Principles of Gender-Specific Medicine

By Marianne Legato J

The field of gender-specific medicine examines how normal human biology and physiology differ between men and women and how the diagnosis and treatment of disease differs as a function of gender. This revealing research covers various conditions that predominantly occur in men as well conditions that predominantly occur in women. Among the areas of greatest difference are cardiovascular disease, mood disorders, the immune system, lung cancer as a consequence of smoking, osteoporosis, diabetes, obesity, and infectious diseases.

The Second Edition of Principles of Gender-Specific Medicine focuses on the essentials of gender-specific medicine and the current study of sex and gender differences in human physiology and pathophysiology. New section editors, new chapter authors, and new chapters have been added to reflect the most up-to-date clinical research and practice.

• Offers insight into how the gender-specific risks of one organ system’s disease affects the health of other organ systems
• Outlines the sex-specific differences of normal anatomy and physiology
• Illustrates the gender-specific features and quantifies "gender" and "sex" as risk factors across all major diseases
• Qualifies and analyzes the results of new drug therapies designed with gender-specific differences in mind: ex, hormone therapy in men and women for the prevention and treatment of cardiovascular disease
• All chapters progress translationally from the basic science to the clinical applications of gender-specific therapies, drugs, or treatments
• Sections on drug metabolism, aging, and meta-analysis of data incorporated into all disease-specific chapters

• Language: English
• Publisher: Academic Press
• Release date: Oct 29, 2009
• ISBN: 9780080921501

Book preview

Table of Contents

Cover image

Front-matter

Copyright

Dedication

Contributors

Foreword: Gender-Specific Medicine – Environment and Biology

Preface

Introduction

Chapter 1. The Effects of Gender in Neonatal Medicine

Chapter 2. Sexual Development, Growth, and Puberty in Children

Chapter 3. Gender Differences in Pediatric Pulmonary Disease

Chapter 4. Gender-Specific Aspects of Pediatric Hematology and Oncology

Chapter 5. Gender Differences in Neurological Conditions of Children

Chapter 6. Gender and Sports

Introduction

Chapter 7. Gender Differences in the Functional Organization of the Brain

Chapter 8. Sexual Differentiation of Brain Structure and Function

Chapter 9. The Sexed and Gendered Brain

Chapter 10. Age and Gender-Specific Patterns of Neurologic Illness

Chapter 11. Gender Differences in Stroke

Chapter 12. Gender Differences in Disorders that Present to Psychiatry

Chapter 13. Hormone Replacement Therapy and Cognitive Function

Introduction

Chapter 14. Gender and the Heart

Chapter 15. Gender-Specific Aspects of Selected Coronary Heart Disease Risk Factors

Chapter 16. Dyslipidemia Management in Women and Men

Chapter 17. Gender Differences in the Role of Stress and Emotion in Cardiovascular Function and Disease

Chapter 18. The Role of Sex and Gender in Cardiothoracic Surgery

Introduction

Chapter 19. Gender Differences in Asthma

Chapter 20. Gender Issues in Venous Thromboembolism

Chapter 21. Sleep in Women

Chapter 22. Are Women More Susceptible to Chronic Obstructive Pulmonary Disease?

Chapter 23. The Gender-Specific Aspects of Lung Cancer

Chapter 24. Gender-Specific Considerations in Pulmonary Hypertension

Chapter 25. Sex and Gender Differences in Pulmonary Manifestations of Autoimmune Disease

Chapter 26. Benign Metastasizing Leiomyoma and Lymphangioleiomyomatosis

Chapter 27. Gender Differences in Susceptibility, Outcomes, and Pathophysiology of Sepsis

Introduction

Chapter 28. Inflammatory Bowel Disease in Women

Chapter 29. Disorders of Defecation in Women

Chapter 30. Idiopathic Gastroparesis

Chapter 31. Liver Disease in Women

Introduction

Chapter 32. Gender Differences in Irritable Bowel Syndrome

Chapter 33. Contraception

Chapter 34. Infertility

Chapter 35. Infertility and In Vitro Fertilization

Chapter 36. Female Sexual Health

Chapter 37. Male Sexual Dysfunction

Chapter 38. Pelvic Pain

Chapter 39. Lower Urogenital Tract Dysfunction in Men and Women

Chapter 40. Aging and the Lower Urogenital System

Chapter 41. Menopause

Introduction

Chapter 42. The Differences between Male and Female Breast Cancer

Chapter 43. Difference in Germ Cell Tumors of the Reproductive Tract in Men and Women

Chapter 44. Gender Differences in Hereditary Cancer Syndromes

Introduction

Chapter 45. Gender Differences in Emerging Infectious Diseases

Chapter 46. Sexually Transmitted Infections in Men and Women

Chapter 47. Infections in Pregnancy

Chapter 48. Adult Immunization in Women and Men

Introduction

Chapter 49. Gender Differences in Autoimmune Diseases

Chapter 50. Hormones and Cytokines

Chapter 51. Prolactin and Autoimmunity

Chapter 52. Sex Hormones and Immune Function

Chapter 53. Pregnancy and Autoimmune Rheumatic Disease

Chapter 54. Oral Contraceptives and Autoimmune Diseases

Chapter 55. Gender-Specific Issues in Organ Transplantation

Introduction

Chapter 56. Endogenous Sex Hormones and Risk of Type 2 Diabetes Mellitus in Men and Women

Chapter 57. Thyroid Disorders and Pregnancy

Chapter 58. Sexual Function and Dysfunction in Men and Women

Chapter 59. Osteoporosis in Men and Women

Chapter 60. Testosterone Replacement Therapy in Men and Women

Index

Front-matter

P rinciples of G ender-S pecific M edicine

P rinciples of G ender-S pecific M edicine

Second Edition

Edited by Marianne J. Legato, MD

Section Editors: William Byne, MD, PhD, Nancy E. Davidson, MD, Adrian Dobs, MD, MHS, Marilyn K. Glassberg, MD, Paula A. Johnson, MD, Robert G. Lahita, MD, PhD, FACP, FACR, FRCP, George M. Lazarus, MD, Linda A. Lee, MD, Michael Rendel, MD, Lauri J. Romanzi, MD, FACOG

Copyright

Academic Press is an imprint of Elsevier

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First edition 2004

Second edition 2010

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Notice

No responsibility is assumed by the publisher for any injury and/or damage to personsor property as a matter of products liability, negligence or otherwise, or from any useor operation of any methods, products, instructions or ideas contained in the materialherein. Because of rapid advances in the medical sciences, in particular, independentverification of diagnoses and drug dosages should be made.

Medicine is an ever-changing field. Standard safety precautions must be followed, but as new research and clinical experience broaden our knowledge, changes in treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current product information provided by the manufacturer of each drug to be administered to verify the recommended dose, the method and duration of administrations, and contraindications. It is the responsibility of the treating physician, relying on experience and knowledge of the patient, to determine dosages and the best treatment for each individual patient. Neither the publisher nor the authors assume any liability for any injury and/or damage to persons or property arising from this publication.

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10 11 12 13 10 9 8 7 6 5 4 3 2 1

Dedication

To Isobel and Marvin Slomowitz, with gratitude for their generosity and support for the science of gender-specific medicine.

Contributors

Nabih I. Abdou, MD, PhD

Clinical Professor of Medicine, University of Missouri School of Medicine and Center for Rheumatic Disease and Center for Allergy and Immunology, Kansas City, MO, USA

Nazia Ahmad, BA

CUNY Hunter College, New York, NY, USA

Muddassir Aliniazee, MD

University of Miami, Miller School of Medicine, Pulmonary and Critical Care Medicine, Miami, FL, USA

Sarah Alvi, BS

University of Massachusetts, Amherst, MA, USA

Joan Amatniek, MD, MSc

Director, Clinical Development, Ortho McNeil–Janssen Scientific Affairs, Titusville, NJ; Associate Visiting Research Scientist, Columbia University, Gertrude H. Sergievsky Center, Graduate School of Public Health, New York, NY, USA

David E. Anderson, PhD

National Institute on Aging, National Institutes of Health, Baltimore, MD, USA

Gaya S. Aranoff, MD

Professor of Clinical Pediatrics, Columbia University College of Physicians and Surgeons, Department of Pediatrics, New York, NY, USA

Gloria Bachmann, MD

Associate Dean for Women’s Health, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, New Brunswick, NJ, USA

Sandhya K. Balaram, MD, PhD, FACS

Attending Surgeon, St Luke’s–Roosevelt Hospital Center, Division of Cardiothoracic Surgery; Assistant Professor of Clinical Surgery, Columbia University College of Physicians and Surgeons, New York, NY, USA

Elizabeth Barbieri, MD, FACOG

Weill Cornell Medical College, Center for Reproductive Medicine and Infertility, New York, NY, USA

Barbara D. Bartlik, MD

Assistant Professor of Psychiatry and Psychiatry in Obstetrics and Gynecology, Weill Cornell Medical College, Department of Psychiatry, New York, NY, USA

Shari S. Bassuk, ScD

Epidemiologist, Brigham and Women’s Hospital, Division of Preventive Medicine, Boston, MA, USA

David Bateman, MD

Associate Professor of Clinical Pediatrics, Columbia University Medical Center, Department of Pediatrics, New York, NY, USA

Kristy A. Bauman, MD

Assistant Professor, University of Michigan, Division of Pulmonary and Critical Care Medicine, Ann Arbor, MI, USA

Jennifer J. Bell, MD

Special Lecturer in Pediatrics, Columbia University College of Physicians and Surgeons, Department of Pediatrics, New York, NY, USA

Kathryn Bilello, MD

Central California Faculty Medical Group and Associate Clinical Professor of Medicine, University of California San Francisco–Fresno Program, Fresno, CA, USA

Justin D. Blasberg, MD

Resident, St Luke’s–Roosevelt Hospital Center, Department of Surgery, New York, NY, USA

Roger S. Blumenthal, MD, FACC, FAHA

Professor of Medicine, The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, MD, USA

Tamara Bockow, BS

Medical Student, University of Pennsylvania Medical School, Philadelphia, PA, USA

Karen Elizabeth Boyle, MD

Director, Reproductive Medicine and Surgery, Sexuality & Aesthetics Chesapeake Urology Associates, Baltimore, MD, USA

Arthur L. Burnett, MD

Professor of Urology, The Johns Hopkins Hospital, James Buchanan Brady Urological Institute, Baltimore, MD, USA

Lara J. Burrows, MD

The Center for Vulvovaginal Disorders, Washington, DC, USA

William Byne, MD, PhD

Staff Physician, Mental Illness Research, Education and Clinical Center, J.J. Peters Veterans Affairs Medical Center, Bronx, NY; Associate Professor of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA

Kenneth R. Chapman, MD, MSc, FRCPC, FCCP

Director, Asthma and Airway Centre, University Health Network, Toronto Western Hospital; Professor of Medicine, University of Toronto; GSK-CIHR Research Chair in Respiratory Health Care Delivery; Toronto, Ontario, Canada

Margaret A. Chesney, PhD

Professor of Medicine, University of Maryland School of Medicine, Center for Integrative Medicine, Baltimore, MD, USA

Debra Chew, MD

Clinical Assistant Professor, New Jersey Medical School of the University of Medicine and Dentistry of New Jersey, Department of Medicine, Newark, NJ, USA

Doreen E. Chung, MD, FRCSC

Weill Cornell Medical College, Department of Urology, New York, NY, USA

Pak H. Chung, MD

Reproductive Endocrinologist and Infertility Specialist, Weill Cornell Medical College, The Center for Reproductive Medicine and Infertility, New York, NY, USA

Wendy K. Chung, MD, PhD

Herbert Irving Assistant Professor of Pediatrics and Medicine, Director of Clinical Genetics, Columbia University, New York, NY, USA

Christine A. Clark, PhD Candidate

Mount Sinai Hospital, University of Toronto, LifeQuest Centre for Reproductive Medicine, Toronto, Ontario, Canada

Maurizio Cutolo, MD

University of Genoa, Research Laboratories and Academic Unit of Clinical Rheumatology, Department of Internal Medicine, Genoa, Italy

Nancy E. Davidson, MD

Hillman Professor of Oncology, Director, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

Serkan Deveci, MD

Memorial Sloan Kettering Cancer Center, Department of Urology, New York, NY, USA

Adrian Dobs, MD, MHS

Professor of Medicine and Oncology, The Johns Hopkins University School of Medicine, Department of Medicine and Oncology, Baltimore, MD, USA

Nora J. Doty

Research Assistant, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, New Brunswick, NJ, USA

Catherine E. Dubeau, MD

Professor of Medicine, University of Massachusetts Medical Center, Departments of Internal Medicine, Family and Community Health, and Obstetrics & Gynecology, Worcester, MA, USA

Diala El-maouche, MD, MS

Post-doctoral Fellow, Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

Karen Feisullin, MD

Community Health Services, Department of Women’s Health; Department of Obstetrics and Gynecology, Hartford Hospital, Hartford, CT, USA

Lauren Frey, MD

Assistant Professor, Department of Neurology, University of Colorado Denver, Denver, CO, USA

James H. Garvin Jr, MD, PhD

Professor of Clinical Pediatrics, Columbia University College of Physicians and Surgeons, New York, NY, USA

Katya Gaynor, BA

Research Coordinator, Mount Sinai School of Medicine, Department of Psychiatry, New York, NY, USA

Susan L. Gearhart, MD

Assistant Professor of Colorectal Surgery, Johns Hopkins Medical Institutions, Baltimore, MD, USA

Khalil G. Ghanem, MD, PhD

Assistant Professor of Medicine, The Johns Hopkins University School of Medicine, Department of Infectious Diseases, Baltimore, MD, USA

Marilyn K. Glassberg, MD

Associate Professor, University of Miami Miller School of Medicine, Department of Medicine/Pulmonary and Critical Care Division, Director, Rare and Interstitial Lung Disease Program, Miami, FL, USA

Sherita Hill Golden, MD, MHS

Associate Professor of Medicine and Epidemiology, The Johns Hopkins University School of Medicine, Division of Endocrinology and Metabolism, Welch Center for Prevention, Epidemiology, and Clinical Research; The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

Andrew T. Goldstein, MD

Johns Hopkins Medicine, Division of Gynecologic Specialties, Department of Gynecology and Obstetrics, Baltimore, MD, USA

Marc Goldstein, MD

Matthew P. Hardy Distinguished Professor of Reproductive Medicine and Urology, Surgeon-in-Chief, Male Reproductive Medicine and Surgery, Cornell Institute for Reproductive Medicine, New York-Presbyterian Hospital/Weill Cornell Medical Center, Weill Cornell Medical College; Senior Scientist, The Population Council, Center for Biomedical Research, New York, NY, USA

Rebecca F. Gottesman, MD, PhD

Assistant Professor of Neurology, The Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD, USA

Raquel E. Gur, MD, PhD

Professor of Psychiatry, Neurology, and Radiology, University of Pennsylvania Medical Center, Pennsylvania, PA, USA

Ruben C. Gur, PhD

Professor of Psychology, University of Pennsylvania Medical Center, Department of Psychiatry, Radiology and Neurology, and the Philadelphia Veterans Administration Medical Center, Philadelphia, Pennsylvania, PA, USA

Meilan K. Han, MD, MS

Medical Director, Women’s Respiratory Health Program and Pulmonary Rehabilitation, University of Michigan, Division of Pulmonary and Critical Care, Ann Arbor, MI, USA

Mary L. Harris, MD

Medical Director, The Center for Inflammatory Bowel and Colorectal Diseases, Mercy Medical Center, Baltimore, MD, USA

W. Allen Hauser, MD

Professor of Neurology and Epidemiology, Columbia University College of Physicians and Surgeons and Mailman School of Public Health, New York, NY, USA

Argye E. Hillis, MD

Professor of Neurology and Physical Medicine and Rehabilitation, The Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD, USA

Sally L. Hodder, MD

Professor of Medicine, New Jersey Medical School of the University of Medicine and Dentistry of New Jersey, Department of Medicine, Newark, NJ, USA

Aaron Holley, MD

Walter Reed Army Medical Center, Division of Pulmonary/Critical Care and Sleep Medicine, Department of Internal Medicine, Washington, DC, USA

Diane Jacobs, PhD

Consulting Neuropsychologist, San Diego, CA, USA

Suzanne M. Jan De Beur, MD

Associate Professor of Medicine, The Johns Hopkins University School of Medicine, Director, Division of Endocrinology, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA

Paula A. Johnson, MD

Executive Director, Connors Center for Women’s Health and Gender Biology and Chief of the Division of Women’s Health, Brigham and Women’s Hospital, Boston, MA, USA

Sonya Kashyap, MD

Reproductive Endocrinologist, University of California at San Francisco, Center for Reproductive Health and Women’s Health Research Center, San Francisco, CA, USA

David M. Kaufman, MD

Assistant Clinical Professor of Pediatrics and Neurology, Mount Sinai School of Medicine, Department of Pediatric Neurology, New York, NY, USA

Howard H. Kim, MD

Fellow in Male Reproductive Medicine and Microsurgery, Department of Urology and Cornell Institute for Reproductive Medicine, New York-Presbyterian Hospital/Weill Cornell Medical Center, Weill Cornell Medical College; Research Fellow, The Population Council, Center for Biomedical Research, New York, NY, USA

Matthew Kim, MD

Assistant Professor of Medicine, The Johns Hopkins Hospital, Division of Endocrinology, Baltimore, MD, USA

Lester Kobzik, MD

Harvard School of Public Health, Department of Environmental Health, and Brigham & Women’s Hospital, Department of Pathology, Boston, MA USA

Julie A. Kolzet, MA

Weill Cornell Medical College, Department of Psychiatry, New York, NY, USA

Ayman Koteish, MD

The Johns Hopkins University School of Medicine, Department of Gastroenterology and Hepatology, Baltimore, MD, USA

Karen Krok, MD

The Johns Hopkins University School of Medicine, Department of Gastroenterology and Hepatology, Baltimore, MD, USA

Robert G. Lahita, MD, PhD, FACP, FACR, FRCP

Chairman of the Department of Medicine, Newark Beth Israel Medical Center, Newark, NJ; Professor of Medicine, New Jersey Medical School, Newark, NJ, USA

Nicole Lanatra, MD

New York University School of Medicine, Division of Oncology, New York, NY, USA

Carl A. Laskin, MD, FRCPC

LifeQuest Centre for Reproductive Medicine; Departments of Medicine (Rheumatology), Obstetrics & Gynecology and Immunology, University of Toronto, Toronto, ON, Canada

George M. Lazarus, MD

Associate Clinical Professor of Pediatrics, Columbia University Medical Center, Morgan Stanley Children’s Hospital, Department of Pediatrics, New York, NY, USA

Linda A. Lee, MD

Assistant Professor, The Johns Hopkins University School of Medicine, Division of Gastroenterology and Hepatology, Baltimore, MD, USA

Marianne J. Legato, MD

Professor Emerita of Clinical Medicine, Columbia University College of Medicine, New York, NY; Adjunct Professor of Medicine, Johns Hopkins, Department of Medicine, Baltimore, USA

Jaswinder K. Leghe, MD, MPH

Clinical Instructor, NYU School of Medicine, Department of Medicine, New York, NY, USA

Sharon Lewin, MD

Fellow, Royal College of Physicians, Canada; Attending Physician, St. Luke’s–Roosevelt Hospital Center, Division of Infectious Disease, New York, NY; Attending Physician, New York Presbyterian Hospital Center, Division of Internal Medicine, New York, NY; Assistant Clinical Professor of Medicine, Columbia University School of Medicine, New York, NY, USA

Robert H. Lim, MD

Research Associate, Harvard School of Public Health, Department of Environmental Health, and Instructor in Pediatrics Children’s Hospital Boston, Division of Respiratory Diseases, Boston, MA, USA

Joann E. Manson, MD, DrPH

Professor of Medicine and the Elizabeth F. Brigham Professor of Women’s Health, Harvard Medical School, Brigham and Women’s Hospital, Division of Preventive Medicine, Boston, MA, USA

Margaret Mccarthy, PhD

Professor of Physiology, University of Maryland Baltimore School of Medicine, Department of Physiology, Baltimore, MD, USA

Taraneh Mehrani, MD

Union Memorial Hospital, Baltimore, MD, USA

Jordan D. Metzl, MD

Co-Founder, The Sports Medicine Institute for Young Athletes, Hospital for Special Surgery, New York, NY

Lisa Moores, MD

Assistant Dean for Clinical Sciences, Professor of Medicine, The Uniformed Services University of the Health Sciences, F. Edward Hebert School of Medicine, Bethesda, MD, USA

Kendall F. Moseley, MD

Clinical Fellow, Division of Endocrinology, The Johns Hopkins Hospital, Baltimore, MD, USA

John P. Mulhall, MD

Director Male Sexual and Reproductive Medicine Program Memorial Sloan Kettering Cancer Center, Department of Surgery/Urology Service, New York, NY, USA

Gerald Mullin, MD

The Johns Hopkins University School of Medicine, Division of Gastroenterology and Hepatology, Baltimore, MD, USA

Melissa Munsell, MD

Clinical Fellow, The Johns Hopkins University School of Medicine, Department of Medicine and Gastroenterology, Baltimore, MD, USA

Susan Murin, MD, MSc

Professor, Division of Pulmonary, Critical Care, and Sleep Medicine, and Vice-Chair for Clinical Affairs, University of California Davis School of Medicine, Department of Internal Medicine, Sacramento, CA, USA

Christian D. Nagy, MD

Fellow, The Johns Hopkins Hospital, Department of Internal Medicine and Pediatrics, Divisions of Cardiology and Pediatric Cardiology, Baltimore, MD, USA

Coral Omene, MD, PhD

New York University Langone Medical Center, Department of Medicine, Division of Oncology, New York, NY, USA

Henry P. Parkman, MD

Associate Professor of Medicine and Physiology, Temple University, Department of Physiology, Philadelphia, PA, USA

Tahmina Parveen, BA

CUNY Hunter College, New York, NY, USA

Michelle Petri, MD, MPH

Professor, The Johns Hopkins University School of Medicine, Department of Medicine, and Director, Johns Hopkins Lupus Center, Baltimore, MD, USA

Octavia Pickett-Blakely, MD

The Johns Hopkins University School of Medicine, Department of Gastroenterology and Hepatology, Baltimore, MD, USA

Bruce Polsky, MD

Interim Chairman, St Luke’s–Roosevelt Hospital Center, Department of Medicine, and Chief, Division of Infectious Diseases, New York, NY, USA

Charles A. Powell, MD

Associate Professor of Medicine, Columbia University, Division of Pulmonary, Allergy, and Critical Care Medicine, New York, NY, USA

Michael Rendel, MD

Senior Attending Physician, St Luke’s-Roosevelt Hospital Center, New York; Attending Physician, New York-Presbyterian Hospital/Weill Cornell Medical Center, Weill Cornell Medical College, New York; Associate Professor, Columbia University School of Medicine, New York, NY, USA

Virginia Rider, PhD

Professor of Biology, Pittsburg State University, Department of Biology, Pittsburg, KS, USA

Lauri J. Romanzi, MD, FACOG

Reconstructive Surgery and Urogynecology, Clinical Associate Professor of Gynecology, New York-Presbyterian Hospital/Weill Cornell Medical Center, Weill Cornell Medical College, New York, NY, USA

Anne M. Rompalo, MD, ScM

Professor of Medicine, The Johns Hopkins University School of Medicine, Department of Infectious Diseases, Baltimore, MD, USA

Tove S. Rosen, MD

Professor of Clinical Pediatrics/Neonatology, Columbia University Medical Center, Department of Pediatrics, New York, NY, USA

Hilary Sanfey, MB BCh, FACS

Professor of Surgery and Vice-Chair for Education, Southern Illinois School of Medicine Department of Surgery, Springfield, IL, USA

Mary Sano, PhD

Director, Alzheimer Disease Research Center; Professor, Department of Psychiatry, Mount Sinai School of Medicine; Director of Research and Development; James J Peters VAMC, New York, NY, USA

Peter N. Schlegel, MD, FACS

Professor and Chairman, Department of Urology, New York-Presbyterian Hospital/Weill Cornell Medical Center, Weill Cornell Medical College, New York; Senior Scientist, The Population Council, Center for Biomedical Research, New York, NY, USA

Mary V. Seeman, MD

Professor Emerita of Psychiatry, University of Toronto, Department of Psychiatry, Toronto, Ontario, Canada

Shirin Shafazand, MD, MS

Assistant Professor of Medicine, University of Miami Miller School of Medicine, Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Miami, FL, USA

Kavita Sharma, MD

The Johns Hopkins Hospital, Department of Internal Medicine, Baltimore, MD, USA

Beverley J. Sheares, MD, MS

Associate Professor of Clinical Pediatrics, Columbia University, Pulmonary Division, Department of Pediatrics, New York, NY, USA

Deborah Shure, MD, Master FCCP

Consultant Medical Reviewer, Center for Devices and Radiological Health, Miami, FL, USA

Marc Sonenshine, MD

The Johns Hopkins University School of Medicine, Department of Internal Medicine, Baltimore, MD, USA

Emilia Mia Sordillo, MD, PhD

Sr, Attending, Medicine and Pathology, Medical Director, Microbiology, and Molecular Diagnostics, St Luke’s–Roosevelt Hospital Center, Department of Clinical Pathology; Associate Professor of Clinical Medicine and Clinical Pathology and Cell Biology. College of Physicians and Surgeons, Columbia University, New York, NY, USA

Karin Sorra, PhD

President and Chief Scientific Officer, Arroscience Inc., Toronto, Ontario, Canada

Karen A. Spitzer, MSc

University of Toronto, LifeQuest Centre for Reproductive Medicine, Toronto, Ontario, Canada

Shobha Swaminathan, MD

Assistant Professor, New Jersey Medical School of the University of Medicine and Dentistry of New Jersey, Department of Medicine, Newark, NJ, USA

Alexis E. Te, MD

Associate Professor of Urology, Weill Cornell Medical College, Department of Urology, New York, NY, USA

Amy Tiersten, MD

Associate Professor of Medicine (Oncology), New York University Langone Medical Center, Department of Medicine, Division of Oncology, New York, NY, USA

Rebecca L. Toonkel, MD

Postdoctoral Research Fellow, Columbia University, Division of Pulmonary, Allergy, and Critical Care Medicine, New York, NY, USA

Renuka Tyagi, MD

Assistant Professor of Urology in Obstetrics and Gynecology, Weill Cornell Medical College, Department of Urology, New York, NY, USA

Sara E. Walker, MD, MACP

Emeritus Professor of Medicine, University of Missouri School of Medicine, Department of Internal Medicine, Columbia, MO, USA

Carolyn Westhoff, MD

Columbia University, Department of Obstetrics and Gynecology, Division of Family Planning and Preventive Services, New York, NY, USA

Foreword: Gender-Specific Medicine – Environment and Biology

Marek Glezerman, MD

Professor and Chairman, Hospital for Women, Rabin Medical Center and Sackler Medical School, Tel Aviv University; Chairman, The Israel Society for Gender Medicine

I vividly recall my first reaction when reading Eve’s Rib by Marianne Legato, about two years ago. It was a strange amalgam between asking myself ‘ Where have I been during the past 30 years of my career?’ and a fair amount of skepticism. In the aftermath of an in-depth journey into the vast and largely unexplored realm of gender-related differences in medicine, I encountered very similar reactions with many peers. Subsequently, an interest group for Gender Medicine was created which included 27 department heads from different disciplines and several months later, the Israel Society for Gender Medicine was born. In less than two years, this organization has attracted 110 active members and is conducting dozens of ongoing research projects, some of which are currently in press. Such is the genesis of my personal involvement with gender medicine.

As recently as two centuries ago, children were regarded as diminutive adults and were treated accordingly, both in social and in medical terms. Demands on their capacity to provide labor were restricted only by realizing their actual physical limitations and not by understanding the special needs of the growing juvenile body. In fact, the notion of physical health and particular medical treatment of children was virtually non-existent until the early eighteenth century and it required several more decades until pediatrics emerged as a distinct medical discipline. Today, no reasonable person would dare to question the profound differences in physiology and pathophysiology between children and adults, and no one would doubt that specific expertise is needed for diagnosing and treating children. Equally, it is unquestionable today that research performed in adults is not necessarily applicable to infants, children and adolescents. It is all the more astonishing that the parallel to gender differences is still not sufficiently appreciated and that even a basic understanding of the profound physiological and pathophysiological differences between men and women is still widely missing. Amazingly, not unlike the prevailing attitude towards children 150 to 200 years ago, women are typically regarded as smaller men. The common perception of the main difference between the sexes is usually confined to their different genital organs and to the fact that women are capable of delivering babies, while men are not. The differences are, alas, far more profound. In fact, these differences pertain to virtually all bodily systems, covering the entire life cycle from the antenatal period through infancy and adulthood. In intra-uterine life, fetal gender is independently associated with increased risks for prematurity, operative and cesarean delivery and fetal growth abnormalities. After birth, female and male infants differ in their development, in mortality and morbidity rates and are affected differently by different diseases. Female infants have a substantially higher prevalence of vesico-ureteral reflux and persistent ductus arteriosus, while male infants have a higher incidence of transposition of large vessels, aortic stenosis, pylorus stenosis and hernia. Girls have more auto immune diseases, such as systemic lupus and thyroiditis, and have more often precocious puberty. Boys suffer more often from autism, growth hormone deficiency and nephrotic syndrome.

In adults, observational studies that indicated the preponderance of many pathologies in women have been available for many years and clinicians observe these differences constantly. For example, the gastrointestinal system functions differently in men and women. Compared to men, women have twice the incidence of colitis or Crohn’s disease, four times the incidence of gallbladder stones, suffer five times more often from irritable bowel syndrome, and 20 times more often from functional bowel disease. Female lungs are more vulnerable to disease than lungs of men. Pulmonary hypertension, asthma, and chronic obstructive lung disease are usually more severe in women than in men. Lung cancer in women is on a steady rise and is currently their most fatal cancer, accounting for 25% of all cancer deaths, with a higher incidence rate than breast cancer. In Europe there are currently about 400000 new lung cancer cases diagnosed annually, 30% of which occur in women. Alarmingly, 80000 out of 400000 new lung cancer patients never smoked and most of those affected are women. Currently, in the United States more women die annually from cardiovascular disease than from all cancers combined. Data from 2005 reveal that 143000 women died from stroke and 650000 from cardiovascular disease, while the death toll from all cancers combined amounted to 560000. The female heart responds differently to continuous stress such as hypertension than the male heart, and diagnostic tools, like the customary stress test, are substantially less significant and less specific in women than in men. Women with myocardial infarction are typically under-diagnosed and under-treated. Yet, until the 1990s almost all research on the cardiovascular system, and indeed on most other bodily systems, was performed exclusively in men and the majority of currently available medications have been evaluated in men only. Moreover, in terms of pharmacokinetics, the large variability of the physiological changes in cyclic women is usually neglected.

The roots of this apparent discrimination date back to the mid-twentieth century, when both the treatment of pregnant women for threatened abortion with the synthetic estrogen diethylstilbestrol (DES) and the use of thalidomide for nausea during the pregnancy lead to catastrophic consequences in their offspring, including genital cancer and phocomelia, respectively. Consequently, and mainly in order to protect women, women were excluded from clinical trials.

The need for gender-specific medicine emerged when it could no longer be denied that diagnosis and treatment of diseases in men and women may not be identical, and that women and men need to be represented equally in clinical trials.

Efforts by the NIH in the mid-1980s to correct this unbalanced state of affairs by declining funding of research projects that did not include both sexes, were ill-fated. As late as the mid-1990s less than one-third of published research included women, and even those data were often incomplete. Out of 120 randomized controlled trials published in the New England Journal of Medicine between 1994 and 1999, only 14% provided gender-specific analysis. This situation is now slowly but gradually changing. It is now well accepted that clinical and basic research needs to be stratified also by gender and that the gender aspect of medicine needs to be introduced in the training of students and residents. Based on this understanding, gender-specific medicine emerged and developed in the past two decades.

Semantics often lag behind the development of new technologies and new scientific endeavors. Sometimes we develop the narrative and terminology before the technology catches up, and sometimes novel approaches are in search of the appropriate terms to explain them. This is also true for gender medicine. So, what is ‘gender medicine’? It is a giant step from the ‘one-size-fits-all’ approach to the direction of personalized medicine, when diagnosis and treatment will become individualized according to the genomics of each individual. This may happen sometime in the future, but first steps are already visible. In breast cancer, for example, genetic testing permits prediction of the efficiency of various medications and is helpful in rendering evidence-based and individualized decisions, concerning the optimal treatment. So, in a sense, gender medicine bridges the gap between past and future medicine. It is based on the understanding that male and female gender is much more than the chromosomal difference between the sexes and requires an in-depth understanding of the profound physiological and pathophysiological differences that have developed as a result of long-term adaptations to environmental effects and the social roles of individuals in their societies. Some of these changes are hard-wired and resulting from millions of years of physiological adaptation and some are the results of short-term expressions of the different roles and lifestyles men and women play in various societies. Being male or female is not synonymous to being masculine or feminine. Both pairs of terms are often but erroneously interchangeably used as synonyms. Yet, they present fundamentally different categories. Maleness or femaleness are chromosomally determined and thus unchangeable. This definition is to some extent a simplification, but is generally accepted in humans. To be feminine or to be masculine are characteristics that are defined by the sociological fabric of our environment, the roles we play in a given society, the functions and habits assigned by the society on us, and the expectations which a given society has set for its members. These roles can change in the course of time and are different in different societies. Whatever is required from us in terms of being feminine or masculine has obviously a strong impact on our health, and may pose gender-specific health risks that are not based on a different biology of men and women, but on the environment in which we live. This immediate impact of our social environment on our health is what I would call ‘environmental gender medicine’ (EGM). If the environment affects our day-to-day life long enough, eventually irreversible biological changes will ensue and even our anatomy will adapt. This aspect of gender medicine would then be reflected in the term ‘biological gender medicine’ (BGM). Both are summarized in the general term gender (specific) medicine.

While talking to various audiences on gender medicine, one encounters sometimes enthusiastic support and sometimes a rather reserved reaction to what is perceived as the promotion of affirmative action, aimed at improving women’s health. Clearly, gender medicine aims to rectify a longstanding neglect of gender differences, which are mostly related to the physiology and pathophysiology of women. But gender medicine is not an advanced form of gynecology, extended to bodily systems beyond the genital organs. Gender medicine aims also at men’s health: from the onset, men are at a health disadvantage and are more susceptible to disease than women throughout their life cycle. Even their life expectancy is shorter.

Male gender is independently associated with adverse pregnancy outcome and male neonates are twice more likely to die at birth. In the first trimester of pregnancy the male : female ratio is 170 : 100, but since male fetuses are spontaneously aborted three times more often than female fetuses, at delivery the male : female prevalence decreases to about 51% to 49%. Actually, all catastrophes that can affect the unborn fetus are more common in males than in females, including brain damage, premature deliveries, skeletal anomalies and stillbirth. Mortality is 20% higher in male than in female newborns and remains higher also throughout infancy and childhood. Morbidity, developmental deficiencies, susceptibility to congenital and acquired diseases are also more common in boys than in girls.

As the life cycle continues, male adolescents are more likely to die from accidents or suicide than girls. Recent figures from Romania indicate that 74% out of 11000 suicides that occurred in 2000 were committed by men. Throughout life, male adults are more susceptible to infectious diseases than women. Because male breast cancer is 100 times rarer in men than in women, this form of deadly cancer has hardly been studied in men. Men are also at a general disadvantage in cancer survival. Osteoporosis is regarded as a female disease with a lifetime risk of 1 : 2 in women but men also suffer from osteoporosis, with a lifetime risk of 1 : 5. Again, research on osteoporosis has been focused almost exclusively on women.

So, gender medicine needs to deal with health issues of men and women alike. It is not a new and distinct medical discipline, but rather a new perspective and nexus between existing disciplines. Modern medicine should therefore not only be evidence-based but also gender-based. To accomplish this objective there is a dire need in extensive basic and clinical research, and also in changes in the curriculum of medical studies and of residencies.

Some universities, such as Georgetown University in the United States, Monash University in Australia and Tel Aviv University in Israel, have already incorporated the gender aspect in their medical curricula, and some residency programs already include explicit gender aspects in their training. The essential prerequisite for these actions is the awareness of the necessity and the willingness to question existing paradigms. Some of these preliminary, but crucial goals are already being met. The World Health Organization has established the ‘Department of Gender, Women and Health’ and NASA has done pioneering work in studying the physiological differences between men and women as related to space travel. Fellowships in women’s health are offered by various universities, such as Columbia in New York, MacNeall in Illinois, East Carolina University, Brigham and Women’s Hospital in Boston, amongst others.

Dozens of books dealing with gender medicine are available today and there are scientific journals devoted to women’s health ( Gender Medicine, Elsevier), and men’s health ( Men’s Health and Gender, Elsevier). An International Society for Gender Medicine has been established, and national societies in Sweden, Germany, Italy, Austria, and Israel are actively involved in the promotion of awareness of gender medicine and research. Gender-medicine-oriented national and international congresses are being held worldwide. The number of research projects conducted and published is mushrooming. Obviously, this development increases the demand for scholarly texts.

One of the most vocal and effective pioneers who has brought gender medicine to the place it occupies today is undoubtedly Professor Marianne Legato. Having devoted the past two decades of her professional life to the promotion of gender medicine, she has contributed tremendously to the worldwide awakening of awareness to this critically important angle from which medicine should be approached. Besides her scientific contributions, the greatest impact on public awareness of the gender differences in medicine has probably derived from her many books that have addressed the educated general public. Marianne Legato, a cardiologist by training, is founder and editor in chief of the first medical journal devoted to gender medicine, and the editor of this textbook.

Now, only five years after the publication of the first edition, this second edition is to be made available to an ever-increasing body of readers. As in the first edition, Dr Legato has succeeded in assembling a formidable group of scholars and pioneers in their respective fields. The book is organized in sections, with section editors who have also provided insightful introductions to the respective chapters. Reading through the table of contents is like browsing through all aspects of medicine. Paradoxically, and on first thought, this may seem to be a disadvantage. Why would I, as an obstetrician and gynecologist, choose to divert precious reading time from my own overwhelming and demanding discipline, to topics like immunology, rheumatology, pulmonology or the nervous system, which are all beyond the areas of my professional expertise? The answer to this question materialized during my extensive reading of gender-based texts for the past two years. It was then that I became fond of peeking into other fields of medicine and began to appreciate the vastness of the unexplored grounds of gender differences. Thus, like an explorer, I was and still am experiencing the privilege of witnessing the re-writing of virtually all chapters of medicine from the gender perspective. This precisely is what is so exciting about gender medicine in general and about this textbook in particular. This textbook serves up to the reader the essence of contemporary gender medicine on a silver platter. It is in a sense a primary teaching instrument for students, residents, and specialists. It is also a reference text, aimed to provide specific answers to specific questions. But most of all, it is an eye-opener, raising scientific curiosity and confronting the reader with a wealth of questions that cover virtually every field of medicine while challenging all of us to embark on the relevant research.

The silent revolution of gender medicine has broken through the first great wall on its path, namely to be accepted as an undeniable and necessary shift of paradigms. But this is still only the beginning. Now it is time to embark on a truly inter-disciplinary journey and to invest academic and clinical efforts in order to establish gender medicine as an integral part of how we teach and apply modern medicine for the benefit of women and men alike. This textbook is a major tool in this formidable quest.

Preface

Marianne J. Legato

Over the arc of the last twenty years, the realization that men and women are significantly different in every system of the body has expanded to inform and refocus all the disciplines of medicine. When we published the first edition of The Principles of Gender-Specific Medicine it was axiomatic that the words ‘gender-specific’ were new and, as my then chairman of internal medicine at Columbia University, Doctor Myron Weisfeldt, pointed out in 1997, very few of us knew what ‘gender-specific’ meant. Indeed, most people who heard the term for the first time assumed it meant women’s medicine. It is still a common misperception. In fact, gender-specific medicine is the study of how the normal function and the experience of disease differs between men and women. It is as dedicated to the study of the unique aspects of men’s biology as it is to that of women; indeed, it is the comparison between the two sexes that has prompted some of the most interesting and novel questions in medicine.

Medicine is a reflection of the society in which it is embedded; how we understand the human condition and tend to its ills is impacted by how society views the roles, competencies, and relative importance of men and women. The revolution called ‘gender-specific medicine’ has its roots in the social fabric of the United States in the wake of the Second World War. The events of that world-wide, all-engrossing effort to preserve our institutions and political systems resulted in two new developments: the emerging awareness of the competence of women to do men’s work and an abiding faith in the power of science to solve the problems of the human condition. On the battlefield, for example, we learned to expand the efficacy and safety of anesthesia, to understand the pathophysiology of shock, that hepatitis was caused by a virus, and that antibiotics could save countless lives that would have been lost without them. Americans came out of the war convinced that science held a virtually limitless ability to improve and preserve human life. That conviction prompted the expansion of the nascent National Institutes of Health, which in the early 1950s was no more than a modest collection of eight buildings in Bethesda that housed the United States Department of Health, Education and Welfare (now renamed the Department of Health and Human Services).

Gender-specific medicine began as an uniquely American concept. It was conceptualized and expanded first in this country simply because most of the other areas of the world were so devastated by the ravages of war that rebuilding functioning societies was their only and all-consuming goal. Miraculously, our own country had escaped the direct destruction that most of the rest of the civilized world had experienced and so the fabric of post-war society here was unique. The American feminist movement was an inevitable outgrowth of the experience women had had in filling the positions men had traditionally – and exclusively – occupied until the war left those positions empty. In this country, gender-specific medicine had its roots in the growing confidence of women in their own power, unique needs, and importance in society. During the war, whole units of male subspecialists left the academic medical centers they had dominated for the battlefield. Women filled the vacancies created with enthusiasm and confidence: the first woman chief resident in internal medicine in the history of Columbia University, Doctor M. Irene Ferrer, was appointed in 1943. She went on to create a spectacular career in investigative medicine that included developing the cardiac catheter as an instrument that defined the fundamental dynamics and the pathophysiology of disease of the cardiovascular system.

By 1985, laywomen had prompted the formation of a governmental Task Force on Women’s Health, which after three years of study concluded that aside from reproductive biology, we knew nothing about the physiology of women but had always assumed that, beyond the pelvis, the physiology of the two sexes was identical. ¹ The traditional subjects of scientific investigation at all levels were males and it was assumed that the results of those investigations could be extrapolated to women without direct testing or modification. The 1990s saw an increasing effort by the National Institutes of Health, academic medical centers, the American Congress, and the Federal Drug Administration to study women as well as men and to compare the results of scientific research in both sexes. It has been a slow, painful progression: many – and perhaps unanticipated – obstacles that have been only partially overcome limited our understanding of the sex-specific differences in human structure and function. One of our thorniest problems is how to safely include the premenopausal woman in clinical trials: the fear of harming women’s reproductive capacity and/or the development of a fetus conceived during the conduct of an investigatory protocol remains largely unsolved. It is no surprise that the largest investigative effort mounted on behalf of women, The Women’s Health Initiative, focused on the postmenopausal female. ² Another profoundly important difference between the sexes is the frequently different age of onset and incidence of specific disease entities that make comparison difficult. The spectrum of co-morbidities that affect the two sexes with that disease may also be entirely different. Nevertheless, the results of gender-specific investigations, often completely unanticipated, have yielded an unexpectedly rich harvest and have prompted questions we never would otherwise even have asked. The value of sex-specific research is now so obvious that we are beginning to turn a sex-specific lens on the unique features of male biology. The reasons for men’s shorter lifespan compared with that of women and the two-decade earlier onset of coronary artery disease in men, for example, are subjects of particular interest and deserve intensive investigation. In a very real sense, we have used men as clinical subjects in an effort to protect women from the risk of harm. But as a matter of justice, women should bear some of the risks of direct investigation, since they benefit from the results of those studies.

Gender-specific medicine has expanded over the past 15 years from this country to other capitals of the world; among others, there are centers for the pursuit of this discipline now in Sweden, Japan, Austria, Germany, Korea, Holland and, most recently, Israel. We have formed the International Society for Gender Specific Medicine and I have established two scientific journals devoted to the new science. Both are included in MEDLINE (Medical Literature Analysis and Retrieval System Online), compiled by the US National Library of Medicine. The first was the The Journal of Gender Specific Medicine, and the second, which supplanted the first, Gender Medicine, published by Elsevier, continues to present new information about the sex-specific characteristics of human physiology and the experience of disease.

Few developments in medicine have been more rewarding than the realization that the study – and comparison – of men and women has and will continue to produce a stunning flood of unexpected, novel information. Hopefully this second edition of The Principles of Gender-Specific Medicine will help to correct and expand our understanding of the enormously important impact of biological sex on human biology.

2009

References

1. USPHS (US Public Health Service), Report of the public health service task force on women’s health issues, Public Health Rep 100 (1) ( 1985) 73–106.

2. The Woman’s Health Initiative, National Institutes of Health, Bethesda, MD, 1991.

Introduction

George M. Lazarus

On a summer Sunday afternoon, my wife and I attended an outdoor concert in Saint Stephen's Green in Dublin, Ireland. As the band played music from children's television programs and popular movies, twenty or thirty young children from about 2 to 4 years of age romped on the grass. The girls danced, ballet-style, to the music. The boys chased and tackled each other like little football players. No one told the children how to play. They just did what came naturally and there was no cross-over behavior between the boys and girls. As I enjoyed watching the children, I was impressed by how different boys and girls are from a young age.

Two-year-old children know their sex. A child that age doesn't know much, but a boy knows he is a boy, a girl knows she is a girl. Young children don't know exactly how or why boys and girls are different, but they know that they are. In that respect, they are exactly like medical scientists!

Pediatricians are well aware of the differences between the sexes that appear from the time of conception. We are learning more and more about gender differences, as will become apparent from reading the chapters in the pediatric section. We can explain the biological reasons for some differences and we can describe many more differences whose etiologies remain obscure.

Sexual differentiation in utero affects more than the external and internal sex organs. The brain is a sexual organ and some of the behavioral differences observed between boys and girls (and men and women) are likely due to the effects of androgens on the male brain before birth. Baby boys are bigger from the time they are only a small bunch of cells. More of them are born. Boys are more susceptible to nearly every disease that affects newborns, so more of them die. Many diseases present differently in boys and girls. For example, attention deficit hyperactivity disorder (ADHD) is readily apparent in a hyperactive boy but is more easily overlooked in a well-behaved but inattentive girl. Treatment of disease also may vary with sex. Boys and girls with cancer respond differently to chemotherapy and radiation, and ideal therapeutic regimens may be sex-specific. Prognosis, too, can vary by sex. Boys with cystic fibrosis tend to live longer. These are just a few examples of the importance of gender in pediatric medicine. Many more examples are to be found in the chapters that follow.

I thank the pediatric authors for a job well done. They have all looked at their specialties from a new, gender-specific perspective and have gathered and clearly presented a great deal of information. Better understanding of gender differences in health and disease already has led to improved medical care for our patients, and the field is still young.

Chapter 1. The Effects of Gender in Neonatal Medicine

Tove S. Rosen¹ and David Bateman²

¹Professor of Clinical Pediatrics/Neonatology, Columbia University Medical Center, Department of Pediatrics, New York, NY, USA

²Associate Professor of Clinical Pediatrics, Columbia University Medical Center, Department of Pediatrics, New York, NY, USA

Introduction

Differences between male and female infants in mortality, growth, and the susceptibility to specific diseases exist during the perinatal period (fetal and neonatal), as is shown by numerous embryologic, physiologic, epidemiologic, and anthropologic observations in humans and by laboratory studies and field observations in animals.

For a cohort of individuals at a given point in life, the sex ratio (simple ratio of males to females) depends not only on the different rates of mortality between the sexes but also on the relative numbers of males and females present at birth. In humans, as in most mammalian species, slightly more males are born than females. At birth the sex ratio is approximately 1.05, representing a proportion of male births of about 51.3%. After birth the mortality of males is higher, and the sex ratio declines progressively. By the end of the first year of life, 120 males have died for every 100 females. Males continue to die at a higher rate throughout childhood and adulthood. ¹.².³. and ⁴.

Males are not only more numerous and more likely to die at birth, they are also larger. Differences in the rates of growth and metabolism between males and females have been reported from the earliest embryologic period onward and may influence sexual organogenesis, the sex ratio during gestation, and relative male–female survival rates during intra-uterine and extra-uterine life. ⁵.⁶.⁷.⁸.⁹. and ¹⁰.

Males are more likely to experience stillbirth, premature birth, congenital malformations, pulmonary hemorrhage, intracranial hemorrhage, respiratory distress, perinatal asphyxia, perinatal infection, cerebral palsy, and developmental delay. Sudden Infant Death Syndrome (SIDS) is more common in males. Infants are at highest risk for SIDS during the first 2–4 months of life. Besides male sex, other risk factors include maternal smoking, exposure to a suboptimal uterine environment, poor fetal growth, and prematurity. Males also face a higher incidence of neurobehavioral and developmental difficulties during childhood. In epidemiologic surveys, attention deficit hyperactivity disorder (ADHD), characterized by poor concentration ability, motoric hyperactivity, impulsivity, and frequently learning difficulties, is four times more common in boys than in girls. The increased male susceptibility to disease depends upon the interplay of environmental risk factors with fundamental genetic, endocrinologic, immunologic, and metabolic differences between the sexes. ¹¹.¹².¹³.¹⁴.¹⁵.¹⁶. and ¹⁷.

The Sex Ratio During Fetal Life

Sex Ratio at Conception

Phenotypic sexual differentiation in mammals consists of a sequence of genetic and hormonal components referred to as the Jost paradigm. The genetic component, consisting of either the XX or XY chromosome complement, is determined at conception. Gonadal differentiation occurs at 6–7 weeks gestation in humans with expression of the Y chromosome-borne SRY gene, resulting in the formation of either male or female gonads. The development of male sex organs and secondary characteristics is an active process controlled by three hormones produced by the testis: Müllerian inhibiting substance (also called anti-Müllerian hormone), testosterone, and insulin-like factor 3 (INSL3). Phenotypic female characteristics develop in the absence of these three testicular hormones. ¹⁸. and ¹⁹.

Evidence of a preponderance of male fetal losses suggests that the sex ratio is even higher around the time of conception than at birth. By assuming a constant male–female ratio of fetal loss during pregnancy, the sex ratio from the earliest point in embryonic life has been estimated to be approximately 1.1 to 1.2. However, the precise point at which male numerical predominance develops is unknown. Several studies have shown that the ratio of Y- to X-bearing spermatozoa in humans is approximately equal; thus, the elevated sex ratio may reflect differences in rates of fertilization, implantation or early survival. The classical explanation for the sex ratio of more rapid arrival to the ovum of lighter, faster-swimming Y-bearing spermatozoa has been discounted, and postulates involving an immunologic or hormonal preference of the ovum for Y-bearing spermatozoa remain unsupported. ³.¹².²⁰.²¹.²².²³. and ²⁴.

An alternative explanation for male predominance is that it occurs after fertilization, at the time of implantation. Two days after fertilization the average number of male embryos exceeds that of female embryos. At the same time the metabolic rate, as measured by glucose and pyruvate uptake and lactate production, is higher in male embryos than female embryos. The higher metabolic rate and larger size of male embryos may confer a survival advantage (albeit temporary) on male embryos at the time of implantation. The enhanced metabolic rate of male embryos may be the result of the action of Y-chromosome-derived transcription factors acting on maternally-derived mitochondria. Higher metabolic rate (and increased temperature) may also play an epigenetic role in male sex differentiation. ⁶.⁷.¹⁹.²⁴.²⁵. and ²⁶.

Sex Ratios and Periconceptional Influences

Male and female fetuses and infants respond differently to biological, environmental, and cultural influences. Environmental stresses including crowding, heat, and natural catastrophes have been found to alter the birth sex ratio in human populations. A sharp decline in the sex ratio at birth was reported 9 months following the 1995 Kobe earthquake and 320 days after both the 1952 London smog and the 1965 Brisbane flood. Similarly, a drop in the sex ratio to 1 was seen in New York City in 2002 following the terrorist attack on September 11, 2001. Using combined Danish registries, Hansen et al. found that severe periconceptional life events (development of cancer or myocardial infarction in her partner or older children) experienced by the mother during the first trimester result in a smaller proportion of male births. Deviations in monthly environmental temperature above the overall mean were associated with a higher birth sex ratio. Data from California support the hypothesis that the fetal death sex ratio varies positively over time with the unemployment rate. Temporary decreases in the sex ratio such as these might be due to alterations of parental hormones, altered quality of semen or an increased rate of early spontaneous abortion of males. It is notable that the peak drop of the sex ratio in New York City occurred 5 months after the September 11 attacks, making increased male fetal loss, rather than altered conception, the likely mechanism. Interestingly, the sex ratio did not change following the severe Dutch famine during the winter of 1944–45. In contrast, the proportion of males born increased sharply after both world wars in combatant countries. ¹³.²⁷.²⁸.²⁹.³⁰.³¹.³².³³.³⁴.³⁵.³⁶. and ³⁷.

Lower birth rank, increased parental age, and decreased frequency of coitus have been associated with a lower sex ratio. Psychological stress in one parent has been shown to favor the production of offspring of the opposite sex. Parental social status may alter the sex ratio. Parents engaged in stereotypical ‘masculine’ occupations (law, politics, natural science, medicine, business, etc.) and ‘dominant women’ were more likely to produce sons than daughters. ³⁸ James has assessed the numerous, often conflicting studies relating the sex ratio in animals and humans to various environmental, social, and disease-related circumstances and has concluded that the relative parental levels of estrogen, testosterone, and gonadotropin at the time of conception contribute to the determination of fetal sex. Others have argued that the birth sex ratio is influenced by the quality of the ovum at different times in the menstrual cycle. ¹.²⁴.²⁶.³⁹.⁴⁰.⁴¹.⁴².⁴³. and ⁴⁴.

Sex Ratio and Fetal Loss

The results of chromosomal analyses to determine the sex ratio in spontaneous abortions have varied. Several of these studies have found a predominance of female tissue. After carefully excluding maternal contamination of tissue and androgenetic 46,XX hydatidiform moles, Hassold et al. estimated the sex ratio for genetically normal spontaneous abortions to be approximately 1.30. The study also noted an overall male predominance among spontaneously aborted fetuses with various trisomies, with the sex ratio lowest for trisomy 9 and highest for trisomy 21. ⁴⁵

Manipulation of the Sex Ratio

Attempts at selecting the sex of an infant by controlling the frequency, timing or position of coitus or insemination in relation to ovulation have a long history of use but have never been shown to be effective. Modern laboratory techniques have been applied to the question of sex selection in an effort to control the expression of serious X-linked diseases. These techniques have attempted to take advantage of potentially differing physical, antigenic, and electrochemical properties that might allow separation of X- and Y-containing spermatozoa. Flow cytometry cell sorting uses fluorescence in-situ hybridization (FISH) to label X- and Y-containing chromosomes, which are then separated by flow cytometry. The technique is advertised to be a highly effective method of sex selection; but several commentators have worried about potential damage to genetic material subjected to fluorochrome staining, laser, and a high voltage electromagnetic field. ⁴⁶.⁴⁷.⁴⁸. and ⁴⁹.

Pre-conceptional sex selection for reasons of parental choice (as opposed to the elimination of genetic disease) is ethically controversial. Nevertheless, post-conceptional sex selection has been a long-standing practice in some cultures, where infanticide or, more recently, selective abortion based on prenatal ultrasonographic determination of fetal sex are the methods of selection. In Korea, the sex ratio climbs with each pregnancy, exceeding 2.0 for the fourth child. In India, where a large gap exists between the expected and actual number of females, the sex ratio for urban births is 1.1–1.2. Similar findings have been described in China where, in census data, the births of girls have not been reported because of early deaths, most likely due to infanticide. The trend toward fewer than expected females in China is now increasingly due to selective abortion after ultrasonographic sex determination. The concept of ‘missing women’ has been advanced to focus attention on the impact of such practices. It has been estimated that there are now 40–50 million missing women in India alone, and perhaps 100 million missing women worldwide. ⁵⁰.⁵¹.⁵².⁵³. and ⁵⁴.

Sex Ratio and Length of Gestation

Male infants are more likely to deliver prematurely. In an analysis involving more than 1.8 million births in six New England states, Cooperstock and Campbell found a 7.2% excess of males among white singleton preterm births (20–37 weeks gestation). Beyond 36 weeks, the proportion of males declined sharply, falling below the mean proportion of all white singleton births (51.3%) by 40 weeks gestation. Among preterm singleton black infants, the male excess was significantly smaller (2.3%). Male excess has also been reported in the birth of preterm twins less than 33 weeks gestation. Female twin pairs have a significantly longer gestation period than either male twin pairs or discordant female/male twin pairs. Mortality also has been reported to be lower in female pair twins than in either male pair or discordant twins. A ‘masculinizing’ effect of the male twin on respiratory morbidity in the female twin partner in very low birthweight (VLBW) male–female twins has been observed. ⁵⁵.⁵⁶.⁵⁷. and ⁵⁸.

Sex Differences in Fetal and Neonatal Growth

Fetal Growth Differences

The earliest attempts to assess the rate and range of fetal growth used cross-sectional data from live born infants to construct percentile charts for growth during the third trimester. In these charts gestational age was calculated from the last menstrual period. Lubchenco et al. provided separate growth charts for male and female newborns. In these the weight of males born at the 50th percentile exceeds that of females born at the 50th percentile by approximately 50 g at 28 weeks gestation and 100 g at term. These percentile charts have been