impact on T levels, leading in extreme
eases, traumatic brain injury, vascular compromise, cases to HH.64 In overweight and obese men, total T
surgical hypophysectomy, and cranial irradiation. Fur decreases concomitantly with decreased SHBG, whereas
thermore, various medications can cause HH, such free T becomes suppressed only in massive obesity. No
as treatment with GnRH analogs, withdrawal from concomitant LH increase occurs in obese men, indi
anabolic-androgenic steroids, and opiates. The latter cating that their hypogonadism is secondary. Causes of
suppress T production by inhibiting GnRH secretion. secondary hypogonadism in obese men are still incom
Dopamine antagonists like metoclopramide decrease pletely understood. It is apparent that the multiple adi-
serum T concentrations by causing hyperprolactin pokines produced by fat cells, including leptin, play
emia, which has an inhibitory effect on gonadotropin a role. Other contributors to hypogonadism in obese
secretion. men include proinflammatory cytokines produced by
The hypogonadism associated with spinal cord fat tissue (e.g., TNFa, IL-2, and IL-6), central nervous
injury is generally at the hypothalamic level. Pituitary system endocannabinoids, and central insulin resis
dysfunction in vasculitis is a rare cause of secondary tance. Increased adipose tissue estrogen production and
hypogonadism. increased feedback inhibition of GnRH-gonadotropin
Hypogonadism in men with sickle cell disease secretion are less important.65 Similar alterations in HPT
can be both primary and secondary,60 due to sick function occur in sleep apnea.
ling and occlusion of vessels in the testes and in the The endocrine-disrupting chemicals (EDC), such
pituitary. Iron overload diseases (hemochromatosis as bisphenol A, phthalates, polychlorinated phenols,
and beta-thalassemia) cause HH mainly due to iron dioxin, and some pesticides, may exert inhibitory
effects on Leydig cell androgen production and REFERENCES

action. Some EDCs are estrogenic or antiandro-
1. Kaprara A, Huhtaniemi IT. The hypothalamus
genic at high concentrations, often orders of mag
pituitary-gonadal axis: Tales of mice and men. Metabo
nitude higher than routine environmental exposure.
lism. 2018;86:3.
Even though several studies have reported correla 2. Watts AG. 60 years of neuroendocrinology: The struc
tions between EDC levels and harmful reproductive ture of the neuroendocrine hypothalamus: The neu-
effects (e.g., anogenital distance and sperm counts) roanatomical legacy of Geoffrey Harris. J. Endocrinol.
in experimental animals and humans, the causal 2015;226:T25-T39.
link of EDCs in inhibition of T production or action 3. Dudas B, Merchenthaler I. Three-dimensional repre
in the general population has not been established, sentation of the neurotransmitter systems of the human
and epidemiological data on their adverse effects on hypothalamus: Inputs of the gonadotrophin hor-
male reproductive health remain controversial.66 mone-releasing hormone neuronal system. J Neuroen-
docrinol. 2006;18:79.
4. Herbison AE. Physiology of the adult gonadotropin
Key Points releasing hormone neural network. In Plant TM,
Zeleznik AJ, eds. Knobil and Neills Physiology of
1. Androgens are quintessential for the structure and Reproduction. 4th ed. Waltham, MA: Academic Press;
function of all aspects of the male phenotype. 2015:399.
2. Disorders of androgen function result in hypogo 5. Skorupskaite K, George JT, Anderson RA. The kiss-
nadism, defined as impairment of testicular andro peptin-GnRH pathway in human reproductive health
gen production or action, expressed as deficient and disease. Hum Reprod Update. 2014;20:485.
androgen-driven masculine development and 6. Hrabovszky E. Neuroanatomy of the human hypo
function, including spermatogenesis. thalamic kisspeptin system. Neuroendocrinology.
2014;99:33.
3. Testosterone (T) is the main testicular androgenic
7. Moore AM, Coolen LM, Porter DT, Goodman RL,
steroid hormone, and it is produced in Leydig cells
Lehman MN. KNDy cells revisited. Endocrinology.
present in the testicular intertubular interstitial
2018;159:3219.
space.
8. Millar RP, Lu ZL, Pawson AJ, Flanagan CA, Morgan K,
4. The hypothalamic-pituitary-testicular (HPT) axis Maudsley SR. Gonadotropin-releasing hormone recep
forms the functional regulatory circuit of endocrine tors. Endocr Rev. 2004;25:235.
regulation of testicular function. At the hypotha 9. Clarkson J, Han SY, Piet R, et al. Definition of the hypo
lamic level, kisspeptin stimulates the secretion of thalamic GnRH pulse generator in mice. Proc Natl Acad
gonadotropin-releasing hormone (GnRH), which Sci U.S.A. 2017;114:E10216.
stimulates gonadotropin (LH and FSH) synthesis 10. Naor Z, Huhtaniemi I. Interactions of the GnRH recep
and secretion in the pituitary gland. tor with heterotrimeric G proteins. Front Neuroendocri-
5. LH stimulates Leydig cell T production, which, after nol. 2013;34:88.
conversion to estradiol (E2), exerts a negative feed 11. Thompson IR, Kaiser UB. GnRH pulse frequency
back effect on the hypothalamic-pituitary level to dependent differential regulation of LH and FSH gene
maintain functional equilibrium of the HPR axis. expression. Mol Cell Endocrinol. 2014;385:28.
6. T exerts its regulatory actions through binding 12. Bousfield GR, Dias JA. Synthesis and secretion of
to androgen receptors ubiquitously expressed gonadotropins including structure-function correlates.
throughout the body. Rev Endocr Metab Disord. 2011;12:289.
13. Fiete D, Srivastava V, Hindsgaul O, Baenziger JU. A
7. A part of T's action is exerted following its metabo
hepatic reticuloendothelial cell receptor specific for
lism to 5 a-di hydrotestosterone and E2.
SO4-4GalNAc beta l,4GlcNAc beta l,2Man alpha
8. The causes of hypogonadism include mutations that mediates rapid clearance of lutropin. Cell. 1991;
in genes regulating HPT function (hormones, tran 67:1103.
scription factors, receptors, metabolic enzymes); 14. Troppmann B, Kleinau G, Krause G, Gromoll J.
other diseases indirectly impairing the HPT func Structural and functional plasticity of the luteinizing
tion; and iatrogenic, acquired, and environmental hormone/choriogonadotrophin receptor. Hum Reprod
factors. Update. 2013;19:583-602.
15. De Pascali F, Trefier A, Landomiel F, et al. Follicle-stim 30. MacConell LA, Leal AM, Vale WW. The distribution
ulating hormone receptor: Advances and remaining of betaglycan protein and mRNA in rat brain, pituitary,
challenges. Int Rev Cell Mol Biol. 2018;338:l. and gonads: Implications for a role for betaglycan in
16. Tremblay JJ. Molecular regulation of steroidogenesis in inhibin-mediated reproductive functions. Endocrinol
endocrine Leydig cells. Steroids. 2015; 103:3. ogy. 2002;143:1066.
17. Papadopoulos V, Miller WL. Role of mitochondria in 31. Matsumoto T, Sakasi M, Okada M, et al. The andro
steroidogenesis. Best Pract Res Clin Endocrinol Metab. gen receptor in health and disease. Annu Rev Physiol.
2012;26:771. 2013;75:201.
18. Fluck CE, Pandey AV. Steroidogenesis of the testis 32. Gottlieb B, Beitel LK, Nadarajah A, Paliouras M, Trifiro
-- New genes and pathways. Ann Endocrinol (Paris). M. The androgen receptor gene mutations database:
2014;75:40. 2012 update. Hum Mutat. 2012;33:887.
19. O’Shaughnessy PJ, Antignac JP, Le Bizec B, et al. Alterna 33. Sutinen P, Malinen M, Palvimo J. Androgen receptor. In
tive (backdoor) androgen production and masculiniza Simoni M, Huhtaniemi I, eds. Endocrinology of the Testis
tion in the human fetus. PLoS Biol. 2019;17(2):e3000002. and Male Reproduction. Cham, Switzerland: Springer;
20. Ruokonen A, Laatikainen T, Laitinen EA, Vihko R. Free 2017:395.
and sulfate-conjugated neutral steroids in human testis 34. Fix C, Jordan C, Cano P, Walker WH. Testosterone acti
tissue. Biochemistry. 1972;11:1411. vates mitogen-activated protein kinase and the cAMP
21. Leinonen P, Ruokonen A, Kontturi M, Vihko R. Effects response element binding protein transcription factor in
of estrogen treatment on human testicular unconju Sertoli cells. Proc Natl Acad Sci U.S.A. 2004; 101:10919.
gated steroid and steroid sulfate production in vivo. 35. Pi M, Nishimoto SK, Quarles LD. GPRC6A: Jack
I Clin Endocrinol Metab. 1981;53:569. of all metabolism (or master of none). Mol Metab.
22. Oduwole 00, Vydra N, Wood NE, et al. Overlapping 2017;6:185-193.
dose responses of spermatogenic and extragonadal tes 36. Aguirre RS, Eugster EA. Central precocious puberty:
tosterone actions jeopardize the principle of hormonal From genetics to treatment. Best Pract Res Clin Endocri
male contraception. FASEB J. 2014;28:2566. nol Metab. 2018;32:343.
23. Martikainen H, Huhtaniemi I, Vihko R. Response of 37. Maione L, Dwyer AA, Francou B, et al. Genetics in endo
peripheral serum sex steroids and some of their pre crinology: Genetic counseling for congenital hypogonad-
cursors to a single injection of hCG in adult men. Clin otropic hypogonadism and Kallmann syndrome: New
Endocrinol (Oxf). 1980;13:157. challenges in the era of oligogenism and next-generation
24. Hammond GL. Plasma steroid-binding proteins: Pri sequencing. Eur J Endocrinol. 2018;178:R55.
mary gatekeepers of steroid hormone action. J Endocri 38. Chevrier L, Guimiot F, de Roux N. GnRH receptor
nol. 2016;230:R13. mutations in isolated gonadotropic deficiency. Mol Cell
25. Vicari E, Mongioi A, Calogero AE, et al. Therapy with Endocrinol. 2011;346:21.
human chorionic gonadotrophin alone induces sper 39. Huhtaniemi I. Male hypogonadism resulting from
matogenesis in men with isolated hypogonadotrophic mutations in the genes for the gonadotropin subunits
hypogonadism-long-term follow-up. Int J Androl. 1992; and their receptors. In Winters SJ, Huhtaniemi IT, eds.
15:320. Male Hypogonadism: Basic, Clinical and Therapeu
26. Page ST, Amory JK, Bremner WJ. Advances in male tic Principles. 2nd ed. Cham, Switzerland: Springer;
contraception. Endocr Rev. 2008;29:465. 2017:127.
27. McLachlan RI, Matsumoto AM, Burger HG, de Kretser 40. Achard C, Courtillot C, Lahuna O, et al. Normal sper
DM, Bremner WJ. Relative roles of follicle-stimulating matogenesis in a man with mutant luteinizing hormone.
hormone and luteinizing hormone in the control N Engl J Med. 2009;361:1856.
of inhibin secretion in normal men. J Clin Invest. 41. Oduwole OO, Peltoketo H, Poliandri A, et al. Consti
1988;82:880. tutively active follicle-stimulating hormone receptor
28. Hayes FJ, Pitteloud N, DeCruz S, Crowley WF Jr, Boep- enables androgen-independent spermatogenesis. J Clin
ple PA. Importance of inhibin B in the regulation of FSH Invest. 2018;128:1787.
secretion in the human male. J Clin Endocrinol Metab. 42. Tapanainen JS, Aittomaki K, Min J, Vaskivuo T, Huhta
2011;86:5541. niemi IT. Men homozygous for an inactivating mutation
29. Pierik FH, Vreeburg JT, Stijnen T, De Jong FH, Weber of the follicle-stimulating hormone (FSH) receptor gene
RF. Serum inhibin B as a marker of spermatogenesis. present variable suppression of spermatogenesis and
J Clin Endocrinol Metab. 1998;83:3110. fertility. Nat Genet. 1997; 15:205.
43. Huhtaniemi I. Mechanisms in endocrinology: Hor A systematic review and meta-analysis of randomized
monal regulation of spermatogenesis: Mutant mice chal controlled trials. BMC Med. 2013; 11:57.
lenging old paradigms. Eur J Endocrinol. 2018;179:R143. 55. Kristensen DM, Desdoits-Lethimonies C, Mackey AL,
44. Auchus RJ, Miller WL. Defects in androgen biosynthesis et al. Ibuprofen alters human testicular physiology to
causing 46,XY disorders of sexual development. Semin produce a state of compensated hypogonadism. Proc
Reprod Med. 2012;30:417. Natl Acad Sci U.S.A. 2018;115:E715.
45. Mongan NP, Tadokoro-Cuccaro R, Bunch T, Hughes IA. 56. Wu FCW, Tajar A, Beynon JM, et al. Identification of
Androgen insensitivity syndrome. Best Pract Res Clin late-onset hypogonadism in middle-aged and elderly
Endocrinol Metab. 2015;29:569. men. N Engl J Med. 2010;363:123.
46. Rajender S, Singh L, Thangaraj K. Phenotypic hetero 57. Kaufman JM, Lapauw B, Mahmoud A, T’Sjoen G, Huht
geneity of mutations in androgen receptor gene. Asian J aniemi IT. Aging and the male reproductive system.
Androl. 2007;9:147. Endocr Rev. 2019;40:906.
47. Huhtaniemi IT, Pye SR, Limer KL, et al. Increased estro 58. Iglesias P, Carrero JJ, Diez JJ. Gonadal dysfunction in
gen rather than decreased androgen action is associ men with chronic kidney disease: Clinical features,
ated with longer androgen receptor CAG repeats. J Clin prognostic implications and therapeutic options.
Endocrinol Metab. 2009;94:277. J Nephrol. 2012;25:31.
48. Gravholt CH, Chang S, Wallentin M, Fedder J, Moore P, 59. Akinola OB, Gabriel MO. Neuroanatomical and molec
Skakkebsek A. Klinefelter syndrome: integrating genet ular correlates of cognitive and behavioural outcomes in
ics, neuropsychology, and endocrinology. Endocr Rev. hypogonadal males. Metab Brain Dis. 2018;33:491.
2018;39:389. 60. Huang AW, Muneyyirci-Delale O. Reproductive endo
49. Winge SB, Dalgaard MD, Belling KG, et al. Transcrip crine issues in men with sickle cell anemia. Andrology.
tome analysis of the adult human Klinefelter testis and 2017;5:679.
cellularity-matched controls reveals disturbed differ 61. Kalyani RR, Gavini S, Dobs AS. Male hypogonadism
entiation of Sertoli- and Leydig cells. Cell Death Dis. in systemic disease. Endocrinol Metab Clin North Am.
2018;9:586. 2007;36:333.
50. Suzuki K, Nakajima K, Kamimura S, et al. Eight case 62. Bergendahl M, Veldhuis JD. Altered pulsatile gonado
reports on sex-hormone profiles in sexually mature tropin signaling in nutritional deficiency in the male.
male Down syndrome. Int J Urol. 2010; 17:137. Trends Endocrinol Metab. 1995;6:145.
51. Ankarberg-Lindgren C, Westphal O, Dahlgren J. Tes 63. Breen KM, Karsch FJ. New insights regarding gluco
ticular size development and reproductive hormones in corticoids, stress and gonadotropin suppression. Front
boys and adult males with Noonan syndrome: A longi Neuroendocrinol. 2006;27:233.
tudinal study. Eur J Endocrinol. 2011;165:137. 64. Fui MN, Dupuis P, Grossmann M. Lowered testosterone
52. Wong N, Levy M, Stephenson I. Hypogonadism in in male obesity: Mechanisms, morbidity and manage
the HIV-infected man. Curr Treat Options Infect Dis. ment. Asian J Androl. 2014;16:223.
2017;9:104. 65. Grossmann M. Hypogonadism and male obesity:
53. Mitchell RT, Stukenborg J-B, Jahnukainen K. Male Focus on unsolved questions. Clin Endocrinol (Oxf).
hypogonadism due to cancer and cancer treatments. 2018;89:ll.
In Winters SJ, Huhtaniemi IT, eds. Male Hypogonad 66. Lymperi S, Giwercman A. Endocrine disruptors and tes
ism: Basic, Clinical and Therapeutic Principles. 2nd ed. ticular function. Metabolism. 2018;86:79.
Cham, Switzerland: Springer; 2017:235. 67. Teerds KJ, Huhtaniemi IT. Morphological and func
54. Schooling CM, Au Yeung SL, Freeman G, Cowling BJ. tional maturation of Leydig cells: From rodent models
The effect of statins on testosterone in men and women: to primates. Hum Reprod Update. 2015;21:310.
Pathophysiology of
Erectile Dysfunction
Chirag N. Dave, Arthur L. Burnett, and Amin S. Herati
INTRODUCTION ■ Nitric oxide (NO) activates guanylate cyclase to gen

erate cyclic guanosine monophosphate (cGMP),
Erectile dysfunction (ED) refers to the inability to leading to sequestration of calcium and smooth
achieve or maintain an erection that is sufficient for muscle relaxation
satisfactory intercourse. It is multidimensional and ■ Phosphodiesterase type 5 (PDE5) inhibitors act by
can arise from organic, relational, and/or psychogenic inhibiting PDE5 and increasing cGMP concentrations
causes.1 The Massachusetts Male Aging Study (MMAS)
reported a 52% prevalence of mild to moderate ED in
men aged 40 to 70, and ED was found to be associated
with age, health status, and emotional function.2,3 ED The penis is composed of 3 cylindrical bodies, the
has detrimental effects on partner satisfaction and the paired communicating corpora cavernosa dorsally, and
couples quality of life. It was previously believed that the corpus spongiosum ventrally. The corpus spongio
most ED was psychogenic; however, more recent evi sum surrounds the urethra and is continuous with the
dence shows that roughly 80% of ED is organic.3 ED glans penis. These cylinders are encased by the dense,
may be a manifestation of endothelial dysfunction. bilayered tunica albuginea, which is relaxed in the flac
Cardiovascular disease, poor general health status, cid state and stretched in the erect state. All 3 corpo
diabetes, smoking, medications, and socioeconomic ral bodies are surrounded by Bucks (deep) and Dartos
status are well-established risk factors for ED. Identi (superficial) fascia. The bulbospongiosus and ischio-
fication of these comorbid conditions offers the men’s cavernosus muscles surround the base of the penis and
health provider an opportunity to diagnose and inter contribute to erection and ejaculation (Fig. 2-1).4
vene on conditions that may otherwise be asymptom The arterial supply to the penis is derived from
atic. This chapter includes a brief discussion of the the internal pudendal artery, which is a branch of
physiology of erection as it relates to a more complex the internal iliac artery. The internal pudendal artery
discussion of the pathophysiology of ED. traverses Alcock canal before dividing into the bulbo
urethral, dorsal, and cavernosal arteries. The venous
PHYSIOLOGY OF ERECTILE drainage of the penis is via the deep and superficial
FUNCTION veins.
The penis is basally in a flaccid state, which is
Key Points: Physiology of Erection mediated by smooth muscle contraction as a result of
sympathetic stimulation, myogenic control, and endo
■ Erections are the result of neural activation, cav- thelium-derived contracting factors such as prosta
ernosal smooth muscle relaxation, increased penile glandin.3 Normal erectile function requires an intact
blood flow, and venous occlusion. somatic and autonomic nervous system.
21
Bladder
,.\&r Rectovesical pouch
Prostate
Pubic
symphysis Rectum
Suspensory Urogenital diaphragm

ligament of penis
Corpus
cavernosum
Urethra
Corpus
spongiosum
Corpus
Glans penis spongiosum
Fascia of
Fossa Denonvilliers
Scrotal septum
navicularis
Scarpa’s
fascia
Tunica albuginea
Corpora cavernosa Buck’s Buck’s

fascia fascia
Colles’
fascia
Corpus spongiosum Colles’ fascia
Urethra
Dartos fascia
FIGURE 2-1. Pelvic and penile anatomy. Top: Relations of the bladder, prostate, seminal vesicles, penis, urethra, and scrotal contents.
Lower left: Transverse section through the penis. The paired upper structures are the corpora cavernosa. The single lower body
surrounding the urethra is the corpus spongiosum. Lower right: Fascial planes of the lower genitourinary tract.
Three types of physiological erections exist and of the penis, which creates afferent signals to spinal
include psychogenic, reflexogenic, and nocturnal centers with autonomic response via the cavernous
erections. Psychogenic erections occur with audi nerves, which induce erection. Nocturnal erections
tory or visual erotic stimuli, which cause supraspinal occur during rapid eye movement (REM) sleep where
impulses to stimulate spinal erection centers to ini cholinergic neurons in the lateral pontine area, amyg
tiate the erectile process reviewed later. In contrast, dala, and anterior cingulate gyrus are stimulated with
reflexogenic erections result from tactile stimulation decreased activity in the prefrontal and parietal cortex.
Chapter 2 PATHOPHYSIOLOGY OF ERECTILE DYSFUNCTION 23
■ ED is a manifestation of generalized atherosclerosis

and endothelial dysfunction; therefore, men with
ED should be screened for cardiovascular disease
(CVD) risk.
■ Many commonly used drugs, such as antihyperten
sives, antiandrogens, and antidepressants, are asso
ciated with ED.
Several classification schemes for ED have been pro

posed and are based on either the etiology or the
FIGURE 2-2. Regulation of smooth muscle relaxation and mechanism of ED. The International Society for Sex
mechanism of action of PDE5 inhibitors. Legend: GTP, guanosine ual Medicine has recommended the following classifi
triphosphate; cGMP, 3'5'-cyclic guanosine monophosphate;
5-GMP, 5'guanosine monophosphate; PDE5, phosphodiesterase cations for male ED (Table 2-1).1
5; PKG, protein kinase G; ATP, adenosine triphosphate; ADP,
adenosine diphosphate; protein-P, phosphorylated protein. Vasculogenic Erectile Dysfunction
(Reproduced with permission from Corbin JD: Mechanisms of action of PDE5
inhibition in erectile dysfunction, IntJImpotRes. 2004 Jun;l 6 Suppl 1:S4-S7.)
Vasculogenic ED is the most common
etiology for
organic ED and is related to arterial insufficiency of
With sexual stimulation, acetylcholine is released the hypogastric-cavernous-helicine arterial tree. Ste
from parasympathetic nerve fibers and NO from nosis leads to decreased perfusion pressure, increas
nonadrenergic noncholinergic (NANC) nerve fibers. ing the time to maximal erection and decreasing the
The ensuing cascade of signaling pathways leads to rigidity of the erect penis. Traumatic vascular injury to
an increase in the second messenger, cGMP, and, to the common penile or cavernous artery during pelvic
a lesser degree, cyclic adenosine monophosphate trauma or surgery can compromise blood flow to the
(cAMP), and eventually decreased intracellular Ca2+ penis and cause ED. Pelvic radiation and long-distance
and smooth muscle relaxation.5 This allows net inflow cycling are also associated with ED.6,7 However, much
of blood into the corpora cavernosa and simultaneous more commonly, vasculogenic ED is part of a gener
compression of subtunical venules, creating venooc- alized atherosclerotic process. Arteriography studies
clusion and erection. The process is reversed when performed by Levine et al. showed diffuse narrowing
cGMP is hydrolyzed by PDE5. Additionally, RhoA, a of the internal pudendal, common penile, and cavern
small monomeric GTPase, activates Rho-associated ous arteries in men with ED and atherosclerosis.8,9
protein kinase (ROCK), which promotes contraction. As ED is often a surrogate marker of endothelial
Various studies have hypothesized that inhibition of and cardiovascular dysfunction, men with ED, even if
ROCK causes smooth muscle relaxation in the penis, they do not have symptoms of CVD, should undergo
thereby enhancing penile erection.6 Disruption of any cardiac evaluation in conjunction with the initiation
of these processes can lead to ED (Fig. 2-2). of treatment for ED, as coronary artery disease and ED
arise on a similar timeline and share common risk fac
CLASSIFICATION AND tors.9 Moreover, penile Doppler ultrasound findings
PATHOPHYSIOLOGY OF MALE of reduced cavernosal artery peak systolic velocity
ERECTILE DYSFUNCTION (PSV), cavernosal artery intima-medial thickness, and
calcification of the cavernosal artery should further
Key Points: Pathophysiology of Erectile raise suspicion of underlying CVD.9
Dysfunction The risk of developing ED is increased in men
with hypertension (odds ratio [OR] 1.35, 95% con
■ Prevalence of ED increases with age, and ED is fidence interval [CI] 0.13-1.84) and the risk is even
a symptom of many underlying conditions and higher in men with hypertension on medications
diseases. (OR 3.04, 95% CI 1.98-4.67), cigarette smoking (OR
TABLE 2-1. Classifications of Erectile Dysfunction hypertension, and fasting blood glucose (>110 mg/dL).
Metabolic syndrome is a risk factor for ED indepen
Organic dent of its individual components.10 The end result of
I. Vasculogenic all vasculogenic ED, regardless of etiology, is hypoxia
A. Arteriogenic from reduced corpora cavernosa oxygenation, which
B. Cavernosal decreases prostaglandin E levels and increases pro-fi-
C. Mixed brotic cytokines, promoting collagen deposition and
II. Neurogenic decreased elasticity of the penis and veno-occlusive
III. Anatomic dysfunction.11
IV. Endocrinologic Veno-occlusive dysfunction refers to the failure of
Psychogenic
the subtunical and emissary veins to close. In addition
to the conditions listed earlier, it can result from trau
I. Generalized
matic injury to the tunica, such as in penile fracture,
A. Generalized unresponsiveness
severe Peyronie disease, or acquired surgical shunts
1. Primary lack of sexual arousability
created during the management of priapism.
2. Aging-related decline in sexual
arousability
Neurogenic Erectile Dysfunction
B. Generalized inhibition
1. Chronic disorder of sexual intimacy Neurogenic ED accounts for 10% to 19% of ED and
II. Situational can result from any deficit in nerve signaling from
A. Partner-related
the central nervous system (CNS) to the corpora cav
ernosa and has been described with many diseases
1. Lack of arousability in specific relationship
affecting the brain, spinal cord, and cavernous and
2. Lack of arousability owing to sexual object
pudendal nerves.12 The end result is decreased neu
preference
ronal NO availability to smooth muscle. Apoptosis
3. High central inhibition owing to partner
of smooth muscle cells and endothelial cells of blood
conflict or threat
vessels, as well as collagenization of smooth muscle,
B. Performance-related
create structural changes that result in veno-occlusive
1. Associated with other sexual dysfunction/s
dysfunction (venous leak).5 The medial preoptic area,
(e.g. rapid ejaculation)
paraventricular nucleus, and hippocampus serve as
2. Situational performance anxiety (e.g. fear
the integration centers in the brain for sexual drive
of failure)
and erection.3 A cerebrovascular accident, Parkinson
C. Psychological distress- or adjustment-related
disease, encephalitis, and temporal lobe epilepsy are
1. Associated with negative mood state (e.g.
disease states that can affect these brain regions and
depression) or major life stress (e.g. death
are associated with ED. Parkinson disease is likely also
of partner)
related to ED due to an imbalance in dopamine path
ways. Shy-Drager syndrome (also known as multiple
system atrophy) is a rare neurodegenerative disorder
that is characterized by the presence of parkinson
1.4, 95% CI 13-1.6), dyslipidemia (OR 1.83, 95% CI ism; however, for many men with this syndrome the
0.76-2.57), and diabetes (OR 2.57, 95% CI 1.3-3.9).3 first presentation is ED. CNS tumors, traumatic brain
The prevalence of ED in diabetic men increases with injury, and vascular dementia and Alzheimer demen
age, concurrent peripheral or autonomic neuropathy, tia can be associated with ED as well.
retinopathy, and poor glycemic control.5 Metabolic The spinal cord contains efferent and afferent path
or insulin-resistance syndrome is a constellation dis ways responsible for erections, ejaculation, and orgasm.
order that includes waist circumference greater than ED can be seen in spinal cord injury and is often
102 cm, high-density lipoprotein cholesterol less affected by the location and extent of the injury. The
than 40 mg/dL, hypertriglyceridemia (>150 mg/dL), sacral parasympathetic pathway plays an important
role in reflexogenic erections, which are preserved in The association between serum testosterone levels and
approximately 95% of complete upper cord lesions ED, however, is more complex. A 2017 meta-analysis
above spinal level T10, whereas they are preserved in inclusive of 14 studies and 2298 patients by Corona
only 25% of lower cord lesions, most commonly at the et al. showed testosterone therapy in hypogonadal men
S2-S4 spinal levels.13 Other diseases of the spinal cord, was associated with a dose-dependent improvement
such as spina bifida, disc herniation, syringomyelia, in erectile function. The authors found a lower magni
multiple sclerosis, spinal cord tumors, and transverse tude of effect of testosterone therapy on erectile func
myelitis, can also be associated with ED. tion when it was administered in the context of other
Iatrogenic injury to the peripheral cavernous nerve metabolic derangements, namely obesity and diabe
from pelvic surgery is a common cause of ED due to tes.21,22 In contrast, a randomized trial of sildenafil plus
the proximity of the cavernous nerves to the pelvic testosterone was not superior to sildenafil plus placebo
organs. High rates of ED have been recorded with rad in men with ED and hypogonadism.22 It is well known,
ical prostatectomy, abdominal perineal resection, and however, that men on long-term androgen depriva
external sphincterotomy.5,14 Postprostatectomy ED tion therapy for prostate cancer complain of ED and
is observed in up to 82% of men.15 Improved under low libido. A recent animal study by Huh et al. showed
standing of pelvic neuroanatomy has led to a signifi the impact of long-term castration in adult male rats.
cant improvement in postoperative erectile function. The authors found reduced penile length, girth, cav-
Nerve-sparing prostatectomy techniques have been ernosal smooth muscle content, and decreased endo
developed with significantly lower ED rates (32%).16 thelial NO synthase activity in the castrated adult male
Diabetes is a well-established risk factor for ED rats compared to controls. These effects were reversed
(OR 2.57), and ED often presents at an earlier age in following 4 weeks of testosterone therapy.23,24 In addi
this patient population.17 Diabetes causes autonomic tion to its potential effects on endothelial NO pro
neuropathy and progressive demyelination of the cav duction, testosterone may have a role in male pelvic
ernous nerve. In addition to the neurogenic aspects of thrust and may relax the penile artery and cavernous
diabetes, elevated blood glucose levels induce endo smooth muscle and increase penile blood flow.24 Men
thelial dysfunction with diminished production of with ED and decreased serum testosterone levels tend
NO.18 Thus, patients with diabetes suffer from neuro to be of advanced age and have uncontrolled diabetes,
genic and vascular ED. hyperlipidemia, and anemia, all of which are known
Sexual dysfunction is impaired in almost two- independent risk factors for ED. Waist circumference
thirds of men following pelvic fractures.19 Mecha was reported to be an important predictor of low tes
nisms for ED include cavernous nerve injury and tosterone and symptomatic testosterone deficiency.
disruption of adjacent vasculature. Clinicians should Altered function and levels of other hypothalamic-
have a high index of suspicion for urethral distraction pituitary hormones can result in ED. Hyperprolactin
injuries with pelvic fracture. Urethral injuries, as well emia, either from a prolactin-secreting tumor or from
as the subsequent repair, can further contribute to ED, medications, can cause inhibition of hypothalamic
though early endoscopic realignment has been associ gonadotropin-releasing hormone (GnRH) and low
ated with lower rates of ED.19 levels of testosterone. Similarly, hyperthyroidism is
associated with low libido, but not often ED. In con
trast, hypothyroidism is associated with ED due to ele
Endocrinological Causes of Erectile Dysfunction
vated prolactin and low testosterone levels.18
Testosterone is an important regulator of male sexual
behavior. In addition to its beneficial effect on bone
Psychogenic Erectile Dysfunction
health, fat deposition, mood, and vitality, testosterone
treatment enhances sexual interest and the frequency Psychogenic, nonorganic, or adrenaline-mediated ED
of sexual acts. Testosterone enhances the frequency was previously thought to be the most common form
and duration of nocturnal erections, which are thought of ED; however, recent literature shows that organic
to require a minimum threshold testosterone level ED is far more common than psychogenic ED.5 ED can
close to the lower limit of the normal male range.20 cause anxiety and social stress that can further impair
sexual function in future sexual encounters. Sexual TABLE 2-2. Common Medications Associated with
function is controlled in part by the hypothalamus, Erectile Dysfunction
cerebral cortex, and limbic system.5 Psychogenic ED
ANTIANDROGENS ANTIHYPERTENSIVES
is thought to arise from excessive sympathetic outflow
and circulating levels of catecholamines (primary anti- 5-alpha reductase Beta blockers
erectile neurotransmitter), as well as direct suprasacral inhibitors
inhibition of the spinal erection center by the brain.
LH-RH agonists/ Thiazide diuretics
This is evidenced by higher levels of serum norepi
antagonists
nephrine in patients with psychogenic ED compared
to vasculogenic ED and controls.25 In patients with H2 blockers Angiotensin-converting
schizophrenia, bipolar disorder, recurrent depressive (cimetidine) enzyme inhibitors
disorder, and substance abuse, ED prevalence was as
Psychiatric Drugs Spironolactone
high as 83%.25
Psychogenic ED is frequently situational, such as in Selective serotonin Miscellaneous
performance anxiety. It can also be partner-related and reuptake inhibitors
may relate to a lack of arousability in a specific rela
Antipsychotics Digoxin
tionship or high central inhibition secondary to part
ner conflict or threat.5 Psychogenic ED is frequently Benzodiazepines Opiates
associated with other sexual dysfunction, such as pre
mature ejaculation, and may be seen during periods
of major life stress, such as the death of a partner or and be associated with decreased serum testoster
during a major depressive episode. one levels, increased estrogen levels, and alcoholic
polyneuropathy.18
Drug-Induced Erectile Dysfunction
Benign Prostatic Hyperplasia/Lower Urinary
An estimated 25% of ED is drug related.26 It is often Tract Symptoms
difficult to differentiate medication-related ED from
disorders of desire, arousal, or orgasm or the under Benign prostatic hyperplasia affects almost two-thirds
lying disease process itself. Many medications list ED of men over the age of 65.28 The presence of lower uri
as a side effect, including almost all antihypertensive nary tract symptoms (LUTS) is an independent risk
medications. In the Treatment of Mild Hypertension factor for ED, although the exact mechanism is not
Study (TOMHS), patients were randomized to life clearly understood.29 Men being treated for ED with
style changes plus placebo or 5 different antihyper daily PDE5 inhibitors have reported improvement in
tensive medications from different classes. At 2 years LUTS, which led to the U.S. Food and Drug Admin
follow-up, the ED rates were 17.1% in the chlorthali istrations approval of daily tadalafil for ED/LUTS
done group vs. 8.1% in placebo. None of the other drug related to prostate enlargement, though no significant
classes had significant differences versus placebo.27 improvement in urinary flow rates were observed.30
Other drugs that have a well-established relation with Furthermore, LUTS arising from pelvic floor dysfunc
ED include most antidepressant medications, espe tion and/or chronic prostatitis/chronic pelvic pain
cially selective serotonin reuptake inhibitors (SSRIs), syndrome is often concomitant with ED. This suggests
digoxin, opiates, antiandrogens, spironolactone, keto possibly reduced blood flow in the internal pudendal,
conazole, and the H2 blocker cimetidine, but interest common penile, and cavernous arteries due to spasms
ingly not ranitidine or famotidine (Table 2-2).18 of the pelvic floor musculature as a cause of ED.31,32
Alcohol, even when consumed in small amounts,
Idiopathic/Genetic Causes of Erectile
can result in ED. Yet the mechanism for this effect is
Dysfunction
not well understood. Alcohol causes central sedation
and decreases libido, which may contribute to ED. The extent of genetic and genomic influence on erec
Alcoholism may also contribute to liver dysfunction tile function is largely unknown. Early twin studies by
Fischer et al. in middle-aged veterans estimated the 3. Yafi FA, Jenkins L, Albersen M, et al. Erectile dysfunc
heritability of ED at 3 5%.33,34 More recently, several tion. Nat Rev Dis Primers. 2016;2:16003. doi:10.1038/
genetic polymorphisms have been linked with ED. nrdp.2016.3
The vascular endothelial growth factor (VEGF) 2578A 4. Tanagho EA, Lue TF. Chapter 1. Anatomy of the geni
tourinary tract. In McAninch JW, Lue TF, eds. Smith &
allele carrier status in the Taiwanese population has
Tanaghos General Urology. 18th ed. New York, NY: The
been identified as a risk factor for ED (OR 1.54,95%
McGraw-Hill Companies; 2013.
CI 1.10-2.15).34 Two additional single nucleotide poly 5. Dean RC, Lue TF. Physiology of penile erection and
morphisms in the endothelial nitric oxide synthase pathophysiology of erectile dysfunction. Urol Clin North
(eNOS) gene, G894T (OR 1.55, 95% CI 1.06-2.28) Am. 2005;32(4):395. doi:I0.1016/j.ucl.2005.08.007
and T-786C (OR 1.68, 95% CI 1.341-2.102), were 6. Sopko NA, Hannan JL, Bivalacqua TJ. Understanding
identified in association with ED.35 Results of a large and targeting the rho kinase pathway in erectile dysfunc
genome-wide association study by Jorgenson et al. tion. Nat Rev Urol. 2014;l 1 (11):622-628. doi:I0.I038/
implicated a locus on chromosome 6 (rsl7185536-T) nrurol.2014.278
near the single-minded family basic helix-loop-helix 7. Goldstein I, Feldman MI, Deckers PJ, Babayan RK,
transcription factor 1 (SIM1) gene in 26% of men with Krane RJ. Radiation-associated impotence. A clinical
study of its mechanism. JAMA. 1984;251(7):903-910.
ED, independent of other known ED risk factors, such
8. Andersen KV, Bovim G. Impotence and nerve entrap
as body mass index (BMI).36,37 Mutations of the locus
ment in long distance amateur cyclists. Acta Neurol
were significantly associated with ED (OR 1.37 (95% Scand. 1997;95(4):233-240.
CI 1.31-1.43). 9. Levine FJ, Greenfield AJ, Goldstein I. Arteriographically
determined occlusive disease within the hypogastric-
cavernous bed in impotent patients following blunt per
CONCLUSION ineal and pelvic trauma. / Urol. 1990;144(5):l 147-1153.
10. Gupta N, Herati A, Gilbert BR. Penile Doppler ultra
The prevalence of ED increases with age and with sound predicting cardiovascular disease in men with
comorbid medical conditions, and ED has been rec erectile dysfunction. Curr Urol Rep. 2015; 16(3): 16.
ognized as a symptom of many underlying condi doi:10.I007/sl 1934-015-0482-1
tions and diseases. Endothelial dysfunction appears 11. Heidler S, Temml C, Broessner C, et al. Is the metabolic
to be a final pathway to ED in patients with diabetes, syndrome an independent risk factor for erectile dys
function? / Urol. 2007;177(2):651-654. doi: 10.1016/j.
hypertension, hyperlipidemia, and vascular disease.
juro.2006.09.043
Medications, psychogenic causes, and endocrine and
12. Nehra A, Goldstein I, Pabby A, et al. Mechanisms of
neurological disorders are other well-established venous leakage: A prospective clinicopathological cor
causes. More recently, idiopathic and genetic causes relation of corporeal function and structure. / Urol.
of ED have been identified. Emerging research in I996;156(4):1320-1329.
molecular biology, stem cells, growth factors, and sig 13. Steers WD. Neural control of penile erection. Semin
nal transduction will continue to progress our under Urol. 1990;8(2):66-79.
standing of the disease, ultimately leading to improved 14. Wermuth L, Stenager E. Sexual aspects of Parkin
patient outcomes. son’s disease. Semin Neurol. 1992;12(2):125-127.
doi:10.1055/s-2008-1041166
15. Nelson CJ, Scardino PT, Eastham JA, Mulhall JP. Back to
baseline: Erectile function recovery after radical pros
REFERENCES tatectomy from the patients’ perspective. / Sex Med.
1. Lizza EF, Rosen RC. Definition and classification of erec 2013;10(6):1636-1643. doi:10.1111/jsm.l2135
tile dysfunction: Report of the nomenclature committee 16. Walsh PC, Donker PJ. Impotence following radical
of the international society of impotence research. Int J prostatectomy: Insight into etiology and prevention. /
Imp ot Res. 1999;11 (3): 141 -143. Urol. 1982;128(3):492-497.
2. Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, 17. Quinlan DM, Epstein JI, Carter BS, Walsh PC. Sex
McKinlay JB. Impotence and its medical and psychoso ual function following radical prostatectomy: Influ
cial correlates: Results of the Massachusetts male aging ence of preservation of neurovascular bundles. J Urol.
study. J Urol. 1994;151(1):54-61. 1991;145(5):998-1002.
18. Kupelian V, Araujo AB, Chiu GR, Rosen RC, McKinlay 28. Grimm RH, Grandits GA, Prineas RJ, et al. Long-term
JB. Relative contributions of modifiable risk factors to effects on sexual function of five antihypertensive drugs
erectile dysfunction: Results from the Boston area com and nutritional hygienic treatment in hypertensive men
munity health (BACH) survey. Prev Med. 2010;50(l- and women. Treatment of mild hypertension study
2): 19-25. doi: 10.1016/j.ypmed.2009.11.006 (TOMHS). Hypertension. 1997;29:8-14.
19. Lue TF. Physiology of penile erection and pathophysi 29. Williams AM, Simon I, Landis PK, et al. Prostatic
ology of erectile dysfunction. In Wein AJ, Kavoussi LR, growth rate determined from MRI data: Age-related
Partin AW, Peters CA, eds. Campbell-Walsh Urology. longitudinal changes. J Androl. 1999;20(4):474-480.
11th ed. Philadelphia, PA: Elsevier; 2016:642.e9 30. Rosen R, Altwein J, Boyle P, et al. Lower urinary tract
20. Mouraviev VB, Coburn M, Santucci RA. The treatment symptoms and male sexual dysfunction: The multina
of posterior urethral disruption associated with pelvic tional survey of the aging male (MSAM-7). Eur Urol.
fractures: Comparative experience of early realignment 2003;44(6):637-649.
versus delayed urethroplasty. J Urol. 2005;173(3):873- 31. Me Vary KT, Roehrborn CG, Kaminetsky JC, et al. Tada-
876. doi:10.1097/01.ju.0000152145.33215.36 lafil relieves lower urinary tract symptoms secondary to
21. Beyer C, Gonzalez-Mariscal G. Effects of sex steroids on benign prostatic hyperplasia. J Urol. 2007;177(4): 1401 -
sensory and motor spinal mechanisms. Psychoneuroen- 1407. doi: 10.1016/j.juro.2006.11.037
docrinology. 1994;19(5-7):517-527. 32. Cohen D, Gonzalez J, Goldstein I. The role of pelvic floor
22. Corona G, Rastrelli G, Morgentaler A, Sforza A, Man- muscles in male sexual dysfunction and pelvic pain. Sex
nucci E, Maggi M. Meta-analysis of results of testosterone Med Rev. 2016;4(l):53-62. doi: 10.1016/j.sxmr.2015.10.001
therapy on sexual function based on international index 33. Anderson RU, Wise D, Sawyer T, Chan CA. Sexual dys
of erectile function scores. Eur Urol. 2017;72(6): 1000- function in men with chronic prostatitis/chronic pelvic
1011. doi:10.1016/j.eururo.2017.03.032 pain syndrome: Improvement after trigger point release
23. Spitzer M, Basaria S, Travison TG, et al. Effect of tes and paradoxical relaxation training. / Urol. 2006; 176(4
tosterone replacement on response to sildenafil citrate Pt 1):1539. doi:10.1016/j.juro.2006.06.010
in men with erectile dysfunction: A parallel, random 34. Fischer ME, Vitek ME, Hedeker D, Henderson WG,
ized trial. Ann Intern Med. 2012;157(10):681-691. Jacobsen SJ, Goldberg J. A twin study of erectile dys
doi:10.7326/0003-4819-157-10-201211200-00004 function. Arch Intern Med. 2004;164(2):165-168.
24. Huh JS, Chung BH, Hong CH, et al. The effects of tes doi: 10.1001 /archinte. 164.2.165
tosterone replacement on penile structure and erec 35. Lee Y, Huang S, Tsai C, et al. Associations of VEGF
tile function after long-term castration in adult male gene polymorphisms with erectile dysfunction and
rats. Int J Impot Res. 2018;30(3):122-128. doi:10.1038/ related risk factors. J Sex Med. 2017;14(4):510-517.
S41443-017-0010-6 doi: 10.1016/j.jsxm.2017.02.009
25. Granata AR, Rochira V, Lerchl A, Marrama P, Carani C. 36. Gao L, Zhao Z, Guo F, et al. Association of endo
Relationship between sleep-related erections and testos thelial nitric oxide synthase polymorphisms with an
terone levels in men. J Androl. 1997;18(5):522-527. increased risk of erectile dysfunction. Asian J Androl.
26. Kim SC, Oh MM. Norepinephrine involvement in 2017;19(3):330-337. doi:10.4103/1008-682X.163300
response to intracorporeal injection of papaverine in 37. Jorgenson E, Matharu N, Palmer MR, et al. Genetic varia
psychogenic impotence. 7 Urol. 1992;147(6):1530-1532. tion in the SIM 1 locus is associated with erectile dysfunc
27. Keene LC, Davies PH. Drug-related erectile dysfunc tion. Proc Natl Acad SciUS A. 2018;l 15(43): 11018-11023.
tion. Adverse Drug React Toxicol Rev. 1999;18(l):5-24. doi: 10.1073/pnas. 1809872115
The Pathophysiology
of Male Infertility
RamyAbou Ghayda and Martin Kathrins
INTRODUCTION spermatogenesis is around 70 days, with another few

weeks spent in transit through the genital ducts. Sper
The sperm is the smallest cell in the human body and matogenesis begins at puberty and persists through
likely one of the most extensively studied. The year out life.
2018 saw the publication of the 100,000th scientific Spermatogenesis (Fig. 3-1) is divided temporally
paper on this topic. Normal spermatogenesis is highly into three main successive stages:
regulated and reproducible. However, this process,
■ Mitotic cell division that results in multiplication of
which results in the production of mature male gam
spermatogonia
etes, is subject to congenital or acquired disturbances,
often leading to infertility. A male factor is thought to ■ Meiotic cell division that leads to reduction of the
be responsible as the sole or contributing factor in 50% diploid chromosomes into haploid ones
of all couples with infertility. Almost 7% of all men are ■ Spermiogenesis leading to differentiation and matu
confronted with fertility problems.1 The pathophysi ration of the round spermatids into a spermatozoa
ological factors leading to male-factor infertility are
divided into pretesticular, testicular, and posttesticu-
lar. Despite all the technological advances and innova SEMEN ANALYSIS
tion in the diagnosis and evaluation of male infertility,
idiopathic etiologies still represent 50% of overall Spermatogenesis is a delicate process affected by
infertility cases. multiple intrinsic factors, such as hormones, and
extrinsic variables, such as ambient temperature and
environmental toxins. Clues to the many causes of
NORMAL SPERMATOGENESIS
male-factor infertility will be evident in an abnor
Spermatogenesis is the process of differentiation and mal semen analysis. Therefore, the first, and often
maturation of germ cells.2,3 This process involves most revealing, diagnostic evaluation of an infertile
mitotic division of spermatogonial stem cells and sub man is the semen analysis. The health care provider
sequent meiotic cell division within the seminiferous should be aware of the intrapatient variability of the
tubular lumen, supported by the Sertoli cells. Mature semen parameters over time. Semen parameters
spermatozoa—with fertilizing potential—are derived cyclically pass through troughs and peaks multiple
from spermatids through a process of differentiation times within a given year. For this reason, diagnosing
and maturation called spermiogenesis. This process or labeling semen parameters as abnormal should
ensures the production of an average of 300 to 600 only be done after 2 semen analyses have been per
sperm per gram of testis per second, an equivalent formed, separated by several weeks, and after at least
of millions of sperm per day. The duration of human 2 to 3 days of abstinence. Occasionally, a third semen
29
Spermatogonia Primary Secondary Spermatids Spermatozoa

spermatocyte spermatocyte
Located along the Undergo meiotic cell division yielding 4 Process of high Further
seminiferous tubule spermatids per spermatogonium. Random cellular and maturation occurs
basement separation of homologous chromosomes. cytoplasmic in the transit
membrane. Crossing over of genetic material differentiation through the
Undergo multiple epididymis.
cycles of mitosis cell
division.
FIGURE 3-1. Summary of the most important characteristics of normal spermatogenesis.2,3
TABLE 3-1. Nomenclature of Sperm Abnormalities TABLE 3-2. Summary of the WHO Manual for the
Found in Male-Factor Infertility Examination and Processing of Human Semen4
TERM DEFINITION PARAMETER REFERENCE VALUE
Oligozoospermia Sperm concentration less Ejaculate volume 1.5 mL
than 15 million sperm/mL or
total sperm number less than PH 7.2
39 million/mL
Sperm concentration 15 million spermatozoa/mL
Asthenozoospermia Less than 32% progressive
Total sperm 39 million spermatozoa/
motility
concentration ejaculate
Teratozoospermia Less than 4% normal
Percentage motility 40%
morphology (strict)
Forward progression 32%
Azoospermia No spermatozoa in the
ejaculate after centrifugation Normal morphology 4%
Cryptozoospermia No spermatozoa in the Sperm agglutination Absent
ejaculate, but observed in
pellet after centrifugation Viscosity Less than 2 cm thread after
liquefaction
Aspermia No ejaculate
Pyospermia More than 1 million

leucocytes in the ejaculate
ENDOCRINOPATHIES
Normal spermatogenesis requires adequate pro
analysis may be necessary if the first 2 analyses are duction of reproductive hormones, which depends
discordant. Special attention should be paid to semen on an intact hypothalamic-pituitary-gonadal axis
volume, sperm concentration, sperm motility, and (Fig. 3-2). Hypogonadism can be due to primary
standardized sperm morphology (Table 3-1). Most testicular causes resulting in hypergonadotropic
institutions have standardized the results accord hypogonadism (primary hypogonadism) or due to
ing to the latest World Health Organization (WHO) hypothalamic-pituitary dysfunction resulting in
Manual for the Examination and Processing of Human hypogonadotropic hypogonadism (HH) (second
Semen, the fifth edition of which was published in ary hypogonadism). Men with HH have deficient
20104 (Table 3-2). The various causes of male infer secretion of the pituitary gonadotropins, follicle-
tility are listed in Table 3-3. stimulating hormone (FSH) and/or luteinizing
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Dampfer hatte uns vom Goldenen Horn nach Haidar-Pascha an der
asiatischen Küste gebracht, und in sieben Tagen erreichten wir mit
der Bahn Aleppo.
Zweimal hatten wir den Zug verlassen müssen, denn die Strecke
der Bagdadbahn bis Aleppo war noch nicht ganz ausgebaut.
Zwischen Bosanti und Gülek im Taurus war zwar schon ein
gewaltiger Tunnel durchs Gebirge gebohrt, er sollte aber erst im
Herbst dem Verkehr übergeben werden. In Bosanti hatten uns zwei
deutsche Offiziere in türkischen Diensten, Oberstleutnant Vonberg
und Major Welsch, die auf dem Wege nach Bitlis waren, ein
Kriegsautomobil zur Verfügung gestellt, das uns auf steilen und
weiten, ohne Brustwehr über schwindelnden Abgründen hängenden
Zickzackwegen über die 1300 Meter ansteigenden Höhen des
Taurus nach Gülek beförderte. Auf der Talfahrt durcheilten wir die
Pylae Ciliciae, den hohlwegartigen Engpaß des Tales Tarsus-tschai,
durch den Xerxes und Darius, Cyrus der Jüngere und Alexander der
Große vorrückten, und in späteren Zeiten Harun-er-Raschid und
Gottfried von Bouillon. Das Wetter war nicht eben einladend
gewesen, es wechselte anmutig zwischen Land- und Platzregen.
Dabei wimmelte die aufgeweichte und schlüpfrige Straße von
Kamelkarawanen, die Baumwolle von Adana brachten, von
Lastautos, requirierten Bauernwagen, Ochsenfuhrwerk mit
Kriegsmaterial, marschierenden Soldaten und Reitern. Am meisten
bemitleideten wir die Züge gefangener Sikhs, die von Bagdad her zu
Fuß nach ihrem Bestimmungsort in Kleinasien wandern mußten,
einen Stock in der Hand, den Brotbeutel auf dem Rücken, die
Uniformen zerrissen und die Turbane zerlumpt. Welche Qual für die
Söhne des Sonnenlandes Indien, dem kalten Regen auf den Höhen
des Taurus schutzlos preisgegeben zu sein! Kleine Gesellschaften
reisender Türken mit Eseln, Kühen und — aufgespannten
Regenschirmen boten dagegen einen lustigen Anblick.
In der Mitte zwischen Bosanti und Gülek, in dem offenen Gebiet
des Taurus, das Schamallan-han genannt wird und ringsum von
spärlich bewaldeten Bergen umgeben ist, lag eine deutsche
Automobilstation, wo man uns mit liebenswürdiger Gastfreundschaft
aufnahm und eine Nacht trefflich beherbergte. In dem welligen
Kesseltal war eine ganze Stadt emporgewachsen von gelben,
grauen und schwarzen Zelten oft riesiger Ausdehnung, Schuppen
und Reparaturwerkstätten. Mannschaftsbaracken und
Offizierszelten. Deutsche und türkische Flaggen wehten darüber.
Von Gülek aus hatten wir Tarsus besucht, den Geburtsort des
Apostels Paulus, ein sehr langweiliges Städtchen.
Zwischen Mamure und Islahije waren die Tunnel ebenfalls schon
fertig, aber nur eine Feldbahn führte hindurch. Diese Strecke über
den Amanus und durch das 300 Meter breite, zwischen
Basaltklippen sich öffnende Amanische Tor, durch das einst König
Darius zog, um seinem Gegner Alexander in den Rücken zu fallen,
mußten wir auf der Landstraße in einem „Jaile“ zurücklegen, einem
hohen, überdeckten, kremserähnlichen Fuhrwerk, das Wilamowitz
„Leichenwagen“ taufte, als ob er geahnt hätte, daß er von seiner
Reise nach Persien nicht mehr zurückkehren werde. Man sitzt nicht,
sondern liegt in dieser merkwürdigen Fahrgelegenheit, polstert sich
den Boden so gut wie möglich mit Stroh und nachgiebigem Gepäck
aus und freut sich, wenn das „gerüttelt Maß“ nicht allzureichlich
ausfällt. Für mich war diese Fahrt noch dadurch besonders
denkwürdig, daß auf ihr meine wohlversorgte große Proviantkiste
aus Konstantinopel spurlos verschwand. Das immer trostloser
werdende Regenwetter hatte uns schließlich gezwungen, in einem
elenden Krug zu Islahije bei einem griechischen Wirt Georgios
Vassili ein etwas romantisches Nachtlager zu bestehen, und
schließlich hatte uns ein Pferdetransportzug in einem Viehwagen um
1 Uhr nachts glücklich nach Aleppo gebracht.
Hier sollte ich nun abwarten, was das Oberkommando der
türkischen Armee über mein weiteres Schicksal beschließen würde.
Minister Enver Pascha hatte mir die Erlaubnis zur Reise durch
Kleinasien bis nach Bagdad nur unter der Bedingung erteilt, daß
Feldmarschall von der Goltz, der von Bagdad aus die 6. Armee
befehligte, keine Bedenken dagegen habe; er allein wollte die
Verantwortung für meine Sicherheit nicht auf sich nehmen, da wilde
Beduinenhorden die Wege unsicher machten. Das endgültige
Ergebnis des Depeschenwechsels zwischen Konstantinopel und
Bagdad sollte mir in Aleppo gemeldet werden.
Aleppo, das Haleb der Araber, nach Smyrna und Damaskus die
größte Stadt Vorderasiens, ist Hauptstadt eines Wilajets, eines
Gouvernements, das das ganze nördliche Syrien umfaßt und im
Osten vom Euphrat begrenzt wird. Die Einwohnerzahl soll 200 bis
250000 betragen; davon sind zwei Drittel Mohammedaner, 25000
Armenier, 15000 Juden, ebensoviele Griechen, die übrigen Lateiner,
Maroniten und unierte Syrer. In der Altstadt herrscht noch der
arabische Stil vor, der nach der Straße zu nur öde Mauern zeigt.
Doch finden sich auch dort schon solide Steinhäuser mit Erkern,
Balkonen und eingebauten Altanen, und die neuen Stadtteile an der
Peripherie haben eine fast europäische Bauart. Mit ihrem
unaufhörlich hin- und herwogenden orientalischen Verkehr bieten
Aleppos Straßen wundervolle Bilder; noch lieber aber verirrt man
sich in die dunkeln Labyrinthe der Basare, deren kleine, enge
Kaufläden mit Teppichen und Stickereien, Gold und Silberschmuck,
Pantoffeln und Lederwaren und all dem Kram angefüllt sind, der von
Europa eingeführt wird.
Graf Wichard von Wilamowitz-Möllendorf.
Der Krieg hatte zwar den Handel ziemlich lahm gelegt; der Han
Wesir, ein Gebäude aus dem 13. Jahrhundert, war fast leer geräumt.
Dennoch herrschte in den Basaren noch immer lebhafter Betrieb.
Selbst französische Weine, Konserven, Lichte usw. konnte man
kaufen, da die Vorräte der Küstenstädte noch nicht erschöpft waren,
so daß ich meine verschwundene Proviantkiste leicht ersetzen
konnte. Manche Artikel aber stiegen unerhört im Wert. Für
Petroleum forderte man das Zwanzigfache des Friedenspreises, und
das türkische Papiergeld stand tief im Kurs: in Konstantinopel galt
ein türkisches Pfund 108 Piaster, in Aleppo nur 90, in Jerusalem
sogar, wie man mir versicherte, nur 73 (ein Piaster hat einen Wert
von etwa 18 Pfennig). In manchen Gegenden weigerte sich die
Landbevölkerung überhaupt Papiergeld anzunehmen; ich hatte mich
glücklicherweise in Konstantinopel mit einer größeren Summe in
Gold und Silber versehen.
In der Mitte der Stadt erhebt sich die Zitadelle auf einer uralten,
wahrscheinlich künstlich geschaffenen Anhöhe. Vom Rundgang des
Minaretts dort oben hat man eine wundervolle Aussicht über das
Häusermeer der Stadt mit seinem sparsamen Grün und die Straßen,
die wie die Speichen eines Rades von diesem Mittelpunkt ausgehen,
auf das weite, hügelige, graugelbe Gelände und das Tal des
Kuwekflusses, wo Platanen, Silberpappeln, Walnußbäume, Oliven
und vor allem Pistazien in den Gärten grünen.
Aleppos Hauptsehenswürdigkeit ist die „große Moschee“
Dschami-kebir oder Dschami-Sakarija. Sie hat ihren Namen vom
Vater Johannes des Täufers, Zacharias, dessen Grab im Innern
hinter vergoldetem Gitter gezeigt wird, und wurde von den
Omaijaden an einer Stelle errichtet, wo vordem eine von der Kaiserin
Helena gestiftete christliche Kirche stand. Ihr gegenüber erhebt sich
die Dschami-el-Halawije, die ebenfalls ein Abkömmling einer von der
Kaiserin Helena erbauten Kirche sein soll. Ihr Inneres zieren Pilaster
und Chornischen mit Akanthusmotiven und ein „Maschrab“, eine
Gebetsnische, von künstlerischem Wert. Vor der Stadt liegt die
vornehme Begräbnisstätte Ferdus mit zahlreichen Heiligengräbern
und den charakteristischen Grabsteinen: immer zwei aufrecht
stehend als Sinnbilder des Lebens, dazwischen ein liegender als
Sinnbild des Todes. Die Ecken des liegenden Steins haben
schalenförmige Vertiefungen: darin sammelt sich das Regenwasser,
und die Vögel kommen, um zu trinken und den Schlaf der Toten mit
ihrem Gesang zu versüßen. Als ich den Friedhof besuchte, küßte
eine alte Türkin weinend die Steine der Heiligengräber, um, wie sie
sagte, Schutz zu erflehen für ihren Sohn, der an der Front gegen die
Russen kämpfte.
Eine andere, teilweise verfallene Grabmoschee trägt den Namen
Salhein. Über ihren Denkmälern erhebt sich ein sehr hübsches
Minarett.
Arabischer Junge in Aleppo.

Vor der Stadt liegt auch die Moschee Scheik-ul-Hussein; ihre
Gebetsnische birgt einen Stein, der nach der Versicherung
Rechtgläubiger alljährlich am 10. Oktober, dem Todestage des
schiitischen Heiligen Hussein, blutet. Nördlich von Aleppo träumt
zwischen Anhöhen das Derwischkloster Scheik Abu Bekr, eine
viereckige Halle unter einer Kuppel, im Innern ausgestattet mit
prächtigen Skulpturen und Fayencen; zahlreiche große Fenster
werfen helles Licht auf die Farbenpracht der Kunstwerke. Im Hof
spiegeln Zypressen ihr ewiges Grün in einem klaren Wasserbecken;
daneben schlummert unter einem von Kletterpflanzen umsponnenen
Grabmal eine Prinzessin. Hier hausen die betenden Derwische von
der Brüderschaft der Mutevelli-Derwische, deren Hauptsitz Konia ist.
Auch die tanzenden Derwische haben in Aleppo ein Haus.
Vor dem Krieg war in Aleppo eine deutsche Kolonie von ungefähr
300 Köpfen. Jetzt war ihre Anzahl bedeutend gesunken. Von den
beiden deutschen Schulen war die katholische vor vier Jahren
gegründet und in einem vornehmen, hundertundfünfzig Jahre alten
arabischen Hause untergebracht; sie beschäftigte sechzehn Lehrer
und acht Borromäerinnen (barmherzige Schwestern) und hatte zur
Zeit meines Besuches 220 Schüler, die nur deshalb ein geringes
Schulgeld zahlen mußten, weil sonst der Unterricht nicht als etwas
Erstrebenswertes gegolten hätte. Im ganzen sollen 400
Borromäerinnen an den verschiedenen Fronten stehen. Die
protestantische, noch jüngere Schule wird von 110 türkischen,
deutschen, jüdischen und armenischen Mädchen besucht; sie gehört
den Kaiserswerther Diakonissen, die auch in Smyrna, Beirut und
Jerusalem Schulen und in Konstantinopel ein großes Krankenhaus
eingerichtet haben. Aus Kairo und Alexandria wurden sie während
des Krieges vertrieben. Andere Lehranstalten in Aleppo stehen unter
der Leitung der Franziskaner und Jesuiten, der Sacré-Coeur- und St.
Josephsschwestern.
Das gesellige Leben der Deutschen hat seinen Mittelpunkt im
Hause des Herrn Koch, dessen Gattin als Schwester Martha mir
zuerst bei Feldmarschall von der Goltz begegnete, als er noch
Generalgouverneur in Brüssel war. Ihr gastliches Heim, das sich seit
dreißig Jahren so manchem Reisenden aufgetan hat, wurde auch
mir jetzt eine Freistätte, und hier im Kochschen Hause entschied
sich mein nächstes Reiseschicksal.
Einige Tage nach meiner Ankunft in Aleppo brachte mir der
Adjutant Neschad Paschas, des dortigen Etappeninspektors, den
Bescheid Enver Paschas, ich könne nach Bagdad reisen und wohin
ich sonst wolle. Ich hatte nur den Weg zu wählen. Aber eben darin
lag die Schwierigkeit. Eine gewisse Vorsicht war durch die
kriegerischen Ereignisse auf jeden Fall geboten. Schon in
Konstantinopel hatte ich gehört, die Russen seien in Persien
ziemlich stark. Kirmanschah hatten sie genommen. Bagdad war also
nicht mehr weit. Im Norden war Erserum gefallen, und wenn es dem
Großfürsten Nikolai gelang, nach Diarbekr vorzustoßen, und die
Engländer, die sich allerdings bei den Dardanellen blutige Köpfe
geholt hatten, etwa eine Landung im Golf von Alexandrette
erzwangen, um sich mit den Russen zu vereinen, schlugen die
Wellen des Krieges rettungslos hinter mir zusammen. Andererseits
hatte uns schon auf der Fahrt nach Aleppo ein Eisenbahningenieur,
ein Kroate, versichert, Bagdad sei von den Engländern besetzt; das
war natürlich leeres Gerede, denn dann hätte der Feldmarschall auf
dem Rückzug nach Westen sein müssen. Enver Paschas
Telegramm strafte all diese Etappengerüchte Lügen. In Islahije
schließlich hatte es geheißen, die Russen kämen Mosul immer
näher. Ob ich überhaupt Bagdad erreichen würde, erschien also
immerhin etwas unsicher, und doppelt unsicher war ich daher über
den Weg, den ich einzuschlagen hatte. Mein Reisekamerad Graf
Wilamowitz sollte eine Trainkolonne den Euphrat entlang führen; ihm
und dem Obersten von Gleich, dem neuen Stabschef bei von der
Goltz, konnte ich mich auf ihrem 800 Kilometer langen Ritt
anschließen. Aber es gibt nichts Einförmigeres als die ewigen
Wüsten an den Ufern des Euphrat. Da war es doch reizvoller, über
Nesibin nach Mosul zu fahren, die Ruinen von Ninive zu sehen, von
dort auf einem „Kellek“, einem Floß, den Tigris hinabzutreiben und
die Altertümer von Nimrud und Assur zu besuchen. Freilich machten
die Schammarbeduinen, die wegen ihrer Überfälle berüchtigt sind,
den Weg bis Mosul unratsam, wenn ich nur auf den Schutz meines
Kutschers angewiesen blieb. Auch waren die Nebenflüsse des
Euphrat, die vom Armenischen Gebirge herkommen, zu reißenden
Strömen angeschwollen. Aber die eigentliche Regenzeit war ja
schon vorüber; in ein paar trocknen Tagen mußten sie wieder fallen.
Ich beschloß also, meinem alten Glück zu vertrauen und mich von
Aleppo aus gleich ostwärts zu wenden. Frau Koch hatte bereits
einen „Arabatschi“, einen Hauderer, gefunden, der mir für 30
türkische Pfund (555 Mark) eine Viktoria und einen Jaile vermieten
wollte, und ich beriet gerade mit dem deutschen
Etappenkommandanten Rittmeister von Abel, Direktor Hasenfratz
und Inspektor Helfiger von der Bagdadbahn und andern deutschen
Freunden, wie Wagen und acht Pferde mit der Bahn nach Ras-el-Ain
befördert werden könnten, als zwei junge deutsche Offiziere in
türkischen Diensten ins Zimmer traten. Der eine von ihnen, Major
Reith, hatte als Chef einer Automobilkolonne den Auftrag, die
Verkehrsmöglichkeiten auf der Straße zwischen Ras-el-Ain und
Mosul zu untersuchen, der andere, sein Bruder, sollte ihn als Arzt
begleiten. Major Reith hatte kaum von unsern Beratungen gehört,
als er rief: „Aber warum so viel Zeit und Geld verschwenden?
Kommen Sie mit mir! Ich habe reichlich Platz für Sie und auch für Ihr
Gepäck, und in drei Tagen sind wir in Mosul!“
Diesem verführerischen Vorschlag zu widerstehen, wäre
übermenschlich gewesen. Eine günstigere Gelegenheit konnte sich
mir ja gar nicht bieten. Also auf nach Mosul!
Pferdebeförderung über den Dschirdschib.
Drittes Kapitel.
Eine mißglückte Autofahrt.
M eine bisherigen Reisekameraden waren bereits aufgebrochen:

Graf Wilamowitz mit Oberst von Gleich den Euphrat entlang,
Vonberg und Welsch nach Ras-el-Ain, wo sie drei Tage auf Pferde
und Wagen für die Fahrt nach Bitlis warten mußten, so daß ich ihnen
am nächsten Tag noch einmal begegnete. Major Welsch sah ich
einige Monate später wieder; Oberstleutnant Vonberg aber sollte von
Bitlis nicht mehr zurückkehren: er starb dort am Flecktyphus.
Am 28. März schlug auch für uns die Stunde des Aufbruchs. Das
Wetter war herrlich geworden, für unsere Autofahrt nach Mosul
mußten die Straßen ausgezeichnet sein. Major Reiths fünf
Automobile, zwei Personen- und drei Lastwagen, wurden auf
offenen Loren verladen, und am Vormittag setzte sich unsre Kolonne
mit neun Chauffeuren und einem türkischen Dolmetscher in
Bewegung. Die Lastautos enthielten reichliche Vorräte an Benzin
und Öl, Ersatzteile, Gummiringe, Werkzeug, Spaten, Zelte, Tische,
Stühle, Betten und Proviant.
Zuerst brachte uns die Bahn nach Muslimije zurück. Dann
wandte sie sich nach Osten durch wenig bebautes Land, wo nur hier
und da die zusammengedrängten Kuppeldächer eines Dörfchens
sichtbar wurden. Diese bienenstockartigen Hütten aus an der Sonne
getrocknetem Lehm finden sich überall da, wo anderes Baumaterial,
Holz oder Stein, fehlt. Weiter entfernt von der Bahnstrecke, wo
Kalkstein zu Tage tritt, sind auch die Dorfhäuschen aus Stein und
ihre Dächer flach. Fast ohne Ausnahme liegt auch die kleinste dieser
Ansiedelungen auf dem Abhang oder am Fuß eines „Tell“, einer
nackten Anhöhe, deren durchweg regelmäßige, flach konische Form
aus dem ebenen Gelände einsam hervorragt. Solch ein Tell birgt die
Geschichte des betreffenden Dorfes; er reicht bis in die
Morgendämmerung der assyrischen und hethitischen Zeit zurück,
beginnt vielleicht vor den frühesten menschlichen Urkunden und war
auf alle Fälle schon uralt, als mazedonische Hopliten und
Hypaspisten, die schweren Fußtruppen und leichter beweglichen
Schildträger, durch diese Gegenden vorrückten. Eine Quelle, ein
Bach oder auch nur die Nähe von Grundwasser reizten zur
Ansiedelung, die dann durch Jahrtausende fortgelebt hat. Alte
Häuser stürzten ein; Schutt und Unrat häuften sich auf; aber die
nachkommenden Geschlechter bauten auf demselben Platze weiter,
und so wuchs der Tell schichtweise zu einem Hügel empor.
Um die Dörfer herum breiten sich Äcker aus, auf denen die
Fellachen, die festansässigen Bauern, mit Ochsen pflügen, und
Frauen und Kinder in buntzerfetzter Kleidung unserem Zuge offenen
Mundes nachschauen. Sonst ist der weiche rote Erdboden
gewöhnlich mit Gras und Kräutern bewachsen, und seine
Einförmigkeit wird nur selten durch eine wandernde Kamelkarawane
unterbrochen. Neben der Eisenbahn wirken die prächtigen Tiere wie
Anachronismen. Wie gut, daß es noch Gegenden gibt, wo die
Menschen ohne das „Schiff der Wüste“ verloren wären!
Die Stationsgebäude sind feste Blockhäuser. Auf dem Bahnsteig
von Akdsche-Kojunli wartet eine Kompagnie Rekruten auf ihren Zug.
Der Ort liegt am Sadschur, einem Nebenfluß des Euphrat, und sein
trübes Wasser verrät, daß in seinem Quellgebiet Regen gefallen ist.
Ein bedenkliches Vorzeichen! Fern im Norden leuchten die Gebirge
Armeniens, die zum Taurus gehören, unter ihrer Schneedecke.
Am Nachmittag stiegen wir in Dscherablus am Euphrat aus.
Hier begrüßten uns der türkische Etappeninspektor des
Flußweges, Oberst Nuri Bei, und Kapitänleutnant von Mücke, der
berühmte Kommandant der „Ayesha“, jetzt Chef der Euphratfluß-
Abteilung, die nicht weit vom Bahnhof am Ufer große Werften und
Werkstätten angelegt hat. Eine kleine Stadt von deutschen und
türkischen Häusern war hier erstanden, und auf der Werft waren
deutsche Matrosen beim Bau gewaltiger Boote von 12 Meter Länge,
4 Meter Breite und einer Tragkraft von 25 Tonnen; sie sollten
Kriegsmaterial den Euphrat abwärts nach Risvanije bringen, von wo
eine Feldbahn es nach Bagdad schaffte. Die türkische Werft liegt 25
Kilometer weiter flußaufwärts in Biredschik. Dort baut man seit alter
Zeit Euphratboote, sogenannte Schahtur, die 6 Meter lang und 2½
Meter breit sind und auf dem Wasser gewöhnlich paarweise
zusammengebunden werden. Das Holz liefern die Gebirgsgegenden
oberhalb Biredschik. Flußabwärts ist Holz sehr selten; was an
solchen Booten oder Fähren dort hinunter kommt, wird daher
gewöhnlich an seinem Bestimmungsort verkauft. Kapitänleutnant
von Mücke wollte aber versuchen, die zahllosen Boote, die von
Dscherablus ausgingen, zu retten, indem er sie durch deutsche
Lotsen mit Motorbooten wieder an ihren Ausgangspunkt
zurückbefördern ließ. Die ganze Stromstrecke bis Feludscha beträgt
über 1000 Kilometer, ein einzelner Lotse kann sich daher nicht mit
ihr vertraut machen. Deshalb sollte sie in zehn Teilstrecken zerlegt
und im Herbst eine genaue Karte des ganzen Stromlaufs hergestellt
werden, denn dann ist die Schiffahrt am schwierigsten. Jetzt war der
Strom im Steigen, aber der Wasserstand wechselte; am 28. März
war er schon fast einen Meter höher gewesen als jetzt; nach der
bevorstehenden Schneeschmelze erwartete man, daß er wieder um
anderthalb Meter steigen werde. Ein während des Hochwassers
aufgenommenes Kartenbild würde leicht irreführen, da alle Untiefen,
Sandbänke und Riffe dann überschwemmt sind und die
Wassermenge bei niedrigem Wasserstand sich zu dem bei
Hochwasser verhält wie 1:12. Obendrein sollten an den Ufern
Signale angebracht werden mit Angaben über den Verlauf der tiefen
Stromrinne und über alles, was der Euphratschiffer wissen muß.
Gleich oberhalb der Werft liegen die Ruinen einer uralten Stadt,
die George Smith 1876 entdeckt hat. Auf einer Reise durch Syrien
und Mesopotamien im Jahre 1879/80 kam auch Professor Sachau
aus Berlin nach Dscherablus — er nennt es Dscherâbîs —, dem
Europus der Römer, dem alten Karkemisch, mit dessen Namen die
Erinnerung an einen glänzenden Sieg verknüpft ist. Hier schlug
Nebukadnezar im Jahr 605 v. Chr., ein Jahr nach Ninives Fall und
ein Jahr vor seiner Thronbesteigung, den Pharao Necho. Dieses
Ereignisses gedenkt auch die Bibel; zum Propheten Jeremias
geschah das Wort des Herrn: „Wider Ägypten. Wider das Heer
Pharao Nechos, des Königs in Ägypten, welches lag am Wasser
Euphrat zu Karchemis, das der König zu Babel, Nebukadnezar,
schlug im vierten Jahr Jojakims, des Sohnes Josias, des Königs in
Juda.“
Als Sachau in Dscherablus eintraf, hatte der englische Konsul
Henderson in Aleppo gerade seine Ausgrabungen begonnen. Sie
deckten zwei Kulturperioden auf: die uralte hethitische mit
künstlerisch ausgeführten Reliefs, breiten Treppen und massiven
Häusern, und die römische. Noch bei Ausbruch des Weltkrieges
waren englische Archäologen hier an der Arbeit gewesen. Jetzt
stand ihr Wohnhaus leer, ihre Betten waren requiriert. Funde und
Sammlungen hatte die türkische Regierung versiegeln lassen, damit
sich niemand daran vergreife. Durch einen Spalt in der Holztüre sah
ich Skulpturen, Vasen usw. auf Regalen und auf dem Boden
aufgestellt. Von den größeren Skulpturen draußen auf dem Hof sind,
fürchte ich, einige durch die Beduinen beschädigt worden. Seit
Dscherablus ein so wichtiger Punkt auf der Etappenstraße nach
Bagdad geworden ist, haben Türken und Deutsche die strengsten
Maßnahmen zum Schutz der ausgegrabenen Altertümer getroffen.
Das Ruinenfeld war auch in bestem Zustand. Da standen in langen
Reihen die aus der Erde gegrabenen mächtigen Steinplatten,
geschmückt mit Löwen und Greifen und den Bildern assyrischer
Könige. Ein etwa einen Meter langer geflügelter Löwe trug außer
seinem eigenen Kopf noch den eines Mannes mit eigentümlicher
Zipfelmütze oder Krone. Die Grundmauern alter Häuser traten
deutlich hervor, oft auch die Einteilung der Räume.
Oberhalb dieses Ruinenfeldes erhebt sich ein Hügel mit Spuren
einer Akropolis, und von hier aus bietet sich eine herrliche Fernsicht.
Flußabwärts verliert man den Euphrat zwischen seinen ziemlich
hohen Ufern bald aus den Augen. Unmittelbar unter uns springt die
Brücke der Bagdadbahn von Ufer zu Ufer, und weiterhin liegt eine
Flottille von Kähnen, die mit dem erwarteten Schneewasser in
wärmere Gegenden fahren soll.
Als die Dunkelheit unsern Studien im Freien ein Ziel setzte,
versammelten wir uns an Kapitänleutnant von Mückes Tisch in der
Offiziersmesse. Hier berichtete nun der Held der „Ayesha“, ein
glänzender Vertreter des Offizierkorps der deutschen Marine, selbst
über seine märchenhaften Abenteuer, wie er auf der nördlichsten
Kokosinsel von der „Emden“ an Land ging, mit seinem kleinen
Schoner über den Indischen Ozean das Rote Meer erreichte und
sich in blutigen Kämpfen mit Araberstämmen durchschlug, bis der
Weg nach Konstantinopel frei war.
Auch hier in Dscherablus gingen allerhand Etappengerüchte um,
die befürchten ließen, daß sich die Russen von Norden her
näherten. Teile einer türkischen Division waren auf dem Marsch
nach Mosul, also auf dem Wege, den wir morgen mit dem Auto
einschlagen sollten, überfallen worden; offenbar hatten die Russen
die Eingeborenen aufgewiegelt, um den Verkehr auf der
Etappenstraße zu stören. Die Türken hatten natürlich die Kurden in
die Flucht gejagt. Aber war die Straße nun wieder frei?
Die Antwort auf diese Frage gab ein Telegramm aus Kut-el-
Amara, das mir in diesem Augenblick ein Matrose überbrachte:
„Habe bereits Großes Hauptquartier benachrichtigt, daß keinerlei
Bedenken gegen Ihre Herreise vorliegen. Freue mich sehr, Sie
wiederzusehen. Goltz.“
Wenn der Feldmarschall „keinerlei Bedenken“ hatte, mußten mir
auch die bedrohlichsten Etappengerüchte gleichgültig sein.
Spät am Abend begleitete uns Kapitänleutnant von Mücke zum
Bahnhof. Unsere Automobile waren schon nach Ras-el-Ain
vorausbefördert, um sich dort reisefertig zu machen; am andern
Morgen sollten wir wieder zu ihnen stoßen.
Gegen Mitternacht rollte unser Zug langsam nach Osten der 950
Meter langen Euphratbrücke zu, die mit zehn eisernen Bogen auf
neun Steinpfeilern das gewaltige Flußbett überspannt. Die Nacht war
sternenhell. Vor ihren Blockhäusern standen die Bahnwärter mit
bunten Laternen unbeweglich wie Statuen. Bald begannen Räder
und Schienen zu singen und zu donnern, die Brücke war erreicht,
und im matten Schein der Sterne breitete der majestätische Strom
seinen weiten Spiegel zu unsern Füßen aus. Dann stieg die
Geschwindigkeit; die Bahn lief am Fuß von Anhöhen entlang und
kletterte zwischen ihnen mit merkbarer Steigung auf das öde,
einförmige Flachland zwischen Euphrat und Tigris hinauf.
Als ich am Morgen erwachte, waren wir schon fast am Ziel. Weit
bis zum Horizont dehnte sich das Land eben wie eine Tischplatte
oder doch nur ganz schwach gewellt. Hier und da verstreut zeigten
sich schwarze Nomadenzelte und trieben Hirten ihre Herden auf die
grüne Steppe. Der Himmel strahlte in sonniger Klarheit, der Tag
versprach heiß zu werden; nur im Norden schwebten über den
Bergen weiße Wolken, und weit im Süden stand der Dschebel
(Bergrücken) Abd-el-Asis da wie ein hellblauer Schild. Wir
überschritten einen kleinen Flußarm und waren im nächsten
Augenblick in Ras-el-Ain.
Die fünf Autos warteten in Ras-el-Ain schon auf uns, und Major
Reith brannte darauf, seinen Auftrag so schnell wie möglich
auszuführen. In der türkischen Etappenkommandantur versicherte
man uns obendrein, die Wege seien gut und trocken und die beiden
Arme des Dschirdschib, die wir einige Kilometer östlich von Ras-el-
Ain zu passieren hatten, jetzt ganz schmal. Also los!
Das ganze elende Dorf war auf den Beinen, als unsre Kolonne
zur Abfahrt bereit stand. Vorauf die beiden Personenwagen, der
erste ein Benz, von Major Reith selbst gelenkt, mit Dr. Reith, einem
Chauffeur und mir als Passagieren; hinterdrein die drei Lastautos.
¾10 Uhr setzten wir uns in Bewegung. Die Straße hätte nicht besser
sein können, das Gelände war eben oder ging in sehr flachen
Wellen, und nach 17 Minuten waren wir schon am ersten Arm des
Dschirdschib. Die Furt war ein paar hundert Meter nördlich von der
Straße. Die Personenwagen brausten schäumend durch das Wasser
und waren bald wieder auf dem Trocknen, aber die Lastautos fuhren
auf der steilen, linken Uferterrasse fest, und es kostete unsere
vereinten Anstrengungen, sie wieder freizumachen.
Nun bogen wir vom Damm der Bagdadbahn allmählich nach links
ab, den Telegraphenstangen nach, die unsere einsame Straße
verfolgten. Wir überholten einen Wanderer, einen Jaile und eine
Karawane von Mauleseln. Sonst sahen wir an Lebewesen nur in
einiger Entfernung einen Wolf, dem der Major vergeblich ein paar
Kugeln nachschickte.
Schon nach 22 Minuten hatten wir auch den zweiten Flußarm
des Dschirdschib erreicht. Er führte kaum drei Kubikmeter Wasser,
sein Bett war hart und voller Kies, und die Uferböschung flach.
Dieses Hindernis wurde also ohne Schwierigkeit genommen. Als wir
dann aber in einen Hohlweg mit weichem Boden gerieten, fuhr ein
Lastauto so gründlich fest, daß wir mit Spaten und Hebeln drei
Stunden schwer zu arbeiten hatten.
In nordöstlicher Richtung ging es weiter, dem Gebirge von Mardin
entgegen. Wie ein breites gelbrotes Band zog sich die Straße in
leichten Krümmungen durch die grüne Steppe. Lerchen, Wildgänse,
Falken und Geier beherrschten die Luft; auf der Erde sah man nur
zahllose Löcher von Feldmäusen und hier und da die Reste eines
gefallenen Kamels oder Maulesels. Ein türkischer Offizier, der uns
auf seinem Jaile begegnete, berichtete uns, der Weg vor uns sei gut;
zwei schwierige Stellen habe man ausgebessert, da Enver Pascha
in Bagdad erwartet werde. Bei dem Dorfe Arade rasteten drei
deutsche Soldaten, die vor einem Monat aus Bagdad aufgebrochen
waren; dort sei es, versicherten sie, schon damals bedeutend
wärmer gewesen als jetzt hier bei Arade.
Beim nächsten Dorf — Bunas mit Namen — standen mehrere
Zelte, deren Bewohner ihre Rinder- und Schafherden
zusammentrieben. Hier lebten Fellachen, Ackerbauer, und
Beduinen, Nomaden, durcheinander, die eintönige Steppe wurde
daher nicht selten durch bestelltes Feld unterbrochen. Die Dörfler
starrten verwundert unsren vorbeisausenden Autos nach, von denen
das erste die türkische — weißer Halbmond und Stern in rotem Feld
—, das zweite die deutsche, schwarzweißrote Flagge führte.
Schon legte sich Abendstimmung über die Landschaft. Die
Sonne verbarg sich hinter den Wolken. Einige Araber zu Pferde
zeigten uns den Weg, der fast geradeaus nach Norden führte, wo
die Berge von Mardin immer schärfer hervortraten. In dem Dorf Abd-
el-Imam zeigten sich prächtige Gestalten, besonders Frauen in roten
Trachten, zwischen den Hütten. Schließlich kamen wir über eine
kleine neuerbaute Steinbrücke, eine seltsame Erscheinung in dieser
Gegend, und an einem Tell ohne Dorf vorüber und bogen ¼7 Uhr
etwa 50 Meter seitwärts von der Straße ab. Hier sollte unser erstes
Nachtquartier auf dem Wege nach Mosul sein.
In militärischer Ordnung wurde unser Lager aufgeschlagen.
Unsere Wagen- und Zeltburg — links die drei Lastautos, rechts die
Personenwagen, vorn zwei Zelte und hinten die offene vierte Seite
nach der Wüste zu — bildete einen kleinen Hof, in dessen Mitte bald
ein Feuer brannte. Mit dem Dolmetsch Gabes waren wir insgesamt
zwölf Mann. Im Handumdrehen waren die beiden Offizierzelte
aufgerichtet, die Betten fertiggemacht, die Zeltstühle um eine Kiste
gestellt, Büchsenkonserven, Suppe, Fleisch und Gemüse, gekocht,
und bald saßen wir beim Schein einer Karbidlampe um unsern
Abendbrottisch, während die Mannschaft es sich in malerischen
Gruppen am Lagerfeuer bequem machte. Dann wurde die Lampe
ausgelöscht, die Zigaretten angezündet, und wir lauschten noch eine
Weile den frischen Gesängen der Chauffeure.
Am 30. März waren wir schon um ½6 Uhr zum Aufbruch fertig.
Da erhob sich plötzlich aus Nordwest ein rasender Sturm, und kalter
Regen peitschte die Steppe. Heraus mit den Regenmänteln! Und
nun vorwärts zum Aufmarsch der Kolonne auf der Straße! Das erste
Lastauto zog an, aber der Erdboden war bereits so feucht, daß die
Räder nicht recht faßten. Noch einmal losgekurbelt! Man hörte ein
betäubendes Knattern und Schleifen — und plötzlich stand die
Maschinerie still. Die Chauffeure sprangen herunter, und eine kurze
Untersuchung ergab als Resultat: das Auto ist ein Wrack, die nötigen
Ersatzteile können nur aus Scham-allan-han am Taurus beschafft
werden — und das kann ein paar Wochen dauern!
Nun kam das zweite an die Reihe. Es fuhr an, ratterte und
krachte — und dann stopp! Genau derselbe Schaden wie beim
ersten! Auch dieser Wagen war also erledigt. Der Major biß die
Zähne zusammen über dies Mißgeschick; aber nur nicht den Mut
verlieren! Umladen, und dann mit dem Rest der Kolonne weiter!
Das dritte Lastauto wurde bis an die Grenze seiner
Leistungsfähigkeit, die drei Tonnen betrug, beladen; genügenden
Vorrat an Benzin, Proviant, Öl und Wasser mußten wir mitnehmen,
außerdem Betten, Kleider, Zelte und anderes. Die beiden Wracks
blieben fast mit ihrer ganzen Last zurück. Darunter befanden sich
mein Zelt, meine Proviantkiste und mein Primuskocher mit Kessel.
Drei Chauffeure, Conrad, Buge und Lopata, und der türkische
Dolmetsch Gabes sollten das unfreiwillige Depot bewachen und auf
Ersatzteile warten. Waffen, Geld und Proviant hatten sie genug.
Gegen 1 Uhr war endlich alles fertig, und nachdem wir noch eine
gründliche Regendusche von Nordwesten her erhalten hatten,
fuhren wir los. Bei Tell-Ermen, einem großen Dorf mit Trümmern von
Kirchen und Moscheen, kamen wir auf die alte Straße von Urfa nach
Nesibin, den Heerweg Alexanders des Großen. Nordwärts führte ein
anderer Weg über Mardin nach Diarbekr und Bitlis. Schon trat
Mardin auf dem Gipfel eines Bergrückens immer deutlicher hervor.
Aber wir kamen nur langsam vorwärts. Der nasse Erdboden klebte
an den Rädern und bildete weiche Ringe von rotem, plastischem
Lehm. Bei dem Dorfe Deguk am Westufer eines kleinen Flußbettes
mußten wir die ganze männliche Bevölkerung aufbieten, um die
Wagen das ziemlich steile Ostufer hinaufzuschieben.
Es regnete nicht mehr. Wenn wir nur erst an Nesibin vorüber und
von dem Gebirge fort wären, wo die Niederschläge am stärksten
sind! Dann wird sich das Wetter wahrscheinlich aufhellen. Aber bis
dahin geht es noch entsetzlich langsam! Das Benzauto fährt voraus,
muß aber immer wieder auf das Lastauto warten, das schnaufend
herankommt; man hört, wie der Motor sich aufs äußerste anstrengt.
Wir lassen es ein Stück voranfahren, folgen ihm, haben es bald
überholt und warten wieder. So geht es in einem fort, bis wir endlich
das kleine Dorf Bir-dava erreicht haben.
Einige Dorfbewohner laufen herbei und winken eifrig. Mein
mangelhaftes Türkisch muß nun zur Verständigung dienen.
„Halt!“ rufen die Leute, „ihr könnt nicht weiterfahren. Gleich
östlich vom Dorf ist eine Senkung, die der Regen in einen Sumpf
verwandelt hat. Da sinken eure Wagen bis zu den Achsen ein, und
ihr kriegt sie nie wieder los.“
„Wie weit geht der Moorboden?“ frage ich.
„Etwa drei Stunden nach Osten. Weiter kennen wir die Gegend
nicht. Aber bis Nesibin wird es wohl nicht anders sein.“
„Gibt es weiter nördlich oder südlich keinen Weg?“
„Nein, die Senkung erstreckt sich sehr weit nach Norden und
Süden.“
„Hat es in der letzten Zeit viel geregnet?“
„Nein, noch gestern war der Weg bis Nesibin ganz trocken.
Heute aber ist er durch Regen unmöglich geworden.“
„Wie lange dauert es gewöhnlich, bis der Boden trocken wird?“
„Einen oder zwei Tage, wenn die Sonne scheint.“
„Glaubt ihr, daß es noch mehr Regen geben wird?“
„Das weiß Gott allein. Auf alle Fälle müßt ihr hier warten; denn
eure schweren Wagen würden im Schlamm versinken.“
Dorfbewohner schleppen unser Auto durch den Schlamm.
Einen Versuch wollten wir dennoch wenigstens mit dem kräftigen
Benzauto machen. Die Straße führte unmittelbar nördlich an den
kleinen elenden Lehmhütten von Bir-dava vorüber, dann senkte sich
das Land zu einer flachen Mulde, an deren tiefster Stelle ein
gemauerter Brunnen stand; er war jetzt von einer Wasserlache
umgeben. Hinab kamen wir ganz gut. Als es aber wieder aufwärts
ging, blieben wir rettungslos in dem zähen Lehm stecken. Unsere
Chauffeure und einige Männer aus dem Dorf mußten aus
Leibeskräften arbeiten, um uns wieder nach Bir-dava
hinaufzubringen. Für heute blieb uns nichts anderes übrig, als hier
auf ein besseres Morgen zu warten.
Die drei Wagen wurden nebeneinandergestellt, daneben das
schwarze Zelt des Majors, das kaum unsre Betten faßte. Darüber
brach die Nacht herein. Die Mannschaft hatte ihr Lager im Lastauto
hergerichtet, und ihr Teekocher brannte lustig zwischen den
Benzinfässern. Aber heute sangen die Chauffeure nicht, die
Anstrengungen des Tages hatten sie übermüdet. Einer von ihnen,
namens Lundgren, war schwedischer Abkunft, aus Umeå, aber in
Deutschland geboren; die andern hießen Hofmeister, Buschkötter,

Essentials of Mens Health 1St Edition Shalender Bhasin Full Chapter

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Essentials of Men’s Health 1st Edition

Shalender Bhasin, MB, BS

Michael P. O’Leary, MD, MPH

eBook conversion by codeMantra

Bradley D. Anawalt, MD Brigham and Women’s Hospital

Zachary Dao, BS Ole-Petter R. Hamnvik, MB, BCh, BAO, MMSc,

Martin Kathrins, MD Manuel Ozambela Jr., MD

Robert Oates, MD, FACS Katherine M. Rodriguez, MD

Joshua D. Safer, MD, FACP, FACE Division of Endocrinology, Department of Medicine,

INTRODUCTION hypogonadism are mutations of genes functional at

^-aminobutyric acid), and neuropeptides (e.g., neu­

(A) (7) P450 Cholesterol side chain

(5) P450 17-Hydroxylase/17,20 lyase

CH3 (J) 3(3-Hydroxysteroid

Classical pathway Alternative/backdoor pathway

STEROID TESTIS SPERMATIC VEIN PERIPHERAL VEIN

Pregnenolone sulfate 2600 430 90

Progesterone 130 23 0.8

17-Hydroxyprogesterone 690 45 3.2

Dehydroepiandrosterone 680 35 8.2

Dehydroepiandrosterone sulfate 2000 1400 1000

5-Androstene-3(3,17(3-diol 820 590 500

Androstenedione 740 45 2.5

Testosterone 2600 720 20

Testosterone sulfate 1400 150 13

Estradiol 15 0.4 0.1

Testicular regulation and function

insufficient gonadotropin production due to distur­ Disorders at the Hypothalamic-Pituitary Level

effects on Leydig cell androgen production and REFERENCES

INTRODUCTION ■ Nitric oxide (NO) activates guanylate cyclase to gen­

Suspensory Urogenital diaphragm

Corpora cavernosa Buck’s Buck’s

■ ED is a manifestation of generalized atherosclerosis

Several classification schemes for ED have been pro­

INTRODUCTION spermatogenesis is around 70 days, with another few

Spermatogonia Primary Secondary Spermatids Spermatozoa

FIGURE 3-1. Summary of the most important characteristics of normal spermatogenesis.2,3

Pyospermia More than 1 million

Arabischer Junge in Aleppo.

M eine bisherigen Reisekameraden waren bereits aufgebrochen:

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^-aminobutyric acid), and neuropeptides (e.g., neu

insufficient gonadotropin production due to distur Disorders at the Hypothalamic-Pituitary Level

INTRODUCTION ■ Nitric oxide (NO) activates guanylate cyclase to gen

Several classification schemes for ED have been pro