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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
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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
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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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foot, and chamber men,” independently of the noble maidens who
tended her, and who seem to have been equally served by three
“valets de main, de pied, et de chambre.”
But short-lived was the glory; no, I will not say that, let me rather
remark that short-lived was the worldly splendor of the chivalrous
my-lady countess. She had rendered all the service she could, when
she fell wounded before Paris, and was basely abandoned for a
while by her own party. She was rescued, ultimately, by D’Alençon,
but only to be more disgracefully abandoned on the one side, and
evilly treated on the other. When as a bleeding captive she was
rudely dragged from the field at Compiègne; church, court, and
chivalry, ignobly abandoned the poor and brave girl who had served
all three in turn. By all three she was now as fiercely persecuted; and
it may safely be said, that if the English were glad to burn her as a
witch, to account for the defeat of the English and their allies, the
French were equally eager to furnish testimony against her.
Her indecision and vacillation after falling into the hands of her
enemies, would seem to show that apart from the promptings of
those who had guided her, she was but an ordinary personage. She,
however, never lost heart, and her natural wit did not abandon her.
“Was St. Michael naked when he appeared to you?” was a question
asked by one of the examining commissioners. To which Jeanne
replied, “Do you think heaven has not wherewith to dress him?” “Had
he any hair on his head?” was the next sensible question. Jeanne
answered it by another query, “Have the goodness to tell me,” said
she, “why Michael’s head should have been shaved?” It was easy, of
course, to convict a prejudged and predoomed person, of desertion
of her parents, of leading a vagabond and disreputable life, of
sorcery, and finally, of heresy. She was entrapped into answers
which tended to prove her culpability; but disregarding at last the
complicated web woven tightly around her, and aware that nothing
could save her, the heart of the knightly maiden beat firmly again,
and as a summary reply to all questions, she briefly and emphatically
declared: “All that I have done, all that I do, I have done well, and do
well to do it.” In her own words, “Tout ce que j’ai fait, tout ce que je
fais, j’ai bien fait, et fais bien de le faire;” and it was a simply-
dignified resume in presence of high-born ecclesiastics, who did not
scruple to give the lie to each other like common ploughmen.
She was sentenced to death, and suffered the penalty, as being
guilty of infamy, socially, morally, religiously, and politically. Not a
finger was stretched to save her who had saved so many. Her
murder is an indelible stain on two nations and one church; not the
less so that the two nations unite in honoring her memory, and that
the church has pronounced her innocent. Never did gallant
champion meet with such base ingratitude from the party raised by
her means from abject slavery to triumph; never was noble enemy
so ignobly treated by a foe with whom, to acknowledge and admire
valor, is next to the practice of it; and never was staff selected by the
church for its support, so readily broken and thrown into the fire
when it had served its purpose. All the sorrow in the world can not
wash out these terrible facts, but it is fitting that this sorrow should
always accompany our admiration. And so, honored be the memory
of the young girl of Orleans!
After all, it is a question whether our sympathies be not thrown away
when we affect to feel for Jeanne Darc. M. Delepierre, the Belgian
Secretary of Legation, has printed, for private circulation, his “Doute
Historique.” This work consists chiefly of official documents, showing
that the “Maid” never suffered at all, but that some criminal having
been executed in her place, she survived to be a pensioner of the
government, a married lady, and the mother of a family! The work in
which these documents are produced, is not to be easily procured,
but they who have any curiosity in the matter will find the subject
largely treated in the Athenæum. This “Historical Doubt” brings us so
closely in connection with romance, that we, perhaps, can not do
better in illustrating our subject, than turn to a purely romantic
subject, and see of what metal the champions of Christendom were
made, with respect to chivalry.
THE CHAMPIONS OF CHRISTENDOM
GENERALLY
AND HE OF ENGLAND IN PARTICULAR.
“Are these things true?
Thousands are getting at them in the streets.”
Sejanus His Fall.
I can hardly express the delight I feel as a biographer in the

present instance, in the very welcome fact that no one knows
anything about the parentage of St. George. If there had been a
genealogical tree of the great champion’s race, the odds, are that I
should have got bewildered among the branches. As there is only
much conjecture with a liberal allowance of assertion, the task is
doubly easy, particularly as the matter itself is of the very smallest
importance.
The first proof that our national patron ever existed at all, according
to Mr. Alban Butler, is that the Greeks reverenced him by the name
of “the Great Martyr.” Further proof of a somewhat similar quality, is
adduced in the circumstance that in Greece and in various parts of
the Levant, there are or were dozens of churches erected in honor of
the chivalrous saint; that Georgia took the holy knight for its especial
patron; and that St. George, in full panoply, won innumerable battles
for the Christians, by leading forward the reserves when the
vanguard had been repulsed by the infidels, and the Christian
generals were of themselves too indolent, sick, or incompetent, to do
what they expected St. George to do for them.
From the East, veneration for this name, and some imaginary person
who once bore it, extended itself throughout the West. It is a curious
fact, that long before England placed herself under the shield of this
religious soldier, France had made selection of him, at least as a
useful adjutant or aide-de-camp to St. Denis. Indeed, our saint was
at one time nearly monopolized by France. St. Clotilde, the wife of
the first Christian king of France, raised many altars in his honor—a
fact which has not been forgotten in the decorations and illustrative
adornments of that splendid church which has just been completed
in the Faubourg St. Germain, and which is at once the pride and
glory of Paris. That city once possessed relics which were said to be
those of St. George; but of their whereabouts, no man now knows
anything. We do, however, know that the Normans brought over the
name of the saint with them, as that of one in whose arm of power
they trusted, whether in the lists or in battle. In this respect we, as
Saxons, if we choose to consider ourselves as such, have no
particular reason to be grateful to the saint, for his presence among
us is a symbol of national defeat if not of national humiliation. Not
above six centuries have, however, elapsed since the great council
of Oxford appointed his feast to be kept as a holyday of lesser rank
throughout England; and it is about five hundred years since Edward
III. established the Order of the Garter, under the patronage of this
saint. This order is far more ancient than that of St. Michael,
instituted by Louis XI.; of the Golden Fleece, invented by that ‘good’
Duke Philip of Burgundy, who fleeced all who were luckless enough
to come within reach of his ducal shears; and of the Scottish Order
of St. Andrew, which is nearly two centuries younger than that of St.
George. Venice, Genoa, and Germany, have also instituted orders of
chivalry in honor of this unknown cavalier.
These honors, however, and a very general devotion prove nothing
touching his birth, parentage, and education. Indeed, it is probably
because nothing is known of either, that his more serious
biographers begin with his decease, and write his history, which, like
one of Zschokke’s tales, might be inscribed “Alles Verkerht.” They tell
us that he suffered under Diocletian, in Nicomedia, and on the 23d of
April. We are further informed that he was a Cappadocian—a
descendant of those savagely servile people, who once told the
Romans that they would neither accept liberty at the hands of Rome,
nor tolerate it of their own accord. He was, it is said, of noble birth,
and after the death of his father, resided with his mother in Palestine,
on an estate which finally became his own. The young squire was a
handsome and stalwart youth, and, like many of that profession, fond
of a military life. His promotion must have been pretty rapid, for we
find him, according to tradition, a tribune or colonel in the army at a
very early age, and a man of much higher rank before he
prematurely died. His ideas of discipline were good, for when the
pagan emperor persecuted the Christians, George of Cappadocia
resigned his commission and appointments, and not till then, when
he was a private man, did he stoutly remonstrate with his imperial
ex-commander-in-chief against that sovereign’s bloody edicts and
fiercer cruelty against the Christians. This righteous boldness was
barbarously avenged; and on the day after the remonstrance the
gallant soldier lost his head. Some authors add to this account that
he was the “illustrious young man” who tore down the anti-Christian
edicts, when they were first posted up in Nicomedia, a conjecture
which, by the hagiographers is called “plausible,” but which has no
shadow of proof to give warrant for its substantiality.
The reason why all knights and soldiers generally have had
confidence in St. George, is founded, we are told, on the facts of his
reappearance on earth at various periods, and particularly at the
great siege of Antioch, in the times of the crusades. The Christians
had been well nigh as thoroughly beaten as the Russians at Silistria.
They were at the utmost extremity, when a squadron was seen
rushing down from a mountain defile, with three knights at its head,
in brilliant panoply and snow-white scarfs. “Behold,” cried Bishop
Adhemar, “the heavenly succor which was promised to you! Heaven
declares for the Christians. The holy martyrs, George, Demetrius,
and Theodore, come to fight for you.” The effect was electrical. The
Christian army rushed to victory, with the shout, “It is the will of God!”
and the effect of the opportune appearance of the three chiefs and
their squadron, who laid right lustily on the Saracens, was decisive of
one of the most glorious, yet only temporarily productive of triumphs.
When Richard I. was on his expedition against enemies of the same
race, he too was relieved from great straits by a vision of St. George.
The army, indeed, did not see the glorious and inspiring sight, but
the king affirmed that he did, which, in those credulous times was
quite as well. In these later days men are less credulous, or saints
are more cautious. Thus the Muscovites assaulted Kars under the
idea that St. Sergius was with them; at all events, Pacha Williams, a
good cause, and sinewy arms, were stronger than the Muscovite
idea and St. Sergius to boot.
Such, then, is the hagiography of our martial saint. Gibbon has
sketched his life in another point of view—business-like, if not
matter-of-fact. The terrible historian sets down our great patron as
having been born in a fuller’s shop in Cilicia, educated (perhaps) in
Cappadocia, and as having so won promotion, when a young man,
from his patrons, by the skilful exercise of his profession as a
parasite, as to procure, through their influence, “a lucrative
commission or contract to supply the army with bacon!” In this
commissariat employment he is said to have exercised fraud and
corruption, by which may be meant that he sent to the army bacon
as rusty as an old cuirass, and charged a high price for a worthless
article. In these times, when the name and character of St. George
are established, it is to be hoped that Christian purveyors for
Christian armies do not, in reverencing George the Saint, imitate the
practices alleged against him as George the Contractor. It would be
hard, indeed, if a modern contractor who sent foul hay to the cavalry,
uneatable food to the army generally, or poisonous potted-meat to
the navy, could shield himself under the name and example of St.
George. Charges as heavy are alleged against him by Gibbon, who
adds that the malversations of the pious rogue “were so notorious,
that George was compelled to escape from the pursuit of justice.” If
he saved his fortune, it is allowed that he made shipwreck of his
honor; and he certainly did not improve his reputation if, as is
alleged, he turned Arian. The career of our patron saint, as
described by Gibbon, is startling. That writer speaks of the splendid
library subsequently collected by George, but he hints that the
volumes on history, rhetoric, philosophy, and theology, were perhaps
as much proof of ostentation as of love for learning. That George
was raised by the intrigues of a faction to the pastoral throne of
Athanasius, in Alexandria, does not surprise us. Bishops were very
irregularly elected in those early days, when men were sometimes
summarily made teachers who needed instruction themselves; as is
the case in some enlightened districts at present. George displayed
an imperial pomp in his archiepiscopal character, “but he still
betrayed those vices of his base and servile extraction,” yet was so
impartial that he oppressed and plundered all parties alike. “The
merchants of Alexandria,” says the historian of the “Decline and
Fall,” “were impoverished by the unjust and almost universal
monopoly which he acquired of nitre, salt, paper, funerals, &c., and
the spiritual father of a great people condescended to practise the
vile and pernicious arts of an informer. He seems to have had as
sharp an eye after the profit to be derived from burials, as a certain
archdeacon, who thinks intramural burial of the dead a very sanitary
measure for the living, and particularly profitable to the clergy. Thus
the example of St. George would seem to influence very “venerable”
as well as very “martial” gentlemen. The Cappadocian most
especially disgusted the Alexandrians by levying a house tax, of his
own motion, and as he pillaged the pagan temples as well, all parties
rose at length against the common oppressor and “under the reign of
Constantine he was expelled by the fury and justice of the people.”
He was restored only again to fall. The accession of Julian brought
destruction upon the archbishop and many of his friends, who, after
an imprisonment of three weeks, were dragged from their dungeons
by a wild and cruel populace, and murdered in the streets. The
bodies were paraded in triumph upon camels (as that of Condé was
by his Catholic opponents, after the battle of Jarnac, on an ass), and
they were ultimately cast into the sea. This last measure was
adopted in order that, if the sufferers were to be accounted as
martyrs, there should at least be no relics of them for men to
worship. Gibbon thus concludes: “The fears of the Pagans were just,
and their precautions ineffectual. The meritorious death of the
archbishop obliterated the memory of his life. The rival of Athanasius
was dear and sacred to the Arians, and the seeming conversion of
those sectaries introduced his worship into the bosom of the Catholic
church. The odious stranger, disguising every circumstance of time
and place, assumed the rank of a martyr, a saint, and a Christian
hero; and the infamous George of Cappadocia has been
transformed into the famous St. George of England, the patron of
arms, of chivalry, and of the garter.”
The romancers have treated St. George and his knightly
confraternity after their own manner. As a sample of what reading
our ancestors were delighted with, especially those who loved
chivalric themes, I know nothing better than “The Famous History of
the Seven Champions of Christendom, St. George of England, St.
Denis of France, St. James of Spain, St. Anthony of Italy, St. Andrew
of Scotland, St. Patrick of Ireland, and St. David of Wales. Shewing
their honourable battles by sea and land. Their tilts, justs,
tournaments for ladies; their combats with gyants, monsters, and
dragons; their adventures in foreign nations; their enchantments in
the Holy Land; their knighthoods, prowess, and chivalry, in Europe,
Africa, and Asia; with their victories against the enemies of Christ;
also the true manner and places of their deaths, being seven
tragedies, and how they came to be called the Seven Saints of
Christendom.” The courteous author or publisher of the veracious
details, prefaces them with a brief address “to all courteous readers,”
to whom “Richard Johnson wisheth increase of virtuous knowledge.”
“Be not,” he says, “like the chattering cranes, nor Momus’s mates
that carp at everything. What the simple say, I care not. What the
spiteful say, I pass not; only the censure of the conceited,” by which
good Richard means the learned, “I stand unto; that is the mark I aim
at,”—an address, it may be observed, which smacks of the Malaprop
school; but which seemed more natural to our ancestors than it does
to us.
For these readers Richard Johnson presents a very highly-spiced
fare. He brings our patron saint into the world by a Cæsarean
operation performed by a witch, who stole him from his unconscious
mother, and reared him up in a cave, whence the young knight
ultimately escaped with the other champions whom the witch, now
slain, had kept imprisoned. The champions, it may be observed,
travel with a celerity that mocks the “Express,” and rivals the
despatch of the Electric Telegraph. They are scarcely departed from
the seven paths which led from the brazen pillar, each in search of
adventures, when they are all “in the thick of it,” almost at the
antipodes. A breath takes St. George from Coventry, his recovered
home, after leaving the witch, to Egypt. At the latter place he slays
that terrible dragon, which some think to imply the Arian overcoming
the Athanasian, and rescues the Princess Sabra, in whose very
liberal love we can hardly trace a symbol of the Church, although her
antipathies are sufficiently strong to remind one of the odium
theologicum. George goes on performing stupendous feats, and
getting no thanks, until he undertakes to slay a couple of lions for the
Soldan of Persia, and gets clapped into prison, during seven years,
for his pains. The biographer I suspect, shut the knight up so long, in
order to have an excuse to begin episodically with the life of St.
Denis.
The mystic number seven enters into all the principal divisions of the
story. Thus, St. Denis having wandered into Thessaly was reduced
to such straits as to live upon mulberries; and these so disagreed
with him that he became suddenly transformed into a hart; a very
illogical sequence indeed. But the mulberry tree was, in fact,
Eglantius the King’s daughter, metamorphosed for her pride. Seven
years he thus remained; at the end of which time, his horse, wise as
any regularly-ordained physician, administered to him a decoction of
roses which brought about the transformation of both his master and
his master’s mistress into their “humane shapes.” That they went to
court sworn lovers may be taken as a matter of course. There they
are left, in order to afford the author an opportunity of showing how
St. James, having most unorthodoxically fallen in love with a Jewish
maiden, was seven years dumb, in consequence. St. James,
however, is a patient and persevering lover. If I had an ill-will against
any one I would counsel him to read this very long-winded history,
but being at peace with all mankind, I advise my readers to be
content with learning that the apostolic champion and the young
Jewess are ultimately united, and fly to Seville, where they reside in
furnished lodgings, and lead a happy life;—while the author tells of
what befell to the doughty St. Anthony.
This notable Italian is a great hand at subduing giants and ladies.
We have a surfeit of combats and destruction, and love-making and
speechifying, in this champion’s life; and when we are compelled to
leave him travelling about with a Thracian lady, who accompanies
him, in a theatrical male dress, and looks in it like the Duchess—at
least, like Miss Farebrother, in the dashing white sergeant of the
Forty Thieves—we shake our head at St. Anthony and think how
very unlike he is to his namesake in the etching by Callot, where the
fairest of sirens could not squeeze a sigh from the anchorite’s
wrinkled heart.
While they are travelling about in the rather disreputable fashion
above alluded to, we come across St. Andrew of Scotland, who has
greater variety of adventure than any other of the champions. With
every hour there is a fresh incident. Now he is battling with spirits,
now struggling with human foes, and anon mixed up, unfavorably,
with beasts. At the end of all the frays, there is—we need hardly say
it—a lady. The bonny Scot was not likely to be behind his fellow-
champions in this respect. Nay, St. Andrew has six of them, who had
been swans, and are now natural singing lasses. What sort of a
blade St. Andrew was may be guessed by the “fact,” that when he
departed from the royal court, to which he had conducted the half
dozen ladies, they all eloped in a body, after him. There never was
so dashing a hero dreamed of by romance—though a rhymer has
dashed off his equal in wooing, and Burns’s “Finlay” is the only one
that may stand the parallel.
When the six Thracian ladies fall into the power of “thirty bloody-
minded satyrs,” who so likely, or so happy to rescue them as jolly St.
Patrick. How he flies to the rescue, slays one satyr, puts the rest to
flight, and true as steel, in love or friendship, takes the half dozen
damsels under his arm, and swings singingly along with them in
search of the roving Scot! As for St. David, all this while, he had not
been quite so triumphant, or so tried, as his fellows. He had fallen
into bad company, and “four beautiful damsels wrapped the drousie
champion in a sheet of fine Arabian silk, and conveyed him into a
cave, placed in the middle of a garden, where they laid him on a bed,
more softer than the down of Culvers.” In this agreeable company
the Welsh champion wiled away his seven years. It was pleasant but
not proper. But if the author had not thus disposed of him, how do
you think he would ever have got back to St. George of England?
The author indeed exhibits considerable skill, for he brings St.
George and St. David together, and the first rescues the second from
ignoble thraldom, and what is worse, from the most prosy enchanter
I ever met with in history, and who is really not enchanting at all. This
done, George is off to Tripoli.
There, near there, or somewhere else, for the romances are
dreadfully careless in their topography, he falls in with his old love
Sabra, married to a Moorish King. If George is perplexed at this,
seeing that the lady had engaged to remain an unmarried maiden till
he came to wed her, he is still more so when she informs him that
she has, in all essentials, kept her word, “through the secret virtue of
a golden chain steeped in tiger’s blood, the which she wore seven
times double about her ivory neck.” St. George does not know what
to make of it, but as on subsequently encountering two lions, Sabra,
while he was despatching one, kept the other quietly with its head
resting on her lap, the knight declared himself perfectly satisfied, and
they set out upon their travels, lovingly together.
By the luckiest chance, all the wandering knights and their ladies met
at the court of a King of Greece, who is not, certainly, to be heard of
in Gillies’ or Goldsmith’s history. The scenery is now on a
magnificent scale, for there is a regal wedding on foot, and
tournaments, and the real war of Heathenism against all
Christendom. As the Champions of Christendom have as yet done
little to warrant them in assuming the appellation, one would
suppose that the time had now arrived when they were to give the
world a taste of their quality in that respect. But nothing of the sort
occurs. The seven worthies separate, each to his own country, in
order to prepare for great deeds; but none are done for the benefit of
Christianity, unless indeed we are to conclude that when George and
Sabra travelled together, and he overcame all antagonists, and she
inspired with love all beholders;—he subdued nature itself and she
ran continually into danger, from which he rescued her:—and that
when, after being condemned to the stake, the young wife gave birth
to three babes in the wood, and was at last crowned Queen of
Egypt, something is meant by way of allegory, in reference to old
church questions, and in not very clear elucidation as to how these
questions were beneficially affected by the Champions of
Christendom!
I may add that when Sabra was crowned Queen of Egypt, every one
was ordered to be merry, on pain of death! It is further to be
observed there is now much confusion, and that the confusion by no
means grows less as the story thunders on. The Champions and the
three sons of St. George are, by turns, East, West, North, and South,
either pursuing each other, or suddenly and unexpectedly
encountering, like the principal personages in a pantomime. Battles,
love-making, and shutting up cruel and reprobate magicians from the
“humane eye,” are the chief events, but to every event there are
dozens of episodes, and each episode is as confusing, dazzling, and
bewildering as the trunk from which it hangs.
St. George, however, is like a greater champion than himself; and
when he is idle and in Italy, he does precisely what Nelson did in the
same place—fall in love with a lady, and cause endless mischief in
consequence. By this time, however, Johnson begins to think, rightly,
that his readers have had enough of it, and that it is time to dispose
of his principal characters. These too, are so well disposed to help
him, that when the author kills St. Patrick, the saint burys himself! In
memory of his deeds, of which we have heard little or nothing, some
are accustomed to honor him, says Mr. Johnson—“wearing upon
their hats, each of them, a cross of red silk, in token of his many
adventures under the Christian Cross.” So that the shamrock
appears to have been a device only of later times.
St. David is as quickly despatched. This champion enters Wales to
crush the pagans there. He wears a leek in his helmet, and his
followers adopt the same fashion, in order that friend may be
distinguished from foe. The doughty saint, of course, comes
conqueror out of the battle, but he is in a heated state, gets a chill
and dies after all of a common cold. Bruce, returning safe from
exploring the Nile, to break his neck by falling down his own stairs,
hardly presents a more practical bathos than this. Why the leek
became the badge of Welshmen need not be further explained.
It is singular that in recounting the manner of the death of the next
champion, St. Denis, the romancer is less romantic than common
tradition. He tells us how the knight repaired to then pagan France;
how he was accused of being a Christian, by another knight of what
we should fancy a Christian order, St. Michael, and how the pagan
king orders St. Denis to be beheaded, in consequence. There are
wonders in the heavens, at this execution, which convert the
heathen sovereign to Christianity; but no mention is made of St.
Denis having walked to a monastery, after his head was off, and with
his head under his arm. Of this prodigy Voltaire remarked, “Ce n’est
que le premier pas qui coute,” but of that the romancer makes no
mention. St. James suffers by being shut up in his chapel in Spain,
and starved to death, by order of the Atheist king. Anthony dies
quietly in a good old age, in Italy; St. Andrew is beheaded by the
cruel pagan Scots whom, in his old age, he had visited, in order to
bring them to conversion: and St. George, who goes on, riding down
wild monsters and rescuing timid maidens, to the last—and his
inclination, was always in the direction of the maidens—ultimately
meets his death by the sting of a venomous dragon.
And now it would seem that two or three hundred years ago, authors
were very much like the actors in the Critic, who when they did get
hold of a good thing, could never give the public enough of it.
Accordingly, the biography of the Seven Champions was followed by
that of their sons. I will spare my readers the turbulent details: they
will probably be satisfied with learning that the three sons of St.
George became kings, “according as the fairy queen had prophesied
to them,” and that Sir Turpin, son of David, Sir Pedro, son of James,
Sir Orlando, son of Anthony, Sir Ewen, son of Andrew, Sir Phelim,
son of Patrick, and Sir Owen, son of David, like their sires, combated
with giants, monsters, and dragons; tilted and tournamented in honor
of the ladies, did battle in defence of Christianity, relieved the
distressed, annihilated necromancers and table-turners, in short,
accomplished all that could be expected from knights of such
prowess and chivalry.
When Richard Johnson had reached this part of his history, he gave
it to the world, awaiting the judgment of the critics, before he
published his second portion: that portion wherein he was to unfold
what nobody yet could guess at, namely, wherefore the Seven
Champions were called par excellence, the Champions of
Christendom. I am afraid that meanwhile those terrible, god-like, and
inexorable critics, had not dealt altogether gently with him. The
Punch they offered him was not made exclusively of sweets. His St.
George had been attacked, and very small reverence been
expressed for his ladies. But see how calmly and courteously—all
the more admirable that there must have been some affectation in
the matter—he turns from the censuring judges to that benevolent
personage, the gentle reader. “Thy courtesy,” he says, “must be my
buckler against the carping malice of mocking jesters, that being
worse able to do well, scoff commonly at that they can not mend;
censuring all things, doing nothing, but (monkey-like) make apish
jests at anything they do in print, and nothing pleaseth them, except
it savor of a scoffing and invective spirit. Well, what they say of me I
do not care; thy delight is my sole desire.” Well said, bold Richard
Johnson. He thought he had put down criticism as St. George had
the dragon.
I can not say, however, that good Richard Johnson treats his gentle
reader fairly. This second part of his Champions is to a reader worse
than what all the labors of Hercules were to the lusty son of
Alcmena. An historical drama at Astley’s is not half so bewildering,
and is almost as credible, and Mr. Ducrow himself when he was
rehearsing his celebrated “spectacle drama” of “St. George and the
Dragon” at old Drury—and who that ever saw him on those
occasions can possibly forget him?—achieved greater feats, or was
more utterly unlike any sane individual than St. George is, as put
upon the literary stage by Master Johnson.
One comfort in tracing the tortuosities of this chivalric romance is
that the action is rapid; but then there is so much of it, and it is so
astounding! We are first introduced to the three sons of St. George,
who are famous hunters in England, and whose mother, the lady
Sabra, “catches her death,” by going out attired like Diana, to
witness their achievements. The chivalric widower thereupon sets
out for Jerusalem, his fellow-champions accompany, and George’s
three sons, Guy, Alexander, and David, upon insinuation from their
mother’s spirit, start too in pursuit. The lads were knighted by the
king of England before they commenced their journey, which they
perform with the golden spur of chivalry attached to their heels. They
meet with the usual adventures by the way: destroying giants, and
rescuing virgins, who in these troublesome times seem to have been
allowed to travel about too much by themselves. Meanwhile, their
sire is enacting greater prodigies still, and is continually delivering his
fellow-champions from difficulties, from which they are unable to
extricate themselves. Indeed, in all circumstances, his figure is the
most prominent; and although the other half-dozen must have
rendered some service on each occasion, St. George makes no
more mention of the same than Marshal St. Arnaud, in his letters on
the victory at the Alma, does of the presence and services of the
English.
It is said that Mrs. Radcliffe, whose horrors used to delight and
distress our mothers and aunts, in their younger days, became
herself affected by the terrors which she only paints to explain away
natural circumstances. What then must have been the end of
Richard Johnson? His scene of the enchantments of the Black
Castle is quite enough to have killed the author with bewilderment.
There is a flooring in the old palace of the Prince of Orange in
Brussels, which is so inlaid with small pieces of wood, of a thousand
varieties of patterns, as to be a triumph of its kind. I was not at all
surprised, when standing on that floor, to hear that when the artist
had completed his inconceivable labor, he gave one wild gaze over
the parquet of the palace, and dropped dead of a fit of giddiness. I
am sure that Richard Johnson must have met with some such
calamity after revising this portion of his history. It is a portion in
which it is impossible for the Champions or for the readers to go to
sleep. The noise is terrific, the incidents fall like thunderbolts, the
changes roll over each other in a succession made with electric
rapidity, and when the end comes we are all the more rejoiced,
because we have comprehended nothing; but we are especially glad
to find that the knight of the Black Castle, who is the cause of all the
mischief, is overcome, flies in a state of destitution to a neighboring
wood, and being irretrievably “hard up,” stabs himself with the first
thing at hand, as ruthlessly as the lover of the “Ratcatcher’s
Daughter.”
Time, place, propriety, and a respect for contemporary history, are
amusingly violated throughout the veracious details. Nothing can
equal the confusion, nothing can be more absurd than the errors. But
great men have committed errors as grave. Shakespeare opened a
seaport in Bohemia, and Mr. Macaulay wrote of one Penn what was
only to be attributed to another. And now, have the dramatists
treated St. George better than the romancers?
The national saint was, doubtless, often introduced in the Mysteries;
but the first occasion of which I have any knowledge of his having
been introduced on the stage, was by an author named John Kirke.
John was so satisfied with his attempt that he never wrote a second
play. He allowed his fame to rest on the one in question, which is
thus described on his title-page: “The Seven Champions of
Christendome. Acted at the Cocke Pit, and at the Red Bull in St.
John’s Streete, with a general liking, And never printed till this yeare
1638. Written by J. K.—London, printed by J. Okes, and are (sic) to
be sold by James Becket, at his Shop in the Inner Temple Gate,
1638.”
John Kirke treats his subject melodramatically. In the first scene,
Calib the Witch, in a speech prefacing her declarations of a love for
foul weather and deeds, tells the audience by way of prologue, how
she had stolen the young St. George from his now defunct parent,
with the intention of making a bath for her old bones out of his young
warm blood. Love, however, had touched her, and she had brought
up “the red-lipped boy,” with some indefinite idea of making
something of him when a man.
With this disposition the old lady has some fears as to the possible
approaching term of her life; but, as she is assured by “Tarfax the
Devill” that she can not die unless she love blindly, the witch, like a
mere mortal, accounting that she loves wisely, reckons herself a
daughter of immortality, and rejoices hugely. The colloquy of this
couple is interrupted by their son Suckabud, who, out of a head just
broken by St. George, makes complaint with that comic lack of fun,
which was wont to make roar the entire inside of the Red Bull. The
young clown retires with his sire, and then enters the great St.
George, a lusty lad, with a world of inquiries touching his parentage.
Calib explains that his lady mother was anything but an honest
woman, and that his sire was just the partner to match. “Base or
noble, pray?” asks St. George. To which the witch replies:—
“Base and noble too;
Both base by thee, but noble by descent;
And thou born base, yet mayst thou write true gent:”
and it may be said, parenthetically, that many a “true gent” is by birth

equal to St. George himself.
Overcome by her affection, the witch makes a present to St. George
of the half-dozen champions of England whom she holds in chains
within her dwelling. One of them is described as “the lively, brisk,
cross-cap’ring Frenchman, Denis.” With these for slaves, Calib yields
her wand of power, and the giver is no sooner out of sight when
George invokes the shades of his parents, who not only appear and
furnish him with a corrected edition of his biography, but inform him
that he is legitimate Earl of Coventry, with all the appurtenances that
a young earl can desire.
Thereupon ensues a hubbub that must have shaken all the lamps in
the cockpit. George turns the Witch’s power against herself, and she
descends to the infernal regions, where she is punningly declared to
have gained the title of Duchess of Helvetia. The six champions are
released, and the illustrious seven companions go forth in search of
adventures, with Suckabus for a “Squire.” The father of the latter
gives him some counsel at parting, which is a parody on the advice
of Polonius to Laertes. “Lie,” says Torpax:—
“Lie to great profit, borrow, pay no debts,

Cheat and purloin, they are gaming dicers’ bets.”
“If Cottington outdo me,” says the son, “he be-whipt.” And so, after
the election of St. George as the seventh champion of Christendom,
ends one of the longest acts that Bull or Cockpit was ever asked to
witness and applaud.
The next act is briefer but far more bustling. We are in that
convenient empire of Trebizond, where everything happened which
never took place, according to the romances. The whole city is in a
state of consternation at the devastations of a detestable dragon,
and a lion, his friend and co-partner. The nobles bewail the fact in
hexameters, or at least in lines meant to do duty for them; and the
common people bewail the fact epigrammatically, and describe the
deaths of all who have attempted to slay the monsters, with a
broadness of effect that doubtless was acknowledged by roars of
laughter. Things grow worse daily, the fiends look down, and general
gloom is settling thick upon the empire, when Andrew of Scotland
and Anthony of Italy arrive, send in their cards, and announce their
determination to slay both these monsters.
Such visitors are received with more than ordinary welcome. The
emperor is regardless of expense in his liberality, and his daughter
Violetta whispers to her maid Carinthia that she is already in love
with one of them, but will not say which; a remark which is answered
by the pert maid, that she is in love with both, and would willingly
take either. All goes on joyously until in the course of conversation,
and it is by no means remarkable for brilliancy, the two knights let fall
that they are Christians. Now, you must know, that the established
Church at Trebizond at this time, which is at any period, was
heathen. The court appeared to principally affect Apollo and Diana,
while the poorer people put up with Pan, and abused him for
denouncing may-poles! Well, the Christians had never been
emancipated; nay, they had never been tolerated in Trebizond, and it
was contrary to law that the country should be saved, even in its dire
extremity, by Christian help. The knights are doomed to die, unless
they will turn heathens. This, of course, they decline with a dignified
scorn; whereupon, in consideration of their nobility, they are
permitted to choose their own executioners. They make choice of the
ladies, but Violetta and Carinthia protest that they can not think of
such a thing. Their high-church sire is disgusted with their want of
orthodoxy, and he finally yields to the knights their swords, that they
may do justice on themselves as the law requires. But Andrew and
Anthony are no sooner armed again than they clear their way to
liberty, and the drop scene falls upon the rout of the whole empire of
Trebizond.
The third act is of gigantic length, and deals with giants. There is
mourning in Tartary. David has killed the king’s son in a tournament,
and the king remarks, like a retired apothecary, that “Time’s plaster
must draw the sore before he can feel peace again.” To punish
David, he is compelled to undertake the destruction of the enchanter
Ormandine, who lived in a cavern fortress with “some selected
friends.” The prize of success is the reversion of the kingdom of
Tartary to the Welsh knight. The latter goes upon his mission, but he
is so long about it that our old friend Chorus enters, to explain what
he affirms they have not time to act—namely, the great deeds of St.
George, who, as we learn, had slain the never-to-be-forgotten
dragon, rescued Sabrina, been cheated of his reward, and held in
prison seven years upon bread and water. His squire, Suckabus,
alludes to giants whom he and his master had previously slain, and
whose graves were as large as Tothill Fields. He also notices
“Ploydon’s law,” and other matters, that could hardly have been
contemporaneous with the palmy days of the kingdom of Tartary.
Meanwhile, David boldly assaults Ormandine, but the enchanter
surrounds him with some delicious-looking nymphs, all thinly clad
and excessively seductive; and we are sorry to say that the Welsh
champion, not being cavalierly mounted on proper principles, yields
to seduction, and after various falls under various temptations, is
carried to bed by the rollicking nymph Drunkenness.
But never did good, though fallen, men want for a friend at a pinch.
St. George is in the neighborhood; and seedy as he is after seven
years in the dark, with nothing more substantial by way of food than
bread, and nothing more exhilarating for beverage than aqua pura,
the champion of England does David’s work, and with more
generosity than justice, makes him a present of the enchanter’s
head. David presents the same to the King of Tartary, that, according
to promise pledged in case of such a present being made, he may
be proclaimed heir-apparent to the Tartarian throne. With this bit of
cheating, the long third act comes to an end.
The fourth act is taken up with an only partially successful attack by
James, David, and Patrick, on a cruel enchanter, Argalio, who at
least is put to flight, and that, at all events, as the knights remark, is
something to be thankful for. The fifth and grand act reveals to us the
powerful magician, Brandron, in his castle. He holds in thrall the King
of Macedon—a little circumstance not noted in history; and he has in
his possession the seven daughters of his majesty transformed into
swans. The swans contrive to make captives of six of the knights as
they were taking a “gentle walk” upon his ramparts. They are
impounded as trespassers, and Brandron, who has some low
comedy business with Suckubus, will not release them but upon
condition that they fight honestly in his defence against St. George.
The six duels take place, and of course the champion of England
overcomes all his friendly antagonists; whereupon Brandron, with his
club, beats out his own brains, in presence of the audience.
At this crisis, the King of Macedon appears, restored to power, and
inquires after his daughters. St. George and the rest, with a use of
the double negatives that would have shocked Lindley Murray,
declare
“We never knew, nor saw no ladies here.”
The swans, however, soon take their pristine form, and the three
daughters appear fresh from their plumes and their long bath upon
the lake. Upon this follows the smart dialogue which we extract as a
sample of how sharply the King of Macedon looked to his family
interests, and how these champion knights were “taken in” before
they well knew how the fact was accomplished.
Mac. Reverend knights, may we desire to know which of you are

unmarried?
Ant., Den., and Pat. We are.
Geo. Then here’s these ladies, take ’em to your beds.
Mac. George highly honors aged Macedon.
The three Knights. But can the ladies’ love accord with us?
The three Ladies. Most willingly!
The three Knights. We thus then seal our contract.
Geo. Which thus we ratifie.
Sit with the brides, most noble Macedon;
And since kind fortune sent such happy chance,
We’ll grace your nuptials with a soldier’s dance.
And, fore George, as our fathers used to say, they make a night of it.
The piece ends with a double military reel, and the audiences at the

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Essentials of Menâ€™s Health - eBook

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

I can hardly express the delight I feel as a biographer in the

and it may be said, parenthetically, that many a “true gent” is by birth

“Lie to great profit, borrow, pay no debts,

“We never knew, nor saw no ladies here.”

Mac. Reverend knights, may we desire to know which of you are

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

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Several classification schemes for ED have been pro