(Download PDF) Essentials of Mens Health 1St Edition Shalender Bhasin Full Chapter PDF

You might also like

Download as pdf or txt
Download as pdf or txt
You are on page 1of 69

Essentials of Men’s Health 1st Edition

Shalender Bhasin
Visit to download the full and correct content document:
https://ebookmass.com/product/essentials-of-mens-health-1st-edition-shalender-bhas
in/
More products digital (pdf, epub, mobi) instant
download maybe you interests ...

Essentials of Health Behavior (Essential Public Health)


2nd Edition

https://ebookmass.com/product/essentials-of-health-behavior-
essential-public-health-2nd-edition/

Essentials of Health Economics (Essential Public


Health) 2nd Edition

https://ebookmass.com/product/essentials-of-health-economics-
essential-public-health-2nd-edition/

Essentials of Management and Leadership in Public


Health (Essential Public Health) 1st Edition, (Ebook
PDF)

https://ebookmass.com/product/essentials-of-management-and-
leadership-in-public-health-essential-public-health-1st-edition-
ebook-pdf/

Essentials of Public Health (Essential Public Health)


3rd Edition, (Ebook PDF)

https://ebookmass.com/product/essentials-of-public-health-
essential-public-health-3rd-edition-ebook-pdf/
Essentials of Health Care Finance 8th Edition, (Ebook
PDF)

https://ebookmass.com/product/essentials-of-health-care-
finance-8th-edition-ebook-pdf/

Essentials of Health Care Marketing 4th Edition, (Ebook


PDF)

https://ebookmass.com/product/essentials-of-health-care-
marketing-4th-edition-ebook-pdf/

Essentials of the U.S. Health Care System 5th Edition

https://ebookmass.com/product/essentials-of-the-u-s-health-care-
system-5th-edition/

Essentials of Health Policy and Law (Essential Public


Health) 4th Edition, (Ebook PDF)

https://ebookmass.com/product/essentials-of-health-policy-and-
law-essential-public-health-4th-edition-ebook-pdf/

Essentials of Public Health Preparedness and Emergency


Management (Essential Public Health) 2nd Edition,
(Ebook PDF)

https://ebookmass.com/product/essentials-of-public-health-
preparedness-and-emergency-management-essential-public-
health-2nd-edition-ebook-pdf/
Essentials of Men's Health
Notice

Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge,
changes in treatment and drug therapy are required. The authors and the publisher of this work have
checked with sources believed to be reliable in their efforts to provide information that is complete
and generally in accord with the standards accepted at the time of publication. However, in view of the
possibility of human error or changes in medical sciences, neither the authors nor the publisher nor
any other party who has been involved in the preparation or publication of this work warrants that the
information contained herein is in every respect accurate or complete, and they disclaim all responsi­
bility for any errors or omissions or for the results obtained from use of the information contained in
this work. Readers are encouraged to confirm the information contained herein with other sources. For
example and in particular, readers are advised to check the product information sheet included in the
package of each drug they plan to administer to be certain that the information contained in this work
is accurate and that changes have not been made in the recommended dose or in the contraindica­
tions for administration. This recommendation is of particular importance in connection with new or
infrequently used drugs.
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
Boston, Massachusetts

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
Boston, Massachusetts

Mc
Graw
Hill
New York Chicago San Francisco Lisbon London Madrid Mexico City
New Delhi San Juan Seoul Singapore Sydney Toronto
Copyright © 2021 by McGraw Hill. All rights reserved. Except as permitted under the United States
Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any
means, or stored in a database or retrieval system, without the prior written permission of the publisher.

ISBN: 978-1-26-013589-3
MHID: 1-26-013589-6

The material in this eBook also appears in the print version of this title: ISBN: 978-1-26-013588-6,
MHID: 1-26-013588-8.

eBook conversion by codeMantra


Version 1.0

All trademarks are trademarks of their respective owners. Rather than put a trademark symbol after every
occurrence of a trademarked name, we use names in an editorial fashion only, and to the benefit of the
trademark owner, with no intention of infringement of the trademark. Where such designations appear in
this book, they have been printed with initial caps.

McGraw-Hill Education eBooks are available at special quantity discounts to use as premiums and sales
promotions or for use in corporate training programs. To contact a representative, please visit the Contact
Us page at www.mhprofessional.com.

TERMS OF USE

This is a copyrighted work and McGraw-Hill Education and its licensors reserve all rights in and to the
work. Use of this work is subject to these terms. Except as permitted under the Copyright Act of 1976
and the right to store and retrieve one copy of the work, you may not decompile, disassemble, reverse
engineer, reproduce, modify, create derivative works based upon, transmit, distribute, disseminate, sell,
publish or sublicense the work or any part of it without McGraw-Hill Education’s prior consent. You may
use the work for your own noncommercial and personal use; any other use of the work is strictly prohib­
ited. Your right to use the work may be terminated if you fail to comply with these terms.

THE WORK IS PROVIDED “AS IS.” McGRAW-HILL EDUCATION AND ITS LICENSORS MAKE
NO GUARANTEES OR WARRANTIES AS TO THE ACCURACY, ADEQUACY OR COMPLETE­
NESS OF OR RESULTS TO BE OBTAINED FROM USING THE WORK, INCLUDING ANY IN­
FORMATION THAT CAN BE ACCESSED THROUGH THE WORK VIA HYPERLINK OR OTHER­
WISE, AND EXPRESSLY DISCLAIM ANY WARRANTY, EXPRESS OR IMPLIED, INCLUDING
BUT NOT LIMITED TO IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FORA
PARTICULAR PURPOSE. McGraw-Hill Education and its licensors do not warrant or guarantee that the
functions contained in the work will meet your requirements or that its operation will be uninterrupted or
error free. Neither McGraw-Hill Education nor its licensors shall be liable to you or anyone else for any
inaccuracy, error or omission, regardless of cause, in the work or for any damages resulting therefrom.
McGraw-Hill Education has no responsibility for the content of any information accessed through the
work. Under no circumstances shall McGraw-Hill Education and/or its licensors be liable for any indi­
rect, incidental, special, punitive, consequential or similar damages that result from the use of or inability
to use the work, even if any of them has been advised of the possibility of such damages. This limitation
of liability shall apply to any claim or cause whatsoever whether such claim or cause arises in contract,
tort or otherwise.
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
This page intentionally left blank
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
Boston, Massachusetts
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
Boston, Massachusetts
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
Boston, Massachusetts
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
Harvard Medical School
Mohit Khera, MD, MBA, MPH
Boston, Massachusetts
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,
Department of Urology
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
Boston, Massachusetts
Department 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
Department of Urology
New York, New York
Massachusetts General Hospital
Alan W. Shindel, MD, MAS Boston, Massachusetts
Associate Professor of Urology
Elena Yanushpolsky, MD
Department of Urology
Assistant Professor, Harvard Medical School
University of California
Center for Infertility and Reproductive Surgery
San Francisco, California
Brigham and Womens Hospital
Ronald S. Swerdloff, MD Boston, Massachusetts
Professor of Medicine
Sigal Yawetz, MD
David Geffen School of Medicine at UCLA
Assistant Professor of Medicine
Senior Investigator
Harvard Medical School
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
Brigham and Womens Hospital
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
David Geffen School of Medicine at UCLA
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
This page intentionally left blank
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
6 Essentials of Men's Health

(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.
Chapter 1 THE PATHOPHYSIOLOGICAL BASIS OF ANDROGEN DISORDERS IN MEN 7

(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.
8 Essentials of Men's Health

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.
Chapter 1 THE PATHOPHYSIOLOGICAL BASIS OF ANDROGEN DISORDERS IN MEN 9

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.
10 Essentials of Men's Health

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).
12 Essentials of Men's Health

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
Chapter 1 THE PATHOPHYSIOLOGICAL BASIS OF ANDROGEN DISORDERS IN MEN 13

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
14 Essentials of Men's Health

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.
Chapter 1 THE PATHOPHYSIOLOGICAL BASIS OF ANDROGEN DISORDERS IN MEN 15

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
16 Essentials of Men's Health

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
Chapter 1 THE PATHOPHYSIOLOGICAL BASIS OF ANDROGEN DISORDERS IN MEN 17

effects on Leydig cell androgen production and REFERENCES


action. Some EDCs are estrogenic or antiandro-
1. Kaprara A, Huhtaniemi IT. The hypothalamus­
genic at high concentrations, often orders of mag­
pituitary-gonadal axis: Tales of mice and men. Metabo­
nitude higher than routine environmental exposure.
lism. 2018;86:3.
Even though several studies have reported correla­ 2. Watts AG. 60 years of neuroendocrinology: The struc­
tions between EDC levels and harmful reproductive ture of the neuroendocrine hypothalamus: The neu-
effects (e.g., anogenital distance and sperm counts) roanatomical legacy of Geoffrey Harris. J. Endocrinol.
in experimental animals and humans, the causal 2015;226:T25-T39.
link of EDCs in inhibition of T production or action 3. Dudas B, Merchenthaler I. Three-dimensional repre­
in the general population has not been established, sentation of the neurotransmitter systems of the human
and epidemiological data on their adverse effects on hypothalamus: Inputs of the gonadotrophin hor-
male reproductive health remain controversial.66 mone-releasing hormone neuronal system. J Neuroen-
docrinol. 2006;18:79.
4. Herbison AE. Physiology of the adult gonadotropin­
Key Points releasing hormone neural network. In Plant TM,
Zeleznik AJ, eds. Knobil and Neills Physiology of
1. Androgens are quintessential for the structure and Reproduction. 4th ed. Waltham, MA: Academic Press;
function of all aspects of the male phenotype. 2015:399.
2. Disorders of androgen function result in hypogo­ 5. Skorupskaite K, George JT, Anderson RA. The kiss-
nadism, defined as impairment of testicular andro­ peptin-GnRH pathway in human reproductive health
gen production or action, expressed as deficient and disease. Hum Reprod Update. 2014;20:485.
androgen-driven masculine development and 6. Hrabovszky E. Neuroanatomy of the human hypo­
function, including spermatogenesis. thalamic kisspeptin system. Neuroendocrinology.
2014;99:33.
3. Testosterone (T) is the main testicular androgenic
7. Moore AM, Coolen LM, Porter DT, Goodman RL,
steroid hormone, and it is produced in Leydig cells
Lehman MN. KNDy cells revisited. Endocrinology.
present in the testicular intertubular interstitial
2018;159:3219.
space.
8. Millar RP, Lu ZL, Pawson AJ, Flanagan CA, Morgan K,
4. The hypothalamic-pituitary-testicular (HPT) axis Maudsley SR. Gonadotropin-releasing hormone recep­
forms the functional regulatory circuit of endocrine tors. Endocr Rev. 2004;25:235.
regulation of testicular function. At the hypotha­ 9. Clarkson J, Han SY, Piet R, et al. Definition of the hypo­
lamic level, kisspeptin stimulates the secretion of thalamic GnRH pulse generator in mice. Proc Natl Acad
gonadotropin-releasing hormone (GnRH), which Sci U.S.A. 2017;114:E10216.
stimulates gonadotropin (LH and FSH) synthesis 10. Naor Z, Huhtaniemi I. Interactions of the GnRH recep­
and secretion in the pituitary gland. tor with heterotrimeric G proteins. Front Neuroendocri-
5. LH stimulates Leydig cell T production, which, after nol. 2013;34:88.
conversion to estradiol (E2), exerts a negative feed­ 11. Thompson IR, Kaiser UB. GnRH pulse frequency­
back effect on the hypothalamic-pituitary level to dependent differential regulation of LH and FSH gene
maintain functional equilibrium of the HPR axis. expression. Mol Cell Endocrinol. 2014;385:28.
6. T exerts its regulatory actions through binding 12. Bousfield GR, Dias JA. Synthesis and secretion of
to androgen receptors ubiquitously expressed gonadotropins including structure-function correlates.
throughout the body. Rev Endocr Metab Disord. 2011;12:289.
13. Fiete D, Srivastava V, Hindsgaul O, Baenziger JU. A
7. A part of T's action is exerted following its metabo­
hepatic reticuloendothelial cell receptor specific for
lism to 5 a-di hydrotestosterone and E2.
SO4-4GalNAc beta l,4GlcNAc beta l,2Man alpha
8. The causes of hypogonadism include mutations that mediates rapid clearance of lutropin. Cell. 1991;
in genes regulating HPT function (hormones, tran­ 67:1103.
scription factors, receptors, metabolic enzymes); 14. Troppmann B, Kleinau G, Krause G, Gromoll J.
other diseases indirectly impairing the HPT func­ Structural and functional plasticity of the luteinizing
tion; and iatrogenic, acquired, and environmental hormone/choriogonadotrophin receptor. Hum Reprod
factors. Update. 2013;19:583-602.
18 Essentials of Men's Health

15. De Pascali F, Trefier A, Landomiel F, et al. Follicle-stim­ 30. MacConell LA, Leal AM, Vale WW. The distribution
ulating hormone receptor: Advances and remaining of betaglycan protein and mRNA in rat brain, pituitary,
challenges. Int Rev Cell Mol Biol. 2018;338:l. and gonads: Implications for a role for betaglycan in
16. Tremblay JJ. Molecular regulation of steroidogenesis in inhibin-mediated reproductive functions. Endocrinol­
endocrine Leydig cells. Steroids. 2015; 103:3. ogy. 2002;143:1066.
17. Papadopoulos V, Miller WL. Role of mitochondria in 31. Matsumoto T, Sakasi M, Okada M, et al. The andro­
steroidogenesis. Best Pract Res Clin Endocrinol Metab. gen receptor in health and disease. Annu Rev Physiol.
2012;26:771. 2013;75:201.
18. Fluck CE, Pandey AV. Steroidogenesis of the testis 32. Gottlieb B, Beitel LK, Nadarajah A, Paliouras M, Trifiro
-- New genes and pathways. Ann Endocrinol (Paris). M. The androgen receptor gene mutations database:
2014;75:40. 2012 update. Hum Mutat. 2012;33:887.
19. O’Shaughnessy PJ, Antignac JP, Le Bizec B, et al. Alterna­ 33. Sutinen P, Malinen M, Palvimo J. Androgen receptor. In
tive (backdoor) androgen production and masculiniza­ Simoni M, Huhtaniemi I, eds. Endocrinology of the Testis
tion in the human fetus. PLoS Biol. 2019;17(2):e3000002. and Male Reproduction. Cham, Switzerland: Springer;
20. Ruokonen A, Laatikainen T, Laitinen EA, Vihko R. Free 2017:395.
and sulfate-conjugated neutral steroids in human testis 34. Fix C, Jordan C, Cano P, Walker WH. Testosterone acti­
tissue. Biochemistry. 1972;11:1411. vates mitogen-activated protein kinase and the cAMP
21. Leinonen P, Ruokonen A, Kontturi M, Vihko R. Effects response element binding protein transcription factor in
of estrogen treatment on human testicular unconju­ Sertoli cells. Proc Natl Acad Sci U.S.A. 2004; 101:10919.
gated steroid and steroid sulfate production in vivo. 35. Pi M, Nishimoto SK, Quarles LD. GPRC6A: Jack
I Clin Endocrinol Metab. 1981;53:569. of all metabolism (or master of none). Mol Metab.
22. Oduwole 00, Vydra N, Wood NE, et al. Overlapping 2017;6:185-193.
dose responses of spermatogenic and extragonadal tes­ 36. Aguirre RS, Eugster EA. Central precocious puberty:
tosterone actions jeopardize the principle of hormonal From genetics to treatment. Best Pract Res Clin Endocri­
male contraception. FASEB J. 2014;28:2566. nol Metab. 2018;32:343.
23. Martikainen H, Huhtaniemi I, Vihko R. Response of 37. Maione L, Dwyer AA, Francou B, et al. Genetics in endo­
peripheral serum sex steroids and some of their pre­ crinology: Genetic counseling for congenital hypogonad-
cursors to a single injection of hCG in adult men. Clin otropic hypogonadism and Kallmann syndrome: New
Endocrinol (Oxf). 1980;13:157. challenges in the era of oligogenism and next-generation
24. Hammond GL. Plasma steroid-binding proteins: Pri­ sequencing. Eur J Endocrinol. 2018;178:R55.
mary gatekeepers of steroid hormone action. J Endocri­ 38. Chevrier L, Guimiot F, de Roux N. GnRH receptor
nol. 2016;230:R13. mutations in isolated gonadotropic deficiency. Mol Cell
25. Vicari E, Mongioi A, Calogero AE, et al. Therapy with Endocrinol. 2011;346:21.
human chorionic gonadotrophin alone induces sper­ 39. Huhtaniemi I. Male hypogonadism resulting from
matogenesis in men with isolated hypogonadotrophic mutations in the genes for the gonadotropin subunits
hypogonadism-long-term follow-up. Int J Androl. 1992; and their receptors. In Winters SJ, Huhtaniemi IT, eds.
15:320. Male Hypogonadism: Basic, Clinical and Therapeu­
26. Page ST, Amory JK, Bremner WJ. Advances in male tic Principles. 2nd ed. Cham, Switzerland: Springer;
contraception. Endocr Rev. 2008;29:465. 2017:127.
27. McLachlan RI, Matsumoto AM, Burger HG, de Kretser 40. Achard C, Courtillot C, Lahuna O, et al. Normal sper­
DM, Bremner WJ. Relative roles of follicle-stimulating matogenesis in a man with mutant luteinizing hormone.
hormone and luteinizing hormone in the control N Engl J Med. 2009;361:1856.
of inhibin secretion in normal men. J Clin Invest. 41. Oduwole OO, Peltoketo H, Poliandri A, et al. Consti­
1988;82:880. tutively active follicle-stimulating hormone receptor
28. Hayes FJ, Pitteloud N, DeCruz S, Crowley WF Jr, Boep- enables androgen-independent spermatogenesis. J Clin
ple PA. Importance of inhibin B in the regulation of FSH Invest. 2018;128:1787.
secretion in the human male. J Clin Endocrinol Metab. 42. Tapanainen JS, Aittomaki K, Min J, Vaskivuo T, Huhta­
2011;86:5541. niemi IT. Men homozygous for an inactivating mutation
29. Pierik FH, Vreeburg JT, Stijnen T, De Jong FH, Weber of the follicle-stimulating hormone (FSH) receptor gene
RF. Serum inhibin B as a marker of spermatogenesis. present variable suppression of spermatogenesis and
J Clin Endocrinol Metab. 1998;83:3110. fertility. Nat Genet. 1997; 15:205.
Chapter 1 THE PATHOPHYSIOLOGICAL BASIS OF ANDROGEN DISORDERS IN MEN 19

43. Huhtaniemi I. Mechanisms in endocrinology: Hor­ A systematic review and meta-analysis of randomized
monal regulation of spermatogenesis: Mutant mice chal­ controlled trials. BMC Med. 2013; 11:57.
lenging old paradigms. Eur J Endocrinol. 2018;179:R143. 55. Kristensen DM, Desdoits-Lethimonies C, Mackey AL,
44. Auchus RJ, Miller WL. Defects in androgen biosynthesis et al. Ibuprofen alters human testicular physiology to
causing 46,XY disorders of sexual development. Semin produce a state of compensated hypogonadism. Proc
Reprod Med. 2012;30:417. Natl Acad Sci U.S.A. 2018;115:E715.
45. Mongan NP, Tadokoro-Cuccaro R, Bunch T, Hughes IA. 56. Wu FCW, Tajar A, Beynon JM, et al. Identification of
Androgen insensitivity syndrome. Best Pract Res Clin late-onset hypogonadism in middle-aged and elderly
Endocrinol Metab. 2015;29:569. men. N Engl J Med. 2010;363:123.
46. Rajender S, Singh L, Thangaraj K. Phenotypic hetero­ 57. Kaufman JM, Lapauw B, Mahmoud A, T’Sjoen G, Huht­
geneity of mutations in androgen receptor gene. Asian J aniemi IT. Aging and the male reproductive system.
Androl. 2007;9:147. Endocr Rev. 2019;40:906.
47. Huhtaniemi IT, Pye SR, Limer KL, et al. Increased estro­ 58. Iglesias P, Carrero JJ, Diez JJ. Gonadal dysfunction in
gen rather than decreased androgen action is associ­ men with chronic kidney disease: Clinical features,
ated with longer androgen receptor CAG repeats. J Clin prognostic implications and therapeutic options.
Endocrinol Metab. 2009;94:277. J Nephrol. 2012;25:31.
48. Gravholt CH, Chang S, Wallentin M, Fedder J, Moore P, 59. Akinola OB, Gabriel MO. Neuroanatomical and molec­
Skakkebsek A. Klinefelter syndrome: integrating genet­ ular correlates of cognitive and behavioural outcomes in
ics, neuropsychology, and endocrinology. Endocr Rev. hypogonadal males. Metab Brain Dis. 2018;33:491.
2018;39:389. 60. Huang AW, Muneyyirci-Delale O. Reproductive endo­
49. Winge SB, Dalgaard MD, Belling KG, et al. Transcrip­ crine issues in men with sickle cell anemia. Andrology.
tome analysis of the adult human Klinefelter testis and 2017;5:679.
cellularity-matched controls reveals disturbed differ­ 61. Kalyani RR, Gavini S, Dobs AS. Male hypogonadism
entiation of Sertoli- and Leydig cells. Cell Death Dis. in systemic disease. Endocrinol Metab Clin North Am.
2018;9:586. 2007;36:333.
50. Suzuki K, Nakajima K, Kamimura S, et al. Eight case 62. Bergendahl M, Veldhuis JD. Altered pulsatile gonado­
reports on sex-hormone profiles in sexually mature tropin signaling in nutritional deficiency in the male.
male Down syndrome. Int J Urol. 2010; 17:137. Trends Endocrinol Metab. 1995;6:145.
51. Ankarberg-Lindgren C, Westphal O, Dahlgren J. Tes­ 63. Breen KM, Karsch FJ. New insights regarding gluco­
ticular size development and reproductive hormones in corticoids, stress and gonadotropin suppression. Front
boys and adult males with Noonan syndrome: A longi­ Neuroendocrinol. 2006;27:233.
tudinal study. Eur J Endocrinol. 2011;165:137. 64. Fui MN, Dupuis P, Grossmann M. Lowered testosterone
52. Wong N, Levy M, Stephenson I. Hypogonadism in in male obesity: Mechanisms, morbidity and manage­
the HIV-infected man. Curr Treat Options Infect Dis. ment. Asian J Androl. 2014;16:223.
2017;9:104. 65. Grossmann M. Hypogonadism and male obesity:
53. Mitchell RT, Stukenborg J-B, Jahnukainen K. Male Focus on unsolved questions. Clin Endocrinol (Oxf).
hypogonadism due to cancer and cancer treatments. 2018;89:ll.
In Winters SJ, Huhtaniemi IT, eds. Male Hypogonad­ 66. Lymperi S, Giwercman A. Endocrine disruptors and tes­
ism: Basic, Clinical and Therapeutic Principles. 2nd ed. ticular function. Metabolism. 2018;86:79.
Cham, Switzerland: Springer; 2017:235. 67. Teerds KJ, Huhtaniemi IT. Morphological and func­
54. Schooling CM, Au Yeung SL, Freeman G, Cowling BJ. tional maturation of Leydig cells: From rodent models
The effect of statins on testosterone in men and women: to primates. Hum Reprod Update. 2015;21:310.
This page intentionally left blank
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
22 Essentials of Men's Health

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
24 Essentials of Men's Health

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
Chapter 2 PATHOPHYSIOLOGY OF ERECTILE DYSFUNCTION 25

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
26 Essentials of Men's Health

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
Chapter 2 PATHOPHYSIOLOGY OF ERECTILE DYSFUNCTION 27

Fischer et al. in middle-aged veterans estimated the 3. Yafi FA, Jenkins L, Albersen M, et al. Erectile dysfunc­
heritability of ED at 3 5%.33,34 More recently, several tion. Nat Rev Dis Primers. 2016;2:16003. doi:10.1038/
genetic polymorphisms have been linked with ED. nrdp.2016.3
The vascular endothelial growth factor (VEGF) 2578A 4. Tanagho EA, Lue TF. Chapter 1. Anatomy of the geni­
tourinary tract. In McAninch JW, Lue TF, eds. Smith &
allele carrier status in the Taiwanese population has
Tanaghos General Urology. 18th ed. New York, NY: The
been identified as a risk factor for ED (OR 1.54,95%
McGraw-Hill Companies; 2013.
CI 1.10-2.15).34 Two additional single nucleotide poly­ 5. Dean RC, Lue TF. Physiology of penile erection and
morphisms in the endothelial nitric oxide synthase pathophysiology of erectile dysfunction. Urol Clin North
(eNOS) gene, G894T (OR 1.55, 95% CI 1.06-2.28) Am. 2005;32(4):395. doi:I0.1016/j.ucl.2005.08.007
and T-786C (OR 1.68, 95% CI 1.341-2.102), were 6. Sopko NA, Hannan JL, Bivalacqua TJ. Understanding
identified in association with ED.35 Results of a large and targeting the rho kinase pathway in erectile dysfunc­
genome-wide association study by Jorgenson et al. tion. Nat Rev Urol. 2014;l 1 (11):622-628. doi:I0.I038/
implicated a locus on chromosome 6 (rsl7185536-T) nrurol.2014.278
near the single-minded family basic helix-loop-helix 7. Goldstein I, Feldman MI, Deckers PJ, Babayan RK,
transcription factor 1 (SIM1) gene in 26% of men with Krane RJ. Radiation-associated impotence. A clinical
study of its mechanism. JAMA. 1984;251(7):903-910.
ED, independent of other known ED risk factors, such
8. Andersen KV, Bovim G. Impotence and nerve entrap­
as body mass index (BMI).36,37 Mutations of the locus
ment in long distance amateur cyclists. Acta Neurol
were significantly associated with ED (OR 1.37 (95% Scand. 1997;95(4):233-240.
CI 1.31-1.43). 9. Levine FJ, Greenfield AJ, Goldstein I. Arteriographically
determined occlusive disease within the hypogastric-
cavernous bed in impotent patients following blunt per­
CONCLUSION ineal and pelvic trauma. / Urol. 1990;144(5):l 147-1153.
10. Gupta N, Herati A, Gilbert BR. Penile Doppler ultra­
The prevalence of ED increases with age and with sound predicting cardiovascular disease in men with
comorbid medical conditions, and ED has been rec­ erectile dysfunction. Curr Urol Rep. 2015; 16(3): 16.
ognized as a symptom of many underlying condi­ doi:10.I007/sl 1934-015-0482-1
tions and diseases. Endothelial dysfunction appears 11. Heidler S, Temml C, Broessner C, et al. Is the metabolic
to be a final pathway to ED in patients with diabetes, syndrome an independent risk factor for erectile dys­
function? / Urol. 2007;177(2):651-654. doi: 10.1016/j.
hypertension, hyperlipidemia, and vascular disease.
juro.2006.09.043
Medications, psychogenic causes, and endocrine and
12. Nehra A, Goldstein I, Pabby A, et al. Mechanisms of
neurological disorders are other well-established venous leakage: A prospective clinicopathological cor­
causes. More recently, idiopathic and genetic causes relation of corporeal function and structure. / Urol.
of ED have been identified. Emerging research in I996;156(4):1320-1329.
molecular biology, stem cells, growth factors, and sig­ 13. Steers WD. Neural control of penile erection. Semin
nal transduction will continue to progress our under­ Urol. 1990;8(2):66-79.
standing of the disease, ultimately leading to improved 14. Wermuth L, Stenager E. Sexual aspects of Parkin­
patient outcomes. son’s disease. Semin Neurol. 1992;12(2):125-127.
doi:10.1055/s-2008-1041166
15. Nelson CJ, Scardino PT, Eastham JA, Mulhall JP. Back to
baseline: Erectile function recovery after radical pros­
REFERENCES tatectomy from the patients’ perspective. / Sex Med.
1. Lizza EF, Rosen RC. Definition and classification of erec­ 2013;10(6):1636-1643. doi:10.1111/jsm.l2135
tile dysfunction: Report of the nomenclature committee 16. Walsh PC, Donker PJ. Impotence following radical
of the international society of impotence research. Int J prostatectomy: Insight into etiology and prevention. /
Imp ot Res. 1999;11 (3): 141 -143. Urol. 1982;128(3):492-497.
2. Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, 17. Quinlan DM, Epstein JI, Carter BS, Walsh PC. Sex­
McKinlay JB. Impotence and its medical and psychoso­ ual function following radical prostatectomy: Influ­
cial correlates: Results of the Massachusetts male aging ence of preservation of neurovascular bundles. J Urol.
study. J Urol. 1994;151(1):54-61. 1991;145(5):998-1002.
28 Essentials of Men's Health

18. Kupelian V, Araujo AB, Chiu GR, Rosen RC, McKinlay 28. Grimm RH, Grandits GA, Prineas RJ, et al. Long-term
JB. Relative contributions of modifiable risk factors to effects on sexual function of five antihypertensive drugs
erectile dysfunction: Results from the Boston area com­ and nutritional hygienic treatment in hypertensive men
munity health (BACH) survey. Prev Med. 2010;50(l- and women. Treatment of mild hypertension study
2): 19-25. doi: 10.1016/j.ypmed.2009.11.006 (TOMHS). Hypertension. 1997;29:8-14.
19. Lue TF. Physiology of penile erection and pathophysi­ 29. Williams AM, Simon I, Landis PK, et al. Prostatic
ology of erectile dysfunction. In Wein AJ, Kavoussi LR, growth rate determined from MRI data: Age-related
Partin AW, Peters CA, eds. Campbell-Walsh Urology. longitudinal changes. J Androl. 1999;20(4):474-480.
11th ed. Philadelphia, PA: Elsevier; 2016:642.e9 30. Rosen R, Altwein J, Boyle P, et al. Lower urinary tract
20. Mouraviev VB, Coburn M, Santucci RA. The treatment symptoms and male sexual dysfunction: The multina­
of posterior urethral disruption associated with pelvic tional survey of the aging male (MSAM-7). Eur Urol.
fractures: Comparative experience of early realignment 2003;44(6):637-649.
versus delayed urethroplasty. J Urol. 2005;173(3):873- 31. Me Vary KT, Roehrborn CG, Kaminetsky JC, et al. Tada-
876. doi:10.1097/01.ju.0000152145.33215.36 lafil relieves lower urinary tract symptoms secondary to
21. Beyer C, Gonzalez-Mariscal G. Effects of sex steroids on benign prostatic hyperplasia. J Urol. 2007;177(4): 1401 -
sensory and motor spinal mechanisms. Psychoneuroen- 1407. doi: 10.1016/j.juro.2006.11.037
docrinology. 1994;19(5-7):517-527. 32. Cohen D, Gonzalez J, Goldstein I. The role of pelvic floor
22. Corona G, Rastrelli G, Morgentaler A, Sforza A, Man- muscles in male sexual dysfunction and pelvic pain. Sex
nucci E, Maggi M. Meta-analysis of results of testosterone Med Rev. 2016;4(l):53-62. doi: 10.1016/j.sxmr.2015.10.001
therapy on sexual function based on international index 33. Anderson RU, Wise D, Sawyer T, Chan CA. Sexual dys­
of erectile function scores. Eur Urol. 2017;72(6): 1000- function in men with chronic prostatitis/chronic pelvic
1011. doi:10.1016/j.eururo.2017.03.032 pain syndrome: Improvement after trigger point release
23. Spitzer M, Basaria S, Travison TG, et al. Effect of tes­ and paradoxical relaxation training. / Urol. 2006; 176(4
tosterone replacement on response to sildenafil citrate Pt 1):1539. doi:10.1016/j.juro.2006.06.010
in men with erectile dysfunction: A parallel, random­ 34. Fischer ME, Vitek ME, Hedeker D, Henderson WG,
ized trial. Ann Intern Med. 2012;157(10):681-691. Jacobsen SJ, Goldberg J. A twin study of erectile dys­
doi:10.7326/0003-4819-157-10-201211200-00004 function. Arch Intern Med. 2004;164(2):165-168.
24. Huh JS, Chung BH, Hong CH, et al. The effects of tes­ doi: 10.1001 /archinte. 164.2.165
tosterone replacement on penile structure and erec­ 35. Lee Y, Huang S, Tsai C, et al. Associations of VEGF
tile function after long-term castration in adult male gene polymorphisms with erectile dysfunction and
rats. Int J Impot Res. 2018;30(3):122-128. doi:10.1038/ related risk factors. J Sex Med. 2017;14(4):510-517.
S41443-017-0010-6 doi: 10.1016/j.jsxm.2017.02.009
25. Granata AR, Rochira V, Lerchl A, Marrama P, Carani C. 36. Gao L, Zhao Z, Guo F, et al. Association of endo­
Relationship between sleep-related erections and testos­ thelial nitric oxide synthase polymorphisms with an
terone levels in men. J Androl. 1997;18(5):522-527. increased risk of erectile dysfunction. Asian J Androl.
26. Kim SC, Oh MM. Norepinephrine involvement in 2017;19(3):330-337. doi:10.4103/1008-682X.163300
response to intracorporeal injection of papaverine in 37. Jorgenson E, Matharu N, Palmer MR, et al. Genetic varia­
psychogenic impotence. 7 Urol. 1992;147(6):1530-1532. tion in the SIM 1 locus is associated with erectile dysfunc­
27. Keene LC, Davies PH. Drug-related erectile dysfunc­ tion. Proc Natl Acad SciUS A. 2018;l 15(43): 11018-11023.
tion. Adverse Drug React Toxicol Rev. 1999;18(l):5-24. doi: 10.1073/pnas. 1809872115
The Pathophysiology
of Male Infertility
RamyAbou Ghayda and Martin Kathrins

INTRODUCTION spermatogenesis is around 70 days, with another few


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

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
Another random document with
no related content on Scribd:
the actor Sato, whom I sent to release Hanako at Antwerp, is now
the husband of the little Japanese doll.
XIX
SARDOU AND KAWAKAMI

“W HO is author of the play that Sada Yacco is playing?” a


writer friend asked me one day.
“Kawakami, her husband.”
“Really. Well, then he ought to belong to the Society of Authors.”
And we proposed his name.
On the appointed day I took him to the Society of Authors. I was
quite surprised to note that the gentlemen of the committee had
turned out to a man to receive him.
We were ushered into the committee room, where these
gentlemen awaited us, seated round a large table.
Sardou, who presided, received us with a very appropriate
address. He greeted Kawakami as the man who first forged a literary
bond between France and Japan. He warmly congratulated
Kawakami on having been the first manager who had the courage to
bring a company from his distant native land to a city where no one
understood a word of Japanese. He complimented Kawakami and
complimented him again, and ended by calling him his “dear
comrade.”
After which he sat down.
There was silence, and I knew that they were expecting some
response from Kawakami. But he seemed in no wise to suspect that
he had furnished the theme for the discourse just ended. He
remained calmly in his seat and surveyed the gentlemen one by one.
I realised the necessity for immediate action. Some one must
sacrifice himself. In the present crisis, cost what it may, it devolved
on me to intervene. Turning toward Kawakami, I asked, in
pantomime: “Do you understand?”
He shook his head to say no.
Thereupon M. Sardou added:
“Speak to him, Miss Fuller. Translate to him what has just been
said.”
Finally, since there was nothing else for it, I summoned all my
strength, and at some length I explained in good English to
Kawakami, who did not understand a syllable of it, that this speech
Sardou had prepared expressly for him because he was a Japanese
author, and because the French were greatly pleased that he had
brought his Japanese company to Paris, and that the Society of
Authors received him with pleasure. I then explained to Kawakami,
with the indispensable assistance of appropriate gestures, that the
time had arrived for him to get up and say something in Japanese.
Was it not the essential fact that these gentlemen believed that
M. Sardou’s words had been translated?
Kawakami immediately arose and delivered an address which
must have been most carefully thought out. To judge from the
seriousness of the orator’s aspect, and from the length of his
harangue Kawakami is a great political orator. When he had finished
he sat down, while everybody looked at him admiringly, with
beaming faces.
No one, however, had understood a single word of what he said.
I, naturally, was in the same plight as the others. There ensued a
second somewhat painful silence, broken by Sardou asking:
“What did he say, Miss Loie?”
That was a poser. For there was no reason why I should
understand Japanese any better than these gentlemen of the
Society of Authors.
As, however, I had a feeling that I was a little responsible for what
took place, in order not to cause them any disappointment I screwed
my courage up again, rose and began to make a speech. Those who
know me can fancy what this speech was like. It was in French, but I
would take my oath that it was as hard to understand as Kawakami’s
Japanese. However, I managed to ring the changes on the words
“Japanese gratitude, Japanese pride,” and I did my best to paint in
glowing colours Kawakami’s joy at having established a bond
between the theatrical worlds of the two countries.
My speech was only a bad imitation of what M. Sardou had said,
and what I had vaguely understood of Kawakami’s views. I tried, in
fact, to say what Kawakami would have said in my place and, with as
much emphasis and big sincere words, I came to a close. Then
before sitting down I asserted once more: “There, gentlemen, that is
what he said.”
My role of being an interpreter without understanding the
language was finished. There was a storm of hurrahs and the ice
was broken. The conversation became general, and the meeting
ended in being a great success so far as Kawakami was concerned.
It was Kawakami’s day. As for me, I was not in it.
The result of this meeting was that Kawakami played Sardou’s La
Patrie in Japan, obtaining for this work a success as great as for the
Shakespearean plays he likewise represents there, and whose parts
he plays with such truth that he is called at home, “the Japanese
Mark Antony.”
He brought to the theatres of his native land certain
modifications, which have radically changed their dramatic methods.
It is customary in Japan to begin a play at nine or ten o’clock in the
morning and to make it last at least until midnight. One lunches and
dines at the theatre during the intervals, which, it is needless to say,
are interminable.
Kawakami changed that condition of things by beginning at half-
past six or at seven o’clock in the evening and ending before
midnight. And how do you suppose he managed to prevent people
eating between the acts? for that was the most difficult innovation.
He made the intervals so short that there was no time even to go to
the refreshment-room. It was really an easy thing to compel the
public to alter its habits. Instead of appealing to people’s reason,
Kawakami simply made it impossible for them to continue doing what
they had previously done.
European theatres are now building in Japan, in order that actors
from Europe may go there and produce their plays. The Nipponese
public is learning to give them a more favourable reception.
All that is due to Kawakami and to his sympathetic reception at
the Society of Authors. I cannot refrain from congratulating myself on
this, for, after all, it was I who “translated” the addresses and thus
sealed in words this new entente cordiale.
That brings to mind a little story.
It happened at the Athénée in 1893. We were rehearsing the
“Salome” of Armand Silvestre and Gabriel Pierné. Behind the scenes
one day I encountered a man with an enormous muffler, which went
several times around his neck, and a tall hat of a style that came
down over his ears. I chatted with him in the indifferent French I had
at command, and this without knowing who he was. While talking to
him I noticed a hole in his shoe. He was aware of my discovery, I
suppose, for he said to me:
“I had that hole made expressly. I prefer a hole in my shoe to a
pain in my foot.”
This man was Victorien Sardou.
A word more about my Japanese friends.
Kawakami has a son who was five years old when I first saw him.
He passed his time drawing everything around him.
I observed in his simple childish drawings a very peculiar manner
he affected in representing people’s eyes. They were always drawn
like billiard balls emerging from the face. I asked Kawakami:
“Don’t you think that it is an odd way to draw eyes?”
“Yes, but it is because the European eye is quite like the eye of a
fish,” the father replied.
That aroused in me a desire to know more intimately his
impressions of our race, and I asked him what Europeans look like
from the Japanese point of view.
“All Europeans,” he said, “resemble pigs. Some of them look like
dirty pigs, some like clean pigs; but they all look like pigs.”
I never said anything about this to M. Sardou.
XX
AN EXPERIENCE

I T happened in February, 1902. I arrived at Vienna with my


Japanese company, headed by Sada Yacco. We had with us an
artist to whom I had been delighted to be of service. In Paris my
close friend, Madame Nevada, the celebrated American singer, had
presented her to me, and the dancer had given me a performance as
an example of her skill. She danced with remarkable grace, her body
barely covered by the flimsiest of Greek costumes, and she bade fair
to become somebody. Since then she has arrived. In her I saw the
ancient tragic dances revived. I saw the Egyptian, Greek and Hindoo
rhythms recalled.
I told the dancer to what height I believed that she could attain,
with study and persistent work. A short time after I left for Berlin,
where she rejoined me. During our stay there she was ill most of the
time and could do hardly any work.
Finally, on our return to Vienna, we began our studies seriously,
and I decided to organise some evening affairs as a means of
bringing her before an audience of people capable of appreciating
and understanding her.
To this end I took her to every drawing-room that was open to me
in Vienna. Our first call was upon the wife of the English
ambassador, whom I had known at Brussels when her husband
represented the United Kingdom there. On this day I came near
going in alone and leaving my dancer in the carriage, because of her
personal appearance. She wore an Empire robe, grey, with a long
train and a man’s hat, a soft felt hat, with a flying veil. Thus gowned
she appeared to so little advantage that I rather expected a rebuff.
However, I pleaded my dancer’s cause so warmly, and I obtained a
promise that both the ambassador and his wife would be present on
the first evening.
I went next to see the Princess of Metternich.
“My dear Princess,” I said to her, “I have a friend, a dancer, who
has not yet succeeded in coming to the front because she is poor
and has no one to launch her. She is very talented, and I am anxious
that Viennese drawing-rooms shall come to know her. Are you willing
to help me?”
“With pleasure. What must I do?”
“To begin with, come to my hotel, and see her dance.”
“Why, certainly. You can count absolutely upon me.”
The princess is impressively simple. Where one expects to find a
grande dame arrayed in finery and of lofty bearing, one discovers a
charming woman, receptive, simple, witty, and possessed of
extraordinary youthfulness of manner. When Prince Metternich was
ambassador at Paris she was given the nickname one applied to
Adelaide of Savoy; she was called “the pretty, homely one.” The
princess went one better by saying, “I am the best dressed ape in
Paris.” I wonder if she could ever have been plain. There is such
intelligence implicit in every feature of her face.
Under the light grey locks the black eyes have preserved the
sprightliness, the sweetness of youth. Her smile gave me
confidence. It was thus that I had always pictured the gentlewoman,
revealed by everything that she is herself and not solely by the
things that surround her or by the high rank she occupies in society.
I had heard it said that this woman had the greatest influence at
the Austrian court, and looking at her I understood it. Her carriage,
her countenance and everything else inspired respect and affection.
When I took leave her last words were:
“I shall be delighted to help your friend since I shall be thus able
to please you.”
I went away, gratified and thankful on my own account as well as
on my friend’s.
Then I went to the Embassy of the United States. I saw the
ambassador immediately, but I was obliged to wait to see his wife.
She entered breezily, bringing with her, as it were, a whiff of her own
far west. Kind, energetic, jolly, she was a free born woman, cordial
and sincere, and I felt at once that I could rely on her.
While I spoke of my protégée, the ambassador’s wife
remembered having seen her dance at her sister’s house in Chicago
some years before. The dancing, to tell the truth, had not particularly
interested her, but if it would be of any help to us she would be very
glad to come to our performance.
Sure of having a good audience I returned to the hotel and told
my friend that the occasion she had desired so long had at last
arrived.
I decided to give an evening for the press on the same day on
which my friend would appear at a matinee before the Princess and
members of the diplomatic corps.
I then sent invitations to the Viennese artists and art critics. When
the day came everything was in readiness. I had engaged an
orchestra; the hall had floral decorations; the buffet was most
appetising.
The English ambassador, his wife and daughter, were among the
first arrivals. There was a great gathering in front of the hotel to
admire their carriage with the magnificent liveries.
Then came the turn of the American ambassador and his wife, in
a black carriage, very simple, but very elegant. Finally all the others
arrived. Suddenly the princess’ turnout, so well known to all Vienna,
paused before the door.
After having welcomed my guests I begged them to excuse me
for a minute and I went in to see the débutante.
It was half-past four. In ten minutes she was due to begin. I found
her with her feet in warm water, in the act of dressing her hair, in a
very leisurely manner. Startled, I begged her to hurry, explaining that
she ran the risk through her negligence of offending an audience that
would definitely give her her start. My words were without effect.
Very slowly she continued her preparations. Feeling that I could do
nothing with her I returned to the drawing-room and made the
greatest effort of my life to get out of this delicate situation.
I was obliged to make a little impromptu address. What I said I
have never known, but I remember having vaguely fashioned
something like a dissertation on dancing and its value in relation to
the other arts and to nature. I said that the young woman whom we
were going to see was not an imitator of the dancers depicted on the
Etruscan vases and the frescoes at Pompeii. She was the living
reality of which these paintings were only an imitation. She was
inspired by the spirit which had made dancers of them.
All at once she made her entrance, calm and indifferent, looking
as if she did not care in the least what our guests thought of her.
But it was not her air of indifference that surprised me most. I
could hardly refrain from rubbing my eyes. She appeared to me
nude, or nearly so, to so slight an extent did the gauze which she
wore cover her form.
She came to the front, and, while the orchestra played a prelude
from Chopin she stood motionless, her eyes lowered, her arms
hanging by her side. Then she began to dance.
Oh, that dance, how I loved it! To me it was the most beautiful
thing in the world. I forgot the woman and all her faults, her absurd
affectations, her costume, and even her bare legs. I saw only the
dancer, and the artistic pleasure she was giving me. When she had
finished no one spoke.
I went up to the Princess. She said to me in a low voice:
“Why does she dance with so little clothing on?”
Then I suddenly realised the strange attitude of the public, and
guided by a sort of inspiration, I answered in tones loud enough so
that everybody should hear:
“I forgot to tell you how kind our artist is. Her trunks upon which
she relied absolutely for the day have not arrived. Accordingly, rather
than give you the disappointment of not seeing her dance, she
appeared before you in the gown in which she practises.”
At nine o’clock the press performance took place. Everybody was
enthusiastic, but none more so than I.
Next day I arranged a third performance for painters and
sculptors, and this affair was likewise a great success.
A lady finally asked my friend to dance at her house. The star
demanded a very high price. Persuaded by me the lady consented to
pay the big fee my dancer claimed to be worth. For several weeks
her success increased day by day.
Then, all at once, people seemed to have forgotten the dancer.
She was engaged only rarely, but I was not discouraged.
Meantime, I had forgotten to mention it, my friend’s mother had
joined us at Vienna, and in place of one guest I now had two.
A little while after these performances we went to Budapesth,
where I gave a new entertainment to launch my protégée. I invited all
the best people of the city to this.
The leading actress of the Théâtre National heard of the affair,
and was anxious to take part in it. I invited the theatrical managers
as I had done at Vienna. This time one of them was to make up his
mind regarding an engagement. The next day he came to see me,
and proposed twenty performances in one of the first theatres of
Budapesth. My friend was to rehearse, beginning the next day. On
that same day I had an interminable rehearsal with my Japanese
actors, and I was detained from home until late in the afternoon. On
returning to the hotel I learned that the dancer and her mother had
gone to Vienna to give there an evening performance I had arranged
for her before our departure. My orchestra leader accompanied
them. I was, I must confess, a little surprised at the abruptness with
which they left, but I thought no more about it until my orchestra
leader returned.
He came back alone. At first he evaded questions. Then he
confessed that these ladies did not expect to rejoin me. I could not,
and would not, believe him.
“Very well,” he said. “These are the precise words which the
mother uttered while we were on the train. ‘Now that she has started
you,’ she said, to her daughter, ‘you have no more use for her.’ To
which the daughter replied, ‘Well, I haven’t the least desire to go
back to Loie.’”
When these ladies were ready to return to Budapesth they
allowed my orchestra leader to go without sending any message to
me. I telegraphed to find out if I was not to see them again. My
dancer replied with a telegram so worded: “Only in case you will
deposit to my credit ten thousand francs in a Viennese bank before
nine o’clock to-morrow morning.”
This proceeding was all the more cruel as she knew that I had
just lost more than one hundred thousand francs through a Viennese
manager who had broken his contract with my Japanese company.
Besides, my expenses were very heavy and I was badly
embarrassed. After I left Budapesth the dancer came there to fill the
engagement I had secured for her. Then she went to Vienna and
gave some performances there. I have been told that she went to all
the people to whom I had presented her and asked them to take
tickets. She thus disposed of seats amounting to some thousands of
florins. Everybody was ready to help her, including the wife of the
English ambassador and the Princess of Metternich. Above all, I
must have gained a reputation as an impostor, for my friend
continued to appear in public in what I had called her practising
gown.
Some years later at Brussels I learned that my dancer said to
somebody who wanted to know whether she was acquainted with
Loie Fuller that she did not know me.
XXI
AMERICAN AFFAIRS

A STRANGER, and especially a Frenchman who has never


travelled in America simply cannot imagine what our country is
like. A Frenchman may get an idea of Germany without having
seen it; of Italy, without having been there; of India even, without
having visited it. It is impossible for him to understand America as it
is.
I had proof of the truth of this observation in certain
circumstances that were altogether unexpected. This experience I
recall frequently as one that was peculiarly amusing, so amusing
indeed that I regard the incident as one of the most comic I have
ever encountered.
The hero of the adventure was a young journalist and man about
town named Pierre Mortier. One might imagine that from the fact of
his profession, which usually gives those who follow it a reasonable
smattering of everything, that he would be less liable to surprise and
astonishment than some shop assistant or railway employee. The
actual occurrences proved the contrary.
But let us view this farce from the rising of the curtain.
I embarked on a steamer at Cherbourg, with my mother and
some friends, bound for New York. Pierre Mortier came on board to
offer his best wishes for a delightful voyage. We made him inspect
our state-rooms, my friends and I, and we shut him in one of them. In
vain he battered the wooden door with fist and foot. We were deaf to
his appeals, for we had decided to release him only when the boat
was already out of the roadstead and bound for the shores of the
new world.
At first he protested, not without vehemence, for he was not at all
equipped as regards wardrobe for such a voyage, but he soon
cooled off and gaily assumed his part in the rather strenuous farce
into which we had precipitated him.
“Be quiet,” I said to him, “everything will come out all right.”
“But how? I haven’t even a spare collar with me.”
His appearance was so disconsolate that I began to laugh
heartily. Gaiety spreads from one person to another as easily as
gloom. He began, in his turn, to laugh.
Arrived in New York we went to the best hotel in Brooklyn. The
first thing that caught Pierre Mortier’s eye in the hotel lobby was the
unusual number of spittoons. They were everywhere, of all sizes and
shapes, for Americans do not hesitate, if they have no receptacle
within easy reach, to spit on the floor, and to throw the ends of their
cigars anywhere, without even taking the trouble to extinguish them.
We reached our rooms. There in an array along the wall some
buckets, filled with water, attracted his attention. “Some more
spittoons!” cried Mortier.
Everybody laughed, and he said in a somewhat peevish tone:
“Then what are those buckets for?”
“Why, in case of fire.”
“I thought,” said Mortier, “that all American buildings were fire-
proof.”
“That is what you hear in Paris, but houses of that sort are really
very rare.”
“Yet you pay enough in your country to have more comfort and
security than anywhere else. For instance, that carriage just now. It
was nothing short of robbery. Twenty-five francs to take us from the
station here. And such an old trap! I don’t understand why your laws
tolerate such things.”
Already he was beginning to protest. There was sure to be
something else the next day.
On awakening on the first morning he pressed once on the
electric button in his bedroom. A bell-boy appeared, bringing a
pitcher of ice water. Thinking this a form of cheap wit Mortier
sputtered some of his worst insults, happily couched in French. The
bell-boy, a huge negro, looked calmly down upon this excited little
man with the fair hair and skin, and then, without asking for his tip,
quietly closed the door and went away.
This attitude of unconcern was not calculated to assuage our
friend’s bellicose mood. He rang the bell again, and three times
instead of once. That was the summons to be made when a guest
wanted a boot-black sent to take his boots. Such a personage
presented himself.
The personage explained to Mortier that if he touched the bell
once that brought ice water; three times a boot-black. But Mortier did
not understand a word of English. Accordingly the boot-black did
what the bearer of ice water had done before, quite unconcernedly
he went away.
Pierre Mortier was in a furious rage when a third boy presented
himself, as black as the two preceding, for all the attendants are
negroes in American hotels. This fellow was willing to remove his
boots. Some minutes passed. Mortier was almost apoplectic with
anger. The boy reappeared. He explained to his client that he gave
the boots back only in return for a dollar. Mortier was still in bed. To
make him understand, the negro lifted his clothes, which were folded
on a chair, and, whistling, all the while, rifled the pockets. He picked
out a dollar, and put it carelessly into his own pocket. Then he left
the boots on the floor and disappeared.
In a paroxysm of rage our friend dressed himself in a great hurry
and went to the hotel desk, where he made the place resound with
curses that no one paid any attention to since no one understood
them.
On the evening of the same day Mortier put his boots outside his
door in order that they might be cleaned before next morning, as is
done everywhere in England and France.
In America when something is left in front of the door it is only as
a sign that the object can be thrown away. Mortier never saw his
shoes again.
He rang, a negro presented himself. Mortier demanded his
shoes. He cried, stormed, threatened. The negro backed up against
the wall and unconcernedly whistled a cakewalk.
Speechless with rage, Mortier hurled himself upon the black. The
hotel negroes, especially when they are not armed, are ordinarily
lacking in courage. Besides, this one had good reasons for believing
that his client had gone mad. So he hastily decamped.
After that nothing could induce any one of the negroes of the
establishment to enter Mortier’s room as long as he remained at this
hotel.
We did our best to explain to M. Mortier that the domestics were
nowise in the wrong. He would not listen to a word, but kept
exclaiming, with his eyes sticking further out of his head than usual
(his eyes were naturally prominent):
“No, no! In America you are savages, all savages. Yes, savages
and thieves. It is much worse here than I had supposed.”
One morning he went down alone into the restaurant for
breakfast. Some minutes after we saw him bounding up the stairs.
He was livid and trembling with rage. On reaching the door of our
apartment, he burst out:
“This time it is too much. What is the matter with these brutes
here? Has some change come over me? Tell me. Am I an object of
ridicule? What is the matter with me? When I entered the restaurant
a great fool looked me over from top to bottom, and said something,
thereupon everybody began to stare at me. What is the trouble with
me? Tell me what is the matter?”
What was the matter? He wore a straw hat with very narrow brim,
one of those hats called “American” in Paris and of a kind that is
never worn in America. He also had “New Yorkey” trousers such as
were never cut in New York. That was enough to let loose the
risibilities of this Yankee public, a public that is far from being
indulgent of little eccentricities in other people.
Instead of calming him our explanations exasperated him, and it
was only after he had spent his violence that we succeeded in
getting him down to breakfast again.
The breakfast was not extraordinarily expensive. But when he
looked over his account Mortier went into a rage. He had ordered the
same things that we did, and his bill was two dollars and a half, that
is about twelve and a half francs, higher than ours. These twelve and
a half francs represented the price of a bottle of very ordinary red
wine, which he had ordered.
“Do you want me to tell you what your Americans are,” he
shouted. “Well, they are, and don’t you forget it either, they are every
one thieves, savages, hogs. They are hogs, hogs! That one word
expresses it.”
One morning at eight o’clock, after we had had coffee together,
he left us.
“I am going to take a little walk,” he said. “I shall be back in half
an hour.”
The half hour lasted until seven o’clock in the evening. You can
imagine how anxious we became.
This is what happened.
Seeing that everybody, almost without exception, was headed in
the same direction, he followed the crowd along the side walk.
Presently he found himself on Brooklyn Bridge, black with people
and burdened with cars, those bound to New York filled to
overflowing, the others returning to Brooklyn completely empty.
Mortier did not know that all Brooklyn goes to work on the New
York side, where the business district is situated, and that everybody
goes to work at the same hour in this peculiar country. Astonished,
curious, a little bewildered, he followed the crowd. Once across the
bridge he found himself in one of the innumerable streets of New
York.
On the New York side he looked round him to establish a
landmark by which he could find his way back. He did not discover
one, but it seemed impossible to get lost, as he had only to return to
the base of this big bridge to retrace his steps to Brooklyn. He kept
on, therefore, until he had completely satisfied his curiosity. Then he
retraced his steps, or at least he thought he was doing so. He looked
for the bridge, but in vain. Everybody walked so quickly that his very
courteous “Pardon, Monsieur,” met with no response. Once or twice
he made a bad effort at asking for “Brooklyn Bridge.” This met with
no better success.
All the while he was unable to find a policeman.
The idea occurred to him, a magnificent idea, of going into a
shop. No one made the slightest effort to help him. The assistants
were interested only in trying to sell him everything which the house
contained. Finally he found himself in a street where there were only
clothing merchants. Hardly had he set foot there when he was
seized and dragged into a shop. An hour passed before Mortier
could escape, more dead than alive, from the merchant’s clutches.
The information he gave led us to suppose that this must have been
the famous Baxter Street, the quarter in which Jewish second-hand
dealers ply their trade. It was past five o’clock when he succeeded
finally in regaining the bridge, and then it was only with difficulty that
he got across, for it was already overcrowded with workers returning
to their homes in Brooklyn.
Finally he found the hotel again, swearing that he was going to
take the first steamer for Europe.
“Anywhere,” he would groan; “I would rather be anywhere in the
world than here. I’m not going to stay another hour in such a country.
A rotten country! Rotten people!”
This time, in Pierre Mortier’s eyes, we were “rotten.” It would be
hard to estimate how many discourteous adjectives this young man
applied to our people in a short time. He must have made a record.
However, the Brooklyn hotel at which we were staying was
equipped “on the European plan” with carefully chosen menus à la
carte.
In the city to which we went later there was a purely American
hotel, at which we put up. A central plate surrounded by a dozen little
plates stood in front of each guest. All these were filled
simultaneously with soup, entrees, fish, meat, vegetables and fruit.
The guests with hasty movements gobbled smoked salmon, roast
beef, chicken, mashed potatoes, badly cooked “pie,” salad, cheese,
fruit, pudding, ice-cream, with apparently no regard for the effect of
the hazardous mixtures on their digestive organs.
Mortier left the table completely disheartened by this spectacle.
“What are those savages made of,” he said. “Upon my word they
make me look back with regret to the thieves in New York. And when
you consider that to urge down their hideous mixtures they
incessantly guzzle ice water and keep chewing olives, just as
civilised people eat bread!”
When we returned to New York Mortier went to the Holland
House, a hotel at which French was spoken, and where things were
done in a manner approximating nearer to what he was accustomed
to.
America—this America which on the steamer he had assured
himself would be perfect—had come to interest him only in places
where it had lost its own character. He found it good only in the few
spots where it resembled Paris. In this was not this young journalist,
after all, like most of his compatriots when they undertake to travel
even in other countries than in America?
At the Holland House Pierre Mortier relaxed a little. He even
became more polite in his expressions regarding America and
Americans. But an incident occurred that brought the young
reporter’s distaste for the country to a head, and precipitated his
departure.
One day on returning to the Holland House he forgot to pay his
cabman and found him ten hours later still standing in front of the
hotel. His charge was a dollar and a half an hour. That meant that
Mortier had to give up fifteen dollars.
Our friend thought at first the house porter should have paid for
the trip, and had the charge made on his bill. Accordingly he
complained at the hotel desk regarding what he called a piece of
negligence.
Although the house was conducted on the French plan they gave
him a thoroughly American answer:
“Well, that has nothing to do with the porter. You ordered the
carriage, didn’t you? Yes. You had the use of it, didn’t you? Yes.
Well, then, what do you expect? If you don’t know what you want, it
isn’t up to the employees to run after you to find out. They’ve got
something else to do.”
By the next steamer Pierre Mortier left the United States for good
and all, swearing never again to set foot there.
Mr. W. Boosey, the English publisher, had some very different
experiences in the United States.
On board the steamer he had become acquainted with a very
interesting and companionable American, who invited him to lunch at
Delmonico’s.
“Thanks awfully,” said the Englishman as he accepted. “On what
day?”
“Any day you please.”
That was a little vague, but Mr. Boosey assured him that he
should be delighted, and would come as soon as he had a free day.
He was afraid of not having said the proper thing, from the American
point of view. This notion bothered him for several days.
Finally, just before sailing, he asked the American again when
they should lunch together at Delmonico’s.
His friend replied: “On Thursday or Saturday, whichever suits you
best.”
The Englishman decided on Thursday.
The day set for the lunch arrived and Mr. Boosey was prompt to
keep the appointment. He asked for Mr. X., and they showed him to

You might also like